Chapter 81

81 

CHAPTER 

Pediatric Features of 

Malignant Hyperthermia 

Renée Krivosic-Horber 

INTRODUCTION 

Malignant hyperthermia (MH) was first described in 1960 as a fatal 

complication of anesthesia occurring in members of the same 

family. 1 A higher incidence in children younger than 18 years was 

observed from the beginning and has been a constant finding 

in all epidemiologic studies of MH. This explains the emotional 

reaction to a “silent disease” that killed many young people. 

However, it is important to note that this higher incidence concerns 

only the triggering of an MH episode by anesthesia and not the 

other phenotypes (i.e., positive in vitro contracture test [IVCT], 

subclinical signs of myopathy, the increase in creatine kinase [CK] 

plasmatic levels, and the rare clinical myopathy called central core 

disease [CCD]). MH is a potentially lethal state of paroxysmal 

hypercatabolism induced in striated muscle by halogenated volatile 

anesthetic agents and/or the depolarizing curare succinylcholine 

in individuals suffering from a specific muscle abnormality, inher - 

ited as autosomal dominant. The designation “MH” persisted over 

time even though hyperthermia is a late symptom of the disease. 

This pharmacogenetic disorder of skeletal muscle is generally 

associated with mutations in the ryanodine receptor isoform 

1 (RyR1) of sarcoplasmic reticulum (SR). MH crises develop not 

only in humans but also in other species, particularly pigs, that have 

been a valuable source for scientific research. Reactions have also 

been described in horses, dogs, and other animals. 2 

EPIDEMIOLOGY 

The evaluation of the incidence of MH crisis is dependent on many 

factors, especially the criteria for diagnosis of the MH crisis and 

the techniques and anesthetic drugs used. Epidemiologic studies 

should be critically analyzed according to the period observed 

and the means of diagnosis: clinical signs and determination of 

the phenotype by an in vitro contracture test (IVCT) or the geno - 

type by the discovery of a causative MH mutation. 3 The estimated 

prevalence of the MH genetic abnormalities in the general 

population may be as great as 1 in 3000 individuals (range 1:3000– 

1:8500). 4 

The MH crisis has been observed among all races, regardless of 

gender, and all ages. The impact of the MH crisis is highest among 

children, with a peak among adolescents, whereas it becomes rarer 

after 40 years of age. Although MH is not a sex-linked trait, males 

are more commonly affected (male-to-female ratio 1:5). 5,6 The first 

case published in France in 1971 was a fulminant fatal crisis in a 

girl aged 13 years old. 7 In the first survey published in Canada in 

1970, the incidence of MH was estimated at 1 in 15,000 pediatric 

anesthesia, much higher than the estimated 1 in 50,000 in adults. 5 

In 1985, Ording and coworkers could gather results based on 

information about 386,250 anesthetics in Denmark and 154 cases 

of suspected MH. 8,9 All cases of MH occurred during general anes - 

thesia, and more than 75% during anesthesia with a combination 

of potent inhalation agents and succinylcholine. The incidence of 

fulminant MH was low: l in 250,000 total anesthetic procedures, 

but 1 in 62,000 anesthetic procedures with a combination of potent 

inhalation agents and succinylcholine. Masseter spasm (MS) 

occurred in 1 of 12,000 anesthetic procedures in which succinyl - 

choline was administered. Suspicion of MH was raised in 1 of 

16,000 anesthetics total, but in 1 of 4200 anesthetics with the pre - 

viously mentioned combination of agents. 8,9 

Information concerning probands whose malignant hyper - 

thermia susceptibility (MHS) has been proved by IVCT is avail - 

able. 10,11 The proband is defined as the first member of a family 

to have a suspected MH reaction. The majority (61%) of the 

197 MHS probands were children and adolescents aged between 

0 and 19 years. In every instance, they were apparently American 

Society of Anesthesiologists (ASA) 1or 2 preoperatively and death 

(24%) was completely unexpected. In 1993, Strazis and Fox 

investigated the epidemiology of MH by analysis of 336 publi - 

cations. 12 Five hundred three cases of MH were reported. The 

patients’ ages ranged from newborn (reaction to cesarean section 

anesthesia) to 73 years. The mean age was 18.3 years. The pediatric 

age group was a much larger proportion of the population studied 

(52.1%, age < 15 y) than the general surgical population (5% in 

the United States). Male gender (65.8%) of MH patients exceeds 

the general surgical population. Congenital defects and muscu - 

loskeletal surgical procedures were clearly associated with MH. 

Previous uneventful anesthesia (20.9%) and absence of positive 

family history (75.9%) were common. Case fatality rates have 

decreased over time from 80% before 1965 to 16% after 1980. One 

limit of this study is the absence of information concerning the 

confirmation of MH by IVCT. 

MH cardiac arrests still concern young people, as was shown 

by Larach and colleagues who analyzed the American database for 

AMRA (adverse metabolic/musculoskeletal reaction to anes - 

thesia) with inclusion criteria as follows: event date between 

January 1, 1987, and December 31, 2006; “very likely” or “almost 

certain” MH as ranked by MH clinical grading scale. 13 The median 

age of the 8 cases of cardiac arrest (2.7%), of whom 4 (1.4%) died 

was 20 years (range 2–31 y), 12 years for the survivors and 22 years 

for the deaths. By contrast with these classical data, an incidence 

of only 18% pediatric patients (

CHAPTER 81 ■ Pediatric Features of Malignant Hyperthermia 1363 

TABLE 81-1. Published Cases of Anesthetic Malignant Hyperthermia in Newborns and Infants 

Associated 

Reference Age/Sex/Death Triggering/Dantrolene Abnormalities IVCT Genetics 

Peltz, 1975 15 19 mo/M/no Halothane and No No No 

succinylcholine 

Mayhew, 1978 16 6 mo 

Faust, 1979 17 6 mo/no No/no No Yes, both No 

parents MHN 

Sewall, 1980 18 Neonate/ No (cesarean No No No 

M/no 

section)/no 

Bailey, 1987 19 3 mo/F/no Halothan/yes Arthrogryposis No No 

Wilhoit, 1989 20 

Dubrow, 1989 21 8 MHS Halothane No Yes, positive No 

children 

Krivosic, 1990 22 , 19 < 3 y Halothane 15 no/1 Becker’s/1 Yes, in patients 5 mutations 

personal data 5/+succinylcholine Duchenne’s/3 or family 11 RYR1 

8/sevoflurane 6. syndromic MHS/8 MHN 

Hinkle, 1993 23 Newborn Succinylcholine CCD No No 

to the mother 

with MS/no 

Semmler, 1994 24 14 mo/M/no Halothane/yes No Yes, father No 

MHS 

Pennington, 1996 25 3 mo/M/no Halothane/no No No No 

Chamley, 2000 26 6 mo Halothane/no No Yes, 13 y Yes 

Kinouchi, 2001 27 9 mo/M/no Sevoflurane/yes King’s syndrome No No 

Bonciu, 2007 28 19 mo/M/no Sevoflurane/no No Yes, father No mutation 

MHS 

CCD = central core disease; IVCT = in vitro contracture test; MHN = malignant hyperthermia nonsusceptible; MHS = malignant hyperthermia susceptible; 

MS = master spasm. 

inpatient database in the United States, was used to identify 

patients discharged with a diagnosis of MH during the years 2000 

to 2005. The occurrence of MH increased from 10.2 to 13.3 

patients per million hospital discharges (372–521/y; P < .001). 

Mortality rates from MH ranged from 6.5% in 2005 to 16.9% in 

2001 (P < .0001). The median age of patients with MH was 

39 (interquartile range 23–54 y). Only 17.8% of the patients were 

children, who had lower mortality than adults (0.7% vs 14.1%, 

P < .0001). However, there are many biases in the study that may 

lead to doubt if these numbers reflect the true incidence of MH 

episode triggered by anesthesia. The authors included all hospital 

discharge records with a diagnosis of MH since October 1997, the 

International Classification of Diseases, 9th edition, Clinical 

Modification coding system has provided a specific diagnosis code 

for MH as a result of anesthetics. 14 They excluded other conditions 

associated with hyperthermia. Yet, they could not get any infor - 

mation concerning the triggering anesthetics and the use of 

dantrolene sodium (DS). Many pediatric cases could be missing 

because the study analyzed only the inpatients, most of the 

children are anesthetized on an outpatient basis, and the authors 

are not sure they have covered all the children’s hospitals. The 

lower mortality rate found in pediatric patients (0.7%) compared 

with in adults (14.1%) was similar to that found in the North 

American Malignant Hyperthermia Registry (NAMHR) study. 

The main limitations of this study are related to the total absence 

of confirmation of the diagnosis of MH either by IVCT or by 

genetic analysis or at least an MH clinical grading scale score. The 

association of hyperthermia and anesthesia is not a proof of MH. 

The fulminant MH crises associated with hyperthermia were 

already the less frequent presentation of MH in 2000 and the 

following years. The predominance of an MH anesthetic reaction 

in adolescents and young adults is obvious but has not been 

explained until now. A possible higher use of the triggering agents 

could be a cause associated with a higher level of sympathetic tone. 

By contrast, the existence of MH crisis in newborns and infants 

remains controversial. 

Some of the most informed published reports of MH are 

gathered in Table 81–1. 15–28 The only newborn case was published 

as a severe muscular rigidity in a premature male infant born by 

cesarean section under general anesthesia. A probable diagnosis of 

MH was supported by the clinical symptoms of muscular rigidity 

and cyanosis, a creatinine phosphokinase of 24,630 IU. The muscle 

tone and laboratory values slowly returned to normal over a 

period of days. 18 In the case of a 6-month-old infant reported by 

Faust and associates, there was no triggering agent used and both 

of the child’s parents had normal creatine phosphokinase (CPK) 

values and negative caffeine-halothane stimulation tests. As far as 

we know, there are very few infant cases proved by the identi - 

fication of a novel RYR1 mutation. 17 

PHYSIOPATHOLOGY 

Understanding the normal muscle contraction is a necessary 

step to understand what happens when the muscle with an MH 

mutation is in contact with a volatile anesthetic. Normally, the 

depolarization of the sarcolemma is induced by the transmission 

of nerve impulses through the motor plate. Acetylcholine is 

released into synaptic cleft and binds to receptors on postsynaptic

1364 PART 4 ■ Special Monitoring and Resuscitation Techniques 

neuron. Action potential is transmitted in sarcolemma and along 

the T-tubule causing the release of calcium from cisternae of SR 

due to the opening of the so-called calcium released channel or 

ryanodine receptors RYR1. The RYR to which the plant alkaloid 

ryanodine specifically binds is the major channel for Ca 2+ release 

from intracellular stores in skeletal muscle. It mediates the 

T-tubular depolarization-induced Ca 2+ release from the SR. The 

increase of the sarcoplasmic level of calcium initiates the contrac - 

tion cycle through the action on thick and thin filaments (i.e., 

calcium binds to troponin, troponin moves, displacing the trop - 

omyosin complex and exposing actin at the active site, myosin 

head forms a cross-bridge and bends toward the H zone, the 

adenosine triphosphate [ATP] allows release of the cross-bridge). 

Relaxation occurs when the process is stopped at the neuro - 

muscular junction, there are no more action potential and no 

more excitation contraction coupling. The calcium ions return 

into the SR, using ATP (Figure 81–1). 

The muscle contraction uses energy coming, first, from the 

creatine phosphate with the action of the enzyme CK, and very 

quickly from the increase of activity of the mitochondriae. This 

aerobic metabolism is very effective, producing 36 ATP molecules 

for 1 molecule of glucose. The increase of O 2 

con sumption and CO 2 

excretion is important and immediate. A percentage of the energy 

is lost in heat, leading to an increase in the body temperature. 

If the production of energy by the aerobic metabolism is not 

sufficient, because the muscle activity is too high (sprint) or too 

long (marathon), the anaerobic metabolism is “solicited.” It is much 

less effective, producing only 3 ATP molecules per 1 molecule of 

glucose, and produces lactic acid. In MH, the mutated calcium 

release channels open abnormally in the presence of an anesthetic 

volatile agent (AVA), producing the same phenomenon. However, 

there is no relaxation as long as the AVA is present (Figure 81–2). 

CLINICAL DESCRIPTION 

The characteristic feature of MH is a hypermetabolic response to 

potent inhalation agents and/or succinylcholine characterized by 

increased CO 2 

production, O 2 

consumption, and muscle mem - 

brane breakdown. 

Figure 81-1. Physiology of the muscle contraction. 

Pharmacologic Triggers of MH Crisis 

All halogenated agents are MH triggers: halothane, 22 methoxy - 

flurane, enflurane, isoflurane, sevoflurane, 28 and desflurane. 29 New 

halogenated agents trigger weaker muscle contracture than 

halothane, on human muscle in vitro as well as in the pig model in 

Figure 81-2. Physiopathology of the malignant 

hyperthermia (MH) crisis.


vivo. 29,30 These data seem to confirm in vivo observations of more 

delayed and pernicious crises that could make diagnosis more 

difficult. An MHS patient presents variable responses to triggering 

agents and the responses may depend on many other factors. 

Thus, she or he may be a victim of a fulminant MH crisis even if 

she or he was previously exposed to the triggering agent without 

any problem. 31 History without anesthetic particularities of a 

patient should never challenge a hypothetical diagnosis of MH. 

The depolarizing curare (succinylcholine) encourages and 

accelerates the MH crisis clinically in the context of MS 32 and 

experimentally on the porcine model. 33 There is currently no 

documented report on the outbreak of a fulminant crisis by 

MH depolarizing curare in the absence of halogenated agent 

in a patient whose HM susceptibility was proved by IVCT. 

Succinylcholine could open the mutated RYR1 channels during 

the depolarizing phase, inducing an increase in muscle tone, 

especially the masseter, but only for less than 3 minutes. By con - 

trast, the nontriggering power of the other anesthetic agents or 

other additives of anesthesia seems now acquired. 34 One report 

suggested that, in patients known to be MHS, the incidence of 

triggering after exposure to a nontriggering anesthetic is not 

zero. 35 In their study of 2214 patients undergoing muscle biopsy to 

rule out MH, 1082 had a positive contracture tests. Of those 

patients found to be positive, 5 developed moderate signs of MH 

in the perioperative period, yielding an incidence rate of 0.46% 

(confidence interval [CI] 0.058–0.866). However, this report is not 

a reason to reconsider the safety of anesthesia without triggering 

agents in MHS patients (Table 81–2). 

Clinical Signs of MH Crisis 

The clinical signs can be gathered in three groups of symptoms 

according to the physiopathology: (1) hypermetabolism, (2) mus - 

cular rigidity, and (3) rhabdomyolysis. The clinical and biologic 

signs are summarized in Figures 81–3 and 81–4. The time to onset 

of the crisis, in the absence of injection of succinylcholine, is highly 

variable after the start of inhalation of halogenated agents. It seems 

unlikely that a crisis can begin in the postoperative period, 

TABLE 81-2. Safe and Unsafe Drugs 

Unsafe Drugs 

Depolarizing muscle relaxants: succinylcholine 

Volatile halogenated anesthetics: halothane, isoflurane, 

enflurane, desflurane, sevoflurane 

Safe Drugs 

Barbiturates 

Propofol 

Benzodiazepines 

Droperidol 

Nitrous oxide 

Local anesthetics amides and esters 

Nondepolarizating muscle relaxants 

Morphine and morphinomimetics 

Ketamine 

Antibiotics 

Antihistamines 

Antipyretics 

Propranolol 

Vasoactive drugs 

Figure 81-3. Clinical signs of the MH crisis. 

after the end of administration of the triggering agents 36,37 (see 

Figure 81–2). 

Hypermetabolism 

Signs of hypermetabolism are early. The first sign is a significant 

increase of arterial carbon dioxide pressure (PaCO 2 

) and end-tidal 

carbon dioxide pressure (PETCO 2 

) visualized on the capnometer 38,39 

(Figure 81–5). The increase in oxygen consumption (VO 2 

) is 

suggested by the decrease of Fractional concentration of end-tidal 

O2 (FETO 2 

). If mixed venous oxygen saturation (SVO 2 

) monitoring 

is available, it will show a dramatic decrease (Figure 81–6). The 

MH crisis does not cause detectable desaturation of arterial blood, 

because of the high fractional con centration of oxygen in inspired 

gas (FI O2 ) most often used during anesthesia. However, attention 

must be drawn by cyanosis of venous blood in the operative field, 

reflecting a considerable increase in muscle VO 2 

and resulting in 

the collapse of SvO 2 

. The tachypnea can be evocative in a patient 

with spontaneous venti lation of a response to a hyperproduction of 

CO 2 

. In the case of controlled ventilation, the sudden increase of 

PETCO 2 

would also be an indication of this hyperproduction. 

Acidosis is initially purely hypercapnic; however, it evolves rapidly 

in a mixed acidosis owing to severe anerobic metabolism (see 

Figure 81–4). Tachycardia is almost always observed; however, 

because it is commonplace in anesthesia in children, it is often not 

Figure 81-4. Biologic signs of the MH crisis.


Figure 81-5. End-tidal carbon dioxide 

pressure (PETCO 2 

). 

considered specific. The ventricular arrhythmias due to sympa - 

thetic hyperactivity and hyperkalemia (from rhabdomyolysis) are 

frequent but not constant. Signs of circulatory failure appear lately, 

because initially, increased cardiac output is proportional to the 

induced hyper metabolism. Hyperthermia is a response to the 

production of heat by the muscular contracture. It is usually 

delayed because of the fact that the whole body must be heated 

before observing a significant raise in temperature. This sign 

occurs earlier in children due to the lower body mass; however, it 

remains a late sign in most cases. The elevation of body tempera - 

ture can reach 43°C in fulminant forms shortly preceding death. 

Muscular Rigidity 

Muscular rigidity is a specific sign, but late and not constant. 

It may be early in patient in whom anesthesia was induced with a 

volatile agent and muscle relaxation was induced with injection of 

succinylcholine. It manifests itself as a severe MS. The reasons for 

this specific localization are the masseter muscles are the strongest 

muscles of the organism and often the first evidence noticed by 

the anesthesiologist while taking care of the airway. If the MH 

episode develops further, the muscle rigidity involves the lower 

limbs and, subsequently, the whole body. In the fulminant MH 

crisis, it is impossible to bend the arms and legs. The rigidity 

remains after death but, unlike the rigor mortis, does not dis - 

appear after mobilization (Figure 81–7). 

Rhadomyolysis 

The muscle contracture induces a suffering of the muscle mem - 

branes, leading to the leakage from the sarcoplasm to the blood of 

intracellular components. Rhabdomyolysis is confirmed by the 

determination of high serum levels of potassium, myoglobin, and 

CK. The time to maximum increase is in relation with the molec - 

ular weight. The hyperkalemia is immediate and can cause sudden 

cardiac arrest; however, it is not constant. It is sometimes replaced 

by hypokalemia. Myoglobinuria, red color urine, is maximal within 

2 to 4 hours. The increase in CK is more delayed with a maximum 

between 12 and 24 hours. Elevated CK is variable depending on 

the duration and severity of the crisis. It can reach up to 1000 times 

the normal value. The results should be inter preted taking into ac - 

count the type of surgery, the position, and possible traumatic con - 

text. It is essential to repeat CK blood levels regularly during the 

first 24 hours, because an increase could reflect a delayed resum - 

ption of rhabdomyolysis. If the MH episode is not stopped early 

enough, cardiovascular shock will occur in association with wide - 

spread vital organ dysfunction, disseminated intravascular coagu - 

lation (DIC), and irreversible cellular damage leading to death. 40 

MANAGEMENT AND TREATMENT 

Despite significant progress made in the diagnosis and treatment 

of this disease, the MH crisis remains potentially fatal if the ad - 

ministration of the triggering agent is continued and treatment is 

not instituted. This medical condition is very rare and statistically 

might be experienced less than once in a lifetime. The fact that it 

occurs often during anesthesia for emergency surgery is unfa - 

vorable to optimal care. The treatment should be initiated as 

soon as the diagnosis is evoked. Stopping the administration of 

halogenated agent and starting the intravenous injection of DS 

are the two therapeutic measures whose success depends on the 

immediate and early decision. The diversity of tasks involves 

the use of all personnel immediately available, coordinated by the 

anesthesiologist. 

Figure 81-6. Mixed venous oxygen saturation (SVO 2 

). 

Figure 81-7. Contracture of the quadriceps during the MH crisis.


Figure 81-8. Dantrolene. 

DS is a hydantoïc compound that has long been used to fight 

against muscle spasticity from pyramidal origin (Figure 81–8). 

It is used in humans since the mid-1970s as a treatment for MH 

crisis. It is a muscle relaxant acting directly on the skeletal muscle, 

most probably at the calcium channel RyR1. The sole mechanism 

of action currently known is the inhibition of the release of 

calcium from the SR toward the sarcoplasm. 41 DS has no effect 

on the neuromuscular transmission. It is also efficient on the 

smooth muscles. For example, it provokes uterine relaxation 

during labor and/or vomiting owing to relaxation of the gastroin - 

testinal muscles. No cardiodepressive effect has been demon - 

strated at therapeutic doses. In the first report of clinical use in 

human MH reactions, DS therapy at a dose of 2.5 mg/kg resulted 

in a statistically significantly lower mortality rate than would have 

normally been expected in MH patients. The study was supported 

by animal data, suggesting that DS was specific in reversing MH 

cellular process. 42 Peak DS plasma concentrations of 4.2 mg/L were 

obtained 3 hours after administering bolus injections of 0.1 mg/kg 

until a twitch depression plateau was reached (2.2- to 2.5-mg/kg 

cumulative dose). 43 Shime and coworkers have shown that 

the administration of DS was safe in 20 pregnant MHS vomen. 44 

The mean maternal predelivery DS level was 0.99 ± 0.5 µg/mL, 

and the mean neonatal cord blood DS level 0.68 ± 0.3 µg/mL. The 

half-life of DS in the neonatal circulation was 20 hours. 44,45 

The combination of DS and verapamil results, in the pig model, 

in severe arrhythmias and possible ventricular fibrillation. The 

simultaneous use of DS and a calcium antagonist in the treatment 

of the MH crisis is strongly discouraged because it is known to be 

potentially dangerous. In France, the availability of DS is under 

the responsibility of the director and the pharmacist of the health 

facility. Eighteen vials (5 mg/kg) and the quantity of distilled water 

needed for injection (60 mL/vial) should be immediately available 

in all areas where anesthesia is provided. The access to 36 vials 

(10 mg/kg), which may be necessary to treat an MH crisis, must 

be well organized and readily available. A poster indicating the 

therapeutic algorithm recommendations in cases of MH should 

be displayed (see Figure 81–4). These guidelines consist of: 

1. Stop the triggering agent and maintain the anesthesia with 

nontriggering anesthetics, such as propofol, opioids, and 

benzodiazepines. 

2. Increase minute ventilation with 100% O 2 

to lower PETCO 2 

. 

3. Get help. 

4. Mix, shake, and administer intravenous DS 2.5 mg/kg initial 

dose (for a 70-kg adult: 175mg = 9 vials for a total volume of 

540 mL; for a 30-kg 11-y-old child: 75 mg = 4 vials or a total 

volume of 225 mL). 

● Titrate DS while following clinical signs such as tachycardia 

and hypercarbia. 

● 10 mg/kg is the suggested upper limit. 

5. Administer bicarbonate 1 to 2 mEq/kg in case of severe 

metabolic acidosis. 

6. Treat arrhythmias as needed. Do not use calcium channel 

blockers. 

7. Begin cooling measures and stop them when the central 

temperature is under 38°C. 

8. Secure blood gases, electrolytes, CK, blood, and urine for 

myoglobin. 

● Coagulation profile check values every 6 to 12 hours. 

9. Treat hyperkalemia with hyperventilation, glucose, and 

insulin as needed. 

10. Continue DS at 1 mg/kg every 4 to 8 hours for 24 to 48 hours. 

Mechanical ventilation is mandatory to compensate for the 

respiratory depression induced by DS. 

11. Monitor urinary output to prevent acute tubular necrosis and 

the presence of myoglobinuria. Administer extra mannitol 

(because it is also present in the DS solution) and saline in 

case of myoglobinuria. 

12. Observe the patient in the intensive care unit for at least 

36 hours. Twenty percent of patients will experience a 

recrudescence of the syndrome. 40 Do not forget to take into 

account the potential respiratory depression induced by the 

myorelaxant effect of DS. The plasma elimination half-life is 

10 to 13 hours in adults and in children. 45 

13. Refer the patient and family to the MH testing center for 

contracture and DNA testing. 

Most patients with MH can be treated successfully with this 

protocol; however, recurrence of the clinical signs and symptoms 

of MH can occur hours after resolution of the initial event. 40 With 

data obtained from AMRA reports in the NAMHR, it was possible 

to show that recurrences happened in 20% of patients. The mean 

time from initial reaction to a second break in the symptoms was 

13 hours (standard deviation [sd] 13 h). Organ failure was more 

frequent in the group subjected to a recurrence of the symptoms 

(32% vs 12%; P < .001). The more severe the MH reaction, the 

more likely is the probability of a second attack of the symptoms. 

These results support the need to manage the patient in the 

intensive care unit after a severe MH reaction. Death may still 

occur. 13 However, brain damage is very rarely reported as sequelae. 

Interestingly, talipes equinus deformity of bilateral lower limbs, a 

condition similar to compartment syndrome, has been reported 

after MH in a previously healthy pediatric patient. 46 

DIFFERENTIAL DIAGNOSIS 

Intraoperative 

Among the signs of an MH crisis, the increase of PETCO 2 

shown 

on the capnograph is the most sensitive (Figure 81–9). 38 The 

clinical diagnosis of MH cannot be certain except in a fulminant 

form with generalized rigidity, hyperthermia exceeding 40°C, and 

hypercapnia exceeding 70 mmHg. This form, often irreversible, 

tends to disappear with an early diagnosis because of the sys - 

tematic use of capnography and a better appreciation of the early 

signs. The analysis of 402 patient charts demonstrated that it is


Figure 81-9. Differential diagnosis. 

often difficult to establish immediately and with certainty the 

diagnosis of MH. It is essential to deal with any clinical suspicion. 11 

The diagnosis is supported by an immediate arterial and venous 

puncture to measure PaCO 2 

, pH, arterial oxygen pressure 

(PaO 2 

), lactates, electrolytes, myoglobin, and CK. This approach 

has helped to diagnose more MH of incomplete or aborted 

presentation as well as those in which the prognosis was much 

better. 

The development of a scoring system helping to determine 

a diagnostic probability was proposed in 1987 by Larach and 

colleagues. 47 The aim of this score is more to compare patient 

groups on the basis of scientific purposes rather than to help to 

treat a patient suspected to present an MH crisis. Any rise of 

postoperative CK plasma concentration can contribute to the 

evaluation of patients who present with the possibility of MH, 

anesthesia-induced rhabdomyolysis, and underlying muscle 

disease. To know the usual profile, 71 patients aged 1 month to 

l 7 years were studied. The median CK elevation (range) for the 

major and minor surgery groups was 43 IU/L (1–647) and 10 IU/L 

(28–122), respectively. The research protocol was similar for 

both groups with halothane for induction and isoflurane for 

maintenance of anesthesia. Owing to its possible effect on CK, 

succinylcholine was avoided during the study. 48 

Masseter Spasm 

The MS describes a lack of relaxation of the jaw muscles after 

injection of a depolarizing curare. Its presence was reported in the 

first description of MH during the initial stage of an MH crisis. 

The link between MS and MH has long been a source of contro - 

versies. In 1984 49 and 1987, 33 a 1% incidence of MS was found in 

children receiving a combination of halothane and succinylcholine 

during anesthesia. These children were classified as MHS 

by the authors at the time, but the use of proper evaluation denied 

the diagnosis. An 18-month retrospective chart review of all 

patients undergoing general anesthesia at the Children’s Hospital 

of Pittsburgh (N = 14,112) was conducted to assess the incidence 

of MS and its management. 50 In the otolaryngology service, the 

incidence of developing MS was observed in 2 out of 206 (1%) 

children who were anesthetized with halothane and received 

succinylcholine. In France, unlike the Anglo-Saxon countries, MS 

appears far less frequently and no MS was reported in a series of 

1055 children intubated after anesthetic induction with halothane 

and succinylcholine. 51 Van der Spek and associates suggested in 

1990 that, in the general population, the depolarizing curare 

caused an increase in the tonus of the muscles of the jaw during 

administration. 52 In 1986 53 and 1989, 54 an incidence of 50% of 

positive IVCT was reported in a population of children having 

MS. More recently, a study reported the results of caffeinehalothane 

muscle contracture testing by using the current North 

American Malignant Hyperthermia Group (NAMHG) protocol, 

on 70 pediatric patients (50 boys and 20 girls) referred for biopsy 

between 1986 and 1991. 55 This was based on evidence of muscle 

masseter rigidity (MMR) after succinylcholine between 1975 and 

1991. The clinical scenario was described as MMR alone or MMR 

followed by signs of MH, including PaCO 2 

tension lower than 

50 mmHg. It was observed in 83% (58 of 70) of anesthetics in 

which halothane-succinylcholine was used. Fifty-nine percent 

(41 of 70) were classified as MHS, and among them, 5 developed 

signs of clinical MH. These results reaffirm the high incidence of 

MHS in patients associated with MMR. 55 In summary, MS should 

be considered a potentially strong indicator of MH. 

MH-Like Syndromes Outside 

the Operating Room 

Neuroleptic Malignant Syndrome 

The neuroleptic malignant syndrome (NMS) is a potentially fatal 

hyperthermic syndrome that occurs as a result of ingestion of 

drugs used in the treatment of mental conditions such as 

schizophrenia. The signs of NMS include muscle rigidity, acidosis, 

high fever reactive to DS, and severe rhabdomyolysis. The 

prognosis is poor, but survival without sequelae can occur after 

2 to 3 weeks of intensive care therapy. The similarities between 

MH and NMS made some doctors suspect the existence of 

a common disorder of the calcium dysregulation of skeletal 

muscle. However, many differences exist between NMS and MH, 

including triggering drugs (neuroleptics vs halogenated agents), 

duration of evolution (a few hours for the MH crisis vs a few days 

for the NMS), and the absence of a hereditary factor in NMS. 

Patients who presented NMS seem today, and according to data 

from literature, not at risk of MH. The largest published series 

do not seem to accredit the thesis of a common mechanism. 56 

The mechanism of NMS is still unknown. It could result from 

dopamine receptor blockade associated with a possible toxic 

action of neuroleptic on the muscle fiber. Dehydration and hypo - 

volemia are factors predisposing to NMS. DS use is recommended 

only for symptomatic treatment of severe hyperthermia and 

muscular rigidity. 

Stress-Related MH 

It is well known that the MH pigs present the porcine stress 

syndrome identified as an “awake” MH episode. The reason why 

the MH humans do not have this risk is unknown. None of the 

few reports of MH reactions in awake patients or patients given


trigger-free anesthetics was totally convincing. Tobin and cowork - 

ers reported a fatal episode in a 13-year-old boy who had expe - 

rienced a clinical episode of MH and developed signs of MH after 

exercise some months later. 57 He and other family members were 

found to have a causative RYR1 mutation. In our own experience, 

we observed a boy with the same clinical features whose autopsy 

showed the existence of a viral cardiomyopathy. 

Exertional heat stroke arises from prolonged and intense 

muscular exercise, usually in a hot and humid atmosphere. It is 

characterized by a hyperthermic response at 40°C, disturbance of 

consciousness, rhabdomyolysis, and cardiovascular collapse. It is 

not possible at present to prove the existence of an association with 

MH. Contracture tests were performed on patients with exerciseinduced 

rhabdomyolysis, and positive IVCT were observed in 

11 out of 12 patients tested and a RYR1 mutation was found in 

3 patients. The authors concluded by recommending that patients 

with exercise-induced rhabdomyolysis should have a muscle 

biopsy performed for histologic study and implementation of 

halothane contracture test/caffeine. 58 

This hypothesis should most probably be evoked in children. 

Recently, the case of a 2-year and 9-month-old child, who was left 

unattended in a car and died of heat stroke, was reported. 59 

Postmortem mutation analysis revealed that the child possessed 

two distinct RYR1 mutations. Because each mutation had pre - 

viously been identified in a separate MHS patient, MHS with 

overresponse to the environmental high temperature might have 

occurred in this child with these RYR1 mutations. 

CONFIRMATION OF 

THE DIAGNOSIS OF MH 

Not Validated Tests 

The existence of elevated CK in susceptible MH individuals was 

first reported in 1970. However, a team found in 1976 that this 

elevation was present in only 45% of subjects. 60 An evaluation of 

the sensitivity and specificity of the assay of CK in the screening 

of individual MHS showed in our center a sensitivity of 38% and 

a specificity of 88%. 61 It was shown that CK assay for screening 

could not be used. However, any rise incidentally discovered, 

which was not explained by a muscular dystrophy, illness, or 

medication, and persistent in spite of taking care of muscular rest, 

absence of trauma, and intramuscular injection suggested a 

increased risk of MHS and encouraged the use of contracture tests. 

Several teams have found, in these circumstances, positive tests. 62 

Many other diagnostic tests have been proposed, seeking a higher 

level of calcium in muscular or blood cells, spontaneously or 

induced by halothane, but none of them was validated. The search 

for abnormalities of muscle metabolism studied by nuclear mag - 

netic resonance spectroscopy has also been proposed. Despite 

some correlation with contracture tests on muscle biopsy, 

sensitivity and specificity are insufficient to make a diagnosis 

of MHS. 

In Vitro Halothane-Caffeine Contracture Test 

Ten years after the description of MH, Kalow and colleagues 

described an exaggerated response to caffeine of muscle sus - 

ceptible to MH. 63 Ellis and Harriman showed the appearance 

of a contracture with halothane. 64 The use of IVCT was born. In a 

patient suspected of having presented an attack of MH during 

anesthesia, or a family member, the certainty of susceptibility to 

MH is achieved by the implementation of the IVCT. Strict 

protocols were established on both sides of the Atlantic Ocean by 

the European Malignant Hyperpyrexia Group (EMHG), 65 and the 

North American Malignant Hyperthermia Group NAMHG. 66 The 

muscle biopsy is performed in the vastus lateralis muscle, under 

locoregional anesthesia of the femoral nerve and cutaneous lateral 

nerve of the thigh (Figure 81–10A). Local infiltration must be 

excluded. The sample is placed immediately in a solution of Krebs- 

Ringer, at ambient laboratory temperature, and buffered and 

oxygenated by carbogen. The muscle fragments (15–20 mm long, 

3 mm in diameter, 100–300 mg) are placed in an insulated testbath 

and stimulated directly (see Figure 81–10B). It is then subjected to 

increasing concentrations of halothane and caffeine. A different 

muscle bundle is used for each test. The protocols vary slightly 

between Europe and North America, but the basic principle is 

similar (Figure 81–11). The twitch responses and the baseline 

tensions are recorded. The threshold value is the minimal concen - 

tration of halothane or caffeine at which a sustained baseline 

contracture of 0.2 g or greater occurs (see Figure 81–10C–E). 

In the EMHG protocol, each test is positive if this threshold is 

2% halothane or 2 mM caffeine or less. The test results led to 

classifying the subjects into three diagnostic groups: (1) MHS (i.e., 

caffeine and halothane positive); 2) MH nonsusceptible (MHN; 

i.e., caffeine and halothane negative); and (3) equivocal halothane 

or caffeine (MHE; i.e., when only one test is positive, these patients 

are considered clinically MHS-positive). On the normal muscle, 

halothane potentiates the twitch but does not induce any con - 

tracture and caffeine induces contracture at a higher concen - 

tration. Tests conducted according to the protocol of the European 

Group can get results with sensitivity of 100% and specificity close 

to 94%. 67 Using the NAMHG protocol, an individual is diagnosed 

as MHS-positive when either the halothane (using a bolus of 

3vol% during 10 min) or the caffeine test is positive and MHN 

when both tests are negative. Ryanodine and chlorocresol are two 

molecules that may appear useful for certain diagnoses. They seem 

to offer better specificity than halothane and caffeine. However, 

because of the difficulty of establishing precise thresholds and 

pending comparative multicenter studies, these two molecules are 

not included in the protocol of the EMH. The IVCT is expensive 

and confined to specialized testing centers. It requires a surgical 

procedure and can yield equivocal as well as false-positive results. 

However, it remains the “gold standard” for diagnosis of MH. 

It shows a phenotype that is considered as a proof of a genetic 

abnormality. It can be expressed as an MH crisis when the patient 

is exposed to the triggering anesthetic agents. 

IVCT in Children 

The policy of the EMHG established by Ellis indicates a lower age 

limit of 10 years because of the inconsistency in muscle responses 

in young children. 65 This is possibly related to immature muscle 

tissue, but also to the difficulty of obtaining viable muscle bundles 

in sufficient quantity. In 1990, Krivosic-Horber and associates 

questioned the realization and reliability of the halothane-caffeine 

contracture tests in children to detect the susceptibility to MH. 22 

The study concerned 26 children aged 2 to 13 years (mean 

9.5 ± 1.3 y) who were tested either because of a personal symp - 

tomatology (14 cases) or as a member of a susceptible MH family 

(12 cases). Half of the children had a positive test (MHS and


A 

B 

C 

D 

E 

Figure 81-10. A: Muscular 

biopsy of the vastus lateralis 

under locoregional anesthesia. 

B: Preparation of the muscle bundles. 

C: Laboratory device for the 

in vitro contracture test (IVCT). 

D: The recorder. E: Recordings of 

halothane test in normal and malignant 

hyperthermia susceptible 

(MHS) muscle and caffeine test in 

normal and MHS muscle.


Figure 81-11. Comparison of 

testing protocols for MH. 

MHE) as found in adults. Comparison of threshold concentrations 

of halothane and caffeine as well as the 32 nmol caffeine-induced 

contractures did not show any significant difference related to 

age. These results supported the possibility to perform under 

good conditions and with good reliability the diagnostic test of 

susceptibility to MH in children from the age of 2 years. Femoral 

and lateral femoral cutaneous block anesthesia with light to 

moderate sedation is well tolerated in children undergoing 

anterior thigh procedures. This was demonstrated in a study of 

179 children, aged younger than 18 years (10 ± 3y). 68 In 1997, 

Ummenhofer and coworkers reported the results of the IVCT 

performed in 24 children between the ages of 6 and 14 years. 69 

Seventeen patients out of 24 were diagnosed as MHS according to 

the protocol of the EMHG and 7 children as MHN. Twenty-one 

children were evaluated postoperatively. Minor side effects of 

wound healing occurred, but none of the patients showed any 

abnormalities of muscle contracture or movement performance. 

Considering the high risk of fatal complications in the presence 

of MHS, muscle biopsy of the upper leg for in vitro diagnosis is a 

justified procedure that is acceptable to children and their parents. 

However, the attitude has changed since the possibility to more 

precisely analyze the sensitivity of the IVCT compared with the 

results of genetic testing. The very few discordant results between 

a negative IVCT and the presence of a causative MH mutation 

analyzed in the EMHG was in most cases related to a poor quality 

of the muscle studied. 70 The only case observed in our laboratory 

while studying 832 IVCT was related to a 4-year-old sister of a boy 

tested with MHS when he was 9 years old and who presented in 

1986 with typical signs of MH after an induction with enflurane 

and succinylcholine. The linkage analysis supported the fact that 

the MHS mother had given the same allele of the RYR1 gene to 

both her children. Since that observation, the policy regarding 

muscle biopsy in our institution was changed. Muscle biopsy is 

not performed in children who are younger than 12 years and less 

than 30 kg. The recommendation is to test both parents of the 

young proband. If the two of them are MHN, they are not at risk 

and cannot transmit any MH mutation to their children. The 

investigation in the family is stopped. However, if the diagnosis 

cannot be eliminated in the proband, the child will be tested by 

IVCT when he or she will be old enough to have this intervention 

done according to the protocol. Only negative IVCT can eliminate 

the diagnosis of MH in individuals at risk. The existence of a 

neomutation, although rare, remains possible. 71 

Genetic Testing 

Mendelian Inheritance 

The inherited character of MH has been recognized since its 

original description in 1960. 1 Transmission is usually autosomal 

dominant. This means that the presence of a mutation in one allele 

of the gene is sufficient to cause the phenotype MH. Heterozygous 

subjects are at risk of MH. They can transmit the mutated allele to 

each child with a probability of 50%. The majority of susceptible 

individuals are heterozygous, but there are some homozygous 

individuals in whom both parents carry the same or different 

mutations in the RYR1 gene mutation. These individuals may 

show no more clinical symptoms than the heterozygous ones. 72 

Despite the high probability that an MHS subject has inherited an 

MH mutation only from one parent, most laboratories routinely 

offer IVCT to both parents according to the protocol. An inci - 

dence of 5% of positive contracture tests in both parents has 

been reported. 73 

Molecular Genetics of MH 

Since 1990, developments in genetics have allowed the location 

and characterization of the gene of the MH at the chromosome 

19, in the region q13,1. 74 Thanks to linkage studies, the MH locus


could be located in pigs. In humans, the ryanodine receptor 

(RyR1) gene encoding the calcium channel of sarcoplasmic retic - 

ulum has also been identified. 75 The location of this gene corre - 

sponds to the physiopathology of MH. The existence of an 

inversion of amino acids in the calcium channel renders it sus - 

ceptible to impregnation by the halogenated agents. and its 

opening causes an increase in the rate of sarcoplasmic calcium, 

leading to symptoms of the MH crisis. Considering the existence 

of a unique mutation in MHS pigs in the RyR1 gene, regardless of 

race, one might have expected the possibility of a simple diagnosis 

by DNA analysis in humans. However, there is no dominant 

mutation in humans. Further research reported that MH has a 

high level of locus heterogeneity. As much as five loci, called 

MHS1 to MHS6, have been published. A single mutation has 

been reported in the CACNA1S gene in two unrelated families. 

The CACNA1S encodes the a 1 

-subunit of the L-type Ca21 channel 

isoform that is expressed in skeletal muscle sarcolemma and is 

known as the dihydropyridine receptor. Both channels are involved 

in excitation-contraction coupling. 76 

The RYR1 is the main candidate gene (Figure 81–12). Its 

structure is known and divided in three domains called MHS1, 

MHS2 and MHS3. It is known to be a polymorphic gene with 

more than 170 missense mutations, several of these having been 

identified as polymorphisms rather than causative mutations. 

A novel mutation must not be used diagnostically before it has 

been proved to be causative, in extensive pedigree analysis com - 

paring molecular genetic results with contracture testing data 

and/or in using experimental techniques. 77 Currently, 29 RYR1 

mutations have been proven to be causative for MH (http:// 

www.emhg.org), but to date, more than 60 mutations have been 

identified in the MHS population. Although most MHS mutations 

map to the MH1 and MH2 domains, a few MHS mutations map 

to the C-terminal MH3 domain of RYR1. Complete screening of 

the entire coding regions of RYR1 has, however, revealed that 

mutations occur in almost all regions of the gene. Owing to the 

high level of locus heterogeneity, the diagnosis of MH suscep - 

tibility cannot be made using a simple genetic test (EMHG 78 ). It is 

important to avoid false MHN diagnoses because of the potential 

risk of MH during general anesthesia for these patients and their 

offspring. However, there may be situations in which genetic data 

provide additional diagnostic information or contribute infor - 

mation independent of IVCT. It is possible to undertake screening 

in a family, only after confirmation that the suspected proband is 

really MHS by performing IVCT, and that she or he bears a known 

causative MH mutation. The genetic study should not be offered 

initially in an individual suspected of having presented an MH 

crisis, because laboratories, having tried this approach, have 

obtained a yield of less than 5%. 

The discovery of a causative MH mutation in an MHS subject 

allows the search of this mutation for diagnosis of MH sensitivity 

in the family (Figure 81–13). This determination should 

be organized while taking into account the requirements and 

Figure 81-12. Gene and protein RYR1.


interest and requires further investigation, but this patient’s MH 

status remains unclear until contracture testing is performed. 

Absence of such mutations does not exclude MHS and warrants 

eventual IVCT. It is generally not recommended to look system - 

atically for an MH mutation in infants and young children, except 

when they need a general anesthesia and a causative mutation has 

been identified in the family history. It is preferred to wait for the 

child to be able to understand the diagnosis. One important reason 

is that the insurance companies do not always reimburse the 

genetic test that can cost more than 1,000 in the United States. 

RISK OF MH-LIKE EPISODE 

IN MYOPATHIC OR 

SYNDROMIC CHILDREN 

The hypothesis of an association of various diseases of striated 

muscle with MH (strabismus, scoliosis) was issued in the 1970s. 

Since then, various studies have not led to such conclusions, 

and the specificity of contracture testing in patients with neuro - 

muscular diseases (NMDs) has been questioned. 8 Now it seems 

that only the CCD and the King Denborough syndrome (KDS) 

can be linked to MH. 80 

1. KDS. 

2. Dystrophinopathies. 

3. Other myopathies. 

4. Sudden infant death syndrome (SIDS). 

5. Other syndromes. 

Figure 81-13. Suggested route for MH susceptibility testing. 

implementation of examinations of the genetic characteristics of a 

person for medical purposes. It is clarified that the requirement 

of an examination of genetic characteristics can take place only 

within a multidisciplinary team comprising clinical and genetic 

experts. The proof of the information should appear in the form 

of a certificate established by the responsible physician. The 

genetic tests should be done in accredited laboratories. A national 

advi sory committee in the examination of genetic characteristics 

for medical purposes must be established. It is essential to remain 

cautious with the use of genetics for the purpose of diagnosis in 

patients with MH susceptibility, given the importance of anes - 

thetic security issues. In particular, the absence in an individual 

of the mutation responsible for MH in his or her family is not 

enough to classify him or her as MHN. This person could bear 

another abnormality producing an MH crisis in the presence of 

the triggering anesthetic agents. One can be classified as MHN 

by IVCT only. Sensitivity of genetic testing is estimated to be 

approximately 25%. 

The only report of MHS in a newborn by molecular genetic 

testing of umbilical cord blood was published in 2006. 79 Sampling 

of umbilical blood is noninvasive. A possible concern might be 

the potential contamination of umbilical cord blood with maternal 

nucleated cells. However, the concentration of maternal cells was 

found to be 10 –4 to 10 –5 times lower than neonatal nucleated cells, 

and therefore, the identical signal intensity of both alleles in the 

analyses represent the neonatal MH mutation. For verification, 

contamination with maternal DNA was excluded by short tandem 

repeat profiling. The genetic variant identified in the case is novel 

and, thus, of no diagnostic value at all. This result is of scientific 

Central Core Disease 80,81 

CCD is an inherited neuromuscular disorder characterized by 

central cores on muscle biopsy and clinical features of a congenital 

myopathy. It is probably more common than other congenital 

myopathies. The CCD typically presents in infancy with hypotonia 

and motor developmental delay. It is characterized by predomi - 

nantly proximal weakness pronounced in the hip girdle, and 

orthopedic complications are common. In the majority of patients, 

weakness is static or only slowly progressive, with a favorable longterm 

outcome. The CCD and MHS are allelic conditions both due 

to mutations in the RYR1 gene. Altered excitability and/or changes 

in calcium homeostasis within muscle cells due to mutationinduced 

conformational changes of the RYR protein are con - 

sidered the main pathogenetic mechanism(s). The diagnosis of 

CCD is based on the presence of suggestive clinical features and 

central cores on muscle biopsy. Mutational analysis of the RYR1 

gene may provide genetic confirmation of the diagnosis. Manage - 

ment is mainly supportive and has to anticipate susceptibility 

to MH. The IVCT should be discussed on an individual basis, 

because discordant results have been observed within the same 

families. 

Native American myopathy is a putative autosomal recessive 

congenital myopathy that was reported to be frequently associated 

with MH. 82 Until now, no IVCT was performed and no MH caus - 

ative mutation was found 

King Denborough Syndrome 

KDS was first reported by King and Denborough in 1973 when 

the authors documented 18 males with MH, 5 of whom had


congenital progressive myopathy, short stature, cryptorchidism, 

pectus carinatum, lumbar lordosis, and thoracic kyphosis. 83 Three 

of the 5 had similar facial features with ptosis, downslanting 

palpebral fissures, micrognathia, crowded teeth, apparently 

low-set ears, and a short webbed neck. The inheritance of KDS is 

unknown, and there is little evidence to conclude that it is a single 

disorder. There are also no strict diagnostic criteria for this syn - 

drome. It may be actually a phenotype resulting from a hetero - 

geneous collection of congenital myopathies with different 

microscopic appearances. 27,84 There was no proof of the link 

between KDS and MH until the recent report of a KDS caused by 

a novel mutation in the ryanodine receptor gene. 85 

Dystrophinopathies 

Acute rhabdomyolysis leading to hyperkalemic cardiac arrest has 

been reported in association with Duchenne muscular dystrophies 

(DMDs) and has been understandably confused with MH. Like 

MH, most reported cases of rhabdomyolysis have been associated 

with the use of halothane and/or succinylcholine. 

DMD and Becker muscular dystrophy (BMD) are neuro - 

muscular disorders characterized by dystrophin deficiency 

(dystrophinopathies). DMD is more frequent, occurs earlier, and 

is more severe than BMD. The prevalence of DMD is 1 in 3300 

male births. The prevalence of BMD varies from 1 in 18,000 to 

1 in 31,000 male births. They affect not only the striated muscle 

but also the heart muscle and sometimes smooth muscle. Diag - 

nosis is generally made at the age of 5 when children present with 

waddling gait and talipes equines with calf hypertrophy (positive 

Gowers’ sign). Inability to walk appears by the age of 10 to 12. 

Scoliosis, cardiomyopathy, and restrictive respiratory failure 

progressively appear. 86 CPK levels are 50- to 200-fold (DMD) 

or 10- to 35-fold (BMD) higher than standard values. Muscular 

biopsy shows dystrophic features (necrotic and regenerative 

fibers). Immunohistochemical studies show a total absence of 

dystrophin (DMD) or altered quantity and/or quality (BMD). 

Molecular analysis most frequently shows deletions of the DMD 

gene, which is located at Xp21.2 and encodes several isoforms. 

In 1992, the Malignant Hyperthermia Association of the 

United States and the NAMHR received reports of cardiac arrest 

in apparently healthy children given succinylcholine. 87 Using data 

from 1990 to 1993, this study analyzed: (1) etiology of all reported 

pediatric arrests (age < 18 y) occurring within 24 hours of anes - 

thesia; (2) whether survival was associated with certain patient or 

treatment variables; and (3) presence of myopathy. Twenty-five 

patients (92% male, median 45 mo old) had a cardiac arrests; 

23 of 25 (92%) were scheduled for minor surgery. Before receiving 

a potent inhalational anesthetic (92%) and/or succinylcholine 

(72%), these patients were evaluated by the anesthesiologist as 

being healthy with no personal or family history of myopathy. 

Serum potassium during cardiac arrest was measured in 18 of 

25 (72%) patients; hyperkalemia (mean [K + ] = 7.4 ± 2.8, median 

7.5 mmol/L) was detected in 13 of 18 (72%) patients. Postarrest 

resuscitations lasted a median of 42 minutes (range 10–296). Ten 

(40%) patients died, 1 (4%) remained neurologically impaired, and 

14 (56%) returned to baseline neurologic function. A previously 

unrecognized DMD (N = 8) or unspecified myopathy (N = 4) was 

diagnosed in 12 (48%) patients. Eight of these 12 patients’ cardiac 

arrests were associated with hyperkalemia. Ten (40%) patients had 

no postarrest evaluation to exclude occult myopathy. No patient or 

treatment variables were statistically associated with survival. The 

authors concluded that, whenever possible, pediatricians should 

evaluate their patients (especially male infants and children) 

preoperatively for the presence of occult myopathy. During 

perianesthetic resuscitations, the pediatric advanced life support 

protocol should be modified to detect and treat hyperkalemia, a 

potentially reversible state even after prolonged resuscitation 

efforts. After anesthetic deaths, pathologists should examine 

body fluid electrolytes and skeletal muscle for myopathy and the 

presence of dystrophin. If a preanesthetic CK screen for myopathy 

in male patients and restrictions on succinylcholine had been 

used, 64% of cardiac arrests and 60% of deaths might have been 

prevented. A formal prospective risk/benefit analysis for preven - 

tive measures is needed. 

In 1996 review of the literature revealed 66 pediatric cases 

(56 boys and 10 girls) of anesthesia-associated rhabdomyolysis. 88 

Forty-nine (74%) cases were caused by an underlying, mostly 

unrecognized congenital muscle disease, and 14 (21%) cases were 

caused by MHS. Hyperkalemia (23 patients), cardiac arrhythmias 

(38 patients), renal failure (4 patients), and death (11 patients) 

were the most serious complications of anesthesia-associated 

rhabdomyolysis. The neuromuscular blocking agent succinyl - 

choline had been used in at least 43 of the patients reported in the 

literature. Breucking and colleagues carried out a prospective 

epidemiologic study (between 1983 and 2000) on a population of 

families including muscular cases of dystrophies: 147 families 

DMD and 53 families BMD. 89 A total of 219 male and 9 female 

underwent 444 anesthesias; 6 cardiac arrests were reported (1.3%, 

much more than the frequency of the cardiac arrests in the 

pediatric population 0.1–0.3%) occurring only in the 45 families 

without diagnosis at the time of the anesthesia. Schulte-Sasse and 

associates reported, in 9 children, on the occurrence of cardiac 

arrests within the minutes after the administration of succinyl - 

choline. 90 It was later shown that all of them had occult NMD. Five 

of the children did not survive the catastrophic event. The clear 

association between succinylcholine and rhabdomyolysis led the 

U.S. Food and Drug Administration to advise against the use of 

succinylcholine in children in 1994. 91 

In conclusion, halogenated agents and succinylcholine should 

be avoided in patients with muscular dystrophy, even if no genetic 

relation and no common mechanism exist with MH. The fragility 

of the muscle of these patients, which is characterized by chronic 

rhabdomyolysis and the presence of a regenerating muscle, carries 

the risk of acute rhabdomyolysis with hyperkalemia when exposed 

to halothane and/or succinylcholine. 92 

Other Myopathies 

Flick and associates examined the risk of MH in children exposed 

to a triggering anesthetic while undergoing muscle biopsy for 

suspected NMD. 93 Between 1992 and 2005, the medical records 

of 351 children younger than 21 years were identified as having 

undergone muscle biopsy for suspected NMD. Among them, 

274 patients received a volatile anesthetic agent and only 3 patients 

were administered succinylcholine. No patient exhibited signs or 

symptoms of MH or rhabdomyolysis. The author concluded that 

the estimated risk of MH or rhabdomyolysis is less than 1% in a 

diverse population of children with suspected NMD. 

McArdle’s disease, an isolated deficiency in glycogen degrada - 

tion in skeletal muscles, has the potential of creating perioperative


problems such as hypoglycemia, rhabdomyolysis, myoglobinuria, 

acute renal failure, and possibly MH. 94 A recent review concluded 

that no clinical association with MH has been established. 92 How - 

ever, it is suggested that halogenated agents and succinylcholine 

should be avoided to help to prevent rhabdomyolysis. 

Sudden Infant Death Syndrome 

Ellis and coworkers report three investigations about the potential 

relationship SIDS and MH. 95 In the first study, 151 MHS families 

completed a questionnaire designed to identify the incidence 

of SIDS within their own pedigree. In the second study, 106 SIDS 

families completed a questionnaire designed to identify the 

incidence of anesthetic-related problems. In the third study, 

14 SIDS parents were subjected to muscle biopsy and IVCT and 

caffeine contracture screening for susceptibility to MH. They 

concluded that there is no association between SIDS and MH. 

Other Conditions Suspected 

to Be at Risk of MH 

Some published case reports relate the observation of signs similar 

to MH during anesthesia with or without triggering agents in 

children with rare syndrome. However, MHS was not confirmed 

by IVCT or genetic analyses. Noonan’s syndrome, characterized 

by short stature, typical facial dysmorphism, and congenital 

heart defects presents a special interest because of the physical 

similarities with KDS. Lee and colleagues reported one patient 

scheduled for spinal arthrodesis whose operation was deferred in 

because MH developed during the induction of anesthesia. 96 It is 

reasonable to propose trigger-free anesthesia to these patients. 

Patients affected with osteogenesis imperfecta are known to have 

a temperature control problem due to a hypothalamic dysfunction; 

however, no relation with MH has been demonstrated. 97 

A new fatal syndrome has been reported in adolescent 

males affected with early diabetes mellitus. The features included 

hyperglycemic hyperosmolar coma complicated by an MH-like 

picture with fever, rhabdomyolysis, and severe cardiovascular 

instability. The authors suggest that a genetic predisposition to 

MH could be an explanation and that DS should be used in this 

situation. There is actually no evidence to support this position. 98,99 

ANESTHESIA OF THE PATIENT 

WITH A RISK OF MH 

Patients who are known to be MHS may be anesthetized with 

regional anesthesia or local anesthesia without any problem. If 

general anesthesia or sedation is required, the potent volatile 

anesthetic agents and succinylcholine should be avoided. It is not 

conceivable today to refuse anesthesia to a patient at risk for 

MH. 100 When precautions are taken, the administration of anes - 

thesia is considered safe. Patients at risk should be identified in 

the preoperative anesthesia consultation (Table 81–3). Referral to 

a specialized anesthesia center should always be considered if the 

patient’s condition allows. It is the responsibility of the anesthe - 

siologist to organize all the investigations necessary, IVCT, and/or 

DNA analysis to precise the exact status of the patient concerning 

MH (Table 81–4). 

Ambulatory surgery and anesthesia are authorized. 

TABLE 81-3. Categories of Risk of Malignant 

Hyperthemia Susceptibility 

Risk of MH Susceptibility 

Categories of patients at risk of MH in the preoperative 

consultation 

1. Card MHS by positive IVCT MH precautions 

2. Card MHN by negative IVCT 

● No exclusion of the triggering agents 

● No risk for the children 

3. Not tested, relatives of suspected MH MH precautions 

4. Member of a family with an MH mutation and positive for 

this mutation MH precautions 

5. Member of a family with an MH mutation and negative for 

this mutation MH precautions until proven MHN by 

IVCT 

6. Proband MH not tested (anesthesia, exercise) and relatives 

MH precautions 

IVCT = in vitro contracture test; MH = malignant hyperthermia; MHN = 

malignant hyperthermia nonsusceptible; MHS = malignant hyperthermia 

susceptible. 

The prophylactic administration of DS to prevent MH crisis 

was recommended by Gronert, who had proved its effectiveness 

in the pig model. 41 Different protocol requirements were subse - 

TABLE 81-4. Management of Malignant Hyperthermia– 

Susceptible Patients 

1. Appreciate the MH risk by preoperative evaluation 

A necessary anesthesia should never be cancelled in an 

MH-risk patient. 

2. Consider completing the investigation if the anesthesia is 

not urgent: 

● Details of the previous triggering anesthesia. 

● Family tree to calculate the risk of a relative of an MHS 

patient. 

● Order IVCT or DNA analysis if indicated. 

3. Discuss the anesthetic alternatives with the surgeon and the 

patient: 

● Monitored anesthetic care with sedation and local 

anesthesia. 

● Regional anesthesia. 

● General anesthetic using nontriggering agents. 

4. Clean machine; remove vaporizers; replace CO 2 

canisters, 

bellows, and gas hose, check the monitoring (PETCO 2 

++). 

5. Flush machine for 20 min with oxygen 10L/min. 

6. Bring the MH cart in the operating room (this cart contains 

dantrolene; stock all the supplies to resuscitate a patient 

with MH). 

7. Schedule the patient as the first case of the day, and notify 

the postanesthesia care unit to be prepared to provide the 

necessary manpower. 

8. After surgery measure central temperature and CK, look at 

the color of the urines, and monitor patient in an appropriate 

setting. 

CK = creatine kinase; IVCT = in vitro contracture test; MH = malignant 

hyperthermia; MHS = malignant hyperthermia susceptible; PETCO 2 

= endtidal 

carbon dioxide pressure.


quently proposed, including oral or intravenous administration. 

Nowadays, because of the many side effects of DS (hypoventilation 

by hypotonia of striated muscles, nausea, vomiting, or uterine 

bleeding by hypotonia of the smooth muscle), and the absence of 

reports of MH without triggering agents, it is not advisable to 

propose a pretreatment by the DS. Patients at risk should not be 

given triggering anesthetic agents (i.e., potent volatile anesthetic 

agents such as halothane, sevoflurane, desflurane, enflurane, 

isoflurane, and the muscle relaxant succinylcholine). All intra - 

venous agents and nondepolarizing relaxants are safe to use. 34 The 

anesthesia machine must be flushed of all halogenated anesthetics 

for a minimum period of 20 minutes (which can be longer 

depending on the characteristics of the anesthesia machine used), 

and a fresh anesthesia circuit must be used before administering 

anesthesia to patients susceptible to MH. The recommendations 

for the new ventilators are to flow 100% oxygen through the 

machine at 10 L/min for at least 20 minutes. 101,102 All patients must 

have their PETCO 2 

monitored. In children, the core temperature 

measurement is mandatory. It is highly recommended to have on 

hand enough DS (at least 18 vials). 

The absence of any sign of MH must be checked pre- and 

postoperatively. Central temperature and blood CK should be 

measured, and looking at the presence of light urine (taking into 

account the type of surgery) should be done before the outcome of 

the patient. No MH crisis studies have been published regarding 

these recommendations. 

CONCLUSION 

MH has nowadays a proteiform presentation that makes the 

diagnosis very difficult. It is necessary to assert the MHS by 

determination of the phenotype by IVCTs and confirmation of 

the genotype by exploration of the RYR1 gene. To have a better 

predictive value, these explorations should be done in the genetic 

proband and, if positive, extended to family members in accord - 

ance with the family tree according to the higher to the lower level 

of risk (i.e., beginning with the father, mother, and siblings, 

followed by the relatives). 

It is well demonstrated in epidemiologic studies that halo - 

genated volatile anesthetic agents can trigger MH. The depolar - 

izing neuromuscular blocker reinforces the crisis and can induce 

a strong MS. For unexplained reasons, MH crisis occurs more 

often in teenagers. However, one must remember that it may 

be observed at all stages of life. The prognosis of MH should be 

excellent if competent anesthesiologists administer the anesthesia. 

Proper monitoring must include PETCO 2 

and temperature. The 

operating room facility should always have immediate availability 

of DS, cold intravenous solutions, and intensive care modalities. 

Although MHS has been proved in patients presenting with 

exercise heat stroke, exercise and heat exposure are not contra - 

indicated in susceptible people. 

The existence of mutations in the RYR1 gene can be responsible 

for a congenital myopathy, CCD. These patients must be con - 

sidered MHS even if there is no sign of clinical myopathy in the 

majority of individuals bearing this MH mutation. Pediatric anes - 

thesiologists should be aware of the sudden risk of hyperkalemiainduced 

cardiac arrest after the administration of succinylcholine 

and volatile anesthetic agents in infants suffering from muscular 

dystrophies. Unfortunately, this clinical presentation is often the 

first indication of this medical condition and can precede the 

clinical diagnosis. Anesthesia is always possible in MHS patients 

providing that special precautions are taken, of which the most 

important is the total removal of all volatile halogenated anes - 

thetics agents and elimination of the depolarizing neuromuscular 

blocking medications. 

REFERENCES 

1. Denborough MA, Lovell RRH. Anesthetic deaths in a family. Lancet. 

1960;2:45. 

2. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet 

J Rare Dis. 2007;24:21. 

3. Dépret T, Krivosic-Horber R. Malignant hyperthermia: new develop - 

ments in diagnosis and clinical management. Ann Fr Anesth Réanim. 

2001;20:838–852. 

4. Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different 

genetic traits in malignant hyperthermia families: implication for genetic 

analysis, diagnosis, and incidence of malignant hyperthermia suscep - 

tibility. Anesthesiology. 2002;97:1067–1074. 

5. Britt B, Kalow W. Malignant hyperthermia: a statistical review. Can 

Anaesth Soc J. 1970;17:293–315. 

6. Britt BA, Nalda Felipe MA, Gottmann S, Khambatta HJ, (eds). Hereditary 

and epidemiologic aspects of malignant hyper thermia. In: Malignant 

Hyperthermia. Current Concepts. Bad Homburg. Normed Verlag; 1988. 

pp. 19–40. 

7. Krivosic-Horber R. Hyperthermie à propos d’un cas. Ann Fr Anesth 

Réanim. 1971;28:597–600. 

8. Ording H, Ranklev E, Fletcher R. Investigation of malignant hyper - 

thermia in Denmark and Sweden. Br J Anaesth. 1984;56:1183–1190. 

9. Ording H. Incidence of malignant hyperthermia in Denmark. Anesth 

Analg. 1985;64:700–704. 

10. Ellis FR, Halsall PJ, Harriman DG. The work of the Leeds malignant 

hyperpyrexia unit, 1971–1784. Anaesthesia. 1986;41:809–815. 

11. Ellis FR, Halsall PJ, Christian AS. Clinical presentation of suspected 

malignant hyperthermia during anaesthesia in 402 probands. Anaesthesia. 

1990;45:838–841. 

12. Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. 

Anesth Analg. 1993;77:297–304. 

13. Larach MG, Brandom BW, Allen GC, et al. Cardiac arrests and deaths 

associated with malignant hyperthermia in North America from 1987 to 

2006: a report from the North American Malignant Hyperthermia 

Registry of the Malignant Hyperthermia Association of the United States. 

Anesthesiology. 2008;108:603–611. 

14. Rosero EB, Adesanya AO, Timaran CH, et al. Trends and outcomes of 

malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 

2009;110:89–94. 

15. Peltz B, Carstens J. An unusual case of malignant hyperpyrexia. First 

reported case in a South African negro. Anaesthesia. 1975;30:346–350. 

16. Mayhew JF, Rudolph J, Tobey RE. Malignant hyperthermia in a sixmonth-old 

infant: a case report. Anesth Analg. 1978;57:262–264. 

17. Faust DK, Gergis SD, Sokoll MD. Management of suspected malignant 

hyperpyrexia in an infant. Anesth Analg. 1979;58:33–35. 

18. Sewall K, Flowerdew RM, Bromberger P. Severe muscular rigidity at 

birth: malignant hyperthermia syndrome? Can Anaesth Soc J. 1980;27: 

279–282. 

19. Bailey AC, Bloch EC. Malignant hyperthermia in a three-month-old 

American Indian infant. Anesth Analg. 1987;66:1043–1045. 

20. Wilhoit RD, Brown RE, Bauman LA. Possible malignant hyperthermia in 

a 7-week-old infant. Anesth Analg. 1989;68:688–691. 

21. Dubrow TJ, Wackym PA, Abdul-Rasool IH, et al. Malignant hyper - 

thermia: experience in the prospective management of eight children. 

J Pediatr Surg. 1989;24:163–166. 

22. Krivosic-Horber R, Adnet P, Krivosic I, et al. Diagnosis of susceptibility 

to malignant hyperthermia in children. Arch Fr Pediatr. 1990;47:421–424. 

23. Hinkle AJ, Dorsch JA. Maternal masseter muscle rigidity and neonatal 

fasciculations after induction for emergency cesarean section. Anesthe - 

siology. 1993;79:175–177. 

24. Semmler A, Rieger C, Lesinski R. A case report of malignant hyper - 

thermia in a 14-month-old boy. Anaesthesiol Reanim. 1994;19:21–22. 

25. Pennington GP, Joeris L. Malignant hyperthermia in a 3-month-old 

infant: a case report. J Med Assoc Ga. 1996;85:162–163.


26. Chamley D, Pollock NA, Stowell KM, et al. Malignant hyperthermia in 

infancy and identification of novel RYR1 mutation. Br J Anaesth. 2000; 

84:500–504. 

27. Kinouchi K, Okawa M, Fukumitsu K, et al. Two pediatric cases 

of malignant hyperthermia caused by sevoflurane. Masui. 2001;50: 

1232–1235. 

28. Bonciu M, de la Chapelle A, Delpech H, et al. Minor increase of endtidal 

CO 2 

during sevoflurane-induced malignant hyperthermia. Paediatr 

Anaesth. 2007;17:180–182. 

29. Ducart A, Adnet P, Renaud B, et al. Malignant hyperthermia during 

sevoflurane administration. Anesth Analg. 1995;80:609–611. 

30. Wedel DJ, Gammel SA, Milde JH, et al. Delayed onset of malignant 

hyperthermia induced by isoflurane and desflurane compared with 

halothane in susceptible swine. Anesthesiology. 1993;78:1138–1144. 

31. Kunst G, Kunst G, Graf BM, et al. Differential effects of sevoflurane, 

isoflurane, and halothane on Ca 2+ release from the sarcoplasmic reticulum 

of skeletal muscle. Anesthesiology. 1999;91:179–186. 

32. Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients 

suspected to be susceptible to malignant hyperthermia before diagnostic 

in vitro contracture test. Acta Anaesthesiol Scand. 1997;41:480–484. 

33. Carroll J. Increased incidence of masseter spasm in children with stra - 

bismus anesthetized with halothane and succinylcholine. Anesthesiology. 

1987;67:559–561. 

34. Krivosic-Horber R, Reyford H, Becq MC, et al. Effect of propofol on the 

malignant hyperthermia susceptible pig model. Br J Anaesth. 1989;62: 

691–693. 

35. Carr AS, Lerman J, Cunliffe M, et al. Incidence of malignant hyper - 

thermia reactions in 2,214 patients undergoing muscle biopsy. Can J 

Anaesth. 1995;42:281–286. 

36. Halsall P, Cain P, Ellis F. Does postoperative pyrexia indicate malignant 

hyperthermia susceptibility? Br J Anaesth. 1992;68:209–210. 

37. Litman RS, Flood CD, Kaplan RF, et al. Postoperative malignant hyperthermia: 

an analysis of cases from the North American Malignant 

Hyperthermia Registry. Anesthesiology. 2008;109:825–829. 

38. Pollock AN, Langton EE, Couchman K, et al. Suspected malignant 

hyperthermia reactions in New Zealand. Anaesth Intensive Care. 2002; 

30:453–461. 

39. Krivosic-Horber R, Theunynck D, Adnet P. Capnography and anestheticinduced 

malignant hyperthermia. Agressologie. 1985;26:929–932. 

40. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables 

associated with recrudescence after malignant hyperthermia reactions. 


41. Gronert GA. Malignant hyperthermia. Anesthesiology. 1980;53:395–423. 

42. Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyper - 

thermia Anesthesiology. 1982;56:254–262. 

43. Flewellen EH, Nelson TE, Jones WP, et al. Dantrolene dose response in 

awake man: implications for management of malignant hyperthermia. 

Anesthesiology. 1983;59:275– 80. 

44. Shime J, Gare D, Andrews J, et al. Dantrolene in pregnancy: lack of 

adverse effects on the fetus and newborn infant. Am J Obstet Gynecol. 

1988;159:831–834. 

45. Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intravenous 

dantrolene in children. Anesthesiology. 1989;70:625–629. 

46. Takehana K, Kawaguchi Y, Kuroda K, et al. Transient talipes equinus 

deformity of bilateral lower limbs following malignant hyperthermia: a 

case report and review of literature. J Orthop Sci. 2004;9:657–661. 

47. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict 

malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771–779. 

48. Yousef MA, Vaida S, Somri M, et al. Changes in creatine phosphokinase 

(CK) concentrations after minor and major surgeries in children. Br J 

Anaesth. 2006;96:786–789. 

49. Schwartz L, Rockoff M, Koka B. Masseter spasm with anesthesia: inci - 

dence and implications. Anesthesiolgy. 1984;61:772–777. 

50. Kosko JR, Brandom BW, Chan KH. Masseter spasm and malignant 

hyperthermia: a retrospective review of a hospital-based pediatric 

otolaryngology practice. Int J Pediatr Otorhinolaryngol. 1992;23:45–50. 

51. Krivosic-Horber R, Sauvage M, Calmes M. Notre expérience à propos de 

6,000 anesthésies à l’halothane chez l’enfant. Ann Chir Inf. 1973;14:91–96. 

52. Van Der Spek AF, Reynolds PI, Fang WB, et al. Changes in resistance to 

mouth opening induced by depolarizing and non-depolarizing neuro - 

muscular relaxants. Br J Anaesth. 1990;64:21–27. 

53. Rosenberg H, Fletcher J. Masseter muscle rigidity and malignant hyperthermia 

susceptibility. Anesth Analg. 1986;654:161–164. 

54. Christian S, Ellis F, Halsall P. Is there a relationship between masseteric 

muscle spasm and malignant hyperpyrexia? Br J Anaesth. 1989;62: 

540–544. 

55. O’Flynn RP, Shutack JG, Rosenberg H, et al. Masseter muscle rigidity and 

malignant hyperthermia susceptibility in pediatric patients. An update 

on management and diagnosis. Anesthesiology. 1994;80:1228–1233. 

56. Adnet P, Krivosic-Horber R, Adamantidis M, et al. The association between 

the neuroleptic malignant syndrome and malignant hyperthermia. Acta 

Anaesthesiol Scand. 1989;33:676–680. 

57. Tobin JR, Jason DR, Challa VR, et al. Malignant hyperthermia and 

apparent heat stroke. JAMA. 2001;286:168–169. 

58. Wappler F, Fiege M, Steinfath M, et al. Evidence for susceptibility to 

malignant hyperthermia in patients with exercise-induced rhabdomyolysis. 


59. Nishio H, Sato T, Fukunishi S, et al. Identification of malignant hyperthermia-susceptible 

ryanodine receptor type 1 gene (RYR1) mutations in 

a child who died in a car after exposure to a high environ mental 

temperature. Leg Med (Tokyo). 2009;11:142–143. 

60. Britt B, Endrenyi L, Peters PL, et al. Screening of malignant hyperthermia 

susceptible families by creatine phosphokinase measurement and other 

clinical investigations. Can Anaesth Soc J. 1976;23(Suppl 3):263–284. 

61. Krivosic-Horber R, Reyford H, Adnet PJ. Unexplained increase in serum 

creatine kinase levels: its relation to malignant hyperthermia sus - 

ceptibility. Minerva Anesthesiol. 1994;60(Suppl 3):107–110. 

62. Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in 

patients with persistently increased serum creatine kinase levels. Anesth 

Analg. 1997;84:1038–1041. 

63. Kalow W, Britt BA, Richter A. The caffeine test of isolated human muscle 

in relation to malignant hyperthermia. Can Anaesth Soc J. 1977;24:678–694. 

64. Ellis FR, Harriman DG. A new screening test for susceptibility to 

malignant hyperpyrexia. Br J Anaesth. 1973;45:638. 

65. Ellis FR. European Malignant Hyperpyrexia Group. Br J Anaesth. 1984; 

56:1181–1182. 

66. Larach MG. Standardization of the caffeine halothane muscle contracture 

test. North American Malignant Hyperthermia Group. Anesth Analg. 

1989;69:511–515. 

67. Ording H. The European Malignant hyperthermia Group in vitro 

contracture test for diagnosis of malignant hyperthermia following the 

protocol of the European MH Group: results of testing patients surviving 

fulminant MH and un-related low-risk subjects. Acta Anaesthesiol Scand. 

1997;41:955–966. 

68. Maccani RM, Wedel DJ, Melton A, et al. Femoral and lateral femoral 

cutaneous nerve block for muscle biopsies in children. Paediatr Anaesth. 

1995;5:223–227. 

69. Ummenhofer W, Roesslein R, Sutter PM, et al. Muscle biopsy for 

malignant hyperthermia screening in children. Eur J Pediatr Surg. 1997; 

7:259–262. 

70. Isaacs H, Badenhorst M. False-negative results with muscle caffeine 

halothane contracture testing for malignant hyperthermia. Anesthesiology. 

1993;79:5–9. 

71. Monnier N, Romero NB, Lerale J, et al. An autosomal dominant con - 

genital myopathy with cores and rods is associated with a neomutation in 

the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum 

Mol Genet. 2000;9:2599–2608. 

72. Lynch PJ, Krivosic-Horber R, Reyford H, et al. Identification of 

heterozygous and homozygous individuals with the novel RYR1 mutation 

Cys35Arg in a large kindred. Anesthesiology. 1997;86:620–626. 

73. Islander G, Bendixen D, Ranklev-Twetman E, et al. Results of in vitro 

contracture testing of both parents of malignant hyperthermia susceptible 

probands. Acta Anaesthesiol Scand. 1996;40:579–584. 

74. McCarthy TV, Healy JM, Heffron JJ, et al. Localisation of the malignant 

hyperthermia susceptibility locus to human chromosome 19q 12–132. 

Nature. 1990;343:562–564. 

75. Monnier N, Kozak-Ribbens G, Krivosic-Horber R, et al. Correlations 

between genotype and pharmacological, histological, functional, and 

clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat. 

2005;26:413–425. 

76. Monnier N, Romero NB, Lerale J, et al. Familial and sporadic forms of 

central core disease are associated with mutations in the C-terminal 

domain of the skeletal muscle ryanodine receptor. Hum Mol Genet. 

2001;10:2581–2592. 

77. Girard T, Litman RS. Molecular genetic testing to diagnose malignant 

hyperthermia susceptibility. J Clin Anesth. 2008;20:161–163.


78. Urwyler A, Deufel T, McCarthy T, et al. European Malignant Hyper - 

thermia Group. Guidelines for molecular genetic detection of suscep - 

tibility to malignant hyperthermia. Br J Anaesth. 2001;86:283–287. 

79. Girard T, Johr M, Schaefer C, et al. Perinatal diagnosis of malignant 

hyperthermia susceptibility. Anesthesiology. 2006;104:1353–1354. 

80. Krivosic-Horber R, Krivosic I. Central core disease associated with 

malignant hyperthermia sensitivity. Presse Med. 1989;18:828–831. 

81. Quinlivan RM, Muller CR, Davis M, et al. Central core disease: clinical, 

pathological, and genetic features. Arch Dis Child. 2003;88:1051–1055. 

82. Stamm SD, AylsworthAS, Stajich JM, et al. Native American myopathy: 

congenital myopathy with cleft palate, skeletal anomalies, and sus - 

ceptibility to malignant hyperthermia. Am J Med Genet. 2008;146A:1832– 

1841. 

83. King JO, Denborough MA. Anesthetic-induced malignant hyperpyrexia 

in children. J Pediatr. 1973;83:37–40. 

84. Habib AS, Millar S, Deballi P, et al. Anesthetic management of a 

ventilator-dependent parturient with the King-Denborough syndrome. 

Can J Anaesth. 2003;50:589–592. 

85. D’Arcy CE, Bjorksten A, Yiu EM, et al. King-denborough syndrome 

caused by a novel mutation in the ryanodine receptor gene. Neurology. 

2008;71:776–777. 

86. Duchenne and Becker muscular dystrophy. Available at: www.orphanet. 

net Accessed September 14, 2010. 

87. Larach MG, Rosenberg H, Gronert GA, et al. Hyperkalemic cardiac arrest 

during anesthesia in infants and children with occult myopathies. Clin 

Pediatr (Phila). 1997;36:9–16. 

88. Pedrozzi NE, Ramelli GP, Tomasetti R, et al. Rhabdomyolysis and 

anesthesia: a report of two cases and review of the literature. Pediatr 

Neurol. 1996;15:254–257. 

89. Breucking E, Reimnitz P, Schara U, et al. Anesthetic complications. 

The incidence of severe anesthetic complications in patients and families 

with progressive muscular dystrophy of the Duchenne and Becker types. 

Anaesthesist. 2000;49:187–195. 

90. Schulte-Sasse U, Eberlein HJ, Schmücker I, et al. Should the use of 

succinylcholine in pediatric anesthesia be re-evaluated? Anaesthesiol 

Reanim. 1996;18:13–19. 

91. Goudsouzian NG. Recent changes in the package insert for succinyl - 

choline chloride: should this drug be contraindicated for routine use in 

children and adolescents? (Summary of the Discussions of the 

Anesthetic and Life Support Drug Advisory Meeting of the Food and 

Drug Administration, FDA Building, Rockville, MD, June 9, 1994.) 

Anesth Analg. 1995;80:204–212. 

92. Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: 

an old anesthesia problem revisited. Paediatr Anaesth. 2008;18: 

100–106. 

93. Flick RP, Gleich SJ, Herr MM, et al. The risk of malignant hyperthermia 

in children undergoing muscle biopsy for suspected neuromuscular 

disorder. Paediatr Anaesth. 2007;17:22–27. 

94. Bollig G, Mohr S, Raeder J. McArdle’s disease and anaesthesia: case 

reports. Review of potential problems and association with malignant 

hyperthermia. Acta Anaesthesiol Scand. 2005;49:1077–1083. 

95. Ellis FR, Halsall PJ, Harriman DG. Malignant hyperpyrexia and sudden 

infant death syndrome. Br J Anaesth. 1988;60:28–30. 

96. Lee CK, Chang BS, Hong YM, et al. Spinal deformities in Noonan syn - 

drome: a clinical review of sixty cases. J Bone Joint Surg Am. 2001;83: 

1495–1502. 

97. Porsborg P, Astrup G, Bendixen D, et al. Osteogenesis imperfecta and 

malignant hyperthermia. Is there a relationship? Anaesthesia. 1996;51: 

863–865. 

98. Hollander AS, Olney RC, Blackett PR, et al. Fatal malignant 

hyper thermia–like syndrome with rhabdomyolysis complicating the 

presen tation of diabetes mellitus in adolescent males. Pediatrics. 2003;111: 

1447–1452. 

99. Kilbane BJ, Mehta S, Backeljauw PF, et al. Approach to management of 

malignant hyperthermia–like syndrome in pediatric diabetes mellitus. 

Pediatr Crit Care Med. 2006;7:169–173. 

100. Yentis SM, Levine MF, Hartley EJ. Should all children with suspected 

or confirmed malignant hyperthermia susceptibility be admitted after 

surgery? A 10-year review. Anesth Analg. 1992;75:345–350. 

101. Crawford MW, Prinzhausen H, Petroz GC. Accelerating the washout of 

inhalational anesthetics from the Dräger Primus anesthetic workstation: 

effect of exchangeable internal components. Anesthesiology. 2007;2: 

289–294. 

102. Gunter JB, Ball J, Than-Win S. Preparation of the Dräger Fabius 

anesthesia machine for the malignant-hyperthermia susceptible patient. 

Anesth Analg. 2008;107:1936–1945.


Figure 82-1. Immune response. 

ANESTHETIC AGENTS AND 

IMMUNE FUNCTION 

Numerous studies using clinical and in vitro techniques have 

examined the effects of inhaled and intravenous anesthetic agents 

on the function of immune cells (Table 82–1). 8–16 The resulting 

data reveal multiple and often conflicting effects on immune cells; 

however, the preponderance of findings suggest that, in most cir - 

cumstances, volatile and intravenous anesthetics depress immune 

cell functions. 

In attempt to understand the immune system effects of 

anesthesia-related drugs during surgery in children, it is important 

to consider the context of the evidence. Procopio and coworkers 

exposed healthy volunteers to mask thiopental isoflurane–nitrous 

oxide general anesthesia and then to lidocaine lumbar epidural 

anesthesia in the absence of surgery; the immune function of 

sampled ex vivo cells from these volunteers was unaffected. 17 

Clearly, the interaction among the stressors of surgery, the per - 

ianesthesia environment, and drugs of anesthesia is necessary to 

account for postoperative immune modulation. In considering the 

extremely complex milieu of a surgical patient under anesthesia, 

the net immune effect of these drugs may not be deleterious, 

because it will be determined not just by the drug’s propensity to 

directly depress immune cell function but also by its efficacy in 

TABLE 82-1. Effect of Anesthetic Drugs and Opioids on Immune Cell Function 

Immune Effects 

Macrophage exposure decreases mediators molecule release. 

Transcription factors blocked in T lymphocytes, cell death (apoptosis) is induced. 

Lymphocyte functions are suppressed. 

Less suppressive in two studies; other investigations found immune cell impairment 

on exposure. 

Inflammation reduced; may favor adaptive immunity 

Direct, M opioid receptor–mediated depression of immune cell function; indirect support 

of adaptive immune function through decreasing stress hormone release; potential antiinflammatory 

effects. 

Anesthesia 

All inhaled anesthetics 

Sevoflurane, isoflurane 

Thiopental, etomidate, ketamine 

Propofol 

Amide local anesthetics 

Opioids

CHAPTER 82 ■ Influence of Anesthesia on the Immune System in Children 1381 

suppressing various aspects of the stress response to the surgical 

intervention. 

Anesthesia and Adaptive Immune Response 

Previous reports had demonstrated that anesthetics can influence 

various aspects of lymphocyte function in vitro and in vivo, but 

the results of these were often contradictory. 18–21 Stevenson and 

colleagues observed that anesthesia and surgery depress both 

T-cell and B-cell responsiveness as well as nonspecific host resist - 

ance mechanisms, including phagocytosis. 22 Barbiturates, such 

as thiopental, have already been shown to reduce the growth of 

phytohemagglutinin (PHA)-stimulated peripheral blood mono - 

nuclear cells (PBMCs) or isolated T lymphocytes. 12,23,24 The effects 

are more pronounced in neonates than in older children. 

The depressed proliferative T-cell response makes patients 

susceptible to postoperative infections, 25 and barbiturates adminis - 

tered over long periods may cause iatrogenic immunosuppression. 

Indeed, a higher incidence of infections has been described in 

head-injured patients receiving prolonged infusions of thiopental 

to control increased intracranial pressure. 26,27 

Thiopental has an elimination half-life of approximately 

11 hours and may accumulate during long-term administration. 

Thus, the in vivo effects of thiopental on the proliferative capacity 

of lymphocytes may be of particular relevance. The reduction of 

mitogen-induced PBMC proliferation is comparable with that 

induced by 10 –7 mol/L methylprednisolone. 28 

Propofol has been shown to produce a mild inhibition of PHAinduced 

PBMC proliferation at high concentrations. 29 These data 

are in accordance with results published by Pirttikangas and 

associates, who observed a proliferation suppressing effect of 

propofol in vitro only in PBMCs obtained from critically ill 

patients, who were primarily immunosuppressed. 29 Devlin and 

coworkers investigated the effects of thiopental and propofol on 

lymphocyte proliferation after PHA stimulation. 12 In their studies, 

neither propofol nor its solvent intralipid caused T lymphocyte 

depression. 12,24 In this context, the authors concluded that propofol 

may be the safest drug for patients undergoing prolonged surgery 

or for sedation in the intensive care unit. 

The activation of T and B lymphocytes is characterized by 

the release of the autocrine growth factor interleukin-2 (IL-2). 

The up-regulation of the high-affinity IL-2 receptor trimmer and 

the simultaneous release of a soluble form of the IL-2 receptor 

α-subunit (shedding) are suggested. Dysregulation of IL-2- 

production and IL-2 receptor expression in the accessory signaling 

pathways have been shown to result in immune defects or autoimmune 

diseases. 30-31 This can explain the immune suppression 

effect of certain anesthetic drugs. Conversely, whereas the release 

of sIL-2R was depressed in the presence of higher propofol 

concentrations, IL-2 production by PBMC was found to increase 

with increasing propofol concentrations. Salo and colleagues did 

not find any effect of propofol on IL-2 production, but described 

an increased production of the Thl cytokine interferon-γ (IFN-γ) 

by isolated T cells with an increase in the IFN-γ/IL-4 ratio at 

propofol concentrations up to 10 pg/mL. 32 In addition, barbi - 

turates, but not propofol, suppressed the activation of transcrip - 

tion factor nuclear κB in human T cells. 33 

Loop and associates described that, with thiopental, there was 

a decrease in the production of the IL-2, IL-6, and IL-8 as well as 

IFN-γ by CD3+ lymphocytes. 11 This group provided data sug - 

gesting that thiopental interferes with activation of nuclear 

transcription factor κB in T-lymphocytes, which is probably 

mediated via the suppression of κB kinase. 

Furthermore, the immunosuppressive effects of thiopental are 

associated with a marked reduction in the density of IL-2 receptors 

on the cell membrane and the numbers of cells expressing 

IL-2 receptors. 12 

In summary, a decrease in lymphocytes, T- and B-cell counts, 

as well as a depression of lymphocyte reactivity and alteration in 

B-cell response to pokeweed mitogen (PWM) due to use of anes - 

thesia were all inversely related to age of children from 1 month to 

12 years. 

Opioid use is ubiquitous in anesthesia practice, because these 

drugs are most effective and essential in the treatment of acute 

surgical pain and are used as an important component of chronic 

pain management. For these reasons and because of their complex 

effects on perioperative immune function, extra space is devoted 

to presenting relevant evidence. Review of the relevant literature 

reveals multiple and often conflicting reports of opioid effects on 

immune system functions (see Table 82–1). 

Of great concern when using opioids to manage perioperative 

pain is evidence that opioid analgesics are immunosuppressive. 

Animal studies have shown the prototypical opioid morphine to 

suppress NK cell activity, mitogen-induced lymphocyte prolif - 

eration, and inflammatory cytokine production. 34 Other drugs 

with mu-opioid receptor agonist effects, including buprenorphine 

and fentanyl, also depress immune function in a naltrexonereversible 

manner. 35 In contrast with these findings, a preclinical 

study found immune suppression associated with fentanyl was 

limited to the first 72 postoperative hours and was nonexistent for 

buprenorphine. 36 Interestingly, in postoperative animals, the im - 

mune suppression associated with surgery was ameliorated with 

morphine administration, whereas buprenorphine restored im - 

mune parameters to normal levels. By using a well-demonstrated 

animal model of postoperative pain and tumor metastasis, 

researchers have shown that animals treated with fentanyl or 

intrathecal morphine/bupivacaine have a significantly lower 

tumor burden than animals without postoperative analgesia. 37 

It is important to note that the fentanyl-associated immune cell 

depression seen in control animals was absent in the postoperative 

group. In contrast with the effects of morphine and fentanyl, 

tramadol, a novel opioid analgesic with inhibitory effects on 

norepinephrine and serotonin uptake, has been found to have no 

depressant effects on immune parameters in a study of postop - 

erative pain treatment in patients with cancer. 38 

However, there are well-documented, dose-dependent, immu - 

nosuppressive effects of morphine that are known to impair mon - 

ocyte and neutrophil functions, NK cell–mediated cytotoxicity, 

lymphocyte proliferation, and cytokine release. Morphine pro - 

motes apoptosis in lymphocytes and macrophages by activating 

enzymes involved in apoptotic cell death. Furthermore, it affects 

nitric oxide release and inhibits cell adhesion. Opioids are known 

to exert their effects via specific opioid receptors expressed on 

immunocompetent cells. It is reported that morphine induces 

DNA damage through the action on the kappa opioid receptor, 

which leads to immune suppression by activation of P53-mediated 

signal transduction. Studies estimating the effects of synthetic 

opioids used in general anesthesia showed no more transient 

immunomodulatory changes. 37–39 

Another study by Yeager and coworkers reported enhanced 

NK-cell cytotoxicity and increased relative number of CD16+ and


CD8+ after an intravenous bolus dose and subsequent infusion of 

fentanyl (1.2 pg/kg/h for 2 h) in healthy volunteers. 40 

In a similar study, fentanyl increased the NK-cell (CDl6+/ 

CD56+) number, but superoxide production of polymorpho - 

nuclear cells and the number of circulating B and T lymphocytes 

remained unchanged. 41 These results suggest a centrally mediated 

rather than a direct effect of fentanyl on NK cells. 

Previous in vitro studies have provided evidence that volatile 

anesthetics might alter the immune response. In cultured human 

leucocytes, halothane inhibited mitogen-induced RNA and 

protein synthesis and depressed the secretion of IFN. 42 

Extended exposure suppressed the mitogen-induced lym - 

phocyte proliferation and the expression of the IL-2 receptor. 

Mitsuhata and colleagues investigated the effects of volatile anes - 

thetics (sevoflurane, isoflurane, enflurane) in clinically relevant 

concentrations on the cytokine release of human PBMC-stimulated 

NK-sensitive tumor cells. 43 None of the anesthetics reduced the 

levels of IL-2. 

ANESTHESIA AND PHAGOCYTOSIS 

An intact phagocytic function is essential for the host defense 

(Figure 82–2). Several human and animal studies of the anesthetic 

effects of phagocytic activity in the past have produced 

contradictory evidence. At the turn of the century, animal studies 

concluded that ether and chloroform inhibited phagocytosis in a 

dose-dependent manner. 

Human studies after either halothane or nitrous oxide–narcotic 

anesthesia without surgery revealed a decrease in phagocytosis of 

latex particles and nitroblue tetrazolium (NBT) reduction in one 

instance, but showed only a minimal inhibition in another after 

halothane 0.5 to 2.5% or nitrous oxide 80%. Reduced phagocytic 

activity by fixed macrophages of the reticuloendothelial system 

has also been reported during anesthesia in humans and in 

animals, although the reduction was only minimal. In addition to 

the effects of volatile inhalational anesthetic agents, a study of the 

effects of intravenous induction and local anesthetic agents on the 

human leukocyte phagocytic activity revealed a dose-dependent, 

statistically significant depression of phagocytic activity after in 

vitro exposure to varying concentrations of intravenous induction 

agents, narcotics, and local anesthetic agents. These observations 

were not the result of a nonspecific drug concentration effect, 

because equimolar concentrations of other nonanesthetic agents 

failed to produce any depression of phagocytosis. 44 

Thus, it would appear that some of the anesthetic agents may 

potentially enhance the risk of perioperative infection by reducing 

the phagocytic activity. This depression may be further compounded 

by the surgical intervention per se, because several other 

studies have shown impaired leukocyte function by the stress of 

surgery both in humans and in animals. 30 

In addition to a decrease in phagocytosis, anesthetic agents can 

also inhibit bactericidal activities. Earlier studies utilized NBT 

reduction as an index of bactericidal activity. 

More recently, utilizing the technique of chemiluminescence, in 

which the light emission by the highly reactive and excited oxygen 

radical is evaluated, it was shown that only enflurane and not 

isoflurane inhibited the bactericidal activity. Similar observations 

were also made after exposure to halothane. Using the superoxideinduced 

chemiluminescence, a dose-dependent depression of bac - 

tericidal activity was also reported with thiopentone and althesin; 

however, methohexitone, morphine, diazepam, and lidocaine 

failed to produce similar effects. These findings support the 

concept that different anesthetic agents may interfere with various 

aspects of the nonspecific immune response. 

A suppression of leukocyte function in particular could be 

relevant in the pathogenesis of postoperative infection. However, 

the true clinical significance of these observations remains to 

be ascertained. 45 

Figure 82-2. Phagocytosis steps in 

neutrophils.

CHAPTER 82 ■ Influence of Anesthesia on the Immune System in Children 1383 

Figure 82-3. Anaphylactic reaction. 

ANESTHESIA AND 

ALLERGIC REACTIONS 

Intraoperative allergic reactions occur once in every 5000 to 

25,000 anesthetics with 3.4% mortality. 46,47 More than 90% of 

allergic reactions evoked by intravenous drugs occur within 

3 minutes of administration; this is usually called an anaphylactic 

reaction (Figure 82–3). In the anesthetized patient, an anaphylactic 

reaction is the most common life-threatening manifestation of an 

allergic reaction and is associated with circulatory collapse, 

reflecting vasodilatation with resulting decreased venous return 

and cardiac output. Although the immune system functions to 

provide host defense, it can respond inappropriately to produce 

various hypersensitivity reactions. A spectrum of life-threatening 

allergic reactions to any drug can occur in the perioperative 

period. The enigma of these reactions lies in their unpredictable 

nature. 

However, a high index of suspicion and vigilance, prompt 

recognition, and appropriate and aggressive therapy can help to 

avoid a disastrous outcome. 

Recognition of Anaphylaxis 

The onset and severity of the reaction relate to the mediator’s 

specific end-organ effects. Antigenic challenge in a sensitized 

individual usually produces immediate clinical manifestations, 

allowing only a short period before appropriate therapy. Indi - 

viduals may vary greatly in their manifestation and course of 

anaphylaxis, ranging from minor clinical features to the full-blown 

syndrome leading to death. The enigma of anaphylaxis lies in the 

unpredictability of its occurrence, severity of attack, and lack of a 

previous allergic history. 46 

Diagnostic Tests 

Tests performed during the reaction include 

● 

Plasma histamine levels 

Plasma histamine levels when elevated, particularly to levels 

greater than 20 nmol, confirm that its involvement in the 

immune reaction is anaphylactic. The converse that no elevation 

in plasma histamine levels means a lack of its involvement is not 

true. Plasma histamine levels rise only transiently and sampling 

must occur within 10 minutes. 47 

Urinary or plasma methylhistamine 

Even though measurement of urinary or plasma methyl - 

histamine has the advantages over plasma histamine because it 

has a more prolonged rise and provides a simple assay, it is less 

sensitive. 

Immunoglobulin E levels 

Drugs specific immunoglobulin E (IgE) can be detected in 

blood taken during an immune reaction or before a reaction 

and postmortem and usually reflects the results of delayed 

sampling at the time of skin testing. 47 

Complement levels 

As a diagnostic tool in clinical anaphylaxis, complement level 

measurement has limited value. Changes in serum complement 

levels and activation of the classic and alternate pathways have 

been demonstrated after clinical anaphylaxis, particularly due 

to adhesion, protamine, and contrast media. 48,49 Activation 

should be measured rather than levels of complement fraction, 

because there are major dilutional effects during anaphylaxis. 50 

Mast cell tryptase 

Mast cell tryptase is an important advance in the diagnosis of 

anaphylactoid reactions during anesthesia. In anaphylactic reac - 

tions, the levels are elevated for 1 to 5 hours after the beginning 

of the reaction, enabling the delay of sampling until resuscitation 

is over, 51 and can be obtained in samples taken postmortem. 52 

Elevated mast cell tryptase levels are highly specific and sensitive 

of an immune reaction, with the exception of reactions to gelatin 

and contrast. All patients with elevated mast cell tryptase levels 

should be considered to have a severe immune reaction and 

investigated further. 

● 

● 

● 

● 

Tests After the Reaction 

● 

Skin testing 

Skin testing is performed 4 to 6 weeks after the reaction. 53 Skin 

tests have the advantages over other tests because of the high 

yield of positive results (reflecting the high incidence of IgE


● 

involve ment in severe reactions) and ease in performing the 

tests. 54–56 Two forms of skin testing are used—intradermal tests 

and prick tests. 

Prick testing is less traumatic to the skin, easily done, and 

safe. Their disadvantage is that they tend to produce more false 

negatives, whereas intradermal tests tend to produce more false 

positives. The consequences of a false-negative test for 

subsequent anesthesia are obviously greater than those of a false 

positive. Skin tests are of little value in reactions to colloids, 

contrast media, and blood products. 

With local anesthetics, genuine anaphylactic reactions are 

rare, and the goal is to exclude allergy. Skin testing on its own is 

inadequate. If there was not a clear-cut history suggestive of 

anaphylaxis and a clear-cut positive wheal and flare reaction 

at 1:100 dilution of 0.5% local anesthetic, the dosage should be 

increased to 2 mL of undiluted local anesthetic solution. It is 

important to note that deaths have occurred in association to 

skin testing. Resuscitation facilities should always be available. 

Radioimmunoassay tests 

Radioimmunoassay (RIA) tests have been used to detect IgE 

drug-specific antibodies. RIA tests have sensitivity similar to 

skin tests. However, RIAs are available for propofol, thiopen - 

tone, succinylcholine, vecuronium, pancuronium, gallamine, 

D-tubocurarine, and alcuronium. Combination of RIA and skin 

tests detects a drug responsible for reaction better than either 

test alone. 

Cross-sensitivities are better determined by RIAs than by 

cutaneous tests. There is significant in vitro cross-sensitivity 

between thiopentone and non-depolarizing muscle relaxants 

(NDMR), which is not reflected clinically. However, in patients 

who are allergic to both, skin tests and RIA inhibition are 

necessary to distinguish. 57 

In practice, when the results of tests disagree, the patient 

should be warned off all positive drugs. 

In summary, an often-overlooked factor in the investigation 

of patients with anesthetic allergy is the need for accurate docu - 

mentation and communication. The patients should be encour - 

aged to wear a warning device (e.g., bracelet) stating the drugs that 

should be avoided. It should also be accompanied with detailed 

information about the potential reaction if the medication is given, 

which tests were performed, the results of those tests, and the 

conclusion. Anesthetic allergy has been shown to persist up to 

27 years, and few patients lose their sensitivity over this period 

of time. 58,59 

Preoperative Testing 

Recently, it has been argued that patients presenting for anesthesia 

should be preoperatively screened by RIA/skin tests to reduce the 

risk of anaphylaxis. The case for this testing is poor. The selection 

of at-risk group, such as women of child-bearing age with or 

without a history of allergy, will improve the cost-effectiveness 

of testing and lead to a major reduction in reactors detected. 

If screening is performed, prick testing would be the only feasible 

and sufficiently reliable test. 

The most important variable in the case of screening is the 

prevalence of anesthetic allergy, which is different from and 

unlikely to be greater than the incidence of reactions, because a 

number of allergic patients will undergo anesthesia without 

exposure to a drug to which they may be allergic. In spite of the 

limitations of diagnostic tests, when patients are investigated using 

skin testing and RIA where available, subsequent anesthesia is 

usually safe, irrespective of whether the reaction was diagnosed as 

anaphylactic or not or whether the drug responsible was detected. 

EFFECT OF ANESTHESIA ON 

VACCINATION OF CHILDREN 

Anesthesia and surgery exert immunomodulatory effects, and 

some authors argue that they may exert additive or synergistic 

influences on vaccine efficacy and safety. Alternatively, inflam - 

matory responses and fever elicited by vaccines may interfere with 

the postoperative course. There is a lack of consensus approach 

among anesthesiologists to the theoretical risk of anesthesia and 

vaccination. Few studies have assessed the influence of anesthesia 

and surgery on pediatric vaccine responses. 60 

Anesthetists are often faced with a child who has been recently 

immunized presenting for either emergency or elective surgery. The 

question is then raised as to whether anesthesia or surgery will 

affect response of child to vaccine in achieving seroconversion or, 

more seriously, whether the vaccine may cause more serious 

adverse reactions in these circumstances. A further question may be 

raised as to how soon after surgery it is safe to administer vaccine. 61 

There is no direct evidence of any major interaction between 

immunization and commonly used anesthetic agents and tech - 

niques in children, but it is possible that immunosuppression 

caused by anesthesia and surgery may lead to decreased vaccine 

effectiveness or an increased risk of complications. 62,63 

Based on the theoretical risk of interaction between anesthesia 

and immunization, it is believed that it could be eliminated by 

ensuring a 3-week delay between the two. An international survey 

was undertaken to discover whether there is a consensus among 

pediatric anesthetists on this issue. 62 Two hundred and ninetysix 

(52.1%) Association of Paediatric Anaesthetists of Great Britain 

and Ireland (APAGBI) and 86 (49.4%) Society of Paediatric 

Anaesthesia in New Zealand and Australia (SPANZA) responses 

were analyzed. There was no consensus of approach to this theore - 

tical risk among respondents. In total, 60% of respondents would 

anesthetize a child for elective surgery within 1 week of receiving 

a live, attenuated vaccine, but 40% would not. Few hospitals have 

formal policies on this issue, and government guidance is based on 

a lack of evidence for adverse events rather than positive evidence 

of safety. An international postal survey failed to find a consensus 

to this risk among pediatric anesthetists. From a risk management 

perspective, a review of the available evidence suggests that it 

would be prudent to adopt a cautious approach in which the 

timing of elective surgery is discretionary. 

In children, few studies have assessed the influence of anes - 

thesia on immune responses. Hence, anesthetists and surgeons are 

confronted with unanswered questions 60 : 

1. Are there interferences between general anesthesia and routine 

vaccination? 

2. Should elective surgery under general anesthesia be postponed 

in recently vaccinated children? 

3. Should elective vaccination be postponed in children scheduled 

for elective surgery? 

4. What are the risks of a general anesthesia in recently vaccinated 

children, particularly when anesthesia must be performed in 

case of emergency? 

Children are routinely immunized from a very early age to 

protect them against the devastating morbidity and mortality


previously associated with many infectious diseases. Such immu - 

nization relies on the activation of the immune system in response 

to modified antigen, the formation of immunologic memory, and 

an enhanced immune response to subsequent exposure to the 

disease. Effective immunization thus requires an intact, func - 

tioning immune system. Exposure to modified antigen, as well as 

triggering the production of protective antibodies, may cause side 

effects ranging from mild fever to development of a noninfectious 

form of the disease. 64 

The first risk the authors identify is that the efficacy of 

vaccination may be reduced by the immunosuppressive effect of 

anesthesia and surgery. The duration of any immunosuppression 

because of anesthesia is short, and there is no evidence from 

humans that any of the routine childhood vaccines have failed 

because of anesthesia or surgery. 65 

If anesthetics or surgery was significantly immunosuppressive, 

then infections such as endogenous bacteremias would be regular 

sequelae, but this is not observed. The example that Short and 

associates cite is a single case report of the failure of postexposure 

rabies vaccination of a child bitten on the face. 62 Such failures are 

recognized irrespective of anesthesia or surgery and are most 

frequent in facial bites and when, as in this case, administration of 

human rabies immunoglobulin is delayed. 

Comparing this scenario with the routine immunization 

program in which children receive multiple doses of all the recom - 

mended vaccines. It is unlikely that anesthesia after any one dose 

of vaccine would have any significant impact on the efficacy of the 

whole series. For example, antibody levels are proxies for immu - 

nity and a poor measure of immunologic priming. Furthermore, 

if there were a concern about the efficacy of a vaccine being 

reduced, the most logical way to ensure that the child is sufficiently 

protected would be to give him or her an additional dose of 

vaccine, not to delay vaccination. 65 

The second risk is of increased complications after vaccination 

at the same time as a child receives an anesthetic and surgery. 

This possibility would again be more important in relation to the 

live, attenuated vaccines such as polio, and measles, mumps, and 

rubella (MMR). 62 

Healthy children receiving immunizations with killed vaccine 

commonly suffer mild reactions with local symptoms of redness, 

swelling at the injection site, mild fever, and irritability. 61 This 

occurs within a limited time of a few days and would be unlikely 

to complicate postoperative assessment. Fever, which would be 

more difficult to distinguish from a postoperative complication, 

occurs less frequently. 66 There has also been a switch to using 

acellular pertussis vaccine rather than whole cell pertussis vaccine, 

because it causes fewer localized reactions. 62 The period of risk 

is again a few days shorter than the 1-week delay in surgery 

suggested by the authors. 65 

After administration of live vaccine, the reaction may be 

delayed and present as a mild form of the illness. The reaction will, 

therefore, depend on the incubation period of the illness itself 

so that mild measles may occur 5 to 10 days after MMR and 

mild mumps 14 to 21 days after MMR. If mild rubella occurs, it is 

hard to distinguish from measles; severe reactions are rare, for 

example 61 : 

1. Polio 

One in 2 or 3 million doses of vaccine can revert toward the 

characteristics of the wild type and could then cause polio in 

nonimmunized persons or close contacts such as other children 

on the ward. 67 The vaccine is genetically unstable and may 

change its structure. 68 

The U.K. Immunization “Green Book” states that the 

possibility of a very small risk of poliomyelitis induced by oral 

vaccine cannot be ignored but is insufficient to warrant a 

change in immunization policy. 64 Since the book was published 

in 1996, however, there has been just such a change in policy, 

and the use of inactivated polio vaccine became routine in the 

United Kingdom at the end of 2004, eliminating the small risk 

of vaccine-associated polio. 62 

2. MMR 

Complications of these illnesses can occur, but more rarely with 

the vaccine than with the illness itself. For example, mumps 

meningitis occurs in about 1 in 300,000 immunizations but in 

approximately 1 in 1000 cases of mumps. Idiopathic thrombo - 

cytopenic purpura occurs as a complication of MMR, but it is 

extremely rare, affecting fewer than 1 in 32,000 children from 

MMR. 69 This reaction occurs up to 6 weeks after vaccination, 

so the 3-week period proposed in papers would not exclude it. 

Similarly, vaccine-derived mumps occurs 3 to 4 weeks after 

vaccination. As a result of the fact that the MMR vaccine con - 

tains live, attenuated viruses, it is also considered biologically 

plausible that it could cause encephalitis, although the risk is 

believed to be small. 62 

It may be policy in some units that anesthesia be delayed for 

up to 6 weeks after an immunization. Parents may also be 

advised not to have their children immunized for 6 weeks after 

surgery. This would make the planning of routine surgery 

difficult in the early months of life and may interfere with the 

immunization schedule. 61 

It is interesting that a recent survey of health professionals 

found a poor knowledge of these rare but serious side effects 

among the general practitioners, health visitors, and practice 

nurses who administer the vaccines. 62 

3. Haemophilus influenzae 

The conjugate Haemophilus influenzae B vaccine may be a risk 

factor for the development of two autoantibodies frequently 

associated with type 1 diabetes. 70 

Given these incubation periods, and the rarity of severe 

reactions, postponing anesthesia for 3 weeks after immunization, 

as recommended by Short and associates, 62 would seem 

appro priate. For inactivated vaccines, delaying anesthesia for 

7 days would allow resolution of the symptoms and should 

eliminate any effect of modulation of the immune system on 

the desired response to the vaccine. 61 

The final risk is that complications of vaccination may confuse 

postoperative assessment (Table 82–2). 65 

There are few definitive studies on human patients that directly 

assess the effect of surgery and anesthesia on the effectiveness of 

immunization. In humans, various studies demonstrated that 

antitetanus toxoid antibody response was reduced after surgery. 71,72 

Celiker and coworkers advised postponing elective tonsillec - 

tomy in a child until postexposure immunization was complete. 73 

Vaccination and anesthesia separately might be harmless but 

in combination could cause problems. However, Salo 74 pointed out 

that no harmful effects have been reported in Finland where 

recent vaccination is not regarded as a contraindication to surgery 

in children. Salo also commented that elective operations should 

not be carried out immediately after vaccination with live or 

weakened viruses (e.g., oral polio vaccine). In theory, the patient


TABLE 82-2. Side Effects of Anesthesia and Surgery 

Local 

Systemic 

Immunization 

Inflammation 

Pain 

Granuloma and necrosis 

(uncommon) 

Lymphadenopathy and 

abscess (uncommon) 

Fever 

Irritability 

Exanthema 

Prolonged inconsolable 

crying (≥3 h) 

Neurodeficiency 

Thrombocytopenic purpura 

Anaphylaxis with shocklike 

state 

Surgery 

Inflammation 

(wound infection) 

Postoperative pain 

Fever (sepsis) 

Irritability 

Anesthesia-induced 

rash 

Crying 

Postanesthesia 

agitation and 

confusion 

Septic petechiae 

Septic shock 

or other patients on the ward may be at risk of infection because 

of operation-induced immunosuppression. There is no such risk 

with toxoid or purified component vaccines. 

It is highly likely that children who have recently been immu - 

nized will present for both elective and emergency surgery. 

In cases of surgical emergency, the immunization history will 

assume very little importance. However, the situation may be 

different when elective surgery is planned. The systemic side 

effects from vaccination may be a relative contraindication to 

anesthesia (e.g., fever, coryza, myalgia, and malaise) and may lead 

to postponement of surgery on the day of admission if present. 

Postoperative confusion may arise between complications of 

the surgical procedure and effects of immunization (e.g., crying, 

pain, fever, vomiting), and significant diagnostic and clinical man - 

agement difficulties may be encountered if the more serious side 

effects present in postoperative children, such as arthritis, throm - 

bocytopenia, hypotonia, or/and encephalopathy. The risk of these 

complications is rare, but their coincidence with the postoperative 

period can be avoided by delaying elective surgery until after the 

period in which symptoms occur. 62 

The immunosuppression caused by anesthesia and surgery lasts 

for approximately 2 days. It would, therefore, seem reasonable 

to advise that a small risk associated with anesthesia in recently 

immunized children can be minimized or eliminated by ensuring 

a delay of 1 week after inactive vaccination and 3 weeks after live, 

attenuated vaccination and by avoiding routine immunization 

until 1 week after surgery has been performed. Because children 

are immunized three times in the first 6 months of life, it would 

seem reasonable to delay the surgery rather than the immu - 

nization in that age group. In older children, immunizations could 

be more easily planned around dates for elective surgery. 60 

The World Health Organization states: “No child should be de - 

nied any indicated immunization without serious thought as to the 

consequences for the individual child or to the larger community.” 61 

Different centers give different recommendations for anesthetic 

procedures in recently vaccinated infants and children. For 

example; the New Zealand Immunization Handbook recommends 

postponing vaccination when elective surgery is planned. 75 Other 

guidelines, such as in the Australian Immunization Handbook 

or the Green Book edited by the U.K. Department of Health, 61 

describe surgery as compatible with vaccination. The U.S. Centers 

for Disease Control and Prevention (CDC), as well as most 

European National Guidelines, do not mention the issue of anes - 

thesia or surgery in relation to immunizations. 

Based on this review, it appears that, although anesthesia exerts 

immunomodulatory effects, these are transient and without major 

impact on recently vaccinated adults and children. According 

to the current evidence and to our understanding of the level 

of immunosuppression that is associated with impaired vaccine 

efficacy, there is no immunologic contraindication to vaccinate 

healthy children scheduled for elective surgery with either live or 

inactivated vaccines. Nevertheless, physicians should be aware 

that vaccine-driven adverse events may arise and should not be 

misinterpreted as a postoperative complication. 

Because children remain at risk of contracting vaccine-pre - 

ventable diseases, including during their stay in hospital, we 

recommend not postponing immunization in children scheduled 

for elective surgery. This consideration is especially important 

during the first year of life, when many vaccines are scheduled. 

Elective surgery should also be postponed only in recently 

vaccinated children if this delay creates no danger. 60 

Overall, the impact of either delaying surgery or delaying 

vaccination is likely to do more harm than good for the individual 

children concerned. The safest outcome for the overwhelming 

majority of children is, when in doubt, to vaccinate. 65 

In summary, the immunomodulatory influence of anesthesia 

during elective surgery is both minor and transient (~48 h) and 

the current evidence does not provide any contraindication to the 

immunization of healthy children scheduled for elective surgery. 

However, Siebert and colleagues suggested the following as a 

guideline 60 (Table 82–3): 

1. Postpone all elective procedures requiring anesthesia rather 

than immunization, especially in infants. 

2. Opportunistic immunization during general anesthesia is 

inadvisable. 

TABLE 82-3. Answers and Recommendations of Effect of 

Vaccination on Anesthesia 

Are there interactions 

between general 

anesthesia and the 

immune system? 

Should anesthesia be 

postponed in recently 

vaccinated children? 

Should vaccination be 

postponed in children 

scheduled for surgery? 

What are the risks of 

general anesthesia in 

recently vaccinated 

children? 

Yes, but minor and transient. 

No, although a delay before 

elective surgery may be useful 

to avoid vaccine related adverse 

events to be misinterpreted as 

postoperative complications: 7 d 

after a non-live vaccine; 21 d 

after a live viral vaccine. 

Not to postpone immunization in 

children scheduled for elective 

surgery. 

Not different from the risk in 

unvaccinated children.


3. Postpone anesthesia for 1 week after vaccination with inactive 

vaccines: diphtheria, tetanus, pertussis, inactive polio. 

4. Postpone anesthesia for 3 weeks after vaccination with live, 

attenuated vaccines: measles, mumps, rubella, oral polio vaccine, 

and bacille Calmette-Guérin (BCG; against tuberculosis). 

5. Delay immunization for 1 week after surgery has been 

performed. 

ANESTHESIA IN HIV- 

INFECTED CHILDREN 

It has been estimated that 20 to 25% of HIV-positive patients 

will require surgery during their illness. Therefore, most anes - 

thesiologists, also pediatric anesthesiologists, will care for HIVpositive 

patients. These anesthesiologists face a complex disease, 

which can vary from asymptomatic patients to multiple organ 

disease with opportunistic infections. 76 

The rapid and early diagnosis of HIV infection in exposed 

infants is complicated by transplacental passage of maternal 

IgG antibodies to the virus. Virtually all these children are HIV 

antibody–positive at birth, although only 15 to 30% is actually 

infected. This antibody usually becomes undetectable by 9 months 

of age but occasionally remains detectable until 18 months of age. 

Therefore, standard anti-HIV IgG antibody tests indicate HIV 

infection in children older than 12 to 18 months. In young infants 

younger than 18 months, the diagnosis of HIV infection now relies 

on virologic assays: HIV DNA polymerase chain reaction (PCR) 

and HIV peripheral blood lymphocyte culture. 77 

Pediatric HIV infection can be classified according to immu - 

nologic status (Table 82–4) and clinical status. 78 Once classified, 

an HIV-infected child cannot be reclassified in a less severe 

category even if the clinical or immunologic status improves. 

CD4+ T lymphocyte depletion is a major consequence of HIV 

infection and is responsible for many severe manifestations of 

HIV infection. However, normal CD4+ counts in infants and 

young children are higher than in adults and decline in the first 

years of life. They vary depending on the age of the child. 

Moreover, children may develop opportunistic infections at higher 

CD4+ levels than adults. Hence, age-specific CD4+ T lymphocyte 

counts and CD4+ percentage of total lymphocytes are used to 

classify the severity of immunosuppression attributable to HIV 

infection in children. Three immunologic categories are described 

based on the signs, symptoms, or diagnoses related to HIV 

infection. 77 

Anesthesia Considerations in 

Pediatric HIV Infection 

Anesthesia in a child with HIV infection is challenging. The 

spectrum of disease varies from asymptomatic to severe multiple 

organ involvement. There is no major anesthetic problem in 

an asymptomatic patient with seropositivity alone, because 

this group of patients is not treated with antiretroviral agents. 

Conversely, careful anesthesia management is needed in patients 

with multiorgan involvement. Anesthesia begins with preoperative 

assessment, which consists of history, physical examination, and 

laboratory studies. History and physical examination focus on the 

current status of HIV infection, coexisting organ involvement, and 

concurrent medications. Children with a lower CD4+ count reveal 

more advanced disease and need particular attention. In patients 

who received multiple medications, adverse drug effects and 

interactions with drug used in anesthesia should be taken into 

consideration. 77 

There is no specific recommended anesthesia technique or 

agent for HIV-infected children. However, general anesthesia is the 

most often used technique in pediatric anesthesia practice. Anes - 

thesia is based on the extent of organ involvement. For example, 

high-inspired oxygen concentration is necessary in children with 

pulmonary complications and impaired gas exchange. In patients 

with cardiovascular involvement, titration of anesthetics with 

careful hemodynamic monitoring is advised. Narcotics and muscle 

relaxants are chosen and dosed according to alterations in renal 

and hepatic function. The use of succinylcholine is avoided in 

progressive neuropathy, myopathy, and muscle weakness because 

of the potential risk of hyperkalemia. Immunologic suppression by 

anesthetic agents may be of minor importance for subjects with 

a normal immune system, but it is important in patients with 

immune dysfunction. 79 

Central neural blockade, especially caudal anesthesia, is a 

common regional anesthesia technique in children. Because there 

is the possibility of neurologic involvement in HIV infection, 

performing central neural blockade in HIV-infected patients is an 

issue for discussion. It is suggested that, before performing central 

neural blockade, the patient should be carefully evaluated for 

central nervous system involvement as well as any contraindication 

to central neural blockade such as thrombocytopenia, which is a 

side effect of antiretroviral agents. 80 

Patients with HIV infection are administered several medi - 

cations concomitantly to combat HIV-related conditions and 

to prevent or treat opportunistic infections. Some of these 

drugs interact with those used in anesthesia. Prolonged neuro - 

muscular blockade after vecuronium in patients with HIV 

infection is described. Protease inhibitors are inhibitors of cyto - 

chrome P450, which is involved in the metabolism of many 

anesthetic and anal gesic agents. Ritonavir, a protease inhibitor, 

can reduce clearance of fentanyl and prolong fentanyl half-life. 81 

If only small bolus doses of fentanyl are administered, a dose 

adjustment of fentanyl is probably not needed, but the dosage 

of fentanyl should be reduced if administered by infusion. 

Saquinavir can inhibit midazolam metabolism and prolong 

midazolam’s effect. 82 

TABLE 82-4. Immunologic Classification of HIV in Children Based on Age-Specific CD4+ T 

Lymphocyte Counts and Percentage of Total Lymphocytes 

Immunologic Categories ≤12 mo, µL (%) 1–5 y, µl (%) 6–12 y, µl (%) 

No evidence of suppression ≥1500 (≥25) ≥1000 (≥25) ≥500 (≥25) 

Evidence of moderate suppression 750–1499 (15-24) 500–999 (15–24) 200–499 (15–24) 

Evidence of severe suppression


ANESTHESIA IN IMMUNOSUPPRESSED 

CHILDREN WITH GRAFT- 

VERSUS-HOST DISEASE 

Preanesthetic evaluation should focus on the extent of systemic 

involvement secondary to graft-versus-host disease (GVHD) and 

the status of immunosuppression. Interaction of anesthetics with 

immunosuppressive drugs is an important consideration. When 

hepatic and renal functions are normal, there are no contrain - 

dications to the use of any anesthetic agent. Inhalational agents 

such as halothane and sevoflurane can be used for induction, and 

agents such as isoflurane, sevoflurane, and desflurane can be used 

for maintenance of anesthesia. Intravenous agents and local anes - 

thetics may also be used. There is no evidence of any increased 

risk associated with central neuraxial blockade in children on 

long-term steroids. 83 

Cyclosporine enhances the effects of muscle relaxants. The 

dosage of nondepolarizing muscle relaxants including atracurium 

should be reduced in patients receiving cyclosporine, and the 

recovery time of nondepolarizing muscle relaxants may be pro - 

longed. Azathioprine has little interaction with nondepolarizing 

muscle relaxants in humans. Propofol infusion does not modify 

cyclosporine blood levels in humans. Atracurium or cisatracurium 

is specifically indicated in children with renal or hepatic im - 

pairment. 83 

The effects of nitrous oxide on the bone marrow cells may be a 

concern. Bone marrow suppression is more likely to occur after 

prolonged exposure (>6 h) at high concentrations. Methotrexate 

impairs folate metabolism and can cause bone marrow depression. 

Nitrous oxide may reduce the therapeutic benefit and increase 

the side effects of methotrexate therapy. Hence, nitrous oxide 

should be used with caution in patients on methotrexate therapy 

(as GVHD prophylaxis). In the presence of pancytopenia and 

refractory thrombocytopenia, it may be better to avoid this agent 

for long procedures. 84 

Because hepatic dysfunction is common in GVHD and renal 

dysfunction, it is imperative to avoid anesthesia agents with poten - 

tial hepatorenal toxicity such as halothane (for maintenance), longacting 

opioids such as morphine and pethidine, benzodiazepines 

undergoing oxidative metabolism (e.g., diazepam), long-acting 

muscle relaxants such as pancuronium, pipecuronium, doxa - 

curium, and non-steroidal anti-inflammatory drugs (NSAIDs). 

NSAIDs may augment the nephrotoxicity of cyclosporine or 

tacrolimus. 83 

REGIONAL ANESTHESIA IN 

IMMUNOCOMPROMISED PATIENTS 

Regional (neuraxial) anesthesia and analgesia provide several 

advantages over systemic opioids, including superior analgesia, 

reduced pulmonary complications, and improved joint mobility 

after major orthopedic surgery. 85 

In addition, neuraxial analgesia may decrease the risk of infec - 

tion through attenuation of the stress response and preservation of 

immune function. Despite these benefits, patients with altered 

immune status because of diabetes, neoplasm, immunosuppres - 

sion after solid organ transplantation, and chronic infection with 

HIV or herpes simplex virus (HSV) are often not considered 

candidates for neuraxial techniques because of the risk of infection 

around the spinal cord or within the spinal canal. These patients 

are more susceptible to infection with opportunistic pathogens 

compared with patients with normal immune function. Thus, a 

depressed immune state increases both frequency and severity 

of infection. 86 

In addition, in terminally ill patients, the risk of infection with 

long-term epidural catheterization is acceptable, but careful moni - 

toring is recommended to avoid serious neurologic sequelae. 87 

Immunocompromised patients often present with pre-existing 

neurologic dysfunction caused by their primary disease process 

(spinal cord compression from vertebral column neoplasm, 

peripheral neuropathy associated with HIV, or diabetes) or 

because of treatment. Based on the “double-crush” theory, which 

hypothesizes that axons injured at primary site may be particularly 

susceptible to damage, these patients may be at increased risk for 

neurologic complications of regional anesthesia. Furthermore, the 

damage of the dual injury exceeds the expected additive damage 

caused by each isolated injury. Thus, the effects of needle trauma, 

ischemia, and local anesthetic toxicity are exaggerated and a 

relatively minor injury applied to a previously dysfunctional nerve 

may result in new (or exacerbation of existing) symptoms. 88 

Recommendations for Safe 

Use of Regional Anesthesia in 

Immunocompromised Patients 86 

1. Clinical series and epidemiologic data provide guidance in the 

administration of spinal or epidural anesthesia in the febrile 

patient. However, as with all clinical judgments, the decision 

to perform a regional anesthetic technique must be made on 

an individual basis considering the anesthetic alternatives, the 

benefits of regional anesthesia, and the risk of central nervous 

system infection (which theoretically are more likely to occur 

in the immunocompromised patient), as well as the risk of 

hemorrhagic or neurologic complications. 

2. Consultation with an infectious disease specialist is advised to 

facilitate initiation of early and effective therapy, because there 

is attenuated inflammatory response within the immuno - 

compromised patient that may diminish the clinical signs and 

symptoms often associated with infection. Likewise, the range 

of microorganisms causing invasive infection in the immuno - 

compromised host is much broader than that affecting the 

general population and includes atypical and opportunistic 

pathogen. 

3. The diagnosis and treatment of central nervous system 

infections should not be delayed because it worsens neurologic 

outcome and increases mortality. 

4. Prolonged duration of epidural catheterization increases the 

risk of epidural abscess. 

5. Central neuronal block has been showing safety in patients 

with recurrent HSV infections, although exacerbations of 

HSV-1 have been reported in association with intrathecal and 

epidural opioids. 

AUTOIMMUNE HEPATITIS CAUSED 

BY VOLATILE ANESTHETICS IN 

PEDIATRIC ANESTHESIOLOGISTS 

Pediatric anesthesiologists are exposed to significant levels of 

volatile anesthetics during frequent facemask inductions of general 

anesthesia and from the practice of using uncuffed endotracheal


tubes. Previous investigations have demonstrated that several 

specific hepatic proteins become covalently trifluoroacetylated 

(TFA) by the reactive metabolites of halothane and isoflurane. 

Similar effect may also be formed at very small levels after exposure 

to desflurane. These TFA neoantigens are important because it is 

thought that they induce immune responses against either the TFA 

neoantigens, the native protein components (autoantigens) of the 

TFA neoantigens, or both of these classes of antigens in individuals 

who are susceptible to inhaled anesthetic-induced hepatitis. 89 

It has been established that cytochrome P450 2E1 (CYP 2E1), 

the primary enzyme responsible for the oxidative metabolism 

of most volatile anesthetics, also becomes TFA-altered when it 

metabolizes halothane. In addition, autoantibodies reacting with 

CYP 2E1 are significantly elevated in the sera of 45 to 70% of 

patients diagnosed with halothane hepatitis, whereas control sub - 

jects did not demonstrate increased levels of these autoantibodies. 

These findings suggest that pathogenic antibodies directed against 

ERp58, CYP 2E1, or both may have a role in the etiology of volatile 

anesthetic hepatitis. 90 

Njoku and associates demonstrated that pediatric anes - 

thesiologists had higher levels of both ERp58 and CYP 2E1 auto - 

antibodies than did general anesthesiologists and control patients, 

whereas general anesthesiologists have increased serum levels 

of CYP 2E1 autoantibodies only when compared with the control 

patients. 91 However, because most anesthesiologists do not develop 

volatile anesthetic–induced liver injury, the results suggest that 

pathogenic ERp58 and CYP 2E1 autoantibodies may not cause 

volatile anesthetic hepatitis. 

These results suggest that chronic occupational exposure to 

volatile anesthetics can lead to continuous hepatic metabolism of 

volatile anesthetics and formation of immunogenic TFA protein 

adducts, including TFA-ERp58 and TFA-CYP 2E1, which can 

induce formation of the ERp58 and CYP 2E1 autoantibodies 

associated with volatile anesthetic hepatitis. 92 

The results have also shown that female anesthesiologists have 

higher levels of ERp58 autoantibodies than male anesthesiologists. 

Also, female pediatric anesthesiologists have higher levels of 

CYP 2E1 autoantibodies than all other anesthesiologists. Only one 

female pediatric anesthesiologist developed liver injury, even when 

all of the pediatric anesthesiologists as a group had increased 

serum levels of anesthetic hepatitis–associated ERp58 and CYP 

2E1 autoantibodies that were not significantly different from 

those of halothane hepatitis patients. These finding suggest that 

ERp58 and CYP 2E1 autoantibodies may not have a role in the 

development of inhaled anesthetic hepatitis. Alternatively, it is 

possible that antigen-specific cytotoxic T cells, instead of autoan - 

tibodies, which are directed against peptides derived from ERp58 

and CYP 2E1, may cause volatile anesthetic hepatitis. By contrast, 

humoral reactions, cellular immune reactions, or both against 

native ERp58 and CYP 2E1 may not have a role in volatile 

anesthetic–induced hepatitis. Perhaps only TFA-altered forms of 

these autoantigens can be targets of pathogenic antibodies or 

cytotoxic T cells. 92 

In this regard, previous studies have demonstrated that only 

halothane hepatitis patients, but not patients exposed to halothane 

who did not develop hepatitis or patients with other forms of 

liver disease, have serum antibodies that react with TFA liver 

microsomal antigens. Furthermore, other cellular targets of the 

reactive acyl halide metabolites of volatile anesthetics that also 

become TFA modified, such as a carboxylesterase, protein disul - 

ide isomerase, ERp72, and glucose-related proteins 78 and 94, 

could potentially become the immunogens that lead to volatile 

anesthetic–induced hepatitis. 92 

In summary, a significantly higher level of ERp58 and CYP 2E1 

serum autoantibodies was found in pediatric anesthesiologists 

than in general anesthesiologists. Female anesthesiologists, both 

pediatric and general, have higher levels of autoantibodies to 

ERp58 than male anesthesiologists, and female pediatric anes - 

thesiologists tend to have higher levels of CYP 2E1 autoantibodies 

than male pediatric anesthesiologists. Still, only one of the female 

pediatric anesthesiologists developed symptoms of anesthetic 

hepatitis, even though these autoantibodies have been associated 

with volatile anesthetic–induced hepatitis. These findings suggest 

that ERp58 and CYP 2E1 serum autoantibodies may not have a 

significant role in volatile anesthetic–induced hepatitis and that 

other immune mechanisms may determine whether halogenated 

volatile anesthetic–induced hepatitis occurs. 92 

CONCLUSION 

Intraoperative anaphylaxis is the most severe complication of 

pediatric anesthesia and it is prevented by careful identification of 

risk groups, identification of causative agent, and serologic and 

skin tests. Postoperative immunosuppressive effects are transient 

for approximately 48 hours irrespective of the mechanism of 

drug actions. 

Immunocompromised patients should be carefully observed 

for fear of postoperative infections and neurologic complications, 

which occur as a result of regional anesthesia technique. Anes - 

thesia should be postponed for 1 week for killed vaccines and for 

3 weeks for live vaccines for fear of increased complications of 

vaccines or a decrease in the effectiveness of vaccines. 

REFERENCES 

1. Sao M. Effects of anaesthesia and surgery on the immune response. Acta 


2. McBride WT, Armstrong MA, McBride SJ. Immunomodulation: an 

important concept in modern anaesthesia. Anaesthesia. 1996;51:465–73. 

3. Delves PJ, Roitt FS. The immune system. First of two parts. N Engl J Med. 

2000;343:37–49. 

4. Goldsby, R. A., Kindt TJ, Osborne BA. Immunoglobulins: structure and 

function. In: Kindt TJ, R. A. Goldsby RA, Osborne BA, (eds.), Kuby 

immunology, 4th ed. W. H. Freeman and Company, New York, N.Y. 2000; 

p. 83–113. 

5. Ni Choileain N, Redmond HP. Cell response to surgery. Arch Surg. 

2006;16:1132–1140. 

6. McMahon SB, Bennett DL. Inflammatory mediators and modulators of 

pain. In: McMahon SB, Koitzenburg M, editors. Wall and Mehack’s 

Textbook of Pain. 5th ed. Philadelphia: Elsevier Churchill Livingstone; 

2006. pp. 49–72. 

7. Moraska A, Campisi J, Nguyen K, et al. Elevated IL-lb contributes to anti - 

body suppression produced by stress. J Appl Physiol. 2002;93:207–215. 

8. Sacerdote P. Opioids and the immune system. Palliat Med. 2006;20(Suppl 

I):s9–s15. 

9. Molina PE. Opioids and opiates: analgesia with cardiovascular, haemo - 

dynamic and immune implications in critical illness. J Intern Med. 2006; 

259:138–154. 

10. Homburger JA, Meiler SE. Anesthesia drugs, immunity and long-term 

outcome. Curr Opin Anaesthesiol. 2006;19:423–428. 

11. Loop T, Dovi-Akue D, Frick M, et al. Volatile anesthetics induce caspasedependent, 

mitochondria-mediated apoptosis in human T-lymphocytes 

in vitro. Anesthesiology. 2005;102:147–1157. 

12. Devlin EG, Clarke RS, Mirakhur RK, et al. Effect of four IV induction 

agents on T-lymphocyte proliferations to PHA in vitro. Br J Anaesth. 

1994;73:315–317.


13. Chang Y, Chen T. Sheu J, et al. Suppressive effects of ketamine on 

macrophage functions. Toxicol Appl Pharmacol. 2005;204:27–35. 

14. Inada T, Yamanouchi Y, Jomura S, et al. Effect of propofol and isoflurane 

anaesthesia on the immune response to surgery. Anaesthesia. 2004;59: 

954–959. 

15. Kelbel I, Weiss M. Anaesthetics and immune function. Curr Opin 

Anaesthesiol. 2001;14:685–691. 

16. Schneemilch CE, Hachenberg T, Ansorge S, et al. Effects of different 

anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol. 

2005;22:616–623. 

17. Procopio M, Rassias AJ, DeLeo JA, et al. The in vivo effects of general and 

epidural anesthesia on human immune function. Anesth Analg. 2000; 

93:460–465. 

18. Correa-Sak’S C, Tosta CE, Rizzo LV. The effects of anesthesia with 

thiopental on T lymphocyte responses to antigen and mitogens in vivo 

and in vitro. Int J Immunopharmacol. 1997;19:117–128. 

19. Hamra JG, Yaksh TL. Halothane inhibits T cell proliferation and 

interleukin-2 receptor expression in rats. Immunopharmacol Immuno - 

toxicol. 1996;18:323–336. 

20. Mikawa K, Akamatsu H, Nishina K, et al. Propofol inhibits human 

neutrophil functions. Anesth Analg. 1998;87:695–700. 

21. Galley HF, Webster NR. Effects of propofol and thiopentone on the 

immune response. Anaesthesia. 1994;52:921–923. 

22. Stevenson GW, Hall SC, Rudnik S, et al. The effects of anesthetic agents 

on the human immune response. Anesthesiology. 1990;72:144. 

23. Spiers EM, Potts RC, Simpson JR, et al. Mechanisms by which barbiturates 

suppress lymphocyte responses to phytohaemagglutinin stimulation. 

Int J Immunopharmacol. 1987;9:505–512. 

24. Devlin EG, Clarke RSJ, Mirakhur RK, et al. The effects of thiopentone 

and propofol on delayed hypersensitivity reactions. Anaesthesia. 1995;50: 

496–498. 

25. Hensler T, Hecker H, Heeg K, et al. Distinct mechanisms of immuno - 

suppression as a consequence of major surgery. Infect Immunol. 1997;65: 

2283–2291. 

26. Stover JF, Stocker R. Barbiturate coma may promote reversible bone 

marrow suppression in patients with severe isolated traumatic brain 

injury. Eur J Clin Pharmacol. 1998;54:529–534. 

27. Eberhardt KE, Thimm BM, Spring A, et al. Dose dependent rate of 

nosocomial pulmonary infection in mechanically ventilated patients with 

brain oedema receiving barbiturates: a prospective case study. Infection. 

1992;20:12–18. 

28. Briggs WA, Eustace J, Gimenez LF, et al. Lymphocyte suppression 

by glucocorticoids with cyclosporine, tacrolimus, pentoxifylline, and 

mycophenoiic acid. J Clin Pharmacol. 1999;39:125–130. 

29. Pirttikangas CO, Perttila J, Salo M. Propofol emulsion reduces prolif - 

erative responses of lymphocytes from intensive care patients. Intensive 

Care Med. 1993;19:299–302. 

30. Angele MK, Faist E. Clinical review: immunodepression in the surgical 

patient and increased susceptibility to infections. Crit Care. 2002;6:298–305 

31. Hanisch UK, Quirion R. Interleukin-2 as a neuroregulatory cytokine. 

1996;21:246–284. 

32. Salo M, Pirttikangas CO, Pulkki K. Effects of propofol emulsion and 

thiopentone on T helper cell type-l/rype-2 balance in vitro. Anaesthesia. 

1997;52:341–344. 

33. Loop T, Liu Z, Humar M, et al. Thiopental inhibits the activation of 

nuclear factor kappaB. Anesthesiology. 2002;96:1202–1213. 

34. Ben-Eliyahu S. The promotion of tumor metastasis surgery and stress: 

immunological basis and indications for psychoneuroimmunology. Brain 

Behav Immun. 2003;17:S27–S36. 

35. Carrigan KA, Saurer TB, James SG, et al. Buprenorphine produces 

naltrexone reversible alterations of immune status. Int Immunopharmacol. 

2004;4:419–428. 

36. Martucci C, Panerai AE, Sacerdote R. Chronic fentanyl or buprenorphine 

infusion in the mouse: similar analgesic profile but different effects on 

immune responses. Pain. 2004;110:385–392. 

37. Tsujikawa H, Shoda T, Mizota T, Fukuda K. Morphine induces DNA 

damage and P53 activation in CD3+ T cells. Biochem Biophys Acta. 

2009;1790:793–793. 

38. Sacerdote P, Bianchi M, Gaspani L, et al. The effects of tramadol and 

morphine on immune responses and pain after surgery in cancer patients. 

Anesth Analg. 2000;90:1411–1414. 

39. Stoelting RK, Hillier SC. Pharmacology and Physiology in Anesthesia 

Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2005, 

p. 850. 

40. Yeager MP, Procopio MA, DeLeo JA, et al. Intravenous fentanyl increases 

natural killer cell cytotoxicity and circulating CD16(+) lymphocytes in 

humans. Anesth Analg. 2002;94:94–99. 

41. Jacobs R, Karst M, Scheinichen D, et al. Effects of fentanyl on cellular 

immune functions in man. Int J Immunopharmacol. 1999;21:445. 

42. Bruce DL. Halothane inhibition of RNA and protein synthesis of PHAinduced 

human lymphocytes. Anesthesiology. 1975;42:11–14. 

43. Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile 

anaesthetics on cytokine release in human peripheral blood mononuclear 

cells. Int J Immunopharmacol. 1995;17:529–534. 

44. Delves PJ, Roitt IM. Advances in immunology: the immune system. 

N Engl J Med. 2000;343:30–36. 

45. Moudgil GC. Update on anesthesia and the immune response. Can J 

Anaesth. 1986:33:354–360. 

46. Fisher MM, More DG. The epidemiology and clinical features of 

anaphylactic reactions in anaesthesia. Anaesth Intensive Care. 1981;9: 

226. 

47. Weiss ME, Adkinson NF, Hirshman CA. Evaluation of allergic reactions 

in the perioperative period. Anaesthesia. 1989,71:43. 

48. Laroche D, Lefrancois C, Gerard JL, et al. Early diagnosis of anaphylactic 

reactions to neuromuscular blocking drugs. Br J Anaesth. 1992;69: 

611–614. 

49. Watkins J, Appleyard TN, Thornton JA, Padfield A. Immune mediated 

reactions to anaesthesia (alphaxalone). Br J Anaesth. 1976,48:881–886. 

50. Best N, Teisner B, Grudzinskas JG, et al. Classic pathway activation during 

an adverse response to protamine sulphate. Br J Anaesth. 1983;55:1149– 

1153. 

51. Cogen FC, Norman ME, Dunsky E, et al. Histamine release and 

complement changes following injection of contrast media in humans. 

J Allergy Clin Immunol. 1979;64:299–303. 

52. Fisher MM. Tiessner B, Charlesworth JC. Significance of sequential 

changes in serum complement levels during anaphylactoid reactions. Crit 

Care Med. 1984;12:351–354. 

53. Schwartz LB, Yunginger JW, Miller J, et al. Time course of appearance and 

disappearance of human mast cell tryptase in the circulation after 

anaphylaxis. J Clin Invest. 1989;83:1551–1555. 

54. Yunginger JW, Nelson DR, Squilace DL, et al. Laboratory investigations 

of death due to anaphylaxis. J Forensic Sci. 1991;36:857–865. 

55. Fisher MM. Intradermal testing after anaphylactoid reaction to 

anaesthetic drugs: practical aspects of performance and interpretation. 

Anaesth Intensive Care. 1984;12:115–120. 

56. Sage D. Intradermal drug testing following anaphylactoid reactions 

during anaesthesia. Anaesth Intensive Care. 1981;6:381–390. 

57. Moscicki RA, Sockin SM, Corsello BF, et al. Anaphylaxis during induction 

of general anaesthesia: subsequent evaluation and management. J Allergy 

Clin Immunol. 1990;86:325–332. 

58. Harle DG, Baldo BA, Smal MA, et al. Detection of thiopentone-reactive 

IgE antibodies following anaphylactoid reactions during anaesthesia. Clin 

Allergy. 1986;16:493–498. 

59. Fisher MM, Baldo BA. Persistence of allergy to anaesthetic drugs. Anaesth 

Intensive Care. 1992;20:143–146. 

60. Siebert J, Posfay-Barbe K, Habre W, et al. Influence of anesthesia on 

immune responses and its effect on vaccination in children: review of 

evidence. Paediatr Anaesth. 2007;17:410–420. 

61. Currie J. Vaccination: is it a real problem for anesthesia and surgery? 

Paediatr Anaesth. 2006;16:501–503. 

62. Short J, Van der Walt J, Zoanetti D. Immunization and anesthesia—an 

international survey. Paediatr Anaesth. 2006;16:514–522. 

63. Van der Walt J, Roberton D. Anaesthesia and recently vaccinated children. 


64. Salisbury D, Begg, N, Noakes K, (eds). Immunization against Infectious 

Disease – The Green Book. 4th edn. London: The Stationery Office, 2006, 

p. 468. 

65. Crowcroft N, Elliman D. Vaccination and anesthesia: the precautionary 

principle is to vaccinate. Paediatr Anaesth. 2007;17:1215–1227. 

66. Kitchin N, Southern J, Morris R. A randomised controlled study of the 

reactogenicity of an acellular pertussis-containing pentavalent infant 

vaccine compared to a quadrivalent whole cell pertussis-containing 

vaccine and oral poliomyelitis vaccine, when given concurrently with 

meningococcal group C conjugate vaccine to healthy UK infants at 2, 3 

and 4 months of age. Vaccine. 2006;24:3964–3970. 

67. Centers for Disease Control and Prevention (CDC). Imported vaccineassociated 

paralytic poliomyelitis. MMWR Morb Mortal Wkly Rep. 2006; 

55:97–99.


68. Karakasiliotis J, Paximadi E, Markoulatos P. Evolution of a rare vaccinederived 

multi recombinant poliovirus. J Gen Virol. 2005;86:3137–3142. 

69. Miller E, Waight P, Farrington C. Idiopathic thrombocytopenic purpura 

and MMR vaccine. Arch Dis Child. 2001;84:227–229. 

70. Song B, Katial R. Update on side effects from common vaccines. Curr 

Allergy Asthma Rep. 2004;4:447–453. 

71. Nielsen H, Hammer J, Moesgaard F. Ranitidine improves postoperative 

suppression of antibody response to preoperative vaccination. Surgery. 

1992;111:69–73. 

72. Clayer M, Drew P, Jamieson G. Antibody responses following splenectomy: 

implications for the timing of prophylactic vaccination. Aust N Z J Surg. 

1992;62:142–146. 

73. Celiker V, Basgu E, Peker L. Rabies vaccine and anesthesia. Paediatr 

Anaesth. 2004;14:365–366. 

74. Salo M. Effects of anesthesia and surgery on the immune response. Acta 


75. Immunization Handbook Working Group (ITWG). New Zealand 

Immunisation Schedule Wellington, New Zealand, New Zealand Ministry 

of Health, April 2006. pp. 23–27. 

76. Eichler A, Eiden U, Kessler P. AIDS and anesthesia. Anaesthesist. 2000;49: 

1006–1017. 

77. Leelaukrom R, Pancharoen C. Anesthesia in HIV-infected children. 


78. Centers for Disease Control and Prevention (CDC). Revised classification 

system for human immunodeficiency virus infection in children less than 

13 years of age. MMWR Morb Mortal Wkly Rep. 1994;43:1–10. 

79. Schneemilch C, Ittenson A, Ansorge S. Effect of 2 anesthetic techniques 

on the postoperative proinflammatory and anti-inflammatory cytokine 

response and cellular immune function to minor surgery. J Clin Anesth. 

2005;17:517–527. 

80. Tom D, Gulevich S, Shapiro H. Epidural blood patch in the HIV-positive 

patient. Review of clinical experience. Anesthesiology. 1992;76:943–947. 

81. Olkkola K, Palkama V, Neuvonen P. Ritonavir’s role in reducing fentanyl 

clearance and prolonging its half-life. Anesthesiology. 1999;91:681–685. 

82. Palkama V, Ahonen J, Neuvonen P. Effect of sanquinavir on the pharma - 

cokinetics and pharmacodynamics of oral and intravenous midazolam. 

Clin Pharmacol Ther. 1999;66:33–39. 

83. Venkatesan T, Jacob R. Anesthesia and graft-vs-host disease after 

hematopoietic stem cell transplantation. Paediatr Anaesth. 2007;17:7–15. 

84. Wyatt S, Gill RS. An absolute contraindication to nitrous oxide. Anaes - 

thesia. 1999;54:307–308. 

85. Liu S, Carpenter R, Neal J. Epidural anesthesia and analgesia. Their role 

in postoperative outcome. Anesthesiology. 1995;82:1474–1506. 

86. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic 

technique on the surgical outcome and duration of rehabilitation after 

major knee surgery. Anesthesiology. 1999;91:8–15. 

87. Terese T, Horlocker M, Denise J, et al. Regional anesthesia in the 

immunocompromised patient. Reg Anesth Pain Med. 2006;31:334–345. 

88. Moen V, Dahlgren N, Irestedt L. Severe neurological complications 

after central neuraxial blockades in Sweden 1990–1999. Anesthesiology. 

2004;101:950–959. 

89. Njoku D, Laster M, Gong D. Biotransformation of halothane, enflurane, 

isoflurane, and desflurane to trifluoroacetylated liver proteins: association 

between protein acylation and hepatic injury. Anesth Analg. 1997;84: 

173–178. 

90. Bourdi M, Chen W, Peter R. Human cytochrome P450–2E1 is a major 

autoantigen associated with halothane hepatitis. Chem Res Toxicol. 1996; 

9:1159–1166. 

91. Njoku D, Greenberg R, Bourdi M, et al. Autoantibodies associated with 

volatile anesthetic hepatitis found in the sera of a large cohort of paediatric 

anaesthesiologists. Paediatr Anaesth. 2002;94:243–249. 

92. Pohl L, Pumford N, Martin J. Mechanism chemical structures and drug 

metabolism. Eur J Haematol. 1996;60:98–100.

83 

CHAPTER 

Specific Problems and Anesthesia 

Management of Extremely Low 

Birthweight Infants 

Richard J. Ing and Allison Kinder Ross 

INTRODUCTION AND DEFINITIONS 

Despite tremendous advances in the care of the extremely low 

birthweight (ELBW) infant since the early 2000s, complication 

rates still remain high. A recent study on morbidity and mortality 

(1998–2003) in 572 live-born infants born at less than 26 weeks’ 

gestation and admitted to a neonatal intensive care unit (NICU) 

showed that 62.3% survived until day 28 and 59.6% were dis - 

charged home. 1 Among infants discharged home, bronchopul - 

monary dysplasia (BPD) was diagnosed in 52.2%, intraventricular 

hemorrhage (IVH) of grade III or greater and/or periventricular 

leukomalacia was present in 15%, and severe retinopathy of 

prematurity (ROP) was seen in 29.8%. 1 Another recent 5-year 

longitudinal cohort neurodevelopmental disability study has 

shown that long-term significant disability was highest (49%) in 

children born at 24 to 28 weeks’ gestation. 2 These unique longterm 

morbidity challenges of the ELBW infant patient group are 

significant and must, therefore, be taken into consideration by the 

pediatric anesthesiologist when caring for these children. 

ELBW infants are usually born at 24 to 30 weeks’ gestation 

and weigh between 401 and 1000 g. The current definitions of 

newborn infants are presented in Table 83–1. The ELBW infant 

accounts for approximately 1% of all live-born infants. Premature 

delivery occurs before intrauterine physiologic transitional 

development and major organ maturation have been completed. 

As a result, the immature ELBW infant is initially ill-prepared to 

regulate body temperature, energy requirements, or electrolyte 

balance. In addition, the infant’s immature cardiovascular and 

respiratory systems in the extrauterine environment predispose 

them to bradycardia, hypotension, apnea, and cyanosis. Transient 

hypoxia, the need for mechanical ventilation, cardiovascular 

resuscitation, inotropes, and surfactant administration at the time 

of birth all increase the risks of iatrogenic morbidity and mortality. 

TABLE 83-1. Definitions 

Neonate 

Premature 

Preterm 

LBW 

VLBW 

ELBW 

First 44 wk postconceptional age 

CHAPTER 83 ■ Specific Problems and Anesthesia Management of Extremely Low Birthweight Infants 1393 

with complete anatomic closure usually achieved by 3 weeks of 

age. In ELBW infants specifically, this process may take longer to 

complete, and commonly, a reversal or an incomplete transitional 

physiologic state remains. In this situation, the ELBW infant’s 

circulation may revert to the fetal state under times of hypoxemia, 

hypercarbia, acidosis, hypothermia, or pain and infection. Apnea 

may be associated with sinus and nonsinus bradycardia, partic - 

ularly in ELBW infants. The etiology may be related to a matu - 

rational immaturity in the ionic channels of the heart associated 

with increased vagal tone. 3,4 Goals during initial resuscitation and 

for the first 72 hours or so of life are directed not only at the basic 

ventilatory and circulatory requirements but also to avoid the 

insults that cause the infant to shunt blood from right-to-left 

through a PDA and right-to-left across a foramen ovale owing to 

persistent pulmonary hypertension of the newborn (PPHN). This 

is particularly challenging in the operating room under conditions 

of surgical stress and fluid shifts. 

RESUSCITATION OF THE 

ELBW INFANT AT BIRTH 

The anesthesiologist may be consulted in the delivery room 

to assist resuscitation in the ELBW who is particularly prone 

to asphyxia and metabolic stress at the time of birth. Early 

resuscitation is important. Intracranial hemorrhages in the very 

preterm infant during a complicated delivery are often anticipated, 

and urgent cesarean section is sometimes advocated to protect 

the ELBW infant’s brain from trauma during vaginal delivery. 

Metabolic stress predisposes the ELBW infant to anaerobic meta - 

bolism and a metabolic acidosis. Complicated protracted labor 

and delivery decrease the ELBW infant’s cardiac output further, 

thus exacerbating the metabolic acidosis. Resuscitation of the 

ELBW infant should begin immediately after delivery by intu - 

bation of the trachea and then gentle ventilation of the lungs to 

increase the PaO 2 

while preventing any lung volume trauma. 

The cardiovascular system resuscitation often responds without 

inotropic support to correction of the metabolic acidosis with 

dilute 4.25% NaHCO 3 

at 1 mEq/kg/min to a pH of 7.3. Ensure the 

blood glucose concentration is in the range 47 to 90 mg/dL. These 

precautions will prevent any further central nervous system injury 

from too rapid an intravascular volume expansion with a hyper - 

tonic solution (8.5% NaHCO 3 

) or hypo- or hyperglycemia. The 

infant should be warmed immediately and kept in a thermoneutral 

zone aiming for a body temperature of 36°C. A prospective, 

randomized trial comparing 55 very low birth weight (VLBW) 

infants to 28 ELBW infants requiring intubation and resuscitation 

in the delivery room found that goal-directed therapy targeting 

arterial oxygen saturation, administration of surfactant, correction 

of acidosis, and intravascular volume resuscitation resulted in a 

matched study control reduction in mortality from 46% to 18%. 5 

The persistence of high lactate levels and a severe metabolic 

acidosis despite resuscitative efforts, together with intrauterine 

growth retardation, was found to be bad prognostic criteria for 

outcome. 5 

EARLY MANAGEMENT 

Tracheal Intubation 

Endotracheal intubation is typically required immediately after 

birth in the ELBW infant for respiratory support, and the provider 

should take several considerations into account. The concern 

during awake intubation in the ELBW infant is that struggling and 

crying increase intrathoracic pressure and decrease cerebral 

venous return. Increased cerebral venous hypertension occurs 

and may lead to increased intracranial pressure and a risk of 

intracranial hemorrhage. 6 Further, complications such as laryn - 

gospasm, oxygen desaturation, breath-holding, bradycardia, in - 

creased systolic blood pressure, or trauma to the airway can 

occur. 7–9 The long-term neurocognitive outcomes of performing 

awake intubation in ELBW infants are not known. Since 2000, 

there has been an increased trend to sedate and administer 

analgesia before intubation in neonates of all ages. 9 The issue 

of whether it is necessary to give analgesic or anesthetic drugs 

before neonatal intubation should now be replaced by a different 

question: Is there a reason not to give analgesic or anesthetic 

drugs before neonatal intubation? 8,9 Current recommendations 

suggest that endotracheal intubation without the use of sedation 

or analgesia should be performed only when required emergently 

during resuscitation in the delivery room or in other lifethreatening 

situations when intravenous access is unavailable. 9–11 

The approach to securing the ELBW infant airway via intu - 

bation requires meticulous attention, patience, and planning. First, 

agents that are used to secure the airway such as succinylcholine, 

pancuronium, midazolam, and fentanyl should be prepared 

undiluted in 1-mL syringes. Resuscitation medications such 

as epinephrine and atropine should also be drawn up in 1-mL 

syringes. Second, preparation of the intubating environment 

is essential. This involves ensuring a selection of appropriate 

laryngoscope blades along with back-up blades. The Miller Zero 

is a blade commonly used for the ELBW infant because of its 

small size and the light positioned near the tip of the blade for 

good visibility. A neonatal McGill forceps and neonatal intubating 

stylet should also be on hand. Suction must be available, with a 

neonatal catheter tip for clearing the pharynx if needed. There 

should be a selection of appropriately small neonatal facemasks, 

oral airways, connectors, and an Ambu bag with free-flowing 

oxygen attached either from the wall mount in the intensive care 

unit or from anesthetic machine if present in the operating room. 

The choice of outer diameter (OD) endotracheal tube (ETT) 

size is very important if airway injury in the VLBW infant is to be 

avoided. A recent study highlights that the VLBW infant airway is 

at risk for injury predominantly in the posterior region of the 

glottis owing to increased elasticity of these structures. 12 This 

elasticity disappears around 37 weeks’ gestational age, and thus, 

the slightly older premature infant then becomes at risk for 

subglottic injury. Although the normal tracheal mucosa capillary 

pressure in preterm infants has not been reported, for cuffed or 

uncuffed ETTs, most clinicians accept a leak around the ETT of 

less than 20 cmH 2 

O. Currently, the recommended safe OD of an 

ETT for a 500-g infant is 3 mm and for an 800-g infant 3.5 mm. 

This corresponds to an internal diameter of 2.0 mm with the 

Mallinckrodt contour ETT. 12 It becomes imperative for the 

pediatric anesthesiologist to know the OD of the ETT that is 

planned to be placed in the ELBW infant. 

Once the practitioner is ready to intubate the VLBW infant, 

brief preoxygenation is performed. The use of 100% oxygenation 

during resuscitation in term asphyxiated infants may have a longer 

deleterious effect as measured by the presence of intraerythrocyte 

oxidized glutathione concentration. 13 This oxidative stress 

may impair the infant’s ability to mount an antioxidant response 

and create a protracted pro-oxidant status in the asphyxiated


newborn infant. 13 More work is needed to determine oxygen’s 

role in this setting, but it is reasonable to allow a brief period of 

denitrogenation with oxygen before laryngoscopy. A sedation 

protocol for intubating ELBW infants can be guided by a recent 

double-blind, randomized study comparing the intubating 

conditions between two dosing regimen. In preterm infants 

weighing less than 1000 g, a 1-minute bolus of midazolam 200 µg/ 

kg plus morphine 150 µg/kg was compared with a 1-minute 

bolus of midazolam 200 µg/kg plus remifentanil 1 µg/kg. 14 

The overall intubating conditions were found to be significantly 

better (P = .0034) in the remifentanil group than in the morphine 

group. 14 However, as discussed later in this chapter in the 

“Intraoperative Management” under “Anesthetic Agents,” there are 

concerns with the use of midazolam and possible accelerated 

neuroapoptosis. The reader is directed to that section and also 

Chapter 3 for further information on this topic. 

Temperature Regulation 

Preterm ELBW infants have poor temperature regulation because 

they have very little insulation with almost no subcutaneous fat 

(see Chapter 14). They have translucent skin through which the 

blood vessels can be seen coursing very close to the surface; as a 

result, exposure to a cold environment will cause them to lose heat 

to the environment and increase their oxygen requirements, which 

are already high at 4.3 to 5.4 mL/kg/min at birth. The thermoge - 

nesis brown fat cells are very sparse in the ELBW infant. They start 

to differentiate at 26 to 30 weeks postconception, and continue 

differentiating up to 46 weeks. Nonshivering thermogenesis is 

immature in the ELBW infant, but does begin to occur at approxi - 

mately 30 weeks. Cold perception causes release of norepine - 

phrine, which leads to adrenergic stimulation and release of fatty 

acids that are combusted exclusively in mito chondria by a unique 

brown fat protein called uncoupling protein (UCP) or thermo - 

genin. Activation of thermogenin depends on a modulator that 

has not yet been identified. 15 The combination of these inabilities 

to adapt to the environment requires the use of body wrap and/ 

or warming devices that preserve heat without drying. Covering 

the head in VLBW infants may preserve heat loss by as much as 

63 to 73%. 16 

Hyperbilirubinemia 

In the ELBW infant, liver conjugation and bilirubin elimination 

is immature, bowel motility immaturity is present, faster red blood 

cell turnover occurs; as a result, these infants are at greater risk for 

kernicterus than neonates born at term. Kernicterus involves 

unconjugated bilirubin deposition in the pons, cerebellum, and 

basal ganglia. Hypoproteinemia and metabolic acidosis increase 

the free bilirubin that could potentially cross the immature 

blood-brain barrier and worsen kernicterus. Some NICUs begin 

phototherapy in ELBW infants at birth; others wait for bilirubin 

to increase by 50% of the level at birth. Exchange transfusion 

is strongly considered in ELBW infants if bilirubin approaches 

10 mg/dL/kg. 

Transfusion Practices 

The blood volume of ELBW infants is 100 mL/kg. Immature 

erythropoiesis in the ELBW infant, together with frequent blood 

sampling in the NICU, creates the need for multiple blood trans - 

fusions if apnea spells and cerebral bleeds are to be minimized in 

these patients. Current management is influenced by two recent 

trials. One was directed at maintaining a more liberal hemoglobin 

level closer to 12 to 14 g/dL because of the potential benefit of less 

intracranial bleeds in ELBW infants. 17 The second study found 

that a restrictive transfusion policy resulted in fewer ELBW infants 

receiving a transfusion. 18 The balance probably lies somewhere 

between the two current views. Clinically controlling the trans - 

fusion practice to the degree of respiratory support required by 

the infant (restrictive) when they are on room air spontaneously 

breathing or (liberal) when intubated and ventilated guides 

practice. 18,19 At least one study has addressed the concern of a 

decrease in hemoglobin oxygen affinity after a VLBW infant 

receives an adult red blood cell transfusion. 20 In this study, 

11 infants weighing 736 g (±125 g) received 26.9 mL/kg of packed 

red cells. The mean fetal hemoglobin (HbF) fell from 92.9 ± 1.1% 

to 42.6 ± 5.7%. Lowering the inspired oxygen concentration and 

targeting an arterial saturation of 85% might be an excellent 

protective strategy against potential hyperoxygenation and free 

radical damage after a blood transfusion in VLBW infants. 20 

Leukoreduction before transfusing blood to ELBW infants has 

been associated with a decreased incidence of BPD, ROP, NEC, 

and IVH in a retrospective study of 515 infants weighing less 

than 1250 g. 21 Further studies are required to assess whether 

leukoreduction has any effect on mortality. Single-donor exposure 

for each ELBW infant is also advocated by many units and blood 

banks. 22 An alternative approach is administration of erythro - 

poietin 200 IU/kg/dose subcutaneously twice a week with 4 to 

6 mg/kg/d iron supplement. This strategy, however, did not 

prevent 2 to 3 blood transfusions/patient/NICU stay in a group of 

ELBW patients. 23 A recent Cochrane review found similar results 

in which fewer blood transfusions are given if erythropoietin is 

used, but no clinically significant evidence is noted in current 

clinical trials. 24 Other factors determining the need for transfusion 

include birthweight; initial hemoglobin value; 5-min Apgar score; 

phlebotomy loss; duration of mechanical ventilation; duration of 

oxygen supplement; and incidence of IVH, surgery, and chronic 

lung disease. 24 Other studies have shown a decrease in the need 

for red blood cell transfusion in ELBW infants when a more 

restrictive transfusion guideline policy is adopted. The incidence 

of complications and chronic disease in these NICU graduates was 

no different in this study. 25 The rational intraoperative strategy 

from these studies informs the anesthesiologist to consider that a 

600-g ELBW infant only has 60 mL of circulating blood volume. 

Any significant surgical losses should be replaced promptly, ideally 

with irradiated leukoreduced red blood cells during anesthesia. 

The clinical signs of acute anemia in VLBW infants are often not 

easily seen until cardiovascular collapse occurs. It may be inferred 

from loss of the pulse oximetry trace or a sudden drop in 

cardiac output associated with a fall in end-tidal carbon dioxide 

measurement. At all times during anesthesia, blood loss must be 

looked for clinically and corrected promptly. Regular checks of 

hemoglobin should be made during protracted surgery. 

RESPIRATORY CONSIDERATIONS 

Bronchopulmonary Dysplasia 

Northway and colleagues published two seminal papers on lung 

disease following mechanical ventilation and oxygen supplemen - 

tation in premature infants. 26-27 They showed that changes in the


lungs that occur at birth can have effects well into adolescence and 

adulthood. BPD is defined as a respiratory disease requiring 

supplemental oxygen for more than 28 days after birth. The grade 

of severity is determined at 36 postgestational weeks for infants 

born less than 32 weeks of age and at 56 days of life for infants 

born at greater than 32 weeks. Mild disease requires no additional 

fractional concentration of oxygen in inspired gas (FI O2 

) over 21%, 

moderate disease requires a supplemental FI O2 of 0.22 to 0.29, and 

severe disease requires an FIO2 of greater than 0.30, continuous 

positive airway pressure, or mechanical ventilation. 28 BPD occurs 

in about 20% of infants less than 1500 g born at less than 30 weeks 

postconception. 29 

The important implications for the anesthesiologist are that 

these babies exhibit bronchospasm more frequently than controls, 

and as many as 50% will require a hospital admission within the 

first year of life. 28,30 In addition, 50 to 60% of adolescents who had 

BPD as neonates will have hyperreactive airways. 31 Under 

anesthesia, the ex-BPD patient may not respond in quite the same 

positive therapeutic way as asthmatics do when given a β 2 

agonist 

bronchodilator or steroidal anti-inflammatory inhalational 

therapy. 28 This puts the anesthesiologist in a difficult position to 

manage any intraoperative bronchospastic events that result in 

desaturations. 

These infants may have a higher baseline arterial carbon 

dioxide pressure (PaCO 2 

), and it is important not to hyperventilate 

them during anesthesia or expose them to too high an FI O2 

concentration despite the natural tendency to do so. In view of 

increased airway reactivity, it would be prudent to plan an 

anesthetic without having to instrument the patient’s airway if at 

all possible in those infants who have a history of BPD but are 

otherwise stable from a respiratory standpoint. Although there are 

no randomized, prospective studies on this topic, it is common 

practice in some centers to try to avoid general anesthesia for these 

children. Regional anesthetic techniques avoid instrumentation 

of the airway. 

Persistent Pulmonary Hypertension 

PPHN is a disease that is found usually secondary to hypoxic 

respiratory failure that was induced by significant lung pathology 

soon after birth. Such insults that can lead to PPHN include 

meconium aspiration, pneumonia, BPD, and infant respiratory 

distress syndrome. Other causes include intrauterine maternal 

factors that induce significant pulmonary hypoplasia such as 

premature rupture of membranes, oligohydramnios, and sepsis. 

Congenital diaphragmatic hernia is another cause of pulmonary 

hypoplasia. Intrauterine renal disorders have also been implicated 

in oligohydramnios and pulmonary hypoplasia. 32 The use of 

inhaled nitric oxide (iNO), a potent pulmonary vasodilator, is 

clearly beneficial in improving arterial oxygenation and reducing 

the rate of extracorporeal membrane oxygenation use in term 

or near-term infants with PPHN. 32–34 This has also been shown in 

animal studies. This same benefit, however, is not seen in the 

ELBW infant or in premature animal studies, and this is probably 

because of the physiologic immaturity of the nitric oxide signaling 

pathways and the anatomic immaturity of the vascular smooth 

muscle in this premature infant population group. 32 A Cochrane 

review 33 and a consensus paper 34 have confirmed that there is 

currently no support for the use of iNO in ELBW and preterm 

infants with respiratory failure. 

High-frequency oscillatory ventilation of the ELBW infant is 

sometimes necessary to prevent lung injury via conventional 

mechanical ventilation. This often prevents an ELBW infant from 

safely being transported to the operating room. If surgery is 

emergent, it should then be instituted at the bedside in the NICU. 

Mechanical Ventilation 

and Weaning Strategies 

The need to intubate the trachea, mechanically ventilate and 

support the respiratory system, in ELBW infants is one of the 

therapeutic cornerstones of NICU care. The challenge is to allow 

transitional physiologic and anatomic growth and development of 

the pulmonary vasculature, bronchial tree, and alveoli to occur 

while avoiding the development of chronic lung disease changes 

of pulmonary hypertension or BPD. A goal of therapy may be to 

allow the ELBW infant to be discharged from the NICU without 

the need for supplemental inspired oxygen at 36 weeks post - 

conceptional age. 

Despite the potential life-saving benefits that are obtained by 

intubating and ventilating critically ill infants, it is still evident that 

mechanical ventilation can cause lung injury. 35,36 Modern NICU 

mechanical ventilation strategies aim at gentle ventilatory support 

with small tidal volumes and low mean airway pressures to avoid 

volume trauma and barotrauma. Experimental evidence indicates 

that low tidal volumes and higher peak pressures are responsible 

for the least amount of lung injury with decreased incidence of 

pulmonary edema, epithelial injury, and hyaline membrane 

disease. 36,37 Experimental evidence also indicates that high endinspiratory 

volume may be the determining factor in ventilatorinduced 

acute lung injury rather than functional residual capacity 

or tidal volume. 36,38 To further protect the neonatal lung, applying 

high positive end-expiratory pressure (PEEP) to each breath cycle 

will decrease damaging repeated opening and collapse of alveoli 

throughout each cycle. 36,39 To confirm the benefits of these venti - 

latory approaches, markers of lung injury including filtration 

coefficient and lymphatic flow remain normal when a low–tidal 

volume, high-pressure strategy of ventilation is used. 36,40 

These ventilator strategies often result in a rise in the patient’s 

PaCO 2 

and a decrease in PaO 2 

and may be considered by the 

terms permissive hypercapnia and permissive hypoxia. Along with 

the administration of aerosolized surfactant, these ventilatory 

strategies that allow permissive hypercapnia and a lower PaO 2 

are 

arguably some of the greatest medical advances in neonatology 

since the early 2000s. In a premature lamb model, high tidal 

volumes reduced lung compliance by at least 50% within 4 hours 

after birth. 41 In addition, in the lamb with surfactant-deficient 

lungs, even six breaths with tidal volumes of 35 to 40 cm 3 /kg will 

reduce lung compliance. 36,41 

It is up to the pediatric anesthesia providers to continue these 

strategies of protective ventilation when the ELBW infant is in the 

operating room under their care. Anesthesia machines and 

operating room ventilators have developed significantly since the 

early 2000s; however, it is not necessarily common practice to have 

a neonatal intensive care ventilator in the operating room. The 

typical operating room ventilator has fewer options than those in 

the NICU in terms of mode of ventilation. In addition, there is 

more deadspace and seldom does an operating room ventilator 

have a decelerating gas insufflation waveform pattern that would 

mimic the physiologic ELBW lung gas flow. It is often beneficial


to bring the infant’s personal intensive care ventilators to the 

operating room for those infants on specialized settings and to 

communicate with the neonatology team as to the ventilatory 

strategy that has worked best for that particular infant. Although 

the goal would be to use the exact respiratory parameters used in 

the NICU, it may be necessary to adjust the operating room 

ventilators to mimic that used in the NICU without being exact 

owing to the differences in ventilators. For example, in the infant 

who is on intermittent positive-pressure ventilation (IPPV) at a 

peak pressure of 16 cmH 2 

O and PEEP of 5 cmH 2 

O in the NICU at 

a rate of 24, these same parameters should be set for the operating 

room. However, once the infant is attached to the operating room 

ventilator, one must watch the chest movement and CO 2 

waveform 

to ensure that there is no hypoinflation or overinflation. Ideally, 

a ventilator with flow volume loops in the operating room 

would be invaluable, but often not practical in many settings. Once 

the infant has her or his parameters adjusted for normal CO 2 

waveform and bilateral breath sounds with normal excursion 

for an ELBW infant, the FIO 2 

should be decreased to a value that 

provides saturations in the low to mid 90s as discussed in Mecha - 

nical Ventilation. An arterial blood gas should be drawn when 

possible to determine adequacy of ventilation and oxy genation at 

steady state. If this is not possible, close monitoring of the CO 2 

by 

end-tidal measurement with particular attention to the plateau of 

the waveform (goal of flat waveform vs sloping that is suggestive 

of obstructive pattern) should be sufficient. 

When an infant is brought to the operating room not mechani - 

cally ventilated, once the trachea of the infant is intubated, settings 

of peak inspiratory pressure of 16 to 18 cmH 2 

O minimum along 

with PEEP of 5 cmH 2 

O and rate of 20 may be considered a safe 

starting point. Modern anesthesia machines are currently able to 

deliver IPPV and PEEP suitable for ELBW infants as part of the 

upgrades for anesthesia delivery systems. However, they remain 

unable to deliver high-frequency oscillation or high-frequency jet 

ventilation, and those infants still require that their ventilator be 

transported to the operating room with them. 

As the ventilated ELBW infant’s lungs mature, an extubation 

strategy needs to be planned. A recent study of weaned ELBW 

infants in the NICU compared delayed extubation (36 h) to imme - 

diate extubation once weaning criteria were met. 42 Re-intubation 

within 7 days of extubation was the primary endpoint. Delayed 

extubation did not prevent re-intubation statistically in this study 

of 86 ELBW infants aged younger than 28 weeks’ gestation. In the 

event that an ELBW infant has been successfully weaned off the 

ventilator, but now must come to the operating room for a surgical 

procedure, the anesthesia team must likewise determine an 

extubation strategy. Although it is difficult to extrapolate NICU 

data regarding weaning to the operating room, the principles 

remain the same and continued vigilance is required when the 

anesthesiologist deems an ELBW infant ready for extubation. The 

risk of apnea and the need for re-intubation are ever present in 

the ELBW infant. Very often, the safest option for these small 

babies is to return them intubated to the NICU after an anesthetic 

is administered in the operating room. 

In the infant who is extubated postoperatively but continues to 

have periods of apnea, therapy is usually supportive with 4 to 6 cm 

of continuous positive airway pressure (CPAP) and/or caffeine at 

a dose of up to 10 mg/kg. 43 Caffeine, a xanthine oxidase inhibitor, 

is thought to act as an adenosine receptor antagonist. 44 Activation 

of adenosine 2A receptors appears to excite GABAminergic inter - 

neurons, and it is hypothesized that released gamma-aminobutyric 

acid (GABA) may contribute to the respiratory inhibition. 44 The 

use of caffeine in ex–premature infants has been well described in 

the literature for use in avoiding apnea during the perioperative 

period. 43 This is primarily recommended for ex–premature infants 

for hernia repair but can be applicable to the rare particularly 

robust ELBW infant. A recent study measured serum caffeine 

concentrations approximately 7 days after starting therapy with a 

20- or 25-mg/kg loading dose and a 6-mg/kg/d maintenance dose 

in 154 infants with a mean gestational age of 29 weeks. 45 The 25th 

to 75th percentile range for the serum caffeine concentrations 

with the two dosing regimens was equivalent, approximately 18 

to 23 mg/L. 45 The authors conclude that routine measurement 

of steady-state serum caffeine concentrations in infants of 24 to 

35 weeks gestational age is not required in the absence of ongoing 

apnea/hypopnea or signs compatible with toxicity. 45 

Chronic Lung Disease 

Preventing chronic lung disease from the complication of severe 

unilateral pulmonary interstitial emphysema is a challenge in 

ELBW infants. It is often unilateral and caused by barotrauma after 

mechanical ventilation. 46 A variety of options exist for therapy 

including selective left or right lung ventilation for 1 to 10 days 

to allow resolution of the emphysema. 47 A recent case report 

highlighting the benefit of a successful single-lung ventilation 

technique in the ELBW infant indicates that single-lung venti - 

lation in these children is often therapeutic. 48 

CARDIOVASCULAR CONSIDERATIONS 

The most commonly used clinical “rule of thumb” is that the 

minimal mean blood pressure in millimeters of mercury in the 

first days after birth should be equal to the gestational age in 

weeks. 49–52 This has been widely recommended since 1992 and is 

often used as the criterion for hypotension; however, there does 

not appear to be any published literature to support this widely 

held recommendation. 51,52 After a few days of birth, the blood 

pressure steadily increases in well ELBW infants. 

The problem for clinicians is what blood pressure value is 

deemed hypotensive? What should it be treated with? What are 

the risks of hypotension in the ELBW infant? 

The initial treatment for hypotension among 96% of Canadian 

neonatologists is the administration of an intravenous fluid bolus. 53 

Despite this, it has been shown repeatedly over many years that 

there is no relationship between blood pressure and intravascular 

volume in ELBW infants. 52,54 Currently, it is not clinically advised 

to treat a low blood pressure number in ELBW infants with an 

intravascular fluid bolus. We now know that administration of 

excessive intravascular fluids is deleterious to the ELBW infant. 

It is, therefore, recommended to look for additional signs of 

organ hypoperfusion such as poor capillary refill time, oliguria, or 

metabolic acidosis or cerebral hypoperfusion. 55,56 The major 

concern for the ELBW infant relates to whether or not cerebral 

blood flow (CBF) will remain adequate preventing an intracerebral 

hemorrhage during a period of systemic hypotension. The concern 

for neonatologists is that CBF may not be autoregulated adequately 

in the presence of systemic hypotension in ELBW infants. 

Neonatologists try to keep the mean blood pressure in ELBW 

infants at 30 mmHg to prevent cerebral white matter injury and 

cerebral hemorrhage. 57 At least one study in 1.5- to 40-hour-old


ELBW infants, utilizing near-infrared spectroscopy to monitor 

cerebral tissue oxygenation has addressed this problem. It was 

found that, in this ELBW patient study group, cerebral autoregu - 

lation is functional in normotensive but not hypotensive infants. 56 

A threshold below which CBF autoregulation fails to adequately 

protect the ELBW infant brain was found to be at 29 to 30 mmHg. 

In this study, the administration of dopamine improved both mean 

arterial pressure (MAP) and CBF. 56 The authors stress that there is 

a ceiling to higher blood pressure, above which the risk of cerebral 

autoregulation would fail and CBF would remain pressure passive 

flow-related. It is believed that this hypertension would increase 

the risk of intracranial hemorrhage. What that blood pressure 

would be is hard to quantify. A recent study in 30 patients looking 

at CBF velocities in ELBW infants found that there was no 

difference in mean CBF velocity (P = .934) in infants with hypo - 

tension (MAP 23 mmHg [range 20–24.9]) compared with infants 

with normal blood pressure (MAP 32.6 mmHg [range 27.5–35.7]). 

Important from this study is that hypotension may not always 

be an indicator of decreased CBF. Therefore, before treating all 

hypotension, one should be observant of other signs of other organ 

hypoperfusion such as lactic acidosis and decreased urine output. 58 

When an ELBW infant receives an inotrope, blood pressure 

must be monitored, ideally utilizing invasive blood pressure 

monitoring. Until randomized, prospective, controlled trials are 

completed comparing long-term outcomes in ELBW infants with 

or without hypotension, it is still recommended to aim for an MAP 

close to the age of the ELBW infant in postconceptional weeks. 

From these data, it can be seen that the pediatric anesthesiologist 

needs to be vigilant in controlling blood pressure in ELBW infants 

during anesthesia, ideally aiming for an MAP of 30 mmHg and 

not being too hasty in administering intravascular volume unless 

it is clear that hypovolemia exists. An inotrope such as dopamine 

at low-dose 3 to 5 µg/kg/min might be a more appropriate choice 

aiming to keep the MAP between 30 and 40 mmHg. Caution 

needs to be exercised with the addition of inotropes because 

raising blood pressure in ELBW infants may be associated with 

intracerebral bleeds. 56,58 

The one area of concern when providing anesthesia during the 

first week of life to ELBW infants is that 30% of these patients may 

have delayed refractory hypotension nonresponsive to fluid, 

inotrope, or hydrocortisone therapy. 59 A differential diagnosis must 

be considered: including PDA, adrenal insufficiency, high mean 

airway pressure during mechanical ventilation, pulmonary air 

leaks, cardiac arrhythmias, electrolyte imbalance (hypocalcemia, 

hyperkalemia, hypomagnesemia), myocardial depression from 

TABLE 83-2. Causes of Severe Hypotension in the 

Extremely Low Birthweight Infant 

PDA 

Adrenal insufficiency 

High mean airway pressure, pulmonary air leaks 

Cardiac arrhythmia 

Myocardial depression from hypoglycemia 

Sepsis, necrotizing enterocolitis 

Metabolic acidosis—inborn errors of metabolism 

Electrolyte imbalance (hypocalcemia, hyperkalemia, 

hypomagnesemia) 

PDA = patent ductus arteriosus. 

From Sakar 2007 reference 117. 

hypoglycemia, sepsis, NEC, or severe metabolic acidosis from 

inborn errors of metabolism. 59 The PDA is often the cause and 

usually follows administration of surfactant. 59 If detected, it should 

be closed medically or surgically as soon as feasible. 

INTRAOPERATIVE MANAGEMENT 

Fluid, Energy, and Acid-Base Considerations 

Perhaps one of the more controversial topics in the management 

of the preterm infant, particularly one who is ELBW, is the use of 

intraoperative fluids. Traditionally, neonatologists manage hypo - 

tension with vasopressors whereas anesthesiologists administer 

volume expanders. One must remember that causes of hypo - 

tension are different in both situations. For instance, the use of 

fluid intraoperatively is supported by the fact that vasoactive 

anesthetics needed for surgical conditions cause a drop in systemic 

vascular resistance (SVR) and hypovolemia that needs to be 

first treated intravascularly with the administration of liberal 

intravenous fluids to make up for any preoperative hypovolemia. 

The current data would support that the neonatologist’s 

viewpoint outside the scope of anesthesia is more appropriate. 

A recent Cochrane review on fluid management of preterm infants 

was designed specifically to look at the effects of water intake on 

postnatal weight loss and the risks of dehydration, PDA, NEC, 

BPD, intracranial hemorrhage, and death in premature infants. 60 

Analysis of five studies that fulfilled the strict criteria for review 

when taken together indicate that restricted water intake signi - 

ficantly increases postnatal weight loss and significantly reduces 

the risks of PDA and NEC. With restricted water intake, there 

are trends toward increased risk of dehydration and reduced 

risks of BPD, intracranial hemorrhage, and death, but these 

trends are not statistically significant. Care should be exercised 

not to overhydrate the ELBW infant perioperatively. 60 However, 

these precautions must be weighed against the risks that occur 

with ongoing surgical losses of fluid and blood during surgical 

procedures. 

Essentially, the three major considerations in the adminis - 

tration of fluids to ELBW infant perioperatively are 

1. Strict control of the volume and rate of infusion of intravenous 

fluids. 

2. Meticulous attention to the infused sodium concentration. 

3. Prevention of hyper- or hypoglycemia. 

Intravascular hypovolemia should be corrected promptly with 

20 to 40 mL/kg of normal saline. 61,62 Currently, particularly in the 

postoperative period, there is a strong trend to limit the average 

fluid maintenance volume to half or two thirds of Holliday and 

Segar’s recommended 4/2/1 rule of maintenance need for water 

in parenteral fluid therapy. 61–63 In ELBW infants, if fluid volumes 

greater than 130 mL/kg are administered daily, the ductus arte - 

riosus is more likely to remain open. This increases the chance of 

congestive heart failure and low cardiac output and may result in 

diminished gastrointestinal perfusion. Diminished gastrointestinal 

perfusion is a major contributor to the risk of developing NEC 

and one of the main reasons why fluids are restricted in ELBW 

infants who are at risk of maintaining a PDA. The other reason to 

restrict fluids in these infants is to try to avoid the development of 

BPD. Overhydration, particularly when associated with hypo - 

natremia less than 120 mEq/L, will predispose ELBW infants to 

seizure development. Should hyponatremia develop, therapy


should be aimed at fluid restriction. It is important for the 

anesthesiologist to be aware that, in the first 12 to 48 hours of life, 

the ELBW infant undergoes a significant shift in potassium from 

the intracellular space to the extracellular fluid compartment. 

During this time, 32 to 50% of ELBW may have a hyperkalemia 

greater than 6.7 mmol/L. 64 Pathologic and significantly dangerous 

hyperkalemia greater than 6.7 mmol/L should be treated by 

insulin and dextrose infusion as the first line of therapy in the 

premature infant. Oral and rectal ion exchange resins should be 

avoided because they are ineffective and associated with signifi - 

cant and potentially life-threatening complications. Exchange 

transfusion may be used as a last-resort therapy. 64 Nonpathologic 

hyperkalemia can also be worrying and require similar therapy. 

It is often seen before ELBW infants have started a diuresis. 65,66 

During the subsequent diuresis stage as they begin to lose 10% 

of their initial birth weight due to maturation in their kidneys 

and glomerular filtration rate, a hypokalemia may be present. 

During this time, potassium supplementation becomes necessary. 

These considerations should be taken into account by the anes - 

thesiologist when planning intravascular blood and fluid replace - 

ment in the ELBW infant undergoing surgery. 

From 24 to 28 weeks’ gestation, the fetus grows at approxi - 

mately 15 g/kg/d, accumulating approximately 25 kcal/kg of new 

tissue per day. 67 In premature infants of approximately 32 to 

34 weeks’ gestational age, in order to continue this type of weight 

gain, an enteral intake of 120 to 130 kcal/kg/d would be required. 68 

The energy requirements of ELBW infants intraoperatively 

have not been fully elucidated. The ELBW infant’s basal glucose 

production is 6 to 10 mg/kg/min. Because of their catabolic state 

immediately after delivery, additional dextrose needs to be admin - 

istered intravenously. The amount administered is important in 

order to prevent any hyperosmolar hypotonic intravascular 

environment from developing. Targeting osmotic diuresis with the 

presence of greater than 1000 mg/dL or 56 mmol/L of urinary 

glucose may suggest a risk of osmolar changes and warrant strict 

glucose control in sick infants. 69,70 

Practice guidelines warn that to discontinue parenteral nutri - 

tion intraoperatively without providing a dextrose infusion could 

precipitously lower the blood glucose level. 71 This lack of energy 

source could potentially contribute to neurologic damage in 

the developing ELBW infant. There appears to be no consensus 

regarding the optimal dextrose content of infused fluids periop - 

eratively. The current trends are to administer only low-dose 

dextrose (0.95 or 1%), rather than a 5 to 10% dextrose-containing 

intravenous fluid solution when measured blood glucose is less 

than 2.8 mmol/L or 50 mg/dL. During long surgeries, frequent 

measurement of the blood glucose level is recommended. 62,72 The 

route of intravenous fluid administration is usually through a 

24- to 26-gauge peripherally placed central catheter. As an aside, 

these lines should not be flushed with syringes smaller than 

10 mL, thus preventing pressure-related catheter rupture. Mainte - 

nance fluids and total parenteral nutrition from the unit should 

be continued while a venous cannula should be inserted in order 

to cautiously administer lactated Ringer’s solution for replacement 

of surgical third space losses. Intravascular fluid requirements are 

titrated to blood pressure and heart rate. Surgical blood loss should 

promptly be replaced with an equal volume of packed red cells 

(see Chapter 53). 

Acid-base management pertains to first ensuring adequate 

cardiac output in the VLBW infant. If a metabolic acidosis occurs, 

the cause should immediately be sought and treated. Cardio - 

vascular resuscitation and support of the infant should be 

instituted before metabolic correction of the pH is attempted. 

Administration of dilute intravenous NaHCO 3 

must always be 

titrated carefully to avoid hypernatremia and the risk of IVH. 

Pain and Sedation Requirements 

Premature infants have a lower pain threshold than term babies, 

and pain activates cortical regions in the preterm infant brain. 73–75 

This finding has been observed by cortical spectroscopy. 74 In 

addition, repeated painful stimuli in preterm infants, particularly 

in the slower maturing inhibitory nerve fibers of the lower limb 

compared with the upper limb, result in wind-up, temporal sum - 

mation, and hyperalgesia. 75 These effects may last for as long as 

30 to 60 minutes poststimulation and may lead to a maturation of 

the cortical response to pain in preterm infants. 73,75 

A recent study concluded that the average NICU infant receives 

as many as 12 to 15 moderate to severely painful procedures per 

day. Despite this, less than 35% of these procedures are preceded 

by any pre-emptive analgesia. 75 Pre-emptive morphine infusions 

have not been found to decrease the frequency of severe IVH, 

periventricular leukoplakia, or death in ventilated preterm 

neonates. However, a loading dose of 100 µg/kg in addition to an 

infusion of morphine 3 to 5 µg/kg/h may provide effective 

sedation and analgesia in the ELBW infant only if they are already 

intubated and ventilated but not tolerating their ventilatory 

support. 75 Because of a more favorable withdrawal profile, metha - 

done is being investigated for use in the ELBW infant. 75 Fentanyl, 

with an onset time of 2 to 3 minutes, short duration of action of 

60 minutes, and stable hemodynamic profile, is a analgesic com - 

monly used by anesthesiologists for infants in the perioperative 

period. Although there is ongoing investigation on the effects 

of fentanyl in the developing brain and an association with peri - 

ventricular leukomalacia, the benefits of using appropriate 

opioids such as fentanyl outweigh the risks of the stress of invasive 

procedures in infants who do not receive opioids. These risks and 

benefits must be considered with all agents used in this fragile 

population. 76 

Adequate analgesia needs to be provided by the anesthe - 

siologist caring for the ELBW infant in the perioperative period. 

However, excessive administration of opioids may be associated 

with hypotension and lead to undesirable secondary effects. 

This is especially true in infants under 750 grams when cortisol 

production can be inhibited by fentanyl in doses of greater than 

20 µg/kg. This decrease in cortisol production can result in 

refractory hypotension. 77 As with many therapeutic modalities in 

the ELBW infant, the administration of analgesia becomes a 

balancing act and the choices must be made when providing nar - 

cotics for analgesia, because the lack of analgesia itself may also 

have deleterious effects secondary to activation of the neuro - 

endocrine stress response. 

The use of sedatives also deserves significant consideration in 

this population of tiny patients. Administration of 0.2 mg/kg of 

midazolam followed by 0.2 mg/kg/h in ELBW infants has been 

shown to be associated with a transient 14.7% decrease in CBF 

velocity as measured by near-infrared spectroscopy. 78 In this same 

study, when 0.05 mg/kg of morphine was followed by 0.01 mg/ 

kg/h, an increase in cerebral blood volume of 11% was seen 

without any significant change in CBF velocity. 78 The conclusion 

for the anesthesia provider from this recent study is that medi - 

cations used in the operating room and NICU can significantly


affect CBF and blood volume. Therefore, attention needs to be 

directed to a judicious and gradually titrated analgesic or sedative 

effect. In addition, as is discussed the following section, there are 

concerns with the use of midazolam and possible accelerated 

neuroapoptosis. 

Anesthetic Agents 

The potential for accelerated neural cell death or apoptosis in 

premature human infant brains exposed to multiple anesthetic 

agents has been suggested and has prompted international interest 

in the use of anesthetic agents in infants with developing brains 79,80 

(see Chapters 3). This speculative frenzy has been fueled by neural 

degeneration evidence from postnatal rodent and primate in vivo 

and in vitro animal models. In these models, control of apoptotic 

variables such as hemodynamics, nutrition, oxygenation, and CO 2 

elimination was achieved. 81–83 For iso flurane, for example, an agedependent 

and duration-dependent relationship has been shown 

between the isoflurane exposure and rodent perinatal neuronal 

death. 79,80,82 A variety of general anes thetics, which act primarily as 

GABA receptor modulators and N-methyl-D-aspartic acid gluta - 

mate receptor antagonists, has been shown to cause this rodent 

neuron degeneration. 81,83,84 At this time, the major question as to 

how these neonatal animal studies may be translated to human 

clinical significance remains unanswered. It is unclear whether 

high-dose anesthetic agent cocktail exposure over several hours 

in immature mice or rat brains and the resultant apoptosis can be 

comparable with anesthetic agent exposure in the premature 

human infant brain that takes many months to develop. 81,82,84 Until 

anesthetic agent–induced neuronal degeneration in humans is 

identified, the applicability of this animal data to premature 

human infants remains speculative. Current analgesic and anes - 

thetic practice in ELBW infants should continue, particularly 

based on past evidence that shows lack of anesthesia or analgesia 

results in significant morbidity or mortality in the fetus and 

infant, 84–87 although it is important to note that our NICU tries to 

avoid the use of intravenous benzodiazepines for sedation in the 

ELBW infant. 

Because of the surrounding issues on the use of anesthetic 

agents in premature infants, it is imperative that the anesthe - 

siologist be aware of the dosing and potential hazards before 

delivering these agents to this fragile population. With years of 

experience and data on safety, inhalational anesthetic agents 

currently continue to be commonly used in premature infants 

undergoing general anesthesia. In a study involving 10 premature 

infants, it was shown that the blood-gas partition coefficients of 

isoflurane, halothane, and sevoflurane in preterm neonates are 

similar to those in full-term neonates and that gestational age 

does not significantly affect the blood-gas solubility. 88 There are, 

however, no reports specifically randomizing ELBW infants to 

different inhalational type anesthetics. In one study, 30 infants less 

than 37 weeks’ gestation and less than 47 weeks’ postconceptional 

age undergoing inguinal herniotomy had an inhalational induc - 

tion with sevoflurane and were randomly allocated to sevoflurane 

or desflurane for maintenance. Median times to first movement, 

tracheal extubation, eye opening, and first cry were all faster when 

anesthesia was maintained with desflurane as compared with 

sevoflurane. No difference in postoperative respiratory apnea 

events was demonstrated between the groups. 89 However, des - 

flurane is not commonly used in young children, particularly for 

induction, owing to its risk of airway reactivity, and there are no 

data to support its use in the ELBW infant. 90 

A recent NICU randomized trial comparing intubation under 

2 to 5% sevoflurane compared with 100% oxygen in 30 premature 

and small neonates found that intubation and glottic visualization 

was easier in the sevoflurane group: no movements: 95.5% 

versus 28% (P < .005); good glottis visualization: 73% versus 33% 

(P = .013) compared with the oxygen-alone group. Untoward 

effects of hypertension in the sevoflurane group 25% versus 

56.3% (P = .04) in the oxygen-only group and the incidence 

of bradycardias 8.3% versus 44.4% (P < .01) were greater in the 

oxygen control group. This important prospective, randomized 

trial confirms the safety of sevoflurane inhalational induction 

of anesthesia for intubation in small infants. 91 Regarding other 

medications used in ELBW infants and children, recently a study 

noted 45% of parenteral medications used in neonates were used 

for off-label purposes. The parenteral medications most frequently 

used were analgesics, vasopressors, and hematologic agents. 92 

The extent of this off-label usage of medications problem warrants 

further drug studies, particularly in small children. 

ANESTHESIA FOR 

SPECIFIC PROCEDURES 

The ELBW infant may present for a variety of procedures with 

some of the more common ones being presented here. Regardless 

of the type of procedures, certain standards must apply to all of 

these young patients. First, the procedure room must be equipped 

with the small supplies appropriate for the size of these patients. 

The room should be warmed during setup so that heat loss is at a 

minimum from any conductive surfaces or instruments. Fluids 

must be setup on pumps to avoid unintentional volume overload, 

and drugs must be put in appropriately sized syringes at concen - 

trations that allow accurate delivery. 

All infants in this age require the usual American Society 

of Anesthesiologists (ASA) monitors, but additional helpful 

information may be obtained by a second pulse oximeter to allow 

preductal and postductal saturation monitoring. 

Intravenous access is essential. Percutaneous intravenous 

central catheter (PICC) lines are often used in small infants, but 

their small diameter and long length do not allow for rapid 

infusion of medications or fluids that are often required in an 

operative setting. In fact, a 24-gauge PICC line requires a 10-mL 

syringe to be used for infusion because smaller syringes allow 

greater pressures that may rupture the catheter. Whether to 

perform procedures in the NICU versus the operating room is 

often institution-dependent. An operating room environment 

typically provides more room, better light, and the ability to use 

the anesthesia team and operating room nurses effectively. The 

primary advantage to operating in the NICU is that transport 

becomes unnecessary, and it is often life-threatening in a severely 

ill premature infant who is on significant respiratory and/or 

hemodynamic support. Each of these cases should be considered 

on an individual basis with an open discussion between the 

anesthesia, the surgical, and the neonatal teams. 

Ligation of PDA 

Owing to the advances in neonatology and improved outcomes 

for the ELBW infant, PDA is the most common congenital heart 

defect (CHD) in the neonate. It is present in 0.05% of term infants,


20% of 32-week-old infants, and as common as 60% in ELBW 

infants less than 28 weeks; postconceptional age. The ductus 

arteriosus is derived from the sixth aortic arch embryologically 

and connects the main pulmonary artery to the descending aorta. 

In fetal life, the high pulmonary vascular resistance (PVR) directs 

90% of right ventricular output through the ductus arteriosus to 

the aorta. Intrauterine ductus arteriosus patency is under control 

of chemical, neural, and hemodynamic blood flow stimuli. Locally 

produced prostaglandin E 2 

(PGE 2 

) maintains ductal patency with 

the production of PGE 2 

decreasing with increasing gestational age. 

Postnatal ductus arteriosus closure usually starts within 

72 hours of life in healthy term neonates. Ductal closure after birth 

is initiated by local and circulating neurohumoral factors as well 

as higher partial oxygen content, both of which initiate ductal 

smooth muscle constriction. This sensitivity to oxygen is maximal 

in term infants and within 24 hours of birth. Ductal closure takes 

longer to initiate in the ELBW infant and often is initiated medi - 

cally by the administration of prostaglandin inhibitors such 

as indomethocin. Delayed closure can be a result of respiratory 

prematurity with a high PVR or respiratory disease in the ELBW 

infant. Another cause of delayed closure of the ductus arteriosus 

is excessive intravenous fluid administration greater than 170 mL/ 

kg/d, particularly on day 3 postnatally in ELBW infants. 93 Other 

factors include hypoxia, hypercarbia, and acidosis, which all 

increase PVR. These causes of a sustained high PVR owing to 

PPHN are important to avoid so that continued shunting at the 

PDA or patent foramen ovale level does not occur. A physiologic 

and anatomic cardiac right-to-left shunt then remains, with 

desaturated blood being shunted into the systemic circulation, 

causing severe systemic hypoxemia. Conversely, if the PDA 

remains open without PPHN, and the PVR continues to drop as 

it should do with increasing postconceptional age, the PDA will 

shunt cardiac blood in a left-to-right manner, and actually cause 

a systemic cardiac output “steal” phenomenon. Less blood will 

reach the systemic circulation (Qs) and more will circulate 

through the lungs (Qp). An increased Qp:Qs often leads to con - 

gested lungs, apnea, cardiac failure, and a low systemic blood 

pressure. Owing to the low-pressure pulmonary circulation acting 

as a “sink,” a low diastolic blood pressure often heralds a PDA in 

the ELBW infant. As a result, this low blood pressure and low sys - 

temic blood flow may be associated with diminished gastro - 

intestinal blood and renal blood flow. This pathophysiology often 

occurs at about the time of introduction of oral feeding in growing 

ELBW infants. This combination of increased requirements 

of gastrointestinal blood flow at a time of decreased supply is 

implicated in the increased incidence of NEC in the ELBW 

infant. 93 To avoid these complications, it is necessary to attempt 

to close the PDA with non-steroidal anti-inflammatory drugs 

(NSAIDs). A recent Cochrane review comparing indomethacin 

with ibuprofen found no statistical difference in ductal closure rate 

with either medication. 94 There are reports of greater pulmonary 

hypertension with ibuprofen; however, studies with outcome 

measurements to school-age children will be needed to make any 

conclusions regarding survival without impairment. 94 If the PDA 

remains open, despite medical intervention, and the cardio - 

vascular system remains compromised, it becomes mandatory to 

close the PDA surgically. 

Repair of PDA in the NICU 

These infants are commonly operated on in the NICU in order 

to avoid a transportation of a critically ill small infant to the oper - 

ating room, where the hazards of accidental tracheal extubation, 

hypothermia, and intravenous line disconnection can be pre - 

vented. If not already on a ventilator, the infant should be 

intubated orally with the appropriately sized ETT. This is usually 

a 2- to 2.5-mm internal diameter ETT secured at 5 to 6 cm at the 

mouth in the ELBW infant. Although the black line on the tube is 

used to ensure that the tip of the ETT is above the carina, it is 

recommended in ELBW infant to confirm the final position of 

the ETT by preoperative x-ray. Preoperative x-ray also confirms 

whether the aorta is left- or right-sided. If the infant is not 

intubated, this will often be completed by the NICU team before 

the surgical team arrives in the NICU. An x-ray will confirm 

correct ETT placement, and once the hemodynamics are stable, 

anesthesia and surgery will begin. Usually, surgical antibiotic 

prophylaxis is not administered in the NICU. 

A left thoracotomy is usually performed with a left-sided 

thoracic aorta. The infant is placed in the right lateral position, a 

small roll is placed under the right shoulder, the head and legs are 

padded for any pressure points, and an infant diathermy dispersive 

electrode pad is placed on the infant’s back. The lowest possible 

setting should always be set on the diathermy machine before 

surgery. The head of the patient should be directed toward the foot 

of the bed or open side of the NICU, and the ventilator is placed 

directly at the foot of the bed. A neonatal resuscitation ventilation 

or Ambu bag with an independent oxygen supply is close at hand 

but not under the drapes, and the oxygen should not be left 

running through the Ambu bag during surgery. The reason for 

this is to avoid an increase in oxygen under the surgical drapes. 

High concentrations of oxygen under surgical drapes may allow 

cautery sparks to be combustible, causing fires. For the same 

reason, an alcohol skin preparation should not be used. A warmed 

iodine skin preparation is preferred. It is imperative to ensure that 

a free flowing 24-gauge intravenous cannula has been sited before 

surgery. This line is attached to a length of extension tubing and a 

three-way stopcock. This allows administration of anesthetic 

drugs and fluids through the cannula insertion site, which will be 

under the surgical drapes during the procedure. It is very difficult 

to administer blood with a syringe through a PICC line. These 

lines are used in the NICU to administer inotropes and total 

parenteral nutrition, and it is safer to leave well enough alone and 

not contaminate by adding an anesthetic infusion line to this 

system. The second reason is that these lines can rupture when 

fluids are administered under pressure and only 10-mL syringes 

should be used. Cross-match one leukoreduced gamma-irradiated 

adult unit of packed red blood cells before surgery and have this 

in a cooler on ice in the unit before surgery. The advantage of this 

is that when the blood is not used (which is the majority of the 

time), it can be returned to the blood bank and re-issued for 

another patient without wastage. Ensure an intravenous blood 

administration set is also at the bedside because these are com - 

monly not present because blood ordered in the NICU is usually 

prefiltered by the blood bank. A blood pressure cuff and pulse 

oximeters should be placed on one of the arms and one of the legs. 

This is important to confirm correct surgical clip placement on 

the ductus during surgery. If end-tidal CO 2 

monitoring is present, 

it may be very useful during these surgical procedures. Sometimes, 

the anatomy of the aorta can be difficult and this ensures that the 

aorta is not inadvertently obstructed at the time of surgery. 

Lung ventilation of these infants during thoracotomy is chal - 

lenging. Usually, a slight increase of 2 to 3 mmHg in the inspired 

ventilatory pressure together with a 10 to 25% increase in the FI O2


together with a 5% increase in respiratory rate is all that is required 

to ensure adequate oxygenation and ventilation during the 

thoracotomy. Pulse oximetry levels of 89 to 94% are aimed for 

during anesthesia. This is essential during thoracotomy and lung 

collapse with surgical swabs and retraction. Should a pulmonary 

hypertensive crisis occur during surgery, it should be treated by 

control of acid-base status and lowering PaCO 2 

by ventilation. 

If right ventricular failure occurs, it may be augmented with an 

epinephrine infusion of 0.03 µg/kg/min titrated to effect. 

Anesthetic drugs used are aimed at providing the correct 

amount to ablate the neuroendocrine stress response to surgery, 

but at the same time, excessive administration of narcotics, benzo - 

diazepines, and muscle relaxants must be avoided. Otherwise, 

depression of the infant’s autonomic nervous system will result in 

a greater requirement for inotrope administration. It is, therefore, 

a balance, and the medication doses recommended are fentanyl 2 

to 5 µg/kg, midazolam 0.1 mg/kg, and pancuronium 0.08 mg/kg. 

It is possible to use ketamine as the anesthetic agent, although this 

is not common practice in the ELBW infant. The administration 

of fluids at this time should not be overzealous. These infants are 

critically balanced fluidwise, and once the duct is clipped and the 

left ventricle is now expected to eject blood in the presence of a 

higher SVR, these infants can progress to cardiac failure requiring 

greater inotropic support. At the end of the surgery, once the 

surgical swabs have been removed from the chest, anesthesia is 

asked to re-expand the collapsed lung. Complications are usually 

infrequent with this surgical procedure. However, a recent report 

has shown that there may be an incidence as high as 67% unilateral 

vocal cord paralysis with respiratory and swallowing difficulties 

after ligation or ductal clipping of the PDA in ELBW patients. 95 

The ELBW infants in this series had significantly longer tube 

feeding (relative risk 8.25; 95% confidence interval 1.93–46.98 

[P = .003]; supplemental oxygen use [P = .004]; and ventilatory 

support [P = .001]) and had a longer hospital stay. 95 

Is there a role for prophylactic surgical closure of the PDA in 

ELBW infants? The current answer is based on a recent Cochrane 

database report indicating that surgical PDA closure prophylaxis 

in ELBW infants at this time is not warranted. 96 Only 84 patients 

have been randomized to any prospective study on this topic. In 

this study, prophylactic PDA surgical closure did not decrease 

mortality or BPD in ELBW infants. Postoperatively, a morphine or 

fentanyl infusion is commonly used to continue ablating the 

deleterious neuroendocrine stress response. 

Eye Surgery 

The retina usually does not fully mature before 42 to 44 weeks’ 

gestation, and most elective surgery should ideally be delayed until 

after 44 weeks’ gestation if at all possible and pulse oximetry 

should be targeted at all times to maintain arterial saturations of 

89 to 95% in the ELBW infant. ROP occurs in infants usually 

weighing less than 1000 g and these infants are not usually 

screened until 31.5 weeks’ gestational age. There is still a high 

incidence of ROP in graduates of the NICU and the reason might 

be that the more aggressive resuscitation and care offered to the 

sicker, more premature infants might be increasing the incidence 

of ROP. 97 It is believed to be caused by multiple etiologies. 

Hypoxia, hyperoxia, hypercarbia, sepsis, and multiple blood 

transfusions have all been implicated. Interestingly, however, ROP 

has also occurred in infants who have received no supplemental 

oxygen. Laser surgery is used to ablate abnormal vessels before 

retinal detachment and progression to blindness. This surgery is 

traditionally done in infants with their trachea intubated and lungs 

mechanically ventilated under general anesthesia. 98 One problem 

with providing anesthesia for this procedure is that many infants 

who are weaned and extubated in the NICU must then return to 

the NICU after surgery still intubated, requiring mechanical 

ventilation and reweaning over a number of days. Overcoming 

this problem is important, and a recent alternative anesthetic 

approach deserves consideration. In a series of 54 infants for laser 

ablation for ROP, 73% of infants had been successfully weaned 

from mechanical ventilation before surgery. 99 If intubation and 

mechanical ventilation were instituted for the surgery alone 

(group 1), 77% of the infants remained intubated and mechani - 

cally ventilated on postoperative day 1. Fifty percent of infants 

intubated for surgery were still intubated and ventilated on 

postoperative day 3. This adds to the cost as well as to the risks of 

the respiratory support in the NICU. An important and novel 

nasopharyngeal prong anesthetic administration technique aimed 

at avoiding intubation for laser surgery in (group 2, N = 24 infants) 

found significantly(P < .001) that only 1 infant of those not intu - 

bated for surgery required a period of postoperative mechanical 

ventilation. 99 Management with nasopharyngeal prongs did 

not result in higher perioperative PaCO 2 

or lower pH values. This 

study is noteworthy because avoiding postoperative intubation 

would be a great benefit to the ELBW infant. A larger series needs 

to be performed to confirm the advantage of this novel anesthetic 

technique. Many NICUs have a procedure room, and with gentle 

sedation, these patients are screened by ophthalmology in the unit 

and laser can then be done after appropriate “laser in use” signs 

and precautions are instituted. These patients may need to be 

followed up by ophthalmology even after discharge from the 

NICU to ensure their eyesight is preserved. 

Gastrointestinal Procedures 

The classic paper on staging and management of NEC published 

by Bell and coworkers in 1978 has guided physicians caring 

for small infants with acquired intestinal disease since then. 100 

The current era of lung maturation steroid administration ante - 

natally to mothers and newborn ELBW infants, together with 

concomitant surfactant and NSAIDs administration soon 

after birth, has seen the emergence of newly acquired neonatal 

intestinal disease syndromes called sudden intestinal perforation 

(SIP) 101,102 and feeding intolerance of prematurity (FIP). 102 SIP is a 

new distinct entity and no longer fits into the classic definitions 

previously described. 100 Feeding intolerance has arisen because of 

the need to feed smaller and smaller infants orally at a time when 

they should still be in utero. 102 The etiology of gastrointestinal tract 

disruption and NEC in ELBW infants is still poorly understood 

and multifactorial. Certainly, neonatal asphyxia, oral feeding, 

overzealous intravenous fluid administration resulting in a PDA, 

and diminished blood flow to the gastrointestinal tract can cause 

bowel ischemia and perforation. Mucosal integrity break-down 

and gastrointestinal bacterial colonization play a role. Unfortu - 

nately, because an increasing number of ELBW infants currently 

survive and must be admitted to a NICU, the in-hospital mortality 

rate postsurgical intervention for NEC or SIP in this age group is 

still approximately 50%. 103 Gastrointestinal disruption in ELBW 

infants tends to follow one of three clinical pathways: SIP with 

sudden free air, metabolic derangement (MD) complicated by


the appearance of free air, or progressive MD without evidence of 

free air. 104 MD is more like classic NEC and includes thrombo - 

cytopenia, metabolic acidosis, neutropenia, left shift of segmented 

neutrophils, hyponatremia, bacteremia, and hypotension. Surgical 

management remains controversial. Absence of MD warrants 

consideration for peritoneal drainage rather than a laparotomy, 

especially for the appearance of sudden free air. 104 Surgery should 

be planned based on degree of MD and organ dysfunction rather 

than the age of the patient. 105 When performing these procedures 

in the NICU, the same presurgery preparation and added 

precautions need to be taken as if preparing an operating room. 

Airway equipment, monitoring, suction, and a modern intensive 

care ventilator should be appropriately set for an ELBW infant 

before beginning anesthesia. The operating room or intensive care 

operating area should be warm. Often, 20 to 80 mL/kg of warmed 

colloid, blood, or fresh frozen plasma fluids may need to be 

administered in severe NEC depending on the extent of third 

space losses and blood loss with surgery. An intravenous catheter 

for this fluid administration should be present independent of 

the intravenous maintenance fluids being administered by the 

NICU. An infant who is diagnosed with NEC will often be on an 

antibiotic regimen that includes coverage for coagulase-positive, 

coagulase-negative, and anaerobic organisms, and this should be 

continued during the procedure. 

Prospective, randomized trials analyzing therapy for more 

major surgery in the ELBW infant being practiced at the bedside 

in the NICU soon after delivery needs to be done; although this is 

widely practiced (e.g., PDA repair, NEC surgery, gastroschesis 

reduction, congenital diaphragmatic hernia), no data currently 

exist to refute or prove the benefit of NICU bedside surgery. 106 

What is clearly emerging is that enterally administered probiotics 

are beneficial in the prevention of NEC in infants only if greater 

than 1000 g. This may become part of standard practice in neo - 

natal intensive care therapy; however, in ELBW infants weighing 

less than 1000 g, further research is needed. 107 

Neurosurgical Procedures 

Currently 60,000 infants in the United States are born with 

a birthweight less than 1500 g. 108 At least 50% of these NICU 

graduates will have some magnetic resonance imaging (MRI) 

evidence of injury to the cerebral white matter. 108–110 Common to 

most of this complex white matter injury is termed encephalopathy 

of prematurity. This is defined by the combination of predo - 

minantly noncystic periventricular leukomalacia and neuronal 

deficits. 110 Neuronal injury leads later in life to degrees of cerebral 

palsy, seizures, and hydrochepalus. These neurologic quality-oflife 

outcomes are currently the most challenging clinical problems 

to solve in neonatology. There are multiple etiologies why pre - 

mature and ELBW infants present for neurosurgery. They include 

posthemorrhagic hydrocephalus (PPH) requiring a ventricular 

shunt after IVH. These bleeds may be caused by birth delivery 

trauma, asphyxia and resuscitation at birth, NSAID medications to 

close a PDA, hypoxia and the need for ventilatory support while 

the lungs mature, periods of hypotension and decreased CBF, or 

hypertension and increased CBF. Periventricular leukomalacia 

is the predominant injury, and it may have multiple etiologies 

including those just listed for brain damage. All of these causes of 

brain damage may lead to cerebral palsy. Recent evidence in a 

rodent model indicates that high oxygen exposure in maturationdependent 

brain tissue causes accelerated apoptosis. 111 Clinical 

studies need to be performed to determine whether this may 

be an additional cause of periventricular leukomalacia in the 

ELBW infant. 

Anesthesia for neurosurgical procedure in ELBW infants 

mostly involves external ventricular drains and Omaya reservoir 

placement. These procedures are often staged to prevent infected 

central nervous system shunts in at least 11% in one series 112 and 

result in multiple neurosurgical procedures in ELBW infants. 

Positioning of the large hydrocephalic occiput in relation to the 

body on the operating table is often eased by placing layers under 

the infant’s body to create a higher horizontal plane with the neck 

in the neutral position. This facilitates the view of the larynx at 

the time of intubation. Infants must be kept warm. Hyperventi - 

lation should be avoided because a drop in PaCO 2 

may adversely 

affect CBF and normocapnea should be the goal. After surgery, 

extubation of the trachea is often not performed in the operating 

room in the ELBW infant for fear of apnea and hypoventilation 

during transport back to the NICU. 

REGIONAL ANESTHESIA 

CONSIDERATIONS 

There are no randomized studies on regional anesthesia in ELBW 

infants, but a recent report of a successful caudal in a 740-g infant 

indicates that further study is warranted. 113 A 22-gauge epidural 

catheter was inserted caudally to a midthoracic level in a 740-g 

ELBW infant undergoing laparotomy for intestinal perforation. 

Analgesia was continued epidurally with ropivicaine 2 mg/mL at 

0.2 mg/h for 48 hours postoperatively. Bowel sounds returned after 

3 hours and stool was passed on the same postoperative day. 

Extubation was achieved on postoperative day 1. The epidural 

catheter was removed after the platelet count was greater than 

80 × 10 9 /L. 113 The pharmacokinetics of local anesthetics in ELBW 

infants have not been fully elucidated. 114 One might expect that 

the clearance of ropivicaine is less in the premature infant than 

in the neonate at term. 114 It is for this reason that regional catheter 

use in ELBW infants for longer than 48 hours is currently not 

recommended. 113 It is imperative that the same vigilance and 

precautions one would take while providing regional anesthesia 

to a larger child should equally be considered when administering 

regional anesthesia to the ELBW infant. 

CHALLENGES OF THE ELBW 

INFANT LATER IN LIFE 

Nearly 50% of ELBW infants discharged home are readmitted 

to hospital mostly for respiratory problems, and this risk persists 

up until school age. 115 The risks of BPD leading to chronic lung 

disease are a major consideration of the anesthesiologist taking 

care of the ELBW infant graduate. There is a greater incidence 

of higher systolic blood pressure in adolescents and adults who 

were ELBW infants and is recorded as a 3- to 8-mmHg increase. 116 

The importance of this hypertension is that a 2-mmHg reduction 

in the diastolic blood pressure would result in a 17% decrease in 

the prevalence of hypertension, a 6% reduction in the risk of CHD, 

and a 15% reduction in the risk of stroke or transient ischemic 

attack later in life. 116 Many of these ELBW children will require 

on-going surgeries and medical care well into adulthood.


CONCLUSION 

The anesthetic care of the ELBW infant is both challenging and 

rewarding. This chapter has highlighted the specific transitional 

physiology and pathophysiology commonly seen in the ELBW 

infant. Keeping these children warm with minimal handling and 

ablating the neuroendocrine stress response with adequate 

analgesia during anesthesia are essential. Careful airway control 

and a thoughtful lung protective ventilation strategy will be re - 

quired when caring for the ELBW infant. In addition, maintaining 

a stable cardiovascular system and delivering appropriate intra - 

venous fluids and red blood cells will ensure continued excellent 

anesthetic outcomes in these patients. 

REFERENCES 

1. Landmann E, Misselwitz B, Steiss JO, et al. Mortality and morbidity of 

neonates born at


44. Wilson CG, Martin RJ, Jaber M, et al. Adenosine A 2A receptors interact 

with GABAergic pathways to modulate respiration in neonatal piglets. 

Respir Physiol Neurobiol. 2004;141:201–211. 

45. Leon AE, Michienzi K, Ma CX, et al. Serum caffeine concentrations in 

preterm neonates. Am J Perinatol. 2007;1:39–47. 

46. Swingle HM, Eggert LD, Bucciarelli RL. New approach to management of 

unilateral tension pulmonary interstitial emphysema in premature 

infants. Pediatrics. 1984;74:354–357. 

47. Meyer MT, Rice TB, Glaspey JC. Selective fiberoptic left mainstem 

intubation for severe unilateral barotrauma in a 24-week premature 

infant. Pediatr Pulmonol. 2002;33:227–231. 

48. Chalak LF, Kaiser JR, Arrington RW. Resolution of pulmonary interstitial 

emphysema following selective left main stem intubation in a 

premature newborn: an old procedure revisited. Paediatr Anaesth. 2007; 

17:183–186. 

49. Versmold HT, Kitterman JA, Phibbs RH, et al. Aortic blood pressure 

during the first 12 hours of life in infants with birth weight 610 to 4,220 

grams. Pediatrics. 1981;67:607–613. 

50. Levene M, Chiswick M, Field D, et al. Joint Working Group of the British 

Association of Perinatal Medicine and the Research Unit of the Royal 

College of Physicians. Development of audit measures and guidelines for 

good practice in the management of neonatal respiratory distress 

syndrome. Arch Dis Child. 1992;67:1221–1227. 

51. Evans JR, Lou Short B, Van Meurs K, et al. Cardiovascular support in 

preterm infants. Clin Ther. 2006;28:1366–1384. 

52. Dempsey EM, Barrington KJ. Treating hypotension in the preterm infant; 

when and with what: a critical and systematic review. J Perinatol. 

2007;27:469–478. 

53. Dempsey EM, Barrington KJ. Diagnostic criteria and therapeutic 

interventions for the hypotensive very low birth weight infant. J Perinatol. 

2006;26:677–681. 

54. Aladangady N, Aitchison TC, Beckett C, et al. Is it possible to predict the 

blood volume of a sick preterm infant? Arch Dis Child Fetal Neonatal Ed. 

2004;89:344–347. 

55. Lee J, Rajadurai VS, Tan KW. Blood pressure standards for very low 

birthweight infants during the first day of life. Arch Dis Child Fetal 

Neonatal Ed. 1999;81:168–170. 

56. Munro MJ, Walker AM, Barfield CP. Hypotensive extremely low birth 

weight infants have reduced cerebral blood flow. Pediatrics. 2004;114: 

1591–1596. 

57. Miall-Allen VM, de Vries LS, Whitelaw AG. Mean arterial blood pressure 

and neonatal cerebral lesions. Arch Dis Child. 1987;62:1068–1069. 

58. Lightburn MH, Gauss CH, Williams DK, et al. Cerebral blood flow 

velocities in extremely low birth weight infants with hypotension and 

infants with normal blood pressure. J Pediatr. 2009;6:824–828. 

59. Sarkar S, Dechert R, Schumacher RE, et al. Is refractory hypotension in 

preterm infants a manifestation of early ductal shunting? J Perinatol. 

2007:27:353–358. 

60. Bell E, Acarregui M. Restricted versus liberal water intake for preventing 

morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 

2008;1:CD000503. 

61. Holliday M, Segar W. Reducing errors in fluid therapy management. 

Pediatrics. 2003;111:424–425. 

62. Paut O, Lacroix F. Recent developments in the perioperative fluid 

management for the paediatric patient. Curr Opin Anaesthesiol. 2006;19: 

268–277. 

63. Holliday M, Segar W. The maintenance need for water in parenteral fluid 

therapy. Pediatrics. 1957;19:823–832. 

64. O’Hare FM, Molloy EJ. What is the best treatment for hyperkalaemia in 

a preterm infant? Arch Dis Child. 2008;2:174–176. 

65. Stefano JL, Norman ME. Nitrogen balance in extremely low birth weight 

infants with nonoliguric hyperkalemia. J Pediatr. 1993;123:632–635. 

66. Lorenz JM, Kleinman LI, Markarian K. Potassium metabolism in 

extremely low birth weight infants in the first week of life. J Pediatr. 1997; 

131:81–86. 

67. Ziegler E, O’Donnell A, Nelson S. Body composition of the reference 

fetus. Growth. 1976;40:329. 

68. Hay W. Nutritional requirements of extremely low birthweight infants. 

Acta Paediatr Suppl. 1994;402:94. 

69. Coulthard MG, Hey EN. Renal processing of glucose in well and sick 

neonates. Arch Dis Child Fetal Neonatal Ed, 1999;2:F92–F98. 

70. Kairamkonda VR, Khashu M. Controversies in the management of 

hyperglycemia in the ELBW infant. Indian Pediatr. 2008;1:29–38. 

71. Siker D. Pediatric fluids, electrolytes, and nutrition. In: Gregory GA, 

editor. Pediatric Anesthesia. 3rd ed. New York: Churchill Livingstone; 

1994. pp. 83–117. 

72. Ayers J, Graves SA. Perioperative management of total parenteral 

nutrition, glucose containing solutions, and intraoperative glucose 

monitoring in paediatric patients: a survey of clinical practice. Paediatr 

Anaesth. 2001;11:41–44. 

73. Fitzgerald M, Millard C, MacIntosh N. Hyperalgesia in premature infants. 

Lancet. 1988;6:8580. 

74. Bartocci M, Bergqvist LL, Lagercrantz H, et al. Pain activates cortical areas 

in the preterm newborn brain. Pain. 2006;122:109–117. 

75. Anand KJS. Pharmacological approaches to the management of pain in 

the neonatal intensive care unit. J Perinatol. 2007;27:S4–S11. 

76. Laudenbach V, Calo G, Guerrini R, et al. Nociceptin/orphanin FQ 

exacerbates excitotoxic white-matter lesions in the murine neonatal brain. 

J Clin Invest. 2001;4:457–466. 

77. Setzer N. Anesthesia, premature infants, and hypotension. Pediatrics. 

1994;5:870. 

78. van Alfen-van der Velden AA, Hopman JC, Klaessens JH, et al. Effects of 

midazolam and morphine on cerebral oxygenation and hemodynamics in 

ventilated premature infants. Biol Neonat. 2006;90:197–202. 

79. Nikizad H, Yon JH, Carter LB, et al. Early Exposure to general anesthesia 

causes significant neuronal deletion in the developing rat brain. Ann N Y 

Acad Sci. 2007;1122:69–82. 

80. Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in 

the developing brain of nonhypoglycemic mice. Neurosurg Anesthesiol. 

2008;20:21–28. 

81. Jevtovic-Todorovic V, Beals J, Benshoff N, et al. Prolonged exposure to 

inhalational anesthetic nitrous oxide kills neurons in adult rat brain. 

Neuroscience. 2003;122:609–616. 

82. Wise-Faberowski L, Zhang H, Ing R, et al. Isoflurane-induced neuronal 

degeneration: an evaluation in organotypic hippocampal slice cultures. 

Anesth Analg. 2005;101:651–657. 

83. Zou X, Patterson TA, Divine RL, et al. Prolonged exposure to ketamine 

increases neurodegeneration in the developing monkey brain. Int J Dev 

Neurosci. 2009;277:727–731. 

84. Culley DJ, Xie Z, Crosby G. General anesthetic-induced neurotoxicity: 

an emerging problem for the young and old? Curr Opin Anaesthesiol. 

2007;5:408–413. 

85. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl 

anaesthesia in preterm babies undergoing surgery: effects on the stress 

response. Lancet. 1987;10:62–66. 

86. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose 

sufentanil for anesthesia and postoperative analgesia in neonatal cardiac 

surgery. N Engl J Med. 1992;1:1–9. 

87. Soriano SG, Anand KJ. Anesthetics and brain toxicity. Curr Opin 

Anaesthesiol. 2005;18:293–297. 

88. Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane, 

halothane, and serum constituent concentrations in neonates and adults. 


89. Sale SM, Read JA, Stoddart PA, et al. Prospective comparison of 

sevoflurane and desflurane in formerly premature infants undergoing 

inguinal herniotomy. Br J Anaesth. 2006;96:774–778. 

90. von Ungern-Sternberg BS, Saudan S, Petak F, et al. Desflurane but not 

sevoflurane impairs airway and respiratory tissue mechanics in children 

with susceptible airways. Anesthesiology. 2008;2:216–224. 

91. Hassid S, Nicaise C, Michel F, et al. Randomized controlled trial of sevo - 

flurane for intubation in neonates. Paediatr Anaesth. 2007;17:1053–1058. 

92. Kumar P, Walker JK, Hurt KM, et al. Medication use in the neonatal 

intensive care unit: current patterns and off-label use of parenteral 

medications. J Pediatr. 2008;3:412–415. 

93. Stephens BE, Gargus RA, Walden RV, et al. Fluid regimens in the first 

week of life may increase risk of patent ductus arteriosus in extremely low 

birth weight infants. J Perinatol. 2008;28:123–128. 

94. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus 

arteriosus in preterm and/or low birth weight infants. Cochrane Database 

Syst Rev. 2008;1:CD003481. 

95. Clement WA, El-Hakim H, Phillipos EZ, et al. Unilateral vocal cord 

paralysis following patent ductus arteriosus ligation in extremely lowbirth-weight 

infants. Arch Otolaryngol Head Neck Surg. 2008;134:28–33. 

96. Mosalli R, Alfaleh K. Prophylactic surgical ligation of patent ductus 

arteriosus for prevention of mortality and morbidity in extremely low 

birth weight infants. Cochrane Database Syst Rev. 2008;1:CD006181.


97. Vyas J, Field D, Draper ES, et al. Severe retinopathy of prematurity and 

its association with different rates of survival in infants of less than 1251 

g birthweight. Arch Dis Child Fetal Neonatal Ed. 2000;82:145–149. 

98. Sullivan TJ, Clarke MP, Tuli R, et al. General anesthesia with endotra - 

cheal intubation for cryotherapy for retinopathy of prematurity. Eur J 

Ophthalmol. 1995;5:187–191. 

99. Woodhead DD, Lamber DK, Molloy DA, et al. Avoiding endotracheal 

intubation of neonates undergoing laser surgery for retinopathy of 

prematurity. J Perinatol. 2007;27:209–213. 

100. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis; 

therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7. 

101. Aschner JL, Deluga KS, Metlay LA, et al. Spontaneous focal gastro intes - 

tinal perforation in very low birth weight infants. J Pediatr. 1988;113: 

364–367. 

102. Gordon PV, Swanson JR, Attridge JT, et al. Emerging trends in acquired 

neonatal intestinal disease: is it time to abandon Bell’s criteria? 

J Perinatol. 2007;27:661–671. 

103. Blakely ML, Lally KP, McDonald S, et al. NEC Subcommittee of the 

NICHD Neonatal Research Network. Postoperative outcomes of 

extremely low birth-weight infants with necrotizing enterocolitis or 

isolated intestinal perforation; a prospective cohort study by NICHD 

Neonatal Research Network. Ann Surg. 2005;241:984–989. 

104. Tepas JJ 3rd, Sharma R, Hudak ML, et al. Coming full circle: an evidencebased 

definition of the timing and type of surgical management of very 

low-birth-weight

84 

CHAPTER 

Miscellaneous Techniques 

Pedro Paulo Vanzillotta 

INTRODUCTION 

The field of anesthesia is expanding considerably as anesthe - 

siologists become more involved in specialized monitoring, in 

invasive and therapeutic procedures that, at first sight, might not 

appear directly related to anesthesia. Some acute illnesses and 

particularly trauma (e.g., fractures, traumatic and septic arthritis, 

different kinds of wounds) may present in emergency pediatric 

patients, requiring medical and surgical care. Pediatric anesthe - 

siologists, therefore, require basic knowledge about traumatic 

and postoperative compartment syndromes, principles of wound 

management, arthrocentesis, and immobilization techniques. 

Continuous infusion techniques are also frequently indicated 

when managing patients on parenteral drug and fluid therapy, 

during intravenous anesthesia, and for postoperative pain control. 

Intraosseous Infusion 

With the renewed interest in the use of intraosseous infusions, 

cases of iatrogenic compartment syndromes after fluid adminis - 

tration through this route are being reported. 1 Symptoms may 

develop within 20 minutes of the infusion. The outcomes vary 

from no residual deficits to through-the-knee amputations. 6 

The compartment presumably becomes congested secondary to 

COMPARTMENT SYNDROMES AND 

MUSCLE PRESSURE MEASUREMENT 

Definition and Anatomic Considerations 

Compartment syndromes occur when the tissues pressure within 

an osteofascial compartment compromises blood flow to that 

compartment resulting in nerve and muscle damage. 1–3 The syn - 

drome may be seen in the forearm and all parts of the leg, the 

lower leg being affected more commonly than the buttocks, thigh, 

or foot. The forearm is divided into dorsal and superficial volar 

and deep volar compartments. The lower leg is divided into four 

compartments: superficial posterior, deep posterior, anterior, 

and anterolateral (Figure 84–1). The thigh is divided into three 

compartments and the foot has four. The back muscles and but - 

tocks also have compartments. 2 

Etiologies 

Trauma 

Compartment syndromes are frequently associated with crush 

injuries, fractures, and blunt trauma. They can also occur with 

penetrating arterial trauma and after reperfusion of an acutely 

ischemic limb. Tissue fluid pressure elevation exceeding 30 mmHg, 

after trauma, ischemia, and reperfusion injury, leads to lymphatic 

vessel collapse, impairing drainage of the edematous muscle. 3,4 

Ultimately, arteriolar spasm occurs, decreasing oxygen delivery 

to the tissue. The adverse effects of the ischemia are time- and 

pressure-related. Elevated pressures might be tolerated for short 

periods, but when abnormal pressures persist, neuronal and then 

muscle damage occurs. 5 

Figure 84-1. Upper view: Mid lower leg sagittal plane. Lower 

view: Fascial compartments of the lower leg: (1) anterior; 

(2) lateral; (3) superficial posterior; and (4) deep posterior 

compartments.

CHAPTER 84 ■ Miscellaneous Techniques 1407 

Figure 84-2. A simple method of 

measuring compartment pressure. 

extravasation of fluid at a puncture site or through the foramina of 

the nutrient vessel. Extravasation may be caused by previous 

infusions, incomplete penetration of a needle through the cortical 

bone, or extension of the cannula through the bone into the 

posterior compartment. Risk of compartment syndrome increases 

with pressure infusion, infusion of irritating drugs, use of inappro - 

priate needles, and extended duration of intraosseous infusion. 7–9 

Other Iatrogenic Causes 

Compartment syndromes may also develop after surgical pro - 

cedures in the limbs (e.g., plastic and orthopedic procedures). 10 

In the postoperative period, early clinical diagnosis may be dif - 

ficult because of residual regional anesthesia/analgesia 11 and the 

immobilization devices usually applied. Other described iatro - 

genic causes of particular interest to anesthetists include arterial 

cannula extravasation, 12 hyperosmolar Bier block, 13 intra-arterial 

barbiturates, 14 and extravasation to pressurized intravenous 

infused fluids. 12,15–17 Prompt recognition of an iatrogenic compart - 

ment syndrome is essential for preservation of limb function. 1 

Clinical Diagnosis 

Although the diagnosis may initially be subtle, failure to recognize 

and aggressively treat this entity can be devastating. The clinical 

findings in patients with incipient compartment syndrome are 

essentially similar, regardless of etiology. The four Ps—pain, pallor, 

paralysis, and pulselessness—are considered diagnostic, but all 

may be absent in early or late compartment syndrome. A high 

index of suspicion and repetitive examination are necessary for 

early diagnosis. Patients often present with pain that seems to 

be out of proportion to the injury they have suffered. A careful 

examination will help in localizing the compartment involved. 

Pain increases on passive stretching of the involved muscles. 1–3 

Measurement of Muscle 

Compartment Pressure 

Measurement of compartment pressure is the most reliable 

method to diagnose compartment syndrome because, in all cases, 

there is an increase in compartment pressure. Compartment 

pressures can facilitate the diagnosis of compartment syndrome 

in patients with peripheral nerve injuries, altered levels of con - 

sciousness, residual effects of anesthesia/analgesia, or equivocal 

clinical findings. The most appropriate time for fasciotomy can be 

identified by repeatedly monitoring the changes in compartment 

pressure. 3 Several available techniques for measuring compart - 

ment pressures have been described. 17–19 One of the simplest and 

easiest methods is to use an 18-gauge needle attached to a mercury 

manometer. More accurate results are obtained if a saline infusion 

is used to prevent the needle from becoming blocked 20 (Figure 

84–2). Solid-state, commercial devices are now readily available, 

such as the solid-state transducer intracompartmental catheter 

(STIC, Stryker Surgical, Kalamazoo, Mich) or the pressure sense 

intracompartmental pressure monitor (Horizon Medical, Inc, 

Santa Ana, Calif). The latter is the most compact of these devices. 3 

It is important to remember that only the pressure in the com - 

partment in which the needle is placed is being measured. Normal 

pressure in one compartment does not mean that there is normal 

pressure in all the compartments of the limb. 2 In humans, com - 

partment syndrome and muscle necrosis do not occur at pressures 

below 45 mmHg but always occur at pressures above 60 mmHg. 5 

The exact pressure at which tissue damage occurs varies in patients 

and is still controversial. 19–21 There is no precise pressure at which 

fasciotomy is invariably indicated, but when one is concerned 

about an impending compartment syndrome, it is best to err on 

the side of early fasciotomy. 3,5 The pressure in each compartment 

should be checked after decompression. 22 Full recovery is possible 

if treatment is initiated within 4 hours. Clinical experience and 

judgment are necessary in selecting the appropriate time for 

surgical intervention. Lack of recognition and delay in instituting 

treatment will lead to an increased incidence of amputation or loss 

of limb function. 

PRINCIPLES OF 

WOUND MANAGEMENT 

One of the most common procedures in the practice of emergency 

medicine is acute traumatic wound management. Pediatric 

patients frequently present for these procedures. The primary 

objectives in wound care are preserving viable tissue, restoring 

tissue continuity and function, optimizing conditions for the 

development of wound strength, preventing excessive or pro - 

longed inflammation, avoiding infection and other delays to 

healing, and minimizing scar formation. 23


Normal Physiology of Wound Healing 

A basic understanding of the process of wound healing in essential 

to achieve these objectives. Wound healing is a nonspecific repair 

process that involves five stages. 24–26 

1. Inflammation: Inflammation is a beneficial response that 

serves to remove bacteria, foreign debris, and devitalized tissue. 

Significant contamination with bacteria of foreign material 

may prolong the inflammatory process, interfering with epi - 

thelialization and fibroplasia and, consequently, impairing 

wound healing. 

2. Epithelialization: An epithelial covering, developed by epi - 

thelial cells migration, makes the surface of sutured wounds 

impermeable to water within 24 to 48 hours. This process is 

impaired by surface debris and eschar. 

3. Fibroplasia refers to collagen and protein polysaccharides 

synthesis by transformed fibroblasts that initiates this stage of 

scar formation. It is influenced by physical forces acting across 

the wound, mainly the stress imposed by movement. 

4. Contraction: The movement of skin edges toward the center 

of the wound, primarily in the direction of underlying muscle, 

is more important during wound healing by secondary 

intention. 

5. Scar maturation: tensile strength improvement begins after the 

fifth day following injury. It increases rapidly for 6 to 17 days, 

more slowly in the next 10 to 14 days, and lasts almost imper - 

ceptibly for as long as 2 years. 

Although the whole process can be divided into these stages, 

they are not independent. Different events during each stage 

are interrelated and influence the final result. Phagocytosis and 

leukocyte death, occurring during the inflammatory process, are 

responsible for the purulent exudates that may accumulate in 

the wound, impairing epithelial cell migration and fibroblastic 

synthesis of new collagen (fibroplasia) as opposed to the lysis of 

old collagen (fibrinolysis). When deciding the best time for suture 

removal, a persistent or prolonged inflammatory response and 

the physical forces exerted on the wound edges should be con - 

sidered. The cosmetic and functional results depend on this 

reparative process and the medical conditions provided during 

wound management. 

Initial Evaluation of the Wound 

Surgical incisions (e.g., those for thoracic drainage, vascular 

cutdown, tunneled catheters, subcutaneous injection device place - 

ment) are the most suitable for management and have the best 

healing scar results. These therapeutic procedures are carried 

out under ideal conditions such as aseptic skin surfaces, lack of 

particulate matter and tissue debris, incisions parallel to flexion 

lines, and minimal tension sutures. Accidental wounds should be 

carefully evaluated and need previous preparation. The “Clinical 

Policy for the Initial Approach to Patients Presenting with Pene - 

trating Extremity Trauma” of the American College of Emergency 

Physicians provides a useful approach to the evaluation of all the 

wounds. 27 Extrinsic and intrinsic factors that impair healing and 

promote infection should be identified before treatment. Higher 

infection rates are reported for patients at extremes of age (e.g., 

infants ≤ 6 mo) and with medical illness. 28 Other factors include 

current medication, allergies, tetanus immunization status, poten - 

tial exposure to rabies, presence of foreign bodies embedded 

in the wound, associated injuries (fracture joint penetration), 

availability for follow-up, and parents’ understanding of wound 

care. 29 Nonaccompanied pediatric patients impose an additional 

difficulty in identifying these historical factors. The same problem 

should be expected when trying to examine a wounded and awake 

infant or child. These situations may contribute to underestimat - 

ing the amount of tissue destruction, the degree of contamination, 

the damage to underlying structures, and the failure to detect the 

presence of foreign bodies. 

Cleaning Procedures 

All wounds must be cleaned immediately after evaluation. 

Removing bacteria, particulate matter, and tissue debris will reduce 

infection rates and shorten the inflammatory response. 30 All 

procedures should be explained to parents and patients, in an 

appropriate manner, to alleviate fears, stimulate cooperation, and 

provide assurance. Despite that, pediatric patients may need some 

intravenous or inhalation sedation associated with local or regional 

anesthesia. 23 The patient’s level of understanding and cooperation 

will determine which anesthetic technique should be used to 

provide the best conditions for evaluating, cleaning, scrubbing, 

irrigating, and suturing wounds. The physician must keep in mind 

that a good surgical result has to be emotionally atraumatic as well. 

The goals of wound cleaning may be accomplished by extensive 

scrubbing with a 1% povidone-iodine solution. Povidone-iodine 

as a 10% solution and other antiseptics (e.g., hexachlorophene and 

chlorhexidine) are harmful to tissues and increase infection rates, 

thus prohibiting their application to intact skin surfaces (Table 

84–1). 30–34 After a through cleansing, surgical débridement, exci - 

sion, and hemostasis, the wound is ready for closure. 

Techniques of Wound Closure 

Overview 

When the wound is considered clean or becomes clean after 

scrubbing, irrigation, and débridement, it must be closed. This 

procedure minimizes inflammation, fibroplasias, contracture, 

scar width, and contamination. 35 Wounds that close by secondary 

intention result in more deformity and loss of function. 36–38 

Despite this, certain wounds should almost always be left open 

or closure delayed. Included in this category are those already 

infected or heavily contaminated by soil, organic matter, or feces; 

those associated with extensive tissue damage (e.g., high-velocity 

missile injuries, explosion injuries of the hand, or complex crush 

injuries); and most bite wounds. 38–40 One of the available closure 

techniques must be selected according to location and config - 

uration of the wound (Table 84–2). 

Hair Tying of Scalp Wounds 

Closure of scalp wounds by hair tying offers an attractive alter - 

native for closure of small superficial scalp wounds (1–2 cm in 

length) in children. 41 It is a particularly humane method and 

relatively painless because a local anesthetic injection is not 

needed. In a series of 25 children younger than 8 years whose scalp 

wounds were closed by hair tying, a 48-hour follow-up showed no 

evidence of wound infection and only 2 cases of mild (2–4 mm) 

wound separation. 42

TABLE 84-1. Cleaning Solutions for Wound Care 


Antiseptic Solution Biologic Activity Indications Comments 

Povidone-iodine detergent 

solution (10%) a 

Povidone-iodine aqueous 


Povidone-iodine diluted 

aqueous solution (l%) a 

Povidone-iodine alcoholic 


Chlorhexidine gluconate 

detergent solution (4%) 

Hexachlorophene detergent 

solution (pHisoHex) 

Hydrogen peroxide 

Strong germicidal 


Same as full-strength solution 


Strongly gram-positive 

bactericidal 

Less strong against gramnegative 

bacteria 

Gram-positive bacteriostatic 

Poor activity against gramnegative 

bacteria 

Very weak antibacterial agent 

Hand and intact skin cleanser 

Wound periphery cleanser 

Mucosal antiseptic 

Open wound cleanser 

Wound irrigation 

Surgical field antiseptic 

Invasive procedures 

antiseptic 

Hand cleanser 

Alternative hand cleanser 

Clean skin encrusted with 

blood and coagulum 

Soak off adherent bloodsoaked 

dressings 

a 

Iodine and chlorhexidine solutions should be applied for at least 2 min to obtain maximal residual bactericidal activity, >60 min. 

Toxic to wound tissues 

Painful to open wounds 

Minimally toxic to wound tissues 

No significant tissue toxicity 

Safest and most effective product 

for open wound cleaning 

Irritating and toxic to open 

wounds and mucosa 

Toxic to cellular components of 

blood (in vitro studies) 

Avoid use in open wounds and 

eye/ear cleaning 

Toxic to wound tissues 

Neurotoxic and teratogenic 

through skin absorption 

No more effective than ordinary 

soap and water 

Toxic to tissue/red cells 

Foaming activity useful to remove 

debris/coagulated blood 

Wound Taping 

The primary indication for tape closure is a superficial straight 

laceration with no significant tension (Figure 84–3). Tape closure 

can be used with deep sutures to reduce tension. Some wounds in 

anxious children, when sutures are not clearly indicated, may be 

closed with tape. The most suitable areas are the hairless surfaces 

of the forehead, chin, malar eminence, thorax, and nonjoint areas 

of the extremities. It should be considered for wounds with 

potential for infection, under plaster casts, and is mandatory when 

reducing the chance of a permanent suture mark scar. 43–45 Several 

brands of tapes are available with specific properties: air and water 

porosity, flexibility, strength, and adhesiveness. 46,47 

Application of Tissue Adhesive 

The tissue adhesive N-2-butylcyanoacrylate (Histoacryl glue) is a 

bonding agent that can be used instead of tape strips on tensionless 

superficial wounds. Its advantage is that there is no limitation to 

hairless surfaces. Some studies found no difference between the 

TABLE 84-2. Techniques of Wound Closure 

Technique Indications Comments 

Hair tying 

Wound tape a 

Tissue adhesive a 

Wound staples a 

Sutures 

Small superficial scalp wounds 

Superficial straight lacerations on hairless 

surfaces, forehead, chin, malar eminence, 

thorax, and nonjoint areas of the extremities 

Tensionless wounds or secondary support to 

skin suture 

Same as wound tape 

Linear lacerations with straight, sharp edges on 

an extremity, the trunk, or the scalp 

Wounds with complex configurations 

Wounds extending into deeper layers 

Wounds in mobile areas 

a 

Must be associated with deep, absorbable sutures, whenever necessary to reduce tension. 

Painless method 

No inflammatory response to suture material 

Painless method 

Can be associated with deep sutures to reduce tension 

No limitation to hairless surfaces 

Three to four times faster than suturing 

Especially useful for agitated, uncooperative pediatric 

patients; probably same cost as that of suturing 

Most commonly used method 

Different materials for two categories to be used 

(absorbable and nonahsorbable sutures) 

Suture materials impair host defenses and infection 

resistance and provoke inflammation


Figure 84-3. Tape closure of a 

superficial wound. 

tensile strength and overall degree of inflammation in wounds 

closed with adhesive and with sutures. 48,49 Cosmetic results were 

also similar. 50,51 

Use of Wound Staples 

Nowadays, the indications for stapling are limited to relatively 

linear lacerations with straight, sharp edges located on an extrem - 

ity, the trunk, or the scalp. The most significant advantage of 

wound stapling over suturing is speed of closure. Although it must 

be performed under local anesthesia, and deep, absorbable sutures 

whenever necessary to reduce tension, it is a procedure three to 

four times faster than suturing and especially useful for agitated, 

uncooperative emergency pediatric patients. 52–55 Many stapling 

devices are commercially available. With the introduction of new 

devices, the cost of wound stapling is comparable with that of 

suturing. 54 Because of the increased availability and versatility 

of stapling instruments, they are being used more frequently in 

traumatic wound management. Four studies have demonstrated 

their application in both adult and pediatric patients in the 

emergency department setting. 52–55 

Sutures 

The traditional and most commonly used method of closure is 

suturing. Suture repair is the most appropriate method for wounds 

with complex configurations, those that extend into deeper layers, 

and those in mobile areas. 35 All sutures will damage host defenses, 

provoke inflammation, and impair the ability of the wound to 

resist infection. 56 For most wounds with more than one layer of 

tissue to be closed, suture materials must be chosen from two 

general categories 57 : (1) an absorbable suture for the subcutaneous 

or deeper layers (e.g., plain gut, chromic gut, polyglactin, poly - 

dioxanone) and (2) a nonabsorbable suture for skin closure (e.g., 

nylon, polypropylene, cotton, silk). Multifilament synthetic ab - 

sorbable sutures (e.g., Vicryl, coated Vicryl) have the best handling 

characteristics, although they provoke more inflammation and 

infection than monofilament sutures. 58,59 Polydioxanone sutures 

provide the advantages of a monofilament synthetic suture in 

an absorbable form, making it a good choice as a subcuticular 

stitch. 60,61 Absorbable gut sutures have many disadvantages— 

including relatively low and variable strength, a tendency to fray 

when handled, stiffness despite being packaged in a softening 

fluid—and are the most reactive. 62,63 Natural suture materials have 

been made obsolete by the newer, synthetic products. They have 

improved handling characteristics, knot security and tensile 

strength, and predictable absorption rates and induce minimal 

tissue reactivity. 56,64,65 In the emergency department, the most 

useful suture materials for wound closure are Dexon or coated 

Vicryl for subcutaneous or deeper layers and nylon or polypro - 

pylene for skin closure. In most situations, 3-0 or 4-0 sutures are 

used to the repair of fascia, 4-0 or 5-0 absorbable sutures in 

subcutaneous closure, and 4-0 or 5-0 nonabsorbable sutures 

in skin closure. 35 

The most important principle applied to suturing is relieving 

tension exerted on edges by tissue plane undermining and layered 

closure (Figure 84–4A). Separate approximation of fascia and 

subcutaneous layers hastens the healing and return of muscle 

function, preventing deformation of the surface of the wound. 66–68


Figure 84-4. Surgical closure of a 

wound. A: Technique of tissue plane 

undermining. B: Interrupted stitches. 

C: continuous stitch. D: Surgical tape 

as support to skin movements. 

Skin closure consists of matching the epidermis and the superficial 

layer of dermis on each side without excessive tension stitches. 

Three general methods should be used: 

1. Interrupted stitch: It is the most frequently used technique for 

skin closure. Although time-consuming, the advantage is that 

each stitch holds the wound together independently from the 

other (see Figure 84–4B). 

2. Continuous stitch: In a continuous stitch, the loops are the 

exposed portions of a helical coil that is tied at each end of the 

wound. It is more rapidly performed and has the advantage of 

strength, fewer knots, and more effective hemostasis. It is 

indicated for closing relatively clean wounds that are under 

little or no tension and are on flat, immobile skin surfaces 

(see Figure 84–4C). 

3. Continuous subcuticular stitch: This stitch is the ideal tech - 

nique for pediatric patients who are likely to be as frightened 

and uncooperative for suture removal as for suture placement. 

An absorbable subcuticular suture (e.g., polydioxanone) may 

be used, obviating the need for later removal. It can be left in 

place for a longer period than a percutaneous suture because 

stitch marks are avoided. 

Repair of Special Structures 

Repair of special structures requires specific procedures. 35,68 

FACIAL WOUNDS: Subcutaneous fat should be preserved, if 

possible, to prevent eventual depression of the scar and preserve 

normal facial contours. Surgical tape is useful as a secondary 

support, protecting the epithelial stitch from the stress produced 

by normal skin movements (see Figure 84–4D). 

EYEBROW AND EYELID LACERATIONS: Minimal, if any, débridement 

should be done. A vertical excision may produce a linear 

alopecia in the eyebrow, whereas with simple closure, the scar 

remains hidden under the hair. The eyebrow must not be shaved 

because it often results in more deformity than the injury itself. 

Eyelid wounds should be carefully evaluated for concomitant 

lesions to other structures (e.g., tarsal plate, levator palpebrae 

muscle, lacrimal duct), and an ophthalmologist’s opinion may be 

required. 

EAR LACERATIONS: The primary goals are expedient coverage of 

exposed cartilage and minimization of wound hematoma. 

LIP AND INTRAORAL LACERATIONS: The vermilion-cutaneous 

junction of the lip is a critical landmark that, if divided, must be 

repositioned with precision. Small flaps of oral mucosa may 

be excised, whereas extensive lesions should be closed with 

interrupted 4-0 Vicryl suturing. 

TONGUE LACERATIONS: Even large (simple or linear) lacerations, 

especially those in the central portion of the tongue, heal quickly 

with minimal risk of infection. Only those lacerations that involve 

the edge or pass completely through the tongue, flap lacerations, 

and excessively bleeding lacerations need to be sutured. Large flaps 

require repair, but small ones on the edge may be excised. Most 

lacerations that need to be sutured in uncooperative children must 

be performed under general anesthesia. Interrupted stitches with 

4-0 absorbable sutures are used including all thicknesses of the 

tongue. In small children, a surface suture is likely to be interfered 

with, and closure of only the muscle layer with a deep absorbable 

suture may be preferred (mucosal healing is rapid). 

SCALP LACERATIONS: The rich vascular network found in the 

scalp fascia results in abundant bleeding from scalp wounds. 

Profuse bleeding may have serious consequences in small infants 

without prompt treatment. 69,70 It is best controlled by expeditious 

suturing with 3-0 nylon or polypropylene, incorporating skin, 

subcutaneous tissue, and galea in a single stitch. 

NAIL LACERATIONS: Injuries to the nail or nailbed are common 

problems in pediatric emergency patients. The finger extremity 

has to be cleaned, simple nailbed lacerations repaired (6-0 or 7-0 

absorbable sutures), and the avulsed nail reapplied to cover the 

sensitive area and maintain the fold for new nail growth. When 

the nailbed has been extensively lacerated or partially avulsed, a 

hand surgeon should be consulted. 71 

Instructions to the Patient Before Discharge 

Wound healing and its result depend on the care given to the 

wound after treatment. Surgical wounds usually need no special 

care before dressing removal. Nurses are advised to inquire about


pain and look for inflammatory signs in hospitalized patients. 

The same instructions should be given to parents in a thorough 

and understandable way before hospital discharge. The dressing 

must be kept clean and dry for the first 24 to 48 hours; after that, 

the wound is essentially impermeable to water and bacteria. 23 

Complicated or infection-prone wounds have to be reviewed in 

2 days. If there is no sign of infection, parents may provide a daily 

gentle washing with mild soap and water until it is time for the 

removal of the sutures. Vigorous scrubbing should be discouraged. 

Rabies and tetanus postexposure prophylaxis schedule must be 

explained as well. 72,73 

Suture Removal 

There is no standard time for suture removal because wounds do 

not heal at a standard rate. As a general rule, sutures are removed 

within 7 days, and if necessary, wound repair can be maintained 

with strips of surgical skin tape. Sutures left in place for longer 

than 7 to 10 days are associated with extensive inflammatory 

response and stitch abscesses that determine the severity of stitch 

marks. 25,74 Whenever possible, absorbable subcuticular sutures 

should be used to avoid this stressful and traumatic procedure for 

infants and children. 

ARTHROCENTESIS 

Arthrocentesis, the puncture and aspiration of a joint, is an 

acknowledged useful diagnostic and therapeutic procedure that is 

easily performed in the emergency department and indicated for 

a variety of clinical situations. 75–77 

Indications and Contraindications 

Because an acutely swollen joint may be indicative of a number 

of disease entities, thorough history and physical examination are 

the cornerstones of evaluation, followed by arthrocentesis. 75,76 

Indications 

The indications for arthrocentesis are 77–80 

● 

● 

● 

● 

● 

● 

● 

Diagnosis of nontraumatic joint disease by synovial fluid analysis 

(e.g., septic arthritis). 

Differential diagnosis between a traumatic and an inflammatory 

joint effusion confirmed by hemarthrosis. 

Differential diagnosis between articular and periarticular 

disease (e.g., tendinitis, bursitis, contusion, cellulites, or phle - 

bitis). 

Diagnosis of an intra-articular fracture by the presence of blood 

with fat globules in the aspiration. 

Pain relief of an acute hemarthrosis of a tense effusion. 

Local injection of medications in acute and chronic inflammatory 

arthritides. 

Obtaining fluid for culture, Gram staining, immunologic studies, 

and cell count in cases of suspected joint infection. 

SEPTIC ARTHRITIS: Acute monoarticular arthritis is a common 

problem in emergency medicine. Although there are many causes 

of acute monoarticular arthritis, the one most requiring urgent 

diagnosis and treatment is septic arthritis. Confirmation requires 

arthrocentesis and synovial fluid culture. 81 Infants aged 6 months 

to 2 years show a higher incidence of Haemophilus influenzae 

cultures, whereas in neonates, staphylococci and Escherichia coli 

predominate this infection. 82 Neisseria gonorrhoeae is the most 

common organism causing septic arthritis among adolescents and 

young adults. 83 Patients with other medical illnesses are more 

likely to have staphylococcal joint infections. 

HEMARTHROSIS: Hemarthrosis after trauma is a frequent occur - 

rence and often denotes significant internal damage (e.g., a tear in 

a ligamentous structure, knee capsule, or a fracture). If the history 

of trauma is vague, arthrocentesis may be required to differentiate 

hemorrhage from other causes of joint effusion. Isolated nontrau - 

matic hemarthrosis may occasionally be seen by the emergency 

physician, especially in patients with bleeding diatheses (e.g., 

hemophilia or oral anticoagulant therapy). 84,85 Distention of the 

joint by effusion or hemorrhage causes considerable pain and 

disability. 86 Therapeutic arthrocentesis to drain a symptomatic 

traumatic effusion is a well-accepted practice. 87 

INTRA-ARTICULAR CORTICOSTEROID INJECTION: The use of 

steroids has proved to be a dependable method for providing 

rapid relief (within 6–12 h after the injection) from pain and 

swelling of inflamed joints, although it is strictly local, usually 

temporary, and rarely curative. 88–90 Corticosteroid injections 

are most helpful when only a few of a patient’s joints are 

actively inflamed. 91 The most serious complication of this practice 

is intra-articular infection. Steroids are contraindicated when an 

infection is suspected. 

Contraindications 

The most important contraindication to arthrocentesis is the 

presence of infection in the tissue overlying the site to be punctured 

(e.g., an abscess or frank cellulitis). However, inflammation with 

warmth, swelling, and tenderness may overlie an acutely arthritic 

joint, and this condition may mimic a soft tissue infection. Once 

convinced that cellulitis does not exist, the clinician should not 

hesitate to obtain the necessary diagnostic joint fluid. 75,76 A relative 

contraindication to joint puncture is the presence of a bacteremia. 

Bleeding diatheses may at times be a relative contraindication, but 

arthrocentesis to relieve a tense hemarthrosis in bleeding disorders, 

such as hemophilia, is an accepted practice after infusion of 

the appropriate clotting factors. Arthrocentesis is also relatively 

contraindicated for a patient receiving anticoagulants or in the 

presence of a joint prosthesis, unless the procedure is being 

performed to exclude infection. 75,79 

General Arthrocentesis Technique 

Although one may successfully aspirate where the joint bulges 

maximally, certain landmarks are important (see Specific Arthro - 

centesis Techniques). 75,76,79 The most crucial part of arthrocentesis 

is spending adequate time in defining the joint anatomy by 

palpating the bony landmarks as a guide. An aseptic technique is 

essential to avoid introducing infection. It is important to have the 

patient relax during the procedure. Even with appropriate local 

anesthesia, arthrocentesis is a relatively distressing procedure to 

pediatric patients. Tense muscles narrow the joint space and make 

the procedure more difficult, requiring repeated attempts at 

aspiration, and which results in inadequate drainage, bleeding, or 

unwarranted cartilage damage. As a general rule, the procedure 

should be performed under general anesthesia associated with a 

regional block.


Figure 84-6. Elbow arthrocentesis 

Figure 84-5. Wrist arthrocentesis. 

Specific Arthrocentesis Techniques 

The following are arthrocentesis techniques for specific parts of 

the body. 75,76 

Wrist 

The dorsal radial tubercle (Lister’s tubercle) is an elevation found 

in the center of the dorsal aspect of the distal end of the radius. 

The extensor pollicis longus tendon runs in a groove on the radial 

side of the tubercle. The tendon can be palpated by active 

extension of the wrist and thumb. The wrist should be positioned 

in approximately 20 to 30 degrees of flexion and accompanying 

ulnar deviation (Figure 84–5). Traction is applied to the hand. 

A 22- to 24-gauge needle is inserted dorsally, just distal to the 

dorsal tubercle on the ulnar side of the extensor pollicis longus 

tendon. The anatomic snuffbox, located more radially, should 

be avoided. 

to the coracoid process and directed posteriorly toward the 

glenoid rim (Figure 84–7). Arthrocentesis of this joint is of mod - 

erate difficulty. Other approaches have been suggested but are less 

well accepted. 

Ankle 

The lateral malleolus and the distal tibia are the main landmarks 

of the ankle. With dorsiflexion of the foot, a 20- to 22-gauge needle 

is inserted 1 cm medial and 1 cm cephalad to the lateral malleolus, 

at the lateral sulcus between the articular surface of the talus and 

the distal fibula, in an anteroposterior direction (Figure 84–8). 

Knee 

The middle or superior portion of the lateral surface of the 

patella is the landmark for the knee joint (Figure 84–9). The knee 

Elbow 

The lateral epicondyle of the humerus and the head of the radius 

are the landmarks for arthrocentesis of the radiohumeral joint 

(Figure 84–6). The depression between the radial head and the 

lateral epicondyle of the humerus is palpated during elbow 

extension. With the elbow flexed 90 degrees, the forearm pronated, 

and the palm placed down flat on a table, a 22-gauge needle is 

inserted from the lateral aspect just below the lateral epicondyle 

and directed parallel to the shaft of the radius. A medial approach 

should not be used, because the ulnar nerve and the superior ulnar 

collateral artery may be damaged. 

Shoulder 

The coracoid process medially and the proximal humerus laterally 

are palpated anteriorly while the shoulder is externally rotated. 

A 20- to 22-gauge needle is inserted at a point inferior and lateral 

Figure 84-7. Shoulder arthrocentesis.


Figure 84-8. Ankle arthrocentesis. 

is fully extended as far as possible. Relaxation of the quadriceps 

muscle greatly facilitates needle placement. The foot is kept 

perpendicular to the floor. An 18-gauge needle is inserted at the 

midpoint or superior portion of the patella approximately 1 cm 

lateral to the anterolateral patellar edge. The needle is directed 

between the posterior surface of the patella and the intercondylar 

femoral notch. 

Hip 

The anterior superior iliac spine, the femoral artery, the inguinal 

ligament, and the greater trochanter should be identified (Figure 

84–10). For the anterior approach, a mark should be made 2 cm 

Figure 84-10. Hip arthrocentesis. A: landmarks. B: anterior 

approach. 

below the inguinal ligament and 2 cm lateral to the femoral artery. 

A 20-gauge needle is inserted at a 60-degree angle to the skin and 

directed posteriorly and medially until synovial fluid is obtained. 

In the lateral approach, the needle is inserted just anterior to the 

greater trochanter and directed medially and slightly cephalad 

toward a point below the middle of the inguinal ligament. This is 

a difficult joint for arthrocentesis, and ultrasound guidance in 

children is very helpful. 92,93 

Complications 

Infection, the most serious complication, is extremely rare. 

Various studies report the incidence of infection after routine 

arthrocentesis to be in the range of 0.001 to 0.005%. 94,95 The most 

common adverse reaction is related to corticosteroid injection and 

consists of corticosteroid crystal-induced synovitis, with a 1 to 2% 

occurrence. 95 Repeated corticosteroid injections into one joint 

carry the risk of necrosis of the juxta-articular bone with subse - 

quent joint destruction and instability. Other rare complications 

include local soft tissue atrophy and calcification, tendon rupture, 

intra-articular bleeding, and transient nerve palsy. 90 

Figure 84-9. Knee arthrocentesis. 

IMMOBILIZATION TECHNIQUES 

Initial Evaluation 

The initial evaluation of a patient with a fracture or another injury 

needing some form of immobilization involves at least the 

following objectives: (1) to relieve pain, (2) to obtain and maintain 

a satisfactory position of the fracture fragments, and (3) to avoid 

secondary damage to soft tissues. 96 The rescuer must not let 

obvious injuries to the extremities be a distraction to the treatment 

of more life-threatening lesions. Special attention to airway, 

breathing, and circulation, as established for routine emergency

Chapter 81

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?