AggiornAmenti in riAnimAzione e terApiA intensivA - Pacini Editore

ARTI
AggiornAmenti in riAnimAzione e terApiA intensivA

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Finito di stampare nel mese di Luglio 2011

presentazione
In questo numero di ARTI vengono commentati, riportando anche voci
bibliografiche ritenute interessanti per eventuali approfondimenti, 3 articoli
originali o di revisione critica provenienti da riviste ad alto impact
factor.
Due di essi rivolgono la loro attenzione all’importanza dell’albumina nella
Medicina Critica.
Il primo articolo sottolinea l’importanza del monitoraggio dell’albuminemia
dimostrando, attraverso una meta-analisi, la possibilità di identificare
nell’ipoalbuminemia un predittore indipendente della lesione renale
acuta (Acute Kidney Injury, AKI) e della mortalità conseguente all’AKI. Lo
stesso primo autore 1 , in un’altra meta-analisi sull’uso dei colloidi e l’AKI,
aveva cercato di dimostrare come l’albumina iperoncotica abbia un effetto
renoprotettivo, concludendo poi come gli effetti renali possano essere
specifici per particolari molecole di colloidi 2-4 .
Il secondo articolo, sempre inerente l’albumina, è uno studio sperimentale
sui ratti, che sottolinea gli effetti benefici dell’albumina iperoncotica
nella sepsi indotta da peritonite. Questo studio documenta gli effetti di
farmaco anti-ossidante e scavenger dell’albumina, e non solo di soluzione
con proprietà oncotiche. Del resto, già dallo studio SAFE si era visto che
l’albumina poteva avere effetti benefici nel sottogruppo di pazienti con
sepsi grave e shock settico 5-8 .
Il terzo articolo si propone di stimare se i difetti trombofilici parentali,
dopo morte fetale, o acquisiti o ereditari, siano più prevalenti che nella
popolazione normale, e si propone altresì di stimare le associazioni tra
questi difetti trombofilici e i differenti casi di morte fetale. Un argomento
questo molto discusso in letteratura, in special modo per i problemi che
una attenta analisi costo-efficacia può sollevare in caso di screening della
trombofilia nelle situazioni ad alto rischio 9-11 .
La consultazione di questi articoli può dunque consegnare al lettore buoni
strumenti di riflessione e di approfondimento.
Buona lettura!
Il Direttore Scientifico
Giorgio Tulli
Direttore del Dipartimento delle Terapie Intensive
e della Medicina Perioperatoria dell’Azienda Sanitaria Fiorentina
Letteratura da consultare
1 Wiedermann CJ, Dunzendorfer S, Gaioni LU, et al. Hyperoncotic colloids and acute
kidney injury: a meta-analysis of randomized trials. Crit Care 2010;14:R191.
2 Schortgen F, Girou E, Deye N, et al. The risk associated with hyperoncotic colloids in
patients with shock. Intensive Care Med 2008;34:2157-68.
3 Rioux JP, Lessard M, De Bortoli B, et al. Pentastarch 10% (250 kDa/0.45) is an independent
risk factor of acute kidney injury following cardiac surgery. Crit Care Med
2009;37:1293-8.
4 Davidson IJ. Acute kidney injury by hydroxyethyl starch: can the risks be mitigated?
Crit Care Med 2009;37:1499-501.
5 Finfer S, Bellomo R, Boyce N, et al.; SAFE Study Investigators. A comparison of albumin
and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;27:2247-
56.
3

4
6 SAFE Study Investigators, Finfer S, Bellomo R, McEvoy S, et al. Effect of baseline serum
albumin concentration on outcome of resuscitation with albumin or saline in patients
in intensive care units: analysis of data from the saline vs. albumin fluid evaluation
(SAFE) study. BMJ 2006;333:1044.
7 SAFE Study Investigators, Finfer S, McEvoy S, Bellomo R, et al. Impact of albumin
compared to saline on organ function and mortality of patients with severe sepsis.
Intensive Care Med 2011;37:86-96.
8 Delaney AP, Dan A, McCaffrey J, et al. The role of albumin as a resuscitation fluid
for patients with sepsis: a systematic review and meta-analysis. Crit Care Med
2011;39:386-91.
9 Alonso A, Soto I, Urgellés MF, et al. Acquired and inherited thrombophilia in women
with unexplained fetal losses. Am J Obstet Gynecol 2002;187:1337-42.
10 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal
thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet
Gynecol Reprod Biol 2002;101:6-14.
11 Wu O, Robertson L, Twaddle S, et al. Screening for thrombophilia in high-risk situations:
systematic review and cost-effectiveness analysis. The Thrombosis: Risk and
Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess
2006;10:1-110.

Hypoalbuminemia and acute kidney injury:
a meta-analysis of observational clinical studies
C.J. Wiedermann
W. Wiedermann
M. Joannidis
Division of Internal Medicine,
Central Hospital of Bolzano,
Italy
PURPOSE: To test the hypothesis that hypoalbuminemia is independently
associated with increased risk of acute kidney injury (AKI).
METhOdS: A meta-analysis was performed of observational clinical studies
evaluating the relationship between serum albumin level and the occurrence
of AKI by multivariate methods. Additionally, the impact was
assessed of lower serum albumin on mortality in patients who developed
AKI. Eligible studies were sought by multiple methods, and adjusted odds
ratios (OR) were quantitatively combined using a random effects model.
RESULTS: Seventeen clinical studies with 3,917 total patients were included:
11 studies (6 in surgical or intensive care unit patients and 5 in other
hospital settings) evaluating the influence of serum albumin on AKI incidence
and 6 studies describing the relationship between serum albumin
and mortality among patients who had developed AKI. Lower serum albumin
was an independent predictor both of AKI and of death after AKI
development. With each 10 g L-1 serum albumin decrement, the odds of
AKI increased by 134%. The pooled OR for AKI was 2.34 with a 95% confidence
interval (CI) of 1.74-3.14. Among patients who had developed AKI,
the odds of death rose 147% (pooled OR 2.47, 95%CI 1.51-4.05) with each
10 g L-1 serum albumin decrement.
COnCLUSIOnS: This meta-analysis provides evidence that hypoalbuminemia
is a significant independent predictor both of AKI and of death following
AKI development. Serum albumin determinations may be of utility
in identifying patients at increased risk for AKI or for death after AKI.
Controlled studies are warranted to assess interventions aimed at correcting
hypoalbuminemia.
Intensive Care Med 2010;36(10):1657-65
5

La lesione renale acuta (Acute Kidney Injury, AKI) si associa ad una significativa morbilità e mortalità nei pazienti critici che presentano
fattori di rischio che includono l’età, l’indice di massa corporea, la funzione renale basale, l’insufficienza circolatoria
o respiratoria acuta, la malattia epatica, l’infezione, la malattia occlusiva vascolare periferica, la malattia polmonare ostruttiva
cronica, l’insufficienza cardiaca cronica, il linfoma o la leucemia, le procedure invasive e la chirurgia ad alto rischio.
L’ipoalbuminemia è un fattore di rischio in alcune condizioni mediche acute, che includono l’ALI/ARDS 1 2 .
Wiedermann et al. hanno cercato, mediante l’uso di una meta-analisi su studi clinici osservazionali, di determinare la relazione
tra livello sierico di albumina ed AKI.
In 17 studi clinici che coinvolgevano 3917 pazienti, il livello sierico di albumina più basso si dimostrava essere un predittore
indipendente sia di AKI che di morte dopo lo sviluppo dell’AKI stessa, con, per ogni g/dl di decremento della albumina serica,
un incremento della probabilità di AKI del 134%. Nei pazienti in cui si era già sviluppata l’AKI, la probabilità della morte saliva
al 147% per ciascun g/dl di decremento della albumina serica. Questi autori concludono che l’ipoalbuminemia è un predittore
indipendente significativo sia di AKI che di mortalità a seguito di AKI, e che la misura dell’albumina serica può identificare i
pazienti ad aumentato rischio di AKI o di morte dopo AKI.
Questa meta-analisi suggerisce una nuova “tendenza” sulla patogenesi dell’AKI: che l’albumina serica possa giocare un ruolo
diretto nello sviluppo e nell’outcome dell’AKI piuttosto che essere semplicemente un marker o un semplice spettatore associato
alla malattia. Nonostante il fatto che l’ipoalbuminemia possa essere indipendentemente associata all’AKI ed alla morte
dopo AKI, l’associazione non prova una relazione causa-effetto. La relazione è indipendente da altri fattori che sono stati riconosciuti,
misurati e tenuti in conto (aggiustati) per la statistica, e per queste ragioni è robusta. Tuttavia gli studi osservazionali,
includendo le grandi revisioni sistematiche come questa, non possono provare il rapporto causa-effetto.
Con questo “caveat” in testa, è interessante speculare se l’ipoalbuminemia potrebbe attualmente contribuire allo sviluppo di
AKI, e se così fosse, in che modo? Se un rapporto potesse essere determinato, esso aprirebbe una nuova comprensione della
patogenesi della malattia e offrirebbe anche una opportunità allo sviluppo di nuovi trattamenti. Potenziali considerazioni sono
i cambiamenti nella nefrotossicità da farmaci, la renoprotezione diretta (attraverso le proprietà antiossidanti e di scavenging
dei radicali liberi, fra molte altre proprietà) o la preservazione delle cellule tubulari e vascolari renali 3-5 .
Riassumendo, la conclusione finale degli Autori, che le misure dell’albumina serica possano aiutare nel prognosticare l’AKI, è
valida. Sfortunatamente poche terapie si possono ottenere solo sulla base del pronostico medico.
Letteratura da consultare
1 Vincent JL, Dubois MJ, Navickis RJ, et al. Hypoalbuminemia in acute illness: is there a rationale for intervention? A metaanalysis
of cohort studies and controlled trials. Ann Surg 2003;237:319-34.
2 Mangialardi RJ, Martin GS, Bernard GR, et al. Hypoproteinemia predicts acute respiratory distress syndrome development,
weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 2000;28:3137-45.
3 Contreras AM, Ramírez M, Cueva L, et al. Low serum albumin and the increased risk of amikacin nephrotoxicity. Rev Invest
Clin 1994;46:37-43.
4 Iglesias J, Abernethy VE, Wang Z, et al. Albumin is a major serum survival factor for renal tubular cells and macrophages
through scavenging of ROS. Am J Physiol 1999;277:F711-22.
5 Lee YJ, Han HJ. Albumin-stimulated DNA synthesis is mediated by Ca2+/PKC as well as EGF receptor-dependent p44/42
MAPK and NF-kappaB signal pathways in renal proximal tubule cells. Am J Physiol Renal Physiol 2008;294:F534-41.
6

Beneficial effects of hyperoncotic albumin on liver
injury and survival in peritonitis-induced sepsis rats
C.M. Tsao
H.C. Huang
Z.F. Chen
W.J. Liaw
W.M. Lue
A. Chen
S.J. Chen
C.C. Wu
Department
of Anesthesiology, Taipei
Veterans General Hospital,
National Yang-Ming
University, Taipei, R.O.C.,
Taiwan; Department
of Anesthesiology
and Pain Clinics, Cheng Hsin
Rehabilitation Medical Center,
Taipei, R.O.C., Taiwan;
Department of Pharmacology,
Department of Pathology
and Department
of Physiology, National
Defense Medical Center,
Taipei, R.O.C., Taiwan;
Department
of Anesthesiology,
Tri-Service General Hospital,
National Defense Medical
Center, Taipei, R.O.C., Taiwan;
Department of Nursing,
Kang-Ning Junior College
of Medical Care
and Management, Taipei,
R.O.C., Taiwan
Liver injury/dysfunction developing in patients with sepsis may lead to
an increased risk of death. Small-volume resuscitation with hyperoncotic
albumin (HA) has been proposed to restore physiologic hemodynamics in
hemorrhagic and septic shock. We evaluated whether HA resuscitation
could alleviate the development of liver injury/dysfunction in rats with
polymicrobial sepsis induced by cecal ligation and puncture (CLP). The
male Wistar rats received 0.9% saline or HA (25%, 3 ml/kg intravenously)
at 3 h after CLP or sham operation. All hemodynamic and biochemical
variables were measured during the 18-h observation. After 18 h of CLP,
the septic rats developed circulatory failure (i.e., hypotension, tachycardia
and poor tissue perfusion), liver injury (examined by biochemical variables
and histologic studies), and a higher mortality. HA not only ameliorated
the deterioration of hemodynamic changes but also attenuated neutrophil
infiltration and cell death in the liver of septic animals. The septic
rats treated with HA had a higher survival when compared with those
with 0.9% saline treatment. Moreover, the increased plasma interleukin
(IL)-1beta, plasma IL-6, plasma nitrite/nitrate concentrations, liver inducible
nitric oxide synthase expression, and liver superoxide levels in CLP rats
were attenuated after administration of HA. Thus, HA may be regarded
as a potential therapeutic agent in the early treatment of septic shock in
order to prevent or reduce subsequent liver failure.
Shock 2011;35(2):210-6
7

Lo shock settico nel corso di una grave infezione microbica può progredire fino ad una Multiple Organs Dysfunction Sindrome
(MODS), nonostante i recenti progressi nella Medicina Critica.
La MODS sequenziale può portare ad un aumento nella mortalità dal 30 al 100% a seconda del numero degli organi coinvolti
1 . Nella patofisiologia della sepsi, i cambiamenti emodinamici, metabolici ed infiammatori che si sviluppano nei pazienti
possono compromettere le funzioni dei vari organi. La disfunzione/insufficienza epatica indotta dalla sepsi è di solito attribuita
a disturbi sistemici o microcircolatori, spillovers di batteri ed endotossina e successiva attivazione di citochine infiammatorie e
mediatori 2 3 . La sovrapproduzione di mediatori secreti localmente e circolanti, come le citochine proinfiammatorie, NO e ROS,
che portano ad ipossia tissutale e morte cellulare, contribuisce alla lesione epatica e sua disfunzione 4 5 .
Il primo passo nella rianimazione cardiovascolare dello shock settico è quello di recuperare e mantenere un adeguato volume
intravascolare con un “challenge” di fluidi. A paragone dei fluidi cristalloidi, l’albumina sembra essere più efficace nell’espansione
del volume intravascolare e sembra migliorare la funzione d’organo nei pazienti critici, specialmente in quelli ipoalbuminemici
6 7 . La somministrazione di albumina iperoncotica al 20% con furosemide migliora l’ossigenazione e la stabilità cardiovascolare
nei pazienti con Acute Lung Injury indotta da sepsi 8 . L’albumina iperoncotica preserva un più alto cardiac output, un
più alto oxygen delivery e più bassi livelli ematici di lattato di quanto non facciano i cristalloidi 9 .
L’albumina è uno scavenger delle specie reattive dell’ossigeno, lega gli ioni metallici di transizione e presenta una ampia varietà
di effetti biologici rimpiazzando le concentrazioni tioliche plasmatiche 10 .
Il beneficio clinico dell’albumina può essere attribuito alle sue proprietà antinfiammatorie oltre che all’espansione del volume
intravascolare e l’effetto antiossidante. Il dialisato di albumina usato in un circuito di emodiafiltrazione in vitro è più efficace
nella clearance del TNF ed IL-6 del dialisato con fisiologica 11 . La rianimazione con albumina iperoncotica attenua moltissimo
la lesione polmonare in un modello di topo con shock emorragico, diminuendo la chemoattrazione dei neutrofili indotta dalle
citochine e la traslocazione sull’NF-kB 12 .
Ci sono ancora molte controversie riguardo all’impatto della albumina iperoncotica sull’outcome 13-15 . In uno studio clinico di
grandi proporzioni, i pazienti con sepsi grave avevano rischi più elevati di morte e lesione renale quando sottoposti a rianimazione
con albumina iperoncotica 14 . Tuttavia altri studi hanno dimostrato che una rianimazione small-volume con albumina
iperoncotica può migliorare la risposta al trattamento ed accorciare la degenza nei pazienti con malattia epatica 15 .
Questo studio effettuato da un gruppo dell’Università di Taipei (Taiwan), assieme alla prevenzione della lesione epatica ed al
miglioramento dell’ipoperfusione con la rianimazione con albumina a piccolo volume, suggerisce che l’albumina iperoncotica al
25% data 3 ore dopo la CLP (cecal ligation and punture) protegge il fegato contro la lesione causata dalle citochine proinfiammatorie,
NO ed O 2 che sono di solito il risultato della proattivazione dei neutrofili. Il risultato intrigante di questo studio potrebbe
fornire una messe di informazione riguardante l’applicazione clinica della terapia con albumina iperoncotica nei pazienti criticamente
ammalati e spiegare rilevanti meccanismi biologici in questa popolazione. Alcuni co-autori di questo studio, nel 2008
avevano pubblicato su Critical Care Medicine 16 uno studio sperimentale sui ratti sugli effetti terapeutici della fisiologica ipertonica
nello shock settico provocato dalla peritonite con MODS. Questi stessi autori concludevano che la fisiologica ipertonica preveniva
l’insufficienza circolatoria, alleviava la MODS e diminuiva la percentuale di mortalità negli animali sottoposti a CLP. Secondo gli
autori gli effetti benefici della fisiologica ipertonica potevano essere attribuiti alla ridotta concentrazione plasmatica dell’NO e
dell’IL-1 beta così come al ridotto livello di O 2 -*, alla diminuita infiltrazione polmonare dei neutrofili ed alla diminuita necrosi
epatica. Sorge spontanea la domanda: albumina ipertonica o salina ipertonica? A quale costo?
Letteratura da consultare
1 Russell JA. Management of sepsis. N Engl J Med 2006;355:1699-713.
2 Dhainaut JF, Marin N, Mignon A, et al. Hepatic response to sepsis: interaction between coagulation and inflammatory
processes. Crit Care Med 2001;29:S42-7.
3 Wang XD, Soltesz V, Andersson R, et al. Bacterial translocation in acute liver failure induced by 90% hepatectomy in the
rat. Br J Surg 1993;80:66-71.
4 Hewett JA, Roth RA. Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 1993;45:382-411.
5 Szabo G, Romics L Jr, Frendl G. Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis 2002;6:1045-66.
6 Ernest D, Belzberg AS, Dodek PM. Distribution of normal saline and 5% albumin infusions in septic patients. Crit Care Med
1999;27:46-50.
7 Dubois MJ, Orellana-Jimenez C, Melot C, et al. Albumin administration improves organ function in critically ill hypoalbuminemic
patients: a prospective, randomized, controlled, pilot study. Crit Care Med 2006;34:2536-40.
8 Martin GS, Moss M, Wheeler AP, et al. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic
patients with acute lung injury. Crit Care Med 2005;33:1681-7.
9 Su F, Wang Z, Cai Y, et al. Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or
ringer’s lactate-does it really make a difference? Shock 2007;27:520-6.
10 Quinlan GJ, Margarson MP, Mumby S, et al. Administration of albumin to patients with sepsis syndrome: a possible beneficial
role in plasma thiol repletion. Clin Sci (Lond) 1998;95:459-65.
11 Awad SS, Sawada S, Soldes OS, et al. Can the clearance of tumor necrosis factor alpha and interleukin 6 be enhanced
using an albumin dialysate hemodiafiltration system? ASAIO J 1999;45:47-9.
12 Powers KA, Kapus A, Khadaroo RG, et al. 25% albumin prevents lung injury following shock resuscitation. Crit Care Med
2003;31:2355-63.
13 Kuper M, Gunning MP, Halder S, et al. The short-term effect of hyperoncotic albumin, given alone or with furosemide, on
oxygenation in sepsis-induced acute respiratory distress syndrome. Anaesthesia 2007;62:259-63.
14 Schortgen F, Girou E, Deye N, et al. The risk associated with hyperoncotic colloids in patients with shock. Intensive Care
Med 2008;34:2157-68.
15 Jacob M, Chappell D, Conzen P, et al. Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized
clinical trials. Crit Care 2008;12:R34.
16 Shih CC, Chen SJ, Chen A, et al. Therapeutic effects of hypertonic saline on peritonitis-induced septic shock with multiple
organ dysfunction syndrome in rats. Crit Care Med 2008;36:1864-72.
8

prevalence of parental thrombophilic defects
after fetal death and relation to cause
F.J. Korteweg
J.J. Erwich
N. Folkeringa
A. Timmer
N.J. Veeger
J.M. Ravisé
J.P. Holm
J. van der Meer
Department of Obstetrics,
Division of Haemostasis,
Trial Coordination Center,
University Medical Center
Groningen, University
of Groningen,
The Netherlands
ObjECTIvE: To estimate whether parental thrombophilic defects after fetal
death, either acquired or inherited, were more prevalent than in the
normal population and to estimate associations between these thrombophilic
defects and different fetal death causes.
METhOdS: In a multicenter, prospective cohort study of 750 fetal deaths,
we tested couples for antithrombin, protein C, total and free protein S,
and von Willebrand factor (vWF) plasma levels. Mothers’ values were compared
with reference values in gestational age-matched healthy pregnant
women, and fathers were compared with healthy men. Prevalence of factor
V Leiden, prothrombin G20210A mutation, and lupus anticoagulant
were compared with the normal population. A panel classified death
cause.
RESULTS: More women with fetal death had decreased antithrombin
(16.8%, p < .001) and protein C (4.0%, p = .03) and increased vWF (15.5%,
p < .001) plasma levels than healthy pregnant women (2.5%). However,
compared with normal ranges in the nonpregnant population, we only
observed more women with increased vWF (12.4%, p < .001). More fathers
had decreased free protein S (6.3%, p < .001) and elevated vWF (12.1%,
p < .001) than healthy men (2.5%). Prevalence of inherited thrombophilias
was not higher in couples with fetal death than in the population. Neither
inherited nor acquired maternal or paternal thrombophilic defects
were associated with the main cause of death. Of placental causes, abruption
and infarction were associated with acquired maternal defects.
COnCLUSIOn: Except for vWF and paternal free protein S, acquired and
inherited thrombophilic defects were not more prevalent after fetal
death. Routine thrombophilia testing after fetal death is not advised.
Obstet Gynecol 2010;116(2 Pt 1):355-64
9

Circa una su 200 gravidanze finisce in aborto come risultato di cause differenti. I difetti trombofilici ereditati dalla madre sono
riconosciuti, con pareri discordanti, come fattori di rischio di complicazioni durante la gravidanza come la pre-eclampsia, la
rottura di placenta, restrizioni nella crescita ed aborto; anche i fattori trombofilici paterni possono essere trasferiti al feto e
alla placenta 1-4 . Molti studi si sono orientati verso l’associazione fra deficienze ereditate trombofiliche e perdita fetale tardiva
in famiglie con deficienze ereditate, anche se studi di coorte e di caso controllo hanno osservato sistematicamente donne
con perdita del feto che erano state testate per trombofilia dopo il parto. In alcune revisioni critiche, un più alto rischio di
perdita fetale è stato segnalato per deficienza di antitrombina e proteina S, fattore V Leiden, mutazione protrombina 20210A
e anticorpi anticardiolipina 5-7 . La patofisiologia della perdita fetale tardiva associata con trombofilia ereditaria si presume si
possa spiegare con una trombosi placentare o nella circolazione materna o nella circolazione fetale della placenta che porta
ad infarto placentare ed insufficienza placentare 8 . È stato difficile provare questa ipotesi a causa dei piccoli numeri coinvolti
negli studi precedenti, ed anche perché la insufficienza placentare era spesso non ben definita e non ben correlata alla causa
di morte 9-12 . La gravidanza è di per sé uno stato ipercoagulabile che risulta da difetti trombofilici acquisiti che espongono la
donna ad un più alto rischio di trombosi 13 . In combinazione con i preesistenti difetti trombofilici ereditati, esso può aumentare
il rischio di morte fetale. Si conosce molto poco circa il contributo dei difetti trombofilici acquisiti allo stato di ipercoagulazione
e alla morte fetale, perché le donne nei precedenti studi erano testate per la trombofilia solo parecchie settimane dopo il
parto. L’obiettivo di questo studio multidisciplinare olandese, è quello di stimare se in una coorte di donne con morte fetale
intrauterina i difetti trombofilici – acquisiti durante la gravidanza o ereditati – e i difetti ereditati nei padri erano più prevalenti
rispetto alla normale popolazione. Inoltre gli autori dello studio hanno cercato di stimare quale fosse l’associazione fra questi
difetti trombofilici e le varie cause di morte fetale all’interno della coorte.
In questo studio più donne che avevano presentato morte fetale avevano un’antitrombina ed una proteina C diminuite ed un
livello plasmatico di vWF aumentato rispetto alle donne gravide sane. Tuttavia, facendo il paragone con gli intervalli normali
nella popolazione non gravida, è stato osservato solamente un maggior numero di donne con un aumentato vWF. Più padri
avevano una proteina S libera diminuita ed un elevato vWF rispetto agli uomini sani. La prevalenza delle trombofilie ereditarie
non era più alta nelle coppie con morte fetale che nella normale popolazione. Né i difetti trombofilici materni o paterni ereditati
o acquisiti erano associati con la principale causa di morte. Delle cause placentari la rottura e l’infarto erano associate
con difetti materni acquisiti. La necessità di effettuare test di routine dei difetti trombofilici dopo morte fetale non è sostenuta
dai risultati di questo studio, eccetto che nelle donne con storia familiare di trombofilia ereditaria o una storia personale di
tromboembolismo venoso e morte fetale intrauterina, nelle quali il fare test orientati potrebbe aiutare a prevenire un ulteriore
tromboembolismo venoso materno. Può anche essere preso in considerazione effettuare test orientati a donne con una morte
fetale causata da rottura o infarto placentare. Tuttavia, lo screening della trombofilia dovrebbe essere effettuato solo nei casi
in cui possa essere offerto poi un appropriato trattamento ed una appropriata assistenza. Fino a quando non ci saranno trial
controllati randomizzati che dimostrino il reale beneficio della terapia anticoagulante in casi con ben riconosciuti fattori trombofilici
in relazione a perdita fetale tardiva, dobbiamo essere prudenti nell’implementazione di un intervento potenzialmente
dannoso per la donna gravida. Nello studio, se si fa eccezione per il vWF e la proteina libera S paterna, i difetti acquisiti ed
ereditati non erano più prevalenti dopo morte fetale. Il fare test di routine della trombofilia dopo morte fetale non è dunque
consigliato. Testare livelli anormali di antitrombina, attività della proteina C, antigene totale della proteina S o vWF potrebbe
solo far identificare dei predittori per un sub-gruppo a rischio di morte fetale causata da rottura o infarto placentari.
Letteratura da consultare
1 Silver RM. Fetal death. Ostet Gynecol 2007;109:153-67.
2 Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine
growth restriction. N Engl J Med 2002;347;19-25.
3 Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of
pregnancy. N Engl J Med 1999;340:9-13.
4 Khong TY, Hague WM. Biparental contribution to fetal thrombophilia in discordant twin intrauterine growth restriction.
Am J Obstet Gynecol 2001;185:244-5.
5 Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost 2007;5(Suppl 1):276-
82.
6 Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:1-8.
7 Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132:171-
96.
8 Redline RW. Thrombophilia and placental pathology. Clin Obstet Gynecol 2006;49:885-94.
9 Alonso A, Soto I, Urgellés MF, et al. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J
Obstet Gynecol 2002;187:1337-42.
10 Arias F, Romero R, Joist H, et al. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and
thrombotic lesions in the placenta. J Matern Fetal Med 1998;7:277-86.
11 Morssink LP, Santema JG, Willemse F. Thrombophilia is not associated with an increase in placental abnormalities in
women with intra-uterine fetal death. Acta Obstet Gynecol Scand 2004;83:348-50.
12 Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum
Reprod 2000;15:1830-3.
13 Stirling Y, Woolf L, North WR, et al. Haemostasis in normal pregnancy. Thromb Haemost 1984;52:176-82.
10

ecipient tissue factor expression is associated
with consumptive coagulopathy in pig-to-primate
kidney xenotransplantation
C.C. Lin
M. Ezzelarab
R. Shapiro
R. Ekser
C. Long
H. Hara
G. Echeverri
C. Torres
H. Watanabe
D. Ayares
A. Dorling
D.K. Cooper
E. Thomas
Starzl Transplantation
Institute, University
of Pittsburgh, PA, USA
Consumptive coagulopathy (CC) remains a challenge in pig-to-primate
organ xenotransplantation (Tx). This study investigated the role of tissue
factor (TF) expression on circulating platelets and peripheral blood mononuclear
cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs
that were either wild-type (n = 2), alpha1,3-galactosyltransferase geneknockout
(GT-KO; n = 1) or GT-KO and transgenic for the complementregulatory
protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the
graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed
TF within 4 h of Tx. In the remaining baboons, TF was detected on
platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation
developed with formation of thrombin. In the six baboons with CC, TF
was not detected on baboon PBMCs until CC was beginning to develop.
Graft histopathology showed fibrin deposition and platelet aggregation
(n = 6), but with only minor or no features indicating a humoral immune
response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation
of platelets to express TF was associated with the initiation of
CC, whereas TF expression on PBMCs was concomitant with the onset of
CC, often in the relative absence of features of acute humoral xenograft
rejection. Prevention of recipient platelet activation may be crucial for
successful pig-to-primate kidney Tx.
Am j Transplant 2010;10(7):1556-68
11

12
thrombotic microangiopathy after kidney
transplantation
M. Noris
G. Remuzzi
Clinical Research Center
for Rare Diseases
“Aldo e Cele Daccò”,
Mario Negri Institute
for Pharmacological Research,
Ranica, Bergamo, Italy
Thrombotic microangiopathy (TMA) is a severe complication of kidney
transplantation that often causes graft failure. TMA may occur de novo,
often triggered by immunosuppressive drugs and acute antibody-mediated
rejection, or recur in patients with previous history of hemolytic uremic
syndrome (HUS). Recurrent TMA is very rare in patients who had developed
end-stage renal failure following HUS caused by Shiga-toxin producing
Escherichia coli, whereas disease recurrence is common in patients
with atypical HUS (aHUS). The underlying genetic defect greatly impacts
the risk of posttransplant recurrence in aHUS. Indeed recurrence is almost
the rule in patients with mutations in genes encoding factor H or factor
I, whereas patients with a mutation in membrane-cofactor-protein gene
have a good transplant outcome. Prophylactic and therapeutic options
for posttransplant TMA, including plasma therapy, combined kidney and
liver transplantation and targeted complement inhibitors are discussed in
this review.
Am j Transplant 2010;10(7):1517-23

Cost-effectiveness of strategies for diagnosing
pulmonary embolism among emergency department
patients presenting with undifferentiated symptoms
R.S. Duriseti
M.L. Brandeau
Department of Veterans
Affairs Palo Alto Health Care
System, Palo Alto, CA,
and the Division
of Emergency Medicine,
Department of Surgery,
Stanford University,
Stanford, CA
STUdy ObjECTIvE: Symptoms associated with pulmonary embolism can
be nonspecific and similar to many competing diagnoses, leading to excessive
costly testing and treatment, as well as missed diagnoses. Objective
studies are essential for diagnosis. This study evaluates the cost-effectiveness
of different diagnostic strategies in an emergency department
(ED) for patients presenting with undifferentiated symptoms suggestive
of pulmonary embolism.
METhOdS: Using a probabilistic decision model, we evaluated the incremental
costs and effectiveness (quality-adjusted life-years gained) of 60
testing strategies for 5 patient pretest categories (distinguished by Wells
score [high, moderate, or low] and whether deep venous thrombosis is
clinically suspected). We performed deterministic and probabilistic sensitivity
analyses.
RESULTS: In the base case, for all patient pretest categories, the most
cost-effective diagnostic strategy is to use an initial enzyme-linked immunosorbent
assay D-dimer test, followed by compression ultrasonography
of the lower extremities if the D-dimer is above a specified cutoff. The
level of the preferred cutoff varies with the Wells pretest category and
whether a deep venous thrombosis is clinically suspected. D-dimer cutoffs
higher than the current recommended cutoff were often preferred for
patients with even moderate and high Wells categories. Compression ultrasonography
accuracy had to decrease below commonly cited levels in
the literature before it was not part of a preferred strategy.
COnCLUSIOn: When pulmonary embolism is suspected in the ED, use of
an enzyme-linked immunosorbent assay D-dimer assay, often at cutoffs
higher than those currently in use (for patients in whom deep venous
thrombosis is not clinically suspected), followed by compression ultrasonography
as appropriate, can reduce costs and improve outcomes.
Ann Emerg Med 2010;56(4):321-32
13

14
mitochondrial dysfunction and resuscitation in sepsis
A.J. Ruggieri
R.J. Levy
C.S. Deutschman
Department
of Anesthesiology
and Critical Care,
University of Pennsylvania
School of Medicine,
Philadelphia,
PA, USA
Sepsis is among the most common causes of death in patients in intensive
care units in North America and Europe. In the United States, it accounts
for upwards of 250,000 deaths each year. Investigations into the
pathobiology of sepsis have most recently focused on common cellular
and subcellular processes. One possibility would be a defect in the production
of energy, which translates to an abnormality in the production
of adenosine triphosphate and therefore in the function of mitochondria.
This article presents a clear role for mitochondrial dysfunction in
the pathogenesis and pathophysiology of sepsis. What is less clear is the
teleology underlying this response. Prolonged mitochondrial dysfunction
and impaired biogenesis clearly are detrimental. However, early inhibition
of mitochondrial function may be adaptive.
Crit Care Clin 2010;26(3):567-75, x-xi

Quality of life after intensive care: a systematic review
of the literature
S.G. Oeyen
D.M. Vandijck
D.D. Benoit
L. Annemans
J.M. Decruyenaere
Department of Intensive Care
Medicine (SGO, DDB, JMD),
Ghent University Hospital,
Ghent, Belgium; Faculty
of Medicine and Health
Sciences (DMV, LA), Ghent
University, Ghent, Belgium
ObjECTIvES: To evaluate quality of life at least 12 months after discharge
from the intensive care unit of adult critically ill patients, to evaluate the
methodology used to assess long-term quality of life, and to give an overview
of factors influencing quality of life.
dATA SOURCES: EMBASE-PubMed, MEDLINE (OVID), SCI/Web of Science,
the Cochrane Library, Google Scholar, and personal files.
dATA ExTRACTIOn: Data extraction was performed independently and
cross-checked by two reviewers using a predefined data extraction form.
Eligible studies were published between 1999 and 2009 and assessed
quality of life ≥ 12 months after intensive care unit discharge by means of
the Medical Outcomes Study 36-Item Short Form Health Survey, the RAND
36-Item Health Survey, EuroQol-5D, and/or the Nottingham Health Profile
in adult intensive care unit patients.
dATA SynThESIS: Fifty-three articles (10 multicenters) were included,
with the majority of studies performed in Europe (68%). The Medical
Outcomes Study 36-Item Short Form Health Survey was used in 55%, and
the EuroQol-5D, the Nottingham Health Profile, the RAND 36-Item Health
Survey, or a combination was used in 21%, 9%, 8%, or 8%, respectively.
A response rate of ≥ 80% was attained in 26 studies (49%). Critically ill
patients had a lower quality of life than an age- and gender-matched
population, but quality of life tended to improve over years. The worst
reductions in quality of life were seen in cases of severe acute respiratory
distress syndrome, prolonged mechanical ventilation, severe trauma,
and severe sepsis. Study quality criteria, defined as a baseline quality of
life assessment, the absence of major exclusion criteria, a description of
nonresponders, and a comparison with a reference population were met
in only four studies (8%). Results concerning the influence of severity of
illness, comorbidity, preadmission quality of life, age, gender, or acquired
complications were conflicting.
COnCLUSIOnS: Quality of life differed on diagnostic category but, overall,
critically ill patients had a lower quality of life than an age- and gender-matched
population. A minority of studies met the predefined methodologic
quality criteria. Results concerning the influence of the patients’
characteristics and illnesses on long-term quality of life were conflicting.
Crit Care Med 2010;38(12):2386-400
15

16
stem cells in sepsis and acute lung injury
S.K. Cribbs
M.A. Matthay
G.S. Martin
Division of Pulmonary,
Allergy and Critical Care
Medicine (SKC, GSM),
Department
of Medicine, Emory
University, Atlanta, GA;
Cardiovascular Research
Institute (MAM), Departments
of Medicine and Anesthesia,
University of California,
San Francisco, CA
ObjECTIvE: Sepsis and acute lung injury continue to be major causes of
morbidity and mortality worldwide despite advances in our understanding
of pathophysiology and the discovery of new management strategies.
Recent investigations show that stem cells may be beneficial as prognostic
biomarkers and novel therapeutic strategies in these syndromes. This article
reviews the potential use of endogenous adult tissue-derived stem
cells in sepsis and acute lung injury as prognostic markers and also as exogenous
cell-based therapy.
dATA SOURCES: A directed systematic search of the medical literature using
PubMed and OVID, with particular emphasis on the time period after
2002, was done to evaluate topics related to 1) the epidemiology and
pathophysiology of sepsis and acute lung injury; and 2) the definition,
characterization, and potential use of stem cells in these diseases.
dATA SynThESIS And fIndInGS: When available, preferential consideration
was given to prospective nonrandomized clinical and preclinical studies.
COnCLUSIOnS: Stem cells have shown significant promise in the field
of critical care both for 1) prognostic value and 2) treatment strategies.
Although several recent studies have identified the potential benefit of
stem cells in sepsis and acute lung injury, further investigations are needed
to more completely understand stem cells and their potential prognostic
and therapeutic value.
Crit Care Med 2010;38(12):2379-85

Cirrhotic patients in the medical intensive care unit:
early prognosis and long-term survival
V. Das
P.Y. Boelle
A. Galbois
B. Guidet
E. Maury
N. Carbonell
R. Moreau
G. Offenstadt
Assistance Publique
(VD, AG, BG, EM, GO),
Hôpitaux de Paris,
Hôpital Saint-Antoine,
Service de Réanimation
Médicale, Paris, France;
INSERM (PYB, BG, EM,
GO), Unité de Recherche
en Epidémiologie Systèmes
d’Information et Modélisation
(U707), Paris, France;
Université Pierre et Marie
Curie (PYB, BG, EM, GO),
Paris, France; Assistance
Publique (NC), Hôpitaux
de Paris, Hôpital Saint-
Antoine, Service
d’Hépatologie, Paris,
France; Assistance Publique
(RM), Hôpitaux de Paris,
Hôpital Beaujon, Service
d’Hépatologie, Clichy, France;
INSERM (RM), U773, Centre
de Recherche Bichat-Beaujon
CRB3, Paris, France
ObjECTIvES: To reassess the prognosis of patients with cirrhosis admitted
to the intensive care unit.
dESIGn: A retrospective study in a medical intensive care unit in a teaching
hospital in France.
PATIEnTS: All patients with cirrhosis without previous liver transplantation
admitted in the period from 2005 to 2008.
InTERvEnTIOnS: None.
MAIn RESULTS: One hundred thirty-eight patients were studied. Survival
rates in the intensive care unit, in hospital, and at 6 months were
59% (95% confidence interval, 50-67%), 46% (95% confidence interval,
38-54%), and 38% (95% confidence interval, 30-47%), respectively. In-hospital
survival rates for patients requiring vasopressors, mechanical ventilation,
or renal replacement therapy were 20%, 33%, and 31%, respectively.
On day 1, independent risk factors for in-hospital mortality were age,
albuminemia, international normalized ratio, and the Sequential Organ
Failure Assessment score computed after discarding points for hematologic
failure (modified Sequential Organ Failure Assessment score). Liver
disease severity, assessed using a clinical classification, did not correlate
with in-hospital mortality. In patients still alive after 3 days, the only prognostic
factor was the modified Sequential Organ Failure Assessment score
computed after 3 days. To predict in-hospital mortality, the modified Sequential
Organ Failure Assessment score on day 1 had a greater area under
the receiver operating characteristic curve (0.84) than the Simplified
Acute Physiology Score II (0.78), the Child-Pugh score (0.76), the model
for end-stage liver disease score (0.77), or the model for end-stage liver
disease-natremia score (0.75). The in-hospital mortality rate with three or
four nonhematologic organ failures on day 1 was not > 70%, whereas it
was 89% with three nonhematologic organ failures after 3 days spent in
the intensive care unit.
COnCLUSIOn: In-hospital survival rate of intensive care unit-admitted
cirrhotic patients seemed acceptable, even in patients requiring life-sustaining
treatments and/or with multiple organ failure on admission. The
most important risk factor for in-hospital mortality was the severity of
nonhematologic organ failure, as best assessed after 3 days. A trial of
unrestricted intensive care for a few days could be proposed for select
critically ill cirrhotic patients.
Crit Care Med 2010;38(11):2108-16
17

18
volume of emergency department admissions for sepsis
is related to inpatient mortality: results of a nationwide
cross-sectional analysis
E.S. Powell
R.K. Khare
D.M. Courtney
J. Feinglass
Department of Emergency
Medicine (ESP, RKK, MC),
Feinberg School of Medicine,
Northwestern University,
Chicago, IL; Institute
for Healthcare Studies
and Division of General
Internal Medicine (ESP, RKK,
JF), Northwestern University,
Feinberg School of Medicine,
Chicago, IL
ObjECTIvES: Emergency department resuscitation plays a significant role
in sepsis care, and it is unknown if patient outcomes vary by institution
based on the level of sepsis experience of the emergency department.
This study examines whether there is an association between the annual
volume of patients admitted via the emergency department with sepsis
and inpatient mortality.
dESIGn: Cross-sectional analysis of the 2007 Nationwide Inpatient Sample.
Setting and patients: We included 87,166 adult emergency department
sepsis admissions from 551 hospitals.
MEASUREMEnTS: Hospitals were categorized into quartiles by 2007
emergency department sepsis volume. Univariate associations of patient
characteristics, hospital characteristics, and inpatient mortality with sepsis
volume level were evaluated by chi-square test. A population-averaged
logistic regression model of inpatient mortality was used to estimate the
effects of age, gender, comorbid conditions, payer status, median zip
code income, hospital bed size, teaching status, and emergency department
sepsis volume.
MAIn RESULTS: Overall inpatient sepsis mortality was 18.0% and early
mortality (2 days after admission) was 6.9%. The risk-adjusted odds ratios
of mortality were 0.73 (95% confidence interval, 0.64-0.83; p < .001)
in quartile 4 (highest volume), 0.83 in quartile 3 (95% confidence interval,
0.74-0.93; p = .001), and 0.90 in quartile 2 (95% confidence interval,
0.82-0.99; p < .05) when compared to quartile 1 (lowest volume). Adjusted
results were similar for early mortality: 0.69 (95% confidence interval,
0.61-0.76; p < .001) in quartile 4, 0.83 in quartile 3 (95% confidence interval,
0.74-0.93; p < .05), and 0.85 in quartile 2 (95% confidence interval,
0.77-0.94; p < .05) when compared to quartile 1.
COnCLUSIOnS: After adjustment for comorbidity and hospital-level factors,
there was a significant relationship between emergency department
sepsis case volume and overall and early inpatient mortality among patients
admitted through the emergency department with sepsis. Patients
admitted to hospitals in the highest-volume quartile had 27% lower odds
of inpatient mortality in this large heterogeneous sample.
Crit Care Med 2010;38(11):2161-8

Fluids after cardiac surgery: a pilot study of the use
of colloids versus crystalloids
S. Magder
B.J. Potter
B. Deverenne
S. Doucette
D. Fergusson
for the Canadian Critical Care
Trials Group
McGill University Health
Center (SM, BJP, BD),
Montreal Quebec, Canada;
Ottawa Hospital Research
Institute (SD, DF), Ottawa,
Ontario, Canada
ObjECTIvES: To determine whether a starch solution for volume resuscitation
in a flow-based protocol improves circulatory status better than a
crystalloid solution, as defined by the need for catecholamines in patients
the morning after cardiac surgery, and whether this can be performed
without increased morbidity.
dESIGn: Concealed, randomized, double-blind, controlled trial.
PARTICIPAnTS: Two hundred sixty-two patients who underwent cardiac
surgery at a tertiary care hospital.
InTERvEnTIOnS: Based on predefined criteria indicating a need for fluids,
and a nurse-delivered algorithm that used central venous pressure and
cardiac index obtained from a pulmonary artery catheter, patients were
allocated to receive 250-ml boluses of 0.9% saline or a 250-molecular
weight 10% solution of pentastarch.
RESULTS: Two hundred thirty-seven patients received volume boluses: 119
hydroxyethyl starches and 118 saline. Between 8:00 am and 9:00 am the
morning after surgery, 13 (10.9%) of hydroxyethyl starch patients and
34 (28.8%) saline patients were using catecholamines (p = .001). Hydroxyethyl
starch patients had less pneumonia and mediastinal infections
(p = .03) and less cardiac pacing (p = .03). There were two deaths in each
group. There was no difference in the daily creatinine, development of
RIFLE risk criteria during hospital stay, or new dialysis. The numbers and
volumes of packed red blood cells were similar in the two groups, but
more hydroxyethyl starch patients received plasma transfusions (p = .05).
COnCLUSIOnS: Use of a colloid solution for volume resuscitation in a
nurse-delivered flow-based algorithm, which included a pulmonary artery
catheter, significantly improved hemodynamic status, an important factor
for readiness for discharge from the intensive care unit.
Crit Care Med 2010;38(11):2117-24
19

20
microcirculation in cardiogenic shock:
from scientific bystander to therapy target
C. Jung
A. Lauten
M. Ferrari
First Department of Internal
Medicine, (Cardiology,
Angiology, Pneumology,
Intensive Care Medicine),
Friedrich Schiller University,
Jena, Germany
Despite diagnostic and therapeutic improvements, mortality rates in
patients with cardiogenic shock remain relatively high. Several studies
showed that cardiogenic shock is associated with alterations in the microvascular
circulation. These alterations may be reversed by extracorporeal
support devices. A study by Munsterman and colleagues adds to the body
of evidence showing that in patients deemed ready for discontinuing
intra-aortic balloon pump (IABP) support, microcirculatory flow in small
vessels increases after ceasing IABP therapy. This study not only highlights
the need for optimal timing of weaning from IABP support but also supports
recent findings that global hemodynamics do not necessarily result
in changes of microvascular perfusion. All modalities of modern treatment
in cardiogenic shock need to be evaluated for their effect on the microcirculation.
Microcirculatory evaluations should be part of randomized
controlled trial protocols. More effort is needed to improve outcomes and
understand the microcirculation as a therapy target and not as a silent
bystander.
Crit Care 2010;14(5):193

Bench-to-bedside review: targeting antioxidants
to mitochondria in sepsis
H.F. Galley
Academic Unit of Anaesthesia
& Intensive Care, School
of Medicine & Dentistry,
University of Aberdeen,
Aberdeen, UK
Development of organ dysfunction associated with sepsis is now accepted
to be due at least in part to oxidative damage to mitochondria. Under
normal circumstances, complex interacting antioxidant defense systems
control oxidative stress within mitochondria. However, no studies have
yet provided conclusive evidence of the beneficial effect of antioxidant
supplementation in patients with sepsis. This may be because the antioxidants
are not accumulating in the mitochondria, where they are most
needed. Antioxidants can be targeted selectively to mitochondria by several
means. This review describes the in vitro studies and animal models of
several diseases involving oxidative stress, including sepsis, in which antioxidants
targeted at mitochondria have shown promise, and the future
implications for such approaches in patients.
Crit Care 2010;14(4):230
21

22
A systematic review of randomized controlled trials
exploring the effect of immunomodulative interventions
on infection, organ failure, and mortality in trauma
N.E. Spruijt
T. Visser
L.P. Leenen
Department of Surgery,
University Medical Centre
Utrecht, The Netherlands
InTROdUCTIOn: Following trauma, patients may suffer an overwhelming
pro-inflammatory response and immune paralysis resulting in infection
and multiple organ failure (MOF). Various potentially immunomodulative
interventions have been tested. The objective of this study is to systematically
review the randomized controlled trials (RCTs) that investigate the
effect of potentially immunomodulative interventions in comparison to a
placebo or standard therapy on infection, MOF, and mortality in trauma
patients.
METhOdS: A computerized search of MEDLINE, the Cochrane CENTRAL
Register of Controlled Trials, and EMBASE yielded 502 studies, of which
18 unique RCTs were deemed relevant for this study. The methodological
quality of these RCTs was assessed using a critical appraisal checklist for
therapy articles from the Centre for Evidence Based Medicine. The effects
of the test interventions on infection, MOF, and mortality rates and inflammatory
parameters relative to the controls were recorded.
RESULTS: In most studies, the inflammatory parameters differed significantly
between the test and control groups. However, significant changes
in infection, MOF, and mortality rates were only measured in studies testing
immunoglobulin, IFN-gamma, and glucan.
COnCLUSIOnS: Based on level 1b and 2b studies, administration of immunoglobulin,
IFN-gamma, or glucan have shown the most promising results
to improve the outcome of trauma patients.
Crit Care 2010;14(4):R150

Cerebral microcirculation is impaired during sepsis:
an experimental study
F.S. Taccone
F. Su
C. Pierrakos
X. He
S. James
O. Dewitte
J.L. Vincent
D. De Backer
Department of Intensive Care,
Erasme Hospital, Université
Libre de Bruxelles, Belgium
InTROdUCTIOn: Pathophysiology of brain dysfunction due to sepsis remains
poorly understood. Cerebral microcirculatory alterations may play
a role; however, experimental data are scarce. This study sought to investigate
whether the cerebral microcirculation is altered in a clinically
relevant animal model of septic shock.
METhOdS: Fifteen anesthetized, invasively monitored, and mechanically
ventilated female sheep were allocated to a sham procedure (n = 5) or
sepsis (n = 10), in which peritonitis was induced by intra-abdominal injection
of autologous faeces. Animals were observed until spontaneous
death or for a maximum of 20 hours. In addition to global hemodynamic
assessment, the microcirculation of the cerebral cortex was evaluated using
Sidestream Dark-Field (SDF) videomicroscopy at baseline, 6 hours, 12
hours and at shock onset. At least five images of 20 seconds each from
separate areas were recorded at each time point and stored under a random
number to be analyzed, using a semi-quantitative method, by an
investigator blinded to time and condition.
RESULTS: All septic animals developed a hyperdynamic state associated
with organ dysfunction and, ultimately, septic shock. In the septic animals,
there was a progressive decrease in cerebral total perfused vessel density
(from 5.9 ± 0.9 at baseline to 4.8 ± 0.7 n/mm at shock onset, p = 0.009),
functional capillary density (from 2.8 ± 0.4 to 2.1 ± 0.7 n/mm, p = 0.049),
the proportion of small perfused vessels (from 95 ± 3 to 85 ± 8%,
p = 0.02), and the total number of perfused capillaries (from 22.7 ± 2.7 to
17.5 ± 5.2 n/mm, p = 0.04). There were no significant changes in microcirculatory
flow index over time. In sham animals, the cerebral microcirculation
was unaltered during the study period.
COnCLUSIOnS: In this model of peritonitis, the cerebral microcirculation
was impaired during sepsis, with a significant reduction in perfused small
vessels at the onset of septic shock. These alterations may play a role in
the pathogenesis of septic encephalopathy.
Crit Care 2010;14(4):R140
23

24
emerging antithrombotic agents:
what does the intensivist need to know?
Z. Iqbal
M. Cohen
Division of Cardiology,
Newark Beth Israel Medical
Center, Newark, NJ, USA
PURPOSE Of REvIEw: As thrombus consists of both fibrin and platelets,
antithrombotic strategies involve anticoagulants and antiplatelets, alone
or in combination.
RECEnT fIndInGS: Traditionally, unfractionated heparin has been the
most commonly used parenteral anticoagulant, but owing to its variable
dose response and narrow therapeutic indices, it is being replaced by low
molecular weight heparin, fondaparinux, and bivalrudin. New oral factor
Xa inhibitors like apixaban and rivaroxaban are still on the horizon,
awaiting definite evaluation in ACS, DVT and atrial fibrillation. On the
contrary, a dramatic advance in the arena of oral anticoagulants has occurred
with the introduction of dabigatran, an oral direct thrombin inhibitor.
This agent showed better outcomes than oral vitamin K antagonists
in patients with atrial fibrillation. The antiplatelet field has also expanded
by the addition of two new agents, prasugrel and ticagrelor. These agents
have been tested against clopidogrel, in patients with ACS, with superior
efficacy outcomes for both agents and higher bleeding events with
prasugrel.
SUMMARy: Bleeding risk associated with antithrombotics is not only a
function of their inherent biochemical properties but also a reflection of
how healthcare professionals choose and dose these agents in individual
patients.
Curr Opin Crit Care 2010;16(5):419-25

microvascular dysfunction in the surgical patient
N.A. Vellinga
C. Ince
E.C. Boerma
Department of Translational
Physiology, Academic Medical
Center, Amsterdam,
The Netherlands
PURPOSE Of REvIEw: This review aims to describe recent research on
perioperative microvascular alterations, with an emphasis on direct visualization
of the human microcirculation.
RECEnT fIndInGS: Despite systemic haemodynamic optimization, perioperative
complications are still occurring. In surgery, recent studies on
both direct visualization of the microcirculation and indirect quantification
of organ perfusion revealed that both the surgical procedure itself
and perioperative interventions like anaesthesia, cardiopulmonary bypass,
vasoactive drugs and fluid therapy may influence organ perfusion at
the microvascular level. As in sepsis and heart failure, these perioperative
microcirculatory abnormalities were associated with prognosis. However,
whether these microcirculatory alterations are culprit or bystander in the
process of developing perioperative complications remains to be established.
SUMMARy: Recent research has elucidated the incidence of perioperative
microvascular alterations, as well as its association with prognosis. Future
research should further unravel the fascinating and complex interplay between
the microcirculation and perioperative interventions.
Curr Opin Crit Care 2010;16(4):377-83
25

26
Fluid therapy in septic shock
E.P. Rivers
A.K. Jaehne
L. Eichhorn-Wharry
S. Brown
D. Amponsah
Department of Emergency
Medicine, Henry Ford
Hospital, Wayne State
University, Detroit, Michigan,
USA
PURPOSE Of REvIEw: To examine the role of fluid therapy in the pathogenesis
of severe sepsis and septic shock. The type, composition, titration,
management strategies and complications of fluid administration will be
examined in respect to outcomes.
RECEnT fIndInGS: Fluids have a critical role in the pathogenesis and treatment
of early resuscitation of severe sepsis and septic shock.
SUMMARy: Although this pathogenesis is evolving, early titrated fluid administration
modulates inflammation, improves microvascular perfusion,
impacts organ function and outcome. Fluid administration has limited impact
on tissue perfusion during the later stages of sepsis and excess fluid
is deleterious to outcome. The type of fluid solution does not seem to
influence these observations.
Curr Opin Crit Care 2010;16(4):297-308

Both passive leg raising and intravascular volume
expansion improve sublingual microcirculatory
perfusion in severe sepsis and septic shock patients
J. Pottecher
S. Deruddre
J.L. Teboul
J.F. Georger
C. Laplace
D. Benhamou
E. Vicaut
J. Duranteau
Unité EA 3509, Département
d’Anesthésie-Réanimation,
Centre Hospitalier
Universitaire de Bicêtre,
Assistance Publique Hôpitaux
de Paris, Université Paris,
Le Kremlin-Bicêtre Cedex,
France
PURPOSE: To assess sublingual microcirculatory changes following passive
leg raising (PLR) and volume expansion (VE) in septic patients.
METhOdS: This prospective study was conducted in two university hospital
intensive care units and included 25 mechanically ventilated patients
with severe sepsis or septic shock who were eligible for VE in the first 24 h
of their admission. Pulse pressure variation (DeltaPP), cardiac output (CO)
and sublingual microcirculation indices were assessed at five consecutive
steps: (1) semi-recumbent position (Baseline 1), (2) during PLR manoeuvre
(PLR), (3) after returning to semi-recumbent position (Baseline 2), (4) at
the time when VE induced the same degree of preload responsiveness as
PLR (VE(PP = PLR)) and (5) at the end of VE (VE(END)). At each step, five
sublingual microcirculation sequences were acquired using sidestream
darkfield imaging to assess functional capillary density (FCD), microcirculatory
flow index (MFI), proportion of perfused vessels (PPV) and flow
heterogeneity index (FHI).
RESULTS: The PLR, VE(PP=PLR) and VE(END) induced a significant increase
in CO and a significant decrease in DeltaPP compared to Baseline 1 and
Baseline 2 values. Both PLR and VE induced significant increases in FCD,
MFI and PPV and a significant decrease in FHI compared to Baseline 1 and
Baseline 2 values.
COnCLUSIOnS: In preload responsive severe septic patients examined
within the first 24 h of their admission, both PLR and VE improved sublingual
microcirculatory perfusion. At the level of volume infusion used
in this study, these changes in sublingual microcirculation were not explained
by changes in rheologic factors or changes in arterial pressure.
Intensive Care Med 2010;36(11):1867-74
27

28
impaired microvascular perfusion in sepsis requires
activated coagulation and p-selectin-mediated
platelet adhesion in capillaries
F. Li
C.G. Ellis
M.D. Sharpe
P.L. Gross
J.X. Wilson
K. Tyml
Critical Illness Research,
Victoria Research
Laboratories, Lawson Health
Research Institute, London,
ON, Canada
PURPOSE: Impaired microvascular perfusion in sepsis is not treated effectively
because its mechanism is unknown. Since inflammatory and coagulation
pathways cross-activate, we tested if stoppage of blood flow
in septic capillaries is due to oxidant-dependent adhesion of platelets in
these microvessels.
METhOdS: Sepsis was induced in wild type, eNOS(-/-), iNOS(-/-), and gp91phox(-/-)
mice (n = 14-199) by injection of feces into the peritoneum.
Platelet adhesion, fibrin deposition, and blood flow stoppage in capillaries
of hindlimb skeletal muscle were assessed by intravital microscopy.
Prophylactic treatments at the onset of sepsis were intravenous injection
of platelet-depleting antibody, P-selectin blocking antibody, ascorbate,
or antithrombin. Therapeutic treatments (delayed until 6 h) were injection
of ascorbate or the glycoprotein IIb/IIIa inhibitor eptifibatide, or local
superfusion of the muscle with NOS cofactor tetrahydrobiopterin or NO
donor S-nitroso-N-acetylpenicillamine (SNAP).
RESULTS: Sepsis at 6-7 h markedly increased the number of stopped-flow
capillaries and the occurrence of platelet adhesion and fibrin deposition
in these capillaries. Platelet depletion, iNOS and gp91phox deficiencies,
P-selectin blockade, antithrombin, or prophylactic ascorbate prevented,
whereas delayed ascorbate, eptifibatide, tetrahydrobiopterin, or SNAP
reversed, septic platelet adhesion and/or flow stoppage. The reversals by
ascorbate and tetrahydrobiopterin were absent in eNOS(-/-) mice. Platelet
adhesion predicted 90% of capillary flow stoppage.
COnCLUSIOn: Impaired perfusion and/or platelet adhesion in septic capillaries
requires NADPH oxidase, iNOS, P-selectin, and activated coagulation,
and is inhibited by intravenous administration of ascorbate and by
local superfusion of tetrahydrobiopterin and NO. Reversal of flow stoppage
by ascorbate and tetrahydrobiopterin may depend on local eNOSderived
NO which dislodges platelets from the capillary wall.
Intensive Care Med 2010;36(11):1928-34

monitoring the microcirculation in the critically ill
patient: current methods and future approaches
D. De Backer
G. Ospina-Tascon
D. Salgado
R. Favory
J. Creteur
J.L. Vincent
Department of Intensive Care,
Erasme University Hospital,
Université Libre de Bruxelles,
Belgium
PURPOSE: To discuss the techniques currently available to evaluate the
microcirculation in critically ill patients. In addition, the most clinically relevant
microcirculatory alterations will be discussed.
METhOdS: Review of the literature on methods used to evaluate the microcirculation
in humans and on microcirculatory alterations in critically
ill patients.
RESULTS: In experimental conditions, shock states have been shown to be
associated with a decrease in perfused capillary density and an increase in
the heterogeneity of microcirculatory perfusion, with non-perfused capillaries
in close vicinity to perfused capillaries. Techniques used to evaluate
the microcirculation in humans should take into account the heterogeneity
of microvascular perfusion. Microvideoscopic techniques, such as
orthogonal polarization spectral (OPS) and sidestream dark field (SDF)
imaging, directly evaluate microvascular networks covered by a thin epithelium,
such as the sublingual microcirculation. Laser Doppler and tissue
O measurements satisfactorily detect global decreases in tissue perfusion
2
but not heterogeneity of microvascular perfusion. These techniques, and
in particular laser Doppler and near-infrared spectroscopy, may help to
evaluate the dynamic response of the microcirculation to a stress test. In
patients with severe sepsis and septic shock, the microcirculation is characterized
by a decrease in capillary density and in the proportion of perfused
capillaries, together with a blunted response to a vascular occlusion
test.
COnCLUSIOnS: The microcirculation in humans can be evaluated directly
by videomicroscopy (OPS/SDF) or indirectly by vascular occlusion tests. Of
note, direct videomicroscopic visualization evaluates the actual state of
the microcirculation, whereas the vascular occlusion test evaluates microvascular
reserve.
Intensive Care Med 2010;36(11):1813-25
29

30
pregnant and postpartum admissions to the intensive
care unit: a systematic review
W. Pollock
L. Rose
C.L. Dennis
School of Nursing
and Midwifery, La Trobe
University/Mercy Hospital
for Women, Heidelberg,
Australia
PURPOSE: To determine the incidence and characteristics of pregnant and
postpartum women requiring admission to an intensive care unit (ICU).
METhOdS: Medline, PubMed, EMBASE and CINAHL databases (1990-2008)
were systematically searched for reports of women admitted to the ICU
either pregnant or up to 6 weeks postpartum. Two reviewers independently
determined study eligibility and abstracted data.
RESULTS: A total of 40 eligible studies reporting outcomes for 7,887 women
were analysed. All studies were retrospective with the majority reporting
data from a single centre. The incidence of ICU admission ranged
from 0.7 to 13.5 per 1,000 deliveries. Pregnant or postpartum women accounted
for 0.4-16.0% of ICU admissions in study centres. Hypertensive
disorders of pregnancy were the most prevalent indication for ICU admission
[median 0.9 cases per 1,000 deliveries (range 0.2-6.7)]. There was
no difference in the profile of ICU admission in developing compared to
developed countries, except for the significantly higher maternal mortality
rate in developing countries (median 3.3 vs. 14.0%, p = 0.002). Studies
reporting patient outcomes subsequent to ICU admission are lacking.
COnCLUSIOnS: ICU admission of pregnant and postpartum women occurs
infrequently, with obstetric conditions responsible for the majority of ICU
admissions. The ICU admission profile of women was similar in developed
and developing countries; however, the maternal mortality rate remains
higher for ICUs in developing countries, supporting the need for ongoing
service delivery improvements. More studies are required to determine
the impact of ICU admission for pregnant and postpartum women.
Intensive Care Med 2010;36(9):1465-74

the rAge axis in systemic inflammation,
acute lung injury and myocardial dysfunction:
an important therapeutic target?
B.C. Creagh-Brown
G.J. Quinlan
T.W. Evans
A. Burke-Gaffney
Unit of Critical Care,
Respiratory Science, National
Heart and Lung Institute
Division, Faculty of Medicine,
Imperial College, London, UK
bACkGROUnd: The sepsis syndromes, frequently complicated by pulmonary
and cardiac dysfunction, remain a major cause of death amongst the
critically ill. Targeted therapies aimed at ameliorating the systemic inflammation
that characterises the sepsis syndromes have largely yielded disappointing
results in clinical trials. Whilst there are many potential reasons
for lack of success of clinical trials, one possibility is that the pathways targeted,
to date, are only modifiable very early in the course of the illness.
More recent approaches have therefore attempted to identify pathways
that could offer a wider therapeutic window, such as the receptor for advanced
glycation end-products (RAGE) and its ligands.
PURPOSE: The objectives of this study were to review the evidence supporting
the role of the RAGE axis in systemic inflammation and associated
acute lung injury and myocardial dysfunction, to explore some of
the problems and conflicts that these RAGE studies have raised and to
consider strategies by which they might be resolved.
METhOdS: MEDLINE was searched (1990-2010) and relevant literature
collected and reviewed.
RESULTS And COnCLUSIOn: RAGE is an inflammation-perpetuating receptor
with a diverse range of ligands. Evidence supporting a role of the
RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial
dysfunction is compelling with numerous animal experiments showing
the beneficial effects of inhibiting the RAGE axis. Despite a number
of unanswered questions that need to be further addressed, the potential
for inhibiting RAGE-mediated inflammation in humans undoubtedly
exists.
Intensive Care Med 2010;36(10):1644-56
31

32
Do chronic liver disease scoring systems predict
outcomes in trauma patients with liver disease?
A comparison of meLD and Ctp
M.J. Seamon
M.J. Franco
S.P. Stawicki
B.P. Smith
H. Kulp
A.J. Goldberg
T.A. Santora
J.P. Gaughan
Division of Trauma
and Surgical Critical Care
(MJS, HK, AJG, TAS),
Department of Surgery;
Biostatistics Consulting
Center (JPG), Temple
University School
of Medicine; Department
of Surgery (MJF, BPS),
Temple University Hospital,
Philadelphia, PA; Division
of Critical Care, Trauma,
and Burn (SPS), Department
of Surgery, Ohio State
University Medical Center,
Columbus, OH
bACkGROUnd: Although the Child-Turcotte-Pugh (CTP) score is an established
outcome prediction tool for patients with liver disease, the Model
for End-Stage Liver Disease (MELD) score has recently supplanted CTP for
patients awaiting transplantation. Currently, data regarding the use of
CTP in trauma is limited, whereas MELD remains unstudied. We compared
MELD and CTP to determine which scoring system is a better clinical outcome
predictor after trauma.
METhOdS: A review of trauma admissions during 2003-2008 revealed 68
patients with chronic liver disease. Single and multiple variable analyses
determined predictors of hepatic complications and survival. MELD and
CTP were compared using odds ratios and area under the receiver operating
curve (AUC) analyses. A p value ≤ 0.05 was significant.
RESULTS: The mean MELD and CTP scores of the population were 13.1 ± 6.0
and 8.3 ± 1.8, respectively (mean ± SD). Overall, 73.5% had one or more
complications and 29.4% died. When survivors were compared with nonsurvivors,
no difference in mean MELD scores was found, although mean
CTP score (survivors, 7.7 ± 1.5; nonsurvivors, 9.4 ± 1.9; p = 0.001) and class
(“C” survivors, 12.1%; “C” nonsurvivors, 56.3%; p = 0.002) were different,
with survival relating to liver disease severity. Odds ratios and AUC determined
that MELD was not predictive of hepatic complications or hospital
survival (p > 0.05), although both CTP score and class were predictive
(p < 0.05; AUC > 0.70).
COnCLUSIOn: Trauma patients suffering from cirrhosis can be expected
to have poorer than predicted outcomes using traditional trauma scoring
systems, regardless of injury severity. Scoring systems for chronic liver
disease offer a more effective alternative. We compared two scoring systems,
MELD and CTP, and determined that CTP was the better predictor of
hepatic complications and survival in our study population.
j Trauma 2010;69(3):568-73

Use of recombinant factor viia in Us military casualties
for a five-year period
C.E. Wade
B.J. Eastridge
J.A. Jones
S.A. West
P.C. Spinella
J.G. Perkins
M.A. Dubick
L.H. Blackbourne
J.B. Holcomb
Center for Translational Injury
Research and Department
of Surgery, University
of Texas Health Science
Center, Houston, TX, USA
bACkGROUnd: Two prospective randomized trauma trials have shown
recombinant factor VIIa (rFVIIa) to be safe and to decrease transfusion
requirements. rFVIIa is presently used in 22% of massively transfused civilian
trauma patients. The US Military has used rFVIIa in combat trauma
patients for five years, and two small studies of massively transfused patients
described an association with improved outcomes. This study was
undertaken to assess how deployed physicians are using rFVIIa and its
impact on casualty outcomes.
METhOdS: US combat casualties (n = 2,050) receiving any blood transfusion
from 2003 to 2009 were reviewed to compare patients receiving rFVI-
Ia (n = 506) with those who did not (n = 1,544). Propensity-score matching
(primary analysis) and multivariable logistic regression were used to compare
outcomes. Differences were determined at p < 0.05.
RESULTS: Twenty-five percent of patients received rFVIIa. Significant differences
were noted between groups in indices of injury severity (Injury
Severity Score, Abbreviated Injury Scale score, and Glasgow Coma Scale
score), admission physiology (systolic blood pressure, diastolic blood pressure,
heart rate, temperature, base deficit, hemoglobin, and international
normalization ratio), and use of blood products, indicating that patients
treated with rFVIIa were more severely injured, in shock, and coagulopathic.
For propensity-score matching, factors associated with death were
used: Injury Severity Score, Glasgow Coma Scale score, heart rate, systolic
blood pressure, diastolic blood pressure, Hgb, and total packed red blood
cell. A total of 266 patients per group were matched; 52% of the rFVIIa
group. After pairing, there were no significant differences in any of the
demographics, including incidence of massive transfusion (53% vs. 51%).
There was no difference in the rate of complications (21% vs. 21%) or
mortality (14% vs. 20%) for patients not treated or receiving rFVIIa, respectively.
COnCLUSIOn: In military casualties, rFVIIa is used in the most severely
injured patients based on physician selection rather than on guideline
criteria. Use of rFVIIa is not associated with an improvement in survival or
an increase in complications. The undetected bias of physician selection of
patients for treatment with rFVIIa, likely, has an impact on case matching
to achieve equivalence similar to that of randomized control studies. This
inability to match populations, thus, prevents definitive interpretation of
this study and others studies of similar design. This problem emphasizes
the need to develop entry criteria to identify patients who could potentially
benefit from use of rFVIIa and the need to subsequently perform
efficacy studies.
j Trauma 2010;69(2):353-9
33

34
prolonged prothrombin time after recombinant
activated factor vii therapy in critically bleeding
trauma patients is associated with adverse outcomes
N.R. McMullin
C.E. Wade
J.B. Holcomb
T.G. Nielsen
R. Rossaint
B. Riou
S.B. Rizoli
Y. Kluger
P.I. Choong
B. Warren
B.J. Tortella
K.D. Boffard
NovoSeven Trauma Study
Group
US Army Institute of Surgical
Research, BAMC-Fort Sam
Houston, TX, USA
bACkGROUnd: In trauma patients with significant hemorrhage, it is
hypothesized that failure to normalize prothrombin time (PT) after recombinant
activated factor VII (rFVIIa) treatment predicts poor clinical
outcomes and potentially indicates a need for additional therapeutic interventions.
METhOdS: To assess the value of PT to predict outcomes after rFVIIa or
placebo therapy, we performed a post hoc analysis of data from 169 severely
injured, critically bleeding trauma patients who had 1-hour postdose
PT measurements from two randomized clinical trials. Baseline characteristics
and outcome parameters were compared between subjects
with 1-hour postdose PT ≥ 18 seconds and PT < 18 seconds.
RESULTS: In rFVIIa-treated subjects, prolonged postdose PT values ≥ 18
seconds were associated with significantly higher 24-hour mortality
(60% vs. 3%; p < 0.001) and 30-day mortality, increased incidence of massive
transfusion, and fewer intensive care unit-free days compared with
postdose PT values < 18 seconds. Recombinant rFVIIa-treated subjects with
postdose PT ≥ 18 seconds had significantly lower baseline hemoglobin levels,
fibrinogen levels, and platelet counts than subjects with postdose PT
values < 18 seconds even though they received similar amounts of blood
products before rFVIIa dosing. Placebo-treated subjects with postdose
PT ≥ 18 seconds had significantly increased incidence of massive transfusion,
significantly decreased intensive care unit-free days, and significantly
lower levels of fibrinogen and platelets at baseline compared with
subjects with postdose PT values < 18 seconds.
COnCLUSIOnS: The presence of prolonged PT after rFVIIa or placebo
therapy was associated with poor clinical outcomes. Because subjects with
postdosing PT ≥ 18 seconds had low levels of hemoglobin, fibrinogen,
and platelets, this group may benefit from additional blood component
therapy.
j Trauma 2010;69(1):60-9

the effect of acute traumatic brain injury
on the performance of shock index
C.G. McMahon
R. Kenny
K. Bennett
R. Little
E. Kirkman
Department of Emergency
Medicine (CGMM); Trinity
College, St. James’s Hospital,
Dublin, Ireland; Department
of Geriartic Medicine (RK);
Institute of Neuroscience,
Trinity College, Dublin,
Ireland; Department
of Pharmacology &
Therapeutics (KB); Trinity
Medical School, Trinity
College, Dublin, Ireland;
Manchester University (RL);
Manchester, United Kingdom;
and Surgical Sciences,
Trauma, Biomedical Sciences
(EK): Salisbury, UK
bACkGROUnd: Shock index (SI) is recognized to be a more reliable early
indicator of hemorrhage than traditional vital signs. Acute traumatic
brain injury (TBI) can be associated with autonomic uncoupling and may
therefore alter the reliability of SI in patients with combined TBI and peripheral
hemorrhage. The aim of this study was to evaluate the performance
of SI when acute TBI of mild and moderate severity were associated
with progressive simple hemorrhage.
METhOdS: This study was undertaken in a laboratory setting. Brian injury
was induced using the lateral fluid percussion model in anesthetized rats.
The fluid percussion device delivered an applied cortical pressure of 1.2
atm and 1.8 atm, producing mild and moderate TBI, respectively. Control
animals underwent identical procedures but with no applied cortical
pressure. Hemorrhage was induced 10 minutes after brain injury, at
a rate of 2% of blood volume per minute until 40% blood volume was
withdrawn.
RESULTS: The SI response to increasing volume of hemorrhage was unaltered
when control and mild TBI groups were compared (test of interaction
p = 0.39). There was a 50% mortality rate observed 20 to 60 minutes
after hemorrhage in the moderate TBI group. The SI response to
hemorrhage in the moderate TBI group compared with the control group
became significantly different at 40% blood volume loss (test of interaction
p = 0.048). Comparison of the SI response with hemorrhage between
survivors and nonsurvivors of moderate TBI revealed a significant difference
(p = 0.007). SI was markedly attenuated in the presence of increasing
hemorrhage in the nonsurvivor subgroup of moderate TBI.
COnCLUSIOnS: SI significantly underestimated underlying hemorrhage
in the presence of acute TBI of moderate severity where attenuation of
the biphasic heart rate and blood pressure response was also most pronounced.
j Trauma 2010;69(5):1169-75
35

36
plasma superoxide dismutase activity and mortality
in patients with septic
M.O. Guerreiro
F. Petronilho
M. Andrades
L. Constantino
F.G. Mina
J.C. Moreira
F.D. Pizzol
C. Ritter
Laboratório de Fisiopatologia
Experimental (MOG, FP, LC,
FGM, FDP, CR), Universidade
do Extremo Sul Catarinense,
Criciúma, SC, Brazil;
Programa de Pós Graduação
em Ciências Biológicas
(FP, MA, JCFM), Bioquímica,
Universidade Federal do Rio
Grande do Sul; Programa
de Pós Graduação em
Ciências Médicas (MOG),
Universidade Federal do Rio
Grande do Sul, Porto Alegre,
RS, Brazil
bACkGROUnd: The aim of this study was to determine whether plasma
superoxide dismutase (SOD) activity, in comparison with other oxidative
parameters, is associated with mortality in humans with septic.
METhOdS: We conducted a prospective observational study including
96 patients with septic. Blood samples were collected immediately after
study inclusion and 24 hours after. We then determined plasma levels of
thiobarbituric acid reactive species, protein carbonyls, SOD, and catalase
activities.
RESULTS: Plasma carbonyls and SOD activity, but not plasma thiobarbituric
acid reactive species and catalase activity, were significantly higher in
non-survivors. SOD activity significantly correlated with Acute Physiology
and Chronic Health Evaluation II and Multiple Organ Dysfunction Score. In
addition, SOD activity presented similar area under the receiver operator
characteristic curve when compared with Acute Physiology and Chronic
Health Evaluation II to predict mortality. A diminution of 25% or more on
SOD activity between D1 and D2 was associated with a better outcome.
COnCLUSIOn: Our data provide some new information on the use of plasma
SOD activity as a biomarker in human sepsis.
j Trauma 2010;69(6):E102-6

inflammatory alterations in a novel combination model
of blunt chest trauma and hemorrhagic shock
D.H. Seitz
M. Perl
U.C. Liener
B. Tauchmann
S.T. Braumüller
U.B. Brückner
F. Gebhard
M.W. Knöferl
Department of Trauma
Surgery, Hand, Plastic
and Reconstructive Surgery
(DHS, MP, UCL, BT, STB, FG,
MWK) and Division
of Surgical Research (UBB),
University of Ulm, Ulm,
Germany
bACkGROUnd: Chest trauma frequently occurs in severely injured patients
and is often associated with hemorrhagic shock. Immune dysfunction
contributes to the adverse outcome of multiple injuries. The aims
of this study were to establish a combined model of lung contusion and
hemorrhage and to evaluate the cardiopulmonary and immunologic response.
METhOdS: Male mice were subjected to sham procedure, chest trauma,
hemorrhage (35 ± 5 mm Hg, 60 minutes), or the combination. Respiratory
rate, heart rate, and blood pressure were monitored. Plasma, Kupffer
cells, blood monocytes, splenocytes, and splenic macrophages were isolated
after 20 hours. Tumor necrosis factor-alpha (TNF-alpha), interleukin
(IL)-6, 10, 12, 18, and macrophage inflammatory protein-2 levels in plasma
and culture supernatants were determined.
RESULTS: Heart rate and blood pressure dropped in all groups, and after
chest trauma and the double hit, these values remained reduced until the
end of observation. Blood pressure was lower after the double hit than
after the single hits. Plasma and Kupffer cell TNF-alpha concentrations
were increased after lung contusion but not further enhanced by subsequent
hemorrhage. Peripheral blood mononuclear cell (PBMC) TNF-alpha
and IL-6 release were suppressed after the combined insult. IL-18 concentrations
were increased in PBMC supernatants after chest trauma and in
splenic macrophage supernatants of all groups.
COnCLUSIOnS: Although physiologic readouts were selectively altered in
response to the single or double hits, the combination did not uniformly
augment the changes in inflammation. Our results suggest that the leading
insult regarding the immunologic response is lung contusion, supporting
the concept that lung contusion represents an important prognostic
factor in multiple injuries.
j Trauma 2011;70(1):189-96
37

38
Liver ischemia/reperfusion injury:
processes in inflammatory networks--a review
M. Abu-Amara
S.Y. Yang
N. Tapuria
B. Fuller
B. Davidson
A. Seifalian
Liver Transplantation
and Hepatobiliary Unit,
Royal Free Hospital,
London, UK
Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response.
Understanding the cellular and molecular events underpinning this
inflammation is fundamental to developing therapeutic strategies. Great
strides have been made in this respect recently. Liver IR involves a complex
web of interactions between the various cellular and humoral contributors
to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils,
and hepatocytes are central cellular players. Various cytokines,
chemokines, and complement proteins form the communication system
between the cellular components. The contribution of the danger-associated
molecular patterns and pattern recognition receptors to the pathophysiology
of liver IR injury are slowly being elucidated. Our knowledge
on the role of mitochondria in generating reactive oxygen and nitrogen
species, in contributing to ionic disturbances, and in initiating the mitochondrial
permeability transition with subsequent cellular death in liver
IR injury is continuously being expanded. Here, we discuss recent findings
pertaining to the aforementioned factors of liver IR, and we highlight
areas with gaps in our knowledge, necessitating further research.
Liver Transpl 2010;16(9):1016-32

Criteria for diagnosing benign portal vein thrombosis
in the assessment of patients with cirrhosis
and hepatocellular carcinoma for liver transplantation
F. Piscaglia
A. Gianstefani
M. Ravaioli
R. Golfieri
A. Cappelli
E. Giampalma
E. Sagrini
G. Imbriaco
A.D. Pinna
L. Bolondi
Bologna Liver Transplant
Group
Division of Internal Medicine,
Department of Digestive
Disease and Internal
Medicine, St. Orsola-Malpighi
University Hospital, Bologna,
Italy
Malignant portal vein thrombosis is a contraindication for liver transplantation.
Patients with cirrhosis and early hepatocellular carcinoma (HCC)
may have either malignant or benign (fibrin clot) portal vein thrombosis.
The aim of this study was to assess prospectively whether well-defined
diagnostic criteria would enable the nature of portal vein thrombosis to
be established in patients with HCC under consideration for liver transplantation.
Benign portal vein thrombosis was diagnosed by the application
of the following criteria: lack of vascularization of the thrombus on
contrast-enhanced ultrasound and on computed tomography or magnetic
resonance imaging, absence of mass-forming features of the thrombus,
absence of disruption of the walls of veins, and, if uncertainty persisted,
biopsy of the thrombus for histological examination. Patients who did not
fulfill the criteria for benign thrombosis were not placed on the transplantation
list. In this study, all patients evaluated at our center during
2001-2007 with a diagnosis of HCC in whom portal vein thrombosis was
concurrently or subsequently diagnosed were discussed by a multidisciplinary
group to determine their suitability for liver transplantation. The
outcomes for 33 patients who met the entry criteria of the study were as
follows: in 14 patients who were placed on the transplantation list and
underwent liver transplantation, no malignant thrombosis was detected
when liver explants were examined histologically; 5 patients who were
placed on the transplantation list either remained on the list or died from
causes unrelated to HCC; in 9 patients, liver transplantation was contraindicated
on account of a strong suspicion, or confirmation, of the presence
of malignant portal vein thrombosis; and 5 patients who were initially
placed on the transplantation list were subsequently removed from it on
account of progression of HCC in the absence of evidence of neoplastic
involvement of thrombosis. In conclusion, for a patient with HCC and portal
vein thrombosis, appropriate investigations can establish whether the
thrombosis is benign; patients with HCC and benign portal vein thrombosis
are candidates for liver transplantation.
Liver Transpl 2010;16(5):658-67
39

40
recurrent preeclampsia: the effect of weight change
between pregnancies
D. Mostello
J. Jen Chang
J. Allen
L. Luehr
J. Shyken
T. Leet
Division of Maternal-Fetal
Medicine, Department
of Obstetrics, Gynecology,
and Women’s Health,
and School of Public Health,
Saint Louis University School
of Medicine, St. Louis, MO,
USA
ObjECTIvE: To estimate whether the risk of recurrent preeclampsia is affected
by interpregnancy change in body mass index (BMI).
METhOdS: We conducted a population-based cohort study using Missouri
maternally linked birth certificates for 17,773 women whose first
pregnancies were complicated by preeclampsia. The women were placed
into three groups: those who decreased their BMIs, those who maintained
their BMIs, and those who increased their BMIs between their first two
pregnancies. The primary outcome was recurrent preeclampsia in the second
pregnancy. Adjusted risk ratios and 95% confidence intervals were
calculated using Poisson regression analysis.
RESULTS: The overall rate of recurrent preeclampsia in women who decreased
their BMIs between pregnancies was 12.8% (risk ratio 0.70, confidence
interval 0.60-0.81) compared with 14.8% if BMI was maintained and
18.5% in those who increased their BMIs (risk ratio 1.29, confidence interval
1.20-1.38). Within the normal weight, overweight, and obese weight
categories, women who decreased BMI between pregnancies were less
likely to experience recurrent preeclampsia. Women in all weight categories
who increased their BMIs between pregnancies were more likely to
experience recurrent preeclampsia.
COnCLUSIOn: Interpregnancy weight reduction decreases the risk of recurrent
preeclampsia and should be encouraged in women who experience
preeclampsia.
Obstet Gynecol 2010;116(3):667-72

Fresh-frozen plasma transfusion strategy in trauma
with massive and ongoing bleeding.
Common (sense) and sensibility
A.M. Ho
P.W. Dion
J.H. Yeung
C.S. Ng
M.K. Karmakar
L.A. Critchley
T.H. Rainer
C.W. Cheung
B.A. Tay
Department of Anaesthesia
and Intensive Care, Prince
of Wales Hospital,
The Chinese University
of Hong Kong, Shatin, NT,
Hong Kong
During trauma resuscitation involving massive transfusion, the best freshfrozen
plasma to packed red blood cells ratio is unknown. No randomised
controlled trial (RCT) is available on this subject, although there are plenty
of observational studies suggesting that the ratio should be about 1:1.
This ratio also makes more physiological sense, and we suggest that in
patients with massive and ongoing bleeding, it is a sensible strategy with
which to start resuscitation.
Resuscitation 2010;81(9):1079-81
41

42
extracorporeal membrane oxygenation in severe trauma
patients with bleeding shock
M. Arlt
A. Philipp
S. Voelkel
L. Rupprecht
T. Mueller
M. Hilker
B.M. Graf
C. Schmid
Department
of Anesthesiology,
University Hospital
Regensburg, Germany
AIM Of ThE STUdy: Death to trauma is caused by disastrous injuries on
scene, bleeding shock or acute respiratory failure (ARDS) induced by trauma
and massive blood transfusion. Extracorporeal membrane oxygenation
(ECMO) can be effective in severe cardiopulmonary failure, but preexisting
bleeding is still a contraindication for its use. We report our first
experiences in application of initially heparin-free ECMO in severe trauma
patients with resistant cardiopulmonary failure and coexisting bleeding
shock retrospectively and describe blood coagulation management on
ECMO.
METhOdS: From June 2006 to June 2009 we treated adult trauma patients
(n = 10, mean age: 32 ± 14 years, mean ISS score 73 ± 4) with percutaneous
veno-venous (v-v) ECMO for pulmonary failure (n = 7) and with venoarterial
(v-a) ECMO in cardiopulmonary failure (n = 3). Diagnosis included
polytrauma (n = 9) and open chest trauma (n = 1). We used a new miniaturised
ECMO device (PLS-Set, MAQUET Cardiopulmonary AG, Hechingen,
Germany) and performed initially heparin-free ECMO.
RESULTS: Prior to ECMO median oxygenation ratio (OR) was 47 (36-90)
mmHg, median paCO was 67 (36-89) mmHg and median norepinephrine
2
demand was 3.0 (1.0-13.5) mg/h. Cardiopulmonary failure was treated effectively
with ECMO and systemic gas exchange and blood flow improved
rapidly within 2 h on ECMO in all patients (median OR 69 (52-263) mmHg,
median paCO 41 (22-85) mmHg. 60% of our patients had recovered com-
2
pletely.
COnCLUSIOnS: Initially heparin-free ECMO support can improve therapy
and outcome even in disastrous trauma patients with coexisting bleeding
shock.
Resuscitation 2010;81(7):804-9

ons formation under restrictive reperfusion
does not affect organ dysfunction early after
hemorrhage and trauma
C. Zifko
A.V. Kozlov
A. Postl
H. Redl
S. Bahrami
Ludwig Boltzmann Institute
for Experimental and Clinical
Traumatology in AUVA
Research Center, Vienna,
Austria
Reactive oxygen species have been implicated in the pathophysiology of
early reperfusion. We aimed to determine 1) reactive oxygen and nitrogen
species (RONS) formation in organs of rats and 2) its pathophysiological
relevance during a phase of restrictive reperfusion after hemorrhagic/
traumatic shock (HTS). Fifty-seven male Sprague-Dawley rats were subjected
to a clinically relevant HTS model, featuring laparotomy, bleeding,
and a phase of restrictive reperfusion. The RONS scavenger 1-hydroxy-3carboxy-2,2,5,5-tetramethyl-pyrrolidine
hydrochloride (continuous i.v. infusion)
and electron paramagnetic resonance spectroscopy were applied
for RONS (primarily superoxide and peroxynitrite) detection. Compared
with sham-operated animals, the organ-specific distribution of RONS
changed during restrictive reperfusion after HTS. Reactive oxygen and
nitrogen species formation increased during restrictive reperfusion in
red blood cells and ileum only but decreased in the kidney and remained
unchanged in other organs. Hemorrhagic traumatic shock followed by
restrictive reperfusion resulted in metabolic acidosis, dysfunction of liver
and kidney, and increased oxidative burst capacity in circulating cells.
Plasma RONS correlated with shock severity and organ dysfunction. However,
RONS scavenging neither affected organ dysfunction nor oxidative
burst capacity nor myeloperoxidase activity in lung when compared with
the shock controls. In summary, a phase of restrictive reperfusion does not
increase RONS formation in most organs except in intestine and red blood
cells. Moreover, scavenging of RONS does not affect the early organ dysfunction
manifested at the end of a phase of restrictive reperfusion.
Shock 2010;34(4):384-9
43

Aggiornamenti in Rianimazione e Terapia Intensiva è una rivista periodica che pubblica articoli brevi, case reports ed
abstracts dalla letteratura internazionale riguardanti tutti gli aspetti legati all’epidemiologia, all’eziologia, alla patofisiologia,
alla diagnosi e al trattamento delle malattie acute e dei traumi.
Gli articoli scientifici originali dovranno essere accompagnati da una dichiarazione firmata dal primo Autore, nella quale
si attesti che i contributi sono inediti, non sottoposti contemporaneamente ad altra rivista, ed il loro contenuto conforme
alla legislazione vigente in materia di etica della ricerca. Gli Autori sono gli unici responsabili delle affermazioni contenute
nell’articolo e sono tenuti a dichiarare di aver ottenuto il consenso informato per la sperimentazione e per la riproduzione
delle immagini. La Redazione accoglie solo i testi conformi alle norme editoriali generali e specifiche per le singole rubriche.
La loro accettazione è subordinata al parere conclusivo del Direttore Scientifico che si riserva inoltre il diritto di richiedere agli
Autori la documentazione dei casi e dei protocolli di ricerca, qualora lo ritenga opportuno.
norme generali
Testo: in lingua italiana e corredato di: titolo del lavoro (in italiano ed in inglese); parole chiave (in italiano ed in inglese);
riassunto strutturato (in italiano ed in inglese); titolo e didascalie delle tabelle e delle figure.
Le bozze dei lavori saranno inviate per la correzione al primo degli Autori salvo diverse istruzioni. Gli Autori si
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Nella prima pagina devono comparire: il titolo (conciso, in italiano ed inglese); le parole chiave in italiano ed inglese ; i nomi
degli Autori e l’Istituto o Ente di appartenenza; la rubrica cui si intende destinare il lavoro (decisione che è comunque subordinata
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siano stati comunicati (tutti o in parte). Tabelle: devono essere contenute nel numero (evitando di presentare lo stesso
dato in più forme) e numerate progressivamente. figure: vanno riprodotte in foto o digitale e numerate con eventuale
indicazione dell’orientamento. I grafici ed i disegni possono essere in fotocopia, purché di buona qualità. bibliografia: va
limitata alle voci essenziali identificate nel testo con numeri arabi ed elencate al termine del dattiloscritto nell’ordine in cui
sono state citate, avvalendosi delle abbreviazioni internazionali.Esempi di corretta citazione bibliografica per:
Articoli e riviste:
Bianchi M, Laurà G, Recalcati D. Il trattamento chirurgico delle rigidità acquisite del ginocchio. Minerva Ortopedica
1985;36:431-438.
Libri: Tajana GF. Il condrone. Milano: Edizioni Mediamix 1991.
Capitoli di libri o atti di Congressi:
Krmpotic-Nemanic J, Kostovis I, Rudan P. Aging changes of the form and infrastructure of the external nose and its importance
in rhinoplasty. In: Conly J, Dickinson JT, eds. Plastic and Reconstructive Surgery of the Face and Neck. New York: Grune and
Stratton 1972, p. 84.
Ringraziamenti, indicazioni di grants o borse di studio, vanno citati al termine della bibliografia. Le note,
contraddistinte da asterischi o simboli equivalenti, compariranno nel testo a piè di pagina. Termini matematici, formule,
abbreviazioni, unità e misure devono conformarsi agli standards riportati in Science 1954;120:1078. I farmaci vanno indicati
col nome chimico.
Solo se inevitabile potranno essere citati col nome commerciale (scrivendo in maiuscolo la lettera iniziale del prodotto).
norme specifiche per le singole rubriche
Articoli originali brevi: comprendono brevi lavori (non più di 3 cartelle di testo) che offrono un contributo nuovo o frutto
di una consistente esperienza, anche se non del tutto originale, in un determinato settore. Devono essere suddivisi nelle
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cieco …), il tipo di trattamento e il tipo di analisi statistica impiegata. Nella sezione Risultati vanno riportati i risultati dello
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Casi clinici: vengono accettati dal Comitato di Redazione solo lavori di interesse didattico e segnalazioni rare. La presentazione
comprende l’esposizione del caso ed una discussione diagnosticodifferenziale. Il testo deve essere conciso e corredato, se
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Editoriale, via Gherardesca, 56121 Ospedaletto (PI) - c.a. Lucia Castelli - Tel. 050 3130224 - E-mail: lcastelli@
pacinieditore.it.

albunorm
RIASSUnTO dELLE CARATTERISTIChE dEL PROdOTTO
1. dEnOMInAZIOnE dEL MEdICInALE
Albunorm 20% “200 g/l, soluzione per infusione”.
2. COMPOSIZIOnE QUALITATIvA E QUAnTITATIvA
Albunorm 20% è una soluzione contenente 200 g/l di proteina totale di cui almeno il 96% è albumina umana.
Un flacone da 50 ml contiene 10 g di albumina umana.
Un flacone da 100 ml contiene 20 g di albumina umana.
Eccipienti:
– Sodio (144-160 mmol/l);
– Albunorm 20% è una soluzione iperoncotica.
Per l’elenco completo degli eccipienti, vedere paragrafo 6.1.
3. fORMA fARMACEUTICA
Soluzione per infusione.
La soluzione è un liquido chiaro, leggermente viscoso, con colorazione gialla, ambra o verde.
4. InfORMAZIOnI CLInIChE
4.1 Indicazioni terapeutiche
Reintegro e mantenimento del volume del sangue circolante in presenza di chiara ipovolemia, e dove l’uso di un colloide
risulta appropriato.
Di norma la scelta dell’albumina al posto del colloide artificiale dipenderà dalle condizioni cliniche individuali del paziente,
in relazione alle raccomandazioni ufficiali.
4.2 Posologia e modo di somministrazione
La concentrazione della preparazione a base di albumina, il dosaggio e la velocità di infusione, devono essere adattate
alle condizioni individuali di ciascun paziente.
Posologia
Il regime di somministrazione dipende dalla costituzione del paziente, dalla gravità del trauma o della malattia, e dalla
entità delle perdite di fluidi e proteine.
Per la determinazione della dose necessaria si devono effettuare misurazioni circa l’adeguatezza del volume circolante e
non dei livelli di albumina nel sangue.
Nel caso fosse necessaria la somministrazione di albumina umana, la funzionalità emodinamica deve essere regolarmente
monitorata; ciò può comprendere:
– pressione arteriosa e frequenza del polso;
– pressione venosa centrale;
– pressione arteriosa polmonare;
– analisi delle urine;
– elettroliti;
– ematocrito/ emoglobina.
Metodo di somministrazione
L’albumina umana può essere infusa direttamente per via endovenosa o può anche essere diluita in una soluzione
isotonica (ad es. glucosio al 5% o cloruro di sodio allo 0,9%).
La velocità di infusione deve essere adeguata alle condizioni individuali ed alle indicazioni.
In corso di plasmaferesi la velocità di infusione deve essere adattata alla velocità della procedura.
4.3 Controindicazioni
Ipersensibilità a preparazioni di albumina o ad uno qualsiasi degli eccipienti.
4.4 Avvertenze speciali e precauzioni di impiego
In presenza di reazioni allergiche o di tipo anafilattico, l’infusione deve essere immediatamente sospesa. In caso di shock,
seguire il trattamento consigliato dalle linee guida per la terapia dello shock.
Quando si somministra albumina, deve essere prestata particolare attenzione a tutte quelle condizioni in cui l’ipervolemia
e le sue conseguenze o l’emodiluizione possono rappresentare un rischio specifico per il paziente.
Esempi di tali condizioni sono:
– insufficienza cardiaca scompensata;
– ipertensione;
– varici esofagee;
– edema polmonare;

– diatesi emorragica;
– anemia grave;
– anuria renale e post-renale.
In uno studio retrospettivo sul follow-up di pazienti critici con trauma cranico, la rianimazione volemica con albumina è
stata associata ad un più alto tasso di mortalità rispetto alla rianimazione volemica con l’utilizzo di soluzione fisiologica.
Mentre i meccanismi alla base di questa differenza osservata nella mortalità non sono chiari, si consiglia cautela nell’uso
di albumina in pazienti con gravi traumi cranici.
L’effetto colloido-osmotico dell’albumina umana al 20 o 25% è approssimativamente 4 volte superiore a quello del
plasma umano. Pertanto, quando si somministra albumina concentrata, bisogna prestare attenzione ed assicurare al
paziente una adeguata idratazione. I pazienti devono essere accuratamente monitorati al fine di evitare un sovraccarico
circolatorio e iperidratazione.
Le soluzioni di albumina umana al 20-25% hanno una concentrazione elettrolitica minore di quella delle soluzioni al
4-5%. Quando viene somministrata albumina, deve essere monitorato lo stato elettrolitico del paziente (vedere paragrafo
4.2) e si devono attuare interventi opportuni per ristabilire o mantenere l’equilibrio elettrolitico normale.
Le soluzioni di albumina non devono essere diluite con acqua per preparazioni iniettabili perché ciò potrebbe causare
una emolisi nei pazienti riceventi.
Se devono essere somministrati volumi relativamente più elevati, sono necessari controlli della coagulazione e
dell’ematocrito. Si deve inoltre assicurare una adeguata sostituzione degli altri componenti ematici (fattori della
coagulazione, elettroliti, piastrine ed eritrociti).
Si può inoltre verificare una ipervolemia se il dosaggio e la velocità di somministrazione non sono adeguate alla funzione
circolatoria del paziente. L’infusione deve essere interrotta immediatamente ai primi sintomi clinici di sovraccarico
cardiovascolare (cefalea, dispnea, congestione giugulare), o di aumento della pressione arteriosa, o della pressione venosa
ed edema polmonare.
L’esperienza sull’uso di Albunorm 20% nei bambini è limitata; perciò il prodotto deve essere somministrato in questi
soggetti solo nel caso in cui i benefici siano nettamente superiori ai potenziali rischi.
Questo medicinale contiene 7,2-8 mmol di sodio per ogni flacone da 50 ml e 14,4-16 mmol di sodio in quelli da 100 ml
di albumina umana in soluzione. Questo deve essere tenuto in considerazione nei pazienti sottoposti ad una dieta a basso
tenore di sodio.
Questo medicinale contiene 1 mmol di potassio nel flacone da 100 ml di albumina umana in soluzione. Questo deve
essere tenuto in considerazione nei pazienti con ridotta funzionalità renale o sottoposti ad una dieta a basso tenore di
potassio.
Le misure standard per la prevenzione delle infezioni causate dall’utilizzo di medicinali derivati da sangue o plasma
umano comprendono la selezione dei donatori, lo screening delle donazioni individuali e dei pool di plasma per
marker specifici di infezione e l’utilizzo di procedure nella fase di produzione atte all’inattivazione/rimozione di
virus.
Nonostante ciò, quando si somministrano specialità medicinali preparate da sangue o plasma umano, non può essere
totalmente escluso il rischio di trasmissione di agenti infettivi.
Ciò si applica anche a virus emergenti o di natura sconosciuta e ad altri agenti patogeni.
Non ci sono segnalazioni di infezioni virali trasmesse a seguito di somministrazione di albumina preparata in accordo alle
specifiche della Farmacopea Europea.
È vivamente raccomandato, ogni volta che si somministra Albunorm 20% al paziente, di trascrivere il nome ed il numero
di lotto del prodotto al fine di stabilire un legame tra paziente e lotto del prodotto.
4.5 Interazioni con altri medicinali ed altre forme di interazione
Non sono note specifiche interazioni dell’albumina umana con altri farmaci.
4.6 Gravidanza e allattamento
La sicurezza di Albunorm 20% per l’uso in gravidanza non è stata valutata in studi clinici specifici. Tuttavia, l’esperienza
clinica con albumina sembra comunque indicare l’assenza di effetti dannosi durante la gravidanza, sul feto o sul
neonato.
Non sono stati condotti studi di tossicità riproduttiva negli animali con Albunorm 20%.
Ad ogni modo, l’albumina umana è un normale componente del sangue umano.
4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari
Albunorm 20% non altera la capacità di guidare veicoli o di usare macchinari.
4.8 Effetti indesiderati
Raramente si verificano reazioni lievi come rossore, orticaria, febbre e nausea.
Queste reazioni di solito scompaiono rapidamente, riducendo la velocità di infusione o con la sospensione dell’infusione.
Molto raramente si possono verificare reazioni più gravi, quali shock. Nel caso di reazioni gravi, l’infusione deve essere
interrotta e si deve iniziare un trattamento appropriato.
Le seguenti reazioni avverse sono state osservate durante la fase post-marketing con soluzioni di albumina umana e
pertanto potrebbero verificarsi anche con Albunorm 20%.

Sistema-Organo-Classe Reazioni (frequenza sconosciuta)*
Disturbi del Sistema Immunitario Shock anafilattico, reazione anafilattica, ipersensibilità
Disturbi psichiatrici Stato confusionale
Patologie del sistema nervoso Cefalea
Patologie cardiache Tachicardia
Bradicardia
Patologie vascolari Ipotensione
Ipertensione
Vampate
Patologie respiratorie, toraciche e mediastiniche Dispnea
Patologie gastrointestinali Nausea
Patologie della cute e del tessuto sottocutaneo Orticaria
Edema angioneurotico
Rash eritematoso
Iperidrosi
Patologie sistemiche e condizioni relative alla sede di
somministrazione
* Non può essere determinata sulla base dei dati disponibili.
Febbre
Brividi
Per informazioni sulla sicurezza relativa agli agenti trasmissibili, vedere il paragrafo 4.4.
4.9 Sovradosaggio
Il sovradosaggio e una velocità di infusione troppo elevata possono indurre ipervolemia.
L’infusione deve essere immediatamente interrotta ai primi sintomi clinici di sovraccarico circolatorio (cefalea, dispnea,
congestione giugulare) o per aumento della pressione arteriosa, della pressione venosa centrale o di edema polmonare,
e devono essere valutati attentamente i parametri emodinamici del paziente.
5. PROPRIETÀ fARMACOLOGIChE
5.1 Proprietà farmacodinamiche
Categoria farmacoterapeutica: succedanei del sangue e frazioni proteiche plasmatiche.
Codice ATC: B05AA01.
L’albumina umana rappresenta quantitativamente più della metà delle proteine totali plasmatiche e rappresenta circa il
10% del risultato della attività di sintesi proteica del fegato.
Dati fisico-chimici
L’albumina umana al 20% o 25% ha un corrispettivo effetto iperoncotico rispetto al plasma umano.
Una delle più importanti funzioni fisiologiche dell’albumina è data dal suo contributo alla pressione oncotica del sangue
ed alla sua funzione di trasporto.
L’albumina stabilizza il volume ematico circolante ed è un trasportatore di ormoni, enzimi, farmaci, tossine ecc.
5.2 Proprietà farmacocinetiche
In condizioni normali la concentrazione totale dell’albumina è di 4-5g/kg di peso corporeo, di questi il 40-50% è presente
nello spazio intravascolare ed il 55-60% in quello extravascolare.
In casi particolari, come ad esempio nelle ustioni gravi o durante uno shock settico, l’incremento della permeabilità
capillare aumenta la capacità di diffusione della albumina e si può avere pertanto una sua anomala distribuzione.
In condizioni normali l’emivita dell’albumina è in media di 19 giorni. L’equilibrio tra la sintesi e la sua eliminazione è
mantenuto normalmente da un meccanismo a feed-back.
L’eliminazione avviene per la maggior parte in sede intracellulare ad opera delle proteasi lisosomiali.
Nei soggetti sani, meno del 10% dell’albumina infusa lascia lo spazio intravascolare durante le prime due ore che
seguono l’infusione. Nei pazienti tuttavia è frequente una notevole variabilità della risposta volemica. In alcuni pazienti,
infatti, il volume plasmatico può aumentare per alcune ore. Comunque, in pazienti critici, l’albumina può diffondere nello
spazio extra vascolare in quantità consistente con una velocità non prevedibile.
5.3 dati preclinici di sicurezza
L’albumina umana è un normale costituente del plasma umano, ed ha le sue stesse proprietà fisiologiche.
Negli animali, i test di tossicità in singola dose hanno scarsa rilevanza clinica e non permettono la determinazione della
dose tossica e della dose letale, né di stabilire un rapporto dose-effetto.
Studi di tossicità a dosi ripetute non sono praticabili nei modelli animali a causa della formazione di anticorpi contro le
proteine eterologhe.
Finora l’albumina non è stata associata a embrio-feto tossicità e ad un potenziale rischio mutageno od oncogeno.
Nei modelli animali non sono stati descritti sintomi di tossicità acuta.

6. InfORMAZIOnI fARMACEUTIChE
6.1 Elenco degli eccipienti
Sodio cloruro 5,7 g/l
Acetiltriptofano 3,9 g/l
Acido caprilico 2,3 g/l
Acqua per preparazioni iniettabili qba 1000 ml
Elettroliti:
Sodio 144-160 mmol/l
6.2 Incompatibilità
L’albumina umana soluzione non deve essere iniettata con altri farmaci, sangue intero, concentrato di emazie e acqua
per preparazioni iniettabili.
6.3 Periodo di validità
2 anni
Dopo l’apertura del flacone, il contenuto deve essere usato immediatamente.
6.4 Precauzioni particolari per la conservazione
Non conservare a temperature superiori ai 25°C.
Conservare i flaconi nella confezione originale per proteggerli dalla luce.
Non congelare.
6.5 natura e contenuto del contenitore
Soluzione per infusione, 50 ml in flacone (vetro tipo II) provvisto di tappo (gomma bromobutilica).
Confezione da 1 flacone.
Confezione da 10 flaconi.
Soluzione per infusione, 100 ml in flacone (vetro tipo II) provvisto di tappo (gomma bromobutilica).
Confezione da 1 flacone.
Confezione da 10 flaconi.
È possibile che non tutte le confezioni siano commercializzate.
6.6 Precauzioni particolari per lo smaltimento e la manipolazione
Il prodotto può essere somministrato per via endovenosa o può anche essere diluito in una soluzione isotonica (ad es.
glucosio 5% o cloruro di sodio 0,9%).
L’albumina in soluzione non deve essere diluita con acqua per preparazioni iniettabili, questo potrebbe causare una
emolisi nei soggetti riceventi.
Nella somministrazione di grossi volumi, si raccomanda di scaldare l’albumina umana a temperatura ambiente prima
dell’infusione.
Non usare soluzioni torbide o con depositi. Questo può indicare che la proteina è instabile o che la soluzione è stata
contaminata.
Una volta che il contenitore della soluzione è stato aperto, il contenuto deve essere usato immediatamente.
Il medicinale non utilizzato ed i rifiuti derivati da tale medicinale devono essere smaltiti in conformità alla normativa locale
vigente.
7. TITOLARE dELL’AUTORIZZAZIOnE ALL’IMMISSIOnE In COMMERCIO
Octapharma Ltd. The Zenith Building 26 Spring Gardens Manchester M21AB UK.
Rappresentante Legale: Octapharma Italy S.p.A. Via Cisanello 145 56100 Pisa.
8. nUMERO(I) dELL’AUTORIZZAZIOnE ALL’IMMISSIOnE In COMMERCIO
Albunorm 20% Confezione da 1 flacone da 50 ml AIC n°: 039187063.
Albunorm 20% Confezione da 10 flaconi da 50 ml AIC n°: 039187075.
Albunorm 20% Confezione da 1 flacone da 100 ml AIC n°: 039187087.
Albunorm 20% Confezione da 10 flaconi da 100 ml AIC n°: 039187099.
9. dATA dELLA PRIMA AUTORIZZAZIOnE/ RInnOvO dELL’ AUTORIZZAZIOnE
Ottobre 2009.
10. dATA dI REvISIOnE dEL TESTO
Maggio 2011.