KUWAIT MEDICAL JOURNAL (KMJ)

VOLUME 38 NUMBER 3 

KMJ 

K M J 

KUWAIT MEDICAL JOURNAL 

The Official Journal of The Kuwait Medical Association 

SEPTEMBER 2006 

EDITORIAL 

Chronic Pain Clinic in Kuwait: Are We Prepared? 169 

Ibrahim Hadi 

REVIEW ARTICLE 

Extended-Spectrum Beta-Lactamases (ESBLs): A Global Problem 171 

Asma M Al-Jasser 

Osler-Weber-Rendu and Liver Transplant 186 

Wafaa Al-Hashash, Ghassan Baidas 

ORIGINAL ARTICLES 

Early Radiological Results of Femoral Varus Derotation Osteotomy in Spastic Cerebral Palsy 191 

Mohamed LFahmy, Mahmoud Al-Rayes, Ahmed Hammouda, Mohamed Al-Leithy 

Comparison of Susceptibility Testing Methods for the Detection of Methicillin /Oxacillin Resistance in 

Staphylococcus Aureus 198 

Hanan Ahmed Habib Babay 

Prevalence and Risk Factors for Diabetic Retinopathy among Kuwaiti Diabetics 203 

Fatma AlKharji, Nouria Alshemmeri, Leyla Mehrabi, Mohammed Hafez, Osama Fakher 

Changing Trends in the Management of Acute Myocardial Infarction: A Five -Year Study 207 

Ibrahim Lasheen, Mohammed Zubaid, Cheriyil G Suresh, Hanan El Sayed Bader 

Frequency and Etiology of Hyponatremia in Adult Hospitalized Patients in Medical Wards of a General 

Hospital in Kuwait 211 

Thomas Abraham Vurgese, Sunil Bahl Radhakrishan, Osman Abdul Wahab Mapkar 

Bacteremia due to Stenotrophomonas Maltophilia in Patients with Haematological Malignancies 214 

Khalid Ahmed Al-Anazi, Asma Marzouq Al-Jasser, Abdulaziz Al-Humaidhi 

Urinary Tract Infection in Boys Less Than Five Years of Age: A General Pediatric Perspective 220 

Hany M Nadi, Yasser AF Shalan, Hanan YAAl-Qatan , Saad Alotaibi 

CASE REPORTS 

Persistent Narrow Complex Tachycardia; What is the Diagnosis? 226 

Ali Al Sayegh, Mousa AJ Akbar 

Fatal Case of Systemic Salmonella Infection with Acute Renal Failure, Haemolytic-Uraemic 

Syndrome and Rhabdomyolysis 229 

Ram Kumar Gupta, Narayanan Nampoory, Kaivilayil Varghese Johny 

Profound Hyperkalemia and the Electrocardiogram. Lack of Correlation : A Case Report 232 

Tarek Abdel Hamed Mostafa Dowod, Jaffer Ismail Ali, Sajid Burud 

Burned-out Testicular Germ Cell Tumour Mimicking Lymphoma 235 

Abrar Hayat, Kamaldine Oudjhane 

Congenital Bronchial Atresia: CT- 3D Image Reconstruction and Virtual Navigation 238 

Shefeek Abubacker,Yousef Al Khulaifi, Jagadesh N Shenoy 

Superior Mesenteric Artery Syndrome: An Uncommon Cause of Intestinal Obstruction; Report of 

Two Cases and Review of Literature 241 

Naheda H Jawad, Abdulla Al-Sanae, Wafa’a Al-Qabandi 

KU ISSN 0023-5776 Continued inside

2Vol. 38 No. 3 

THE KUWAIT MEDICAL JOURNAL September 2006 


C O N T E N T S 

Continued from cover 

SELECTED ABSTRACTS OF ARTICLES PUBLISHED ELSEWHERE BY 

AUTHORS IN KUWAIT 245 

FORTHCOMING CONFERENCES AND MEETINGS 248 

WHO-FACTS SHEET 254 

1. Health Consequences of Excessive Solar UV Radiation 

2. Global Disease Burden from Solar Ultraviolet Radiation 

3. Launch of Global Early Warning System for Animal Diseases Transmissible to Humans 

ARABIC ABSTRACTS OF ARTICLES PUBLISHED IN THIS ISSUE 259 

❈ ❈ ❈ 

View these articles at 

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P U B L I S H E R : The Kuwait Medical Journal (KU ISSN-0023-5776) is a quarterly publication of THE KUWAIT MEDICALA S S O C I AT I O N . 

Address: P.O. Box 1202, 13013 Safat, State of Kuwait; Telephone: 5316023, 5317972, 5333278 Fax: 5312630, 5333276. 

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KMJ 

Kuwait Medical Journal (KMJ) 

Published by the Kuwait Medical Association 

Previously known as The Journal of the Kuwait Medical Association (Est. 1967) 

Allan Templeton, UK 

Ananda S Prasad, USA 

Anders Lindstrand, Sweden 

Andrew J Rees, UK 

Arie van Dalen, Netherlands 

Belle M Hegde, India 

Bengt Jeppsson, Sweden 

Charles A Dinarello, USA 

Christian Imielinski, Poland 

Elizabeth Dean, Canada 

Fiona J Gilbert, UK 

Abdulla Behbehani 

Abdul Mohsen Jaffar 

Abeer K Al-Baho 

Alexander E Omu 

Ali Al-Mukaimi 

Ali Al-Sayegh 

Asmahan Al-Shubaili 

Chacko Mathew 

Eiman M Mokaddas 

Faisal A Al-Kandari 

Habib Abul 

Honorary President: Abdulaziz Al-Babtain 

EDITORIAL BOARD 

Editor-in-Chief: Fuad Abdulla M Hasan 

Editor: Adel Khader Ayed 

International Editor: Pawan K Singal 

Associate Editors: Adel A Alzayed 

Mousa Khoursheed 

Mustafa M Ridha 

Nasser Behbehani 

Circulation Manager: Homoud Fahad Al-Zuabi 

INTERNATIONALADVISORY BOARD 

Frank D Johnston, UK 

Gabrielle M Hawksworth, UK 

George Russell, UK 

Graeme RD Catto, UK 

Jan T Christenson, Switzerland 

Jaroslav Slipka, Czech Rep 

Jasbir S Bajaj, India 

John V Forester, UK 

Julian Little, Canada 

Lubomir Karagiosov, Bulgaria 

Lewis D Ritchie, UK 

REGIONAL ADVISORY BOARD 

Hilal Al-Sayer 

Jasbir Singh Juggi 

John F Greally 

Joseph C Longenecker 

Kamal Al-Shoumer 

Kefaya AM Abdulmalek 

Khalid Al-Jarallah 

Marie T Greally 

Mazen Al Essa 

Mohamed AA Moussa 

Mohammed Al-Jarallah 

Neva E Haites, UK 

Nirmal K Ganguli, India 

Oleg Eremin, UK 

Peter JB Helms, UK 

Peter RF Bell, UK 

Raymond M Kirk, UK 

S Muralidharan, India 

Tulsi D Chugh, India 

William ATweed, Canada 

William B Greenough, USA 

Zoheir Bshouty, Canada 

Mousa Khadadah 

Mubarak Al-Ajmi 

Mustafa Al-Mousawi 

Nasser J Hayat 

Nebojsa Rajacic 

Sadika Al-Awadi 

Saleema Al-Ramadan 

Sami Asfar 

Soad Al-Bahar 

Sukhbir Singh Uppal 

Waleed Alazmi 

ARABIC TRANSLATION: Arabization Centre for Medical Science (ACMLS), Kuwait 

EDITORIAL OFFICE 

Editorial Manager : Babichan K Chandy 

Language Editor : Abhay U Patwari 

EDITORIALADDRESS 

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KUWAIT MEDICAL JOURNAL (KMJ) 

Instructions for Authors 

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i 

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ii 

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Philips SJ, Whisnam JP. Hypertension and 

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iii 

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Kuwait Medical Journal 

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Instructions for Authors

September 2006 


Editorial 

Chronic Pain Clinic in Kuwait: Are We Prepared? 

Ibrahim Hadi1,2 1Department of Anesthesia and Perioperative Medicine, University of Western Ontario, St Joseph Health Care, London, 

Canada 

2Department of Anesthesia and Intensive Care, Farwaniya Hospital, Ministry of Health, Kuwait 

Chronic pain is a common condition in adults 

with a median prevalence of 15% (2 - 40%) across 

different countries worldwide [1] . Although access to 

treatment for chronic pain is a compelling need, 

under treatment continues to be a major concern 

and has been clearly documented in those patient 

populations for which there is broad consensus 

about the nature of optimal care. A recent local 

survey reported a prevalence of 35.7% for 

musculoskeletal pain in females and 20.2% in 

m a l e s [ 2 ] . The authors concluded that musculoskeletal 

pain is a major health problem among Kuwaitis 

and deserves intense government attention. 

Unfortunately until this day, an integrated, 

c o m p rehensive pain management service for 

patients with chronic non-cancer pain condition 

does not exist and we are seriously behind other 

gulf states in the region who have established 

multidisciplinary pain services with demonstrated 

positive outcomes. Deficiencies in pain management 

still exist, but pain medicine is rapidly approaching 

responsibility and recognition, and we hope that in 

time, pain medicine will become an independent 

specialty. Nevertheless, the days of the omnipotent, 

omnipresent physician who “waves his hand” over 

a silent, awestruck patient are over. Therefore, are 

we prepared to establish such chronic pain clinics at 

our local hospitals in the ministry of health? Is it 

cost-effective? And how can we communicate with 

other various medical disciplines (e.g., surgeons, 

internist and general practitioners) to provide their 

patients with professional chronic pain management? 

Often, chronic pain syndrome reflects the 

endpoint in a sequence of events. Patients become 

aware of their initial symptoms and seek help from 

their primary care physician or treating surgeon. 

Should treatment or passage of time be unsuccessful 

in resolving their symptoms, they frequently are 

referred to specialists or seek out other medical 

opinions and treatment on their own. As patients 

continue through the medical system, they are 

Kuwait Medical Journal 2006, 38 (3): 169-170 

subjected to multiple diagnostic studies, are treated 

with a variety of medications, and may be referred 

to physical therapy or biofeedback and counselling. 

Surgical interventions are sometimes attempted to 

resolve the problem. When pain continues, patients 

become frustrated and desperate. They increase 

pain behavior in an attempt to communicate their 

level of discomfort and its devastating impact on 

their lives. Frustrated as well, physicians or other 

health care professionals may begin to probe the 

impact of other factors such as stress level or 

lifestyle. Patients begin to fear abandonment 

because they perceive that the reality of their 

symptoms is being questioned or that their 

problems are being attributed to a psychological 

cause. 

Chronic pain is increasingly recognized as a 

major health problem in many countries. It has 

been shown to affect psychological health, social 

and economic well-being, and health-related quality 

of life in diff e rent communities [ 3 ] . As a re s u l t , 

c h ronic pain and its consequences have been 

reported to cause considerable burden to the health 

care cost. In the United States and United Kingdom, 

the economic cost for back pain was estimated to 

exceed US$ 54-86 billion and US$ 20 billion a year, 

respectively [4] . Similarly in the Netherlands, neck 

pain alone was estimated to cost US$ 686 million [5] . 

In a study by Okifuji et al, they analyzed the cost 

benefits and cost-effectiveness of interdisciplinary 

pain management programs [6] . Cost savings were 

dramatic for persons who had been involved in 

i n t e rdisciplinary treatment programs. Patients 

treated in interdisciplinary programs would spend 

US$ 280 million less for medical costs in the year 

following treatment and additional surgery, than 

those treated conventionally. Similarly, annual 

savings for subsequent surgical costs would be 

approximately US$ 63 million when patients were 

treated in an interdisciplinary program rather than 

surgically. Cost savings were much more dramatic 

Address correspondence to: 

Dr. Ibrahim Hadi, MB ChB, FRCPC, 268 Grosvenor Street, St Joseph’s Health Care Room E 147, London, Ontario, Canada N6A4L6. Tel: (519) 

646-6000 - Ext: 64219, Fax: (519) 646-6116, E-mail: Ibrahim.hadi@gmail.com

170 

when costs of lifetime disability benefits were 

included. Okifuji et al found that interdisciplinary 

treatment was nine times more cost-effective than 

conservative treatment and 3.5 times more effective 

than surgical treatment in helping patients return to 

work. 

In 1990, the International Association for the 

Study of Pain (IASP) struck a task force to define 

desirable characteristics for pain tre a t m e n t 

facilities [7] . The task force defined the structure of 

these facilities as follows: 

Pain-treatment facility: a generic term used to 

describe all forms of pain-treatment facilities, 

without regard to personnel involved or types of 

patients served. Pain unit is a synonym for paintreatment 

facility. 

Multidisciplinary pain centre: an organization of 

healthcare professionals and basic scientists that 

includes research, teaching and patient care related 

to acute and chronic pain. A wide array of healthcare 

specialists is required, such as physicians, 

psychologists, nurses, physiotherapist, occupational 

therapists, vocational counselors, social workers 

and other specialized health-care providers. The 

members of the team must communicate with each 

other on a regular basis, both about specific patients 

and about overall program development. 

Multidisciplinary pain clinic: a health-care 

delivery facility staffed with physicians of different 

specialties and other non-physician health-care 

p roviders who specialize in the diagnosis and 

management of patients with chronic pain. It does 

not include research and teaching activities in its 

regular programs. 

Pain clinic: a health-care delivery facility focusing 

on the diagnosis and management of patients with 

chronic pain. A pain clinic may specialize in a 

specific diagnosis or in pain related to a specific 

region of the body. A pain clinic may be large or 

small, but it should never be a label for an isolated 

solo practitioner. A single physician functioning 

within a complex health-care institution that offers 

appropriate consultative and therapeutic services 

could qualify as a pain clinic, if patients with 


chronic pain were suitably assessed and managed. 

It differs from a multidisciplinary pain centre or 

clinic due to the absence of interd i s c i p l i n a r y 

assessment and management of patients. 

In conclusion, there are probably a large number 

of patients in our health care system who suffers 

daily from chronic pain as consequence of either 

trauma, surgical procedure or other causes. These 

patients are often inadequately treated not because 

of negligence, but due to lack of access to 

professional chronic non-cancer pain clinics that 

have the ability to diagnose and possibly treat such 

c h ronic conditions. I believe, the time has arrived to 

formally and materially acknowledge the essential 

need to establish a chronic pain facility center in 

Kuwait. Therefore, we need to initiate a strategic 

plan for the chronic pain service in our health care 

system that includes the process of determining our 

goals for the future and finding the best way to 

achieve them. This will be possible only through 

the continuous support and understanding of our 

medical colleagues and the health care system, 

besides financial support from our government. The 

ultimate aim is better improvement in health care 

provision with greater clinical effectiveness and 

efficiency. 

REFERENCES 

1. Verhaak PF, Kerssens JJ, Dekker J, et al. Prevalence of 

chronic benign pain disorder among adults: a review of the 

literature. Pain 1998; 77:231-239. 

2. Al-Awadhi AM, Olusi SO, Moussa M, et al. Musculoskeletal 

pain, disability and health-seeking behavior in adult 

Kuwaitis using a validated Arabic version of the WHO- 

ILAR COPCORD Core Questionnaire. Clin Exp Rheumatol 

2004; 22:177-183. 

3. Latham J, Davis BD. The socioeconomic impact of chronic 

pain. Disabil Rehabil 1994; 16:39-44. 

4. Maniadakis N, Gray A. The economic burden of back pain 

in the UK. Pain 2000; 84:95-103. 

5. Borghouts JA, Koes BW, Vondeling H, Bouter LM. Cost-ofillness 

of neck pain in the Netherlands in 1996. Pain 1999; 

80:629-636. 

6. Okifuji AA, Turk DC, Kalauokalani D. Clinical outcomes 

and economic evaluation of the Multidisciplinary Pain 

Centers. In: Block A, Kremer EE, Fernandez E, editors. 

Handbook of Pain Syndromes. Mahwah, NJ: Lawrence 

Erlbaum Publishers; 1999, p 77-97. 

7. International Association for the Study of Pain. Task Force 

on Guidelines for Desirable Characteristics for Pain 

Treatment Facilities. Desirable Characteristics for Pain 

Treatment Facilities, 1990.



Review Article 

Extended-Spectrum Beta-Lactamases (ESBLs): A Global 

Problem 

Asma M Al-Jasser 

Department of Microbiology, Armed Forces Hospital, Riyadh, Saudi Arabia 

ABSTRACT 

Extended-spectrum beta-lactamases (ESBLs) constitute a 

growing class of plasmid-mediated ß-lactamases which 

confer resistance to broad spectrum beta-lactam 

antibiotics. They are commonly expressed by 

Enterobacteriaceae but the species of organisms producing 

these enzymes are increasing and this is a cause for great 

concern. The prevalence of ESBL - producing organisms 

is increasing worldwide and several outbreaks have been 

reported. Serious infections with these organisms are 

INTRODUCTION 

The accelerated emergence of antibiotic 

resistance among the prevalent pathogens is the 

most serious threat to the management of infectious 

diseases. ß-lactam antibiotics are the most common 

treatment for bacterial infections [1] . Production of ßlactamases 

is the main mechanism of bacterial 

resistance to these classes of antibiotics [2] . The first ß 

-lactamase was identified in Escherichia coli prior to 

the release of penicillin for use in medical practice [3] . 

Many Gram-negative bacteria possess naturally 

occurring, chromosomally mediated ß-lactamases 

(e . g . , AmpC cephalosporinases of E n t e ro b a c t e r i a c e a e . ) 

These enzymes may have some physiological role 

in peptidoglycan assembly or may arise to defend 

bacteria against ß-lactams produced by 

e n v i ronmental bacteria and fungi [ 2 ] . The first 

plasmid-mediated ß-lactamase in Gram - negatives, 

TEM-1, was reported in 1965 from an Escherichia coli 

isolate belonging to a patient in Athens, Greece, 

named Temoniera (hence the designation TEM) [4] . 

The TEM-1 ß-lactamase has spread worldwide and 

is now found in different species of members of 

E n t e robacteriaceae, Pseudomonas aeruoginosa, Haemophilus 

influenzae and Neisseria gonorrh o e a e [ 2 ] . A n o t h e r 

common plasmid-mediated ß-lactamase found in 

Klebsiella pneumoniae and Escherichia coli is SHV-1 

(named after the sulfhydryl “variable” active site) [2] . 


associated with high mortality rates as therapeutic 

options are limited. The emergence of ESBLs creates a 

real challenge for both clinical microbiology laboratories 

and clinicians because of their dynamic evolution and 

e p i d e m i o l o g y, wide substrate specificity with its 

therapeutic implications, their significant diagnostic 

challenges and their prevention and infection control 

issues. The aim of this review is to increase awareness 

about this serious antibiotic resistance threat. 

KEY WORDS: broad spectrum beta-lactam antibiotics, Enterobacteriaceae, plasmidmediated ß-lactamases 

The extended-spectrum ß-lactams (ESBLs) 

became widely used in the treatment of serious 

infections due to Gram-negative bacteria in the 

1980’s [5] . Resistance to these newer ß-lactams due to 

ß-lactamases emerged quickly [5,6] . The first report of 

plasmid-encoded ß-lactamases capable of hydro l y z i n g 

the extended-spectrum cephalosporins w a s 

published in 1983 [7] . A Klebsiella ozaenae isolate from 

Germany possessed a ß-lactamase, SHV-2, which 

efficiently hydrolyzed cefotaxime and to a lesser 

extent ceftazidime [7] . Sequencing showed that this 

ß-lactamase differed from the parent enzyme SHV- 

1, by replacement of glycine by serine at the 238 th 

position. Later on, many plasmid-encoded 

e x t e n d e d - s p e c t rum ß-lactamases were re c o g n i z e d [ 5 , 9 ] . 

They spread relatively quickly worldwide and 

became well entrenched in many hospitals [5,8,9,10] . 

DEFINITION 

ESBLs are known as extended-spectru m 

because they are able to hydrolyze a bro a d e r 

spectrum of ß-lactam antibiotics than the simple 

parent ß-lactamases from which they are derived. 

They are acquired plasmid-mediated ß-lactamases. 

They have the ability to inactivate ß- l a c t a m 

antibiotics containing an oxyimino-group such as 

oxyimino-cephalosporins (e . g . ,ceftazidime, ceftriaxone, 

cefotaxime) as well as oxyimino-monobactam 


Dr Asma Marzouq Al-Jasser, KSUF (Micro), JB (Micro & Immuno), CIC, Consultant Microbiologist, Department of Microbiology, Armed Forces 

Hospital, Box - 966, P.O Box 7897, Riyadh - 11159, Kingdom of Saudi Arabia. Tel: 966 -1- 479100 Ext: 4096, Fax: 966 -1- 4568477, E-mail: 

asjass2002@yahoo.com.

172 

Extended-Spectrum Beta-Lactamases (ESBLs): A Global Problem September 2006 

( a z t re o n a m ) [ 5 , 9 ] . They are not active against 

cephamycins and carbapenems. Generally, they are 

inhibited by ß-lactamase-inhibitors such as clavulanate 

and tazobactam . 

F U N C T I O N A L AND MOLECULAR GROUPING 

In the ß-lactamase functional classification 

scheme by Bush, Jacoby and Medeiros, ESBLs are 

located in two subgroups of group 2, namely 

subgroups 2be (extended-spectrum ß-lactamases, 

Ambler’s class A enzymes) and 2 d (cloxacillinh 

y d rolyzing ß-lactamases, A m b l e r’s class D 

ESBLs) [11] . 

ESBL PRODUCING ORGANISMS 

ESBLs have been found in a wide range of 

Gram-negative rods. However, the vast majority of 

strains expressing these enzymes belong to the 

family E n t e ro b a c t e r i a c e a e [ 5 ] . Klebsiella pneumoniae 

seems to remain the major ESBLproducer. Another 

very important organism is Escherichia coli. It is 

important to note the growing incidence of ESBLs 

in Salmonella spp [ 1 2 ] . ESBLs have become more 

prevalent among species with inducible AmpC ßlactamases 

[13] . 

N o n -E n t e ro b a c t e r i a c e a e E S B L p roducers are 

relatively rare with Pseudomonas aeruginosa being 

the most important organism [14] . ESBL has also been 

reported in Acinetobacter spp, Burkholderia cepacia 

and Alcaligenes fecalis [5] . 

THE ORIGIN AND GENETIC DETERMINANTS 

OF ESBLS 

ESBL activity is demonstrated by enzymes with 

substantial diversity in terms of stru c t u re and 

evolutionary origin [15,16] . The most prevalent ESBL 

types have evolved through point mutations of key 

amino acid substitutions in the parent TEM and 

SHV enzymes [15] . TEM-1 is the most commonly 

e n c o u n t e red: ß-lactamase in Gram-negative bacteria. 

Upto 90% of ampicillin resistance in E.coli is due to 

production of TEM-1 [2] . TEM-1 is able to hydrolyze 

penicillin and early cephalosporin. TEM-2, the first 

derivative of TEM-1, has a single amino acid 

substitution when compared to the original ßlactamase 

[17] . A number of amino acid residues are 

especially important for producing the ESBL 

phenotype when substitutions occur at that 

position. They include glutamate to lysine at 

position 104, arginine to either serine or histidine at 

position 164, glycine to serine at position 238 and 

glutamate to lysine at position 240. The SHV-1 ßlactamase 

is most commonly found in K.pneumoniae 

and is responsible for up to 20% of the plasmidmediated 

ampicillin resistance in this species [18] . The 

changes that have been observed to give rise to 

SHV variants occur in fewer positions within the 

structural gene. Mutations in the OXAenzymes can 

also give the ESBL phenotype, which is the only 

E S B L belonging to class D. The OXA-type ßlactamases 

are so named because of their oxacillinh 

y d rolyzing abilities. These ß-lactamases are 

characterized by hydrolysis rates for cloxacillin and 

oxacillin greater than 50% that for benzylpenicillin 

and the fact that they are poorly inhibited by 

clavulanic acid [11] . They predominantly occur in 

Pseudomonas aeruginosa, but have been detected in 

many other Gram-negative bacteria [ 1 4 ] . The genealogy 

of other ESBL types is more mysterious, however, 

genetic studies revealed similarities between some 

of them and certain species specific ß-lactamases 

belonging to Bush subgroup 2be and 2e [19,20] . 

The amino acid substitutions have been found 

to affect enzyme structures and activity in different 

w a y s [ 5 , 1 5 ] . These substitutions that occur within 

TEM, SHV and OXA enzymes occur at a limited 

number of positions. The combination of these 

amino acid changes results in various subtle 

alterations in the ESBL phenotype such as the 

ability to hydrolyze specific oxyimino-cephalosporins 

or changes in their isoelectric points. The most 

important are the spectrum-extending mutations 

which result in the expansion of the active site that 

allows the increased activity against expanded 

spectrum cephalosporins and may result in the 

i n c reased susceptibility to ß-lactamase inhibitors [ 1 5 , 1 6 , 2 1 ] . 

The selection pressure that drives the emergence 

of ESBLs has usually been attributed to the intense 

use of oxyimino-beta lactams, mainly the thirdgeneration 

cephalosporins [ 1 5 , 2 2 , 2 3 ] . However, the 

constant or fluctuating pressure of various ß-lactam 

antibiotics including diverse oxyimino-compounds 

as well as pencillins and early generation 

cephalosporins has recently been proposed to affect 

ESBL variation [24] . ESBL is characterized by highly 

selective substrate preference. The selection of a 

particular enzyme variant in a given center has 

frequently been attributed to the specific profile of 

antibiotic use but such a correlation has not always 

been observed [25] . 

The strong selective pressure for the use of ßlactam 

drugs exerted on ESBL producer strains 

may lead to the selection of strains that 

h y p e r p roduce ESBL, the emergence of strains 

expressing different types of ESBLs, the selection of 

complex mutant enzymes with inhibitor resistant 

phenotype or porin alteration which lead to the 

development of resistance to cephamycins and 

other antimicrobials [10,26-28] . ESBL producing isolates 

are frequently resistant to other antimicrobials [26] . 

The plasmids that harbor genes encoding ESBLs 

f requently contain other genes encoding mechanisms 

of resistance to aminoglycoside and cotrimoxazole [ 2 9 ] . 

Quinolone resistance is frequently found in ESBL


producer strains although the mechanism of coresistance 

is not clear [30] . 

The total number of ESBLs that are 

characterized exceeds 200. These are detailed on the 

authoritative website on the nomenclature of ESBLs 

hosted by George Jacoby and Karen Bush. 

(http:www.lahey.org/studies/webt.htm). 

ESBL TYPES 

TEM - beta - lactamases : 

The TEM-type ESBL are derivatives of TEM-1 

and TEM-2. Klebsiella pneumoniae isolates detected 

in France as early as 1984 were found to harbor a 

novel plasmid-mediated ß-lactamases originally 

named CTX-1 because of its enhanced activity 

against cefotaxime [31] . This enzyme, now termed 

TEM-3, differs from TEM-2 by two amino acid 

s u b s t i t u t i o n s [ 3 2 ] . More than 100 TEM-type ßlactamases 

have been described, the majority of 

which are ESBLs. The amino acid changes in 

comparison with TEM-1 and TEM-2 are documented 

at http://www. l a h e y. o rg/studies/ temtable.htm. 

Some mutants of TEM ß-lactamases are being 

recovered. They maintain the ability to hydrolyze 

t h i rd-generation cephalosporins but also demonstrate 

an inhibitor resistance. These are referred to as 

complex mutants of TEM (CMT-1 to 4) [33] . Although 

TEM-type ESBLs are most often found in E.coli and 

K.pneumoniae, they are also found in other species 

of Gram-negative bacteriae with incre a s i n g 

frequency [2] . TEM-type ESBLs have been reported in 

other genera of E n t e ro b a c t e r i a c e a e such as 

E n t e robacter aerogenes, Enterobacter cloacae, 

Morganella morganii, Proteus mirabilis and Salmonella 

spp [34-36] . Furthermore, TEM-type ESBL have been 

found in non-E n t e ro b a c t e r i a c e a e g r a m - n e g a t i v e 

bacteriae, e.g., Pseudomonas aeruginosa [14] . 

SHV - beta - lactamases: 

The SHV-type of ESBL may be found in clinical 

isolates more frequently than any other type of 

ESBLs [37] . Unlike the TEM-type ß-lactamases, there 

a re relatively few derivatives of SHV-1. The 

majority of SHV variants possessing an ESBL 

phenotype are characterized by the substitution of 

a serine for glycine at position 238. Also some have 

a substitution of lysine for glutamate at position 

240. The serine residue at position 238 is critical for 

e fficient hydrolysis of ceftazidime and lysine 

residue is critical for the efficient hydrolysis of 

c e f o t a x i m e [ 3 8 ] . More than 50 SHV varieties are 

described worldwide. The majority possess the 

ESBL phenotype and inhibitor-resistant phenotype 

have been reported in few of the SHV enzymes [39] . 

SHV-type of ESBLs has been detected in a wide 

range of Enterobacteriaceae [37,39,40] . Outbreaks of SHV- 

KUWAIT MEDICAL JOURNAL 173 

producing Pseudomonas aeruginosa and Acinetobacter 

spp. have been reported [41,42] . 

CTX - M and Toho- beta - lactamases: 

CTX-M is a recently described family of the 

extended-spectrum ß-lactamases [43] . The name CTX 

reflects the potent hydrolytic activity of these ßlactamases 

against cefotaxime [44] . These enzymes 

hydrolyze cephalothin better than benzylpenicillin 

and they preferentially hydrolyze cefotaxime over 

ceftazidime. While ceftazidime MICs are usually in 

the apparently susceptible range, some of the CTX- 

M-type ß-lactamases confer resistance to this 

drug [45] . Aztreonam MICs have been found to be 

variable. CTX-M-type ß-lactamases hydro l y z e 

cefipime with high efficiency [43] . They are inhibited 

better by the ß-lactamase inhibitor tazobactam than 

by sulbactam and clavulanate [ 4 6 ] . Rather than 

arising by mutation, they represent examples of 

plasmid acquisition of beta - lactamase genes that 

are normally found on the chromosome of K l u y v e r a 

s p e c i e s [ 4 7 ] . CTX-M-ESBLs were pre d o m i n a n t l yfound 

in three geographic areas: South America, the Far 

East and Eastern Europe [43,48-50] . However, in recent 

years, CTX-M-type ESBLs have been reported in 

Western Europe, North America, China, Japan and 

India [51-55] . CTX-M type ß-lactamases may be the 

most frequent type of ESBLs worldwide. The 

number of CTX-M-type ß-lactamases is rapidly 

expanding. More than 40 CTX-M variants are 

c u r rently known [ 4 3 ] . They have been found in 

d i ff e rent E n t e ro b a c t e r i a c e a e including Salmonella 

spp [56] . Toho-1 and Toho-2 are ß-lactamases that are 

structurally related to CTX-M-type ß-lactamases 

and they have similar hydrolytic activity against 

cefotaxime (Toho refers to the To h o - U n i v e r s i t y 

School of Medicine, Omari Hospital in To k y o , 

where a child who was infected with Toho-1 ßl 

a c t a m a s e - p roducing Escherichia coli w a s 

hospitalized) [57,58] . 

OXA - beta - lactamases : 

The OXA-type ß-lactamases are another 

growing family of ESBLs. The OXA-type ESBLs 

w e re originally discovered in P s e u d o m o n a s 

a e r u g i n o s a isolates from a single hospital in 

Ankara,Turkey [59] . Several of the OXA-type ESBLs 

have been derived from the original OXA-10 ßlactamase 

(e.g., OXA -11, 14, 6 and 17) [59,60,61] . In 

contrast to the majority of OXA-type ESBLs, which 

confer resistance to ceftazidime, the OXA-17 ßlactamase 

confers resistance to cefotaxime and 

ceftriaxone but provides only marginal protection 

against ceftazidime [62] .A novel ESBL (OXA-18) was 

reported to be inhibited by clavulanic acid [63] . Many 

of the newer members of OXA-type of ESBLs have 

been found mainly in Pseudomonas aeruginosa 

isolates originating from Turkey and France [59, 63] .

174 


Other ESBLS: 

A variety of other ß-lactamases which are 

plasmid-mediated or integron-associated class A 

enzymes have been recently discovered. They are 

not simple point mutations of any known ßlactamases. 

They are characterized by their 

geographic diversity. 

PER: 

The PER-type-ESBLs share only around 25 to 

27% homology with the known TEM- and SHVtype 

ESBLs [ 6 4 ] . PER-1 ß-lactamase eff i c i e n t l y 

hydrolyzes penicillins and cephalosporins and is 

susceptible to clavulanic acid inhibition. The PER-1 

ß-lactamase was first detected in strains of 

Pseudomonas aeruginosa isolated from Tu r k e y [ 6 5 ] . 

Later, it was found among isolates of Salmonella 

e n t e r i c a s e rovar Ty p h i m u r i u m and A c i n e t o b a c t e r 

baumanii, Porteus mirabilis and Alcaligenes fecalis [9,66,67] . 

Although PER-1 enzyme has been predominantly 

found in Turkey, it was detected also in France, 

Italy, Belgium and Korea [5,9,66] . PER-2, which shares 

86% homology to PER-1, has been detected in 

Salmonella enterica s e rovar Typhimurium, E.coli, 

K.pneumonia, Proteus mirabilis, and Vibrio cholera O1, 

El Tor [9,68,69] . Hoewever, PER-2 has only been found 

in South America [68, 69] . 

VEB: 

VEB-1 has greatest homology to PER-1 and PER- 

2 (38%). It confers high level of resistance to 

ceftazidime, cefotaxime and aztreonam,which is 

reversed by clavulanic acid. VEB-1 was first found 

in a single isolate of E.coli from Vietnam [70] . An 

identical beta-lactamase has also been found in 

K.pneumonia, Enterobacter cloaca and Pseudomonas 

aeruginosa isolates in Thailand [ 7 1 ] . Other VEB enzymes 

have also been detected in Kuwait and China [72] . 

A few ESBLs have been reported but are 

uncommon and are found at a limited number of 

geographic sites [5,9] . GES and IBC beta-lactamases 

are found mainly in P.aeroginosa [73,74] . Other rare 

ESBLs found in Enterobacteriaceae are BES, SFO and 

TLA [75,76,77] . 

EPIDEMIOLOGY 

E S B Lp roducing organisms have been incre a s i n g l y 

detected worldwide. Their prevalence varies from 

one country to another and from institution to 

institution. A survey on 81,213 bloodstre a m 

infecton pathogens during 1997 - 2002 showed that 

the Klebsiella spp. with an ESBL phenotype was 

isolated at a rate of 42.7% in Latin America, 21.7% 

in Europe and 5.8% in North America [78] . The Pan 

E u ropean A n t i m i c robial Resistance using Local 

Surveillance (PEARLS) study (2001 - 2002) showed 

that the percentages of ESBL production among E. 

coli and K. pneumoniae and Enterobacter spp. were 

5.4, 18.2 and 8.8% respectively for all the study 

sites. The overall ESBL production rate for the 

combined Enterobacteriaceae was 10.5%. The highest 

rates were encountered in Egypt (38.5%) and 

Greece (27.4%) and lowest in the Netherlands (2%) 

and Germany (2.6%) [79] . In Japan, the percentage of 

E S B L p roduction in E . c o l i and K. pneumoniae 

remains low [80] . Elsewhere in Asia the percentage 

varies form 4.8% in Korea to 12% in Hong Kong [81, 

82] . Although the exact prevalence of ESBL in the 

Kingdom of Saudi Arabia (KSA) is c u r re n t l y 

unknown, the PEARLS study (2001 - 2002) showed 

that the overall ESBL p roduction rate fro m 

Enterobacteriaceae was (18.6%) and other reports 

f rom KSA suggest that ESBL p roducers are 

common and began to disseminate between 

hospitals [79,83-86] . In a tertiary care hospital in Riyadh, 

48.4% of K. pneumoniae and 15.8% of E.coli blood 

c u l t u re isolates collected from January 2003 

through December 2004 were ESBL producers [86] . 

Infection and colonization with ESBLproducing 

organisms are usually hospital-acquired especially 

in intensive care units (ICUs) [51,87] . Other hospital 

units that are at increased risk include surgical 

wards, pediatrics and neonatology, rehabilitation 

units and oncology wards [88-90] . Community clinics 

and nursing homes have also been identified as a 

potential re s e r v o i r 

[ 9 1 ] . Recent studies have demonstrated 

the danger of ESBL producers in livestock [12] . Risk 

factors for infection or colonization with ESBL - 

producing organisms include: length of hospital or 

ICU stay, presence of vascular or urinary catheters, 

undergoing hemodialysis, emergency abdominal 

surgery, gut colonization, low birth weight, prior 

e x p o s u re to any antibiotic (e . g . , q u i n o l o n e s , 

trimethoprim-sulfamethoxazole, aminoglycoside 

and metronidazole), prior ceftazidime or aztero n a m 

administration and prior residence in a long term 

care facility [5,8 ,9,23,24,87] . 

It is interesting that specific ESBLs appear to be 

unique to a certain country or region although 

recent reports suggest worldwide dissemination [5,8] . 

An ESBL variant may appear in a Center due to de 

novo selection which may result in a novel type of 

enzyme or in one that have been pre v i o u s l y 

identified in another institution (coverg e n t 

evolution) [92] . Once selected, the ESBL variant may 

s p read in the Center by diff e rent means that 

include clonal dissemination of producer strain or 

horizontal transmission of the ESBL- gene carrying 

plasmid among non-related strains [15,25,29] . 

Several outbreaks have been reported and they 

mostly occurred in tertiary hospitals where patients 

transfer rate is high [8,25,27] . Transfer of a colonized 

ICU patient in the hospital has enormous 

opportunity for dissemination. These outbre a k s


may be large, often start in ICUs and then they 

spread to other parts of the hospital [93,94] . Very often 

the exact source of outbreak is never identified. 

However, the lower digestive tract of colonized 

patients has been recognized as the major source of 

E S B L - p roducing organisms and their cro s s - 

transmission among patients has been attributed to 

the hands of medical and nursing personnel [93,94,95] . 

Environmental foci have also been reported but 

they are rare. They include: ultrasound gel, 

thermometers, blood pre s s u re cuffs and contaminated 

b ro n c h o s c o p e s [ 9 7 - 1 0 0 ] . Other studies demonstrated 

that cockroaches infesting a neonatal ICU in South 

Africa carried the same ESBL strain responsible for 

an outbre a k [ 1 0 1 ] . Many investigators are using 

molecular methods such as pulse field gel 

e l e c t ro p h o resis (PFGE) to examine the epidemiology 

of the outbreaks [97,101-103] . 

SPECTRUM OF CLINICAL DISEASE 

Initially ESBL-producing organisms were only 

seen to cause nosocomial infections [103,104] . Later on 

they were shown to cause a long-term carriage in 

the community [ 9 2 , 9 5 ] . Recently there have been 

several reports of true community-acquire d 

infections (e.g., urinary tract infections) with ESBLp 

roducing E . c o l i [ 1 0 5 ] . It was found that diabetes 

mellitus, prior quinolone use, recurrent urinary 

tract infections, prior hospital admission and older 

age were independent risk factors [105] . 

E S B L s - p roducing organisms cause a wide 

s p e c t rum of clinical diseases ranging fro m 

colonization to serious infections [ 1 5 , 1 0 3 , 1 0 4 ] . The 

common types of infections include urinary tract 

infections, peritonitis, cholangitis and intraabdominal 

abscess. They are a common cause of 

nosocomial penumonia and central venous linerelated 

bacteremia [89,101,103,104] . In hospitalized patients 

u n d e rgoing neuro s u rgical pro c e d u res, ESBL 

producers may also cause meningitis [106] . 

LABORATORY DETECTION 

The significance of ESBL detection: 

The accurate detection of ESBL production in 

clinical isolates is crucial [107,108] . The concern for this 

is two fold: 

1. The therapeutic implications: Infections with 

E S B L p roducers have an important impact on 

clinical outcomes [108,109] . They are associated with 

high rates of morbidity and mortality, a prolonged 

hospital stay and a higher cost [ 1 0 9 - 111 ] G e n e r a l l y 

patients infected with ESBL p roducer are at 

increased risk of treatment failure with extended 

spectrum - beta-lactams [112] . The failure rate is high 

and may exceed 90% when cephalosporins were 

used for serious infections caused by ESBL- 


producing organisms, particularly when the MICs 

for used cephalosporins are elevated (e.g., 4 or 8 

µg/ml) but are still within susceptible range [112-114] . 

The Clinical Laboratory Standard Institute (CLSI) 

indicates that cephalosporin susceptibility is 

indicated by MICs ≤ 8µg/ml [115] . The reporting of 

cephalosporin resistance varies and depends on the 

national breakpoints [9] . ESBL detection originated 

because some ESBL-producing organisms appeare d 

susceptible to cephalosporins using conventional 

breakpoints [116] . 

Many strains of the ESBL- producing organisms 

demonstrate an inoculum effect in that (MICs) of 

the extended-spectrum cephalosporins rises as the 

inoculum increases. There f o re, MIC determined 

with standard inoculum (10 CFU/ml) [5] may remain 

below the standard breakpoints for resistance [116,117] . 

The inoculum effect has been demonstrated in 

some animal models of endocarditis and intraabdominal 

abscess [118] . This effect may be clinically 

relevant in similar type of infections or in infections 

at sites in which drug penetration is poor (e.g., 

meningitis. The inoculum effect will increase MICs 

to levels unattainable even with aggressive dosing 

leading to treatment failure [87,112] . The co-existence of 

resistance to other antimicrobial classes has lead to 

the availability of few treatment options [ 11 0 ] . 

Therefore, accurate in vitro detection of ESBL is 

essential to guide therapy selection [119,120] . 

2. The epidemiological and infection control 

aspects: This is an important reason in favor of 

ongoing efforts aimed at ESBL detection. Although 

several reports show that there is an increasing 

prevalence of ESBLs worldwide, the extent of the 

problem is under-recognized due to unawareness 

and poor laboratory detection and reporting [121] . 

Monitoring prevalence is important to define the 

magnitude of the problem and may help to 

implement appropriate infection control measures. 

These measures can control endemic situations as 

well as arrest outbreaks [93,94] . 

Diagnostic problems of ESBL detection: 

Detection of ESBL is not straight forward for 

many reasons: 

1. There is no simple marker for its presence 

unlike methicillin-resistant Staphylococcus aure u s 

(MRSA) or vancomycin resistant E n t e ro c o c c u s 

(VRE). Ceftazidime resistance is no longer a 

suitable marker for the presence of ESBLs since in 

many hospitals ceftazidime is being replaced by 

cefipime and therefore, no longer tested. Also CTX- 

M ESBLs are not in general ceftazidime hydrolysers. 

2. Not all ESBL p roducers are universally 

resistant to any one of extended spectrum ßlactams. 

They vary in their substrate specificity and

176 


may not phenotypically express resistance to its 

own substrate [15] . 

3. An ESBL p roducer may harbor multiple 

ESBLs or other different enzymes which may alter 

the antibiotic resistance phenotype (e.g., AmpC ßlactamases, 

metallo-ß-lactamases) [13,26,28,33,104,116,122] . 

4. The importance of the inoculum effect on 

MICs determination [117] . 

Many clinical microbiology laboratories make 

no effort to detect ESBL p roduction by Gramnegative 

bacteria. There is an ongoing argument by 

many investigators that detection of ESBLs is too 

complex and costly since many diagnostic 

p roblems are encountered. They suggest that 

changes of cephalosporins breakpoints for 

Enterobacteriaceae is a more appropriate approach 

than expanding efforts to detect ESBLs and dispute 

that the inoculum effect is important [123] . However, 

such an approach would require a substantial effort 

by antimicrobial susceptibility testing committees 

and the MICs alone may give erro n e o u s 

information as a result of the inoculum effect. 

It is still recommended by CLSI that clinical 

microbiology laboratories perform specialized tests 

for detection of ESBLs [ 9 , 11 5 ] . Clinical laboratories 

which look for ESBLs vary in their success in 

identifying these enzymes since criteria for ESBL 

detection have changed over time and the need for 

improved detection is well recognized [124,125] . It may 

be necessary to detect ESBL producers in all or 

specific clinical isolates especially those associated 

with serious infections without having to identify 

them specifically [9] . There is no widely accepted 

screening test but an inexpensive and an easy to use 

screening test may be introduced into the routine 

susceptibility testing. Positive screening re s u l t s 

must still be verified with a confirmatory test [5,9,115] . 

A comprehensive study needs to be carried out 

initially comparing the abilities of all available 

tests, their merits and shortcomings and their 

suitability for a given laboratory before adopting 

any of them [5,9,125] . 

DETECTION METHODS 

The detection methods can be divided into: 

a) Phenotypic methods 

b) Molecular methods 

a) Phenotypic methods: 

They are based upon the resistance that ESBLs 

confer to oxyimino-beta-lactams (e.g. ceftriaxone, 

cefotaxime, ceftazidime and aztreonam) and the 

ability of a beta-lactamase inhibitor, usually 

clavulanate, to block this resistance. Several tests 

have been proposed. 

Double disk diffusion test: The Jarlier double disk 

approximation or double disk synergy (DDS) was 

the first detection test described in 1980’s [126] . DDS is 

a disk diffusion test in which 30 µg antibiotic disks 

of ceftazidime, ceftriaxone, cefotaxime a n d 

aztreonam are placed on the plate, 30 mm (center to 

center) from the amoxicillin/clavulanate (20µg/10µg) 

disk. A clear extension of the edge of the antibiotic’s 

inhibition zone toward the disk containing 

clavulanate is interpreted as synergy, indicating the 

presence of an ESBL. The use of cefpodoxime as the 

expanded spectrum cephalosporin of choice has been 

suggested as evaluation of DDS has shown 

sensitivities and specificities ranging from 79% to 

97% and 94% to 100% re s p e c t i v e l y [ 1 2 7 , 1 2 8 ] . Falsenegative 

results have been observed with isolates 

harboring SHV-2, SHV-3 and TEM-12 [ 1 2 8 - 1 3 0 ] . In 

isolates which are suspicious for harboring ESBLs 

but are negative using the standard distance of 30 

mm between disks, the test may be repeated with 

closer (e.g., 20 mm) or more distant (e.g., 40 mm) 

disks [128,129] . The test remains a reliable, convenient 

and inexpensive method of screening for ESBLs. 

However, the interpretation of the test is quite 

subjective. Sensitivity may be reduced when ESBL 

activity is very low leading to wide inhibition zones 

around the cephalosporin and aztreonam [130] . 

Cephalosporin/clavulanate combination: T h e 

British Society for Antimicrobial Chemotherapy has 

recommended the disk diffusion method for 

phenotypic confirmation of ESBL presence using 

ceftazidime/clavulanate and cefotaxime/clavulanate 

combination disks with semi-confluent growth on 

Iso-Sensitest agar [131] . The zone diameter of each 

combination is compared with zone diameter of 

cephalosporin alone and a ratio of cephalosporin/ 

clavulanate zone size to cephalosporin zone size is 

calculated. A ratio of 1.5 or greater indicates the 

presence of ESBL. Once the sensitivity of the test is 

i n c reased to 93% for both antibiotics, it is 

c o n s i d e red that the test does not detect ESBL 

production by strains producing SHV-6. 

Agar supplemented with clavulante: Antibiotic 

disks of ceftazidime (30 µg), cefotaxime (30 µg), 

ceftriaxone (30 µg) and aztreonam (30 µg) are 

placed on Mueller-Hinton agar supplemented with 

4 µg/ml clavulanate and on clavulanate fre e 

Mueller-Hinton agar plate. A difference in ß-lactam 

zone width of ≥ 10 mm on the two media is 

considered positive for ESBL production [130] . The 

sensitivity is 93-96% and specificity is 100% for the 

ceftazidime [129] . A major disadvantage of test is the 

need to freshly pre p a re clavulanate containing 

media.


Disk replacement method: T h ree amoxicillin/ 

clavulanate disks are applied to a Mueller-Hinton 

plate inoculated with the test organism. After one 

hour at room temperature, these antibiotic disks are 

removed and replaced on the same spot by disks 

containing ceftazidime, cefotaxime and aztreonam. 

C o n t rol disks of these three antibiotics are 

simultaneously placed at least 30 mm from these 

locations. A positive test is indicated by a zone 

increase of ≥ 5 mm for the disks which have 

replaced the amoxicillin/clavulanate disks compare d 

to the control disks [132] . 

Three dimensional test: The three dimensional test 

was described by Thomson and Sanders [128] . It gives 

phenotypic evidence of ESBL-induced inactivation 

of extended-spectrum cephalosporins or aztreonam 

without relying on the demonstration of inactivation 

of the ß-lactamases by a ß-lactamase inhibitor [128] . 

The test depends on the ability of a culture of the 

test organism to distort the zone of inhibition 

around an oxyimino-beta lactam disk. This test was 

determined to be sensitive but it is more technically 

challenging and labor intensive than other 

methods. 

Etest for ESBL: The Etest ESBL strip is a two-sided 

strip in which clavulanate is added to one side of a 

dual oxyimino-beta lactam gradient looking for a 

reduction in the MIC of cephalosporins in the 

p resence of clavulanate [ 1 3 3 ] . The availability of 

cefotaxime as well as ceftazidime strips improves 

the ability to detect ESBLtypes which preferentially 

h y d rolyze cefotaxime such as CTX-M-types 

enzymes. This method is useful for both screening 

and phenotypic confirmation of ESBL production. 

The reported sensitivity as a phenotypic 

confirmatory test for ESBL is 87 to 100% and 

specificity is 95 to 100% [129,132,133] . The test is limited by 

its indeterminate results, difficulties in recognizing 

subtle zone deformities and cost. 

E S B L detection methods by the automated 

antimicrobial susceptibility test systems: T h e 

automated antimicrobial susceptibility test systems 

( Vitek, MicroScan and BD phoenix) have also 

produced ESBL tests. The Vitek ESBL test utilizes 

cefotaxime and ceftazidime alone and in combination. 

A predetermined reduction in the growth of the 

cefotaxime or ceftazidime wells containing 

clavulanate, compared with the level of growth in 

the well with cephalosporin alone indicates a 

positive test [135] . Sensitivity and specificity of the 

method exceed 90% [ 1 3 5 ; 1 3 6 ] . False-negative re s u l t s 

have been observed in Klebsiella pneumoniae isolates 

producing both an ESBL and AmpC-type beta- 


l a c t a m a s e [ 1 3 7 ] . Klebsiella oxytoca strains hyperpro d u c i n g 

the K1 ß-lactamase will usually be recorded as 

positive on the Vitek ESBLtest [135] . MicroScan panels 

which contain combinations of ceftazidime or 

cefotaxime plus ß-lactamase inhibitors have 

appeared highly reliable [138] . The Phoenix ESBL test 

uses growth response to cefpodoxime, ceftazidime, 

ceftriaxone and cefotaxime with or without 

clavulanate to detect the production of ESBLs. The 

results are usually available within six hours [139] . 

The Phoenix ESBLmethod detects ESBLproduction 

in greater than 90% of strains genotypically 

confirmed to produce ESBL [ 1 3 6 , 1 3 9 ] . The method 

c o r rectly detects ESBL p roduction by K l e b s i e l l a, 

E.coli, Enterobacter, Proteus and Citrobacter spp [139] . 

In the laboratory of the Riyadh Armed Forces 

Hospital, which is a major tertiary care hospital in 

Riyadh, Saudi Arabia, ESBL detection in clinical 

isolates was initially done by the E-test method. 

Later on, MicroScan panels for ESBLdetection were 

introduced. 

CLSI recommended methods for ESBL detection: 

The CLSI has provided guidelines for ESBL 

detection for both disk diffusion and standard 

broth microdilution methods [115] . 

Disk diffusion screening methods: CLSI proposed 

disk diffusion methods for screening for ESBL 

production by E. coli, Klebsiella spp and Proteus 

m i r a b i l i s. Ceftriaxone, cefotaxime, ceftazidime, 

cefpodoxime and aztreonam are used. If any of the 

zone diameters indicate suspicion for ESBL 

production, phenotypic confirmatory tests should 

be used to verify the diagnosis [115] . The use of more 

than one antimicrobial agent for scre e n i n g 

improves the sensitivity of detection. 

Screening by dilution tests: CLSI has proposed 

dilution methods for screening for ESBLproduction 

by E.coli and Klebsiella spp [115] . CLSI recommends the 

use of ESBL b reakpoints for indicator dru g s 

(ceftriaxone, cefotaxime, ceftazidime, cefpodoxime 

or aztreonam) to screen for ESBL. When the initial 

screen is positive, CLSI recommends a phenotypic 

confirmatory test. 

Phenotypic confirmatory tests for ESBL p r o d u c t i o n : 

Cephalosporin/clavulanate combination disks are 

used. The CLSI recommend use of cefotaxime (30 

µg) or ceftazidime (30 µg) disks with or without 

clavulanate for phenotypic confirmation for the 

presence of ESBLs in Klebsiella and E.coli. The CLSI 

recommends that the disk test performed with 

confluent growth on Mueller-Hinton agar. A 

difference of ≥ 5 mm between the zone diameters 

of either of the cephalosporin disks and their

178 


respective cephalosporin/clavulanate disk is 

considered to be phenotypic confirmation of ESBL 

production [115] . The use of both antibiotic disks is 

advisable since the use of ceftazidime alone has 

resulted in the inability to detect CTX-M-producing 

organisms [140] . 

Phenotypic confirmatory testing can also be 

performed by broth microdilution assays using 

ceftazidime (0.25 to128 µg/ml), ceftazidime plus 

clavulanic acid (0.25/4,128/4), cefotaxime (0.25 µg 

to 64 µg/ml) and cefotaxime plus clavulanic acid 

(0.25/4 to 64/4). The use of both antibiotics is 

recommended. The test is done using standard 

methods. Phenotypic confirmation is considered as 

≥ 3-twofold-serial-dilution decrease in MIC of 

either cephalosporin in the presence of clavulanic 

acid to its MIC when used alone. 

Quality control recommendations of CLSI 

should be followed in both screening and 

confirmatory tests [ 11 5 ] . For all phenotypically 

confirmed ESBL producing strains according to 

CLSI criteria, the test should be reported as 

resistant for all penicillins, cephalosporins (except 

the cephamycins, cefoxitin and the cefotetan) and 

aztreonam regardless of the routine susceptibility 

test results. ß-lactam / ß-lactamase inhibitor 

combinations (for example: piperacillin/tazobactam 

and ticarcillin/clavulanate) are reported as 

susceptible, if MICs or zone diameters are within 

the appropriate range. 

The phenotypic confirmatory tests are highly 

sensitive and specific compared to genotypic 

confirmatory tests. However, false positive 

confirmatory tests have been reported in Klebsiella 

pneumoniae or E.coli isolates which lack ESBLs but 

hyperproduce SHV-1 [141] . The coexistence of both 

ESBLs and plasmid-mediated AmpC-type ßlactamases 

in Klebsiella pneumoniae may result in 

false negative tests. AmpC-type ß-lactamases resist 

inhibition by clavulanate and hence obscure the 

synergistic effect of clavulanate and cephalosporin 

against ESBL [137] . There are a number of instances 

whereby the screening tests are positive but the 

confirmatory tests are negative or indeterminate [140] . 

The use of cefipime alone and cefipime plus 

clavulanate or the utilization of CLSI ESBL disk 

d i ffusion confirmatory tests may sometimes 

determine whether clavulanate effect truly occurs 

in such cases [140] . Also cefoxitin susceptibility may 

be used as a means of deducing mechanism of 

resistance. Cefoxitin resistant isolates may produce 

AmpC-type enzymes or possess porin changes, 

although it must be recognized that these can 

coexist with ESBL production [140] . 

An evaluation of the use of CLSI methods for 

Enterobacteriaceae other than E.coli and Klebsiella 

spp. has shown that they might apply quite well to 

S a l m o n e l l aspp. but not to the other E n t e ro b a c t e r i a c e a e 

or non-fermentative bacteria such as Pseudomonas 

aeruginosa and Acinetobacter baumannii [142] . 

T h e re have been numerous reports of both 

Enterobacter spp. harboring ESBLs in addition to 

chromosomal AmpC-type ß-lactamases [13,139,143] . The 

inhibitor-based ESBL detection methods are less 

reliable in detecting ESBL in Enterobacter spp. In 

organisms that produce both ESBL and AmpC, 

clavulanate may induce hyperproduction of the 

AmpC ß-lactamase leading to hydrolysis of the 

third generation cephalosporin thus masking any 

s y n e rgy arising from inhibition of the ESBL. 

Modification of the conventional DDS in which a 30 

µg cefipime (or cefpirome) disks are placed at 

distance of 30 or 20 mm (center to center) from a 

disk containing 20 µg amoxicillin plus 10 µg 

clavulanate has been used to detect ESBLs in 

Enterobacter spp. [144] . Enhancement of the zone of 

inhibition in the area between amoxicillin/ 

clavulanate disk and the cefepime may still be 

observed since cefipime is less subject to hydrolysis 

by AmpC ß-lactamases than third generation 

cephalosporins. The sensitivity and specificity are 

higher with disks spacing 20 mm apart (90% and 

97% respectively) rather than 30 mm (61% and 

92%) [144 ] . 

b) Molecular Methods: 

There are a number of methods which can be 

used to characterize ESBLs. The most fundamental 

of these is iso-electric focusing as used by D’Agata 

et al which can give a presumptive identification 

since many of them possess identical isoelectric 

points [145] . Early detection of ß-lactamase genes was 

performed using DNAprobes that were specific for 

TEM and SHV enzymes [146] . The first ESBLs studied 

with probes belong to the TEM family [146,147] . The 

using of DNA p robes can sometimes be labor 

intensive. 

PCR with oligonucleotide primers that are 

specific for a ß-lactamase gene is the easiest and 

most common molecular methods used to detect 

the prescence of a ß-lactamase belonging to a family 

of enzymes [5] . However, PCR will not discriminate 

among different variants of TEM or SHV [147] . 

Several molecular methods that will aid in the 

detection and diff e rentiation of ESBLs without 

sequencing have been suggested. The oligotyping 

method was used to discriminate between TEM-1 

and TEM-2 [148] . This method used oligonucleotide 

probes that are designed to detect point mutations 

under stringent hybridization conditions. Several 

new TEM variants were identified using this 

method [147] . These probes are less sensitive for the 

detection of mutations which are responsible for 

the extended substrate range [148] . In some cases these


mutations lead to the appearance or disappearance 

of restriction sites. Amplification of the relevant 

part of the gene by PCR followed by restriction 

enzyme analysis can thus indicate the presence or 

absence of specific TEM or SHV derived ESBLs [149] . 

PCR-single-strand conformation polymorphism 

(PCR-SSCP) has also been applied to the study of 

ESBLs with satisfactory results [150] . This method has 

been used to detect a single base mutation at 

specific location within the beta-lactamase gene. 

The combination of PCR-SSCPwith PCR-restriction 

fragment length polymorphism (PCR-RFLP) allows 

the identification of newer SHV variants. The ligase 

chain reaction (LCR) is used for the identification of 

SHV genes. LCR allows the discrimination of DNA 

sequences that differ by a single base pair [151] . 

A novel sequence-specific peptide nucleic acid 

(PNA)-based multiplex PCR detection method 

provides an accurate means of identification of bla 

(GES-2) compared to the standard PCR and the 

gene sequencing techniques [73] . 

In Turkey, the distribution of PER-1 ESBL was 

investigated by southern blot analysis with a PER- 

1 gene-specific pro b e [ 6 7 ] . Nucleotide sequencing 

remains the standard for determination of the 

specific ß-lactamase gene present in a strain [5,147,152] . 

H o w e v e r, this too can give variable re s u l t s 

depending on the method used. 

TREATMENT OPTIONS 

In the absence of data from randomized 

c o n t rolled trials to guide optimal therapy, the 

choice of treatment option is based on data from in 

vitro and observational studies [110,120] . These studies 

suggest that carbapenems should be regarded as 

d rugs of choice for serious life-thre a t e n i n g 

infections due to ESBL-producing organisms since 

they have been associated with the best outcome in 

terms of survival and bacteriologic clearance [110,120] . 

The choice between imipenem and meropenem is 

d i fficult. Published experience is greatest with 

imipenem, but MICs are slightly lower for 

meropenem. In nosocomial meningitis, meropenem 

should be re g a rded as the drug of choice. 

Intrathecal polymyxin B should also be considered 

along with removal of neurosurgical hardware in 

cases of CSF shunt infections [ 1 0 6 ] . There is no 

evidence that combination therapy with a 

carbapenem and antibiotics of other classes is 

superior to the use of carbapenem alone [153] . Synergy 

has been exhibited in some but not in all studies. 

Unfortunately carbapenem resistance has been 

observed in organisms commonly harbouring 

ESBLs. There f o re, the appropriate use of these 

valuable agents should be strictly followed [74,154] . For 

non-life threatening infections with ESBLproducers, 

therapy should be streamlined based on 


the initial treatment response and the sensitivity 

results [120] . 

The third generation cephalosporins should not 

be used to treat serious infections with ESBLproducing 

organisms because clinical outcome is 

poor even in the presence of appare n t 

susceptibility [112,120] . The clinical experience with use 

of cefipime and cephamycins is limited. Cefepime 

should not be used as the first line therapy against 

ESBL-producing organisms [110,120,155] . If it is to be used 

(for example against organisms with cefepime MIC 

< 2 µg/ml), it should be given in high dosage, at 

least 2 g twice a day [9,120,123] . In vitro synergy may be 

achievable between cefepime and amikacin [9,120,156] . 

Cefipime resistance may be more frequent in 

strains which produce the CTX-M-type ESBLs [157] . 

Cephamycins are not recommended as first line 

therapy for ESBL-producing organisms despite 

their good in vitro activity [9,120] . In one of the reports, 

selection of porin resistant mutants occurre d 

during therapy, resulting in cefoxitin resistance and 

relapse of infection [ 2 8 ] . In addition, combined 

cephamycins and carbapenem resistance in 

Klebsiella pneumoniae has been observed in the 

setting of widespread cephamycin use in response 

to an outbreak of infection with ESBL-producing 

organisms [154] . 

However, ß-lactam / ß-lactamase inhibitors (for 

example piperacillin-tazobactam) are not regarded 

as suitable first line therapy for serious infections 

caused by ESBL producer [9,120] . Data regarding their 

use in the treatment of serious infections is sparse 

and treatment failures have been reported [120] . The 

activity of ß-lactam / ß-lactmase inhibitors is 

inoculum-dependent [117] . Some animal studies have 

shown that ß-lactam / ß-lactamase inhibitor to be 

less active than carbapenem against ESBL-pro d u c i n g 

o rg a n i s m s [ 1 5 8 ] . They are usually active against 

o rganisms producing a single ESBL. Their 

e ffectiveness may be reduced in org a n i s m s 

producing multiple ESBLs [26] . The hyper-production 

of the parent enzymes (for example, TEM-1 or SHV- 

1) in ESBL- producing organisms or the combination 

of ß-lactamase production and porin loss can also 

lead to a reduction in activity of ß-lactamase 

inhibitor [159] . In vitro resistance to ß-lactam / ßlactamase 

inhibitors is increasing [51] . Amoxicillin/ 

clavulanate may be regarded as second line therapy 

for urinary tract infection [9,120] . It is noteworthy that 

the use of beta-lactamase inhibitors has been shown 

to be a protective factor for infection or colonization 

with ESBL-producing K. pneumoniae [160] . 

Treatment with non-ß-lactam containing 

regimens was described in a small number of 

patients [110,120] . Quinolones may be considered as 

therapy of choice for urinary tract infection and 

second line therapy for bacteremia, hospital

180 


a c q u i red pneumonia and intra-abdominal infections 

caused by ESBL-producing organisms provided the 

organism is susceptible [9,120] . The observed increase 

in quinolones resistance will limit their role in 

t reatment options [ 1 6 1 ] . In general, the newer 

quinolones are unlikely to provide great additional 

benefits over ciprofloxacin. An observational clinical 

study found that carbapenems were superior to 

quinolones, whereas another study found that they 

w e re equivalent in eff e c t i v e n e s s [162,163] . It is possible 

that suboptimal dosing of quinolones in the 

presence of strains with elevated quinolone MICs, 

but still in the susceptible range, may account for 

those differences [9] . In vitro studies have suggested 

that synergy may occur when ciprofloxacin is 

added to ß-lactam antibiotic against ESBLp 

roducers (e . g . ,cefipime, cefotaxime or imipenem) [ 1 6 4 ] . 

The use of aminoglycosides for serious infection 

should be probably limited to combination with ßlactam 

antibiotics [9,120] . More outcome studies are 

still needed to optimize therapy selection. 

PREVENTION AND CONTROL 

Many of the reported outbreaks were managed 

using two types of interventions: implementation 

of infection control measures and restriction of use 

of oxyimino-cephalosporins [93,94,164] . However, it has 

been reported that a long lasting outbreak was 

successfully controlled by isolation measure s [ 9 4 ] . 

This emphasize the importance of infection control 

measures and the necessity to ensure compliance 

with them [94] . ESBL - producing organisms may be 

endemic in many hospitals and measures to control 

their spread should be considered [9] . 

Laboratory detection and reporting: C l i n i c a l 

microbiology laboratory plays a vital role in the 

c o n t rol of ESBL-producing organisms. The 

implementation of appropriate ESBL d e t e c t i o n 

methods is recommended by CLSI and several 

other studies [ 1 0 7 , 11 5 ] . It is recommended by some 

investigators that laboratories should also report 

the presence of ESBL to the infection contro l 

practitioners and some suggest to the clinicians 

also [124,125] . This approach is implemented in our 

institution in an attempt to increase awareness, 

guide therapy and to institute appro p r i a t e 

infection control precautions. 

Surveillance systems: The surveillance systems 

help to establish a baseline prevalence data and 

monitor changing of rates. These data will be used 

to identify selective pressures and determinants 

which are crucial for follow up in the intervention 

programs [121] . 

Admission screening policies: These policies will 

help to identify colonized or infected patients with 

E S B L p roducing organisms especially those 

admitted to ICUs or other high risk areas [94,125] . 

Antibiotic policies: The use of third generation 

cephalosporins especially at widespread empiric 

level should be restricted either by formal 

restriction of availability or by education and 

i n c reased availability of alternatives [ 1 2 5 , 1 6 4 ] . The 

judicious use of other antimicrobials is essential for 

the control of ESBL-producing organisms. 

Infection control measures: Implementation of 

a p p ropriate infection control measures and 

monitoring the adherence to them are crucial to 

control spread of antibiotic resistant organisms. The 

importance of hand hygiene should be reinforced 

and the recommended isolation precautions for 

patients colonized or infected with ESBL producer 

should be followed [93,94,125] . 

Education programs: Continuous education 

programs are necessary to address the problem of 

ESBLs and their control measures. 

Research projects: Research studies which include 

d i ff e rent aspects of ESBLs will help in their 

treatment and control. 

CONCLUSION 

ESBLs have become a widespread serious 

problem and several aspects of them are worrying. 

These enzymes are becoming incre a s i n g l y 

expressed by many strains of pathogenic bacteria 

with a potential for dissemination. They compro m i s e 

the activity of wide-spectrum antibiotics creating 

major therapeutic difficulties with a significant 

impact on the outcome of patients. The continued 

emergence of ESBLs presents diagnostic challenges 

to the clinical microbiology laboratories, who need 

to be more aware of the need for their detection. 

ESBLs occurrence and spread need to be controlled. 

Appropriate antimicrobial selection, surveillance 

systems and effective infection control procedures 

are the key partners in their control. 

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ABSTRACT 

Introduction: Osler-Weber-Rendu (OWR) or Hereditary 

Hemorrhagic Telangiectasia (HHT) is a rare autosomal 

dominant disease characterized by angiodysplastic 

lesions that may affect many organs. Hepatic involvement 

in HHT is observed in 8-31% of cases and can lead to 

arteriovenous shunts within the liver causing high 

output cardiac failure. Liver transplantation may 

provide cure for patient with severe hepatic i n v o l v e m e n t , 

cholangitis and / or perturbed hemodynamics causing 

high output cardiac failure. The aim of this article is to 

review reported cases in the literature, the indication for 

liver transplantation and the outcomes. 

KUWAIT MEDICAL JOURNAL September 2006 

Review Article 

Osler-Weber-Rendu and Liver Transplant 

Wafaa Al-Hashash 1 , Ghassan Baidas 2 

1 Department of Internal Medicine, Gastroenterology, Hepatology and Liver Transplant, Al Sabah Hospital, Kuwait 

2 Department of Internal Medicine, Al-Sabah Hospital, Kuwait 


Material and Methods: A MEDLINE search was 

performed (1970-present) for all case reports and case 

series of HHT requiring liver transplantation. 

Results: A total of 22 cases were reported in the literature. 

95.4% were females. Indications for transplantation 

included decompensated liver disease, congestive heart 

failure and biliary sepsis. Nine patients (41%) required 

transplantation for more than one indication. The overall 

survival was 90.9% ranging from one month to 7.5 years 

of follow up period. 

C o n c l u s i o n : Liver transplant is a viable option for 

patients suffering from HHT with complications related 

to liver involvement. 

KEY WORDS: hereditary hemorrhagic telangiectasia, liver, liver transplantation, Osler-Weber-Rendu 

INTRODUCTION 

Hereditary Hemorrhagic Telangiectasia (HHT) 

is a systemic autosomal dominant disease that 

occurs in all races with equal gender distribution. It 

is characterized by multiorgan involvement with 

angiodysplastic lesions of the skin, lungs, 

gastrointestinal tract, and the brain. The classic 

clinical triad includes re c u r rent epistaxis and 

muco-cutaneous telangiectasia in the setting of 

h e reditary transmission [ 1 - 8 ] . The estimated 

f requency of HHT is 1-2/100,000 in Euro p e a n 

populations with a penetrance of 97% [ 3 , 8 , 9 ] . In 

retrospective studies, the reported prevalence of 

hepatic involvement in patients with HHT has 

ranged from 8 to 31% and out of these, 30-50 % are 

asymptomatic [1,2,10-12] . 

Synthetic function is generally well preserved, 

but liver failure caused by significant replacement 

of hepatic parenchyma with or without hepatocellular 

[ 1 , 2 , 5 , 1 3 - 1 5 ] 

c a rcinoma has been re p o r t e d . When symptoms 

are present, clinical features vary but the most 

common presentation is right upper q u a d r a n t 

abdominal pain. Recurrent encephalopathy can occur, 

especially after gastrointestinal bleeding despite 

normal hepatocellular function [2,13,15] . Patients often 

p resent with significant right-sided congestive 

heart failure secondary to left to right intrahepatic 

shunts correlating with the size of the arteriovenous 

fistula. Portal hypertension and variceal 

formation can result from increased sinusoidal 

blood flow leading to increased deposition of 

f i b rous tissue and nodularity. C o n v e r s e l y, 

hypoperfusion of the peribiliary plexus may result in 

ischemic necrosis of the extrahepatic or 

intrahepatic biliary tree leading to biliary stricture, 

bilomas and biliary sepsis [1,5,11,16-24] . 

Treatment for liver involvement in HHT is 

generally conservative unless complications occur. 

Medical therapy is of marginal value in high 

cardiac output failure. Two invasive techniques for 

reduction of left-to-right intrahepatic shunting 

have been described: embolization; and ligation of 

hepatic artery. The results of these techniques are 

c o n t ro v e r s i a l [ 5 , 8 , 1 7 , 2 1 - 2 6 ] . Liver transplantation may 

provide a cure for patient with severe hepatic 

involvement in the form of cholangitis or portal 

hypertension and / or perturbed hemodynamics 

causing high output cardiac failure. There have 

been many case reports and several small series 

re g a rding the utility of orthotropic liver 

t r a n s p l a n t a t i o n (OLT) for HHT with symptomatic 

liver involvement [5,7-9,12,20,22,23,27-30] (Table 1). 


Dr. Wafaa Ahmed Jassim Al-Hashash, Kaifan, Block no. 2, House no. 29, Street no. 29, Postal code: 71802, Kuwait. Tel: (Work): 4815000 ext. 

5611/5612, Fax: (Home): 482-2799, Mobile: 677-7877, E-Mail: walhashash@yahoo.com


Table 1: Case reports and case series of HHT requiring liver transplantation 

The aim of this article is to review the reported 

cases in the literature, indication for liver 

transplantation, and the outcomes. 

MATERIAL AND METHODS 

A Medline search of English language literature 

from 1970 to July 2004 was performed using the key 

w o rds: hereditary hemorrhagic telangiectasia, 

Osler-Weber-Rendu, liver and liver transplantation. 

Articles were considered by review of their titles 

and abstracts when available. From this initial body 

of literature, we identified additional articles using 

the bibliographies of the original set. A total of 35 

articles dating back to 1978 were thoro u g h l y 

examined. Of these, 12 articles w e re found to 


Author Age Gender Cardiac output Reason for OLT Period of 

(pre and post F/U / post 

OLT ) OLT complications 

Amaris J et al. [20] 48 F Pre OLT :18L/min High cardiac output failure and infectious cholangitis - / None 

Bauer et al. [9] 33 F Pre OLT :12 L/min High cardiac output failure and liver failure due to biliary 

necrosis and sepsis 24 months /None 

Neuman et al. [22] 45 F Pre OLT : 8.8 L/min High cardiac output failure treated with hepatic artery ligation 

Decompensated liver cirrhosis (variceal bleeding) 

Developed recurrent bile duct necrosis post hepatic artery ligation - / None 

Le Corre et al. [28] 40 F Pre OLT: 12.5 L/min High cardiac output failure 1 month / None 

Post OLT: 8.0 L/min 

McInory et al. [18] F ND Spontaneous progressive biliary necrosis after pregnancy - / None 

Hillert et al. [12] 39 F ND RUQ pain during pregnancy. Hemobilia treated with hepatic artery 

embolization complicated by progressive cholestasis & therapy 

resistant biliary sepsis followed by liver failure 1 yr / None 

Saxena R et al. [8] 43 F ND End stage liver disease and fibropolycystic liver disease 

Rec. biliary strictures post surgical dearterialization - / Severe bleeding 

during OLT 

Odorico et al. [27] 48 F ND Embolization of hepatic artery for mesenteric ischemia followed 12 months /Splenic 

by biliary sepsis and liver failure rupture 

47 F 9 months /Delayed 

closure 

Boillot et al. [5] 36 F Pre OLT: 9.5 L/min RUQ pain during pregnancy developed CHF necessitating 65 months /None 

Post OLT:5.5 L/min premature delivary followed by biliary sepsis and liver failure 

50 F Pre OLT: 11.3 L/min Refractory ascites. Portal HTN 53 months /None 


42 F Pre OLT: 10.8 L/min Right sided heart failure; ascites 29 months / None 


Pfitzman et al. [23,29] 45 F Pre OLT : Right sided heart failure; dyspnea 12-65 months / 

8.0-13.3L/min None 

Post OLT : 

4.5-6.3L/min 

69 F Right sided heart failure; dyspnea; ascites; biliary 

ischemia; ventricular arrhythmia 

54 F Right sided heart failure; ascites; pulmonary HTN 

55 F Right sided heart failure ; arrhythmias 

Azoulay et al. [30] 38-66 5 F Pre OLT: 3 Cases: recurrent cholangitis with or without 2 Patients died : 

1 M 9.2+/-3.0 L/min hepatic abscesses Day 2 ** 

Post OLT : 2 Cases: Severe portal HTN, intractable ascites, Day 11*** 

5.7+/- 0.5 L/min and recurrent variceal bleeding 4 Patients are 

1 Case: High cardiac output failure with cholangitis alive: 3-7.5yrs 

/None 

** Secondary to intracerebral hemorrhage 

*** Secondary to massive gastric bleeding due to large AVM 

F = Female, M = Male, OLT = Orthotropic Liver Transplantation, HTN = Hypertension, ND = Not Done, F/U = Follow up, RUQ = Right Upper Quadrant 

specifically address liver transplantation in patients 

with HHT. The remainders addressed the 

e p i d e m i o l o g y, clinical manifestation, natural 

history, diagnosis and other forms of treatment for 

patients with HHT and hepatic involvement other 

than liver transplantation. The results are presented 

in Table 1. 

RESULTS 

In the 12 articles reviewed for patients with 

HHT requiring liver transplantation, a total of 22 

cases were identified (Table 1). Seven of these were 

case reports and the rest were small case series, 

ranging from 2-6 cases, transplanted between year 

1992 and 2001.

188 

The age range was between 33 and 69 years. 

Although the disease is autosomal dominant with 

equal gender distribution, 95.4% (21/22) of 

transplanted patients were women and out of these 

t h ree were either diagnosed or decompensated 

during pregnancy. 

The indications for liver transplantation 

included: decompensated liver cirrhosis (portal 

hypertension, ascites, variceal bleeding) in seven 

patients (31.8%), congestive heart failure in 11 

patients (50%) and recurrent cholangitis and biliary 

sepsis secondary to biliary ischemia either 

spontaneous or post hepatic artery ligation or 

following massive gastrointestinal bleeding in 11 

patients (50%). Nine patients (40.9%) required liver 

transplantation for more than one indication. 

Most authors did not report pre - t r a n s p l a n t 

details of liver synthetic function. Neuman et al 

reported only elevated bilirubin; and Pfitzman et al 

documented Child-Pugh score pre o p e r a t i v e l y. 

Furthermore, liver pathology has been documented 

only by Le Corre et al as absence of cirrhosis 

whereas Saxena et al confirmed the presence of 

portal fibrosis in the explant. 

The survival rate was 90.9% (20/22) and ranged 

from one month to 7.5 years of follow up period 

with two deaths occurring on day two and 11 post 

transplant secondary to intracerebral hemorrhage 

and massive gastric bleeding due to large AVM 

respectively. 

Liver transplantation was associated with a 

reduction of cardiac output and improvement of 

hemodynamic circulation, the median pre - 

transplant and post- transplant cardiac output was 

11.1 l/min and 6.7 l/min respectively. 

The cited period of follow up following 

transplant varied from one month to 7.5 years. The 

patients remained asymptomatic during the cited 

period of follow up. 

DISCUSSION 

The treatment of HHT with liver involvement is 

generally conservative unless complications occur. 

Beta-blockade is attempted to reduce the hyperkinetic 

syndrome and hepatic blood flow, but their use is 

limited by their cardio-depressive effects [5] . Digitalis 

and diuretics are used for heart failure but medical 

therapy is of marginal value in high cardiac output 

failure. 

Transjugular intrahepatic portosystemic shunts 

(TIPS) failed to palliate the symptoms of two 

patients with HHT and liver cirrhosis presenting 

with refractory gastrointestinal bleeding fro m 

telangiectasia, portal hypertension and ascites as 

reported by Lee [31] . 

Devascularization of feeding arteries has been 

attempted for reduction of left-to-right intrahepatic 

Osler-Weber-Rendu and Liver Transplant September 2006 

shunting by ligation or embolization. Serious and 

fatal complications have resulted from the 

procedures in up to 42% of cases. These measures 

are particularly dangerous in these patients with 

c o m p romised portal venous systems [1,2,5, 8,17,21-26,32] . 

Hepatic and biliary necroses are the most 

significant complications, with development of 

recurrent cholangitis and biliary sepsis. If ligation 

or embolization is successful, revascularization of 

the AVM usually occurs within months with 

recurrence of symptoms. Embolization and hepatic 

ligation are therefore, not viable options [1,2,17,22,25-27,32] . 

Liver failure after arterial ligation or embolization 

required rescue OLT. Neuman et al reported a 45y 

e a r-old woman having HHT with multiple 

intrahepatic arteriovenous fistulas and high cardiac 

output failure treated initially with hepatic artery 

ligation. Fourteen months later the patient 

presented with elevated levels of bilirubin, alkaline 

phosphatase reflecting bile duct necroses; and 

re c u r rent bleeding episodes from esophageal 

varices for which the patient underwent successful 

OLT with excellent recovery [22] . 

Liver transplantation can be considered as a 

successful curative treatment for patients with 

HHT and liver involvement having high output 

cardiac failure and / or biliary sepsis as reported by 

Bauer T et al, Amaris J and Le Corre et al [9,20,28] . 

The clinical manifestations of liver involvement 

may fluctuate overtime with spontaneous 

exacerbations and remissions. Development of 

heart failure may present at around 24 weeks of 

p regnancy necessitating aggressive therapy [ 5 , 11 , 1 2 , 3 3 - 3 4 ] . 

McInory et al treated a woman who presented 

during pregnancy with abdominal pain and 

spontaneous pro g ressive biliary necro s i s [ 1 8 ] . The 

case reported by Hillert et al had a much more 

complicated course. A 3 9 - y e a r-old woman pre s e n t e d 

in her second pregnancy with right upper quadrant 

pain and massive hemorrhage from gastric ulcer, 

necessitating surgical therapy (Billroth-I). Persistent 

bleeding from the biliary tree was treated with 

hepatic artery embolization. Progressive cholestasis 

and biliary sepsis ensued, followed by liver failure 

requiring OLT. The patient was followed for one 

year with uncomplicated course [12] . 

It has been postulated that deterioration during 

pregnancy maybe due to increase in the level of sex 

hormones particularly in view of progression of 

arteriovenous malformations during pre g n a n c y. 

H o w e v e r, combined estro g e n - p ro g e s t e one r tre a t m e n t 

at high doses has been reported as being beneficial 

for recurrent epistaxis. The exact mode of action of 

sex hormones is therefore, far from clear and their 

place in management of severe visceral vascular 

malformations uncertain. Receptors for pro g e s t e ro n e 

have been detected in the mucosa of patients


suffering from HHT, but their significance needs to 

be defined [17,32-35] . 

Several case series of patients undergoing OLT 

for HHT have been reported. The first case series by 

Odorico et al reported two women with hepatic 

AVMs that caused mesenteric angina-like symptoms 

that were treated with hepatic artery embolization 

(pancreatico-duodenal artery in one and hepatic 

artery in the other); however, within two weeks and 

two months re s p e c t i v e l , ythey 

developed pare n c h y m a l 

and bile duct necrosis, intrahepatic bilomas, and 

refractory biliary sepsis, subsequently leading to 

liver failure. This was treated successfully by liver 

t r a n s p l a n t a t i o n [ 2 7 ] . Boillot et al reported three women 

with right sided congestive heart failure and/or 

liver failure which were treated successfully by 

liver transplantation. The follow up periods of 29, 

53 and 65 months after transplantation for these 

three patients were uneventful [5] . 

Pfitzmann et al reported four women with HHT 

and liver involvement requiring liver transplant 

between 1995 and 1999 with a follow up time of 12 

to 65 months. All patients had normal graft function 

and good cardiopulmonary status [23,29] . 

In the largest series, Azoulay et al reported six 

cases (five women and one man) analyzing the 

technical and hemodynamic aspects pre and post 

liver transplantation for patients with HHT and 

liver involvement. Two patients died at day two 

and 11 secondary to intracranial hemorrhage and 

massive gastric bleeding due to large arteriovenous 

malformations respectively. The remaining patients 

were alive 3 - 7.5 years (median = 4 years and 9 

months) after transplantation with normal liver 

function and without any cardiac symptoms [30] . 

CONCLUSION 

Liver transplantation appears to offer a viable 

therapeutic option for the treatment of end organ 

disease in HHT. It can restore cardiac function and 

normalize arterial and venous hepatic blood flow. 

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telangiectasia. Am J Rhinol 1999; 13:319-322.


ABSTRACT 

Objectives: The aim of the study was to evaluate the 

early radiological changes after femoral varus derotation 

osteotomy (VDRO) in spastic cerebral palsy (CP) patients 

with hip subluxations and correlating the effects of 

healing and remodeling of the osteotomy on the 

containment of the hip on a short term basis. 

Venue: Al-Razi Orthopedic Hospital, Kuwait 

Subjects and methods: We performed a femoral varus 

d e rotation osteotomy on 17 patients (29 hips) with 

spastic cerebral palsy presenting with hip subluxations 

or dislocation. The radiological changes occurring after 

healing of the osteotomies were followed up for a 

maximum of 16 months. The radiological assessment 

included Reimers migration percentage (MI%), femoral 

neck shaft (FNS) angle and acetabular index (AI). These 

parameters were assessed pre o p e r a t i v e l y, immediate 

postoperative films, and 14-16 months postoperatively. 

Results: The results were graded as good, fair and poor. 

A good result is achieved when the hip is contained, the 


Original Article 

Early Radiological Results of Femoral Varus Derotation 

Osteotomy in Spastic Cerebral Palsy 

Mohamed L Fahmy, Mahmoud Al-Rayes, Ahmed Hammouda, Mohamed Al-Leithy 

Al-Razi Orthopedic Hospital - Kuwait 


migration percentage is less than 5%, and the femoral 

neck shaft angle is from 100-115 degrees. A poor result is 

achieved when the Reimer’s index is > 25% and femoral 

neck shaft angle is > 130 degrees. Analysis of the results, 

and the reasons for poor results are presented. 

Conclusion: Spastic cerebral palsy with hip subluxation 

may progress to complete dislocation. Femoral VDRO 

improves the containment of the hip and its stability on a 

short-term basis. Remodeling at the osteotomy site may 

cause recurrence of the coxa valga especially in the 

younger age groups. This recurrence may affect the 

containment and stability of the hip especially in those 

patients with high MI% and high AI. To decrease this 

effect of remodeling of the osteotomy on the containment 

of the hip, the femoral neck shaft angle at the time of the 

osteotomy should be kept below 115 degrees. In patients 

with a high MI% and high AI, VDRO alone does not 

maintain the hip containment adequately. 

KEYWORDS: cerebral palsy, dislocation, femoral varus-derotation osteotomy, hip subluxation 

INTRODUCTION 

Cerebral palsy is a disorder of movement and 

posture caused by non-progressive defect or lesion 

in the immature brain. The clinical presentation of 

cerebral palsy varies according to the extent and 

location of the lesion in the brain. Spastic cerebral 

palsy constitutes the majority of patients referred to 

the orthopedic surgeon for management of 

deformities resulting from contractures developing 

during growth of the affected children. Dislocation 

of the hip in these patients is common and usually 

occurs around the age of seven years [ 1 ] . The 

incidence of the dislocation varies in the literature 

and is estimated to be between 2.5 - 28% [2-4] . In the 

s e v e rely affected children the incidence of hip 

dislocation may reach up to 75% [3,5] . 

The combination of delayed weight bearing, 

spasticity, muscle weakness with the presence of 

the flexion adduction contractures contributes 

largely to the development of hip subluxation and 

dislocation in spastic CP children. 

The important muscular forces that lead to 

dislocation are over activity of the adductors and 

hamstrings [6,7] , over activity of the iliopsoas [1,3,6] and 

weakness of the gluteus medius and maximus [8] . 

Increased coxa valga with persistent anteversion [6,7,9] 

by the previous muscle imbalances lead to shifting 

of the center of rotation of the hip to the lesser 

trochanter [10,11] . All these forces lead to lateralization 

of the femoral head with subsequent subluxation 

and eventual posterior dislocation. Following the 

posterior dislocation, acetabular index increases [7] . 

Several studies have documented a 50% incidence 

of pain in cerebral palsy patients with hip 

dislocations [12-14] . In Bagg et al series [15] , he showed 

that hips with MI < 50% may reduce spontaneously 

or at least remain subluxated. Hips with MI > 50% 

remained subluxated or progressed to dislocation. 

To prevent and/or treat this problem a 

combination of soft tissue releases with or without 

Address Correspondence to: 

Dr. Mohamed Ahmed Lotfy Fahmy FRCS Ed.Orthopedic Senior Specialist, Al-Razi Orthopedic Hospital-Kuwait. P.O.Box 4235-13043 Safat, 

Kuwait. E-mail address: malfahmy@hotmail.com

192 

Early Radiological Results of Femoral Varus Derotation Osteotomy in Spastic Cerebral Palsy September 2006 

Fig. 1: Case No. 17, Preoperative X-ray showing right hip subluxation Fig. 2: Case No. 14, Preoperative X-ray showing right hip dislocation 

Fig. 3: Diagram showing the Reimer migration index (MI) 

osteotomies of the proximal femur and/or acetabulum 

are usually performed. 

In this study we performed proximal femoral 

varus derotation osteotomy (VDRO) in patients 

with spastic cerebral palsy with hip subluxation or 

dislocation and assessed the effect of healing of the 

osteotomy on the containment of the hip on a short 

term basis. Though it is well known, that re m o d e l i n g 

of the femoral neck following varus derotation 

osteotomy continues to occur till the physes of the 

femoral neck closes [16] , we wanted to correlate the 

direct effects of healing of the osteotomy one to one 

and half years postoperatively eliminating the 

c o r rection that occurs through remodeling by 

g rowth contribution from the upper femoral 

physes. 

Fig. 4: Diagram showing lines drawn to measure femoral neck shaft angle 

(FNS) and acetabular index (AI) 

MATERIALS AND METHODS 

We performed a femoral VDRO on 17 consecutive 

patients (29 hips) with spastic cerebral palsy. These 

patients were assessed radiologically pre o p e r a t i v e l y 

and postoperatively for a maximum of 16 months. 

Out of 17 patients, eight were female and nine 

were male. The ages at the date of presentation for 

surgery ranged from two years and six months up 

to 10 years 8 months. Eleven patients were between 

three and five years. A total number of 29 hips were 

operated. Twelve patients had bilateral VDRO and 

five patients had unilateral VDRO. 

Out of 17 patients, ten were diplegics, two were 

quadriplegics and five had total body involvement 

with global developmental delay. The usual reasons 

for presentation to our clinic were adduction 

flexion deformity of the hips with scissoring gait 

(10 patients) and delayed walking (all 17 patients). 

Only one patient presented with pain. All patients 

had spastic form of cerebral palsy, five patients did 

not have sitting balance (total body involvement), 

eight patients were wheelchair dependant and 

eight out of the ten diplegic patients could walk 

with some form of assistance. All patients had 

either hip subluxation or dislocation.


The main indications for surgery were 

correction of hip subluxations (14 patients, 25 hips) 

and dislocations (3 patients, 4 hips, Fig. 1 and 2). In 

addition, secondary goals were to correct deformity 

to achieve balance (sitting or standing) in all 17 

patients and to facilitate personal hygiene in four 

patients. 

Our routine procedures were to perform open 

soft tissue releases of adductors and iliopsoas, 

manual repositioning of the hips (16 patients), 

apply above knee cast with broomstick with the 

hips in the position of abduction and internal 

rotation for three weeks followed by a second stage 

surgery VDRO. One patient had a closed adductor 

tenotomy abroad (case No. 7). Two patients had 

anterior obturator neurectomy because the abduction 

angle was less than 20 degrees (case No. 6), and 

early presentation of complete hip dislocation (case 

No. 15) and one patient had a hip flexor release (case 

No. 2). None of the patients had open reduction of 

the hips and none had pelvic osteotomy to augment 

the acetabular dysplasia. 

All the patients had femoral varus derotation 

osteotomy (VDRO, 29 hips). The usual methods of 

fixation were plates and screws. Postoperatively 

the patients had plaster spica for 4 - 6 weeks. 


Fig. 5: Case No. 1, Preoperative X-ray showing right hip subluxation Fig. 6: Case No. 9, Operative X- rays showing measurement of FNS angle 

at time of soft tissue releases 

Fig. 7: Case No. 9, Postoperative X-rays after 16 months showing a good 

result 

Fig. 8: Case No. 1, Postoperative X-rays after 16 months showing a good 

result 

All patients had sound clinical and radiological 

union and none had infections. One patient had a 

sacral sore which healed in less than 21 days. One 

patient had a hypertrophic scar. One case had 

bilateral supracondylar fractures of the femora 

following removal of the hip spica (case No. 12). 

Radiological assessment of the operated hips 

was made using migration percentage of Reimers 

(MI%) [17] , the acetabular index (AI) and the femoral 

neck shaft angles (FNS, Fig. 3 and 4). A MI of < 5% 

is a contained hip, 25% or less is mild subluxation, 

26 - 50% is moderate subluxation, 51-100 is severe 

subluxation and > 100% is a dislocation. 

The preoperative films were used to assess the 

acetabular index and migration percentage (Fig. 5). 

According to Reimer’s method [17] , this is taken in 

the supine position with the hips in neutral rotation 

and neutral abduction - adduction (knees beside 

each other and patellae facing strictly forwards). 

Because all these patients had excessive anteversion 

of the femoral neck as assessed clinically by 

i n c reased range of internal rotation (> 80 - 90 degre e s 

with the hips extended), we measured the femoral 

neck shaft angles at the time of adductor iliopsoas 

release and after manual repositioning of the hip 

with an X-ray taken in full internal rotation. This 

helped us to properly visualize the APprofile of the

194 


Table 1: Preoperative radiological parameters of 29 hips 

Case Preoperative 

No. MI% AI FNSº 

R L R L R L 

1. 70 —- 31 —- 129 —- 

2. 42 —- 32 —- 133 —- 

3. 25 50 26 30 170 165 

4. 26 26 19 25 146 140 

5. 50 21 27 23 136 143 

6. 57 81 31 35 148 149 

7. 35 25 20 16 134 137 

8. 100 100 35 35 154 154 

9. 76 76 15 15 144 148 

10. 21 25 22 25 140 143 

11. 31 42 25 27 138 136 

12. 73 55 36 32 138 143 

13. 54 35 26 21 138 143 

14. 100 —- 40 —- 142 —- 

15. —- 100 —- 33 —- 144 

16. 64 27 35 29 157 154 

17. 58 —- 25 —- 130 —- 

Table 2: Postoperative radiological parameters of 29 hips 

Case Immediate Late postoperative 

No. postoperative 

MI% FNSº MI% AI FNSº 

R L R L R L R L R L 

1. 0 —- 107 —- 0 —- 14 —- 109 —- 

2. 0 —- 115 —- 24 —- 31 —- 110 —- 

3. 6 24 119 120 25 35 26 26 125 127 

4. 0 0 113 126 8 12 27 23 122 125 

5. 17 0 108 121 17 8 30 22 118 120 

6. 19 27 122 126 14 19 20 28 130 125 

7. 0 0 112 116 0 4 20 19 115 121 

8. 27 19 117 109 27 26 33 32 120 115 

9. 4 4 117 118 4 4 18 18 111 120 

10. 0 0 118 127 4 4 18 16 117 120 

11. 0 0 108 120 13 17 27 27 110 120 

12. 22 28 110 111 4 6 34 31 109 112 

13. 19 11 121 121 22 3 28 16 130 125 

14. 25 —- 118 —- 50 —- 39 —- 130 —- 

15. —- 0 —- 103 —- 0 — 30 —- 105 

16. 0 14 115 113 36 27 35 30 124 138 

17. 0 —- 110 —- 0% —- 26 —- 108 —- 

* values plotted in bold in late postoperative parameters are those with 

poor results (MI% > 25%). 

femoral neck by correction of the ante-version in 

accordance with Samilson’s method [1] (Fig. 6). The 

anteversion was not measured in all cases based on 

the observations of Kay [18] , that it is the external 

rotation that can change the apparent femoral neck 

shaft angle measurements to more than 10 degrees. 

The immediate postoperative films were used to 

assess the migration percentage and femoral neck 

shaft angles. These films were also compared with 

films taken at 14-16 months. All postoperative 

measurements were taken with the legs in neutral 

position with knees beside each other (rotation had 

Table 3: Number of hips with measured FNS angle at 

preoperative and postoperative periods 

Number of Hips 

Period FNS FNS FNS FNS FNS 

< 100º 100-120º 121-130º 131-145º > 145º 

Preoperative — — 2 17 10 

Immediate 

postoperative — 22 7 — — 

Late 

postoperative — 17 11 1 — 

been corrected by the surgical maneuver), patellae 

facing strictly forwards with no external rotation 

allowed. 

RESULTS 

The preoperative, immediate postoperative and 

the late postoperative values of FNS, MI% and AI 

are shown in Table 1 and 2. 

A. Femoral neck shaft angle (FNS): 

In preoperative films, all 29 hips had FNS angle of 

121º or above (27/29 hips had an angle > 131 

d e g rees). In the immediate postoperative films 

22/29 hips were corrected to angles between 100- 

120 degrees (Table 3). The late postoperative X-rays 

showed that five out of 22 hips had an increase in 

the FNS angle to more than 121 degrees during the 

process of union (22.7%). 

While comparing the immediate postoperative 

films with those 16 months postoperatively, out of 

the 12 hips with FNS angle of > 121 degrees, we noticed 

that there is an increase in the FNS angle r a n g i n g 

f rom 4 - 25 degrees in the late postoperative group 

with an average of 9.3 degrees due to the process of 

remodeling of the osteotomy. All these patients 

were younger than five years of age (Table 4). 

B. Migration percentage (MI%): 

This was measured at preoperative films, immediate 

and late postoperative films respectively (Table 5). 

At preoperative films, all hips had subluxation or 

dislocation as assessed by the migration perc e n t a g e . 

Out of these, 24/29 hips had a migration 

percentage > 25. At the immediate postoperative 

films, only 16/29 hips could be brought to 

containment with a migration percentage < 5. At 

late postoperative films, only 11/29 hips had a MI % 

< 5. This denotes a recurrence of subluxation in 

5/29 hips. 

C. Acetabular index (AI): 

This was also measured at preoperative films and 

compared with late postoperative films (Table 6). 

At preoperative films, 17/29 hips had a AI value of 

< 30 degrees. At late postoperative films 19/29 hips 

had an AI < 30 degrees.


Table 4: The effect of remodeling of osteotomy on the 

measurement of FNS angle, age related, recurrence of 

valgisation (> 121 degrees) in 10/29 operated hips. The 

containment grade in these cases is also shown. 

Case Age at Hip Immediate Late 

No. surgery side post- post- Change Grade 

operative operative 

FNSº FNSº 

3. 3 y 5 m R 119 125 + 6 F 

L 120 127 + 7 P 

4. 4 y R 114 122 + 8 F 

L 126 125 ≤ 1 F 

6. 4 y R 122 130 + 8 F 

L 126 125 ≤ 1 F 

7. 2 y 6 m L 116 121 + 5 G 

13. 4 y 9 m R 121 130 + 9 F 

L 121 125 + 4 G 

14. 4 y R 118 130 + 12 P 

16. 2 y 8 m R 115 1 24 + 9 P 

L 113 138 + 25 P 

* Cases marked as ≤ 1 giving a margin of error in measurement 

+ or - one degree. F = fair, G = good, P= poor, y = year, m = month 

Containment of the hip: 

The results were graded as good, fair and poor by 

assessing the hip containment as below. A good 

result is a MI% of < 5% and FNS angle 100-115. A 

fair result is MI% of 6-25% and a FNS angle 115-130. 

A poor result is given to a MI% > 25 and a FNS 

angle > 130 degrees. A lower grade is given to 

mixed results e.g., if the MI% is 6 - 25 (fair) and FNS 

angle is 100-115 (good) the grade is fair. The same 

grade is given if the MI% is < 5 (good) and FNS 

shaft angle is 115-130 (fair). 

A good result denotes a well contained hip. A 

fair result denotes mildly dysplastic hip, with a mild 

hip subluxation. A poor result denotes a moderately 

dysplastic and moderately subluxated hip (Fig. 7 and 8). 

Out of 29 hips, 11 were good, 12 were fair and 6 

were graded as a poor result. Statistical analysis 

using the Wilcoxon two sample test (Table 7) 

revealed that results for the poor outcome are 

significant for the FNS (p value = 0.01) and MI (p 

value = 0.02) and not significant for AI. Comparing 

the figures in the immediate postoperative and 16 

months films, the median for FNS was 116 degrees 

(IQR 113-118), and 125.5 degrees (IQR 120-130) 

respectively. The median for the migration index 

was 21.5% (IQR 14-25%), and 31% (IQR 27-36%) 

respectively. 

DISCUSSION 

We tried to assess the direct effects of healing 

and early remodeling of the femoral VDRO on the 

femoral neck shaft angle obtained at immediate 

postoperative period with that after a period less 

than one and half year and correlate the effects of 


Table 5: Number of hips comparing MI% at preoperative 

and postoperative periods 

Migration Number of Hips 

percentage Preoperative Immediate 14-16 

postoperative months 

< 5 --- 16 11 

6-25 5 10 12 

26-50 10 3 6 

>50 14 --- --- 

this healing on the containment of the femoral head 

inside the acetabulum by measuring two parameters, 

femoral neck shaft angle (FNS) and the R e i m e r’ s 

migration index (MI%). These measure m e n t s w e re 

c o m p a red with the preoperative measure m e n t s .We 

did not use the acetabular index (AI) as in these 

cases we did not attempt to do any acetabular 

procedures or pelvic osteotomies to augment the 

acetabular dysplasia. 

Comparing the immediate and the late 

postoperative films of the 12 hips with FNS angle 

> 121 degrees, we noticed that there is an increase 

in the FNS angle ranging from 4 - 25 degrees with 

an average of 9.3 degrees due to the process of 

remodeling of the osteotomy (Table 4). In comparison 

to Hoffer et al s e r i e s [ 11 ] the remodeling of the 

osteotomy at FNS angle resulted in valgisation of 

10-14 degrees. It is to be noted that his cases were 

followed for an average of seven years compared to 

this series where the follow up was for less than one 

and half years. 

Returning to the surgical pro c e d u re, the 

question is of how much varus should be attempted 

at osteotomy? In Samilson’s series [1] , he advocates 

an angle of 90-100 degrees. In Hoffer’s series [11] he 

advocates an angle of 100 -120 and angles upto 130 

were acceptable. He compared the remodeling in 

patients < 9 years old to those > 9 years. In the 

younger age group, the remodeling averaged 14 

degrees compared to 10 degrees in the older age 

group [11] . Root and Siegal [19] suggested an angle of 

100-110 for patients < 8 years and 115 -120 for 

patients > 8 years. In our series, there was a 

recurrence of valgisation averaging 9.3 degrees. In 

Mazur’s series [16] of 75 hips with proximal femoral 

osteotomies, he found that remodeling was variable 

between patients. In children younger than four 

years, remodeling was more than in children above 

this age. In our series we did not attempt to predetermine 

at preoperative films the exact FNS angle 

we desired, rather we attempted to bring it to the 

best contained position and we decide the amount 

of wedge needed to be resected. All the patients 

who had early recurrences of valgisation were less 

than five years old. 

We feel it is reasonable to follow the age

196 


Table 6: Number of hips with AI < 30 and > 30 degrees at 

preoperative and postoperative periods 

Period Number of Hips 

Acetabular index Acetabular index 

≤ 30º ≥ 30º 

Preoperative 17 12 

14-16 months 19 10 

Table 7: Statistical analysis of radiological parameters 

related to containment grade using Wilcoxon-2 sample 

test. 

Parameter Result Grade 

Good Fair Poor 

FNS 

MI 

AI 

Immediate 116 119.5 *116 

postoperative (110-118) (112-121.5) (113-118) 

16 M postoperative 115 121 *125.5 

(109-120) (115-125) (120-130) 

Immediate 0% 3% ** 21.5% 

postoperative (0-4%) (0-19%) (14-25%) 

16 M postoperative 4% 15.5% ** 31% 

(0-4%) (10-20.5%) (27-36%) 

Preoperative 22 26.5 35 

(16-31) (25-31.5) (30-35) 

16 M postoperative 18 27 32.5 

(16-26) (24.5-29) (30-35) 

Wilcoxon-two sample test 

* p value= 0.01 

** p value = 0.02 

all values are median 

( ) values are IQR (interquartile range) 

M = month 

guidelines suggested by Root and Seigal and to 

keep the neck shaft angle at the time of the 

osteotomy below 115 degrees to avoid the re c u r re n c e 

of valgisation by anticipated remodeling. 

Looking at the cases with a preoperative MI% 50 

or more (16 hips), the containment grade after a 16 

months period is shown in Table 8. 

Out of the six poor results, four cases had a 

preoperative MI% of 60 -100 % with a high AI (> 30 

degrees) raising the question of the need for a p e l v i c 

osteotomy to correct the acetabular dysplasia. In 

Song’s series [20] , he concluded that the incidence of 

postoperative hip instability was higher in the 

patients with preoperative femoral head uncoverage 

ranging from 30-70%. He suggested that in unstable 

hips with > 70% uncoverage of the femoral head, 

the patients should undergo a combined femoral 

and pelvic procedure. Hoffer [11] advocates a pelvic 

osteotomy if the acetabular index is > 30 degrees. In 

Noonan’s series [21] of 73 hips operated by femoral 

varus derotation osteotomy followed up for an 

average of 5.2 years, he concluded that the age at 

which surgery is done and the degree of pre o p e r a t i v e 

Table 8: Showing 16/29 hips with MI% > 50% at 

preoperative assessment. Late postoperative MI% show 

5/29 hips had a poor containment grade. 

Case Hip Migration % Acetabular Migration % grade 

No. side (preoperative) index (Late postoperative) 

1. R 70 31 0 G 

3. L 50 30 35 P 

5. R 50 27 17 F 

6. R 57 31 14 F 

L 81 35 19 F 

8. R 100 35 27 P 

L 100 35 26 P 

9. R 76 15 4 G 

L 76 15 4 G 

12. R 75 36 4 G 

L 55 32 6 F 

13. R 54 26 22 F 

14. R 100 40 50 P 

15. L 100 33 0 G 

16. R 64 35 36 P 

17. R 58 25 0 G 

*Acetabular indices 30 degrees or more, Migration % > 25% and Poor grades 

are shown in bold 

displacement had the most significant effects on 

outcome. Though we did not attempt to do a pelvic 

osteotomy in those patients with a poor uncoverage 

of the femoral head, we now feel that femoral varus 

d e rotation osteotomy alone is not enough to 

maintain hip stability in patients with high acetabular 

index and high preoperative migration index 

denoting a severe subluxation or complete dislocation. 

CONCLUSION 

Spastic cerebral palsy with hip subluxation may 

progress to complete dislocation. Femoral VDRO 

i m p roves the containment of the hip and its 

stability on a short term basis. Remodeling at the 

osteotomy site may cause recurrence of the coxa 

valga especially in the younger age groups. This 

recurrence may affect the containment and stability 

of the hip especially in those patients with high MI% 

and high AI. To decrease this effect of remodeling of 

the osteotomy on the containment of the hip, the 

femoral neck shaft angle at the time of the 

osteotomy should be kept below 115 degrees. In 

patients with a high MI% and high AI, VDRO alone 

does not maintain the hip containment adequately. 

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American Academy of Orthopedic Surgeons, St. Louis: C.V. 

Mosby; 1979; 28:7-36. 

11. Hoffer M, Stein GA, Koffman M, Prietto M. Femoral Varus- 

Derotation Osteotomy in Spastic Cerebral palsy. JBJS 1985; 

67:1230-1235. 

12. Pope DF, Bueff HU, DeLuca P. Pelvic Osteotomies for 

Subluxation of the Hip in Cerebral Palsy. J Pediatr Orthop 

1994; 146:724-730. 


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Dislocation in Spastic Cerebral Palsy, long-term 

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15. Bagg MR, Farber J, Miller F. Long-Term Follow up of Hip 

Subluxation in Cerebral Palsy Patients. J Pediatr Orthop 

1993; 13:32-36. 

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Cummings RJ. Remodeling of the proximal femur after 

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Child Neurol 2004; 46:412-415. 

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ABSTRACT 

Objective: To compare the accuracy of disk diffusion 

method and E-test for the detection of methicillin 

resistance and low-level methicillin-resistance in 

Staphylococcus aureus (S. aureus) and the PBP2a latex 

agglutination test for confirmation. 

Materials and Methods: A total of 76 methicillin 

resistant S. aureus (MRSA) isolates from different clinical 

specimens were tested by disk diffusion method. Disk 

d i ffusion method was performed using methicillin 

(MET) 5µg disk, oxacillin (OX) 1 µg disk, moxalactam 

(MOX), and cefoxitin (FOX) 30 µg each on Mueller 

Hinton agar (MHA) plates supplemented with 2% NaCl 

and incubated at 35 ºC for 24 hours. Minimum inhibitory 

concentration (MIC) was performed by E-test for MET 

and OX on MHA plates containing 2% NaCl. Results for 

all tests were read according to NCCLS re c o m m e n d a t i o n s 

for zone of inhibition and break points. Low-level MRSA 

strains were confirmed by PBP2a latex agglutination test. 

All strains were tested for ß-lactamase production. 



Comparison of Susceptibility Testing Methods for the 

Detection of Methicillin/Oxacillin Resistance in 

Staphylococcus Aureus 

Hanan Ahmed Habib Babay 

Department of Pathology/Microbiology, King Khalid University Hospital, College of Medicine, Riyadh, Saudi Arabia 


R e s u l t s : All M R S A strains were detected by disk 

diffusion methods using MET, OX and FOX (100%). Four 

(5.2%) strains were low-level MRSA by MOX disk. E-test 

detected 72 (94.7%) using MET and 74 (97.3%) MRSA 

strains using OX. No heterogeneous growth within the 

zones of inhibitions was noticed. One M R S A w a s 

misclassified as methicillin sensitive by MET E-test (MIC 

6 µg /ml), but was 32 µg/ml by OX E-test .Two strains 

were low-level MRSA by E-tests but showed resistance 

by MET, OX and FOX disk diffusion method. One strain 

had MIC of 12 µg/ml both by OX and MET E-tests. All 

four strains showed low-level resistance by MOX disk 

and were positive for PBP2a latex agglutination test. All 

the strains produced ß-lactamase. 

Conclusion: Disk diffusion method using MET, OX, and 

FOX can reliably be used to detect methicillin resistance 

in S. aureus. MOX and E-test can be used to detect lowlevel 

methicillin resistance and these can further be 

confirmed by PBP2a latex agglutination test in diagnostic 

laboratories. 

KEYWORDS: cefoxitin, E-test, latex agglutination test, low-level MRSA, moxalactam, oxacillin, PBP2a 

INTRODUCTION 

Methicillin /oxacillin resistant S. aure u s i s 

considered a major nosocomial and community 

acquired pathogen throughout the world [1-3] . It is 

implicated in serious clinical conditions such as 

bacteremia, pneumonia, intra-abdominal infection 

and others [2] . Accurate detection and confirmation 

of M R S A is essential for the institution of 

a n t i m i c robial therapy and implementation of 

infection control measures. However, low-level 

( b o rderline) M R S A is often misdiagnosed as 

methicillin sensitive S. aure u s (M S S A) [ 4 ] . These 

strains are characterized by an OX MIC at or just 

above the susceptibility break point (4-8 µg/ml) 

and called borderline oxacillin resistant S. aureus 

(BORSA) [5-7] . These strains may carry mecA and are 

extremely heterogeneous or produce PBP2a or be 

penicillinase hyperproducers [5-7] . 

Bacterial populations that express the resistant 

phenotype may be heterogeneous and resistance 

e x p ression may vary according to culture 

c o n d i t i o n s [ 5 ] . Several studies have focused on 

failure of conventional methods to identify lowlevel 

M R S A s t r a i n s [ 8 - 1 0 ] . This has led to the 

modification of laboratory protocols such as 

i n c reased salt concentration in culture media, 

decreased temperature of incubation (30-35 ºC) and 

i n c reased incubation time (24 hrs) to enhance 

expression of resistance. These are presented by 

several tests such as OX agar screening test, OX 

disk diffusion, broth microdilution and rapid tests 

such as latex agglutination MRSA screen test, rapid 

ATB Staph and automated Vitek system [9,11-13] . These 

differ in sensitivity and specificity. The molecular 

method, PCR detects mecA gene (the structural 

gene for penicillin binding protein 2a (PBP2a) which 


Dr. Hanan A.H. Babay, MD.KSFel Path (Mic), King Khalid University Hospital, Department of Pathology/Microbiology (32), P.O. Box 

2925,Riyadh 11461, Saudi Arabia. Tel: 01-4672457, Fax: 01-4672462, E-mail: hahabib@ksu.edu.sa


is found in methicillin resistant Staphylococcus 

strains) and is considered the ‘gold standard ’ 

m e t h o d [ 11 , 1 4 ] . However, it is not available in all 

clinical laboratories. Recent reports from Japan on 

the use of cephamycin, cefoxitin (FOX) and 

moxalactam (MOX) for routine detection of all 

classes of MRSA have proved to be good for the 

detection of low-level methicillin resistance in S. 

aureus. 

The purpose of this study was to compare the 

accuracy of different methods for the detection of 

methicillin resistance and low-level methicillin 

resistance in S. aureus i.e., the METOX, FOX, and 

MOX disk diffusion method, E-test and confirmation 

by PBP2a latex agglutination test . 


Bacterial strains: This prospective study took place 

at King Khalid University Hospital, Riyadh, Saudi 

Arabia between 28/1/2003 and 31/8/2003 on 76 

unselected clinical isolates of MRSA. The strains 

w e re re c o v e red from diff e rent cultures of specimens 

(wound, skin, sputum, tracheal aspirates, nose 

swabs, blood, eyes, central lines and urine) of 

patients admitted to the hospital. Only one isolate 

was considered from each patient. Control used 

was a susceptible S. aureus ATCC 25923 strain 

(Remel, USA). 

Susceptibility testing methods: Inocula: the 

inocula for susceptibility testing were made using 

suspensions from overnight cultures of MRSA on 

Mueller Hinton broth (Mueller Hinton, Becton 

Dickinson, USA). An inoculum equivalent to 0.5 

McFarland (10 8 CFU/ml) turbidity standard was 

used for each test. 

Disk diffusion method for MET, OX, FOX, and 

M O X : this was performed on MHA p l a t e s 

supplemented with 2% NaCl (Mueller Hinton, 

Becton Dickinson, USA). After inoculation with the 

MRSA strains, 5 µg MET, 1 µg OX, 30 µg each of 

FOX, and MOX disks (Oxoid Basingstoke, 

Hampshire, England) were applied on the surface 

of the plates and then incubated at 35 ºC for 24 

hours. Resistance was determined according to 

National Committee for Clinical Laboratory standard s 

(NCCLS) where a zone diameter of < 9 mm was 

considered resistant for MET and < 10 mm for 

OX [15,16] . For FOX and MOX a zone < 14 mm and < 

19mm were respectively considered resistant [16] . For 

all, no zone was also considered homogeneous 

resistance. Heterogeneous resistance was defined 

as the presence of small colonies in the circular 

growth inhibition area [4] . 

E-test: E-test (AB Biodisk, Solna, Sweden) done 

to determine MICs for OX and MET were 


Table 1: Percentages of MRSA and low-level MRSA 

strains obtained by different tests 

Test MRSA n (%) Low level MRSA n (%)* 

Disk Diffusion 

MET 5 µg 76 (100) - 

OX 1 µg 76 (100) - 

FOX 30 µg 76 (100) - 

MOX 30 µg 72 (94.7) 4 (5.2) 

E-test 

MET 72 (94.7) 4 (5.2) 

OX 74 (97.3) 2 (2.6) 

*All low-level MRSAstrains were positive for PBP2a latex agglutination test. 

performed on MHA containing 2% NaCl (Mueller 

Hinton II, Becton Dickinson, USA) according to 

manufacturer’s instructions. MIC for OX and MET 

susceptible strains were < 2 µg/ml and < 8 µg/ml 

respectively, according to NCCLS break points. 

PBP2a latex agglutination test (Oxoid, Basingstoke, 

UK): This was performed for confirmation on 

isolates with low-level methicillin resistance . 

ß-lactamase test: All strains were tested for ßlactamase 

production by streaking colonies from 

the edge of S. aure u s onto a nitrocefin disk 

(Cefinase, Becton Dickinson, USA). ß-lactamase 

production was noticed by the appearance of pink 

color within a minute and no change in color 

indicated negative test. 

RESULTS 

MRSA strains in this study were isolated from 

wound and skin swabs 30 (39.4%), sputum / 

tracheal aspirate 20 (26.3%), nose swabs 14 (18.4%), 

blood and central lines four each (5.2%), eye swabs 

three (3.9%), and one urine specimen (1.3%). All 

MRSA isolates were detected by disk diffusion 

using MET, OX, and FOX disks but MOX detected 

72 MRSA (94.7%) and four (5.2%) low-level MRSA 

isolates. Similarly, E-test detected 72 MET and 74 

OX MRSA strains (sensitivity 94.7% and 97.3 % 

respectively, Table 1). Table 2 shows the results of 

susceptibility testing of 76 M R S A strains as 

determined by different methods. The range of 

inhibition zone diameters for FOX were between 5- 

18 mm for 11 (14.4%) of the strains and for MOX 

between 7-20 mm for 12 (15.7%) of the strains. All 

MRSA strains showed no zone with MET disk 

diffusion test (100%) and only two MRSA strains 

showed 9 and 10 mm zones with OX disk 

respectively (2.6%). No heterogeneous growth was 

observed within the inhibition zones. In the 

shadowed column, one MRSA (1.3%) strain was 

misclassified as MSSA by MET E-test, with an MIC 

of 6 µg/ml whilst the OX MIC was 32 µg/ml. Two 

strains were low-level MRSA by both MET and OX 

E-test (2.6%) and one strain had an MIC of 12

200 

Comparison of Susceptibility Testing Methods for the Detection of Methicillin/Oxacillin .... September 2006 

Table 2: Results of susceptibility testing of 76 M R S Aisolates 

No. of Disk diffusion (zone diameter) E-test (µg/ml) 

isolates MET OX FOX MOX MET OX 

(256 

1 0 10 18 19 12 12 

1 0 9 17 19 8 4 

1 0 0 16 17 12 4 

1 0 0 18 20 6 32 

1 0 0 8 8 >256 32 

1 0 0 6 8 >256 >256 

1 0 0 14 10 >256 >256 

1 0 0 0 9 >256 >256 

1 0 0 0 10 >256 >256 

1 0 0 14 14 >256 >256 

1 0 0 5 0 >256 >256 

1 0 0 13 14 128 >256 

Control Zone Zone Zone Zone MIC 0.25-2.5 

range range range range range µg/ml 

(18-27mm) (19-28mm) (24-36mm) (25-33mm) (0.25-4µg/ml) for 

for control for control for control for control for control control 

0*; (no zone) homogeneous resistance; 2: low-level resistant MRSA, 1: MSSA 

and 1: intermediate resistant, all 4 were positive for PBP2a latex agglutination 

test 

µg/ml to both OX and MET (Table 1). PBP2a latex 

agglutination test was positive for these four lowlevel 

MRSA strains. In addition, these were isolated 

from wound and skin swabs. Seventy one (93%) of 

the strains had MET MIC > 256 µg/ml and 70 

(92.1%) had OX MIC > 256 µg/ml which belonged 

to one or the other of the minor classes of Tomasz et 

al classification of M R S A, where classes one to thre e 

w e re hetero g e n e o u s , and class four was 

homogeneous; the methicillin MIC for class four 

was > 800 mg/l. For the major populations of class 

one to three isolates, methicillin MICs were 1.5 to 

100 mg/l, re s p e c t i v e l y, and for the minor 

populations, 10 -8 to 10 -2 , respectively methicillin 

MICs were 100 mg/l [17] . All strains produced ßlactamase. 

DISCUSSION 

Many laboratories have problems with MRSA 

and/or low-level MRSA detection, even for those 

that do use more than one method for detection or 

screening. However, most diagnostic laboratories 

used disk diffusion method for the detection of 

MRSA [1,4,7,8,18] . In one study involving 40 laboratories, 

the sensitivity of detection of MRSA by disk 

diffusion using 1 µg OX disk was 100% and 97.2% 

with 5 µg MET disk whilst a sensitivity of 99% was 

reported for both MET and OX agar screening 

m e t h o d s [ 1 9 ] . However, other laboratories have 

reported a failure rate of 64% in detecting MRSA 

using 1 µg OX disk [10] . Most laboratories used OX 

rather than MET in USA where OX has replaced 

MET because of its instability [ 6 ] . However, one 

should be mindful of the study of Van Griethuysen 

et al, which showed the sensitivity of OX screen 

agar to be only 93.6% and lower than the sensitivity 

of MRSA screen test and concluded that the risk of 

misclassification of MRSA as MSSA was 4.3 times 

higher by OX agar screen test [13] . Although most of 

the references in this paper used OX 6 µg/ml as 

against OX 1 µg/ml in our work, our results are 

quite similar to the re f e renced ones [ 4 , 1 2 , 1 3 , 2 0 ] . 

Mackenzie et al, suggest that differences in media of 

d i ff e rent manufacturers are important for disk 

diffusion test in which there is no supplemental 

salt [18] . Bowers et al used mannitol salt agar, Baired- 

Parker agar with ciprofloxacin and bromocresol 

purple for the isolation of S.aureus as a preliminary 

step to testing for M R S A and found that all 

selective media performed equally well with 80% 

MRSA isolation rate [21] . Atoum et al, compared the 

disk diffusion with PCR and micro d i l u t i o n 

methods and reported least sensitivity with disk 

diffusion method [14] . Similarly, Chambers in 1997 

stated that disk diffusion suffers from low 

specificity averaging 80% relative to other 

methods [5] . Although the NCCLS recommend the 

use of OX disk method on a swab inoculate using 

MHA plate supplemented with 2% NaCl at 35 ºC 

and OX agar screen test using MHAwith 4% NaCl, 

most laboratories do not comply with these 

recommendations [4] . Mackenzie et al, in two studies, 

reported that there is no correlation between the 

accuracy of the results and compliance with 

NCCLS recommendations and he recommended 

the use of low-expression class MRSA strain as a 

control for the NCCLS disk test [8,18] . 

Cephamycins were extensively used in early 

1980s in Japan and resulted in some MSSA and 

MRSA became resistant to FOX [4] . Moriyasu et al 

(1994) and Okonogi et al (1989) reported that FOX 

induced production of PBP2a in vitro in MSSA for 

which FOX MIC were high and proved that disk 

diffusion with cephamycins is a good assay for 

detection of low-level M R S A in Japan [ 2 2 , 2 3 ] . In 

addition, cephamycins have good affinity for S. 

aureus PBP4 which is involved in cell wall cross 

linkage [24] . Although our sample was small, the 

results with the use of FOX and MOX were 

comparable to OX and MET disk diffusion methods 

and to the results of Felten et al, although MOX 

detected low-level MRSA compared to FOX in our 

study [4] . Felten et al, found that FOX and MOX disk 

d i ffusion methods are suitable for detection of 

MRSA of all classes, have 100 % specificity and can 

be useful alternatives to OX [4] . Skov et al used FOX 

5 and 10 mug discs and all Staphylococcus isolates 

were tested on Iso-sensitest agar and MHA plates 

and the results were superior to OX with > 99% 

sensitivity and specificity for both discs [25] . In a


study comparable to our study, Velasco et al, tested 

51 MRSA isolates using OX and FOX in addition to 

cefazolin, cefotaxime and imipenem discs. The 

results showed 100% sensitivity for FOX disc and 

reported to be the best predictor of methicillin 

resistance in S.aureus whilst other discs showed 

100% specificity [26] . However, Chambers reported 

that the use of ß- lactam antibiotics other than MET 

or OX especially, cephamycin is not recommended 

since it further reduces the accuracy of the test [5] . 

Frebourg et al reported that OX E-test is reliable 

alternative to conventional agar or broth dilution 

methods [9] . It showed 98.4% agreement with OX 

agar screen plate test in their study and is 

considered a very reliable method by the NCCLS 

although it has a maximum sensitivity of 95.9% 

according to Van Griethuysen et al [13] . E-test with 

MET was less sensitive than OX E-test for the 

detection of low-level MRSA in our study. 

All our isolates produced ß- lactamase. The role 

of ß- lactamase is unclear, however, it has been 

reported that even in low-level resistance, ßlactamase 

stable antibiotics could be hydrolysed by 

Staphylococcus ß- lactamase, and over- production 

of ß- lactamase could result in borderline MIC [5] . It 

has been observed that culture conditions used to 

enhance M R S A also favor production of ßl 

a c t a m a s e [ 5 ] . Chambers reported that bord e r l i n e 

strains that hyperproduce ß- lactamase are mecA 

negative, show high levels of ß- lactamase activity , 

and lowered the MIC into susceptible range upon 

addition of ß- lactamase inhibitors [5] . 

Most of our MRSA and low-level MRSA strains 

came from wound and skin swabs. This is similar to 

the study of Felten et al, in which it was reported 

that MSSA isolates from skin lesions pro b a b l y 

acquired the mecAgene by horizontal transfer from 

other skin Staphylococcus species [4,27] . The clinical 

implication of low-level MRSA is the possibility of 

fatal community acquired invasive sepsis as 

reported by the Centers for Disease Control and 

P re v e n t i o n [ 2 8 ] . Fortunately, our isolates did not 

result in serious infections or death. 

PBP2a latex agglutination test is latex particles 

sensitized with a monoclonal antibody against 

PBP2a and react specifically with MRSA to cause 

agglutination in three minutes. It is reported to 

have a 97.6% sensitivity and it distinguishes 

between very low-level M R S A f rom MSSA [ 4 , 1 7 ] . 

Bowers et al, reported MRSA-latex agglutination 

test as a reliable and rapid detection test from both 

pure culture and selective media as well as being a 

reliable alternative to mec A PCR for the definitive 

diagnosis of MRSA [21] . A problem was raised by 

Atoum et al when they reported strains of negative 

mecAbeing MET resistant and positive mecAbeing 

MET sensitive. These observations are explained as 


being due to non-functional mecA gene or nonactive 

PBP2a protein. Consequently, they re c o m m e n d e d 

the use of a combination of both molecular and 

microbiological methods for detection of MRSA [14] . 

However, PBP2a latex agglutination method has 

demonstrated 100% agreement for both mecApositive 

and negative strains [6] . Furthermore, most 

diagnostic laboratories do not have eff i c i e n t 

re s o u rces to provide molecular techniques on 

routine basis. 

In conclusion, disk diffusion method using 

MET, OX, and FOX disks is reliable for detection of 

MRSA. For low-level MRSA, MOX disk diffusion 

and E-test OX and MET are reliable and for 

confirmation PBP2a latex agglutination test can be 

used. Laboratories should be aware of the 

shortcomings of tests available to detect MRSA and 

low-level MRSA. The best approach would be to 

have several methods available and use an 

alternative test when resistance is suspected but not 

detected by routine methods. 

ACKNOWLEDGMENT 

We would like to thank Dr Kingsley Twum- 

Danso for revising the manuscript and Mr. Kutubu 

Manneh for technical assistance. 

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ABSTRACT 

Aim: To estimate the prevalence of diabetic retinopathy 

in a population attending a diabetic clinic in Kuwait and 

to evaluate the medical risk factors associated with its 

development and progression. 

Patients and Methods: Fundi of 451 type 2 diabetic 

patients were examined by fundus photography. 

Retinopathy was graded according to EURODIAB IDDM 

complication study. Files were reviewed for clinical and 

social information about the patients. SPSS version 9 was 

used for analysis of the findings. 

R e s u l t s : The overall prevalence of retinopathy was 



Prevalence and Risk Factors for Diabetic Retinopathy 

among Kuwaiti Diabetics 

Fatma AlKharji 1 , Nouria Alshemmeri 1 , Leyla Mehrabi 1 , Mohammed Hafez 1 , Osama Fakher 2 

1 Rabya Diabetic Clinic, Ministry of Health, State of Kuwait, 

2 Preventive Medicine Department, Ministry of Health, State of Kuwait 

INTRODUCTION 

Prevalence of diabetes mellitus, especially type 

2 diabetes mellitus is rising worldwide [1] . Diabetes 

mellitus is a major health problem in Kuwait. The 

prevalence of type 2 diabetes was estimated to be 

14.8% in 1998 [2] . 

Diabetic retinopathy is the most frequent cause 

of visual impairment among adults aged 20-74 

years in the United States. After twenty years of 

diabetes duration, nearly all type 1 diabetics and 

more than 60% type 2 diabetics have retinopathy [3] . 

In England and Wales, diabetic retinopathy re m a i n s 

the commonest cause of blindness among people of 

working age [4] . 

Diabetic retinopathy has few visual or ophthalmic 

symptoms until visual loss develops. Upto 21% of 

type 2 diabetics have retinopathy at the time of 

diagnosis [3] . Laser photocoagulation is effective in 

slowing the pro g ression of retinopathy and 

reducing visual loss. However, treatment does not 

restore lost vision [5] . Therefore, it is important to 

examine the patients with type 2 diabetes at the 

time of diagnosis and then annually [3] . 

T h e re are many factors influencing the occurre n c e 

and the progression of diabetic retinopathy. The 

UKPDS (UK Prospective Diabetes Study) [6] showed 

that intensive glucose control reduced the risk of a 


KEYWORDS: diabetic retinopathy, risk factors, Kuwait 

23.5%, mild retinopathy constituting 11.3%, moderatesevere 

retinopathy 11.08% and proliferative retinopathy 

1.12%. Insulin treatment, duration of diabetes, age at 

examination, HbA1c, systolic blood pressure, cholesterol, 

triglyceride and microalbumin were found to be 

s i g n i f i c a n t l y related to the development and the 

progression of retinopathy. 

Conclusion: Caring for diabetic patients should include 

screening for risk factors associated with retinopathy and 

controlling them to delay or prevent the development 

and/or progression of diabetic retinopathy. 

two-step change in retinopathy by 21% at 12 years 

follow up. Moreover, tight blood pressure control 

reduced the risk by 34%. Other studies showed that 

glycemic control played an important part in the 

development of microvascular complications [7] . 

The aim of this study was to estimate the 

prevalence rate of diabetic retinopathy in patients 

attending a diabetic clinic in Kuwait and to evaluate 

the medical risk factors underlying its development 

and progression. 

PATIENTS AND METHODS 

T h e re is no national screening program for 

diabetic retinopathy in Kuwait. However, recently 

diabetologists were trained to perform dire c t 

fundoscopy and some diabetic clinics were 

supplied with fundus cameras in an attempt to 

detect conditions that need direct attention by 

retina specialists. 

Patients seen in a fundus clinic attached to a 

primary care diabetic clinic in Rabia A rea in 

Farwania Governorate were recruited from March 

2002 to December 2002. A total number of 451 type 

2 diabetic patients were included in the study. Their 

pupils were dilated using 1% tro p i c a m i d e . 

Photograph of each retina was taken using nonmydriatic 

retinal camera (Canon model CR6- 

Address Correspondence to: 

Dr. AlKharji F, P.O. Box 34509, AlAdailya 73256, Kuwait. Tel: (965)9709965, Fax: (965)4730848, E-mail: Fatma_al_kharji@hotmail.com

204 

Prevalence and Risk Factors for Diabetic Retinopathy among Kuwaiti Diabetics September 2006 

Fig 1: Duration of diabetes in relation to retinopathy 

Duration in years Age in years 

45NM). One shot was taken for each eye. The films 

were processed and the pictures (18 x 15 cm) were 

examined by two trained diabetologists. 

Retinopathy was graded according to 

EURODIAB IDDM complication study [8] . 

Grade A = no retinopathy 

Grade B = mild non-proliferative retinopathy 

Grade C = moderate to severe non-proliferative 

retinopathy 

Grade D = Proliferative or photocoagulated 

Grade E = not classified due to media opacities 

In this study, it was not possible to assess retinal 

thickening and elevation as a consequence of not 

taking stereo retinal photographs. There f o re , 

maculopathy per se was not gradable. Mild 

retinopathy cases were followed up in our clinic, 

while moderate to severe retinopathy and pro l i f e r a t i v e 

or photocoagulated cases were re f e r red to an 

ophthalmology service. 

The files of the patients were reviewed for 

recognized data such as age, gender, duration of 

diabetes, BP m e a s u rement, lipid profile, micro a l b u m i n 

and HbA1c (glycosylated hemoglobin) values. 

Lipid profile was measured by standard laboratory 

methods. HbA1c levels were determined by 

immunological assay for the in vitro quantitative 

determination of HbA1c in whole blood on an 

automated clinical chemistry analyzer (Roche 

Diagnostics Corporation, Indianapolis USA). 

Microalbumin was determined by Beckman array 

system using early morning collected urine sample 

(Beckman Caulter IMMAGE). 

Statistical Analysis: All data were computerized 

using SPSS version 9.0. Means and standard 

deviations were used for simple data analysis. 

ANOVA test, t-test and chi- square test were used 

for analysis of quantitative and qualitative data as a 

test for significance. P-values of 0.05 and 0.001 

levels were used for all significant tests. 

Fig 2: Age in relation to retinopathy 

RESULTS 

This study included 451 type 2 diabetic patients. 

42.8% (193) were male and 57.2% (258) were female. 

Prevalence of retinopathy in general was 23.5%. 

Prevalence of mild retinopathy was 11.3% while 

p revalence of moderate-severe retinopathy was 

11.08%. There were five cases of proliferative or 

photocoagulated retinopathy (1.12%). Fundi in 

twenty-eight patients were not visualized because 

of corneal or lenticular opacities (6.2%). 

There were 354 Kuwaiti patients (78.49%), 31 

non-Kuwaiti Arabs (6.8%) and 66 non-Kuwaiti 

Asians (14.6%). Prevalence of retinopathy was 

22.2% in Kuwaitis, 22.58% in non-Kuwaiti Arabs 

and 28.78% in non-Kuwaiti Asians. 

P revalence of any retinopathy diff e red in 

patients treated with insulin (43.1%) and in patients 

treated with oral hypoglycemic agents or diet only 

(15.8%). This difference was found to be significant 

using the chi-square test (p < 0.000). 

Prevalence of retinopathy increased with longer 

duration of diabetes, ranging from 10% at < 5 years 

to 51% at > 20 years (Fig. 1). This difference was 

found to be statistically significant when tested by 

t-test (p < 0.000, Table 1). ANOVA test indicated a 

strong influence of duration on the severity of 

retinopathy (p < 0.000, Table 2). 

Table 1: Medical risk factors in relation to the presence or 

absence of retinopathy (t-test) 

No retinopathy Any retinopathy p-value 

(n = 317) (n = 134) of t-test 

Mean value Mean value 

Age (years) 50.5 55.2 0.000* 

Duration (years) 8.23 12.32 0.000* 

Systolic BP(mmHg) 131.8 135.2 0.028* 

Diastolic BP(mmHg) 83.6 84.01 0.67 

HbA1c (%) 7.95 9.06 0.000* 

Cholesterol (mmol/L) 5.39 5.84 0.000* 

Triglyceride (mmol/L) 1.94 2.23 0.019* 

Microalbumin (mg/L) 69.65 122.57 0.011* 

* significant (p < 0.05)


Table 2: ANOVA analysis of risk factors for different 

grades of retinopathy 

No Mild Moderate ANOVA 

retinopathy (n = 51) -severe test 

(n = 317) Mean (n = 55) p value 

Mean value value Mean value 

Age (years) 50.5 56.51 54.13 0.001* 

Duration (years) 8.22 11.33 13.23 0.000* 

Systolic BP (mmHg) 131.88 137.35 133.36 0.03* 

Diastolic BP(mmHg) 83.61 84.61 83.45 0.712 

HbA1c (%) 7.95 9.09 9.04 0.001* 

Cholesterol (mmol/l) 5.39 5.70 5.97 0.001* 

Triglyceride (mmol/l) 1.94 2.27 2.18 0.059 

Microalbumin (mg/l) 69.65 101.1 142.48 0.020* 

* significant (p < 0.05) 

An increasing frequency of retinopathy was 

found with increasing age at examination, from 

9.7% at age group < 40 years to 33% at age group 

60-69 years (Fig. 2). This difference was found to be 

highly significant for the presence of any re t i n o p a t h y 

(p < 0.001, Table 1). Age at examination was found 

to be a significant factor indicating the severity of 


Higher levels of glycosylated hemoglobin 

HbA1c was found to be related to higher frequency 

of retinopathy, from 10.6% at levels < 7% to 33.7% at 

levels > 10% (Fig. 3). This difference was found to 

be highly significant (p < 0.000, Table 1). Moreover, 

HbA1c was found to be a significant indicator of 

the severity of retinopathy (p < 0.001, Table 2). 

The results showed that systolic blood pressure 

was a significant factor for the presence of any 

retinopathy (p < 0.028, Table 1), and in determining 

the severity of retinopathy (p < 0.03, Table 2). On 

the other hand the diastolic blood pressure showed 

no significant relationship to the presence of any 

retinopathy (p = 0.67, Table 1), or to the severity of 

retinopathy (p = 0.712, Table 2). 

Level of cholesterol was found to be significantly 

related to the presence of any retinopathy (p < 

0.000, Table 1), and the association to severity was 

also significant (p < 0.001, Table 2). Triglyceride 

levels were significantly related to the presence of 

any retinopathy (p < 0.019, Table 1), but levels were 

marginally significant in relation to the severity of 


Microalbumin levels were higher in patients 

with any retinopathy (p < 0.011, Table 1). Moreover, 

severity of retinopathy increased with increased 

levels of micoalbumin (p < 0.02, Table 2). 

DISCUSSION 

The prevalence of any retinopathy in type 2 

diabetes in this study was similar to some previous 

studies. It was reported as 26.2% in North Italy [9] , 

25.3% in Liverpool [10] and 26.8% in Southern India [11] . 


HbA1c 

Fig 3: HbA1c in relation to retinopathy 

P revalence of non-proliferative retinopathy was 

27.3% in a Chinese population with type 2 

diabetes [12] . The prevalence of any retinopathy in 

this study was lower than some reported studies. It 

was 42% in the Omani diabetic population [13] and 

48% in a study reported from the USA [14] . 

These differences in prevalence rates reported 

may be due to many factors. Some studies 

considered each type of diabetes separately [10,15] , 

which gave rise to diff e rent prevalence rates. 

Moreover, the distribution of patients according to 

therapy (either oral hypoglycemics or insulin) 

d i ffers among populations considerably. This 

depends on many factors and affects the prevalence 

of re t i n o p a t h y. Finally, the prevalence of re t i n o p a t h y 

may vary depending on the method of detection 

and the presence of experienced specialist who 

interprets the findings. In our study, only one-field 

pictures were studied by trained diabetologists and 

this can cause some underestimation of mild 

changes. The main purpose of these examinations 

was the detection of sight threatening lesions that 

needed referral to retina specialist. 

Our findings suggest that prevalence of 

retinopathy was higher in non-Kuwaiti A s i a n s 

(28.78%) than in non-Kuwaiti Arabs (22.58%) and in 

Kuwaitis (22.2%). However, the small number of 

the non-Kuwaiti patients did not allow for any 

generalization of this statement. More compre h e n s i v e 

studies would be needed to verify this point. 

Our findings were in agreement with the wellestablished 

statement that the prevalence and 

severity of retinopathy are strongly associated with 

the duration of diabetes [9, 10, 12-14] . 

A significant association between presence and 

p ro g ression of retinopathy and HbA1c was 

confirmed in accordance with other studies [13-16] . 

In our study, only systolic blood pressure was 

associated with higher risk of developing and 

progression of retinopathy. This is in accordance 

with some studies [6, 9, 13, 17] . However, diastolic blood 

p re s s u re had no significant association to re t i n o p a t h y 

development or progression [14] .

206 

Prevalence and Risk Factors for Diabetic Retinopathy among Kuwaiti Diabetics September 2006 

Serum cholesterol and triglyceride levels had 

positive association with retinopathy in our study. 

This is in agreement with some previous studies [13] , 

but not in agreement with Segato, 1991, who did 

not find any significant relationship between 

p revalence of retinopathy and cholesterol or 

triglyceride levels [9] . 

Our study supports previous findings by other 

workers that higher levels of microalbumin are 

associated with higher prevalence of re t i n o p a t h y [12, 18] . 

Insulin treatment was found to be an important 

factor in the occurrence and pro g ression of 

retinopathy as reported in several studies [9, 10, 15] . 

CONCLUSION 

As recommended by American Diabetes 

Association guidelines 2004 all type 2 diabetic 

patients should have comprehensive fundus 

examination shortly after diagnosis. Subsequent 

examinations should be repeated annually. 

However, examination would be required more 

frequently if retinopathy is progressing [3] . 

Caring for diabetic patients should include 

s c reening for risk factors associated with 

retinopathy and controlling them to delay or 

prevent the development and/or the progression of 

re t i n o p a t h y. More comprehensive studies are 

needed to confirm the true prevalence of 

retinopathy among Kuwaiti diabetic patients. 

REFERENCES 

1. Amos AF, McCarty DJ, Zimmet P. The rising global burden 

of diabetes and its complications: estimates and projections 

to the year 2010. Diabet Med 1997; 14:1-85. 

2. Abdellah N, Al Arouj M, Al Nakhi A, Al Assoussi A, 

Moussa M. Non-insulin-dependent diabetes in Kuwait: 

prevalence rates and associated risk factors. Diabetes Res 

Clin Pract 1998; 42:187-196. 

3. Fong DS, Aiello L, Gardner T, King GL, Blankenship G, 

Cavallerano JD, et al. Retinopathy in Diabetes [American 

Diabetic Association: Clinical Practice Recommendations 

2004: Position Statement]. Diabetes Care 2004; 27:S84-87. 

4. Evans J, Rooney C, Ashwood F, Dattani N, Wormald R. 

Blindness and Partial Sight in England and Wales: April 

1990-March 1991. Health Trends 1996; 28:5-12. 

5. Early Treatment Diabetic Retinopathy Study re s e a rc h 

group. Photocoagulation for diabetic macular edema: Early 

Treatment Diabetic Study Report Number 1. A rc h 

Ophthalmol 1985; 103:1796-1806. 

6. Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman 

RR, Manley SE, et al. UKPDS 50: Risk factors for incidence 

and progression of retinopathy in type II diabetes over 6 

years from diagnosis. Diabetologia 2001; 44:156-163. 

7. The Diabetes Control and Complications Research Group. 

The Effect of Intensive Treatment of Diabetes on the 

Development and Progression of Long-Term Complications 

in Insulin-Dependent Diabetes Mellitus. N Engl J Med 1993; 

329:977-986. 

8. Aldington SJ, Kohner EM, Meuer S, Klein R, Sjolie AK (for 

the EURODIAB IDDM Complications Study Gro u p ) . 

Methodology for retinal photography and assessment of 

diabetic retinopathy: the EURODIAB IDDM Complications 

Study. Diabetologia 1995; 38:437-444. 

9. Segato T, Midena E, Grigoletto F, Zucchetto M, Fedele D, 

Piermarocchi S, Crepaldi G (Veneto Group for Diabetic 

Retinopathy). The epidemiology and Prevalence of Diabetic 

Retinopathy in the Veneto Region of North East Italy. 

Diabet Med 1991; 8 :S11-S16. 

10. Younis N, Broadbent DM, Harding SP, Vora JP. Prevalence 

of diabetic eye disease in patients entering a systematic 

primary care-based eye screening programme. Diabet Med 

2002; 19:1014. 

11. N a rendran V, John RK, Raghuram A, Ravindran RD, 

Nirmalan PK, Thulasiraj RD. Diabetic retinopathy among 

self reported diabetics in Southern India: a population 

based assessment. B J Ophthalmol 2002; 86:1014-1018. 

12. Liu DP, Molyneaux L, Chua E, Wang YZ, Wu CR, Jing H, et 

a l . Retinopathy in a Chinese population with type 2 

diabetes: factors affecting the presence of this complication 

at diagnosis of diabetes. Diabetes Res Clin Pract 2002; 

56:125-131. 

13. El Haddad OAW, Saad MK. Prevalence and risk factors for 

diabetic retinopathy among Omani diabetics. British J 

Ophthalmol 1998; 82:901-906. 

14. West SK, Klein R, Rodriguez J, Broman AT, Sanchez R, 

Snyder R, et al. Diabetes and Diabetic Retinopathy in a 

Mexican-American Population. Diabetes Care 2001; 

24:1204-1209. 

15. Henricsson M, Nilsson A, Groop L, Heijl A, Janzon L 

Prevalence of diabetic retinopathy in relation to age at onset 

of the diabetes, treatment, duration and glycemic control. 

Acta Ophthalmol Scand 1996; 74:523-527. 

16. UK Prospective Diabetes Study (UKPDS) Group. Intensive 

blood-glucose control with sulphonylureas or insulin 

c o m p a red with conventional treatment and risk of 

complications in patients with type 2 diabetes (UKPDS 33). 

The Lancet 1998; 352:837-854. 

17. Cignarelli M, De Cicco ML, Damato A, Paternostro A, 

Pagliarini S, Santoro S, et al. High systolic blood pressure 

increases prevalence and severity of retinopathy in NIDDM 

patients. Diabetes Care 1992; 15:1002-1008. 

18. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The 

Wisconsin epidemiologic study of diabetic retinopathy III. 

Prevalence and risk of retinopathy when age at diagnosis is 

30 years or more. Arch Ophthalmol 1984; 102:527-532.


ABSTRACT 

Background: Over the past two decades, there has been 

considerable pro g ress in the treatment of acute 

myocardial infarction (AMI) that led to substantially 

lower mortality and morbidity. Therefore, we carried out 

this study to evaluate the changes in our practice as 

related to AMI treatment over a five year period. 

Patients and Methods: This is a retrospective analysis 

that included all patients with a diagnosis of AMI, 

admitted to the coronary care unit between the first of 

January 1998 and the end of December 2002. 

Results: The total number of patients with AMI was 

2,280. Comparing the first year to the last year of the 

study, the use of medications at discharge increased 

significantly for beta-blockers (76 vs 88, p < 0.0001); for 

angiotensin converting enzyme inhibitors (ACEI) (40 vs 



Changing Trends in the Management of Acute Myocardial 

Infarction: A Five-Year Study 

Ibrahim Lasheen 1 , Mohammed Zubaid 2 , Cheriyil G Suresh 1 , Hanan El Sayed Bader 3 

1 Department of Medicine, Mubarak Al Kabeer Hospital, Kuwait 

2 Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait 

3 Department of Public Health, Faculty of Medicine, Kuwait University, Kuwait 


45%, p = 0.02) and for lipid lowering drugs (25 vs 66%, p 

< 0.0001). Similarly, the use of thrombolytic dru g s 

increased significantly (60 vs 66%, p < 0.001). The time to 

administration of thrombolytic treatment shortened 

significantly (104 vs 70 minutes, p < 0.001). The use of inhospital 

cardiac catheterization increased as well (7 vs 

14%; p = 0.006). 

Conclusions: Our study showed significant changes in 

the practice of AMI treatment over the five year study 

period. The use of therapies with proven benefit such as 

beta- blockers, ACEI, lipid lowering drugs, thrombolysis 

and in-hospital cardiac catheterization has increased. 

Although the time to thrombolytic treatment did shorten, 

it needs to be shortened further to obtain the maximum 

benefit from such therapy. 

KEYWORDS: acute myocardial infarction, practice pattern, thrombolysis 

INTRODUCTION 

Coronary artery disease (CAD) is a major health 

problem in Kuwait. In 1995, CAD was responsible 

for death in 15.4% Kuwaitis and 23.6% expatriates [ 1 ] . 

One of the means of fighting CAD is the provision 

of evidence-based therapies to patients diagnosed 

with CAD. Despite the presence of enormous amount 

of data supporting the use of certain therapies, proven 

therapies continue to be underutilized [2-6] . One of 

the facets of CAD is acute myocardial infarction 

(AMI). The use of different therapies in AMI has 

been studied extensively in western countries [7-12] . 

We aimed to evaluate our own practice, as it relates 

to AMI treatment over a five year period. 

METHODS 

The data for this re t rospective study were 

collected from the computerized database of the 

coronary care unit (CCU) at Mubarak Al Kabeer 

Hospital, a 476-bed teaching hospital that provides 

service to almost 450,000 residents in the Hawally 

Governorate. All patients with AMI who were 

admitted to the CCU between January 1998 and 

December 2002 were included in the study. The 

diagnosis AMI was based on any two of the three 

following criteria: ischemic type chest pain, 

diagnostic serial ECG changes (ST- s e g m e n t 

elevation and non ST-segment elevation) and twofold 

rise in total creatinine kinase (CK) with MB 

fraction contributing at least 3% of the total CK 

level. Troponin assay was not routinely done 

between 1998 and 2002 in our institution. Patients 

w e re eligible for thrombolytic therapy, if they 

p resented within 12 hours and had acute STsegment 

elevation (> 0.1 mV in two or more limb 

leads, or > 0.2 mV in two or more contiguous 

precordial leads) or a new LBBB on the admission 

ECG. 

The variables analyzed from the database 

included detailed information on medical history, 


Dr. Ibrahim Lasheen, FRCP (UK), Department of Medicine, Mubarak Al Kabeer Hospital, P.O. Box 48707, Kuwait. Tel: (965) 6520825, Fax: (965) 

5338907, E-Mail: ibraheemlasheen@hotmail.com

208 

Changing Trends in the Management of Acute Myocardial Infarction: A Five-Year Study September 2006 

Table 1 : Baseline patients’ characteristics 

risk factors, admission and discharge diagnoses, inhospital 

mortality and number of in-hospital 

transfers to the catheterization laboratory. 

Hypercholesterolemia was defined as known 

history of hypercholesterolemia on treatment or a 

fasting cholesterol > 5.5 mmol/l (212 mg/dl) within 

24 hours of admission. Diabetes mellitus was 

defined as known history of diabetes on treatment 

or a fasting blood sugar of > 7.0 mmol/l (120 

mg/dl) during the present hospital admission. 

Hypertension was labeled, if the patient had a 

known history of hypertension. 

STATISTICAL ANALYSIS 

The mean time between diagnostic ECG and 

administration of thrombolytic treatment was 

skewed. Non-parametric Kruskal-Wallis test was 

used to investigate the difference in the mean times 

throughout the five years. Chi-square test was used 

to examine the diff e rence of the associations 

between the studied variables. Level of significance 

was considered at p < 0.05. 

RESULTS 

The clinical characteristics of patients are shown 

in Table 1. During the five years a total of 2,280 

patients were admitted with AMI, out of whom 

85% were male. The mean age of the patient 

population was 54.7 ± 11.7 years. Of note, is the 

high rate of smoking and diabetes among our AMI 

population (50% and 39% respectively). Hypertension 

was present in 32% of the patients. Significant 

increase in hypertension was noted over the years 

(p = 0.02). Hypercholesterolemia was found in 

17.4% of the patients and showed an increasing 

trend over the study period (p < 0.01). 

We studied our practice pattern over the five 

years in relation to the use of thrombolytic therapy; 

d i s c h a rge medication; in-hospital transfer to 

catheterization laboratory and in-hospital mortality 

(Table 2). Out of the 2280 patients admitted with 

AMI, thrombolytic therapy was administered to 

1394 (62%) patients. Among the 421 (38%) who did 

1998 1999 2000 2001 2002 P-value 

N=424 N=436 N= 486 N=462 N=472 

Male 362 (85) 393 (90) 399 (82) 402 (87) 413 (88) NS 

Mean age 54.4 ± 11.6 54.1 ± 11.2 54.9 ± 12 54.9 ± 11.4 54.9 ± 12.3 NS 

Smoker 228 (54) 222 (51) 229 (47) 228 (49) 226 (48) NS 

Diabetes 143 (34) 168 (39) 208 (43) 173 (37) 182 (39)


Table 2: Changing pattern of different utilization therapies 

shortfall which was about 30% in a recent European 

report [7] . Also, we found that the mean time from 

the first diagnostic ECG to the start of thrombolytic 

treatment was 90 minutes. This mean time was 104 

minutes in 1998 and it shortened to 70 minutes in 

2002. The overall mean time showed significant 

i m p rovement over the study period. This shortening 

of the time to thrombolysis, has probably resulted 

f rom the change of policy from April 2002 of 

administering thrombolytic treatment in the 

Emergency Room. Prior to this date, thrombolytic 

therapy was being administered in CCU only. 

Several published guidelines re c o m m e n dan optimal 

time of 30 minutes between hospital arrival and 

treatment [16,17] . Though our thrombolytic timing has 

improved, there remains a considerable in-hospital 

delay. We believe that the absence of emergency 

department triage protocols to be the major 

contributing factor to in-hospital delay in 

thrombolysis. This factor was previously shown to 

i n c rease the time to treatment and should be 

a d d ressed, so that maximum benefit fro m 

thrombolytic treatment is achieved [18,19] . 

The use of beta-blockers, ACEI, and lipid 

lowering drugs, which are therapies of proven 

benefit, improved significantly over the years. The 


1998 1999 2000 2001 2002 P-value 

N=424 N=436 N= 486 N=462 N=472 

Discharge Medicine 

Aspirin 384 (91) 414 (96) 454 (94) 432 (94) 453 (96) NS 

Beta-blockers 324 (76) 342 (78) 391 (81) 406 (88) 416 (88)

210 

Changing Trends in the Management of Acute Myocardial Infarction: A Five-Year Study September 2006 

clinicians are now more aware of the benefit of 

intervention. 

Despite this significant change in the positive 

direction, the rate of in-hospital death did not 

change over the study period. It is possible that 

larger number of patients is needed to show the 

effect of these changing practices on mortality. 

CONCLUSIONS 

This study reflects the actual trend in AMI 

management in our institution over a five year 

period. Our study population is relatively young 

with high rates of smoking, diabetes and 

hypercholesterolemia. There was a clear trend for 

an increase in the utilization of proven beneficial 

therapy over this 5-year period. 

REFERENCES 

1. Health Kuwait, ed 32. Kuwait, Health and vital Statistics 

Division, Ministry of Health, 1995. 

2. European Secondary Prevention Study Group: Translation 

of clinical trials into practice: A European population based 

study of the use of thrombolysis for acute myocardial 

infarction. Lancet 1996; 347:1203-1207. 

3. Gottlieb SS, Mc Carter RJ, Vogel RA. Effect of beta-blockade 

on mortality in high-risk and low-risk patients after 

myocardial infarction. N Engl J Med 1998; 339:489-497. 

4. Barron HV, Bowlby LJ, Breen T, Rogers WJ, Canto JG, 

Zhang Y, Tiefenbrunn AJ, Weaver WD. Use of reperfusion 

therapy for acute myocardial infarction in the United States: 

Data from the National Registry of Myocardial Infarction 2. 

Circulation 1998; 97:1150-1156. 

5. Barron HV, Michaels AD, Maynard C, Every NR. Use of 

angiotensin-converting enzyme inhibitors at discharge in 

patients with acute myocardial infarction in the United 

States: Data from the National Registry of Myocardial 

Infarction 2. J Am Coll Cardiol 1998; 32:360-367. 

6. Fonarow GC, French WJ, Parsons LS, Sun H, Malmgren JA. 

Use of lipid -lowering medications at discharge in patients 

with acute myocardial infarction in the United States: Data 

from the National Registry of Myocardial Infarction 3. 

Circulation 2001; 103:38-44. 

7. Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, 

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elevation myocardial infarction; findings from The 

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359:373-377. 

8. Fibrinolytic therapy trialists’ (FTT) collaborative group: 

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9. Granger CB, Weaver WD. Reducing cardiac events after 

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acute myocardial infarction: Systematic overview of 

individual data from 100.000 patients in the randomized 

trials. Circulation 1998; 97:2202-2212. 

12. Ferrieres J, Cambou JP, Gueret P, Boultabi Y, Lablanche IM, 

Hanania G, Genes S, Cantet C, Danchin N. Effect of early 

initiation of statins on survival in patients with acute 

m y o c a rdial infarction (the USIC 2000 Registry). Am J 

Cardiol 2005; 95:486-489. 

13. Rashed W, Zubaid M, David T, Mohammed B, Bashruthula 

MS, Smid J Khan H, Memon A. Patient characteristics and 

practice patterns in the treatment of acute myocardial 

infraction in Kuwait: a pilot study. Med Princ Pract 2002; 

11:196-201. 

14. Abdella N, Khogali M, Al -Ali S, Gumaa K, Bajaj J. Known 

type 2 diabetes mellitus among Kuwaiti population: A 

prevalence study. Acta Diabetol 1996; 33:145-149. 

15. Taha TH, Moussa MA, Fenech FF. Diabetes mellitus in 

Kuwait: incidence in the first 29 years of life. Diabetologia 

1983; 25:306-308. 

16. Emergency Cardiac Care Committee and Subcommittee, 

American Heart Association: Guidelines for card i o p u l m o n a r y 

resuscitation and emergency cardiac care, 11: adult 

advanced cardiac life support. JAMA1992; 268:2199-2241. 

17. National Heart Attack Alert Program Coord i n a t i n g 

Committees, 60 Minutes to Treatment Working Group: 

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of patients with acute myocardial infarction. Ann Emerg 

Med 1994; 23:311-329. 

18. Sharkey SW, Burnette DD,Ruiz E, Hession WT, Wysham 

DG, Goldenberg IF, Hodges M.: An analysis of time delays 

preceding thrombolysis for acute myocardial infarction. 

JAMA. 1989; 262:3171-74. 

19. Hirvonen TPJ, Halinen MO, Kala RA, Olkinuora JT for the 

Finish Hospitals’ Thrombolysis Survey Group: Delays in 

thrombolytic therapy for acute myocardial infarction in 

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study. Eur Heart J 1998; 19:885-892. 

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of the thrombolysis in myocardial infarction (TIMI) IIIB 

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patients with acute non-Q-wave myocardial infarc t i o n 

randomly assigned to an invasive as compared with a 

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338:1785-1792. 

22. Fragmin and Fast Revascularization during Instability in 

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ABSTRACT 

Objective: To determine the incidence and etiology of 

hyponatremia in adult hospitalized patients in medical 

wards of a general hospital. 

Setting: The four medical wards comprising a total of 

140 beds in a 500 bedded general hospital in Kuwait. 

Design: Retrospective study of hyponatremia analyzed 

and reported by the biochemistry laboratory from June to 

December 2004. 

Subjects: All adult patients admitted to medical wards 

during the six month period from June to December 2004 

having serum sodium < 130 mmol/l. 

Results: Out of a total of 1825 patients analyzed over a 

six months period (from June - December 2004), 66 

patients (3.6%) had hyponatremia. Of these 37 (56%) 

were male and 29 (44%) female. Their mean age was 

57.05 years. The commonest age group was 45 - 64 years 

and the least affected group was 12-25 years. Their mean 

serum sodium level was 122 mmol/l. Among the major 



Frequency and Etiology of Hyponatremia in Adult 

Hospitalized Patients in Medical Wards of a General 

Hospital in Kuwait 

Thomas Abraham Vurgese, Sunil Bahl Radhakrishan, Osman Abdul Wahab Mapkar 

Department of Medicine, Al Jahra Hospital, Kuwait 


causes of hyponatremia was the Syndrome of 

inappropriate secretion of antidiuretic hormone (SIADH) 

with pneumonia. Next to SIADH, renal failure and 

cardiac failure were the two common causes. 

C o n c l u s i o n : Overall incidence of hyponatremia was 

3.6% in all medical patients reviewed. The commonest 

cause of hyponatremia was found to be SIADH due to 

pneumonia. Renal failure and cardiac failure were the 

other two common causes. Identification of the cause of 

hyponatremia is important in order to impart specific 

t reatment. Correction of hyponatremia improves pro g n o s i s 

of the underlying disease and prevents further complications 

due to hyponatremia itself. It is important to be cautious 

not to correct hyponatremia too rapidly and also not to 

exceed a level of 120 to 125 mmol/l (acutely), in order to 

p revent the complication of osmotic demyelinating 

syndrome. 

K E Y WORDS: cardiac failure, osmotic demyelinating syndrome, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 

INTRODUCTION 

H y p o n a t remia is defined as serum sodium 

levels of ≤ 130 mmol/l. It can be classified on the 

basis of serum osmolality, volume status and 

urinary sodium into hypertonic, isotonic and 

hypotonic types. Hypotonic hyponatremia is 

further classified into hypervolemic, euvolemic 

and hypovolemic. It is the most common 

electrolyte abnormality in the medical wards. Its 

incidence and prevalence are about 1.0 and 2.5% 

re s p e c t i v e l . yMild 

hyponatremia may be asymptomatic 

but may lead to poor treatment outcome in the 

patient. Severe hyponatremia may pro g ress to 

seizures, status epilepticus or coma. The treatment 

of hyponatremia will depend on the volume status 

of the patient. The aim of our study was to define 

the most common causes of hyponatremia in the 

medical wards of our hospital and to compare it 

with other studies. We also wanted to increase 

a w a reness re g a rding the causes and the re c o m m e n d e d 

t reatment in order to prevent complications 

including osmotic demyelinating syndrome. 


A retrospective study was carried out involving 

all adult patients admitted to the medical wards 

over a period of six months (from June to 

December 2004) for the presence of hyponatremia. 

H y p o n a t remia was defined as serum sodium of 

≤ 130 mmol/l. All blood samples were analyzed in 

the biochemistry department on LX-20 machine. 

Information regarding age and sex distribution, the 

lowest serum sodium levels (whenever there were 

several results in a single patient), the clinical 

diagnosis and further clinical information 

suggesting the cause of hyponatremia were 

collected. 

RESULTS 

Out of the 1825 patients analyzed over the six 

months period (from June -Decemeber 2004), 66 


Dr. Thomas Abraham Vurgese, P.O. Box 62276, Jahra 02153, Kuwait. Tel: (00965) 9567681, Email: thomasvurgese@hotmail.com

212 

Frequency and Etiology of Hyponatremia in Adult Hospitalized Patients in Medical..... September 2006 

Table.1: Sexwise distribution of hyponatremia 

Sex No. of patients Percentage 

Male 37 56.1 

Female 29 43.9 

Total 66 100 

patients (3.6%) had hyponatremia. Out of these, 37 

(56%) were male and 29 (44%) female. The age and 

severity wise distribution of all cases is shown in 

Table 2. The mean age was found to be 57.05 years 

± 2SD. The commonest age group affected was 45 - 

64 years and the least affected group was 12 - 25 

years. The mean serum sodium level was 122 

mmol/l. There was a seasonal variation between 

the summer and winter months. 39 (59.1%) patients 

presented during the earlier summer months as 

compared to 27(40.9%) who presented during the 

winter months. 

The diff e rent etiological factors causing 

hyponatremia are shown in Table 3. Among the 

major causes of hyponatremia, syndrome of 

i n a p p ropriate secretion of antidiuretic hormone 

(SIADH) [due to diff e rent etiological factors] 

constituted the major cause. SIADH is defined as 

non-osmotically stimulated anti diuretic hormone 

release causing euvolemic hyponatremia. In our 

study pneumonia was the commonest cause of 

S I A D H leading to hyponatremia. Renal failure and 

congestive cardiac failure were the next frequent 

causes of hyponatraemia. 

DISCUSSION 

The incidence of hyponatremia (3.6%) in our 

study correlates well with most of the other 

s t u d i e s [ 1 ] . The male preponderance seen in our 

study is in variance with a number of other studies 

that show female preponderance [2] . A majority of 

our patients (82%) showed mild to moderate 

h y p o n a t remia (120-130 mmol/l) which again 

correlates well with the other studies. 

A number of studies have evaluated the 

incidence and etiology of hyponatremia in general, 

but there are very few relevant studies related to 

hyponatremia in inpatients in medical wards. 

In our study SIADH [4] was the commonest cause 

of hyponatremia. This was confirmed by the 

diagnostic criteria for SIADH in the form of 

decreased serum sodium and serum osmolality, 

i n c reased urinary osmolality, urinary Na > 20 

mmol/l with normal renal, adrenal, thyroid and 

cardiac function in euvolemic patients. In our study 

pneumonia was the commonest etiological factor 

for SIADH. 

Many of the causes of hyponatremia have 

multifactorial pathophysiology. Patients with 

Table 2: Age and severity wise distribution of hyponatremia 

Age Number Mild Moderate Severe Percentage 

(126 -130 (120 - 125 (< 120 

mmol/l ) mmol/l) mmol/l) 

12 - 25 yrs 8 3 3 2 12.1 

26 - 45 yrs 10 5 3 2 15.1 

46 - 64 yrs 30 10 15 5 45.5 

> 65 yrs 18 4 11 3 27.3 

Total 66 22 32 12 100 

congestive cardiac failure have hypervolemic 

hyponatremia due to the salt and water retention. 

They also have hyponatremia due to low salt diet 

and diuretic therapy. 

Similarly patients with DM have hyponatremia 

possibly due to the associated renal failure, SIADH 

due to drug therapy and also some amount of 

pseudohyponatremia due to the excess blood sugar 

causing hyperosmolar hyponatremia. In cerebrovascular 

accidents [5] hyponatremia is usually due to 

SIADH and hyperosmolar hyponatremia secondary 

to mannitol therapy. Two cases of pseudohyponatremia 

in our study where due to hyperlipidemia 

with triglyceride concentration more than 6 

mmol/l. There were two cases of drug induced 

SIADH, one due to carbemazepine in an epileptic 

patient and the other due to paroxetine (serotonin 

specific reuptake inhibitors) [ 6 ] used to tre a t 

depression. One of our cases of SIADH was due to 

human immunodeficiency virus (HIV) infection as 

reported in some other studies [7] . Three cases of 

SIADH in our study were due to bronchogenic 

carcinoma [8] . Seasonal variation was noted in our 

study with 59.1% patients presenting in the 

summer months. This was probably due to 

variations in the ambient temperature influencing 

insensible fluid losses that could possibly have 

altered hydration status and sodium balance. It is 

important to delineate the underlying cause of 

hyponatremia as the treatment may differ in each 

case. For example, hypervolemic and euvolemic 

hypotonic hyponatremia may be treated with salt 

and water restriction but hypovolemic hypotonic 

hyponatremia will require volume repletion with 

normal saline. As SIADH causes euvolemic 

h y p o n a t remia the main stay of treatment is 

restriction of fluid intake to 800 to 1000 ml per day. 

Since the intake is almost always exceeded by 

urinary output a negative water balance ensues and 

a gradual increase in serum sodium is seen with 

symptomatic improvement. Unless and until the 

underlying cause of the SIADH can be corrected, 

fluid intake should be restricted continuously to 

maintain normonatremia until serum Na exceeds 

135 mmol/l. Drugs that block the effect of argentine 

vasopressin like demecocycline can help normalize


Table 3: Etiological factors associated with hyponatre m i a . 

S. No. Disorders No. of patients Percentage 

1 Congestive cardiac failure. 12 18.18 

2 Renal failure (acute and chronic) 13 19.69 

3 Acute gastro-enteritis 2 3.03 

4 SIADH due to 23 34.8 

- Pneumonia 13 19.69 

- Drugs 2 3.03 

- COPD 3 4.54 

- Malignancy (bronchogenic 

carcinoma) 3 4.54 

- HIV 1 1.51% 

- CVA 1 1.51% 

5 Hypertension 4 6.06% 

6 Addisons disease 1 1.51% 

7 Cirrhosis 4 6.06% 

8 DM 4 6.06% 

9 Others 

- (psedo-hyponatremia 

due to increased triglyceride) 2 3.03% 

- IV drip etc. 1 1.51% 

TOTAL 66 100% 

serum sodium by antagonizing the action of ADH 

in the collecting duct. Demecocycline is administere d 

in the dose of 900 to 1200 mg per day. An important 

point to note here is that chronic hyponatremia 

should be corrected slowly (@ 0.5 - 1 mmol/l/hour) 

and not more than 12 mmol/l in 24 hours [9] in order 

to prevent central pontine myelinolysis (osmotic 

demyelinating syndrome: quadriplegia and 

pseudobulbar palsy caused by demyelination of 

corticospinal and corticobulbar tracts within the 

pons) [10] . Hyponatremia in the range of 110 - 120 

mmol/l and lower values are treated with 3% 

hypertonic saline (0.05 ml/kg/minute) especially if 

symptomatic [9] . The serum sodium should be reestimated 

in two to three hours before deciding 

whether to continue or stop the drip, aiming to 

bring the serum sodium upto 120 mmol/l. 

CONCLUSION 

The overall incidence of hyponatremia in our 

study was 3.6% in all the patients reviewed. The 

commonest cause of hyponatremia was found to be 

SIADH. The commonest etiology for SIADH in our 

study was pneumonia. Next to SIADH, the other 


common causes in our study were renal failure and 

congestive cardiac failure. Delineating the cause of 

h y p o n a t remia is important in order to impart 

specific treatment tailored to the etiology. The 

correction of hyponatremia also helps improve the 

p rognosis of the underlying disease and helps 

p revent further complications due to the 

hyponatremia itself. There is a need to be cautious 

not to correct the hyponatremia too fast (rate not 

more than 0.5-1 mmol/l/hour) and not to exceed a 

level of 120-125 mmol/l (acutely), in order to 

prevent the complication of osmotic demyelinating 

syndrome. 

ACKNOWLEDGEMENTS 

We acknowledge all the help provided by Mr 

Humayun Minhas from the biochemistry 

department in performing all the tests and Mr 

Sunny J Parackal for his secretarial services. 

REFERENCES 

1. Kende M, Udayan R, Benjamin H. Review of cases of 

Hyponatremia in Port Moresby General Hospital. PNG 

Med J 1999; 42:84-89. 

2. Grikiniene I, Volbehar V, Stablsati D. Gender differences of 

Sodium. Metabolism & Hyponatremia. Medicina 2004; 

40:935-936. 

3. Conrad MJ, Meinders AE. Causes of Hyponatremia in 

department of Internal Medicine and Neurosurgery. Eur J 

Internal Med 2003; 14:302-309. 

4. Kumar Sumit, Beel Tomas. Sodium. The Lancet 1998; 

352:220-228. 

5. Lim JK,Yap KB. Hyponatremia in hospitalized elderly 

patients. Med J Malaysia 2001; 56:232-235. 

6. Arinzon Z, Lehman Y, Fidelman Z. Delayed Recurrent 

SIADH associated with SSRIs. Ann Pharmacother 2002; 

36:1175-1177. 

7. Tang W, Kaptun EM, MassrySG. Hyponatremia in 

hospitalized patients with AIDS. Am J Med 1993; 94:169- 

174. 

8. B e rghmans T, Body JJ. A p rospective study on hyponatre m i a 

in medical cancer patients: epidemiology, etiology and 

differential diagnosis. Support Care Cancer 2000; 8:192-197. 

9. Garry G, Brenner BM. Fluid and Eelectrolyte Disturbances. 

In: Kasper DL, Braunwald E, editors. Harrison’s Principles 

of Internal Medicine, 16th Edition, Mcgraw Hill; 2005, p 

256-257. 

10. Martin RJ. Central pontine and extrapontine myelinolysis: 

the osmotic demyelination syndromes. J Neurol Neurosurg 

Psychiatry 2004; 75:22-28.

ABSTRACT 

B a c k g r o u n d : The incidence of S t e n o t ro p h o m o n a s 

m a l t o p h i l i a infections in immunocompromised cancer 

patients has increased re c e n t l y. Treatment of these 

infections is usually difficult because drug resistance of 

S. maltophilia renders therapeutic options limited. 

Materials and Methods: A retrospective study of S. 

maltophilia bacteremia was carried out at the Riyadh 

Armed Forces Hospital between January 1993 and 

December 2002. The records of patients confirmed to 

have S. maltophilia bacteremia were reviewed. 

Results: Seventeen episodes of bacteremia caused by S. 

maltophilia were identified. The main risk factors were: 

underlying hematological malignancy, administration of 



Bacteremia due to Stenotrophomonas Maltophilia in 

Patients with Hematological Malignancies 

Khalid Ahmed Al-Anazi 1 , Asma Marzouq Al-Jasser 2 , Abdulaziz Al-Humaidhi 3 

1 King Faisal Cancer Centre, Department of Adult Haematology and Bone Marrow Transplant, King Faisal Specialist 

Hospital and Research Centre, Riyadh, Saudi Arabia 

2 Department of Microbiology, Armed Forces Hospital, Riyadh, Saudi Arabia 

3 Department of Oncology, King Fahad Medical City, Riyadh, Saudi Arabia 


i m m u n o s u p p ressive therapy and broad spectru m 

antibiotics particularly carbapenems, having indwelling 

intravascular catheters and prolonged hospitalization. 

A n t i m i c robial susceptibility testing showed cotrimoxazole 

to be the most active agent, followed by ceftazidime, 

colistin and piperacillin/tazobactam. Eight episodes of 

bacteremia were successfully treated. 

Conclusions: Stenotrophomonas maltophilia is a significant 

cause of morbidity and mortality in immunocompro m i s e d 

hosts especially those with underlying hematological 

malignancies receiving broad spectrum antibiotics. Early 

administration of appropriate antibiotics is vital to 

overcome these life threatening infections. 

KEYWORDS: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), intensive care unit (ICU), non-Hodgkin’s 

lymphoma (NHL), S.maltophilia (Stenotrophomonas maltophilia) 

INTRODUCTION 

Stenotrophomonas maltophilia (previously called 

Pseudomonas maltophilia and Xanthomonas maltophilia) 

was first described by Hugh and Ryschenkow in 

the year 1961 [1,2] . It is a non-fermentative gram 

negative bacillus which is widespread in the 

e n v i ro n m e n t [ 2 - 4 ] . It is an important nosocomial 

pathogen in immunocompromised patients [ 1 , 3 , 5 ] . 

Incidence of infection is increasing in debilitated 

individuals due to the advances in medical 

therapeutics including the aggressive treatment of 

malignancy and the increased utilization of broad 

spectrum antibiotics [1-11] . 

B a c t e remia is a common manifestation of 

infection with this organism although the organism 

can be isolated from clinical specimens in the 

absence of infection [ 1 , 2 , 4 , 9 - 1 2 ] . Treatment of S. maltophilia 

infections is difficult as isolates are fre q u e n t l y 

resistant to most of the ß-lactams and aminoglycosides 

[1,2,4-8] . 

In the light of reports of increasing frequency of 

infection with S. maltophilia worldwide, a re t ro s p e c t i v e 

study of bacteremia due to S. maltophilia at our 

institution was undertaken. 


The Riyadh Armed Forces Hospital is a tertiary 

care centre comprising 1200 beds with specialty 

services including intensive care and solid organ 

and bone marrow transplantation. Cases of S . 

maltophilia were identified through review of the 

clinical microbiology reports and the medical 

records of these patients over a ten-year period 

(January 1993 to December 2002). 

Definitions 

Bacteremic episode: positive blood cultures for S. 

maltophilia in one or more culture bottles. Multiple 

isolates belonging to the same patient were 

considered to be the same bacteremic episode if 

they occurred within a 10 day period. Each blood 

culture was evaluated to determine whether the 

isolate re p resented a clinically significant bactere m i a 

or a contaminant. This decision was based on 


Dr. Khalid Ahmed Al-Anazi, Assistant Consultant, King Faisal Cancer Centre, P.O.Box 3354, Riyadh 11211, Saudi Arabia. Tel: 966-1-4568477, 

Fax: 966-1-4568477, E-Mail: khalid_alanazi@yahoo.com


Table 1: Details of patients in the study 

several factors including: clinical manifestations of 

the systemic infection, sampling procedures (direct 

or catheter-sampled specimen), number of positive 

blood culture bottles in each episode and the 

culture results from other body sites. 

Nosocomial bacteremia: bacteremia occurring at 48 

hours or more, after admission. 

Prolonged hospitalization: hospital stays for two 

or more weeks prior to bacteremia 

Primary site or focus of infection: was considered 

to be the portal of entry, if the organism was 

isolated from that site prior to the day on which 

blood cultures became positive for the first time. 

Immunosuppressive therapy: included stero i d 

therapy, cytotoxic chemotherapy or radiotherapy 

given within one month prior to the episode of 

bacteremia. 

Prior antibiotic therapy: administration of antibiotics 

(intravenous route usually) within four weeks prior 

to the onset of bacteremia. 

Appropriate antibiotic therapy: use of IV anitibiotic(s) 

to which the organism was susceptible within 72 

hours of blood culture collection. 

Polymicrobial bacteremia: more than one clinically 

significant organism isolated from a single blood culture 

or from separate blood cultures within ten days. 

Outcome: death within two weeks of bacteremic 

episode or survival beyond two weeks. 

Microbiological analysis and antibiotic susceptibility 

testing: isolates from positive blood cultures were 

identified by Gram stain and subculture on blood, 

chocolate and MacConkey agars. Formal identification 

was done by using the Analytic Profile Index (API 

20NE) system, Biomeriuex, France. Sensitivities of 


Patient Sex Age Primary Number of Number of Primary Length of 

number (Years) diagnosis courses of positive site of stay in 

chemotherapy blood infection hospital 

given culture sets (days) 

1 M 13 ALL 1 9 Central line 28 

2 M 30 NHL 10 1 Lungs 23 

3 M 20 NHL 5 13 Lungs 31 

4 M 30 AML 5 4 Lungs 180 

5 M 25 ALL 1 2 Unknown 22 

6 M 26 AML 3 5 Pharynx 46 

7 M 22 ALL 4 2 Unknown 36 

8 M 25 AML 1 12 Skin ( EG ) 14 

9 M 33 AML 1 4 Unknown 30 

10 M 30 AML 2 5 Lungs 20 

11 M 16 ALL 1 2 Central line 14 

12 F 30 ALL 1 7 Unknown 29 

13 F 72 AML 0 3 Central line 10 

14 F 62 ALL 1 11 Abdomen 29 

15 F 42 AML 4 3 Unknown 48 

16 F 39 AML 1 4 Pharynx 31 

17 F 34 ALL 1 11 Central line 47 

ALL: acute lymphoblastic leukemia, EG: ecthyma gangrenosum, AML: acute myeloid leukemia, M: male, NHL: non - Hodgkin’s lymphoma, F: female 

the isolates were determined for nine antibiotics 

using disc diffusion method according to National 

Committee for Clinical Laboratory Standard s 

(NCCLS) criteria. Sulphamethoxazole-trimethoprim 

were routinely tested as one agent (cotrimoxazole). 

For patients with multiple positive blood cultures, 

the sensitivity results from the first isolates were 

used in the analysis of data. 

RESULTS 

Seventeen episodes of S. maltophilia bacteremia 

were encountered in 17 patients over a ten year 

period. All their records were retrieved for analysis. 

All the positive blood cultures represented true 

infection based on clinical and laboratory findings. 

Very few cases were reported between the years 

1992 and 1994. An increase in the number of cases 

was noted in the year 1995 and then a large peak 

(six cases) was reached in the year 1996. Thereafter, 

the number of cases declined to one to two cases 

per year till a smaller peak (three cases) was seen in 

the year 2002. Details of the patients studied are 

shown in Table 1. 

Of the 17 patients, 11 were male and six were 

female. The mean age of patients was 32.4 years 

(range: 13-72 years). The main risk factors were: 

underlying hematological malignancy, presence of 

neutropenia, other coexisting infections and central 

venous catheters; administration of cytotoxic 

c h e m o t h e r a p y, steroids and broad spectru m 

antibiotics including carbapenems; admission to 

ICU and artificial ventilation; prolonged duration 

of hospitalization and travel to hospital by air. The 

details are shown in Tables 2 and 3.

216 

Bacteremia due to Stenotrophomonas Maltophilia in Patients with Hematological ... September 2006 

Table 2: Risk factors for infection with S. maltophilia 

Risk Factor Number Percentage 

Hematological malignancy 17 100 

Cytotoxic chemotherapy 16 94.1 

Steroid therapy 10 58.8 

Radiotherapy 2 11.8 

Bone marrow transplant 3 17.6 

Neutropenia 17 100 

Presence of central venous catheter 17 100 

Treatment with broad spectrum antibiotics 17 100 

Prior treatment with carbapenems 15 88.2 

Polymicrobial 16 94.1 

Monomicrobial 1 5.9 

Admission to ICU/artificial ventilation 11 64.7 

Travel to hospital by air 8 47 

Out of the 17 patients studied, 15 (88.2%) had 

acute leukemia and two (11.8%) had lymphoma. All 

patients were neutropenic at the time of bacteremia. 

Sixteen episodes were polymicrobial and only one 

episode was monomicrobial. The coexisting infections 

were predominantly bacterial (16 patients, 88.2%) 

although candida and cytomegalovirus infections 

were present in a substantial proportion of patients 

(35.3% and 17.65% respectively). Indwelling 

intravascular catheters were present in all 17 

patients. Cytotoxic chemotherapy was administere d 

to 16 patients (94.1%) and only one patient did not 

receive chemotherapy because of her old age and 

the presence of other medical illnesses. Ten patients 

(58.8%) received steroid therapy during the last 

month prior to the bacteremic episode (as part of 

acute lymphoblastic leukemia protocols in seven 

patients, as part of lymphoma treatment in two 

patients and as graft versus host disease treatment 

in one patient). Only two patients (11.8%) received 

radiotherapy prior to the bacteremic episode. All 

patients were on broad spectrum antibiotics at the 

time of S. maltophilia bacteremia. Eleven patients 

(64.7%)were admitted to the general ICU and they 

received artificial ventilation during the bacteremic 

episodes. 

The mean duration of ventilation was 8.4 days 

per patient ventilated. Eleven episodes of bactere m i a 

(64.7%) were complicated by septic shock and nine 

of these patients died within two weeks of the 

bacteremic episode. It was noted that eight patients 

(47%) traveled to hospital by air prior to the 

bacteremic event. 

The mean duration of stay in hospital prior to 

b a c t e remia was 37.5 days. All the bactere m i c 

episodes were nosocomial. The primary sites of 

infection were: lungs (four cases), central venous 

catheters (four cases) and upper respiratory tract 

(two cases). However, the portal of entry was not 

identified in five cases (primary bacteremia). 

Table 3: Characteristics of infections with S. maltophilia 

in this study 

Feature Number Percentage 

Number of patients ventilated 11 64.7 

Septic shock 11 64.7 

Other coexisting Infections : 16 94.1 

Bacterial 6 35.3 

Cytomegalovirus 3 17.6 

Candida 6 35.3 

Pneumocystis carinii 1 5.9 

Relapses of primary disease 12 70.6 

Before infection episode 6 35.3 

After infection episode 6 35.3 

Surgical Procedures (required) : 9 52.9 

During septic episode 2 11.8 

Before septic episode 6 35.3 

After septic episode 1 5.9 

Appropriate antibiotic treatment : 

Not Given 7 41.2 

Given : 10 58.8 

1 antibiotic 4 23.5 

2 antibiotics 6 35.3 

Outcome of treatment of episode : 

Successful 8 47.1 

Unsuccessful 9 52.9 

The sources of the positive blood cultures were 

central lines in nine patients (53%) and both central 

lines and peripheral veins in eight patients (47%). 

O rganisms were never grown from peripheral 

venous cultures alone. The number of positive 

blood culture sets ranged between one and 13 sets 

per episode and the mean was 5.7 positive blood 

culture set per bacteremic episode . 

All the isolates were found to be sensitive to 

cotrimoxazole and all of them were resistant to 

carbapenems. Approximately 82% of the isolates 

w e re sensitive to ceftazidime and 70% were 

sensitive to colistin. Sensitivity to other antibiotics 

was as follows: 53% to piperacillin/tazobactam, 

35% to ciprofloxacin and approximately 23.5% to 

aminoglycosides (Fig. 1). 

All the 17 episodes of bacteremia were treated 

with IV antibiotics. Appropriate antibiotic therapy 

was administered to 10 patients: four patients 

received one antibiotic to which organism was 

susceptible and six patients were given two 

antibiotics to which the organism was sensitive. All 

four patients who had catheter related sepsis were 

successfully treated by removal of infected catheters 

and administration of appropriate antibiotic 

t h e r a p y, while all the four patients who had 

pneumonia died, even though appropriate antibiotic 

therapy had been given to one of them . 

Follow up of patients who survived the 

bacteremic episode revealed interesting data: five 

patients who had successful treatment for their 

b a c t e remic episodes died in the following two 

years from conditions including relapse of


Fig. 1: Shows antibiotic sensitivity for S. Maltophilia 

leukemia and presence of other bacterial or fungal 

infections. A relationship was observed between 

the episodes of S. maltophilia bacteremia and relapse 

of the malignant hematological disorders. Six 

patients (35.3%) suff e red relapses of their 

malignant hematological disorders within the last 

two months prior to the bacteremic episode. Out of 

the eight patients who survived the bacteremic 

episode, six patients (35.3%) had relapses of their 

hematological malignancy within the next two 

years. Also another relationship was noted between 

s u rgical pro c e d u res and the episodes of S . 

maltophilia bacteremia: nine of the patients studied 

(52.9%) required surgical interventions, six of them 

(35.3%) needed surgery prior to bactere m i c 

episode, two patients (11.8%) re q u i red surg i c a l 

intervention during the bacteremic episode and 

only one patient (5.9%) had surgery after treatment 

of the septic episode . 

DISCUSSION 

S. maltophilia is a free living, motile, oxidase 

negative, glucose non-fermenting and strictly 

aerobic Gram-negative bacillus [2,4,6] . It is widespread 

in environment and has been isolated from water, 

soil, sewage, fish, raw milk and feces of humans 

and rabbits [ 2 , 4 - 6 ] . The organism can cause colonization 

and contamination of various items of hospital 

equipment and even hands of hospital staff [1,2,5] . It 


causes a wide variety of infections particularly in 

debilitated hosts [1-8,10] . The vast majority of infections 

are nosocomial [1-3,7-10,13] . The following risk factors 

p redispose to infection with S. maltophilia: 

underlying disease especially hematological and 

non-hematological malignancy, immunosuppre s s i v e 

therapy including corticosteroids and cytotoxic 

chemotherapy, prolonged neutropenia and bone 

marrow aplasia, admission to intensive care units 

and artificial ventilation, the use of broad spectrum 

antibiotics particularly carbapenems and air 

travel [1-12,13-24] . In our study, all episodes of infection 

with S. maltophilia w e re nosocomial. The main 

p redisposing factors for infection were: hematological 

malignancy (mostly acute leukemia), presence of 

neutropenia, central venous catheters and other 

infections especially bacterial infections, administration 

of immunosuppressive therapy, broad spectrum 

antibiotics including carbapenems, ICU admission, 

mechanical ventilation and recent travel by air. It 

was observed that 35.3% of patients had surgical 

intervention and an equivalent proportion had 

relapse of their malignant hematological disorders 

before the development of the bacteremic episode 

of S. maltophilia. These previously undescribed 

observations can be explained as follows: both, 

surgical procedures and relapse of hematological 

malignancy are associated with pro l o n g e d 

hospitalization and further reduction of immunity;

218 

Bacteremia due to Stenotrophomonas Maltophilia in Patients with Hematological ... September 2006 

thus development of more serious infections and 

drug resistance are the likely consequences. 

Clinical manifestations of infections with S . 

maltophilia depend on the sites involved and they 

include primary bacteremia, endocarditis, meningitis, 

pneumonia and upper respiratory tract infections, 

primary and metastatic cellulitis, keratitis and 

conjunctivitis, wound infections, gut and urinary 

tract infections [1-6,9,11,13-19,22,25] . High mortality rates are 

encountered in immunocompromised hosts, ICU 

residents and patients having lung involvement or 

b a c t e remia in addition to patients exposed to 

carbapenems [2,4,5,10,12-14,26] . In our group of patients, the 

primary sites of infection were as follows: central 

venous catheter related sepsis (four episodes: 

23.5%), pneumonia (four episodes: 23.5%), pharyngitis 

(two episodes: 11.8%), skin (one episode: 5.9%) and 

abdominal sepsis (one episode: 5.9%). The primary 

focus of infection was unknown in five episodes 

(29.4%). Two of the patients with lung involvement 

had pleural effusions. The patient with skin 

involvement developed ecthyma gangre n o s u m 

which unfortunately progressed into necrotizing 

cellulitis. The ultimate outcome of the bacteremic 

episode depends to a large extent on the primary 

site of infection. As demonstrated in other studies. 

All four patients with catheter related sepsis 

survived after removal of the infected catheters and 

giving the appropriate antibiotics, while all patients 

with lung involvement died. On the other hand, 

giving appropriate antibiotic alone might not save a 

patient, if his or her condition is far advanced. For 

example: two of our patients with bacteremia died 

despite receiving two antibiotics to which the 

o rganism was susceptible (cotrimoxazole a n d 

piperacillin / tazobactam). One of these patients had 

s e v e re pneumonia and the other one had 

complicated ecthyma gangrenosum. 

Most studies indicate that the organism is 

usually resistant to carbapenems, aminoglycosides, 

quinolones, aztreonam and most of the cephalosporins 

and antipseudomonal penicillins [ 1 - 7 , 1 3 - 1 7 , 2 6 , 2 7 ] . It has 

been found to be susceptible to: trimethoprim 

sulphamethoxazole, ticarcillin - clavulanate, salbactamcefoperazone, 

minocycline, doxycycline, chloramphenicol, 

moxalactam, lactamoxef and ceru m o n a m 

[ 1 - 6 , 8 , 1 0 , 1 3 - 1 5 , 1 8 , 1 9 , 2 2 , 2 5 - 

2 7 , 3 0 ] . Successful management of infections depends 

upon: administration of antibiotics to which the 

organism is sensitive, removal of infected catheter 

or foreign material, recovery of bone marro w 

function and taking enough preventive and 

isolation measure s [ 1 , 3 , 4 , 6 , 7 , 1 0 , 2 2 , 2 7 ] . In our study, S . 

m a l t o p h i l i a was found to be susceptible to: 

cotrimoxazole, which is regarded as the agent of 

choice for treatment of S. maltophilia infections. Also 

in full agreement with other studies, the lowest 

sensitivity rates were encountered with carbapenems 

and aminoglycosides. In contrast with other 

studies, the organism showed more than 50% 

sensitivity rates to: ceftazidime, colistin and 

piperacillin/tazobactam. However, the rate of 

sensitivity to ciprofloxacin was unexpectedly low 

(35.3%) and therefore its use as empirical therapy 

should be considered with care. Treatment with 

imipenem or meropenem has been found to 

i n c rease the incidence of infection with S. maltophilia 

considerably, sometimes upto 10 to 15 fold [5,9,12,15] . 

Fifteen of our patients (88.2%) were re c e i v i n g 

imipenem or meropenem at the time of S . 

maltophilia bacteremia or within two weeks before 

the onset of sepsis. 

CONCLUSION 

S t e n o t rophomonas maltophilia is an important 

nosocomial pathogen. It causes significant morbidity 

and mortality in immunocompromised individuals. 

Patients with acute leukemia having chemotherapyinduced 

neutropenia, indwelling intravascular 

catheters and those receiving broad spectru m 

antibiotics are particularly affected. Successful 

management depends upon: having high index of 

suspicion, removal of infected intravascular 

catheters and early administration of appropriate 

antibiotics, preferably in combinations, including 

cotrimoxazole and one of the following: ceftazidime, 

colistin or piperacillin / tazobactam. 

ACKNOWLEDGEMENT 

We are grateful to: (1) all medical, nursing and 

technical staff in hematology ward, laboratories 

and intensive care unit at the Riyadh Armed Forces 

Hospital who participated in the management of 

these patients, (2) Prof. David Alan Price Evans 

(Senior Consultant, Department of Medicine, 

Riyadh Armed Forces Hospital) for his help in 

writing and reviewing this paper. 

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ABSTRACT 

Objectives: To examine the pattern of urinary tract 

infection (UTI) in boys < 5 years admitted to general 

pediatric wards and to identify the approach to imaging 

investigations. 

Design: During the period from January 2002 through 

December 2002, 34 boys < 5 years of age were admitted 

to Farwania Hospital with UTI. Age at diagnosis, 

presenting features, urinalysis, pathogens, acute phase 

reactants and imaging procedures were reviewed for 

these patients. 

Results: All 34 patients in this study were less than one 

year. Fever was the most common presenting feature and 

was seen in 70.6% of patients. Pyuria was found in 77% , 

positive leukocyte esterase (LE) test in 85.7% and 

positive nitrite test in 45.7% of patients. Significant 

leukocytosis was found in 39.3%, high C-reactive protein 

(CRP) in 46.8% and high erythrocyte sedimentation rate 

(ESR) in 50% of children. Escherichia coli (E.coli) were the 

most common pathogen affecting 77.1% patients. 

Radiological investigations were recommended as 

follows: ultrasound scan (US) for all patients (94.2% did 



Urinary Tract Infection in Boys Less Than Five Years of 

Age: A General Pediatric Perspective 

Hany M Nadi, Yasser A F Shalan, Hanan YA Al-Qatan , Saad Alotaibi 

Department of Pediatrics, Farwania Hospital, Kuwait 


the test, 46.8% had normal scans and 43.7% had dilatation 

of pelvicalyceal system); Early-scheduled 99m Tc dimercaptosuccinic 

scan (DMSA) was done in seven patients. Five 

or 71% had evidence of acute pyelonephritis; Latescheduled 

DMSA was recommended for 25 patients. 

Only 52% did the test and out of those 46% had evidence 

of chronic involvement of the kidney(s); Micturating 

cystourethrogram (MCUG) was advised for 32 patients. 

43.8% failed to carry out the procedure. Vesicoureteric 

reflux (VUR) was found in 38.8% of those who performed 

the test. 

Conclusion: Unexplained fever in young boys should 

suggest UTI. Absence of fever does not exclude UTI, if 

other suggestive features exist particularly in the very 

young. UTI is commonly suggested by findings on 

urinalysis, on the other hand, negative urinalysis should 

not exclude the infection. Empiric antibiotics should 

cover gram-negative bacilli. Innovative strategies to 

e n s u re compliance to radiological investigations are 

needed. 

KEYWORDS: dimercaptosuccinic (DMSA), Farwania hospital, micturating cystourethrogram (MCUG), urinalysis, 2002 

INTRODUCTION 

Urinary tract infection (UTI) is a condition that 

causes acute morbidity and may result in long-term 

complications including hypertension and reduced 

renal function [ 1 ] . UTI is a relatively common 

condition in infants and young children. Age and 

gender are important factors influencing 

prevalence. As males are more likely to be born 

with structural abnormalities of the urinary tract, 

UTI is common in their first six months of life [3] . 

Few infections are encountered in boys in the age 

range of 1 - 5 years. In preschool years symptomatic 

infections occur 10 to 20 times more frequently in 

girls than in boys [ 2 ] . Since boys may be less 

suspected of having UTI than girls, it was our aim 

to profile the condition in Kuwait, highlighting the 

age of highest vulnerability, common presenting 

features and common pathogens. 

Microorganisms reach the urinary tract by the 

way of ascending, hematogenous, or lymphatic 

routes. The ascending route accounts for almost 

95% of cases of UTI [4] . This is particularly common 

for Escherichia coli (E.coli) and other Entero - 

bacteriaceae. Compromised host’s natural defenses 

(e . g . , o b s t ruction, catheterization) decrease the 

v i rulence re q u i rements of the bacterial species. 

Certain bacterial strains are virulent enough to 

induce infection with no predisposing factors in the 

host [4,5] . 

The clinical presentation of UTI in infants and 

children can be very subtle and atypical, and a high 

index of suspicion must be kept in order to 

diagnose UTI [ 6 ] . Unexplained fever particularly 

should raise suspicion but very young infants may 

present without fever. 

Accurate diagnosis of UTI is needed for two 

reasons: to permit identification, treatment, and 

evaluation of the children who are at risk for 

kidney damage and to avoid unnecessary 

treatment and evaluation of children who are not at 


Dr. Hany M Nadi, Farwania Hospital, P.O. Box 18373, Kuwait 81004. Tel: 00965-5662357, 00965-6514466, E-mail: hmnadi@yahoo.com


r i s k [ 1 ] . Urine specimen that is unlikely to be 

contaminated is needed for this purpose. 

Although the outcome of UTI is usually benign, 

parenchymal scarring develops in 10 to 15%, with 

greater risk in those less than one year of age [2] . On 

the other hand, some recent studies do not support 

age distinction and indicate that the risk of renal 

scarring may not decrease with age [ 7 ] . Renal 

scarring is associated with complications such as 

hypertension, renal damage and end-stage renal 

failure [8] . 

Renal scars can be detected by the use of 

imaging procedures. These are also essential for 

detection of anatomical abnormalities of the urinary 

tract, which increase the risk of renal scarring [4] . 

The main imaging modalities include ultra 

sound scan (US), dimercaptosuccinic scan (DMSA), 

and Micturating cystourethrogram (MCUG). In this 

review the scheme of radiological investigations 

carried out in Farwania Hospital is outlined. 


The medical records of male patients five years 

and less diagnosed to have UTI and who were 

admitted to the general pediatric wards in 

Farwania Hospital from January 2002 thro u g h 

December 2002 were retrospectively reviewed. UTI 

was defined by the presence of two cultures of pure 

bacterial growth > 10 5 colony forming units/ml 

(CFU/ml) if the samples were collected by clean 

catch or midstream urine, one culture of pure 

bacterial growth > 10 3 (CFU/ml), if urine were 

collected by catheter. A total number of 34 boys 

were admitted during the study period with the 

diagnosis of UTI. The medical records of these boys 

were reviewed to determine age at presentation, 

main presenting feature, urinalysis, type of 

organism, acute phase reactants i.e., blood white 

cell count, C-reactive protein (CRP) and erythrocyte 

sedimentation rate (ESR) and type and results of 

radiological procedures. 

The main presenting feature was the feature that 

led the treating physician to suspect UTI and carry 

out urine cultures. Urinalysis included dipstick 

testing in all patients and microscopic examination 

in 26 patients. Leukocyte esterase (LE) and nitrite 

test were selected from the dipstick criteria for 

review. On microscopic examination pyuria was 

defined by the presence of 10 or more white cells 

per seven high power field (7 hpf) and hematuria 

by the presence of 10 or more red cells per 7 hpf. 

Leukocytosis above 15x10 9 /l was considere d 

significant. CRP was considered high, if above the 

cutoff point of 20 mg/l and ESR was considered 

high, if above 20 mm/hr. 

The main radiological modalities were US, 

MCUG and DMSA. US was recommended for all 


Table 1: Distribution of 34 cases of urinary tract infection 

according to presenting features, urinalysis, pathogen 

and acute phase reactants 

Variables n % 

Presenting features: 

Fever 24 70.6 

Urinary symptoms 11 32.4 

Vomiting 7 20.5 

Neonatal jaundice 3 8.8 

Nonspecific symptoms 4 11.7 

Urinalysis 

Pyuria 26 77.1 

Hematuria 14 40.0 

Positive LE test 29 85.7 

Positive nitrite test 16 45.7 

Pathogens 

E.coli 26 77.1 

K.pneumoniae 7 20.0 

P.aeruginosa 1 2.8 

Acute phase reactants 

Significant leukocytosis 13 39.3 

High CRP 15 46.8 

High ESR 16 50.0 

patients during the actual infection, MCUG was 

recommended for all patients except two, 3-4 weeks 

following clearance of the infection. Early-scheduled 

DMSA (DMSA done during or shortly after the 

actual infection) was recommended for nine 

patients, late-scheduled DMSA (DMSA done 3-4 

months following the infection) was recommended 

for patients with evidence of pyelonephritis on the 

initial DMSA. Late-scheduled DMSA was also 

recommended for a further 20 patients. 

Data extracted were recorded using an Excel 

( M i c rosoft Corporation, Redmond, VA) spre a d s h e e t 

and then subjected to descriptive statistical 

analysis. 

RESULTS 

The age of the boys enrolled in this study ranged 

from three days to 11 months. The median hospital 

stay was 10 days and the median duration of 

antibiotic treatment was 8.2 days. 

The main presenting features included fever, 

urinary symptoms (these include difficulty in 

passing urine, crying on micturition, and frequency 

of urination, and change in the color or smell of 

urine), vomiting, neonatal jaundice and nonspecific 

symptoms. Patients who presented with 

non-specific symptoms were suspected to have UTI 

because of abnormalities found on urinalysis. The 

number of patients and their percentage of total in 

relation to presenting features are shown in Table 1. 

Children who presented without fever were all less 

than three months of age. Vomiting was usually 

associated with other features. Infants who 

presented with jaundice were all less than one

222 

Urinary Tract Infection in Boys Less Than Five Years of Age: A General Pediatric ..... September 2006 

Table 2: Number of patients for whom radiological 

investigations were recommended with percentage of 

failure to perform the procedures (n = 34) 

Number of patients Number of patients 

Radiological test for whom the test was who failed to perform 

recommended the requested test 

n % n % 

US* 34 100 2 5.8 

MCUG** 32 94.1 14 43.8 

DMSA $ 

early 9 26.4 2 22.2 

DMSA $ late 25 73.5 12 48 

*Ultrasound, **Micturating cystoure t h rogram, $ 9 9 m Tc dimercaptosuccinic scan 

Table 4: Distribution of 32 urinary tract infection cases 

who performed US according to performance and results 

of DMSA 

US DMSA* 

Not Normal Acute Renal scar Other Total 

done pyelone- or chronic abnorma- 

phritis pyelonephritis lities 

Normal 10 2 2 0 1 15 

Pelvicalycealdilatation 

5 4 3 1 0 13 

Other 0 1 0 2 1 3 

Total 15 7 5 3 2 32 

*Not including those done for the second time in the same patient 

month of age i.e., 20% of all infants under one 

month of age. 

All patients had urinalysis (i.e., dipstick testing) 

in addition to microscopic examination of urine in 

26 patients. The abnormal findings are shown in 

Table 1. 

The pathogens were all gram negative 

Enterobacteriaceae, except one patient in whom the 

o ffending organism was gram-negative P s e u d o m o n a s 

aeruginosa (P. aeruginosa). The types of pathogens 

and the number and percentage of affected patients 

are shown in Table 1. 

White blood cell count was estimated in 33 

patients, CRP and ESR were measured in 32 

patients. Number of patients with significantly 

elevated acute phase reactant is shown in Table 1. 

The number and percentage of patients for 

whom radiological tests were recommended and 

those who failed to do the test are demonstrated in 

Table 2. 

Thirty-two patients had an US examination and 

in 15 out of them there were no abnormalities 

found on the scans. Of those 15 patients with 

normal scans, seven had no further radiological 

investigation. Five had both MCUG and DMSA 

done, two had only MCUG done and one had only 

DMSAdone. For the 17 patients with abnormalities 

Table 3: Distribution of 32 urinary tract infection cases 

who performed US according to performance and results 

of MUCG 

US MCUG 

Not done Normal VUR* Others Total 

Normal 9 4 1 1 15 

Pelvicalycealdilatation 

3 5 5 0 13 

Other abnormalities 3 0 1 0 4 

Total 15 9 7 1 32 

*Vesicoureteric reflux 

on ultrasound, seven had both DMSA and MCUG 

done, four only DMSA and four only MCUG. Two 

patients had neither of these investigations. 

Most common abnormality found on US was a 

dilated pelvicalyceal system; gross hydronephrosis 

was found in six patients, mild to moderate 

dilatation was found in eight subjects. One patient 

had horseshoe kidney, an upper pole scar was 

detected in one patient and the left kidney was not 

visualized in one patient. MCUG results in relation 

to findings on the US are shown in Table 3. On the 

whole, 18 patients underwent MCUG and in 10 out 

of them the study was normal. VUR was detected 

in seven patients and posterior urethral valve in 

one patient. 

Out of the seven patients who did an earlyscheduled 

DMSAfive were found to have evidence 

of pyelonephritis. Late-scheduled DMSA w a s 

recommended for those five patients; four of them 

performed the test plus further nine patients who 

did not have an early-scheduled DMSA. In those 13 

patients three were found to have renal scars, three 

had evidence of chronic pyelonephritis, small 

kidney with decreased function, in one patient 

there was a horseshoe kidney demonstrated and in 

the remaining seven DMSA was normal. In nine 

patients DMSA was considered unnecessary 

because of normal radiological investigation (i.e. US 

and MCUG in two patients, normal US in three 

patients and normal early-scheduled DMSA in two 

patients). In the other two children other radiological 

investigations were preferred. Results of DMSA in 

relation to US findings are shown in Table 4. 

All the patients were scheduled for follow-up in 

the general pediatric outpatient; however, in two 

patients urosurgical consultation was sought. One 

patient had posterior urethral valve, while the other 

was re f e r red to exclude the possibility of 

pelviureteric junction obstruction. 

DISCUSSION 

In our study we attempted to examine the 

pattern of UTI in boys less than five years, since 

UTI is more common in younger boys than in later


age [3] . In our group of patients we found that all 

affected boys were less than one year old and 47% 

were one month or younger. There was complete 

absence of cases in the age range of one to five 

years. We could not find a definite explanation for 

this finding but it may be related to the fact that 

almost all boys living in Kuwait would have been 

circumcised by one year of age. Vulnerability of 

uncircumcised boys to UTI has been suggested in 

many other studies [9,10] . 

As UTI is a disease that seldom features physical 

signs [5] , we tried in this study to elucidate possible 

presenting features. Fever was the most common 

presenting feature, affecting 70.6%; it is prudent to 

keep a high index of suspicion for febrile young 

boys. However, 10 patients in this study had no 

fever at presentation; these were all infants three 

months of age or younger. UTI should not be 

automatically ruled out in the absence of fever 

particularly in young infants. 

As urinary symptoms are difficult to evaluate in 

the very young, an observant mother is invaluable 

in this aspect and such observations must be taken 

into serious consideration. Jaundice was one of the 

features that led to the diagnosis of UTI. Infants less 

than eight weeks who present with jaundice should 

be screened for UTI [11] . In our study 8.8% of all 

affected boys or 19% of those less than one month 

p resented with jaundice. Similar findings were 

reported by Francisco et al who described diagnosing 

UTI in 7.5% of asymptomatic, afebrile, jaundiced 

infants (both boys and girls) younger than eight 

weeks [11] . 

Abnormalities found on urine analysis may be 

the instigating factor in the diagnosis of UTI. Thus 

it is imperative that the test be sensitive enough not 

to miss cases. Both dipstick testing and microscopic 

examination of urine should probably be used. The 

dipstick findings had 81% sensitivity and 95% 

specificity [3] . Urine microscopy was found to be less 

sensitive (60 and 70%) [2,3] . In our group of patients, 

three or 8.8% had negative urine testing. Urinalysis 

should be performed in all suspected cases so that 

treatment can be started early and before the results 

of culture. However, the treating physician should 

p roceed to urine culture if despite negative urinalysis 

the child presents with suggestive symptoms [ 8 ] , 

particularly in the very young. Urine culture 

should be done as a part of the septic workup. 

In correlating elevated acute phase reactants 

(leukocytosis, high ESR and high CRP) with 

pyelonephritis as diagnosed by DMSA, there were 

five patients diagnosed to have pyelonephritis; in 

three out of them all acute phase reactants were not 

elevated, one patient had all acute phase reactants 

elevated and in one patient only ESR was elevated. 

The number of cases was small and yet it was 


obvious that acute phase reactants were not helpful 

in predicting pyelonephritis. Ross et al had similar 

conclusions as they found that ESR, CRP, and 

peripheral WBC counts were not helpful in 

identifying UTI in febrile infants [12] . Fretzayas et al, 

also concluded that CRP is not a very sensitive 

marker for localizing UTI site. They found that CRP 

was less sensitive than the other two inflammatory 

parameters (ESR and polymorphonuclear elastasea1-antitrypsin 

complex or E-a1-Pi); its accuracy was 

only slightly inferior to that of E-a1-Pi. ESR was less 

sensitive than E-a1-Pi (90% vs. 96%) but the overall 

accuracy of these two markers was quite similar. 

They commented that their results were in 

agreement with other studies [13] . Stokland et al, on 

the other hand, concluded that children with high 

levels of CRP, high fever, and dilating reflux had a 

risk of renal damage up to 10 times higher than 

c h i l d ren with normal or slightly elevated CRP 

levels, no or mild fever, and no reflux [14] . 

The offending organisms in this study were 

exclusively of the gram negative Entero b a c t e r i a c e a e 

family, the majority being E.coli and a significant 

minority being Klebseilla pneumoniae (K.pneumoniae). The 

knowledge of the possible offending pathogens is 

useful in the initial choice of antibiotics since there 

is evidence that early treatment before obtaining 

the results of culture and sensitivity may be 

associated with less chance of developing renal 

scarring [15] . 

US has replaced intravenous pyelogram in the 

initial radiological evaluation of children with UTI. 

US can measure renal size and shape, identify 

h y d ro n e p h rosis and structural or anatomical 

abnormalities of the kidneys and urinary tract and 

can diagnose renal calculi. It is convenient, 

relatively cheap and easy and has no radiation risk. 

However, US is not reliable for detection of VUR 

reflux, renal scarring or inflammatory changes; 

pyelonephritis cannot be reliably diagnosed on US. 

US is largely operator-dependent [16] . In our study 

US was performed in most of the patients and 

p roved to be reasonably reliable in detecting 

hydronephrosis and anatomical abnormalities and 

in indicating the possibility of VUR. It was not 

useful in the diagnosis of pyelonephritis. Contrary 

to the other radiological methods, there was a low 

rate of refusal or non-compliance. That low rate of 

refusal may call for more reliance on US through 

introducing techniques that may compensate for 

MCUG, like cystosonography enhanced with SH U 

508A, a galactose-based echo-enhancing agent, 

which has as much a diagnostic value as traditional 

MCUG in diagnosing VUR [17,18] . 

DMSA is the most reliable technique in the 

diagnosis of chronic renal cortical scarring as 

compared to other imaging modalities such as US

224 

Urinary Tract Infection in Boys Less Than Five Years of Age: A General Pediatric ..... September 2006 

examination and intravenous urography [19] . DMSA 

scintigraphy has also been used in the diagnosis of 

renal infarcts, horseshoe kidney, multicystic 

dysplastic kidney, and ectopic kidney. A c u t e 

pyelonephritis may cause residual scan abnormalities 

for at least three months after infection. In the 

detection of renal cortical scars, it is advocated to 

perform the DMSA study 3-6 months following the 

infection; however, these abnormalities may last for 

up to 12 months [19] . In our group of patients DMSA 

was performed in seven patients during the acute 

stage to diagnose pyelonephritis and in five 

patients there was scintigraphic evidence of 

pyelonephritis. Follow-up scans in these patients 

showed renal scarring in two patients, reduced 

function of one kidney in one, was normal in one 

patient and one patient failed to do the follow-up 

study. Seven patients, out of thirteen had evidence 

of scarring and/or chronic pyelonephritis on latescheduled 

DMSA. 

In boys, initial work-up should include MCUG, 

which is needed for the diagnosis of VUR and for 

detection of urethral abnormalities such as urethral 

diverticulum or posterior urethral valves as normal 

US and/or DMSA do not exclude VUR [13,20] . VUR 

was found in six of our patients who had underg o n e 

MCUG (42.9%). This is similar to findings in many 

other studies [21] . One of the significant findings in 

this study is the high rate of failure to perform 

MCUG. Out of 30 boys for whom MCUG was 

recommended, 12 or 40% did not carry out the 

procedure. McDonald et al found in their study that 

in hospitalized children who underwent MCUG 

within a week after diagnosis of UTI, the presence 

of reflux was not significantly different from those 

studied later [22] . They also had a high rate of failure 

(to perform the procedure) in those who were given 

late scheduled appointments. They concluded that 

the traditional recommendation to perform the 

MCUG at three to six weeks after the diagnosis of 

UTI should be re c o n s i d e red, especially f o r 

hospitalized childre n [ 2 2 ] . MCUG remains essential in 

the evaluation of UTI, particularly to exclude 

VUR [20] . 

CONCLUSION 

Those who care for children should be aware 

that there is a high prevalence of UTI among 

children. He or she should have knowledge of the 

various presenting features, which are commonly 

atypical and be aware of the need to have a high 

index of suspicion. Medical care providers should 

keep track of the best ways to screen for and to 

diagnose UTI in children, particularly in infants. 

Early detection and treatment of the first infection 

in infants may be the only way to reduce the 

incidence of reflux nephropathy and to prevent 

renal damage [ 2 3 ] . However, diagnosis should be 

p roperly documented to avoid unnecessary 

investigation. Those with documented UTI should 

have radiological investigation to detect any 

structural abnormalities. These should include an 

US scan shortly after diagnosis to detect any 

anatomical abnormalities and MCUG after clearance 

of the infection, as it is the most reliable method to 

diagnose VUR. DMSA3-6 months after the infection 

is important to diagnose renal scars. Early DMSAis 

valuable as the most accurate way to d i a g n o s e 

pyelonephritis as a definite diagnosis may be essential 

in some cases. Children who have stru c t u r a l 

abnormalities will need long term follow up [10] . 

REFERENCES 

1. Committee on Quality Improvement, Subcommittee on 

Urinary Tract Infection, American Academy of Pediatrics. 

Practice Parameter: The Diagnosis, Treatment, and 

Evaluation of the Initial Urinary Tract Infection in Febrile 

Infants and Young Children. Pediatrics 1999; 103:843-852. 

2. Schlager TA. Urinary tract infections in infants and 

children. Infectious Disease Clinics of North America 2003; 

17:2. 

3. Shaw KN, McGowan KL, Gorelick MH, Schwartz JS. 

Screening for Urinary Tract Infection in Infants in the 

Emergency Department: Which Test Is Best?. Pediatrics 

1998; 101:1. 

4. Goldman M, Lahat E, Strauss S, et al. Imaging After Urinary 

Tract Infection in Male Neonates. Pediatrics 2000; 105:1232- 

1235. 

5. Naber KG, Bergman B, Bishop MC, et al. Euro p e a n 

Association of Urology guidelines on urinary and male 

genital tract infections. Urologe 2003; 42:104-112. 

6. Gorelick MH, Shaw KN. Screening Tests for Urinary Tract 

Infection in Children: A Meta-analysis. Pediatrics 1999; 104: 

54. 

7. Gauthier M, Chevalier I, Sterescu A, et al. Treatment of 

Urinary Tract Infections Among Febrile Young Children 

With Daily Intravenous Antibiotic Therapy at a Day 

Treatment Center. Pediatrics 2004; 114:e469-e476. 

8. Ahmed SM, Swedlund SK. Evaluation and Treatment of 

Urinary Tract Infections in Children. Am Fam Physician 

1998; 57:1573-1580, 1583-1584. 

9. Ginsburg CM, McCracken GH. Urinary Tract Infections in 

Young Infants. Pediatrics 1982; 69:409-412. 

10. McCracken GH. Options in antimicrobial management of 

urinary tract infections in infants and children. Pediatr 

Infect Dis J 1989; 8:552-555. 

11. Francisco J, Garcia FJ, Nager AL. Jaundice as an Early 

Diagnostic Sign of Urinary Tract Infection in Infancy. 

Pediatrics 2002; 109:846-851. 

12. Lin DS, Huang SH, Lin CC, et al. Urinary Tract Infection in 

Febrile Infants Younger Than Eight Weeks of A g e . 

Pediatrics 2000; 105:20. 

13. Fretzayas A, Moustaki M, Gourgiotis D, Bossios A, et al. 

Polymorphonuclear Elastase as a Diagnostic Marker of 

Acute Pyelonephritis in Children. Pediatrics 2000; 105:28. 

14. Stokland E, Hellstrom M, Jacobsson B, Jodal U, Sixt R. Renal 

damage one year after first urinary tract infection: role of 

d i m e rcaptosuccinic acid scintigraphy. Pediatrics 1996; 

129:815-820. 

15. Bachur R. Nonresponders: Prolonged Fever Among Infants 

With Urinary Tract Infections. Pediatrics 2000; 105:e59. 

16. Strouse PJ. Imaging and the child with abdominal pain.


Singapore Med J 2003; 44:312-322. 

17. Berrocal T, Gayá F, Arjonilla A, Lonergan GJ. Vesicoureteral 

Reflux: Diagnosis and Grading with Echo-enhanced 

Cystosonography versus Voiding Cystour e t h ro g r a p h y. 

Radiology 2001; 221:359-365. 

18. Darge K, Troeger J, Duetting T, et al. Reflux in Young 

Patients: Comparison of Voiding US of the Bladder and 

Retrovesical Space with Echo Enhancement versus Voiding 

C y s t o u re t h rography for Diagnosis. Radiology 1999; 

210:201-207. 

19. Rossleigh MA. Renal Cortical Scintigraphy and Diuresis 

Renography in Infants and Children. J Nucl Med 2001; 


42:191-195. 

20. Burbige KA, Retic AB, Colodny AH, Bauer SB, Lebowitz R. 

Urinary tract infection in boys. J Urol 1984; 132:541-542. 

21. Ross JH, Kay R. Pediatric urinary tract and reflux, Am Fam 

Physician 1999; 15; 59:1472-1478, 1485-1486. 

22. McDonald A, Scranton M, Gillespie R, et al. Vo i d i n g 

C y s t o u re t h rograms and Urinary Tract Infections: How 

Long to Wait? Pediatric 2000; 105:50. 

23. K e ren R, Chan E. A Meta-analysis of Randomized 

C o n t rolled Trials Comparing Short- and Long-Course 

Antibiotic Therapy for Urinary Tract Infections in Children. 

Pediatrics 2000; 105:59.

ABSTRACT 

Supraventricular tachycardia (SVT) with long RPinterval 

and short PR interval is a unique form of tachycardia. 

The differential diagnosis includes sinus tachycardia, 

focal atrial tachycardia, atrial flutter with two to one 

ventricular response and atrioventricular reciprocating 


Case Report 

Persistent Narrow Complex Tachycardia: What is the 

Diagnosis? 

t a c h y c a rdia with slow re t rograde ventriculoatrial 

conduction. In this report, we present a case of long RP 

SVT and a review of the electrocardiographic features of 

each type of tachycardia. 

KEYWORDS : atrial flutter, long RPtachycardia, supraventricular tachycardia. 

INTRODUCTION 

N a r row complex tachycardia (NCT) is a commonly 

presenting condition to the emergency room. The 

optimal short-term and long-term patient’s 

management will be influenced by understanding 

the exact mechanism of the tachycardia. The 

routine use of AV node blocking agent or 

maneuvers such as intravenous adenosine is not 

always successful in terminating Supraventricular 

tachycardia (SVT), as the case with atrial flutter 

(AFL) or focal atrial tachycardia (AT ) 

demonstrated. The long-term medical and catheterbased 

therapy will vary from one tachycardia to the 

other. SVT with long RP, where the P wave is seen 

before each QRS complex, is a more challenging 

diagnostic condition, since it has a wide range of 

d i ff e rential diagnosis. A c a reful electro c a rd i o g r a p h i c 

assessment, during tachycard i a , even before 

termination, is the most important step to 

understand the tachycardia mechanism and to 

apply the appropriate treatment plan. 

Case: 

A 45-year-old man was referred with a history of 

palpitation at rest accompanied by dyspnea. He 

had a previous history of myocardial infarction and 

mild congestive heart failure. The 12-lead electro - 

c a rd i o g r a mshown in Fig. 1 was recorded after two 

days of heart failure stabilization. 

DISCUSSION 

This ECG shows narrow complex re g u l a r 

tachycardia at a rate of 140 bpm with P wave 

p receding every QRS complex. The P to R 

Ali Al Sayegh 1 , Mousa A J Akbar 2 

1 Department of Cardiology- Chest Disease Hospital, Kuwait 

2 Department of Medicine-Farwania Hospital Kuwait 



Dr. Mousa Akbar FRCPC, P.O Box: 498, Al-Omariya - 85159, Kuwait, E-mail: mousaakbar@hotmail.com 

relationship is at ratio of 1:1 with abnormal P wave 

vector of negative P wave in the inferior leads (II, 

III and AvF). The normal sinus rhythm P wave is 

usually positive in the II, III and AvF leads and 

biphasic in V1 lead. These features categorize the 

tachycardia as supraventricular tachycardia with 

long RP interval. The defferential diagnosis of long 

RP SVT is the following: 

1. Sinus tachycardia, which was ruled out by the 

abnormal P wave morphology. This patient also 

has persistent tachycardia at a fixed heart rate inspite 

of good heart failure stabilization. Sinus 

tachycardia usually has warming-up and coolingdown 

characteristics, as a result of autonomic tone 

fluctuation. 

2. Paroxysmal supraventricular tachycard i a 

(PSVT) or Re-entrant AV tachycardia, with atypical 

slow return pathway from the ventricle to the 

atrium causing delay of atrial activation. 

Atrioventricular nodal re-entrant tachycard i a 

hyper (AVNRT) with slow-slow physiology and AV 

re c i p rocating tachycardia (AV RT) using a re t ro g r a d e 

slow accessory pathway, both can present with 

long RP tachycardia instead of the common variant 

of short RPinterval. In the typical form of PSVT, RP 

usually is short and measures equal or less than 90 

mseconds with longer PR interval [1] . As a result, P 

wave is falling in the T wave in the service ECG, 

which makes the P wave either invisible or seen as 

small squiggles within the T-wave when using unfiltered 

ECG [2] . While in the long RP PSVT, the P 

wave is falling later in diastole with abnormal 

morphology due to different sequence of activation 

of the atria in caudo-cranial direction, i.e., low to


Fig. 1: Regular narrow complex tachycardia during initial presentation, with a heart rate of 140 bpm. 

high atrium. 

3. Atrial flutter and/or atrial tachycardia with 

2:1 conduction from the atria to the ventricles over 

the AV node [3-4] . The second flutter wave cannot be 

seen because it is hidden in the QRS complex. The 

flutter cycle length is usually 200-240 mseconds, 

equivalent to a rate of 280-300 bpm in the atria. 

With 2:1 conduction, the ventricular rate will be 

around 140 -150 bpm. 

To verify the arrhythmia further, the patient was 

given a small dose of intravenous Propranolol. The 

rate of the tachycardia was slowed down only to 

130 bpm, without causing tachycardia termination 


Fig. 2: Tachycardia after 2 mg of IV propranolol was given. Heart became 130 bpm with longer PR intervals and presence of variable conduction block. 

V1-V3 shows 2:1 pattern (arrows) and V4-V6 shows regularly irregular rhythm. Notice the typical morphology of flutter wave in lead II, III and AvF 

(asterisks). 

(Fig. 2). Slowing of the tachycardia helps in two 

ways to confirm the presence of atrial flutter with 

2:1 AV block as the definitive diagnosis of this case. 

First, the appearance of the second P wave at the 

slower rhythm ECG clearly demonstrates the 

presence of 2:1 atrioventricular activation (Fig. 2 

a r rows). Second, the prolongation of the RR 

interval due to AV node block during sustained 

tachycardia, which proves that the tachycardia is 

AV node independent and the AV node is not part 

of the tachycardia mechanism. Therefore, it is not 

likely for the tachycardia to be AV node dependent 

tachycardia such as AVNRT or AVRT (differential

228 

Persistent Narrow Complex Tachycardia; What is the Diagnosis? September 2006 

Fig. 3: Schematic diagram for the various forms of tachycardia, from top 

to bottom: sinus tachycardia, typical PSVT, atypical PSVT and atrial 

flutter with 2:1 conduction. Following the administration of intravenous 

adenosine (vertical dotted line), different effects are seen in different 

tachycardia. See text for details. * For sinus Pwave, ↓ for Pwave inscribed 

in T wave, • for Pwave of late RPPSVT and fl for flutter wave. 

diagnosis number 2) were the tachycardia either 

terminated or sustained, but not slowed down 

when treated with AV blocking agent. Besides, the 

atrial signal clearly has the classical saw-tooth 

appearance with the descending slope being slower 

than the ascending slope, which supports the 

presence of the typical atrial flutter wave (Fig. 2). 

The presence of high autonomic tones make the 

AV node less sensitive to AV blocking agent in 

particular in patients with decompensated heart 

function. The use of higher dose of beta-blocker 

should be made with caution since it might carry 

some paradoxical effect on the sympathetic tone 

through its hypotensive effect. When necessary, a 

very short acting drug can be used such as 

intravenous esmolol or adenosine with rapid ECG 

recording after the slowing phase of tachycardia. 

Effect of AV node blockade in different forms of 

tachycardia is illustrated in Fig. 3. 

During an electrophysiology study of this 

patient, an atrial flutter circuit was identified inside 

the right atrium, with counterclockwise movement 

down the free wall and up the septum, passing 

t h rough the narrow cavo-triuspid isthmus. 

Radiofrequency ablation with a linear lesion was 

performed at this area, which caused termination 

and cure of the atrial flutter. The patient was treated 

with amiodarone and small dose beta-blocker for 

many days before the ablation procedure. 

In conclusion, long RP s u p r a v e n t r i c u l a r 

t a c h y c a rdia can be missed as an inappro p r i a t e 

sinus tachycardia. When left untreated, it can cause 

further deterioration of left ventricular function [5] . 

Atrial flutter with fixed 2:1 ratio conduction to the 

ventricle might be overlooked because of 

simultaneous occurrence of the QRS complex and 

the second flutter wave. Rare forms of re-entrant 

t a c h y c a rdia can be manifested as long RP 

tachycardia due to late retrograde atrial activation. 

The use of short acting AV blocking agent and 

repeat electrocardiograms helps to make the precise 

diagnosis at bedside level. 

REFERENCES 

1. Josephson ME: Paroxysmal supraventricular tachycardia: 

an electrophysiologic approach. Am J Cardiol 1978; 41:1123- 

1126. 

2. Bar FW, Brugada P, Dassen WR, Wellens HJ: Differential 

diagnosis of tachycardia with narrow QRS complex. Am J 

Cardiol 1984; 54:555-560. 

3. Brugada P, Farre J, Green M. Observations in patients with 

supraventricular tachycardia having a P-R interval shorter 

than the R-P interval: diff e rentiation between atrial 

t a c h y c a rdia and re c i p rocating tachycardia using an 

accessory pathway with long conduction time. Am Heart J 

1984; 107:556. 

4. Waldo AL: Some observations concerning atrial flutter in 

man. PACE 1983; 6:1181. 

5. Shinebane JS, Wood MA. Ta c h y c a rdi-Induced Card i o m y o p a t h y : 

A review of animal models and clinical studies. J Am Coll 

Cardiol 1997; 29:709-15.


ABSTRACT 


Case Report 

Fatal Case of Systemic Salmonella Infection with Acute 

Renal Failure, Hemolytic-Uremic Syndrome and 

Rhabdomyolysis 

Ram Kumar Gupta, Narayanan Nampoory, Kaivilayil Varghese Johny 

Department of Medicine, Mubarak Al-Kabeer Hospital and Faculty of Medicine, Kuwait University, Kuwait 


Acute renal failure (ARF) is an uncommon complication 

of typhoid fever. Reports of hemolytic-uremic syndrome 

(HUS) or rhabdomyolysis producing ARF in systemic 

salmonellosis are scanty in the medical literature. We 

report a case of a systemic salmonella infection complicated 

by HUS, rhabdomyolysis and ARF with a fatal oucome. 

A 27 year old male was transferred to the nephrology 

service with oliguria and rapid deterioration of renal 

function. He showed features of HUS and rh a b d o m y o l y s i s . 

Blood and stool culture grew salmonella typhi. Ultrasound 

kidneys, CT brain, virological, immunological and 

cerebrospinal fluid studies showed normal findings. He 

was treated with ciprofloxacillin, cefuroxime, haemodialysis 

and supportive measures including ventilatory support. 

He died six days after admission. Delayed presentation, 

severity of bacteremia and toxemia could have 

contributed to HUS, rhabdomyolysis and fatal outcome 

in our patient. 

KEYWORDS: acute renal failure, hemolytic uremic syndrome, rhabdomyolysis, salmonella 

INTRODUCTION 

Enteric fever is seen world wide, but acute renal 

failure (ARF) in this setting is a relatively rare 

c o m p l i c a t i o n [ 1 ] . Reports of hemolytic-ure m i c 

syndrome (HUS) and rhabdomyolysis producing 

ARF in systemic salmonellosis are scanty in 

literature [2] . We report a case of fatal ARF in a 

patient with enteric fever. 

CASE REPORT 

A 27-year-old Indian gentleman, previously in 

good health presented to a general hospital with 

oliguria and rapid deterioration of renal function. 

He had come as a new recruit from India, just about 

a month ago. His illness had started a week earlier 

with watery diarrhea and high fever. He was 

t r a n s f e r red to the Nephrology service from a 

peripheral hospital where he received intravenous 

c r y s t a l l o y i dand colloid solutions. On admission, he 

was febrile (40 ºC) with generalized muscle 

tenderness. His blood pressure (120/70 mmHg) 

and pulse rate (100/m) were normal. He showed 

meningism without any neurological lateralizing 

signs. He did not have any skin rash and systemic 

examination including cardiovascular and re s p i r a t o r y 

systems were normal. Optic fundi showed normal 

findings. His condition deteriorated rapidly, 

becoming drowsy and hypoxemic and requiring 

ventilatory support. 

Laboratory investigations showed: leucopenia 

(3.2 x 10 9 

/l), thrombocytopenia (21 x 10 9 

/l) and 

normal hemoglobin (126 mgs/l). Repeated peripheral 

blood smear examination showed large number of 

fragmented erythrocytes suggesting micro a n g i o p a t h y 

(Fig. 1), reticulocyte count 2%, S. haptoglobulin 200 

mgs% and negative Coomb’s test. He had low 

serum fibrinogen (1.21 gm/l) and high D dimer 

(42000 ng/ml) but prothrombin time (PT = 11 

seconds), activated partial thromboplastin time 

(APTT = 30 seconds) and thrombin time (TT = 14 

seconds) were normal. He had myoglobinuria with 

no significant urinary sediments and urine was 

sterile on culture. Serum creatinine was 11 5 0 

µmols/l and blood urea was 50.5 mmol/l. Cre a t i n i n e 

phosphokinase (CPK 3800 U/l) and lactic 

dehydrogenase (LDH 430 U/l) had increased to 

58,000 U/Land 36,000 U/L respectively by day five 

and six. Serum bilirubin (40 mmols/L), GGT (9210 

U/l), AST (76 U/l) and ALT (86 U/l) were high 

(Table 1). CT brain and cerebrospinal fluid study 

showed normal findings. Blood and stool c u l t u re 

g rew Salmonella typhi sensitive to ceftriaxone. Viral 

studies for CMV, EBV, HSV, HBsAg, Hepatitis-A 

specific IgM and antihepatits-C antibody were 

negative. Immunological studies including serum 

complements C3, C4 were normal. ANA, anti-DNA 


Professor K V Johny, MD, FRCP, FACP, Chairman, Department of Medicine, Faculty of Medicine, P.O. Box 24923, Safat 13110, Kuwait.

230 

Fatal Case of Systemic Salmonella Infection with Acute Renal Failure, Hemolytic-Uremic ....September 2006 

Fig. 1: Peripheral smear showing fragmented red-blood-cells 

a n t i b o d y, A N C A and anticard i o l i p i nantibody were 

negative. Ultrasound showed normal sized kidneys 

with normal pelvicalyceal systems. 

The patient did not develop any cutaneous 

rashes and muscle swelling or tenderness. He was 

t reated with intravenous ciprofloxacin 750 mgs 

twice a day, cefuroxine 2 gms once a day, daily 

hemodialysis, fresh frozen plasma, ventilation and 

other supportive measures. He remained toxic, 

febrile, oliguric and unresponsive. He died six days 

after admission. 

DISCUSSION 

Even though there is a progressive decline in the 

incidence of typhoid fever, it continues to occur 

sporadically in this country, mainly in the e x p a t r i a t e 

work force. Overseas travel and existence o f 

reservoirs of long term carriers add to the 

occurrence of these cases. Unusual life threatening 

combination of typhoid hepatitis, rhabdomyolysis, 

HUS and ARF are rare in classical typhoid fever [1-3] . 

This prompted us to report this case. 

Haemolysis due to G6PD deficiency, chloramphenicol 

and septicemia have been reported to 

accompany enteric fever, with or without acute 

renal failure. Hemolytic uremic syndrome is a 

condition in which ARF is associated with 

microangiopathic hemolytic anaemia. Occurrence 

of HUS is frequent in Gram negative coliform 

enteric infections [4] . Endotoxin produced by these 

organisms are known to play a pathogenetic role in 

HUS [5] . Salmonella organisms producing HUS, even 

though rare are also reported [6-9] . It was proposed 

that salmonella endotoxin could cause glomerular 

m i c roangiopathy with renal intravascular coagulation, 

leading to features of red cell fragmentation and 

renal failure [10,11] . 

Rhabdomyolysis and myoglobulinemia can 

occur in severe septicaemia with high fever. Even 

though the exact pathogenesis is unclear, very high 

fever and severe septicemia with toxic state could 

have contributed to rhabdomyolysis in our patient 

Table 1: Relevant clinical and laboratory parameters 

Parameters Day 1 Day 3 Day 6 

Temperature (in ºCentigrade) 41 39 38 

Blood pressure in mm Hg 110/70 120/80 100/70 

Urine output - ml/24 hrs 160 cc 90 cc 50 cc 

WBC in 10 9 /l 3.2 3.9 4.2 

Hb in gms/l 126 118 120 

Platelets in 10 9 /l 36 30 20 

Blood Urea in mmol/l 69 60 43 

S. Creatinine in µmol/ 1190 950 880 

ALT/AST U/L 70/65 75/68 50/40 

Bilirubin T/D mol/l 40/23 60/29 45/25 

S. Alkaline Phosphatase U/l 130 126 116 

S. Albumin gms/l 26 30 32 

S. Creatinine Phosphokinase U/l 630 46,000 58,000 

S. Lactodehydrogenase U/l 420 31,000 36,000S 

Fibriogen mg/l 1.2 1.1 1.5 

D. Dimer ng/ml 6,000 12,000 42,000 

PT, APTT and TT were within normal limits 

[3, 7, 8] . Rhabdmyolysis and bacteremia also could 

have definitely contributed to the hypermetabolic 

state. Polymyositis was also considered as a 

probability but absence of cutaneous rashes and 

normal immunological parameters makes it 

unlikely. 

It is possible that HUS could have been the 

cause for ARF in our patient, but one cannot rule 

out combined insults from rhabdomyolysis and 

septicemia producing renal damage. Arenal biopsy 

would have given more information but could not 

be done since the patient was critically ill. 

Acute renal failure due to sepsis usually carries 

a higher mortality than ARF from other causes. 

P resence of added complications of HUS and 

rhabdomyolysis could have contributed to the 

unfortunate outcome in this patient. The patient 

was treated with daily hemodialysis and systemic 

alkalisation. Continuous renal replacement therapy 

(CRRT) in the form of continuous arteriovenous 

hemodiafiltration (CAVHDF) or continuous 

venovenous hemodiafiltration (CVVHDF) are known 

to markedly improve the prognosis and outcome in 

such critically ill patients with acute renal failure [12] . 

Hence, we recommend prompt introduction of 

CRRT along with antibiotics and other supportive 

measures in such critically ill patients. 

To conclude, this case indicates that salmonella 

infection can present with severe complications like 

HUS, rhabdomyolysis and A R F. Prompt active 

management should be instituted in the course of 

illness to prevent mortality in such cases. 

ACKNOWLEDGMENT 

We wish to express our sincere thanks to Mr 

George Varughese for the help rendered in the 

preparation of this manuscript.


REFERENCES 

1. Sion ML, Hatzitolios A, Toulis E. Rhabdomylysis and acute 

renal failure associated with salmonella enteritidisbacteremia. 

Nephrol Dia Transplant 1998; 13:532. 

2. Retornaz F, Fournier PE, Seux V. A case of salmonella 

enteritidis septicemia complicated by disseminated 

intravascular coagulation, severe hepatitis, rhabdomyolysis 

and acute renal failure. Eur J Clin Microbio Infect Dis 1999; 

18:830-831. 

3. Khan M, Coovadia Y, Sturm AW. Typhoid fever complicated 

by acute renal failure and hepatitis: Case reports and 

review. Am J Gastroenterol 1998; 93:1001-1003. 

4. Ornt DB, Griffin PM, Wells JG, Power KR. Hemolytic 

uremic syndrome due to Escherichia coli 0157: H7 in a child 

with multiple infections. Pediatr Nephrol 1992; 6:270-272. 

5. Ali Al-Baqali, Adel Ghuloom, Ahmed Al-Arrayed, Abdull 

Al Azmi, Durjoy K. Shome, Afaf Jamsheer, Hayat A l 

Mahroos, Srdjan Jelacic, Philip I. Tarr, Bernard S. Kaplan 

and Radha K. Dhiman. Hemolytic uremic syndrome in 

association with typhoid fever. Am Jour Kid Diseases 2003; 

41:709-713. 

6. Glover SC, Smith CC, Porter IA. Fatal salmonella-septicemia 


with disseminated intravascular coagulation and re n a l 

failure. J Med Microbiol 1982; 15:117-121. 

7. Srivastava RN, Moudgil A, Bagg A. Hemolytic uremic 

syndrome in children in northern India. Pediatr Nephrol 

1991; 5:284-288. 

8. Vergara de Campos A, GilCebrian J. Rhabdomyolysis and 

renal insufficiency as complication of acute gastroenteritis 

caused by salmonella enteritides. An Med Interna 1991; 

8:361. 

9. Abdulla AJ, Moorhead JF, Sweny P. Acute tubular necrosis 

due to rhabdomyolysis and pancreatitis associated with 

salmonella enteritidis food poisoning. Nephrol Dial 

Transplant 1993; 8:672-673. 

10. Fica A, Coarsi B, Piemonte P. Dysentric syndrome, acute 

renal failure and lethal septic shock associated to 

salmonella enteritidis infection. Report of 3 cases. Rev Med 

Chil 1997; 125:1055-1082. 

11. Shibusawa N, Arai T, Hashimoto K. Fatality due to severe 

salmonella enteritis associated with acute renal failure and 

septicemia. Inter Med 1997; 36: 674-675. 

12. Vab Bommel EFH, Leunissen KML, Weimar W. Continuous 

renal replacement therapy for critically ill patients: An 

Update. J Intensive Care Med 1994; 9: 265-280.

ABSTRACT 

We report a case of severe hyperkalemia as a result 

of treatment with potassium sparing diure t i c s , 

digoxin and angiotensin receptor antagonist valsartan 

in the presence of renal insufficiency. Inspite of a 

maximal serum potassium concentration of 10.3 


Case Report 

Profound Hyperkalemia and the Electrocardiogram. Lack of 

Correlation : A Case Report 

Tarek Abdel Hamed Mostafa Dowod, Jaffer Ismail Ali, Sajid Burud 

Department of Medicine, Al-Adan Hospital, Kuwait 

INTRODUCTION 

The effects of hyperkalemia on card i a c 

e l e c t rophysiology have been extensively investigated 

in humans and animals both in-vivo and in-vitro 

and are well described in several reviews [1-4] and 

medical textbooks [5-6] . 

The most serious consequence of hyperkalemia 

is slowing of electrical conduction in the heart. The 

ECG begins to change when serum potassium (SK) 

concentration reaches 6.0 mmol/l and it is nearly 

always abnormal when serum potassium reaches 

8.0 mmol/l [7] . 

The earliest change in the ECG is a tall tapering 

‘tented’ T wave that is most evident in precordial 

leads (V2-V3). Similar peaked T waves have been 

observed in metabolic acidosis. As the hyperkalemia 

progresses, the Pwave amplitude decreases and the 

PR interval lengthens. The P wave eventually 

disappears and the QRS duration prolongs. The 

final event is ventricular asystole [8] . 

Although it is generally recognized that the 

ECG is not a reliable indicator of moderate 

hyperkalemia (SK < 7.0 mmol/l); more severe 

elevations of serum potassium (SK > 8.0 mmol/l) 

almost invariably exhibits ECG abnormalities [9] . The 

ECG is often used by physicians to confirm the 

p resence of severe hyperkalemia and to guide 

therapeutic maneuvers in such instances. 

This report describes a case of severe 

hyperkalemia (SK > 10.3 mmol/l) in which ECG 

revealed none of the abnormalities classically 

associated with hyperkalemia. 


KEYWORDS: electrocardiogram (ECG), hyperkalemia 

mmol/l, only non-specific ECG changes were 

found. The patient survived after an uneventful 

dialysis. Thus severe hyperkalemia may present 

without typical ECG changes, and values 

exceeding 10.3 mmol/l may not necessarily be fatal. 

CASE REPORT 

A 56-years-old woman with a history of 

ischemic cardiomyopathy, coronary artery bypass 

graft, diabetes mellitus, hypertension and chronic 

renal insufficiency was admitted with one week 

history of general ill-health, anorexia, nausea, body 

aches and reduced exercise tolerance. 

The patient was taking insulin mixtard, modure t i c 

(hydrochlorothiazide 50 mg + amiloride 5 mg) once 

daily, spironolactone 25 mg twice daily, valsartan 

80 mg once daily, digoxin 0.125 mg once daily, 

atenolol 100 mg once daily and isosorbide 

mononitrate 40 mg twice daily. 

On examination: vital signs revealed a regular 

pulse rate of 93 bpm, blood pressure of 130/80 

mmHg, temperature of 36.8 ºC, a respiratory rate of 

14/min and oxygen saturation of 100% on room air 

by pulse oximetry. There was clinical evidence of 

mild dehydration; otherwise systemic examination 

was unremarkable. 

Investigation results were as follows: CBC: 

WBC = 7.8 X 10 9 /l, Hb = 11.2 g/dl, Platelets= 212 X 

10 9 /l. Biochemical profile: SNa = 135 mmol/l, SK = 

9.6 mmol/l, blood urea = 20.6 mmol/l, S creatinine 

= 229 mmol/l, S Mg = 0.83 mmol/l, S PO4 = 1.05 

mmol/l, SCl = 113.8 mmol/l, blood sugar = 9.2 

mmol/l, pH = 7.17, HCO3 = 11.7 mmol/l, base 

excess = -15.5 mmol/l, PO2 = 12.1 KPa and PCO2 = 

4.3 KPa. 

The blood sample was not hemolyzed and was 

obtained without mechanical difficulty or pro l o n g e d 

ischemia. Repeated determination of the S. 


Dr. Tarek Dowod, P. O. Box 47854, Fahaheel, Kuwait. Tel: +965-6052897, +965-3718245, E-mail: doriya70@hotmail.com


Fig 1: ECG of the patient obtained on admission when the serum 

potassium concentration was 9.6 mmol/l. Note that the T waves are not 

peaked, QRS complexes are of normal duration and that the Pwaves are 

also present. There are minor ST and T wave changes in I, II aVL, V3-V6. 

potassium concentration confirmed the initial 

value. 

Despite the severe hyperkalemia, the ECG (Fig. 

1) showed normal sinus rhythm, normal axis, PR = 

0.19 ms, QRS = 0.07 ms with normal P and QRS 

morphology and non-specific minor ST and T wave 

changes. 

Management: The patient was admitted to the 

ICU for close monitoring and management. She 

was given intravenous fluids, calcium gluconate, 

glucose-insulin infusion and sodium bicarbonate. 

The repeated S. potassium level continued to 

remain high (SK > 9.6 mmol/l); so another cycle of 

calcium gluconate, glucose-insulin infusion and 

sodium bicarbonate was administered with no 

effect; when the repeated S. potassium level was 

10.3 mmol/l, an emergency dialysis was ordered. 

Dialysis was performed for three hours without 

complications and after one session of dialysis, the 

patient recovered quickly and the S. potassium 

became normal (SK= 4.8 mmol/l). The blood urea 

and S. creatinine also returned to their usual baseline 

values (blood urea =11 mmol/l, S. creatinine = 140 

mmol/l). There were no enzyme changes suggestive 

of recent myocardial infarction. When the S. 

potassium was 4.8 mmol/l, a repeat ECG was 

unchanged from the one taken on admission. 

DISCUSSION 

Hyperkalemia in this case obviously developed 

due to progressive deterioration in renal function 

and was probably further accentuated by the 

potassium sparing diuretics, digoxin and valsartan 

therapy. 

In hyperkalemia of such severity, typical ECG 

changes have been documented [10-11] . In two human 

studies, volunteers who ingested large quantities of 

potassium salts developed the expected ECG 


a b n o r m a l i t i e s [ 1 2 - 1 3 ] [ 1 4 ] 

. In another human study, Thomson 

found that oral administration of potassium 

chloride or potassium citrate increased the height 

of the T waves in 15 out of 24 subjects but all 

individuals who developed S. potassium > 6.5 

mmol/l exhibited peaked T waves. When Dreifus 

and Pick [ 1 5 ] c o r related ECG and electro l y t e 

abnormalities, they found that while only half of 

the patients with S. potassium ≥ 5.6 mmol/l had 

associated ECG changes, all had such changes 

when the S. potassium exceeded 6.7 mmol/l. In 

contrast, Tarail [16] found that patients with renal 

i n s u fficiency did not consistently have ECG 

changes typical of hyperkalemia until the S. 

potassium concentration exceeded 7.6 mmol/l. 

Laboratory errors could possibly have explained 

one of the high potassium values. However, 

persistent elevated values with a consistent time 

pattern were obtained, with no indication of 

hemolysis in the plasma samples. Hyperkalemia, 

although less pronounced, without ECG changes 

have been reported in diabetics on amiloride, 

Addison patients and in those on triametrene [17] . 

There is no explanation for the lack of ECG 

changes correlated with the severe hyperkalemia. 

P e rhaps, if the S. potassium rises suff i c i e n t l y 

slowly, the myocardial transmembrane potential is 

maintained by other compensatory changes. In this 

regard, there is some evidence that the rate of 

change in S. potassium concentration rather than 

the final value achieved is more important in 

producing cardio-toxicity [18] . This may explain the 

observation that patients with chronic renal failure 

appears to tolerate higher levels of S. potassium 

than patients without chronic renal failure and this 

may be related to the lack of ECG changes as seen 

in our case. 

I n c rease in S. calcium concentration may 

minimize the effect of hyperkalemia on the heart [2-4] . 

In our case, the S. calcium level was normal. 

However since the ionized calcium level was not 

m e a s u red and the patient was acidemic this 

possibility cannot be excluded. Two additional 

explanations can also be proposed. Increased S. 

sodium concentration can also abolish the ECG 

e ffects of an elevated S. potassium level [ 2 - 4 ] . 

Therefore, the elevated S. sodium level might have 

counteracted the ECG changes of hyperkalemia; 

however this is not the case in our patient as the S. 

sodium level was normal. Finally, patients may 

have had ECG changes suggestive of myocardial 

damage which might have obscured changes 

typical of hyperkalemia. Whatever the explanation, 

this case underscores the lack of corre l a t i o n 

between ECG changes and profound hyperkalemia.

234 

Profound Hyperkalemia and the Electrocardiogram. Lack of Correlation : A Case Report September 2006 

CONCLUSION 

An ECG without typical findings of hyperkalemia 

does not exclude the presence of significant 

hyperkalemia and the ECG may not re l i a b l y 

monitor changes in the S. potassium concentration. 

REFERENCES 

1. Surawicz B. Role of electrolytes in etiology and 

management of cardiac arrhythmias. Prog Cardiovasc Dis 

1966; 8:364-386. 

2. Surawicz B. Relationship between electrocardiogram and 

electrolytes. Am Heart J 1967; 73:814-836. 

3. Fisch C. Relation of electrolyte disturbances to cardiac 

arrhythmias. Circulation 1973; 47:408-419. 

4. Ettinger PO, Regan TS, Oldewurtel HA. Hyperkalemia, 

cardiac conduction and the electrocardiogram: Overview. 

Am Heart J 1974; 88:360-371. 

5. Cohen JJ, Gennari FJ, Harrington JT: Disorders of potassium 

balance. In: Brenner BM, Rector FC, editors. The kidney. 

Philadelphia: Saunders; 1981, p 908-939. 

6. Fisch C. Electrolytes and the heart, In: Hurst JW, editor. The 

Heart, Arteries and Veins. New York: McGraw-Hill; 1982, p 

1599-1612. 

7. Williams ME, Rosa RM. Hyperkalemia disorders of internal 

and external potassium balance. J Intensive care Med 1988; 

3:52-64. 

8. Dreyfuss D, Jondeau G, Couturier R, et al. Tall T waves 

during metabolic acidosis without hyperkalemia. 

Prospective study. Crit Care Med 1989; 17:404-408. 

9. Yap V, Patel A, Thomson J. Hyperkalemia with cardiac 

arrhythmia. Introduction by salt substitutes, spironolactone 

and azotemia. JAMA1976; 236:2775-2776. 

10. Pongpaew C, Songkhla RN, Kozam RL. Hyperkalemic 

cardiac arrhythmias secondary to spironolactone. Chest 

1973; 63:1023-1025. 

11. Feinfeld DA, Carvounis CP. Fatal hyperkalemia and 

hyperchloremic acidosis. Association with spironolactone 

in the absence of renal impairement. JAMA1978; 240:1516. 

12. Keith NM, Osterberg AE, Burchell HB. Some effects of 

potassium salts in man. Ann Intern Med 1942; 16:879-892. 

13. Keith NM, Osterberg AE. Human tolerance for potassium. 

Mayo Clin Proc 1946; 21:385-392. 

14. Thomson WAR. The effect of potassium on the heart in 

man. Br Heart J 1939; 1:269-282. 

15. Dreifus LS, Pick A. A clinical correlative study of the 

e l e c t ro c a rdiogram in electrolyte imbalance. Circ u l a t i o n 

1956;14:815-825. 

16. Tarail R. Relationship of abnormalities in concentration of 

serum potassium to electrocardiographic disturbances. Am 

J Med 1948; 5:828-837. 

17. McNay JL, Oran E. Possible predisposition of diabetic 

patients to hyperkalemia following administration of 

potassium retaining diuretic, Amiloride (MK 870). 

Metabolism 1970; 19:58-70. 

18. Harold M, Szerlip MD, James Weiss MD, Irwin Singer MD. 

P rofound hyperkalemia without electro c a rd i o g r a p h i c 

manifestations. Am J Kid Dis 1986; 461-465.


ABSTRACT 

Burned-out germ cell tumor of the testis is a rare entity 

which, with its metastatic spread often mimics other 

conditions such as lymphoma. Scrotal sonography is 


Case Report 

Burned-out Testicular Germ Cell Tumor Mimicking 

Lymphoma 

Abrar Hayat, Kamaldine Oudjhane 

Department of Diagnostic Imaging, Montreal Children’s Hospital, McGrill University Health Centre, Montreal, QC, Canada 


pivotal in the initial diagnosis of such a neoplasm with 

extragonadal metastases. 

KEYWORDS: burned-out tumor, germ cell tumor, sonography, testis 

INTRODUCTION 

Germ cell tumors constitute the large majority of 

all testicular tumors, which overall are relatively 

rare, and are mainly encountered in young adults 

and teenagers [ 1 ] . The “burned-out” form of germ cell 

tumor refers to the situation in which widespread 

metastases are on the clinical frontline whereas the 

primary neoplasm has involuted [2] . Its mode of 

presentation may simulate other neoplasms [3,4] . We 

report such an example for which a systematic 

scrotal sonography rectified the initial erroneous 

diagnosis of lymphoma. 

Case Report 

A 1 7 - y e a r-old boy was transferred to our 

institution for staging / work-up of Hodgkin’s 

lymphoma. He presented one month earlier to his 

physician with complaints of right-sided abdominal 

pain, back pain, night sweats, fever, fatigue, 

anorexia and weight loss of eight pounds over one 

month. A sonographic examination at the local 

hospital revealed re t roperitoneal lymphadenopathy. 

There was no significant past medical history apart 

from smoking since twelve years of age. 

On clinical examination, he was found to be 

short of breath, with inspiratory and expiratory 

wheezing, extensive non-tender cervical lymphadenopathy 

and hepatosplenomegaly. Examination of the 

scrotum revealed no abnormalities. The WBC count 

was 14.3 x 10 9 /l (normal: 4.5-13.0 x 10 9 /l), with 11% 

n e u t rophils and 86% monocytes. ESR was 37 

mm/hr (normal: 3 -13). Electrolytes were normal. 

A bone marrow aspirate showed no evidence of 

malignant cells. Abdominal sonography showed 

enlarged prevertebral soft tissue masses (Fig. 1). CT 

of the chest / abdomen / pelvis showed extensive left 

s u p r a c l a v i c u l , a mediastinal r lymph node enlarg e m e n t . 

R e t roperitoneal lymphadenopathy involved the 

i n t e r-aortocaval chain and the left para aortic 

nodes, some of which had a hypodense centre (Fig. 2). 

As part of the search for a primary malignancy 

a scrotal sonogram was done and it demonstrated 

no testicular enlargement, but a focus of coarse 

calcification (0.3 cm) with no associated obvious 

mass in the left testis (Fig. 3). The clinical working 

diagnosis was burned-out testicular primary tumor 

with metastatic spread. Bone scan was normal and 

the Lactate Dehydrogenase (LDH) level was 

elevated (1,089 IU/l; normal: 105-333 IU/l). A 

Gallium scan showed focal increased uptake at the 

left supraclavicular area (Fig. 4). The serum alphafetoprotein 

level was normal but the beta HCG 

level was elevated (293 IU/l; normal: 0-4 IU/l). 

At surg e r y, a radical left orchidectomy was 

performed along with a left cervical lymph node 

b i o p s y. Testicular histology specimen re v e a l e d 

diffuse intratubular germ cell neoplasia including 

focal intratubular seminoma and focal extratubular 

extension, foci of mature teratoma components as 

well as foci of regressed (burned-out) germ cell 

lesion with fibrosis and dystrophic calcification. 

The left cervical lymph node showed a metastatic 

malignant mixed germ cell tumor with pre d o m i n a n t 

embryonal cell carcinoma and focal choriocarc i n o m a . 

The therapy of this stage three malignant mixed 

germ cell tumor included a left orchidectomy and a 


Abrar Hayat MD, FRCPSC. Department of Clinical Radiology, Al-Sabah Hospital, P.O.Box: 4078, 13041 Safat, Kuwait. Tel: (965) 4812417, 

9731994, E-mail:abyat@yahoo.com

236 

Burned-out Testicular Germ Cell Tumor Mimicking Lymphoma September 2006 

Fig. 1: Abdominal sonography showing a cluster of enlarged lymph 

nodes in the prevertebral region (between cursors) 

Fig 3: Left scrotum sonography: focal calcification (boxed) with acoustic 

shadowing in the lower pole of the left testicle 

chemotherapy regimen of bleomycin, etoposide, 

amifostine and cisplatin followed by extensive 

intra-abdominal lymph node resection. The 

histology specimen of the latter showed similar 

pathology to the specimen of the left cervical lymph 

node. 

DISCUSSION 

Clinical presentation of a burned-out tumor of 

the testis is often due to its metastatic spread to 

cervical, axillary, supraclavicular lymph nodes as 

well as to the mediastinum and retroperitoneum. 

CT and MRI are optimal for assessing the extent of 

the disease. The clinical impression is of a process 

such as lymphoma or even a rhabdomyosarcoma, 

besides the possibility of germ cell tumor. 

Extragonadal germ cell tumors are only about 5% 

of all germ cell tumors [5] . Metastases from a gonadal 

primary tumor are highly likely. It is known that 

palpation of the testicles is not very sensitive at 

detecting small testicular masses. The burned-out 

tumor is hence an occult gonadal germ cell 

neoplasm with primary metastases. Two pathologic 

types are described. The first variety includes 

Fig. 2: Abdominal CT Scan at the lumbar level demonstrating 

lymphadenopathy (N) adjacent to the major vessels, with central 

hypodensity in some lymph nodes (arrow). (A = Aorta, C = Cava or 

inferior vena cava, L= Left, R = Right) 

Fig 4: Gallium scan showing increased uptake at the left supraclavicular 

area (arrow) 

testicular atrophy, and small intratesticular scars 

with no histologic sign of neoplasm. The scar has, 

however, some stigmata of neoplastic origin such as 

the presence of hematoxyphilic bodies, hemosiderin 

pigmentation and calcium phosphate deposits [6] . 

The second form is the in situ testicular tumor with 

intratubular localization of the neoplasm. Chemotherapy 

may not be as effective because of the blood-testis 

b a r r i e r, which is incriminated in the possible 

recurrence of local tumor [5] or the metachronous 

contralateral involvement [ 4 ] . The non-seminoma 

component has the highest risk of regression of the 

primary neoplasm [2] . The mechanism of regression 

of the tumor is yet to be elucidated. However, 

immune response, versus ischemia mechanism due 

to a high metabolic rate of the neoplasm outgro w i n g 

its blood supply has been implicated [7] . 

High resolution sonography of the scrotum with 

linear high frequency transducers allows the 

detection of small highly echogenic foci, hypoechoic 

zones, microlithiasis or macrocalcifications as in 

our patient [3-5,8] . The hyperechogenic foci are related 

to non-tumoral lesions such as hemorrh a g e ,


infarction or fibrotic scar. The slightly echogenic 

areas may correspond to the tumor itself. Testicular 

microlithiasis has been associated with testicular 

germ cell neoplasm or intratubular germ cell 

neoplasia but the clinical significance and 

malignant potential of microlithiasis are still under 

investigation [9] . 

Multiple histologic types are often found 

t o g e t h e r, as a mixed germ cell tumor, because 

besides the seminoma component, totipotential 

cells can develop along several pathways, either in 

u n d i ff e rentiated embryonal carcinoma or in 

d i ff e rentiated embryonic teratoma or extraembryonic 

c h o r i o c a rcinoma. Metastatic spread pathway is 

mainly lymphatic except for choriocarc i n o m a 

which favors a hematogenous pattern. This 

explains why histologic characteristics of metastases 

can be diff e rent from features of the primary 

neoplasm [1,7] . 

In summary, in the work up of a male patient 

presenting with widespread lymphadenopathy, it is 

mandatory to perform a testicular ultrasound 

examination, despite a normal physical examination 

of the scrotum. The sonographic detection of a 

primary testicular tumor is crucial for the 

therapeutic and prognostic parameters. 


REFERENCES 

1. Woodward PJ, Sohaye R, O’Donoghue MJ, Green DE. 

Tumors and tumor like lesions of the testis: radiologicpathologic 

correlation. Radiographics 2002; 22: 189-216. 

2. Comiter CV, Renshaw AA, Benson CB, Loughlin KR. 

Burned-out primary testicular cancer: sonographic and 

pathological characteristics. J Urol 1996; 156: 85-88. 

3. Kebapci M, Can C, Isiksoy S, Aslan O, Oner U. Burned-out 

tumor of the testis presenting as supraclavicular lymphadenopathy. 

Eur Radiol 2002; 12:371-373. 

4. Tasu JP, Faye N, Eschwege P, Rocher L, Blery M . Imaging of 

burned-out testis tumor. J Ultrasound Med 2003; 22:515-521. 

5. Choyke PL, Hayes WS, Sesterhenn IA. Primary extragonadal 

germ cell tumors of the retroperitoneum: differentiation of 

primary and secondary tumors. Radiographics 1993; 

13:1365-1375. 

6. A z z o p a rdi JG, Mostofi F, Theiss E. Lesions of testes 

observed in certain patients with widespread choriocarcinoma 

and related tumors : the significance of hematoxylin 

-staining bodies in the human testes. Am J Pathol 1961; 

38:207-225. 

7. Ulbright TM, Amin MB, Young RH. Tumors of the testis 

,adnexa, spermatic cord, and scrotum. In: Atlas of Tumor 

Pathology, Fasc 25, ser 3. Washington, DC: Armed Forces 

Institute of Pathology, 1999; 1: 1-290. 

8. Van Dijk R, Hitge-Boetes C, Debruyne FM, Rosensbusch G. 

Sonographic detection of a non palpable regressed germcell 

tumor in an atrophic testis. J Clin Ultrasound 1989; 

17:594-597. 

9. Kim B, Winter TC, Ryu JA. Testicular microlithiasis: clinical 

significance and review of the literature . Eur Radiol 2003; 

13:2567-2576.

ABSTRACT 

We present a case of congenital bronchial atresia and 

discuss the imaging features with special reference to 


Case Report 

Congenital Bronchial Atresia: CT- 3D Image Reconstruction 

and Virtual Navigation 

Shefeek Abubacker, Yousef Al Khulaifi, Jagadesh N Shenoy 

Department of Clinical Radiology, Al Sabah Hospital, Kuwait 


new imaging modalities like spiral CT and image post 

p rocessing-3 D image re c o n s t ruction and virtual navigation. 

KEYWORDS: congenital bronchial atresia, spiral CT, 3D image, virtual navigation 

INTRODUCTION 

Congenital Bronchial Atresia (CBA) is a rare 

congenital anomaly of the lung first described by 

Falor and Kyriakides in 1949 [1] . It results from a 

congenital focal obliteration of a pro x i m a l 

segmental/sub-segmental bronchus with normal 

development of distal structures. The bronchus 

distal to the stenosis becomes filled with mucous 

resulting in a “bronchocele”. The alveoli to be 

supplied by these obstructed bronchi are ventilated 

by a collateral air draft resulting in air trapping and 

focal hyperinflation around the bronchocele [2] . This 

abnormality is found as an incidental finding in 

a p p roximately 50% of such cases - mostly in 

asymptomatic young men. 

The diagnostic imaging modalities include Xray 

chest, Spiral CT and image post processing - 3D 

and virtual navigation. Though the chest radiograph 

can be highly suggestive of bronchial atresia other 

modern imaging techniques like spiral CT, 3D image 

reconstruction and virtual navigation can provide 

confirmative diagnostic criteria for CBA w i t h 

exclusion of secondary causes for bronchial atresia. 

Our experience with these imaging modalities is 

discussed with review of the relevant literature. To 

the best of our knowledge this is the first case 

report of CBA from this region demonstrated by 

virtual navigation. 

Case Presentation 

A 25-year-old asymptomatic man was referred 

to the Radiology department for assessment of a 

branched tubular shadow in the left upper lobe 

seen on the chest radiograph during pre - 

employment evaluation (Fig. 1A and 1B). The 

p resumptive diagnosis was a “vascular malformation” 

Vs. a ‘’bronchocele’’. The patient was taken up for a 

Dynamic contrast enhanced spiral CT of the chest. 

The CT (oblique sagittal reformation) re v e a l e d 

hyperinflation in the left upper lobe and a branched 

“non-enhancing” tubular structure in the left hilum 

extending into the left upper lobe, which did not 

satisfy the criteria of a vascular malformation (Fig. 

2). The chest radiograph was reviewed again, which 

revealed definite surro u n d i n g hyperinflation. Post 

p rocessing of the CT data was done with 3D 

re c o n s t ruction which revealed left upper lobe 

hyperinflation and a dilated bro n c h o c e l e(Fig. 3) in 

the left upper lobe. Spiral CT data did not reveal 

any endobronchial growth proximal to the dilated 

bronchocele. Virtual navigation through the left 

hemithorax revealed the ectatic bronchocele (Fig. 4). 

The final radiologic imaging criteria are 

diagnostic of a “Congenital (Primary) Bronchial 

Atresia” involving the left upper lobe. 

DISCUSSION 

Bronchial atresia is the second most common 

congenital malformation of the tracheo-bronchial 

tree [3] . The left upper lobe is involved in 64% of 

cases, the left lower lobe in 14% and the right 

middle and lower lobes in 8% of cases [4] . It usually 

involves a single lung segment although multiple 

lung segment involvement has been reported [5] . In 

utero, the bronchial development of the lung occurs 

during 4 to 15 weeks of gestation [6] . A vascular 

insult during this time interval disrupts the normal 

development resulting in an atretic segment. Our 

patient had the bronchocele located in the most 

common site - the left upper lobe. 

Most patients are asymptomatic at the time of 

diagnosis. However, cases can present with 


Dr Shefeek Abubacker, P.O.Box 43470, Hawally 32049, Kuwait. Tel: 5326860, 7830991(M), E-mail: Shefeek_radiol@hotmail.com


Fig. 1A: CXR PA and LATERAL views reveals a branched tubular 

s t ru c t u re (arrows) in the left upper lobe. Note the surro u n d i n g 

hyperinflation in the left upper lobe. 

Fig. 2: SPIRALCT of the chest with oblique sagittal reconstruction shows 

a branched tubular structure (arrows in A, B and C) with no enhancement 

(#). Note the surrounding hyperinflation (*). 

dyspnoea, pneumonia and bronchial asthma [5] . Our 

patient was a young man who had this incidental 

shadow picked up on his chest radiograph during 

his job processing formalities. 

Imaging plays a very important role in establishing 

the diagnosis of CBA. The “chest radiograph” 

typically shows the bronchocele as a ro u n d e d 

branching structure emanating from the hilum and 

the adjacent lung with features of air trapping seen 

as an area of hypertranslucency around the affected 

bronchi [7] . This is virtually pathognomonic of CBA 

and should suggest the diagnosis on the plain CXR. 

Our case showed a branched tubular structure with 

evidence of air trapping (on retrospective analysis). 

“CT” is a very sensitive method for demonstrating 

the typical features of CBA. The v i r t u a l l y 

pathognomonic feature is that of branching nonenhancing 

tubular stru c t u re re p resenting the 

bronchocele. This is characteristically surrounded by 

h y p e r t r a n s l u c e n c yrepresenting air trapping [8] . Our 

case demonstrated both these features. The impro v e d 

spatial resolution helps to distinguish the bro n c h o c e l e 

f rom intrapulmonary vascular malformation, 

which will show definite “branching enhancement” 

on dynamic imaging [8] . The high resolution CT 


Fig. 1B: 

images also help to identify a pro x i m a l 

e n d o b ronchial growth resulting in a secondary 

bronchocele, which was not seen in our case. “Data 

analysis” - 3D re c o n s t ruction of the lung and 

virtual navigation gives the cardio-thoracic surgeon 

a clear-cut idea of the segment involved and how to 

plan the surgical approach. The images of 3D 

re c o n s t ruction of the affected lobe and virtual 

navigation in our case speak for themselves. 

“Magnetic Resonance Imaging” does not have a 

definite role [9] . It displays the bronchocele as a 

branching stru c t u re radiating from the hilum 

which is hyperintense on T1 + T2 weighted images. 

The disadvantage of MRI is that it is not able to 

define the surrounding hypertranslucency that is 

clearly seen on CT. 

B ronchoceles are not only seen in primary 

congenital atresia but are also seen secondary to 

p roximal bronchial obstruction - like an endobro n c h i a l 

g rowth. With high resolution Spiral CT these 

endobronchial growths can be easily depicted. In 

doubtful cases, it is necessary to perform a fiber 

optic bronchoscopy (FOB). In CBA, the FOB is 

usually normal or it may reveal blind ending 

bronchi [3] . Bronchography has virtually no role in 

the present diagnostic scenario [5] . Bronchoceles may 

also be associated with A l l e rgic Broncho - Pulmonary

240 

Congenital Bronchial Atresia: CT- 3D Image Reconstruction and Virtual Navigation September 2006 

Fig. 3: 3D RECONSTRUCTION of the lung reveals the dilated 

bronchocele (arrows) with the surrounding hyperinflation (*). 

Aspergillosis (ABPA) complicating asthma [10] . ABPA 

can be confirmed by immunological tests and is not 

localized to a lung segment [5] . Other differential 

diagnosis to be considered here include vascular 

anomalies, intra-lobar sequestration and bronchial 

cysts. Vascular anomalies on dynamic spiral CT 

assessment present as an “enhancing tubular 

structure. Intralobar sequestration and bronchial 

cysts are very rarely associated with surrounding 

hyperaeration around the mass [9] . 

The pathological diagnosis is based on gross 

morphological analysis of the resected lung. A 

proximal blind ending bronchus with associated 

dilated distal segmental bronchi that is encased by 

hyperinflated lung parenchyma is diagnostic [ 5 ] . 

Hyperinflated lung parenchyma is based on the 

reduction of number of alveoli and the macroscopic 

absence of anthracotic pigment within the affected 

alveoli [3] . In some cases the connection between the 

bronchocele and the proximal atretic segment is not 

visualized. In such cases the dilated bronchocele 

can be erroneously diagnosed for a bronchogenic 

cyst histologically. However, it is the presence of 

hyperinflated, non-anthracotic lung pare n c h y m a 

encompassing the bronchial cyst that should point 

to CBA. 

In asymptomatic patients, no surgical intervention 

is required. In patients with repeated episodes of 

Fig. 4: VIRTUAL NAVIGATION through the left hemithorax reveals the 

dilated bronchocele. 

chest infection (especially in children), the surgical 

option - resection of the affected lung segment is to 

be considered [3] . Our patient is asymptomatic and 

needs follow-up to see the clinical course. 

CONCLUSION 

A branched non-enhancing tubular stru c t u re 

with surrounding hyperinflation in the left upper 

lobe is virtually diagnostic of CBA. Modern imaging 

techniques like spiral CT with 3D reconstruction 

and virtual navigation help in picking up the 

s u r rounding hyperinflation which is pathognomonic 

and gives the physician and thoracic surgeon a 

good 3D view of the pathological lesion for 

definitive therapy. 

REFERENCES 

1). Falor WH, Kyriakides AH. Ectopia bronchi. J Thorac 

Cardiovasc Surg 1949; 18:252-260. 

2). Culiner TS, Grimes OF. Localised emphysema in association 

with bronchial cysts of mucocele. J Thoracic Cardiovasc 

Surg 1961; 41:306-313. 

3). Remy- Jardin M, Remy J, Ribet M, et al. Bronchial atresia: 

diagnostic criteria and embryologic considerations. Diagn 

Interv Radiol 1989; 1:45-51. 

4). Kinsella D, Sissons G, Williams MP. The radiological 

imaging of bronchial atresia. Br J Radiol 1992; 65:681-685. 

5). Jederlinc PJ, Sicilian L, Baigelman W, et al. Congenital 

Bronchial Atresia - A report of 4 cases and review of 

literature. Medicine 1986; 65:73-83. 

6). Bucher U, Reid L. Development of intrasegmental bronchial 

tree: The pattern of branching and the development of 

cartilage at various stages of life. Thorax 1961; 16:207-218. 

7). Haller JA, Tepas JJ, White JJ, et al. The natural history of 

bronchial atresia. J Thoracic Cardiovasc Surg 1980; 79:868- 

872. 

8). Beigelman C, Howarth NR, Chartrand-Lefebvre C, et al. 

Congenital anomalies of tracheobronchial branching 

patterns: Spiral CT aspects in adults. Eur Radiol 1998; 8:79- 

85. 

9). Kos F, Lee TY, Kao CL, et al. Bronchial atresia associated 

with epibronchial right pulmonary artery and aberrant 

right middle lobe artery. Br J Radiol 1998; 71:217-220. 

10). Felson B. Mucoid impaction (inspissated secretions) in 

segmental bronchial obstruction. Radiology 1979; 133:9-16.


ABSTRACT 

Superior mesenteric artery (SMA) syndrome is caused by 

the compression of the third part of the duodenum 

leading to upper intestinal obstruction which is 

aggravated when the patient is lying in the supine 

position. Predisposing factors include rapid weight loss, 

application of a body cast after spinal surgery, prolonged 

recumbency, and abnormal position of the ligament of 


Case Report 

Superior Mesenteric Artery Syndrome: An Uncommon 

Cause of Intestinal Obstruction ; 

Report of Two Cases and Review of Literature 

Naheda H Jawad 1 , Abdulla Al-Sanae 1 , Wafa’a Al-Qabandi 2 


Treitz. Diagnosis may be difficult but can be confirmed 

by upper gastrointestinal contrast studies. Treatment is 

mainly conservative and if failed, surgical intervention is 

warranted. We report two children who were diagnosed 

with SMA syndrome and discuss the clinical picture, 

ways of diagnosis and methods of treatment. 

KEYWORDS: aortomesenteric angle, duodenojejunostomy, intestinal obstruction, nasojejunal tube, superior mesenteric artery 

INTRODUCTION 

Superior mesenteric artery (SMA) syndrome is 

an uncommon but well recognized clinical entity. It 

is caused by the compression of the third part of the 

duodenum between the superior mesenteric artery 

and the aorta causing upper gastrointestinal tract 

obstruction. 

In the following, we report two children who 

were diagnosed with SMA syndrome and discuss 

the predisposing factors, diagnosis and modalities 

of treatment. 

Case No. 1: 

An 11-year-old girl was diagnosed 18 months 

earlier with multiple sclerosis of the relapsingprogressive 

type. She had suffered from frequent 

relapses, nearly once per month, which resulted in 

significant physical disability. She presented with 

history of abdominal distension, nausea and 

voluminous greenish vomiting. On examination: 

she was completely bed-ridden and unable to sit or 

stand without support. She also had right facial 

palsy and bulbar palsy, which manifested by 

drooling, inability to swallow and slurred nasal 

speech. She was noticed to have a weight loss of 

seven kilograms within a four-week period. In 

addition, she had squint, intention tre m o r s 

indicating cerebellar involvement, and was 

incontinent to both urine and stool. Examination of 

1 Department of Pediatrics, Al-Amiri Hospital, Kuwait 

2 Department of Pediatrics, Faculty of Medicine, Kuwait 

the abdomen revealed distension in the epigastric 

area with succusion splash. A nasogastric tube was 

inserted and 1700 ml of greenish gastric aspirate 

was removed. A plain abdominal X-ray showed 

aeric distension of stomach and pro x i m a l 

duodenum with paucity of distal bowel gas (Fig. 1). 

An upper gastrointestinal contrast series showed a 

hugely dilated stomach, dilatation of the first and 

second parts of the duodenum, with an abrupt 

vertical cutoff of the barium flow at the level of the 

third part of the duodenum with normal mucosal 

folds (Fig. 2). These findings were highly 

suggestive of SMA s y n d rome. The diagnosis was 

confirmed by performing a spiral-computed 

tomography with angiography (CTA), which 

showed a sharp narrow angle of 15º between the 

aorta and the SMA (Fig. 3). A nasojejunal tube to 

feed the patient was inserted beyond the site of the 

o b s t ruction under fluoroscopic contro l ; 

unfortunately the patient pulled it out twice. 

T h e re f o re, a Hickman central line was placed 

t h rough which she received total pare n t e r a l 

nutrition (TPN). After six months from starting her 

on TPN, her weight increased by 10 kg, from 23 to 

33 kg and she was able to tolerate small amounts of 

nasogastric tube feeds which were gradually 

i n c reased and included high caloric n u t r i t i o n a l 

supplement Pediasure (Abbott Laboratories). Since she 

was still unable to chew and swallow properly, a 


Dr. Naheda H. Jawad, PO Box 28358, Safat13144, Kuwait. Tel: (965) 2464728, Pager: 9174332, Res: 2517480, E-mail: naheda@consultant.com

242 

Superior Mesenteric Artery Syndrome: An Uncommon cause of Intestinal ..... September 2006 

Fig. 1: A plain abdominal X-ray showing distension of stomach and 

proximal duodenum with paucity of distal bowel gas. 

gastrostomy tube was fixed to prevent recurrence. 

She was discharged home after staying in hospital 

for seven months. The gastrostomy tube was 

removed one year later when her facial and bulbar 

palsy improved and she continued to maintain her 

weight within the normal range, with no recurrence 

of symptoms. 

Case No. 2: 

A 12-year-old girl was admitted complaining of 

epigastric pain of one month duration. The pain 

was marked after food intake, lasting for 4-6 hours, 

relieved by vomiting and usually it contained 

undigested food. This was associated with decre a s e d 

appetite and a loss of weight of about four 

kilograms since the onset of her symptoms. On 

examination: the girl was tall and thin (her height 

was on the 90 th percentile while her weight was just 

below the 25 th percentile) with a body mass index 

(BMI) of 13.6. Examination of the abdomen showed 

no significant abnormality. Barium meal and follow 

through showed a markedly elongated stomach, 

moderate dilatation of the duodenal loop with an 

abrupt cutoff of the flow of barium at the site of the 

t h i rd part of the duodenum. This obstru c t i o n 

i m p roved in the prone position. There was 

significant delayed-emptying of the stomach; after 

Fig. 2: An upper gastrointestinal contrast study showing a hugely dilated 

stomach, dilatation of the first and second parts of duodenum with an 

abrupt vertical cutoff of barium flow at the level of third part of 

duodenum. 

five hours at least 50% of the barium was still in the 

stomach. After 20 hours, barium was located in the 

cecum, sigmoid colon, and rectum. An endoscopy 

showed retained fluid in the stomach, which was 

dilated with an extrinsic pressure at the third part 

of the duodenum precluding the passage of the 

scope. A biopsy was taken from that part of the 

duodenum and it showed normal histology. She 

was diagnosed as having SMA syndrome and was 

treated conservatively with cisapride (0.2 mg/kg), 

which was prescribed as a prokinetic agent. She 

was advised to lie on her left side after meals to 

enhance emptying of the stomach. She improved 

slowly with relief of symptoms allowing her to be 

d i s c h a rged from the hospital. She re m a i n e d 

symptom free when she was seen during follow-up 

two years from the onset of her symptoms. 

DISCUSSION 

Superior mesenteric artery syndrome was first 

described in 1861 by Von Rokitansky [1] and since 

then more than 400 cases have been re p o r t e d 

worldwide making it an uncommon but well 

recognized clinical entity. Although there is no 

precise incidence, there are reports that from 0.013-


Fig. 3:A spiral-computed tomography with angiography showing a sharp 

narrow angle (arrow) between the aorta and the superior mesenteric 

artery. 

0.3% of barium studies of the upper gastrointestinal 

tract have shown changes to support the diagnosis [ 2 ] . It 

usually affects young females from 10-39 years of 

age [3] and in one study in children the mean age was 

13 years (10-16 years) [4] . The pathophysiology of 

this disorder relates to the angle between the SMA 

and the abdominal aorta at the level of the first 

lumbar vertebra. It is caused by trapping of the 

third part of the duodenum as it crosses between 

the SMA anteriorly and the aorta and vertebral 

column posteriorly. The normal angle between the 

SMAand the abdominal aorta is approximately 45º 

(range 38-56º) in standing position. Any factor that 

sharply narrows this angle to between 6-16º results 

in a vascular, extrinsic compression of the duodenum 

as it passes between the SMA and the aorta [5] . 

Although the exact aetiology is not known, 

certain predisposing conditions are well recognized: 

(1) Diseases associated with rapid severe weight 

loss with decrease in the re t roperitoneal and 

mesenteric fat such as anorexia nervosa [ 6 ] , 

malabsorption syndrome, increased catabolic states 

as in cancer and burns. 

(2) Neurological disorders causing dystonic 

denervation of the abdominal wall and spinal 


muscles such as acute trauma to the spine [ 7 ] , 

patients who had spinal surgery, the use of a body 

cast in the treatment of scoliosis or vertebral 

f r a c t u res, traumatic brain injury, spastic quadriplegia, 

and prolonged recumbency [8,9] . 

(3) Anatomical anomalies such as abnormally 

high and fixed position of the ligament of Treitz, or 

an unusually low origin of the superior mesenteric 

artery [10] . 

(4) Constitutional factors such as tall thin body 

build which is reported in 80% of patients [ 11 ] , 

exaggerated lumbar lordosis, visceroptosis, and 

rapid linear growth without compensatory weight 

gain, particularly during adolescence. 

Clinical symptoms can be acute, or chronic with 

intermittent exacerbations. The patient usually 

p resents with symptoms of gastrointestinal obstru c t i o n , 

which includes postprandial nausea, epigastric 

pain, bilious vomiting or vomiting of partially 

digested food. The symptoms are typically relieved 

when the patient is lying prone, in the left lateral 

decubitus, or in the knee-chest position; and they 

are aggravated when the patient is lying in the 

supine position. 

Diagnosis of SMA syndrome is difficult and 

re q u i res confirmation by radiographic studies. 

Upper gastrointestinal contrast series will show the 

characteristic criteria described by Hines et al [12] : 

1) Dilatation of the first and second parts of the 

duodenum with or without gastric dilatation 

2) A b rupt, partial or complete, vertical obstru c t i o n 

of barium flow at the site where SMA crosses the 

third part of the duodenum (duodenal clamp) 

3) Antiperistaltic waves proximal to the 

obstruction producing a “to-and-fro” movement. 

4) Relief of the obstruction when the patient is 

placed in the left lateral, prone, or knee-chest 

position. 

However, these findings may not be apparent in 

the chronic intermittent form of SMA syndrome; 

t h e re f o re, their absence does not exclude the 

disease and if they are negative, the procedure 

should be repeated during an acute attack. 

Recently, the use of contrast-enhanced spiralcomputed 

tomography can confirm the diagnosis 

by evaluating the aortomesenteric angle. It can also 

assess the amount of re t roperitoneal and 

mesenteric fat [13] . 

Many therapeutic options have been proposed 

to manage SMA syndrome and these vary from 

conservative non-operative to operative pro c e d u re s . 

Conservative treatment is recommended in all 

patients with SMA s y n d rome and it aims at 

identifying and correcting reversible predisposing 

factors and restoring retroperitoneal fat to relieve 

the obstruction. It involves decompression of the 

stomach and correction of dehydration and

244 

Superior Mesenteric Artery Syndrome: An Uncommon cause of Intestinal ..... September 2006 

electrolyte imbalance by intravenous fluids. Then 

feeding starts with small meals of liquids and 

proper positioning of the patient after meals either 

p rone or in the left lateral decubitus position. 

Furthermore, metoclopramide administration may 

be used to enhance emptying of the stomach. 

Patients with severe rapid weight loss may benefit 

from TPN or enteral feeding by the insertion of a 

nasojejunal tube, which is passed distal to the site 

of obstru c t i o n [ 1 4 ] . Medical treatment has a high 

success rate in cases with an acute presentation of 

SMA syndrome but most chronic cases require 

surgery. 

Several surgical solutions have been suggested 

including gastrojejunostomy, dissection and cutting 

of the ligament of Treitz with mobilization of the 

duodenum [15] , and duodenojejunostomy. The latter 

is agreed upon by most surgeons as the mainstay of 

treatment to prevent recurrence with a success rate 

of 90% [ 1 6 ] . Recently, successful laparo s c o p i c 

duodenojejunostomy was reported as a feasible 

alternative to open surgery with the advantages of 

a much lower operative time and rapid 

postoperative recovery [17] . 

Indications for surgery: 

(1) Failure of conservative medical therapy 

(2) A long history of indigestion, progressive 

weight loss, and pronounced dilatation of the 

duodenum with stasis 

(3) Complicated peptic ulcer disease [18] 

In our patients, each had a diff e rent pre d i s p o s i n g 

factor; the first patient had a neurological disorder 

resulting in facial and bulbar palsy with inability to 

chew and swallow food which led to rapid weight 

loss. In addition, she had significant physical 

handicap and prolonged recumbency. The second 

patient had a disproportionate increase in height 

over the weight with the onset of the growth spurt 

at puberty. Each of these two patients required a 

different approach to treatment, which was tailored 

according to their pre-existing medical conditions, 

predisposing factors and the progress observed 

after initiating treatment. 

CONCLUSION 

In cases of high intestinal obstruction with the 

presence of a dilated stomach and absent gas in the 

small intestine, a high index of suspicion for SMA 

syndrome should be entertained. An abrupt cutoff 

at the third part of the duodenum after an oral 

contrast and a decreased angle (6-16%) between 

SMA and the aorta on CT-angiogram will confirm 

the diagnosis. 

REFERENCES 

1) Rokitansky CV. Lehrbuch der Patologische Anatomie, 3rd 

ed, vol 3. Vienna: Braumuller,1861:187. 

2) Baltazar U, Dunn J, Floresguerra C, Schmidt L, Browder W. 

Superior Mesenteric Artery Syndrome: an uncommon 

cause of intestinal obstruction. South Med J 2000; 93:606- 

608. 

3) Kaushik R, Attri AK. Acute superior mesenteric artery 

syndrome. Indian Pediatr 2003; 40:1014-1015. 

4) Philip PA. Superior mesenteric artery syndrome: an 

unusual cause of intestinal obstruction in brain-injured 

children. Brain Inj 1992; 6:351-358. 

5) Shetty AK, Schmidt-Sommerfeld E, Hayman ML, Udall JN. 

Radiological case of the month. Arch Pediatr Adolesc Med 

1999; 153:303-304. 

6) Adson DE, Mitchell JE, Trenkner SW. The superior 

mesenteric artery syndrome and acute gastric dilatation in 

eating disorders: a report of two cases and a review of the 

literature. Int J Eat Disord 1997; 21:103-114. 

7) Laffont I, Bensmail D, Rech C, Prigent G, Loubert G, Dizien 

O. Late superior mesenteric syndrome in paraplegia: case 

report and review. Spinal Cord 2002; 40:88-91. 

8) Delgadillo X, Belpaire-Dethiou MC, Chantrain C, et al. 

Arteriomesenteric syndrome as a cause of duodenal 

obstruction in children with cerebral palsy. J Pediatr Surg 

1997; 32:1721-1723. 

9) Kishi T, Kawahara H, Tanaka T, et al. Superior mesenteric 

artery syndrome complicating mitochondrial encephalopathy. 

J Pediatr Gastroenterol Nutr 1998; 26:464-467. 

10) Wilson-Storey D, MacKinlay GA. The Superior mesenteric 

artery syndrome. J R Coll Surg Edinb 1986; 31:175-178. 

11) Barnes JB, Lee M. Superior mesenteric artery syndrome in 

an intravenous abuser after rapid weight loss. South Med J 

1996; 89:331-334. 

12) Hines JR, Gore RM, Ballantyne GH. Superior mesenteric 

artery syndrome: diagnostic criteria and therapeutic 

approaches. Am J Surg 1984; 148:630-632. 

13) Lippel F, Hanning C, Weiss W, Allescher HD, Classen M, 

Kurjak M. Superior mesenteric artery syndrome: diagnosis 

and treatment from the gastro e n t e rologist’s view. J 

Gastroenterol 2002; 37:640-643. 

14) Roth EJ, Fenton LL, Gaebor-Spira DJ, Frost FS, Yarkony GM. 

Superior mesenteric artery syndrome in acute traumatic 

quadriplegia: case reports and literature review. Arch Phys 

Med Rehabil 1991; 72:417-420. 

15) Murthi GV, Raine PA. Superior mesenteric artery syndrome 

in children. Scott Med J 2001; 46:153-154. 

16) Ylinen P, Kinnunen J, Hockerstedt K. Superior mesenteric 

artery syndrome: A follow-up study of 16 operated 

patients. J Clin gastroenterol 1989; 11:386-391. 

17) Kim IY, Cho NC, Kim DS, Rhoe BS. Laparo s c o p i c 

duodenojejunostomy for management of superior mesenteric 

artery syndrome: two cases report and a review of the 

literature. Yonsei Med J 2003; 44:526-529. 

18) Fromm S, Cash J. Superior mesenteric artery syndrome: an 

a p p roach to the diagnosis and management of upper 

gastrointestinal obstruction of unclear etiology. S D J Med 

1990; 43:5-10.



Selected Abstracts of Articles Published 

Elsewhere by Authors in Kuwait 


Levosimendan or Milrinone in the Type 2 Diabetic Patient with 

Low Ejection Fraction Undergoing Elective Coronary Artery Surgery 

Al-Shawaf E, Ayed A, Vislocky I, Radomir B, Dehrab N, Tarazi R 

Department of Anesthesia, The Chest Diseases Hospital, Ministry of Health, Safat, Kuwait. 

E-mail:ealshawaf@hsc.edu.kw 

J Cardiothorac Vasc Anesth 2006; 20:353-357 

Objectives: The purpose of this study was to compare the hemodynamic profiles and the 

postoperative insulin re q u i rements in 2 groups of type 2 diabetic patients with depre s s e d 

myocardial function who underwent elective surgery for coronary artery disease and who received 

levosimendan or milrinone for postcardiopulmonary bypass low-output syndrome. 

Design: Randomized controlled trial. 

Setting: The Chest Diseases Hospital, Safat, Kuwait. 

Participants: Type 2 diabetic patients undergoing elective surgery for coronary artery disease. 

Interventions: Fourteen patients and 16 patients received levosimendan and milrinone infusions, 

respectively, for treatment of the low-output syndrome. 

Measurements And Main Results: The hemodynamic, mixed venous oxygen saturation, oxygen 

extraction ratios, arterial lactate concentrations, and postoperative insulin infusion rates were 

serially documented for the first 48 hours after the diagnosis. The cardiac index and mixed venous 

oxygen saturation were significantly higher in the levosimendan group. The pulmonary capillary 

wedge pressure, systemic vascular resistance, and oxygen extraction ratios were significantly higher 

in the milrinone treatment group. The insulin requirements were similar for both of the treatment 

groups. 

Conclusions: Levosimendan was more efficient than milrinone for treating the hemodynamic 

manifestations of the postcardiopulmonary bypass low-output syndrome. However, all the values 

in the milrinone treatment group were normalized. In this small population, both treatment groups 

had similar postoperative insulin requirements. 

Clinicoepidemiological Features and Course of 43 Cases of Bullous 

Pemphigoid in Kuwait 

Nanda A, Al-Saeid K, Al-Sabah H, Dvorak R, Alsaleh QA. 

As’ad Al-Hamad Dermatology Centre, Al-Sabah Hospital, Kuwait. E-mail: artinanda@hotmail.com 

Clin Exp Dermatol 2006; 31:339-342 

Background: The clinicoepidemiological characteristics and course of bullous pemphigoid (BP) 

have not been described in populations from the Arabian Gulf. Hypothesis. Ethnic and regional 

variations can influence the clinical behaviour and course of autoimmune diseases. 

Methods: In this study, 43 patients with BP, registered in our autoimmune bullous diseases (ABD) 

clinic over a span of 14 years, were studied to determine the clinicoepidemiological features and 

course of the disease in our region. 

Results: BP was observed to be the second commonest ABD in our clinic (27%), with a minimum 

estimated incidence of 2.6 cases/million/year among the referral population. The largest proportion 

(93%) of the patients was of Arab ethnicity and the female to male ratio was 5.1 :1. Mean +/- SD age

246 


at diagnosis was 65.20 +/- 18.80 years. Most of the patients (96%) had moderate to severe disease, 

and mucosal involvement was seen in 37% of the patients. Systemic steroids (prednisolone 20-60 mg 

daily) alone or in combination with azathioprine, intravenous immunoglobulins, tetracyclines, 

mycophenolate mofetil or dapsone were used to treat theses cases. At the last follow-up, 32% of 

patients were in complete remission and off treatment. The first-year mortality was 30%. Old age and 

poor general medical condition were the significant risk factors (P < 0.05) contributing to the 

mortality. 

Conclusions: The study highlights the regional variations of BP and thus a need to uncover the 

ethnic, genetic and geographical influences, if any, responsible for these variations. 

Aspiration versus Tube Drainage in Primary Spontaneous 

Pneumothorax: a Randomised Study 

Ayed AK, Chandrasekaran C, Sukumar M 

Department of Surgery, Kuwait University, Faculty of Medicine, and Dept of Thoracic Surgery, Chest Diseases 

Hospital, P.O. Box 24923, Safat 13110, Kuwait. E-mail: Adel@hsc.edu.kw 

Eur Respir J 2006; 27:477-482 

This randomised study was designed to compare clinical outcomes for simple aspiration versus tube 

thoracostomy, in the treatment of the first primary spontaneous pneumothorax (PSP) attack. A 

randomised trial, comparing simple aspiration with tube thoracostomy, in 137 patients with a first 

episode of PSP was carried out. Immediate success was obtained in 40 out of the 65 patients (62%) 

randomly assigned to undergo simple aspiration and in 49 out of the 72 patients (68%) who had been 

randomly assigned to undergo tube thoracostomy. The 1-week success rates were: 58 (89%) patients 

in the intention-to-treat simple aspiration group and 63 (88%) patients in the tube thoracostomy 

group. In the aspiration group, there were more recurrences during the 3-month follow-up period 

(15 versus 8%), though the difference was not significant. Recurrence rates at 1 and 2 yrs were 16 

(22%) and 20 (31%) for patients who had undergone simple aspiration, respectively, and 17 (24%) 

and 18 (25%) for patients who had undergone tube thoracostomies, respectively. Complications 

occurred in 5 (7%) patients who had undergone a tube thoracostomy and 1 (2%) patient who had 

undergone simple aspiration. Analgesia was required in 22 (34%) patients of the simple aspiration 

group versus 40 (56%) patients of the tube thoracostomy group. These findings suggest that simple 

aspiration could be an acceptable alternative to tube thoracostomy in the treatment of primary 

spontaneous pneumothorax. 

Do Differences in Age Specific Androgenic Steroid Hormone Levels 

Account for Differing Prostate Cancer Rates between Arabs and 

Caucasians? 

Kehinde EO, Akanji AO, Al-Hunayan A, Memon A, Luqmani Y, Al-Awadi KA, Varghese R, Bashir AA, 

Daar AS 

Department of Surgery (Division of Urology), Faculty of Medicine, Kuwait University, Kuwait. 

E-mail: ekehinde@hsc.edu.kw 

Int J Urol 2006; 13:354-361 

Objective: Factors responsible for the low incidence of clinical prostate cancer in the Arab 

population remain unclear, but may be related to differences in androgenic steroid hormone 

metabolism between Arabs and other populations, especially as prostate cancer is believed to be 

androgen dependent. We therefore measured the levels of serum androgenic steroids and their 

binding proteins in Arab men and compared results obtained with values reported for Caucasian 

populations to determine if any differences could at least partially account for differences in 

incidence of prostate cancer rates between the two populations.



Methods: Venous blood samples were obtained from 327 unselected apparently healthy indigenous 

Arab men (Kuwaitis and Omanis) aged 15-79 years. Samples were also obtained from 30 Arab men 

with newly diagnosed prostate cancer. Serum levels of total testosterone (TT), sex hormone binding 

globulin (SHBG), derived free androgen index (FAI); adrenal C19 -steroids, dehydroepiandrosterone 

sulfate (DHEAS) and androstenedione (ADT) were determined by chemiluminescent immunoassay. 

Age specific reference intervals, mean and median for each analyte were determined. Frequency 

distribution pattern for each hormone was plotted. The reference range for hormones with normal 

distribution was mean +/- 2SD and 2.5-97.5% for those with non-normal distribution. The mean 

serum levels of the hormones in Arab men with prostate cancer were compared with values in 

healthy age-matched Arab men. 

Results: There was a significant decrease between the 21-29 years age group and the 70-79 years age 

group for TT (-38.77%), DHEAS (-70%), ADT (-36%) and FAI (-63.25%), and an increase for SHBG 

(+64%). The calculated reference ranges are TT (2.73-30.45 nmol/L), SHBG (6.45-65.67 nmol/L), FAI 

(14.51-180.34), DHEAS (0.9-11.0 micromol/L) and ADT (0.54-4.26 ng/mL). The mean TT, SHBG, 

DHEAS and ADT in Arab men were significantly lower than those reported for Caucasians 

especially in the 21-29 years age group. Arab men with newly diagnosed prostate cancer had higher 

serum TT (P < 0.7), ADT (P < 0.2), SHBG (P < 0.2) and lower DHEAS (P < 0.008) compared to aged 

matched controls. 

Conclusions: Serum TT, SHBG, DHEAS and ADT levels are significantly lower in Arab men 

compared to those reported for Caucasian men, especially in early adulthood. Arab men with newly 

diagnosed prostate cancer have higher circulating androgens compared to healthy controls. We 

suggest that low circulating androgens and their adrenal precursors in Arab men when compared to 

Caucasians may partially account for the relatively lower risk for prostate cancer among Arab men. 

Long term Effects of Ketogenic Diet in Obese Subjects with High 

Cholesterol Level 

Dashti HM, Al-Zaid NS, Mathew TC, Al-Mousawi M, Talib H, Asfar SK, Behbahani AI 

Department of Surgery, Kuwait University, Safat, Kuwait. E-mail: info@drdashti.com 

Mol Cell Biochem 2006; 286:1-9 

Objective: Various studies have convincingly shown the beneficial effect of ketogenic diet (in which 

the daily consumption of carbohydrate is less than 20 grams, regardless of fat, protein and caloric 

intake) in reducing weight in obese subjects. However, its long term effect on obese subjects with 

high total cholesterol (as compared to obese subjects with normal cholesterol level is lacking. It is 

believed that ketogenic diet may have adverse effect on the lipid profile. Therefore, in this study the 

effect of ketogenic diet in obese subjects with high cholesterol level above 6 mmol/L is compared to 

those with normocholesterolemia for a period of 56 weeks. 

Materials And Methods: In this study, 66 healthy obese subjects with body mass index (BMI) greater 

than 30, having high cholesterol level (Group I; n = 35) and those subjects with normal cholesterol 

level (Group II; n = 31) were selected. The body weight, body mass index, total cholesterol, LDLcholesterol, 

HDL-cholesterol, urea, creatinine, glucose and triglycerides were determined before and 

after the administration of the ketogenic diet. Changes in these parameters were monitored at 8, 16, 

24, 32, 40, 48 and 56 weeks of the treatment. 

Results: The body weight and body mass index of both groups decreased significantly (P < 0.0001). 

The level of total cholesterol, LDL cholesterol, triglycerides and blood glucose level decreased 

significantly (P < 0.0001), whereas HDL cholesterol increased significantly (P < 0.0001) after the 

treatment in both groups. 

Conclusion: This study shows the beneficial effects of ketogenic diet following its long term 

administration in obese subjects with a high level of total cholesterol. Moreover, this study 

demonstrates that low carbohydrate diet is safe to use for a longer period of time in obese subjects 

with a high total cholesterol level and those with normocholesterolemia.

World Congress of Cardiology 

Sep 02-06, 2006 

Barcelona, Spain 

Contact: Congress Secretariat 

E-Mail: congress@escardio.org 

16th World Congress on Ultrasound in Obstetrics 

and Gynecology 

Sep 03-07, 2006 

London, England, United Kingdom 


Tel: 44-0-2-074-719-955; Fax: 44-0-2-074-719-959 

E-Mail: congress@isuog.org 

7th World Congress of the International Hepato- 

Pancreato Biliary Association 

Sep 03-07, 2006 

Edinburgh, Scotland, United Kingdom 

Contact: Camilla O’Brien 

Tel: 441-413-310-123; Fax: 441-413-310-234 

E-Mail: info@ihpba2006.com 

10th International Congress of Obesity 

Sep 03-08, 2006 

Sydney, NSW, Australia 

Contact: Event Planners Australia 

Tel: 61-292-411-478; Fax: 61-292-513-552 

E-Mail: enquiries@ico2006.com 

Hand-Assisted Laparoscopic Surgery Workshop 

Sep 06, 2006 

Minneapolis, MN, United States 

Contact: Mallory Johnson 

Tel: 612-626-7600, Fax: 612-626-7766 

E-Mail: mallory@umn.edu 

Diabetes & the Heart 

Sep 06-07, 2006 

Cairo, Egypt 

Contact: Mahmoud Ibrahim , MD 

Tel: 20-122-131-868 / 20-101-560-794; Fax: 20-22- 

723-693 / 20-22-564-365 

E-Mail: mahmoud@arab-diabetes.com 

Reproductive Health 2006 

Sep 06-09, 2006 

La Jolla, CA, United States 

Contact: Carole Berke 

Tel: 202-466-3825; Fax: 202-466-3826 

E-Mail: cberke@arhp.org 


Forthcoming Conferences and Meetings 

Compiled and edited by 

Babichan K Chandy 


Basic and Intermediate Dermoscopy 

Sep 07-09, 2006 

Warsaw, Poland 

Contact: Lidia Rudnicka 

Tel: 48-228-242-200; Fax: 48-225-081-492 

E-Mail: lidiarudnicka@yahoo.com 

Perioperative Transesophageal Echocardiography 

Review Course 2006 

Sep 08-10, 2006 

Boston, MA, United States 

Contact:Meeting Organiser 

Tel:617-384-8600, Fax:617-384-8686 

E-Mail:hms-cme@hms.harvard.edu 

9th Annual West Hawaii Cancer Symposium 

Sep 08-09, 2006 

Kona, HI, United States 

Contact: Daryl Kurozawa, MD 

Tel: 808-987-3707, Fax: 808-334-4492 

E-Mail: dkuro@aloha.net 

I n t roducing the Neuroscience of Addictive 

Behaviours - Including Obesity 

Sep 09-10, 2006 

Sydney, NSW, Australia 

Contact: Dr Sue Boyd 

Tel: 61-2-94-373-322 Fax: 61-2-94-373-322 

E-Mail: practiceofhealth@ihug.com.au 

Pediatric & Adult Interventional Therapies for 

Congenital & Valvular Heart Disease 

Sep 10- 13, 2006 

Las Vegas, NV, United States 

Contact: M2 Meeting Management, 7 Learning Elm 

Drive, Reading, MA 01867, USA 

Tel: 781-942-5703, Fax: 781-942-5716 

E-Mail: pics@m2usa.com 

Breast Cancer and Melanoma: Biology, Diagnosis 

and Therapy 

Sep 11-15, 2006 

Varese, Italy 

Contact: Fulvia Riganti 

Tel: 39-0-332-228-548, Fax: 39-0-332-223-747 

E-Mail: info@canardsrl.it


6th SGHG International Otology Symposium 

Sep 12-14, 2006 

Jeddah, Saudi Arabia 

Contact: Dr. Khairy Abu Basr 

Tel: 00-966-26-829-000 ext. 6510, Fax: 00-966-26-835- 

874 

E-Mail: ent1.jed@sghgroup.net, aad.jed@sghgroup.net 

27th Annual Hepatopathology 2006 Course 

Sep 13-15, 2006 

Bethesda, MD, United States 

Contact: Rene Sutton 

Tel: 202-782-2634, Fax: 202-782-5020 

E-Mail: sutton@afip.osd.mil 

International Workshop on Diagnostic and 

Therapeutic Digestive Endoscopy 

Sep 14-15, 2006 

Zagreb, Croatia 

Contact: Sanja Suhic 

Tel: 38-514-921-720, Fax: 38-514-813-010 

E-Mail: sanja.suhic@otours.hr 

The 6th Conference for Clinical Endocrinology, 

Diabetes and Infertility 

Sep 14-17, 2006 

Cairo, Egypt 

Contact: Dr Muhammed Gharib 

Tel: 00-20-101-661-950 

E-Mail: magmaim@gmail.com 

The 8th Congress on Controversies in Obstetrics, 

Gynecology and Infertility (COGI) Sep 14-17, 2006 

Bahia, Brazil 

Contact: Ms. Michal Pink 

Tel: 972-3-56-66-166; Fax: 972-3-56-66-177 

E-Mail: michal@comtecint.com 

Anti-Ageing Conference London 2006 

Sep 15-17, 2006 


Contact: Maria Somers 

Tel: 44-2-075-816-962, Fax: 44-2-075-891-273 

E-Mail: conference@antiageingconference.com 

2006 Adult Congenital Heart Association National 

Conference 

Sep 15-17, 2006 

San Francisco, CA, United States 

Contact: UCSF Office of Continuing Medical 

Education, 3333 California Street, Room 450, San 

Francisco, CA 94118 

Tel: 415-476-4251 / 415-476-5808, Fax: 415-476-0318 

/ 415-502-1795 

E-Mail: info@ocme.ucsf.edu 


Molecular Biology of Hepatitis B Viruses 

Sep 17-20, 2006 

Vancouver, BC, Canada 

Contact: Ms. Fonta Reilly 

Tel: 215-489-4900 

E-Mail: fonta@hepB.org 

Clinical Endocrinology and Diabetes 

Sep 17, 2006 

Sharm El Sheikh, Egypt 

Contact: Dr Mohamed Garib 

Tel: 010-166-1950 

E-Mail: magmaim@gmail.com 

The 4th Annual Scientific Meeting of The Saudi 

Thoracic Society & The 10th Annual Meeting of 

The Pan-Arab Thoracic Association 

Sep 19-21, 2006 

Jeddah, Saudi Arabia 

Contact: Professor Mohamed Al-Hajjaj 

Tel: 00-96-612-488-966; Fax: 00-96-612-487-431 

E-Mail: msalhajjaj@yahoo.com 

See My Heart TM: Keeping the Beat 

Sep 21-24, 2006 

Orlando, FL, United States 

Contact: Jennifer Dutrow, Registrar 

Tel: 336-716-4505, Fax: 336-716-2447 

E-Mail: cmu@wfubmc.edu 

13th International Symposium of The Mycology 

Section Polish D e r m a t o l o g y Society “Mycology 

2006” 

Sep 21-23, 2006 

Bialowieza, Podlaskie, Poland 

Contact: Prof. Roman Nowicki 

Tel: 00-48-583-492-590; Fax: 00-48-583-492-586 

E-Mail: rnowicki@amg.gda.pl 

2nd Asia Pacific Congress in Maternal Fetal 

Medicine 

Sep 21-23, 2006 

Guangzhou, China 

Contact: Dr TY Leung 

Tel: 852-26-322-810; Fax: 852-26-360-008 

E-Mail: apcmfm@med.cuhk.edu.hk 

Radiology in Italy 

Sep 24-30, 2006 

Fiuggi, Japan 

Contact: D. Beatty Crawford, M.D. 

Tel: 00-1-860-364-502 / 800-659-0872; Fax: 860-364- 

5040 

E-Mail: info@radiologyintl.com

250 

5th Advanced Symposium on Congenital Heart 

Disease in the Adult 

Sep 25-27, 2006 


Contact: Prof Michael A Gatzoulis 

Tel: 44-0-20-73-51-82-27; Fax: 44-0-20-73-51-86-29 

E-Mail: m.gatzoulis@rbht.nhs.uk 

Mayo Clinic Nutrition in Health & Disease 

Sep 28-29, 2006 

Minneapolis, MN, United States 

Contact: Meeting Organiser 

Tel: 1-800-323-2688; Fax: 507-284-0532 

E-Mail: cme@mayo.edu 

39th Southeast Pediatric Cardiology S o c i e t y 

Annual Meeting 

Sep 28-30, 2006 

Atlanta, GA, United States 

Contact: Marsha Elixson, Program Coordinator 

Tel: 1-770-448-9202 ext 270; Fax: 1-678-542-9410 

E-Mail: info@kidsheart.com 

From Human Genetic Variations to Prediction of 

Risks and Responses to Drugs and to the 

Environment 

Sep 28-Oct 02, 2006 

Thira - Santorini, Greece 

Contact: Pr Gerard Siest 

Tel: 00-33-0-383-682-170 / 71 / 63 / 65; Fax: 00-33- 

0-383-321-322 

E-Mail: gerard.siest@pharma.uhp-nancy.fr 

4th Annual World Congress on the I n s u l i n 

Resistance Syndrome 

Oct 05-07, 2006 


Contact: Nava Mekel 

Tel: 818-342-1889; Fax: 818-342-1538 

E-Mail: insulinresistance@pacbell.net 

Advanced Heart and Lung 

Oct 05-07, 2006 

Cambridge, MA, United States 

Contact: CME Office 

Tel: 617-384-8600; Fax: 617-384-8686 

E-Mail: hms-cme@hms.harvard.edu 

Advanced Cross-Sectional Pediatric Imaging: US, 

CT and MRI 

Oct 06-07, 2006 



Tel: 617-384-8600; Fax: 617-384-8686 

E-Mail: hms-cme@hms.harvard.edu 

Forthcoming Conferences and Meetings September 2006 

Management of Asymptomatic Patients with 

Valvular Disease 

Oct 06-07, 2006 

Sophia-Antipolis, France 

Contact: Stephanie Deambrosis 

Tel: 33-492-947-600; Fax: 33-492-941-824 

E-Mail: sdeambrosis@escardio.org 

Carotid and Transcranial Doppler 

Oct 06-08, 2006 


Contact: Kelly Winters 

Tel: 914-921-5700; Fax: 914-921-6048 

E-Mail: info@iame.com 

Current Practice of Vascular Ultrasound 

Oct 06-08, 2006 



Tel: 914-921-5700; Fax: 914-921-6048 


International Conference of Immunogenomics and 

Immunomics 

Oct 08-12, 2006 

Budapest, Hungary 

Contact: Zoltan Prohaszka 

Tel: 361-212-9351; Fax: 361-212-9351 

E-Mail: prohoz@kut.sote.hu 

Sexual Health 2006 Conference 

Oct 09-11, 2006 

Melbourne, VIC, Australia 

Contact: Nicole Robertson 

Tel: 61-282-040-700, Fax: 61-292-124-670 

E-Mail: conferenceinfo@ashm.org.au 

3rd National Congress on Palliative Care 

Oct 11-13, 2006 

Porto, Portugal 

Contact: Jo‹o Mota Dias 

Tel: 351-969-083-502 

E-Mail: jmdia@netcabo.pt 

Geriatric Medicine 

Oct 11-15, 2006 

Salt Lake City, UT, United States 

Contact: Sherri Woodward 

Tel: 800-274-2237, ext. 6523; Fax: 913-906-6092 

E-Mail: swoodwar@aafp.org 

Thrombosis and Thromboembolism 

Oct 12-13, 2006 



Tel: 617-384-8600; Fax: 617-384-8686 

E-Mail: hms-cme@hms.harvard.edu


11 World Congress on Internet in Medicine 

Oct 13-20, 2006 

Toronto, ON, Canada 

Contact: Gunther Eysenbach 

Tel: 416-786-6970 

E-Mail: geysenba@uhnres.utoronto.ca 

2 3 rd Annual Symposium C a r d i o l o g y for the 

Practitioner 

Oct 16-18, 2006 

Yosemite, CA, United States 




Tel: 415-476-4251 / 415-476-5808; Fax: 415-476-0318 

/ 415-502-1795 


Canadian Diabetes Association/Canadian Society 

of Endocrinology & Metabolism P ro f e s s i o n a l 

Conference & Annual Meetings 

Oct 18-21, 2006 

Toronto, ON, Canada 

Contact: John Boggan 

Tel: 416-408-7077, Fax: 416-363-7465 

E-Mail: john.boggan@diabetes.ca 

Allergy Abroad 

Oct 19-28, 2006 

Zurich, Switzerland 

Contact: Susan OConnor 

Tel: 800-325-9862, Fax: 314-362-1087 

E-Mail: cme@wustl.edu 

2006 International Osteoporosis Conference 

Oct 19-23, 2006 

Chengdu, China 

Contact: M.D.Yanling Zhao 

Tel: 86-1-082-898-872; Fax: 86-1-082-898-875 

E-Mail: 2006ioc@cof.org.cn 

Oncology and Clinical trials-2006 

Oct 21-22, 2006 

Kiev, Ukraine 

Contact: Dr Markov 

Tel: 00-380-445-331-270, Fax: 00-380-445-331-270 

E-Mail: markov@nbscience.com 

Integrative (natural) Medicine-2006 

Oct 21-25, 2006 

Kiev, Ukraine 


Tel: 00-380-445-331-270, Fax: 00-380-445-331-270 



Acute Cardiac Care 2006 

Oct 21-24, 2006 

Prague, Czech Republic 


E-Mail: EuroACCsecretariat@escardio.org 

Musculoskeletal R a d i o l o g y for the Practicing 

Radiologists 

Oct 22-29, 2006 

Athens, Greece 

Contact: Ryals and Associates Inc, P.O. Box 380, 

Springville, AL 5146 

Tel: 205-467-3158; Fax: 205-467-3199 

E-Mail: info@ryalsmeet.com / wryals@ryalsmeet.com 

2006 Transcatheter Cardiovascular Therapeutics 

Oct 23-27, 2006 

Washington DC, United States 

Contact: Cardiovascular Reasearch Foundation 

Tel: 212-851-9137; Fax: 212-851-9397 

E-Mail: kgerecitano@crf.org 

Generics-2006 

Oct 24-25, 2006 

Kiev, Ukraine 


Tel: 00-380-445-331-270, Fax: 00-380-445-331-270 


6th International Congress of the Wo r l d 

Association of Laser Therapy (WALT) 

Oct 25-28, 2006 

Limassol (Lemesos), Cyprus 

Contact: Mr Nicolas Nicolaides 

Tel: 35-725-720-554 

E-Mail: registrations@walt2006.com 

1st Mediterranean Workshop on Clinical Immunology 

Oct 26-29, 2006 

Evora, Portugal 

Contact: Mrs. Greta Martins 

Tel: 351-214-407-900, Fax: 351-214-407-970 

E-Mail: mwci.evora@gmail.com 

Obstetric Ultrasound in the High Risk Patient 

Oct 26-28, 2006 



Tel: 914-921-5700; Fax: 914-921-6048 


Joint World Congress on Stroke 

Oct 26-29, 2006 

Cape Town, South Africa 

Contact: Kenes International, Global Congre s s 

Organizers and Association Management Services, 

17 Rue du Cendrier, PO Box 1726, CH-1211 Geneva 

1, Switzerland 

Tel: 41-229-080-488; Fax: 41-227-322-850 

E-Mail: stroke2006@kenes.com

252 

18th International Congress on Pediatrics 

Oct 28-Nov 02, 2006 

Tehran, Iran 

Contact: Dr Gh. Valizadeh 

Tel: 98-2-166-428-998; Fax: 98-2-166-923-054 

E-Mail: pedcong@tums.ac.ir 

7th JOPEOI (7th European/Indian Ocean Mother& 

Child Health Meeting) 

Oct 28 - Nov 04, 2006 

New Delhi, India 

Contact: Kamel BARGAOUI 

Tel: 33-607-686-118, Fax: 33-143-839-985 

E-Mail: kamelbargaoui@wanadoo.fr 

The 1st International Congress of Central Asia 

Infectious Diseases 

Oct 30 - Nov 02, 2006 

Bishkek, Kyrgyzstan 

Contact: Salih Hosoglu 

Tel: 904-122-488-473, Fax: 904-122-488-473 

E-Mail: hosoglu@hotmail.com 

Global Aspects of Diabetes:Shaping the Future 

Oct 30-Nov 02, 2006 

Jabriya, Kuwait 

Contact: Professor Nabila Abdella 

Tel: 009-654-986-418 / 00-965-519-601; Fax: 00-915- 

318-455 

E-Mail: teena@hsc.edu.kw 

Infectious Diseases Update, International & Travel 

Medicine 

Nov 03 - 04, 2006 

Victoria, BC, Canada 

Contact: Cindy Lundy 

Tel: 250-658-6056, Fax: 250-658-6109 

E-Mail: info@novaclinical.com 

Current Practice of Vascular Ultrasound 

Nov 03-05, 2006 



Tel: 914-921-5700; Fax: 914-921-6048 


Title: Spine Management for the PCP 

Nov 05-12, 2006 

Fort Lauderdale, FL, United States 

Contact: Continuing Education Inc, 5700 4th St. N, 

St. Petersburg FL 33703 

Tel: 1-800-422-0711 / 727-526-1571; Fax: 727-527- 

3228 

E-Mail: jbarnhart@continuingeducation.net 

Forthcoming Conferences and Meetings September 2006 

International Rhinology Congress 

Nov 07-10, 2006 

Tehran, Iran 


Tel: 982-166-703-037, Fax: 982-166-760-245 

E-Mail: info@IRC2006.ir 

1st International Meeting on the Treatment of 

Human Brucellosis 

Nov 09-12, 2006 

Ioannina, Greece 

Contact: Dr. Georgios Pappas 

Tel: 30-2-651-049-453 

E-Mail: gpele@otenet.gr 

Continuing Professional Development (CPD) 

Symposium: 5th Practical Diabetes Updates Nov 

09-12, 2006 

Kuala Lumpur, Malaysia 

Contact: The Secretariat 

Tel: 60-378-761-676; Fax: 60-378-761-679 

E-Mail: nadi@myjaring.net 

American College of A l l e r g y, Asthma & 

Immunology Annual Meeting 2006 

Nov 10-15, 2006 

Philadelphia, PA, United States 


Tel: 847-427-1294, Fax: 847-427-1200 

E-Mail: mail@acaai.org / meetings@acaai.org 

R E S P I R AT I O N S - International Clean A i r 

Conference 

Nov 11- 12, 2006 

Paris, France 

Contact: Peter Vines 

Tel: 33-0-172-041-006 

E-Mail: peter@lymthedog.com 

Women’s Health, Sexual Health And H e a l t h y 

Aging 

Nov 11-18, 2006 

Fort Lauderdale, FL, United States 

Contact: Cindy Smyth 

Tel: 1-877-536-6736, Fax: 204-453-0839 

E-Mail: vacations@kennedyseminars.com 

Gynecology and Women’s Health: An Update in 

Primary Care and Emergency Medicine 

Nov 13-17, 2006 

Bradenton-Sarasota, FL, United States 

Contact: Eva or Cristina 

Tel: 1-866-267-4263 / 1-941-388-1766, Fax: 1-941- 

365-7073 

E-Mail: mail@ams4cme.com


Infant, Child and Adolescent Medicine 

Nov 15-18, 2006 

St. Petersburg, FL, United States 

Contact: Karla Krause 

Tel: 800-274-2237, ext. 6522, Fax: 913-906-6092 

E-Mail: kkrause@aafp.org 

Vascular Diseases-2006 

Nov 18 -19, 2006 

Kiev, Ukraine 


Tel: 00-380-445-331-270, Fax: 00380-445-331-270 


5th International Congress on Autoimmunity 

Nov 29 - Dec 03, 2006 

Sorrento, Italy 

Contact: 5th International Congress on A u t o i m m u n i t , y 

c/o Kenes International - Global Congre s s 

Organizers and Association Management Services, 

17 Rue du Cendrier; P.O. Box 1726, CH-1211 

Geneva 1, Switzerland 

Tel: 41-229-080-488, Fax: 41-227-322-850 

E-Mail: autoim06@kenes.com 

7th International Symposium on Diabetic Neuropathy 

Nov 29 - Dec 02, 2006 

Somerset West, South Africa 

Contact: Amy Groves 

Tel: 404-443-1596, Fax: 404-506-9393 

E-Mail: amy.groves@intmedpress.com 

Internal Medicine: Diabetes/Endocrinology 

Dec 02-09, 2006 

Tampa, FL, United States 

Contact: Continuing Education Inc, 5700 4th St. N, 

St. Petersburg FL 33703 

Tel: 1-800-422-0711 / 727-526-1571, Fax: 727-527- 

3228 

E-Mail: jbarnhart@continuingeducation.net 

IDF 2006 19th World Diabetes Congress 

Dec 05-07, 2006 

Cape Town, South Africa 

Contact: Congress Unit, International Diabetes 

Federation, Avenue Emile De Mot 19, B-1000 

Brussels 

Tel: 32-25-431-631, Fax: 32-25-385-114 

E-Mail: WorldDiabetesCongress@idf.org 

The Medical Management of AIDS: A C o m p re h e n s i v e 

Review of HIV Management 

Dec 07-09, 2006 

San Francisco, CA, United States 




Tel: 415-476-4251 / 415-476-5808; Fax: 415-476-0318 

/ 415-502-1795 



Exacerbations of Airway Disease 

Dec 08-10, 2006 

San Juan, Puerto Rico 

Contact: Roni LaVine 

Tel: 732-438-0622 Fax: 732-438-6672 

E-Mail: TheMacraeGroup@comcast.net 

Clinical Genetics 

Dec 14-15, 2006 

Coventry, England, United Kingdom 

Contact: Dr Charlotte Moonan 

Tel: 02-476-523-540, Fax: 02-476-523-701 

E-Mail: Charlotte.Moonan@warwick.ac.uk 

Medical Devices, Ultrasound - 2006 

Dec 16-17, 2006 

Kiev, Ukraine 


Tel: 00-380-445-331-270, Fax: 00-380-445-331-270 


Immunological Intervention in Human Disease (A2) 

Jan 06-11, 2007 

Big Sky, MT, United States 

Contact: Kellie McConnell 

Tel: 800-253-0685 / 970-262-1230, Fax: 970-262-1525 

E-Mail: info@keystonesymposia.org 

Obesity: Peripheral and Central Pathways 

Regulating Energy Homeostasis (J2) 

Jan 14 -17, 2007 

Keystone, CO, United States 


Tel: 800-253-0685 / 970-262-1230, Fax: 970-262-1525 


Women’s Malignancies 

Feb 02-04, 2007 

Tehran, Iran 

Contact: Dr Akbari or mrs Shadi 

Tel: 00-982-122-724-090, Fax: 00-982-122-724-090 

E-Mail: crc@sbmu.ac.ir 

Mast Cells, Basophils, and IgE: Host Defense and 

Disease (A6) 

Jan 20 - 24, 2007 

Copper Mountain, CO, United States 


Tel: 800-253-0685 / 970-262-1230, Fax: 970-262-1525 


2nd Scientific Conference of the Saudi Cancer 

Foundation: CANCER FORUM 2007 

Feb 21-22, 2007 

Al-Khobar, Saudi Arabia 

Contact: Dr/ Ibrahim F. Al-Sheneber 

Tel: 96-68-647-557, Fax: 96-638-649-884 

E-Mail: info@scf.org.sa


WHO-Facts Sheet 

1. Health Consequences of Excessive Solar UV Radiation 

2. Global Disease Burden from Solar Ultraviolet Radiation 

3. Launch of Global Early Warning System for Animal Diseases Transmissible to Humans 

1. HEALTH CONSEQUENCES OF EXCESSIVE 

SOLAR UV RADIATION 

New WHO report shows breakdown of disease 

caused by UV radiation 

Ultraviolet radiation from the sun causes a 

considerable global disease burden, including 

specific cancers, a new World Health Organization 

(WHO) report finds. Much of the UV-related illness 

and death can be avoided through a series of 

simple prevention measures. 

The report, Global Burden of Disease of Solar 

Ultraviolet Radiation estimates that up to 60,000 

deaths a year worldwide are caused by too much 

exposure to ultraviolet radiation (UVR). Of those 

60,000 deaths, an estimated 48,000 are caused by 

malignant melanomas, and 12,000 by skin 

carcinomas. 

In total, more than 1.5 million DALY S 

(“disability-adjusted life years”) - a measure of the 

loss of full functioning due to disease and death are 

lost every year due to excessive UVR exposure. The 

most serious consequence of excess UVR is 

malignant melanoma, which has high cure rates 

only if detected early. Up to 90% of the global 

burden of disease from melanoma and other skin 

cancers are estimated to be due to UVR exposure. 

The new WHO report is the first-ever 

systematic examination of the global health burden 

due to UVR. It investigates nine adverse health 

outcomes from excess UVR exposure. The main 

three, which cause the greatest burden of disease 

from UVR, are cutaneous malignant melanomas, 

and non-melanoma skin cancers developing in 

different cell layers of the skin (squamous cell 

carcinomas and basal cell carcinomas). In addition, 

UVR causes sunburn, skin photoageing, cortical 

cataracts (eye lens opacities), pterygium (a fleshy 

growth on the surface of the eye), reactivation of 

Compiled and edited by 

Babichan K Chandy 


herpes of the lip (cold sores) and the rare squamous 

cell carcinomas of the eye. 

“This global assessment of the health risks of 

UV radiation provides a good basis for public 

health action. We all need some sun, but too much 

sun can be dangerous - and even deadly. 

Fortunately, diseases from UV such as malignant 

melanomas, other skin cancers and cataracts are 

almost entirely preventable through simple 

protective measures,” said Dr Maria Neira, Director 

for Public Health and the Environment at WHO. 

The report notes that UVR does have beneficial 

effects, mainly in the production of vitamin D 

following skin exposure to the UVB (shorter 

wavelength) component of UVR. Adequate vitamin 

D prevents the development of bone diseases such 

as rickets, osteomalacia and osteoporo s i s . 

Moreover, the possible beneficial effects on some 

cancers and immune disorders are under 

investigation. 

WHO notes, in most cases minimal casual 

exposure to UVR should be sufficient to maintain 

vitamin D levels at a range that avoids these health 

problems. The dangers are much greater from overexposure 

to the sun’s radiation. 

A few easy-to-implement sun safety measures 

could prevent much of the cancer and other death 

and disease burden due to UV radiation, WHO 

says: 

Limit time in the midday sun 

Use shade wisely: seek shade when UV rays 

are most intense 

Wear protective clothing including hats and 

sunglasses 

Use a bro a d - s p e c t rum sunscreen of sun 

protection factor 15+ 

Avoid sunlamps and tanning parlours; for 

youth under the age of 18, WHO recommends 

that they do not use them at all 

Address correspondence to: Office of the Spokesperson, WHO, Geneva. Tel.: (+41 22) 791 2599; Fax (+41 22) 791 4858; Email: inf@who.int; Web 

site: http://www.who.int/


Know the UV index: when the UV Index 

p redicts radiation levels of 3 (moderate) or above 

sun safety practices should be taken 

Protect children from the sun 

For more information contact:Ms Nada Osseiran, 

Communications and Advocacy Officer, Department for 

Public Health and Environment, World Health 

Organization, Geneva, Tel: (+41 22) 791 4475; Fax 

(+41 22) 791 4127, Email: osseirann@who.int. 

2. GLOBAL DISEASE BURDEN FROM SOLAR 

ULTRAVIOLET RADIATION 

Introduction 

Everyone is exposed to ultraviolet radiation 

(UVR) from the sun. Small amounts of UV 

radiation are beneficial to health, and play an 

essential role in the production of vitamin D. 

H o w e v e r, overe x p o s u re to UV radiation is associated 

with a variety of health problems, most notably 

skin cancer and eye cataracts. WHO has recently 

assessed the global disease burden that can be 

attributed to solar UV radiation. This information 

p rovides an important basis for national and 

international UV public health and health pro t e c t i o n 

programmes to assist people to avoid inappropriate 

sun exposure. 

UV Radiation 

UVR reaching the earth’s surface is larg e l y 

composed of long-wavelength UVA with a small 

amount of the shorter wavelength UVB. Most UVB 

and the very short wavelength UVC is filtered out 

by the atmosphere. UV radiation levels are 

influenced by: 

Sun elevation: the higher the sun in the sky, 

the higher the UVR level, with an increase in 

UVB relative to UVA. Thus UVR levels vary 

with time of day and time of year. 

Latitude: the closer to equatorial regions, the 

higher the UVR levels. 

Cloud cover: UVR levels are highest under 

cloudless skies. However, even with cloud 

cover, UVR levels can be high due to scattering 

within the atmosphere. 

Altitude: at higher altitudes, the atmosphere is 

thinner and the air mass is decreased; less 

UVR is absorbed. 

Ozone: ozone present in the atmosphere 

absorbs some of the UVR that would 

otherwise reach the earth’s surface. Ozone 

depletion leads to increased UVB levels with 

little impact on UVA levels. 

Ground reflection: grass, soil and water reflect 

less than 10% of UVR; fresh snow reflects as 

much as 80%; dry beach sand about 15% and 

sea foam about 25%. 


UVR can neither be seen nor felt. Therefore, 

UVR measurements are necessary to determine 

precisely the extent of ground level (ambient) UVR. 

UVR measurements such as the global solar UV 

index (see www.who.int/uv) add up all the solar 

UVR, taking account of its ability to cause skin 

damage. If measurements are not available, an 

approximation of ambient UVR levels can be based 

on geographic latitude. 

For individuals, the UVR exposure additionally 

depends on factors such as behaviour and use of 

sun protectants, e.g., clothing, hats, sunscreen and 

sunglasses, during outdoor (including occupational) 

activities. A person’s skin type is also important. 

Fair skinned people suffer from sunburn much 

more readily than dark-skinned people. 

Health consequences of excessive UVR exposure 

Using evidence systematically collected from 

the scientific literature, WHO has identified nine 

adverse health outcomes that are clearly caused by 

UVR exposure. An assessment of the global disease 

burden, comprising both mortality and morbidity, 

was completed for these health outcomes. The nine 

diseases assessed were: 

Cutaneous malignant melanoma (CMM): Melanoma 

of the skin is a malignant cancer of great 

s e v e r i t y. Although treatment is improving, 

melanoma still carries a significant risk of 

death. Between 50% and 90% of the burden of 

disease from melanoma estimated in the WHO 

report is due to UVR exposure. 

Squamous cell carcinoma of the skin (SCC): This is 

another type of malignant skin cancer which 

generally pro g resses less rapidly than 

melanoma and is less likely to cause death or 

ongoing disability. Of the total SCC disease 

b u rden, 50-70% is attributable to UVR exposure. 

Basal cell carcinoma of the skin (BCC): This skin 

cancer appears predominantly in older people 

and grows slowly by local spread. The 

incidence and mortality of BCC were estimated 

to be 50-90% attributable to UVR exposure. 

Squamous cell carcinoma of the cornea or 

conjunctiva (SCCC): This is a rare tumour of the 

surface of the eye. Some 50-70% of the disease 

burden due to SCCC is attributable to UVR 

exposure. 

The following conditions are also the consequence 

of excess UVR, but there is considerable uncertainty 

about the overall burden of disease estimates, since 

few data are available on incidence and/or UVattributable 

fraction: 

Photoageing: Chronic sun damage is associated 

with the development of skin conditions 

called solar keratoses. On rare occasions, these 

are pre-malignant conditions. The burden of

256 

disease due to solar keratoses is 100% 

attributable to UVR exposure. 

S u n b u r n : Sunburns may be severe and 

blistering, and the resulting disease burden is 

100% attributable to UVR exposure. 

Cortical cataract: Cataract is an eye disease 

where the lens becomes increasingly opaque, 

resulting in impaired vision and eventual 

blindness. Long term sun exposure to the eye 

increases the risk of developing a specific 

cataract type called cortical cataract. Five 

percent of all cataract-related disease burden is 

directly attributable to UVR exposure. 

P t e r y g i u m : This is a wing-shaped fleshy 

growth on the surface of the eye. 40-70% of the 

disease burden is attributable to UVR exposure . 

Reactivation of herpes of the lip (RHL): Excessive 

UVR exposure causes immunosuppression 

and reactivation of the herpes simplex virus 

(“cold sores”). 25-50% of the disease burden is 

attributable to UV exposure. 

Estimates of global UV disease burden 

WHO uses disability adjusted life years 

( D A LYs) to measure the health detriment 

associated with a particular health outcome. 

DALYs combine the life years lost due to premature 

mortality associated with the disease and the 

number of years lost due to disability. Thus, one 

DALY is equivalent to one lost year of life in full 

health. 

The following table summarizes the DALYs and 

mortality attributable to excessive UVR exposure 

for the nine diseases listed above and calculated for 

the year 2000. The upper and lower estimates 

indicate the variation that depends on actual 

assumptions and values used in the calculations. 

Globally, around 1.5 million DALYs (0.1% of the 

total global burden of disease) are lost every year 

due to excessive UVR exposure. The estimates 

concerning sunburn and reactivation of the Herpes 

Simplex virus (cold sores) are re g a rded as 

particularly uncertain. Therefore, summary DALY 

estimates are also presented excluding these health 

problems(Table 1). 

In terms of mortality, only the three skin cancers 

contribute to deaths that can be attributable to 

excessive UVR exposure. Between 41,000 and 

71,000 deaths, with a best estimate of around 60,000 

were attributed to excessive UVR exposure in 2000. 

Regional differences 

The main health effects contributing to the UVRrelated 

disease burden differ by region: 

In the WHO European region, with a 

predominantly fair-skinned population, melanoma 

is by far the largest cause of UVR-attributable 

WHO-Facts Sheet September 2006 

Table 1: DALYs (000) Deaths Estimates 

Disease Upper Lower Upper Lower 

Estimate estimate estimate estimate 

CMM 621 345 58645 32581 

SCC of skin 83 59 9474 6767 

BCC of skin 52 29 2921 1623 

Solar keratoses 8 8 0 0 

Sunburn 294 294 0 0 

Cortical cataract 529 529 0 0 

Pterygium 35 20 0 0 

SCCC 2 1 0 0 

RHL 68 34 0 0 

Total 1692 1319 71 039 40970 

Total* 1330 991 71 039 40970 

*(excluding sunburn and RHL) 

disease burden. Similar results are found in some 

countries of the WHO Western Pacific re g i o n , 

notably Australia, Brunei, Japan, New Zealand and 

Singapore. In most of the Americas, melanoma 

represents the greatest UVR-attributable disease 

burden, but sunburn also contributes significantly. 

In the WHO African Region, the main burden of 

disease attributable to UVR is cataract. Even 

though cutaneous malignant melanoma is 

uncommon in deeply pigmented populations, it 

accounts for the second greatest burden of disease 

in this region. 

Cataract also causes the greatest UVRassociated 

disease burden in some countries of the 

WHO American region such as Bolivia, Ecuador, 

Guatemala, Haiti, Nicaragua, and Peru and in the 

Eastern Mediterranean Region notably in Egypt, 

Saudi Arabia, Iran and Iraq. Similarly, in WHO 

South East Asia Region, in countries like Indonesia, 

Thailand, India, and Bangladesh, cataract is the 

most important cause of disease. In several Western 

Pacific countries including China, Malaysia and the 

Philippines, sunburn and cataract are the leading 

U V- related ill health effects, followed by 

melanoma. 

Beneficial effects of UVR exposure 

UVR exposure has beneficial effects, mainly in 

the production of vitamin D. Adequate vitamin D 

prevents the development of bone diseases such as 

rickets, osteomalacia and osteoporosis. Possible 

beneficial effects on some cancers and immune 

disorders are under intense scientific investigation. 

Populations living at low latitudes (who have not 

evolved a diet high in vitamin D) and deeply 

pigmented populations particularly rely on UVR to 

produce adequate Vitamin D levels. 

For the purpose of a theoretical assessment of


the effect of lack of UV, WHO has conducted model 

calculations. If zero exposure to UV leading to 

widespread and profound Vitamin D deficiency 

were assumed, more than 3.3 million DALYS would 

be lost annually from diseases related to Vitamin D 

d e f i c i e n c y. Importantly, this is not the curre n t 

situation. Although research suggests that many 

people may have lower vitamin D levels than might 

be optimal, these are not in the range that causes 

the above-mentioned bone diseases. Indeed, rickets 

and osteomalacia are uncommon diseases. In most 

circumstances, minimal casual exposure to UVR is 

sufficient to maintain vitamin D at a level that 

avoids these health problems. 

O v e r- e x p o s u re to UVR, rather than underexposure, 

therefore remains the primary public 

health concern. The detailed and appropriate sun 

exposure advice to avoid diseases of excessive UVR 

e x p o s u re and of vitamin D deficiency is best 

framed by local health authorities, taking into 

account the skin type of local populations and 

ambient UVR of the region. 

Prevention of UVR overexposure - WHO 

recommendations 

Limit time in the midday sun: The sun’s UV 

rays are the strongest between 10 am and 2 pm ( = 

2 hours each side of the solar noon). To the extent 

possible, limit exposure to the sun during these 

hours. 

Use shade wisely: Seeking shade when UV 

rays are the most intense is re c o m m e n d e d , 

however, shade structures such as trees, umbrellas 

or canopies do not offer complete sun protection. 

The shadow rule: “Watch your shadow - Short 

shadow, seek shade!” serves as a simple aidememoire. 

Wear protective clothing: A hat with a wide 

brim offers good sun protection for eyes, ears, face, 

and the back of your neck. Sunglasses, with 

adequate side protection that provide 99 to 100 

percent UV-A and UV-B protection will greatly 

reduce eye damage from sun exposure. Tightly 

woven, loose fitting clothes will provide additional 

protection from the sun. 

Use sunscreen: Liberal application of a broadspectrum 

sunscreen of SPF 15+ and re-application 

every two hours, or after working, swimming, 

playing or exercising outdoors, can help protect the 

skin from UVR. The application of sunscre e n s 

e x p o s u re should not be used to prolong sun 

e x p o s u re but rather to protect the skin when 

exposure is unavoidable. 

Avoid sunlamps and tanning parlours: 

Sunbeds damage the skin and unprotected eyes 

and are best avoided entirely. WHO recommends 


that youth under the age of 18 do not use them at 

all. 

Know the UV index: The UV index is a 

measure of UV radiation (see www.who.int/uv). 

The higher the UV index, the higher the risk of skin 

and eye damage. Use the UV index to plan sun-safe 

outdoor activities. When the UV Index predicts 

radiation levels of 3 (moderate) or above, sun safety 

practices should be taken. 

Protect children: Children are generally more 

susceptible to environmental hazards than adults. 

During outdoor activities, they should be protected 

f rom high UV exposure as above, and babies 

should always remain in the shade. The promotion 

of sun protection in schools is particularly 

important to make children aware of the risks of 

o v e re x p o s u re and how to avoid it. WHO has 

developed special programmes to address this 

issue. For more information see www.who.int/UV. 

Prevention of vitamin D deficiency 

The risks of vitamin D deficiency due to undere 

x p o s u re to UVR have been much publicized 

re c e n t l y. Considerable re s e a rch is curre n t l y 

underway to better understand these risks and 

appropriate levels of sun exposure. Populations 

who have very low sun exposure, such as 

institutionalized individuals (e . g . , prisoners), deeply 

pigmented persons living in low UVR settings (e.g., 

at high latitude) or those who, for religious or 

cultural reasons cover their entire body surface 

when they are outdoors, should, in consultation 

with their doctor, consider a vitamin D nutritional 

supplement. For the large majority of people 

worldwide, prevention of overexposure to UVR 

(using the above advice) remains the main health 

concern. 

For more information contact: 

mediaenquiries@who.int or phone: 041 22 791 22 22; 

fax: 41 22 791 48 58 

3. LAUNCH OF GLOBAL EARLY WARNING 

SYSTEM FOR ANIMAL DISEASES 

TRANSMISSIBLE TO HUMANS 

A global early warning system for animal 

diseases transmissible to humans (zoonoses) was 

formally launched in July 2006 by the UN Food and 

A g r i c u l t u re Organization (FAO), the Wo r l d 

O rganization for Animal Health (OIE) and the 

World Health Organization (WHO). 

The Global Early Warning and Response System 

(GLEWS) is the first joint early warning and 

response system conceived with the aim of 

p redicting and responding to animal diseases 

including zoonoses worldwide. This system

258 

builds on the added value of combining and 

coordinating the tracking, verification and alert 

mechanisms of OIE, FAO and WHO. 

“ F rom an animal health point of view, 

c o n t rolling contagious animal diseases in their 

early stages is easier and less expensive for the 

international community. In cases of zoonoses this 

system will enable control measures that can also 

benefit public health ,” explained Dr Bernard 

Vallat, Director General of the OIE. 

As demonstrated throughout much of the globe, 

weaknesses of early detection and rapid response 

for animal diseases, and the inability to control 

major diseases at their source, have contributed to 

the spread across borders of diseases of animal 

origin such as bovine spongiform encephalitis 

(BSE), Severe Acute Respiratory Syndrome (SARS) 

and avian influenza. 

“In such a context, the main expected outputs of 

GLEWS are better prediction and prevention of 

animal disease threats, through sharing of 

information, epidemiological analysis and joint 

field missions to assess and control outbreaks in 

animals and humans. That will lead to the 

development of improved coordinated response to 

emergencies worldwide,” said Dr. Samuel Jutzi of 

FAO’s A g r i c u l t u re, Biosecurity, Nutrition and 

Consumer Protection Department. 

WHO-Facts Sheet September 2006 

“History shows us that the earlier we can detect 

a zoonosis, the early we can take action to reduce 

the threats to people. Today, the spread of avian flu 

reinforces the fact that the animal and human 

health sectors must work closely together, and that 

early detection and coordination is critical. This 

new network is an important step forward , ” 

explained Mrs Susanne We b e r-Mosdorf, WHO 

Assistant Dire c t o r-General, for Sustainable 

Development and Healthy Environments. 

The information gathered through the tracking 

and verification channels of each organization will 

be shared using the GLEWS web-based electronic 

platform and jointly analyzed to decide whether to 

issue common early warning messages. These alert 

messages will describe the possible implications of 

disease spread among animals at national, regional 

and international level and its potential public 

health impact. If there is a clear indication that a 

joint on-site assessment or intervention is required, 

the response mechanisms of the three organizations 

will be activated together. 

For more information contact:Gregory Hartl, 

telephone +41 22 791 3576,email hartlg@who.int 

or Franczois Meslin, 

telephone +41 22 791 2575, email meslinf@who.int

KUWAIT MEDICAL JOURNAL (KMJ)

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