AggiornAmenti in riAnimAzione e terApiA intensivA - Pacini Editore
AggiornAmenti in riAnimAzione e terApiA intensivA - Pacini Editore
AggiornAmenti in riAnimAzione e terApiA intensivA - Pacini Editore
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ARTI<br />
<strong>AggiornAmenti</strong> <strong>in</strong> <strong>riAnimAzione</strong> e <strong>terApiA</strong> <strong>in</strong>tensivA
© Copyright 2011 by Pac<strong>in</strong>i <strong>Editore</strong> S.p.A. – Pisa<br />
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F<strong>in</strong>ito di stampare nel mese di Luglio 2011
presentazione<br />
In questo numero di ARTI vengono commentati, riportando anche voci<br />
bibliografiche ritenute <strong>in</strong>teressanti per eventuali approfondimenti, 3 articoli<br />
orig<strong>in</strong>ali o di revisione critica provenienti da riviste ad alto impact<br />
factor.<br />
Due di essi rivolgono la loro attenzione all’importanza dell’album<strong>in</strong>a nella<br />
Medic<strong>in</strong>a Critica.<br />
Il primo articolo sottol<strong>in</strong>ea l’importanza del monitoraggio dell’album<strong>in</strong>emia<br />
dimostrando, attraverso una meta-analisi, la possibilità di identificare<br />
nell’ipoalbum<strong>in</strong>emia un predittore <strong>in</strong>dipendente della lesione renale<br />
acuta (Acute Kidney Injury, AKI) e della mortalità conseguente all’AKI. Lo<br />
stesso primo autore 1 , <strong>in</strong> un’altra meta-analisi sull’uso dei colloidi e l’AKI,<br />
aveva cercato di dimostrare come l’album<strong>in</strong>a iperoncotica abbia un effetto<br />
renoprotettivo, concludendo poi come gli effetti renali possano essere<br />
specifici per particolari molecole di colloidi 2-4 .<br />
Il secondo articolo, sempre <strong>in</strong>erente l’album<strong>in</strong>a, è uno studio sperimentale<br />
sui ratti, che sottol<strong>in</strong>ea gli effetti benefici dell’album<strong>in</strong>a iperoncotica<br />
nella sepsi <strong>in</strong>dotta da peritonite. Questo studio documenta gli effetti di<br />
farmaco anti-ossidante e scavenger dell’album<strong>in</strong>a, e non solo di soluzione<br />
con proprietà oncotiche. Del resto, già dallo studio SAFE si era visto che<br />
l’album<strong>in</strong>a poteva avere effetti benefici nel sottogruppo di pazienti con<br />
sepsi grave e shock settico 5-8 .<br />
Il terzo articolo si propone di stimare se i difetti trombofilici parentali,<br />
dopo morte fetale, o acquisiti o ereditari, siano più prevalenti che nella<br />
popolazione normale, e si propone altresì di stimare le associazioni tra<br />
questi difetti trombofilici e i differenti casi di morte fetale. Un argomento<br />
questo molto discusso <strong>in</strong> letteratura, <strong>in</strong> special modo per i problemi che<br />
una attenta analisi costo-efficacia può sollevare <strong>in</strong> caso di screen<strong>in</strong>g della<br />
trombofilia nelle situazioni ad alto rischio 9-11 .<br />
La consultazione di questi articoli può dunque consegnare al lettore buoni<br />
strumenti di riflessione e di approfondimento.<br />
Buona lettura!<br />
Il Direttore Scientifico<br />
Giorgio Tulli<br />
Direttore del Dipartimento delle Terapie Intensive<br />
e della Medic<strong>in</strong>a Perioperatoria dell’Azienda Sanitaria Fiorent<strong>in</strong>a<br />
Letteratura da consultare<br />
1 Wiedermann CJ, Dunzendorfer S, Gaioni LU, et al. Hyperoncotic colloids and acute<br />
kidney <strong>in</strong>jury: a meta-analysis of randomized trials. Crit Care 2010;14:R191.<br />
2 Schortgen F, Girou E, Deye N, et al. The risk associated with hyperoncotic colloids <strong>in</strong><br />
patients with shock. Intensive Care Med 2008;34:2157-68.<br />
3 Rioux JP, Lessard M, De Bortoli B, et al. Pentastarch 10% (250 kDa/0.45) is an <strong>in</strong>dependent<br />
risk factor of acute kidney <strong>in</strong>jury follow<strong>in</strong>g cardiac surgery. Crit Care Med<br />
2009;37:1293-8.<br />
4 Davidson IJ. Acute kidney <strong>in</strong>jury by hydroxyethyl starch: can the risks be mitigated?<br />
Crit Care Med 2009;37:1499-501.<br />
5 F<strong>in</strong>fer S, Bellomo R, Boyce N, et al.; SAFE Study Investigators. A comparison of album<strong>in</strong><br />
and sal<strong>in</strong>e for fluid resuscitation <strong>in</strong> the <strong>in</strong>tensive care unit. N Engl J Med 2004;27:2247-<br />
56.<br />
3
4<br />
6 SAFE Study Investigators, F<strong>in</strong>fer S, Bellomo R, McEvoy S, et al. Effect of basel<strong>in</strong>e serum<br />
album<strong>in</strong> concentration on outcome of resuscitation with album<strong>in</strong> or sal<strong>in</strong>e <strong>in</strong> patients<br />
<strong>in</strong> <strong>in</strong>tensive care units: analysis of data from the sal<strong>in</strong>e vs. album<strong>in</strong> fluid evaluation<br />
(SAFE) study. BMJ 2006;333:1044.<br />
7 SAFE Study Investigators, F<strong>in</strong>fer S, McEvoy S, Bellomo R, et al. Impact of album<strong>in</strong><br />
compared to sal<strong>in</strong>e on organ function and mortality of patients with severe sepsis.<br />
Intensive Care Med 2011;37:86-96.<br />
8 Delaney AP, Dan A, McCaffrey J, et al. The role of album<strong>in</strong> as a resuscitation fluid<br />
for patients with sepsis: a systematic review and meta-analysis. Crit Care Med<br />
2011;39:386-91.<br />
9 Alonso A, Soto I, Urgellés MF, et al. Acquired and <strong>in</strong>herited thrombophilia <strong>in</strong> women<br />
with unexpla<strong>in</strong>ed fetal losses. Am J Obstet Gynecol 2002;187:1337-42.<br />
10 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal<br />
thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet<br />
Gynecol Reprod Biol 2002;101:6-14.<br />
11 Wu O, Robertson L, Twaddle S, et al. Screen<strong>in</strong>g for thrombophilia <strong>in</strong> high-risk situations:<br />
systematic review and cost-effectiveness analysis. The Thrombosis: Risk and<br />
Economic Assessment of Thrombophilia Screen<strong>in</strong>g (TREATS) study. Health Technol Assess<br />
2006;10:1-110.
Hypoalbum<strong>in</strong>emia and acute kidney <strong>in</strong>jury:<br />
a meta-analysis of observational cl<strong>in</strong>ical studies<br />
C.J. Wiedermann<br />
W. Wiedermann<br />
M. Joannidis<br />
Division of Internal Medic<strong>in</strong>e,<br />
Central Hospital of Bolzano,<br />
Italy<br />
PURPOSE: To test the hypothesis that hypoalbum<strong>in</strong>emia is <strong>in</strong>dependently<br />
associated with <strong>in</strong>creased risk of acute kidney <strong>in</strong>jury (AKI).<br />
METhOdS: A meta-analysis was performed of observational cl<strong>in</strong>ical studies<br />
evaluat<strong>in</strong>g the relationship between serum album<strong>in</strong> level and the occurrence<br />
of AKI by multivariate methods. Additionally, the impact was<br />
assessed of lower serum album<strong>in</strong> on mortality <strong>in</strong> patients who developed<br />
AKI. Eligible studies were sought by multiple methods, and adjusted odds<br />
ratios (OR) were quantitatively comb<strong>in</strong>ed us<strong>in</strong>g a random effects model.<br />
RESULTS: Seventeen cl<strong>in</strong>ical studies with 3,917 total patients were <strong>in</strong>cluded:<br />
11 studies (6 <strong>in</strong> surgical or <strong>in</strong>tensive care unit patients and 5 <strong>in</strong> other<br />
hospital sett<strong>in</strong>gs) evaluat<strong>in</strong>g the <strong>in</strong>fluence of serum album<strong>in</strong> on AKI <strong>in</strong>cidence<br />
and 6 studies describ<strong>in</strong>g the relationship between serum album<strong>in</strong><br />
and mortality among patients who had developed AKI. Lower serum album<strong>in</strong><br />
was an <strong>in</strong>dependent predictor both of AKI and of death after AKI<br />
development. With each 10 g L-1 serum album<strong>in</strong> decrement, the odds of<br />
AKI <strong>in</strong>creased by 134%. The pooled OR for AKI was 2.34 with a 95% confidence<br />
<strong>in</strong>terval (CI) of 1.74-3.14. Among patients who had developed AKI,<br />
the odds of death rose 147% (pooled OR 2.47, 95%CI 1.51-4.05) with each<br />
10 g L-1 serum album<strong>in</strong> decrement.<br />
COnCLUSIOnS: This meta-analysis provides evidence that hypoalbum<strong>in</strong>emia<br />
is a significant <strong>in</strong>dependent predictor both of AKI and of death follow<strong>in</strong>g<br />
AKI development. Serum album<strong>in</strong> determ<strong>in</strong>ations may be of utility<br />
<strong>in</strong> identify<strong>in</strong>g patients at <strong>in</strong>creased risk for AKI or for death after AKI.<br />
Controlled studies are warranted to assess <strong>in</strong>terventions aimed at correct<strong>in</strong>g<br />
hypoalbum<strong>in</strong>emia.<br />
Intensive Care Med 2010;36(10):1657-65<br />
5
La lesione renale acuta (Acute Kidney Injury, AKI) si associa ad una significativa morbilità e mortalità nei pazienti critici che presentano<br />
fattori di rischio che <strong>in</strong>cludono l’età, l’<strong>in</strong>dice di massa corporea, la funzione renale basale, l’<strong>in</strong>sufficienza circolatoria<br />
o respiratoria acuta, la malattia epatica, l’<strong>in</strong>fezione, la malattia occlusiva vascolare periferica, la malattia polmonare ostruttiva<br />
cronica, l’<strong>in</strong>sufficienza cardiaca cronica, il l<strong>in</strong>foma o la leucemia, le procedure <strong>in</strong>vasive e la chirurgia ad alto rischio.<br />
L’ipoalbum<strong>in</strong>emia è un fattore di rischio <strong>in</strong> alcune condizioni mediche acute, che <strong>in</strong>cludono l’ALI/ARDS 1 2 .<br />
Wiedermann et al. hanno cercato, mediante l’uso di una meta-analisi su studi cl<strong>in</strong>ici osservazionali, di determ<strong>in</strong>are la relazione<br />
tra livello sierico di album<strong>in</strong>a ed AKI.<br />
In 17 studi cl<strong>in</strong>ici che co<strong>in</strong>volgevano 3917 pazienti, il livello sierico di album<strong>in</strong>a più basso si dimostrava essere un predittore<br />
<strong>in</strong>dipendente sia di AKI che di morte dopo lo sviluppo dell’AKI stessa, con, per ogni g/dl di decremento della album<strong>in</strong>a serica,<br />
un <strong>in</strong>cremento della probabilità di AKI del 134%. Nei pazienti <strong>in</strong> cui si era già sviluppata l’AKI, la probabilità della morte saliva<br />
al 147% per ciascun g/dl di decremento della album<strong>in</strong>a serica. Questi autori concludono che l’ipoalbum<strong>in</strong>emia è un predittore<br />
<strong>in</strong>dipendente significativo sia di AKI che di mortalità a seguito di AKI, e che la misura dell’album<strong>in</strong>a serica può identificare i<br />
pazienti ad aumentato rischio di AKI o di morte dopo AKI.<br />
Questa meta-analisi suggerisce una nuova “tendenza” sulla patogenesi dell’AKI: che l’album<strong>in</strong>a serica possa giocare un ruolo<br />
diretto nello sviluppo e nell’outcome dell’AKI piuttosto che essere semplicemente un marker o un semplice spettatore associato<br />
alla malattia. Nonostante il fatto che l’ipoalbum<strong>in</strong>emia possa essere <strong>in</strong>dipendentemente associata all’AKI ed alla morte<br />
dopo AKI, l’associazione non prova una relazione causa-effetto. La relazione è <strong>in</strong>dipendente da altri fattori che sono stati riconosciuti,<br />
misurati e tenuti <strong>in</strong> conto (aggiustati) per la statistica, e per queste ragioni è robusta. Tuttavia gli studi osservazionali,<br />
<strong>in</strong>cludendo le grandi revisioni sistematiche come questa, non possono provare il rapporto causa-effetto.<br />
Con questo “caveat” <strong>in</strong> testa, è <strong>in</strong>teressante speculare se l’ipoalbum<strong>in</strong>emia potrebbe attualmente contribuire allo sviluppo di<br />
AKI, e se così fosse, <strong>in</strong> che modo? Se un rapporto potesse essere determ<strong>in</strong>ato, esso aprirebbe una nuova comprensione della<br />
patogenesi della malattia e offrirebbe anche una opportunità allo sviluppo di nuovi trattamenti. Potenziali considerazioni sono<br />
i cambiamenti nella nefrotossicità da farmaci, la renoprotezione diretta (attraverso le proprietà antiossidanti e di scaveng<strong>in</strong>g<br />
dei radicali liberi, fra molte altre proprietà) o la preservazione delle cellule tubulari e vascolari renali 3-5 .<br />
Riassumendo, la conclusione f<strong>in</strong>ale degli Autori, che le misure dell’album<strong>in</strong>a serica possano aiutare nel prognosticare l’AKI, è<br />
valida. Sfortunatamente poche terapie si possono ottenere solo sulla base del pronostico medico.<br />
Letteratura da consultare<br />
1 V<strong>in</strong>cent JL, Dubois MJ, Navickis RJ, et al. Hypoalbum<strong>in</strong>emia <strong>in</strong> acute illness: is there a rationale for <strong>in</strong>tervention? A metaanalysis<br />
of cohort studies and controlled trials. Ann Surg 2003;237:319-34.<br />
2 Mangialardi RJ, Mart<strong>in</strong> GS, Bernard GR, et al. Hypoprote<strong>in</strong>emia predicts acute respiratory distress syndrome development,<br />
weight ga<strong>in</strong>, and death <strong>in</strong> patients with sepsis. Ibuprofen <strong>in</strong> Sepsis Study Group. Crit Care Med 2000;28:3137-45.<br />
3 Contreras AM, Ramírez M, Cueva L, et al. Low serum album<strong>in</strong> and the <strong>in</strong>creased risk of amikac<strong>in</strong> nephrotoxicity. Rev Invest<br />
Cl<strong>in</strong> 1994;46:37-43.<br />
4 Iglesias J, Abernethy VE, Wang Z, et al. Album<strong>in</strong> is a major serum survival factor for renal tubular cells and macrophages<br />
through scaveng<strong>in</strong>g of ROS. Am J Physiol 1999;277:F711-22.<br />
5 Lee YJ, Han HJ. Album<strong>in</strong>-stimulated DNA synthesis is mediated by Ca2+/PKC as well as EGF receptor-dependent p44/42<br />
MAPK and NF-kappaB signal pathways <strong>in</strong> renal proximal tubule cells. Am J Physiol Renal Physiol 2008;294:F534-41.<br />
6
Beneficial effects of hyperoncotic album<strong>in</strong> on liver<br />
<strong>in</strong>jury and survival <strong>in</strong> peritonitis-<strong>in</strong>duced sepsis rats<br />
C.M. Tsao<br />
H.C. Huang<br />
Z.F. Chen<br />
W.J. Liaw<br />
W.M. Lue<br />
A. Chen<br />
S.J. Chen<br />
C.C. Wu<br />
Department<br />
of Anesthesiology, Taipei<br />
Veterans General Hospital,<br />
National Yang-M<strong>in</strong>g<br />
University, Taipei, R.O.C.,<br />
Taiwan; Department<br />
of Anesthesiology<br />
and Pa<strong>in</strong> Cl<strong>in</strong>ics, Cheng Hs<strong>in</strong><br />
Rehabilitation Medical Center,<br />
Taipei, R.O.C., Taiwan;<br />
Department of Pharmacology,<br />
Department of Pathology<br />
and Department<br />
of Physiology, National<br />
Defense Medical Center,<br />
Taipei, R.O.C., Taiwan;<br />
Department<br />
of Anesthesiology,<br />
Tri-Service General Hospital,<br />
National Defense Medical<br />
Center, Taipei, R.O.C., Taiwan;<br />
Department of Nurs<strong>in</strong>g,<br />
Kang-N<strong>in</strong>g Junior College<br />
of Medical Care<br />
and Management, Taipei,<br />
R.O.C., Taiwan<br />
Liver <strong>in</strong>jury/dysfunction develop<strong>in</strong>g <strong>in</strong> patients with sepsis may lead to<br />
an <strong>in</strong>creased risk of death. Small-volume resuscitation with hyperoncotic<br />
album<strong>in</strong> (HA) has been proposed to restore physiologic hemodynamics <strong>in</strong><br />
hemorrhagic and septic shock. We evaluated whether HA resuscitation<br />
could alleviate the development of liver <strong>in</strong>jury/dysfunction <strong>in</strong> rats with<br />
polymicrobial sepsis <strong>in</strong>duced by cecal ligation and puncture (CLP). The<br />
male Wistar rats received 0.9% sal<strong>in</strong>e or HA (25%, 3 ml/kg <strong>in</strong>travenously)<br />
at 3 h after CLP or sham operation. All hemodynamic and biochemical<br />
variables were measured dur<strong>in</strong>g the 18-h observation. After 18 h of CLP,<br />
the septic rats developed circulatory failure (i.e., hypotension, tachycardia<br />
and poor tissue perfusion), liver <strong>in</strong>jury (exam<strong>in</strong>ed by biochemical variables<br />
and histologic studies), and a higher mortality. HA not only ameliorated<br />
the deterioration of hemodynamic changes but also attenuated neutrophil<br />
<strong>in</strong>filtration and cell death <strong>in</strong> the liver of septic animals. The septic<br />
rats treated with HA had a higher survival when compared with those<br />
with 0.9% sal<strong>in</strong>e treatment. Moreover, the <strong>in</strong>creased plasma <strong>in</strong>terleuk<strong>in</strong><br />
(IL)-1beta, plasma IL-6, plasma nitrite/nitrate concentrations, liver <strong>in</strong>ducible<br />
nitric oxide synthase expression, and liver superoxide levels <strong>in</strong> CLP rats<br />
were attenuated after adm<strong>in</strong>istration of HA. Thus, HA may be regarded<br />
as a potential therapeutic agent <strong>in</strong> the early treatment of septic shock <strong>in</strong><br />
order to prevent or reduce subsequent liver failure.<br />
Shock 2011;35(2):210-6<br />
7
Lo shock settico nel corso di una grave <strong>in</strong>fezione microbica può progredire f<strong>in</strong>o ad una Multiple Organs Dysfunction S<strong>in</strong>drome<br />
(MODS), nonostante i recenti progressi nella Medic<strong>in</strong>a Critica.<br />
La MODS sequenziale può portare ad un aumento nella mortalità dal 30 al 100% a seconda del numero degli organi co<strong>in</strong>volti<br />
1 . Nella patofisiologia della sepsi, i cambiamenti emod<strong>in</strong>amici, metabolici ed <strong>in</strong>fiammatori che si sviluppano nei pazienti<br />
possono compromettere le funzioni dei vari organi. La disfunzione/<strong>in</strong>sufficienza epatica <strong>in</strong>dotta dalla sepsi è di solito attribuita<br />
a disturbi sistemici o microcircolatori, spillovers di batteri ed endotoss<strong>in</strong>a e successiva attivazione di citoch<strong>in</strong>e <strong>in</strong>fiammatorie e<br />
mediatori 2 3 . La sovrapproduzione di mediatori secreti localmente e circolanti, come le citoch<strong>in</strong>e pro<strong>in</strong>fiammatorie, NO e ROS,<br />
che portano ad ipossia tissutale e morte cellulare, contribuisce alla lesione epatica e sua disfunzione 4 5 .<br />
Il primo passo nella rianimazione cardiovascolare dello shock settico è quello di recuperare e mantenere un adeguato volume<br />
<strong>in</strong>travascolare con un “challenge” di fluidi. A paragone dei fluidi cristalloidi, l’album<strong>in</strong>a sembra essere più efficace nell’espansione<br />
del volume <strong>in</strong>travascolare e sembra migliorare la funzione d’organo nei pazienti critici, specialmente <strong>in</strong> quelli ipoalbum<strong>in</strong>emici<br />
6 7 . La somm<strong>in</strong>istrazione di album<strong>in</strong>a iperoncotica al 20% con furosemide migliora l’ossigenazione e la stabilità cardiovascolare<br />
nei pazienti con Acute Lung Injury <strong>in</strong>dotta da sepsi 8 . L’album<strong>in</strong>a iperoncotica preserva un più alto cardiac output, un<br />
più alto oxygen delivery e più bassi livelli ematici di lattato di quanto non facciano i cristalloidi 9 .<br />
L’album<strong>in</strong>a è uno scavenger delle specie reattive dell’ossigeno, lega gli ioni metallici di transizione e presenta una ampia varietà<br />
di effetti biologici rimpiazzando le concentrazioni tioliche plasmatiche 10 .<br />
Il beneficio cl<strong>in</strong>ico dell’album<strong>in</strong>a può essere attribuito alle sue proprietà ant<strong>in</strong>fiammatorie oltre che all’espansione del volume<br />
<strong>in</strong>travascolare e l’effetto antiossidante. Il dialisato di album<strong>in</strong>a usato <strong>in</strong> un circuito di emodiafiltrazione <strong>in</strong> vitro è più efficace<br />
nella clearance del TNF ed IL-6 del dialisato con fisiologica 11 . La rianimazione con album<strong>in</strong>a iperoncotica attenua moltissimo<br />
la lesione polmonare <strong>in</strong> un modello di topo con shock emorragico, dim<strong>in</strong>uendo la chemoattrazione dei neutrofili <strong>in</strong>dotta dalle<br />
citoch<strong>in</strong>e e la traslocazione sull’NF-kB 12 .<br />
Ci sono ancora molte controversie riguardo all’impatto della album<strong>in</strong>a iperoncotica sull’outcome 13-15 . In uno studio cl<strong>in</strong>ico di<br />
grandi proporzioni, i pazienti con sepsi grave avevano rischi più elevati di morte e lesione renale quando sottoposti a rianimazione<br />
con album<strong>in</strong>a iperoncotica 14 . Tuttavia altri studi hanno dimostrato che una rianimazione small-volume con album<strong>in</strong>a<br />
iperoncotica può migliorare la risposta al trattamento ed accorciare la degenza nei pazienti con malattia epatica 15 .<br />
Questo studio effettuato da un gruppo dell’Università di Taipei (Taiwan), assieme alla prevenzione della lesione epatica ed al<br />
miglioramento dell’ipoperfusione con la rianimazione con album<strong>in</strong>a a piccolo volume, suggerisce che l’album<strong>in</strong>a iperoncotica al<br />
25% data 3 ore dopo la CLP (cecal ligation and punture) protegge il fegato contro la lesione causata dalle citoch<strong>in</strong>e pro<strong>in</strong>fiammatorie,<br />
NO ed O 2 che sono di solito il risultato della proattivazione dei neutrofili. Il risultato <strong>in</strong>trigante di questo studio potrebbe<br />
fornire una messe di <strong>in</strong>formazione riguardante l’applicazione cl<strong>in</strong>ica della terapia con album<strong>in</strong>a iperoncotica nei pazienti criticamente<br />
ammalati e spiegare rilevanti meccanismi biologici <strong>in</strong> questa popolazione. Alcuni co-autori di questo studio, nel 2008<br />
avevano pubblicato su Critical Care Medic<strong>in</strong>e 16 uno studio sperimentale sui ratti sugli effetti terapeutici della fisiologica ipertonica<br />
nello shock settico provocato dalla peritonite con MODS. Questi stessi autori concludevano che la fisiologica ipertonica preveniva<br />
l’<strong>in</strong>sufficienza circolatoria, alleviava la MODS e dim<strong>in</strong>uiva la percentuale di mortalità negli animali sottoposti a CLP. Secondo gli<br />
autori gli effetti benefici della fisiologica ipertonica potevano essere attribuiti alla ridotta concentrazione plasmatica dell’NO e<br />
dell’IL-1 beta così come al ridotto livello di O 2 -*, alla dim<strong>in</strong>uita <strong>in</strong>filtrazione polmonare dei neutrofili ed alla dim<strong>in</strong>uita necrosi<br />
epatica. Sorge spontanea la domanda: album<strong>in</strong>a ipertonica o sal<strong>in</strong>a ipertonica? A quale costo?<br />
Letteratura da consultare<br />
1 Russell JA. Management of sepsis. N Engl J Med 2006;355:1699-713.<br />
2 Dha<strong>in</strong>aut JF, Mar<strong>in</strong> N, Mignon A, et al. Hepatic response to sepsis: <strong>in</strong>teraction between coagulation and <strong>in</strong>flammatory<br />
processes. Crit Care Med 2001;29:S42-7.<br />
3 Wang XD, Soltesz V, Andersson R, et al. Bacterial translocation <strong>in</strong> acute liver failure <strong>in</strong>duced by 90% hepatectomy <strong>in</strong> the<br />
rat. Br J Surg 1993;80:66-71.<br />
4 Hewett JA, Roth RA. Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 1993;45:382-411.<br />
5 Szabo G, Romics L Jr, Frendl G. Liver <strong>in</strong> sepsis and systemic <strong>in</strong>flammatory response syndrome. Cl<strong>in</strong> Liver Dis 2002;6:1045-66.<br />
6 Ernest D, Belzberg AS, Dodek PM. Distribution of normal sal<strong>in</strong>e and 5% album<strong>in</strong> <strong>in</strong>fusions <strong>in</strong> septic patients. Crit Care Med<br />
1999;27:46-50.<br />
7 Dubois MJ, Orellana-Jimenez C, Melot C, et al. Album<strong>in</strong> adm<strong>in</strong>istration improves organ function <strong>in</strong> critically ill hypoalbum<strong>in</strong>emic<br />
patients: a prospective, randomized, controlled, pilot study. Crit Care Med 2006;34:2536-40.<br />
8 Mart<strong>in</strong> GS, Moss M, Wheeler AP, et al. A randomized, controlled trial of furosemide with or without album<strong>in</strong> <strong>in</strong> hypoprote<strong>in</strong>emic<br />
patients with acute lung <strong>in</strong>jury. Crit Care Med 2005;33:1681-7.<br />
9 Su F, Wang Z, Cai Y, et al. Fluid resuscitation <strong>in</strong> severe sepsis and septic shock: album<strong>in</strong>, hydroxyethyl starch, gelat<strong>in</strong> or<br />
r<strong>in</strong>ger’s lactate-does it really make a difference? Shock 2007;27:520-6.<br />
10 Qu<strong>in</strong>lan GJ, Margarson MP, Mumby S, et al. Adm<strong>in</strong>istration of album<strong>in</strong> to patients with sepsis syndrome: a possible beneficial<br />
role <strong>in</strong> plasma thiol repletion. Cl<strong>in</strong> Sci (Lond) 1998;95:459-65.<br />
11 Awad SS, Sawada S, Soldes OS, et al. Can the clearance of tumor necrosis factor alpha and <strong>in</strong>terleuk<strong>in</strong> 6 be enhanced<br />
us<strong>in</strong>g an album<strong>in</strong> dialysate hemodiafiltration system? ASAIO J 1999;45:47-9.<br />
12 Powers KA, Kapus A, Khadaroo RG, et al. 25% album<strong>in</strong> prevents lung <strong>in</strong>jury follow<strong>in</strong>g shock resuscitation. Crit Care Med<br />
2003;31:2355-63.<br />
13 Kuper M, Gunn<strong>in</strong>g MP, Halder S, et al. The short-term effect of hyperoncotic album<strong>in</strong>, given alone or with furosemide, on<br />
oxygenation <strong>in</strong> sepsis-<strong>in</strong>duced acute respiratory distress syndrome. Anaesthesia 2007;62:259-63.<br />
14 Schortgen F, Girou E, Deye N, et al. The risk associated with hyperoncotic colloids <strong>in</strong> patients with shock. Intensive Care<br />
Med 2008;34:2157-68.<br />
15 Jacob M, Chappell D, Conzen P, et al. Small-volume resuscitation with hyperoncotic album<strong>in</strong>: a systematic review of randomized<br />
cl<strong>in</strong>ical trials. Crit Care 2008;12:R34.<br />
16 Shih CC, Chen SJ, Chen A, et al. Therapeutic effects of hypertonic sal<strong>in</strong>e on peritonitis-<strong>in</strong>duced septic shock with multiple<br />
organ dysfunction syndrome <strong>in</strong> rats. Crit Care Med 2008;36:1864-72.<br />
8
prevalence of parental thrombophilic defects<br />
after fetal death and relation to cause<br />
F.J. Korteweg<br />
J.J. Erwich<br />
N. Folker<strong>in</strong>ga<br />
A. Timmer<br />
N.J. Veeger<br />
J.M. Ravisé<br />
J.P. Holm<br />
J. van der Meer<br />
Department of Obstetrics,<br />
Division of Haemostasis,<br />
Trial Coord<strong>in</strong>ation Center,<br />
University Medical Center<br />
Gron<strong>in</strong>gen, University<br />
of Gron<strong>in</strong>gen,<br />
The Netherlands<br />
ObjECTIvE: To estimate whether parental thrombophilic defects after fetal<br />
death, either acquired or <strong>in</strong>herited, were more prevalent than <strong>in</strong> the<br />
normal population and to estimate associations between these thrombophilic<br />
defects and different fetal death causes.<br />
METhOdS: In a multicenter, prospective cohort study of 750 fetal deaths,<br />
we tested couples for antithromb<strong>in</strong>, prote<strong>in</strong> C, total and free prote<strong>in</strong> S,<br />
and von Willebrand factor (vWF) plasma levels. Mothers’ values were compared<br />
with reference values <strong>in</strong> gestational age-matched healthy pregnant<br />
women, and fathers were compared with healthy men. Prevalence of factor<br />
V Leiden, prothromb<strong>in</strong> G20210A mutation, and lupus anticoagulant<br />
were compared with the normal population. A panel classified death<br />
cause.<br />
RESULTS: More women with fetal death had decreased antithromb<strong>in</strong><br />
(16.8%, p < .001) and prote<strong>in</strong> C (4.0%, p = .03) and <strong>in</strong>creased vWF (15.5%,<br />
p < .001) plasma levels than healthy pregnant women (2.5%). However,<br />
compared with normal ranges <strong>in</strong> the nonpregnant population, we only<br />
observed more women with <strong>in</strong>creased vWF (12.4%, p < .001). More fathers<br />
had decreased free prote<strong>in</strong> S (6.3%, p < .001) and elevated vWF (12.1%,<br />
p < .001) than healthy men (2.5%). Prevalence of <strong>in</strong>herited thrombophilias<br />
was not higher <strong>in</strong> couples with fetal death than <strong>in</strong> the population. Neither<br />
<strong>in</strong>herited nor acquired maternal or paternal thrombophilic defects<br />
were associated with the ma<strong>in</strong> cause of death. Of placental causes, abruption<br />
and <strong>in</strong>farction were associated with acquired maternal defects.<br />
COnCLUSIOn: Except for vWF and paternal free prote<strong>in</strong> S, acquired and<br />
<strong>in</strong>herited thrombophilic defects were not more prevalent after fetal<br />
death. Rout<strong>in</strong>e thrombophilia test<strong>in</strong>g after fetal death is not advised.<br />
Obstet Gynecol 2010;116(2 Pt 1):355-64<br />
9
Circa una su 200 gravidanze f<strong>in</strong>isce <strong>in</strong> aborto come risultato di cause differenti. I difetti trombofilici ereditati dalla madre sono<br />
riconosciuti, con pareri discordanti, come fattori di rischio di complicazioni durante la gravidanza come la pre-eclampsia, la<br />
rottura di placenta, restrizioni nella crescita ed aborto; anche i fattori trombofilici paterni possono essere trasferiti al feto e<br />
alla placenta 1-4 . Molti studi si sono orientati verso l’associazione fra deficienze ereditate trombofiliche e perdita fetale tardiva<br />
<strong>in</strong> famiglie con deficienze ereditate, anche se studi di coorte e di caso controllo hanno osservato sistematicamente donne<br />
con perdita del feto che erano state testate per trombofilia dopo il parto. In alcune revisioni critiche, un più alto rischio di<br />
perdita fetale è stato segnalato per deficienza di antitromb<strong>in</strong>a e prote<strong>in</strong>a S, fattore V Leiden, mutazione protromb<strong>in</strong>a 20210A<br />
e anticorpi anticardiolip<strong>in</strong>a 5-7 . La patofisiologia della perdita fetale tardiva associata con trombofilia ereditaria si presume si<br />
possa spiegare con una trombosi placentare o nella circolazione materna o nella circolazione fetale della placenta che porta<br />
ad <strong>in</strong>farto placentare ed <strong>in</strong>sufficienza placentare 8 . È stato difficile provare questa ipotesi a causa dei piccoli numeri co<strong>in</strong>volti<br />
negli studi precedenti, ed anche perché la <strong>in</strong>sufficienza placentare era spesso non ben def<strong>in</strong>ita e non ben correlata alla causa<br />
di morte 9-12 . La gravidanza è di per sé uno stato ipercoagulabile che risulta da difetti trombofilici acquisiti che espongono la<br />
donna ad un più alto rischio di trombosi 13 . In comb<strong>in</strong>azione con i preesistenti difetti trombofilici ereditati, esso può aumentare<br />
il rischio di morte fetale. Si conosce molto poco circa il contributo dei difetti trombofilici acquisiti allo stato di ipercoagulazione<br />
e alla morte fetale, perché le donne nei precedenti studi erano testate per la trombofilia solo parecchie settimane dopo il<br />
parto. L’obiettivo di questo studio multidiscipl<strong>in</strong>are olandese, è quello di stimare se <strong>in</strong> una coorte di donne con morte fetale<br />
<strong>in</strong>trauter<strong>in</strong>a i difetti trombofilici – acquisiti durante la gravidanza o ereditati – e i difetti ereditati nei padri erano più prevalenti<br />
rispetto alla normale popolazione. Inoltre gli autori dello studio hanno cercato di stimare quale fosse l’associazione fra questi<br />
difetti trombofilici e le varie cause di morte fetale all’<strong>in</strong>terno della coorte.<br />
In questo studio più donne che avevano presentato morte fetale avevano un’antitromb<strong>in</strong>a ed una prote<strong>in</strong>a C dim<strong>in</strong>uite ed un<br />
livello plasmatico di vWF aumentato rispetto alle donne gravide sane. Tuttavia, facendo il paragone con gli <strong>in</strong>tervalli normali<br />
nella popolazione non gravida, è stato osservato solamente un maggior numero di donne con un aumentato vWF. Più padri<br />
avevano una prote<strong>in</strong>a S libera dim<strong>in</strong>uita ed un elevato vWF rispetto agli uom<strong>in</strong>i sani. La prevalenza delle trombofilie ereditarie<br />
non era più alta nelle coppie con morte fetale che nella normale popolazione. Né i difetti trombofilici materni o paterni ereditati<br />
o acquisiti erano associati con la pr<strong>in</strong>cipale causa di morte. Delle cause placentari la rottura e l’<strong>in</strong>farto erano associate<br />
con difetti materni acquisiti. La necessità di effettuare test di rout<strong>in</strong>e dei difetti trombofilici dopo morte fetale non è sostenuta<br />
dai risultati di questo studio, eccetto che nelle donne con storia familiare di trombofilia ereditaria o una storia personale di<br />
tromboembolismo venoso e morte fetale <strong>in</strong>trauter<strong>in</strong>a, nelle quali il fare test orientati potrebbe aiutare a prevenire un ulteriore<br />
tromboembolismo venoso materno. Può anche essere preso <strong>in</strong> considerazione effettuare test orientati a donne con una morte<br />
fetale causata da rottura o <strong>in</strong>farto placentare. Tuttavia, lo screen<strong>in</strong>g della trombofilia dovrebbe essere effettuato solo nei casi<br />
<strong>in</strong> cui possa essere offerto poi un appropriato trattamento ed una appropriata assistenza. F<strong>in</strong>o a quando non ci saranno trial<br />
controllati randomizzati che dimostr<strong>in</strong>o il reale beneficio della terapia anticoagulante <strong>in</strong> casi con ben riconosciuti fattori trombofilici<br />
<strong>in</strong> relazione a perdita fetale tardiva, dobbiamo essere prudenti nell’implementazione di un <strong>in</strong>tervento potenzialmente<br />
dannoso per la donna gravida. Nello studio, se si fa eccezione per il vWF e la prote<strong>in</strong>a libera S paterna, i difetti acquisiti ed<br />
ereditati non erano più prevalenti dopo morte fetale. Il fare test di rout<strong>in</strong>e della trombofilia dopo morte fetale non è dunque<br />
consigliato. Testare livelli anormali di antitromb<strong>in</strong>a, attività della prote<strong>in</strong>a C, antigene totale della prote<strong>in</strong>a S o vWF potrebbe<br />
solo far identificare dei predittori per un sub-gruppo a rischio di morte fetale causata da rottura o <strong>in</strong>farto placentari.<br />
Letteratura da consultare<br />
1 Silver RM. Fetal death. Ostet Gynecol 2007;109:153-67.<br />
2 Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with <strong>in</strong>trauter<strong>in</strong>e<br />
growth restriction. N Engl J Med 2002;347;19-25.<br />
3 Kupferm<strong>in</strong>c MJ, Eldor A, Ste<strong>in</strong>man N, et al. Increased frequency of genetic thrombophilia <strong>in</strong> women with complications of<br />
pregnancy. N Engl J Med 1999;340:9-13.<br />
4 Khong TY, Hague WM. Biparental contribution to fetal thrombophilia <strong>in</strong> discordant tw<strong>in</strong> <strong>in</strong>trauter<strong>in</strong>e growth restriction.<br />
Am J Obstet Gynecol 2001;185:244-5.<br />
5 Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost 2007;5(Suppl 1):276-<br />
82.<br />
6 Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:1-8.<br />
7 Robertson L, Wu O, Langhorne P, et al. Thrombophilia <strong>in</strong> pregnancy: a systematic review. Br J Haematol 2006;132:171-<br />
96.<br />
8 Redl<strong>in</strong>e RW. Thrombophilia and placental pathology. Cl<strong>in</strong> Obstet Gynecol 2006;49:885-94.<br />
9 Alonso A, Soto I, Urgellés MF, et al. Acquired and <strong>in</strong>herited thrombophilia <strong>in</strong> women with unexpla<strong>in</strong>ed fetal losses. Am J<br />
Obstet Gynecol 2002;187:1337-42.<br />
10 Arias F, Romero R, Joist H, et al. Thrombophilia: a mechanism of disease <strong>in</strong> women with adverse pregnancy outcome and<br />
thrombotic lesions <strong>in</strong> the placenta. J Matern Fetal Med 1998;7:277-86.<br />
11 Morss<strong>in</strong>k LP, Santema JG, Willemse F. Thrombophilia is not associated with an <strong>in</strong>crease <strong>in</strong> placental abnormalities <strong>in</strong><br />
women with <strong>in</strong>tra-uter<strong>in</strong>e fetal death. Acta Obstet Gynecol Scand 2004;83:348-50.<br />
12 Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state <strong>in</strong> women with adverse pregnancy outcome? Hum<br />
Reprod 2000;15:1830-3.<br />
13 Stirl<strong>in</strong>g Y, Woolf L, North WR, et al. Haemostasis <strong>in</strong> normal pregnancy. Thromb Haemost 1984;52:176-82.<br />
10
ecipient tissue factor expression is associated<br />
with consumptive coagulopathy <strong>in</strong> pig-to-primate<br />
kidney xenotransplantation<br />
C.C. L<strong>in</strong><br />
M. Ezzelarab<br />
R. Shapiro<br />
R. Ekser<br />
C. Long<br />
H. Hara<br />
G. Echeverri<br />
C. Torres<br />
H. Watanabe<br />
D. Ayares<br />
A. Dorl<strong>in</strong>g<br />
D.K. Cooper<br />
E. Thomas<br />
Starzl Transplantation<br />
Institute, University<br />
of Pittsburgh, PA, USA<br />
Consumptive coagulopathy (CC) rema<strong>in</strong>s a challenge <strong>in</strong> pig-to-primate<br />
organ xenotransplantation (Tx). This study <strong>in</strong>vestigated the role of tissue<br />
factor (TF) expression on circulat<strong>in</strong>g platelets and peripheral blood mononuclear<br />
cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs<br />
that were either wild-type (n = 2), alpha1,3-galactosyltransferase geneknockout<br />
(GT-KO; n = 1) or GT-KO and transgenic for the complementregulatory<br />
prote<strong>in</strong>, CD46 (GT-KO/CD46, n = 6). In the baboon where the<br />
graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed<br />
TF with<strong>in</strong> 4 h of Tx. In the rema<strong>in</strong><strong>in</strong>g baboons, TF was detected on<br />
platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation<br />
developed with formation of thromb<strong>in</strong>. In the six baboons with CC, TF<br />
was not detected on baboon PBMCs until CC was beg<strong>in</strong>n<strong>in</strong>g to develop.<br />
Graft histopathology showed fibr<strong>in</strong> deposition and platelet aggregation<br />
(n = 6), but with only m<strong>in</strong>or or no features <strong>in</strong>dicat<strong>in</strong>g a humoral immune<br />
response (n = 3), and no macrophage, B or T cell <strong>in</strong>filtration (n = 6). Activation<br />
of platelets to express TF was associated with the <strong>in</strong>itiation of<br />
CC, whereas TF expression on PBMCs was concomitant with the onset of<br />
CC, often <strong>in</strong> the relative absence of features of acute humoral xenograft<br />
rejection. Prevention of recipient platelet activation may be crucial for<br />
successful pig-to-primate kidney Tx.<br />
Am j Transplant 2010;10(7):1556-68<br />
11
12<br />
thrombotic microangiopathy after kidney<br />
transplantation<br />
M. Noris<br />
G. Remuzzi<br />
Cl<strong>in</strong>ical Research Center<br />
for Rare Diseases<br />
“Aldo e Cele Daccò”,<br />
Mario Negri Institute<br />
for Pharmacological Research,<br />
Ranica, Bergamo, Italy<br />
Thrombotic microangiopathy (TMA) is a severe complication of kidney<br />
transplantation that often causes graft failure. TMA may occur de novo,<br />
often triggered by immunosuppressive drugs and acute antibody-mediated<br />
rejection, or recur <strong>in</strong> patients with previous history of hemolytic uremic<br />
syndrome (HUS). Recurrent TMA is very rare <strong>in</strong> patients who had developed<br />
end-stage renal failure follow<strong>in</strong>g HUS caused by Shiga-tox<strong>in</strong> produc<strong>in</strong>g<br />
Escherichia coli, whereas disease recurrence is common <strong>in</strong> patients<br />
with atypical HUS (aHUS). The underly<strong>in</strong>g genetic defect greatly impacts<br />
the risk of posttransplant recurrence <strong>in</strong> aHUS. Indeed recurrence is almost<br />
the rule <strong>in</strong> patients with mutations <strong>in</strong> genes encod<strong>in</strong>g factor H or factor<br />
I, whereas patients with a mutation <strong>in</strong> membrane-cofactor-prote<strong>in</strong> gene<br />
have a good transplant outcome. Prophylactic and therapeutic options<br />
for posttransplant TMA, <strong>in</strong>clud<strong>in</strong>g plasma therapy, comb<strong>in</strong>ed kidney and<br />
liver transplantation and targeted complement <strong>in</strong>hibitors are discussed <strong>in</strong><br />
this review.<br />
Am j Transplant 2010;10(7):1517-23
Cost-effectiveness of strategies for diagnos<strong>in</strong>g<br />
pulmonary embolism among emergency department<br />
patients present<strong>in</strong>g with undifferentiated symptoms<br />
R.S. Duriseti<br />
M.L. Brandeau<br />
Department of Veterans<br />
Affairs Palo Alto Health Care<br />
System, Palo Alto, CA,<br />
and the Division<br />
of Emergency Medic<strong>in</strong>e,<br />
Department of Surgery,<br />
Stanford University,<br />
Stanford, CA<br />
STUdy ObjECTIvE: Symptoms associated with pulmonary embolism can<br />
be nonspecific and similar to many compet<strong>in</strong>g diagnoses, lead<strong>in</strong>g to excessive<br />
costly test<strong>in</strong>g and treatment, as well as missed diagnoses. Objective<br />
studies are essential for diagnosis. This study evaluates the cost-effectiveness<br />
of different diagnostic strategies <strong>in</strong> an emergency department<br />
(ED) for patients present<strong>in</strong>g with undifferentiated symptoms suggestive<br />
of pulmonary embolism.<br />
METhOdS: Us<strong>in</strong>g a probabilistic decision model, we evaluated the <strong>in</strong>cremental<br />
costs and effectiveness (quality-adjusted life-years ga<strong>in</strong>ed) of 60<br />
test<strong>in</strong>g strategies for 5 patient pretest categories (dist<strong>in</strong>guished by Wells<br />
score [high, moderate, or low] and whether deep venous thrombosis is<br />
cl<strong>in</strong>ically suspected). We performed determ<strong>in</strong>istic and probabilistic sensitivity<br />
analyses.<br />
RESULTS: In the base case, for all patient pretest categories, the most<br />
cost-effective diagnostic strategy is to use an <strong>in</strong>itial enzyme-l<strong>in</strong>ked immunosorbent<br />
assay D-dimer test, followed by compression ultrasonography<br />
of the lower extremities if the D-dimer is above a specified cutoff. The<br />
level of the preferred cutoff varies with the Wells pretest category and<br />
whether a deep venous thrombosis is cl<strong>in</strong>ically suspected. D-dimer cutoffs<br />
higher than the current recommended cutoff were often preferred for<br />
patients with even moderate and high Wells categories. Compression ultrasonography<br />
accuracy had to decrease below commonly cited levels <strong>in</strong><br />
the literature before it was not part of a preferred strategy.<br />
COnCLUSIOn: When pulmonary embolism is suspected <strong>in</strong> the ED, use of<br />
an enzyme-l<strong>in</strong>ked immunosorbent assay D-dimer assay, often at cutoffs<br />
higher than those currently <strong>in</strong> use (for patients <strong>in</strong> whom deep venous<br />
thrombosis is not cl<strong>in</strong>ically suspected), followed by compression ultrasonography<br />
as appropriate, can reduce costs and improve outcomes.<br />
Ann Emerg Med 2010;56(4):321-32<br />
13
14<br />
mitochondrial dysfunction and resuscitation <strong>in</strong> sepsis<br />
A.J. Ruggieri<br />
R.J. Levy<br />
C.S. Deutschman<br />
Department<br />
of Anesthesiology<br />
and Critical Care,<br />
University of Pennsylvania<br />
School of Medic<strong>in</strong>e,<br />
Philadelphia,<br />
PA, USA<br />
Sepsis is among the most common causes of death <strong>in</strong> patients <strong>in</strong> <strong>in</strong>tensive<br />
care units <strong>in</strong> North America and Europe. In the United States, it accounts<br />
for upwards of 250,000 deaths each year. Investigations <strong>in</strong>to the<br />
pathobiology of sepsis have most recently focused on common cellular<br />
and subcellular processes. One possibility would be a defect <strong>in</strong> the production<br />
of energy, which translates to an abnormality <strong>in</strong> the production<br />
of adenos<strong>in</strong>e triphosphate and therefore <strong>in</strong> the function of mitochondria.<br />
This article presents a clear role for mitochondrial dysfunction <strong>in</strong><br />
the pathogenesis and pathophysiology of sepsis. What is less clear is the<br />
teleology underly<strong>in</strong>g this response. Prolonged mitochondrial dysfunction<br />
and impaired biogenesis clearly are detrimental. However, early <strong>in</strong>hibition<br />
of mitochondrial function may be adaptive.<br />
Crit Care Cl<strong>in</strong> 2010;26(3):567-75, x-xi
Quality of life after <strong>in</strong>tensive care: a systematic review<br />
of the literature<br />
S.G. Oeyen<br />
D.M. Vandijck<br />
D.D. Benoit<br />
L. Annemans<br />
J.M. Decruyenaere<br />
Department of Intensive Care<br />
Medic<strong>in</strong>e (SGO, DDB, JMD),<br />
Ghent University Hospital,<br />
Ghent, Belgium; Faculty<br />
of Medic<strong>in</strong>e and Health<br />
Sciences (DMV, LA), Ghent<br />
University, Ghent, Belgium<br />
ObjECTIvES: To evaluate quality of life at least 12 months after discharge<br />
from the <strong>in</strong>tensive care unit of adult critically ill patients, to evaluate the<br />
methodology used to assess long-term quality of life, and to give an overview<br />
of factors <strong>in</strong>fluenc<strong>in</strong>g quality of life.<br />
dATA SOURCES: EMBASE-PubMed, MEDLINE (OVID), SCI/Web of Science,<br />
the Cochrane Library, Google Scholar, and personal files.<br />
dATA ExTRACTIOn: Data extraction was performed <strong>in</strong>dependently and<br />
cross-checked by two reviewers us<strong>in</strong>g a predef<strong>in</strong>ed data extraction form.<br />
Eligible studies were published between 1999 and 2009 and assessed<br />
quality of life ≥ 12 months after <strong>in</strong>tensive care unit discharge by means of<br />
the Medical Outcomes Study 36-Item Short Form Health Survey, the RAND<br />
36-Item Health Survey, EuroQol-5D, and/or the Nott<strong>in</strong>gham Health Profile<br />
<strong>in</strong> adult <strong>in</strong>tensive care unit patients.<br />
dATA SynThESIS: Fifty-three articles (10 multicenters) were <strong>in</strong>cluded,<br />
with the majority of studies performed <strong>in</strong> Europe (68%). The Medical<br />
Outcomes Study 36-Item Short Form Health Survey was used <strong>in</strong> 55%, and<br />
the EuroQol-5D, the Nott<strong>in</strong>gham Health Profile, the RAND 36-Item Health<br />
Survey, or a comb<strong>in</strong>ation was used <strong>in</strong> 21%, 9%, 8%, or 8%, respectively.<br />
A response rate of ≥ 80% was atta<strong>in</strong>ed <strong>in</strong> 26 studies (49%). Critically ill<br />
patients had a lower quality of life than an age- and gender-matched<br />
population, but quality of life tended to improve over years. The worst<br />
reductions <strong>in</strong> quality of life were seen <strong>in</strong> cases of severe acute respiratory<br />
distress syndrome, prolonged mechanical ventilation, severe trauma,<br />
and severe sepsis. Study quality criteria, def<strong>in</strong>ed as a basel<strong>in</strong>e quality of<br />
life assessment, the absence of major exclusion criteria, a description of<br />
nonresponders, and a comparison with a reference population were met<br />
<strong>in</strong> only four studies (8%). Results concern<strong>in</strong>g the <strong>in</strong>fluence of severity of<br />
illness, comorbidity, preadmission quality of life, age, gender, or acquired<br />
complications were conflict<strong>in</strong>g.<br />
COnCLUSIOnS: Quality of life differed on diagnostic category but, overall,<br />
critically ill patients had a lower quality of life than an age- and gender-matched<br />
population. A m<strong>in</strong>ority of studies met the predef<strong>in</strong>ed methodologic<br />
quality criteria. Results concern<strong>in</strong>g the <strong>in</strong>fluence of the patients’<br />
characteristics and illnesses on long-term quality of life were conflict<strong>in</strong>g.<br />
Crit Care Med 2010;38(12):2386-400<br />
15
16<br />
stem cells <strong>in</strong> sepsis and acute lung <strong>in</strong>jury<br />
S.K. Cribbs<br />
M.A. Matthay<br />
G.S. Mart<strong>in</strong><br />
Division of Pulmonary,<br />
Allergy and Critical Care<br />
Medic<strong>in</strong>e (SKC, GSM),<br />
Department<br />
of Medic<strong>in</strong>e, Emory<br />
University, Atlanta, GA;<br />
Cardiovascular Research<br />
Institute (MAM), Departments<br />
of Medic<strong>in</strong>e and Anesthesia,<br />
University of California,<br />
San Francisco, CA<br />
ObjECTIvE: Sepsis and acute lung <strong>in</strong>jury cont<strong>in</strong>ue to be major causes of<br />
morbidity and mortality worldwide despite advances <strong>in</strong> our understand<strong>in</strong>g<br />
of pathophysiology and the discovery of new management strategies.<br />
Recent <strong>in</strong>vestigations show that stem cells may be beneficial as prognostic<br />
biomarkers and novel therapeutic strategies <strong>in</strong> these syndromes. This article<br />
reviews the potential use of endogenous adult tissue-derived stem<br />
cells <strong>in</strong> sepsis and acute lung <strong>in</strong>jury as prognostic markers and also as exogenous<br />
cell-based therapy.<br />
dATA SOURCES: A directed systematic search of the medical literature us<strong>in</strong>g<br />
PubMed and OVID, with particular emphasis on the time period after<br />
2002, was done to evaluate topics related to 1) the epidemiology and<br />
pathophysiology of sepsis and acute lung <strong>in</strong>jury; and 2) the def<strong>in</strong>ition,<br />
characterization, and potential use of stem cells <strong>in</strong> these diseases.<br />
dATA SynThESIS And fIndInGS: When available, preferential consideration<br />
was given to prospective nonrandomized cl<strong>in</strong>ical and precl<strong>in</strong>ical studies.<br />
COnCLUSIOnS: Stem cells have shown significant promise <strong>in</strong> the field<br />
of critical care both for 1) prognostic value and 2) treatment strategies.<br />
Although several recent studies have identified the potential benefit of<br />
stem cells <strong>in</strong> sepsis and acute lung <strong>in</strong>jury, further <strong>in</strong>vestigations are needed<br />
to more completely understand stem cells and their potential prognostic<br />
and therapeutic value.<br />
Crit Care Med 2010;38(12):2379-85
Cirrhotic patients <strong>in</strong> the medical <strong>in</strong>tensive care unit:<br />
early prognosis and long-term survival<br />
V. Das<br />
P.Y. Boelle<br />
A. Galbois<br />
B. Guidet<br />
E. Maury<br />
N. Carbonell<br />
R. Moreau<br />
G. Offenstadt<br />
Assistance Publique<br />
(VD, AG, BG, EM, GO),<br />
Hôpitaux de Paris,<br />
Hôpital Sa<strong>in</strong>t-Anto<strong>in</strong>e,<br />
Service de Réanimation<br />
Médicale, Paris, France;<br />
INSERM (PYB, BG, EM,<br />
GO), Unité de Recherche<br />
en Epidémiologie Systèmes<br />
d’Information et Modélisation<br />
(U707), Paris, France;<br />
Université Pierre et Marie<br />
Curie (PYB, BG, EM, GO),<br />
Paris, France; Assistance<br />
Publique (NC), Hôpitaux<br />
de Paris, Hôpital Sa<strong>in</strong>t-<br />
Anto<strong>in</strong>e, Service<br />
d’Hépatologie, Paris,<br />
France; Assistance Publique<br />
(RM), Hôpitaux de Paris,<br />
Hôpital Beaujon, Service<br />
d’Hépatologie, Clichy, France;<br />
INSERM (RM), U773, Centre<br />
de Recherche Bichat-Beaujon<br />
CRB3, Paris, France<br />
ObjECTIvES: To reassess the prognosis of patients with cirrhosis admitted<br />
to the <strong>in</strong>tensive care unit.<br />
dESIGn: A retrospective study <strong>in</strong> a medical <strong>in</strong>tensive care unit <strong>in</strong> a teach<strong>in</strong>g<br />
hospital <strong>in</strong> France.<br />
PATIEnTS: All patients with cirrhosis without previous liver transplantation<br />
admitted <strong>in</strong> the period from 2005 to 2008.<br />
InTERvEnTIOnS: None.<br />
MAIn RESULTS: One hundred thirty-eight patients were studied. Survival<br />
rates <strong>in</strong> the <strong>in</strong>tensive care unit, <strong>in</strong> hospital, and at 6 months were<br />
59% (95% confidence <strong>in</strong>terval, 50-67%), 46% (95% confidence <strong>in</strong>terval,<br />
38-54%), and 38% (95% confidence <strong>in</strong>terval, 30-47%), respectively. In-hospital<br />
survival rates for patients requir<strong>in</strong>g vasopressors, mechanical ventilation,<br />
or renal replacement therapy were 20%, 33%, and 31%, respectively.<br />
On day 1, <strong>in</strong>dependent risk factors for <strong>in</strong>-hospital mortality were age,<br />
album<strong>in</strong>emia, <strong>in</strong>ternational normalized ratio, and the Sequential Organ<br />
Failure Assessment score computed after discard<strong>in</strong>g po<strong>in</strong>ts for hematologic<br />
failure (modified Sequential Organ Failure Assessment score). Liver<br />
disease severity, assessed us<strong>in</strong>g a cl<strong>in</strong>ical classification, did not correlate<br />
with <strong>in</strong>-hospital mortality. In patients still alive after 3 days, the only prognostic<br />
factor was the modified Sequential Organ Failure Assessment score<br />
computed after 3 days. To predict <strong>in</strong>-hospital mortality, the modified Sequential<br />
Organ Failure Assessment score on day 1 had a greater area under<br />
the receiver operat<strong>in</strong>g characteristic curve (0.84) than the Simplified<br />
Acute Physiology Score II (0.78), the Child-Pugh score (0.76), the model<br />
for end-stage liver disease score (0.77), or the model for end-stage liver<br />
disease-natremia score (0.75). The <strong>in</strong>-hospital mortality rate with three or<br />
four nonhematologic organ failures on day 1 was not > 70%, whereas it<br />
was 89% with three nonhematologic organ failures after 3 days spent <strong>in</strong><br />
the <strong>in</strong>tensive care unit.<br />
COnCLUSIOn: In-hospital survival rate of <strong>in</strong>tensive care unit-admitted<br />
cirrhotic patients seemed acceptable, even <strong>in</strong> patients requir<strong>in</strong>g life-susta<strong>in</strong><strong>in</strong>g<br />
treatments and/or with multiple organ failure on admission. The<br />
most important risk factor for <strong>in</strong>-hospital mortality was the severity of<br />
nonhematologic organ failure, as best assessed after 3 days. A trial of<br />
unrestricted <strong>in</strong>tensive care for a few days could be proposed for select<br />
critically ill cirrhotic patients.<br />
Crit Care Med 2010;38(11):2108-16<br />
17
18<br />
volume of emergency department admissions for sepsis<br />
is related to <strong>in</strong>patient mortality: results of a nationwide<br />
cross-sectional analysis<br />
E.S. Powell<br />
R.K. Khare<br />
D.M. Courtney<br />
J. Fe<strong>in</strong>glass<br />
Department of Emergency<br />
Medic<strong>in</strong>e (ESP, RKK, MC),<br />
Fe<strong>in</strong>berg School of Medic<strong>in</strong>e,<br />
Northwestern University,<br />
Chicago, IL; Institute<br />
for Healthcare Studies<br />
and Division of General<br />
Internal Medic<strong>in</strong>e (ESP, RKK,<br />
JF), Northwestern University,<br />
Fe<strong>in</strong>berg School of Medic<strong>in</strong>e,<br />
Chicago, IL<br />
ObjECTIvES: Emergency department resuscitation plays a significant role<br />
<strong>in</strong> sepsis care, and it is unknown if patient outcomes vary by <strong>in</strong>stitution<br />
based on the level of sepsis experience of the emergency department.<br />
This study exam<strong>in</strong>es whether there is an association between the annual<br />
volume of patients admitted via the emergency department with sepsis<br />
and <strong>in</strong>patient mortality.<br />
dESIGn: Cross-sectional analysis of the 2007 Nationwide Inpatient Sample.<br />
Sett<strong>in</strong>g and patients: We <strong>in</strong>cluded 87,166 adult emergency department<br />
sepsis admissions from 551 hospitals.<br />
MEASUREMEnTS: Hospitals were categorized <strong>in</strong>to quartiles by 2007<br />
emergency department sepsis volume. Univariate associations of patient<br />
characteristics, hospital characteristics, and <strong>in</strong>patient mortality with sepsis<br />
volume level were evaluated by chi-square test. A population-averaged<br />
logistic regression model of <strong>in</strong>patient mortality was used to estimate the<br />
effects of age, gender, comorbid conditions, payer status, median zip<br />
code <strong>in</strong>come, hospital bed size, teach<strong>in</strong>g status, and emergency department<br />
sepsis volume.<br />
MAIn RESULTS: Overall <strong>in</strong>patient sepsis mortality was 18.0% and early<br />
mortality (2 days after admission) was 6.9%. The risk-adjusted odds ratios<br />
of mortality were 0.73 (95% confidence <strong>in</strong>terval, 0.64-0.83; p < .001)<br />
<strong>in</strong> quartile 4 (highest volume), 0.83 <strong>in</strong> quartile 3 (95% confidence <strong>in</strong>terval,<br />
0.74-0.93; p = .001), and 0.90 <strong>in</strong> quartile 2 (95% confidence <strong>in</strong>terval,<br />
0.82-0.99; p < .05) when compared to quartile 1 (lowest volume). Adjusted<br />
results were similar for early mortality: 0.69 (95% confidence <strong>in</strong>terval,<br />
0.61-0.76; p < .001) <strong>in</strong> quartile 4, 0.83 <strong>in</strong> quartile 3 (95% confidence <strong>in</strong>terval,<br />
0.74-0.93; p < .05), and 0.85 <strong>in</strong> quartile 2 (95% confidence <strong>in</strong>terval,<br />
0.77-0.94; p < .05) when compared to quartile 1.<br />
COnCLUSIOnS: After adjustment for comorbidity and hospital-level factors,<br />
there was a significant relationship between emergency department<br />
sepsis case volume and overall and early <strong>in</strong>patient mortality among patients<br />
admitted through the emergency department with sepsis. Patients<br />
admitted to hospitals <strong>in</strong> the highest-volume quartile had 27% lower odds<br />
of <strong>in</strong>patient mortality <strong>in</strong> this large heterogeneous sample.<br />
Crit Care Med 2010;38(11):2161-8
Fluids after cardiac surgery: a pilot study of the use<br />
of colloids versus crystalloids<br />
S. Magder<br />
B.J. Potter<br />
B. Deverenne<br />
S. Doucette<br />
D. Fergusson<br />
for the Canadian Critical Care<br />
Trials Group<br />
McGill University Health<br />
Center (SM, BJP, BD),<br />
Montreal Quebec, Canada;<br />
Ottawa Hospital Research<br />
Institute (SD, DF), Ottawa,<br />
Ontario, Canada<br />
ObjECTIvES: To determ<strong>in</strong>e whether a starch solution for volume resuscitation<br />
<strong>in</strong> a flow-based protocol improves circulatory status better than a<br />
crystalloid solution, as def<strong>in</strong>ed by the need for catecholam<strong>in</strong>es <strong>in</strong> patients<br />
the morn<strong>in</strong>g after cardiac surgery, and whether this can be performed<br />
without <strong>in</strong>creased morbidity.<br />
dESIGn: Concealed, randomized, double-bl<strong>in</strong>d, controlled trial.<br />
PARTICIPAnTS: Two hundred sixty-two patients who underwent cardiac<br />
surgery at a tertiary care hospital.<br />
InTERvEnTIOnS: Based on predef<strong>in</strong>ed criteria <strong>in</strong>dicat<strong>in</strong>g a need for fluids,<br />
and a nurse-delivered algorithm that used central venous pressure and<br />
cardiac <strong>in</strong>dex obta<strong>in</strong>ed from a pulmonary artery catheter, patients were<br />
allocated to receive 250-ml boluses of 0.9% sal<strong>in</strong>e or a 250-molecular<br />
weight 10% solution of pentastarch.<br />
RESULTS: Two hundred thirty-seven patients received volume boluses: 119<br />
hydroxyethyl starches and 118 sal<strong>in</strong>e. Between 8:00 am and 9:00 am the<br />
morn<strong>in</strong>g after surgery, 13 (10.9%) of hydroxyethyl starch patients and<br />
34 (28.8%) sal<strong>in</strong>e patients were us<strong>in</strong>g catecholam<strong>in</strong>es (p = .001). Hydroxyethyl<br />
starch patients had less pneumonia and mediast<strong>in</strong>al <strong>in</strong>fections<br />
(p = .03) and less cardiac pac<strong>in</strong>g (p = .03). There were two deaths <strong>in</strong> each<br />
group. There was no difference <strong>in</strong> the daily creat<strong>in</strong><strong>in</strong>e, development of<br />
RIFLE risk criteria dur<strong>in</strong>g hospital stay, or new dialysis. The numbers and<br />
volumes of packed red blood cells were similar <strong>in</strong> the two groups, but<br />
more hydroxyethyl starch patients received plasma transfusions (p = .05).<br />
COnCLUSIOnS: Use of a colloid solution for volume resuscitation <strong>in</strong> a<br />
nurse-delivered flow-based algorithm, which <strong>in</strong>cluded a pulmonary artery<br />
catheter, significantly improved hemodynamic status, an important factor<br />
for read<strong>in</strong>ess for discharge from the <strong>in</strong>tensive care unit.<br />
Crit Care Med 2010;38(11):2117-24<br />
19
20<br />
microcirculation <strong>in</strong> cardiogenic shock:<br />
from scientific bystander to therapy target<br />
C. Jung<br />
A. Lauten<br />
M. Ferrari<br />
First Department of Internal<br />
Medic<strong>in</strong>e, (Cardiology,<br />
Angiology, Pneumology,<br />
Intensive Care Medic<strong>in</strong>e),<br />
Friedrich Schiller University,<br />
Jena, Germany<br />
Despite diagnostic and therapeutic improvements, mortality rates <strong>in</strong><br />
patients with cardiogenic shock rema<strong>in</strong> relatively high. Several studies<br />
showed that cardiogenic shock is associated with alterations <strong>in</strong> the microvascular<br />
circulation. These alterations may be reversed by extracorporeal<br />
support devices. A study by Munsterman and colleagues adds to the body<br />
of evidence show<strong>in</strong>g that <strong>in</strong> patients deemed ready for discont<strong>in</strong>u<strong>in</strong>g<br />
<strong>in</strong>tra-aortic balloon pump (IABP) support, microcirculatory flow <strong>in</strong> small<br />
vessels <strong>in</strong>creases after ceas<strong>in</strong>g IABP therapy. This study not only highlights<br />
the need for optimal tim<strong>in</strong>g of wean<strong>in</strong>g from IABP support but also supports<br />
recent f<strong>in</strong>d<strong>in</strong>gs that global hemodynamics do not necessarily result<br />
<strong>in</strong> changes of microvascular perfusion. All modalities of modern treatment<br />
<strong>in</strong> cardiogenic shock need to be evaluated for their effect on the microcirculation.<br />
Microcirculatory evaluations should be part of randomized<br />
controlled trial protocols. More effort is needed to improve outcomes and<br />
understand the microcirculation as a therapy target and not as a silent<br />
bystander.<br />
Crit Care 2010;14(5):193
Bench-to-bedside review: target<strong>in</strong>g antioxidants<br />
to mitochondria <strong>in</strong> sepsis<br />
H.F. Galley<br />
Academic Unit of Anaesthesia<br />
& Intensive Care, School<br />
of Medic<strong>in</strong>e & Dentistry,<br />
University of Aberdeen,<br />
Aberdeen, UK<br />
Development of organ dysfunction associated with sepsis is now accepted<br />
to be due at least <strong>in</strong> part to oxidative damage to mitochondria. Under<br />
normal circumstances, complex <strong>in</strong>teract<strong>in</strong>g antioxidant defense systems<br />
control oxidative stress with<strong>in</strong> mitochondria. However, no studies have<br />
yet provided conclusive evidence of the beneficial effect of antioxidant<br />
supplementation <strong>in</strong> patients with sepsis. This may be because the antioxidants<br />
are not accumulat<strong>in</strong>g <strong>in</strong> the mitochondria, where they are most<br />
needed. Antioxidants can be targeted selectively to mitochondria by several<br />
means. This review describes the <strong>in</strong> vitro studies and animal models of<br />
several diseases <strong>in</strong>volv<strong>in</strong>g oxidative stress, <strong>in</strong>clud<strong>in</strong>g sepsis, <strong>in</strong> which antioxidants<br />
targeted at mitochondria have shown promise, and the future<br />
implications for such approaches <strong>in</strong> patients.<br />
Crit Care 2010;14(4):230<br />
21
22<br />
A systematic review of randomized controlled trials<br />
explor<strong>in</strong>g the effect of immunomodulative <strong>in</strong>terventions<br />
on <strong>in</strong>fection, organ failure, and mortality <strong>in</strong> trauma<br />
N.E. Spruijt<br />
T. Visser<br />
L.P. Leenen<br />
Department of Surgery,<br />
University Medical Centre<br />
Utrecht, The Netherlands<br />
InTROdUCTIOn: Follow<strong>in</strong>g trauma, patients may suffer an overwhelm<strong>in</strong>g<br />
pro-<strong>in</strong>flammatory response and immune paralysis result<strong>in</strong>g <strong>in</strong> <strong>in</strong>fection<br />
and multiple organ failure (MOF). Various potentially immunomodulative<br />
<strong>in</strong>terventions have been tested. The objective of this study is to systematically<br />
review the randomized controlled trials (RCTs) that <strong>in</strong>vestigate the<br />
effect of potentially immunomodulative <strong>in</strong>terventions <strong>in</strong> comparison to a<br />
placebo or standard therapy on <strong>in</strong>fection, MOF, and mortality <strong>in</strong> trauma<br />
patients.<br />
METhOdS: A computerized search of MEDLINE, the Cochrane CENTRAL<br />
Register of Controlled Trials, and EMBASE yielded 502 studies, of which<br />
18 unique RCTs were deemed relevant for this study. The methodological<br />
quality of these RCTs was assessed us<strong>in</strong>g a critical appraisal checklist for<br />
therapy articles from the Centre for Evidence Based Medic<strong>in</strong>e. The effects<br />
of the test <strong>in</strong>terventions on <strong>in</strong>fection, MOF, and mortality rates and <strong>in</strong>flammatory<br />
parameters relative to the controls were recorded.<br />
RESULTS: In most studies, the <strong>in</strong>flammatory parameters differed significantly<br />
between the test and control groups. However, significant changes<br />
<strong>in</strong> <strong>in</strong>fection, MOF, and mortality rates were only measured <strong>in</strong> studies test<strong>in</strong>g<br />
immunoglobul<strong>in</strong>, IFN-gamma, and glucan.<br />
COnCLUSIOnS: Based on level 1b and 2b studies, adm<strong>in</strong>istration of immunoglobul<strong>in</strong>,<br />
IFN-gamma, or glucan have shown the most promis<strong>in</strong>g results<br />
to improve the outcome of trauma patients.<br />
Crit Care 2010;14(4):R150
Cerebral microcirculation is impaired dur<strong>in</strong>g sepsis:<br />
an experimental study<br />
F.S. Taccone<br />
F. Su<br />
C. Pierrakos<br />
X. He<br />
S. James<br />
O. Dewitte<br />
J.L. V<strong>in</strong>cent<br />
D. De Backer<br />
Department of Intensive Care,<br />
Erasme Hospital, Université<br />
Libre de Bruxelles, Belgium<br />
InTROdUCTIOn: Pathophysiology of bra<strong>in</strong> dysfunction due to sepsis rema<strong>in</strong>s<br />
poorly understood. Cerebral microcirculatory alterations may play<br />
a role; however, experimental data are scarce. This study sought to <strong>in</strong>vestigate<br />
whether the cerebral microcirculation is altered <strong>in</strong> a cl<strong>in</strong>ically<br />
relevant animal model of septic shock.<br />
METhOdS: Fifteen anesthetized, <strong>in</strong>vasively monitored, and mechanically<br />
ventilated female sheep were allocated to a sham procedure (n = 5) or<br />
sepsis (n = 10), <strong>in</strong> which peritonitis was <strong>in</strong>duced by <strong>in</strong>tra-abdom<strong>in</strong>al <strong>in</strong>jection<br />
of autologous faeces. Animals were observed until spontaneous<br />
death or for a maximum of 20 hours. In addition to global hemodynamic<br />
assessment, the microcirculation of the cerebral cortex was evaluated us<strong>in</strong>g<br />
Sidestream Dark-Field (SDF) videomicroscopy at basel<strong>in</strong>e, 6 hours, 12<br />
hours and at shock onset. At least five images of 20 seconds each from<br />
separate areas were recorded at each time po<strong>in</strong>t and stored under a random<br />
number to be analyzed, us<strong>in</strong>g a semi-quantitative method, by an<br />
<strong>in</strong>vestigator bl<strong>in</strong>ded to time and condition.<br />
RESULTS: All septic animals developed a hyperdynamic state associated<br />
with organ dysfunction and, ultimately, septic shock. In the septic animals,<br />
there was a progressive decrease <strong>in</strong> cerebral total perfused vessel density<br />
(from 5.9 ± 0.9 at basel<strong>in</strong>e to 4.8 ± 0.7 n/mm at shock onset, p = 0.009),<br />
functional capillary density (from 2.8 ± 0.4 to 2.1 ± 0.7 n/mm, p = 0.049),<br />
the proportion of small perfused vessels (from 95 ± 3 to 85 ± 8%,<br />
p = 0.02), and the total number of perfused capillaries (from 22.7 ± 2.7 to<br />
17.5 ± 5.2 n/mm, p = 0.04). There were no significant changes <strong>in</strong> microcirculatory<br />
flow <strong>in</strong>dex over time. In sham animals, the cerebral microcirculation<br />
was unaltered dur<strong>in</strong>g the study period.<br />
COnCLUSIOnS: In this model of peritonitis, the cerebral microcirculation<br />
was impaired dur<strong>in</strong>g sepsis, with a significant reduction <strong>in</strong> perfused small<br />
vessels at the onset of septic shock. These alterations may play a role <strong>in</strong><br />
the pathogenesis of septic encephalopathy.<br />
Crit Care 2010;14(4):R140<br />
23
24<br />
emerg<strong>in</strong>g antithrombotic agents:<br />
what does the <strong>in</strong>tensivist need to know?<br />
Z. Iqbal<br />
M. Cohen<br />
Division of Cardiology,<br />
Newark Beth Israel Medical<br />
Center, Newark, NJ, USA<br />
PURPOSE Of REvIEw: As thrombus consists of both fibr<strong>in</strong> and platelets,<br />
antithrombotic strategies <strong>in</strong>volve anticoagulants and antiplatelets, alone<br />
or <strong>in</strong> comb<strong>in</strong>ation.<br />
RECEnT fIndInGS: Traditionally, unfractionated hepar<strong>in</strong> has been the<br />
most commonly used parenteral anticoagulant, but ow<strong>in</strong>g to its variable<br />
dose response and narrow therapeutic <strong>in</strong>dices, it is be<strong>in</strong>g replaced by low<br />
molecular weight hepar<strong>in</strong>, fondapar<strong>in</strong>ux, and bivalrud<strong>in</strong>. New oral factor<br />
Xa <strong>in</strong>hibitors like apixaban and rivaroxaban are still on the horizon,<br />
await<strong>in</strong>g def<strong>in</strong>ite evaluation <strong>in</strong> ACS, DVT and atrial fibrillation. On the<br />
contrary, a dramatic advance <strong>in</strong> the arena of oral anticoagulants has occurred<br />
with the <strong>in</strong>troduction of dabigatran, an oral direct thromb<strong>in</strong> <strong>in</strong>hibitor.<br />
This agent showed better outcomes than oral vitam<strong>in</strong> K antagonists<br />
<strong>in</strong> patients with atrial fibrillation. The antiplatelet field has also expanded<br />
by the addition of two new agents, prasugrel and ticagrelor. These agents<br />
have been tested aga<strong>in</strong>st clopidogrel, <strong>in</strong> patients with ACS, with superior<br />
efficacy outcomes for both agents and higher bleed<strong>in</strong>g events with<br />
prasugrel.<br />
SUMMARy: Bleed<strong>in</strong>g risk associated with antithrombotics is not only a<br />
function of their <strong>in</strong>herent biochemical properties but also a reflection of<br />
how healthcare professionals choose and dose these agents <strong>in</strong> <strong>in</strong>dividual<br />
patients.<br />
Curr Op<strong>in</strong> Crit Care 2010;16(5):419-25
microvascular dysfunction <strong>in</strong> the surgical patient<br />
N.A. Vell<strong>in</strong>ga<br />
C. Ince<br />
E.C. Boerma<br />
Department of Translational<br />
Physiology, Academic Medical<br />
Center, Amsterdam,<br />
The Netherlands<br />
PURPOSE Of REvIEw: This review aims to describe recent research on<br />
perioperative microvascular alterations, with an emphasis on direct visualization<br />
of the human microcirculation.<br />
RECEnT fIndInGS: Despite systemic haemodynamic optimization, perioperative<br />
complications are still occurr<strong>in</strong>g. In surgery, recent studies on<br />
both direct visualization of the microcirculation and <strong>in</strong>direct quantification<br />
of organ perfusion revealed that both the surgical procedure itself<br />
and perioperative <strong>in</strong>terventions like anaesthesia, cardiopulmonary bypass,<br />
vasoactive drugs and fluid therapy may <strong>in</strong>fluence organ perfusion at<br />
the microvascular level. As <strong>in</strong> sepsis and heart failure, these perioperative<br />
microcirculatory abnormalities were associated with prognosis. However,<br />
whether these microcirculatory alterations are culprit or bystander <strong>in</strong> the<br />
process of develop<strong>in</strong>g perioperative complications rema<strong>in</strong>s to be established.<br />
SUMMARy: Recent research has elucidated the <strong>in</strong>cidence of perioperative<br />
microvascular alterations, as well as its association with prognosis. Future<br />
research should further unravel the fasc<strong>in</strong>at<strong>in</strong>g and complex <strong>in</strong>terplay between<br />
the microcirculation and perioperative <strong>in</strong>terventions.<br />
Curr Op<strong>in</strong> Crit Care 2010;16(4):377-83<br />
25
26<br />
Fluid therapy <strong>in</strong> septic shock<br />
E.P. Rivers<br />
A.K. Jaehne<br />
L. Eichhorn-Wharry<br />
S. Brown<br />
D. Amponsah<br />
Department of Emergency<br />
Medic<strong>in</strong>e, Henry Ford<br />
Hospital, Wayne State<br />
University, Detroit, Michigan,<br />
USA<br />
PURPOSE Of REvIEw: To exam<strong>in</strong>e the role of fluid therapy <strong>in</strong> the pathogenesis<br />
of severe sepsis and septic shock. The type, composition, titration,<br />
management strategies and complications of fluid adm<strong>in</strong>istration will be<br />
exam<strong>in</strong>ed <strong>in</strong> respect to outcomes.<br />
RECEnT fIndInGS: Fluids have a critical role <strong>in</strong> the pathogenesis and treatment<br />
of early resuscitation of severe sepsis and septic shock.<br />
SUMMARy: Although this pathogenesis is evolv<strong>in</strong>g, early titrated fluid adm<strong>in</strong>istration<br />
modulates <strong>in</strong>flammation, improves microvascular perfusion,<br />
impacts organ function and outcome. Fluid adm<strong>in</strong>istration has limited impact<br />
on tissue perfusion dur<strong>in</strong>g the later stages of sepsis and excess fluid<br />
is deleterious to outcome. The type of fluid solution does not seem to<br />
<strong>in</strong>fluence these observations.<br />
Curr Op<strong>in</strong> Crit Care 2010;16(4):297-308
Both passive leg rais<strong>in</strong>g and <strong>in</strong>travascular volume<br />
expansion improve subl<strong>in</strong>gual microcirculatory<br />
perfusion <strong>in</strong> severe sepsis and septic shock patients<br />
J. Pottecher<br />
S. Deruddre<br />
J.L. Teboul<br />
J.F. Georger<br />
C. Laplace<br />
D. Benhamou<br />
E. Vicaut<br />
J. Duranteau<br />
Unité EA 3509, Département<br />
d’Anesthésie-Réanimation,<br />
Centre Hospitalier<br />
Universitaire de Bicêtre,<br />
Assistance Publique Hôpitaux<br />
de Paris, Université Paris,<br />
Le Kreml<strong>in</strong>-Bicêtre Cedex,<br />
France<br />
PURPOSE: To assess subl<strong>in</strong>gual microcirculatory changes follow<strong>in</strong>g passive<br />
leg rais<strong>in</strong>g (PLR) and volume expansion (VE) <strong>in</strong> septic patients.<br />
METhOdS: This prospective study was conducted <strong>in</strong> two university hospital<br />
<strong>in</strong>tensive care units and <strong>in</strong>cluded 25 mechanically ventilated patients<br />
with severe sepsis or septic shock who were eligible for VE <strong>in</strong> the first 24 h<br />
of their admission. Pulse pressure variation (DeltaPP), cardiac output (CO)<br />
and subl<strong>in</strong>gual microcirculation <strong>in</strong>dices were assessed at five consecutive<br />
steps: (1) semi-recumbent position (Basel<strong>in</strong>e 1), (2) dur<strong>in</strong>g PLR manoeuvre<br />
(PLR), (3) after return<strong>in</strong>g to semi-recumbent position (Basel<strong>in</strong>e 2), (4) at<br />
the time when VE <strong>in</strong>duced the same degree of preload responsiveness as<br />
PLR (VE(PP = PLR)) and (5) at the end of VE (VE(END)). At each step, five<br />
subl<strong>in</strong>gual microcirculation sequences were acquired us<strong>in</strong>g sidestream<br />
darkfield imag<strong>in</strong>g to assess functional capillary density (FCD), microcirculatory<br />
flow <strong>in</strong>dex (MFI), proportion of perfused vessels (PPV) and flow<br />
heterogeneity <strong>in</strong>dex (FHI).<br />
RESULTS: The PLR, VE(PP=PLR) and VE(END) <strong>in</strong>duced a significant <strong>in</strong>crease<br />
<strong>in</strong> CO and a significant decrease <strong>in</strong> DeltaPP compared to Basel<strong>in</strong>e 1 and<br />
Basel<strong>in</strong>e 2 values. Both PLR and VE <strong>in</strong>duced significant <strong>in</strong>creases <strong>in</strong> FCD,<br />
MFI and PPV and a significant decrease <strong>in</strong> FHI compared to Basel<strong>in</strong>e 1 and<br />
Basel<strong>in</strong>e 2 values.<br />
COnCLUSIOnS: In preload responsive severe septic patients exam<strong>in</strong>ed<br />
with<strong>in</strong> the first 24 h of their admission, both PLR and VE improved subl<strong>in</strong>gual<br />
microcirculatory perfusion. At the level of volume <strong>in</strong>fusion used<br />
<strong>in</strong> this study, these changes <strong>in</strong> subl<strong>in</strong>gual microcirculation were not expla<strong>in</strong>ed<br />
by changes <strong>in</strong> rheologic factors or changes <strong>in</strong> arterial pressure.<br />
Intensive Care Med 2010;36(11):1867-74<br />
27
28<br />
impaired microvascular perfusion <strong>in</strong> sepsis requires<br />
activated coagulation and p-select<strong>in</strong>-mediated<br />
platelet adhesion <strong>in</strong> capillaries<br />
F. Li<br />
C.G. Ellis<br />
M.D. Sharpe<br />
P.L. Gross<br />
J.X. Wilson<br />
K. Tyml<br />
Critical Illness Research,<br />
Victoria Research<br />
Laboratories, Lawson Health<br />
Research Institute, London,<br />
ON, Canada<br />
PURPOSE: Impaired microvascular perfusion <strong>in</strong> sepsis is not treated effectively<br />
because its mechanism is unknown. S<strong>in</strong>ce <strong>in</strong>flammatory and coagulation<br />
pathways cross-activate, we tested if stoppage of blood flow<br />
<strong>in</strong> septic capillaries is due to oxidant-dependent adhesion of platelets <strong>in</strong><br />
these microvessels.<br />
METhOdS: Sepsis was <strong>in</strong>duced <strong>in</strong> wild type, eNOS(-/-), iNOS(-/-), and gp91phox(-/-)<br />
mice (n = 14-199) by <strong>in</strong>jection of feces <strong>in</strong>to the peritoneum.<br />
Platelet adhesion, fibr<strong>in</strong> deposition, and blood flow stoppage <strong>in</strong> capillaries<br />
of h<strong>in</strong>dlimb skeletal muscle were assessed by <strong>in</strong>travital microscopy.<br />
Prophylactic treatments at the onset of sepsis were <strong>in</strong>travenous <strong>in</strong>jection<br />
of platelet-deplet<strong>in</strong>g antibody, P-select<strong>in</strong> block<strong>in</strong>g antibody, ascorbate,<br />
or antithromb<strong>in</strong>. Therapeutic treatments (delayed until 6 h) were <strong>in</strong>jection<br />
of ascorbate or the glycoprote<strong>in</strong> IIb/IIIa <strong>in</strong>hibitor eptifibatide, or local<br />
superfusion of the muscle with NOS cofactor tetrahydrobiopter<strong>in</strong> or NO<br />
donor S-nitroso-N-acetylpenicillam<strong>in</strong>e (SNAP).<br />
RESULTS: Sepsis at 6-7 h markedly <strong>in</strong>creased the number of stopped-flow<br />
capillaries and the occurrence of platelet adhesion and fibr<strong>in</strong> deposition<br />
<strong>in</strong> these capillaries. Platelet depletion, iNOS and gp91phox deficiencies,<br />
P-select<strong>in</strong> blockade, antithromb<strong>in</strong>, or prophylactic ascorbate prevented,<br />
whereas delayed ascorbate, eptifibatide, tetrahydrobiopter<strong>in</strong>, or SNAP<br />
reversed, septic platelet adhesion and/or flow stoppage. The reversals by<br />
ascorbate and tetrahydrobiopter<strong>in</strong> were absent <strong>in</strong> eNOS(-/-) mice. Platelet<br />
adhesion predicted 90% of capillary flow stoppage.<br />
COnCLUSIOn: Impaired perfusion and/or platelet adhesion <strong>in</strong> septic capillaries<br />
requires NADPH oxidase, iNOS, P-select<strong>in</strong>, and activated coagulation,<br />
and is <strong>in</strong>hibited by <strong>in</strong>travenous adm<strong>in</strong>istration of ascorbate and by<br />
local superfusion of tetrahydrobiopter<strong>in</strong> and NO. Reversal of flow stoppage<br />
by ascorbate and tetrahydrobiopter<strong>in</strong> may depend on local eNOSderived<br />
NO which dislodges platelets from the capillary wall.<br />
Intensive Care Med 2010;36(11):1928-34
monitor<strong>in</strong>g the microcirculation <strong>in</strong> the critically ill<br />
patient: current methods and future approaches<br />
D. De Backer<br />
G. Osp<strong>in</strong>a-Tascon<br />
D. Salgado<br />
R. Favory<br />
J. Creteur<br />
J.L. V<strong>in</strong>cent<br />
Department of Intensive Care,<br />
Erasme University Hospital,<br />
Université Libre de Bruxelles,<br />
Belgium<br />
PURPOSE: To discuss the techniques currently available to evaluate the<br />
microcirculation <strong>in</strong> critically ill patients. In addition, the most cl<strong>in</strong>ically relevant<br />
microcirculatory alterations will be discussed.<br />
METhOdS: Review of the literature on methods used to evaluate the microcirculation<br />
<strong>in</strong> humans and on microcirculatory alterations <strong>in</strong> critically<br />
ill patients.<br />
RESULTS: In experimental conditions, shock states have been shown to be<br />
associated with a decrease <strong>in</strong> perfused capillary density and an <strong>in</strong>crease <strong>in</strong><br />
the heterogeneity of microcirculatory perfusion, with non-perfused capillaries<br />
<strong>in</strong> close vic<strong>in</strong>ity to perfused capillaries. Techniques used to evaluate<br />
the microcirculation <strong>in</strong> humans should take <strong>in</strong>to account the heterogeneity<br />
of microvascular perfusion. Microvideoscopic techniques, such as<br />
orthogonal polarization spectral (OPS) and sidestream dark field (SDF)<br />
imag<strong>in</strong>g, directly evaluate microvascular networks covered by a th<strong>in</strong> epithelium,<br />
such as the subl<strong>in</strong>gual microcirculation. Laser Doppler and tissue<br />
O measurements satisfactorily detect global decreases <strong>in</strong> tissue perfusion<br />
2<br />
but not heterogeneity of microvascular perfusion. These techniques, and<br />
<strong>in</strong> particular laser Doppler and near-<strong>in</strong>frared spectroscopy, may help to<br />
evaluate the dynamic response of the microcirculation to a stress test. In<br />
patients with severe sepsis and septic shock, the microcirculation is characterized<br />
by a decrease <strong>in</strong> capillary density and <strong>in</strong> the proportion of perfused<br />
capillaries, together with a blunted response to a vascular occlusion<br />
test.<br />
COnCLUSIOnS: The microcirculation <strong>in</strong> humans can be evaluated directly<br />
by videomicroscopy (OPS/SDF) or <strong>in</strong>directly by vascular occlusion tests. Of<br />
note, direct videomicroscopic visualization evaluates the actual state of<br />
the microcirculation, whereas the vascular occlusion test evaluates microvascular<br />
reserve.<br />
Intensive Care Med 2010;36(11):1813-25<br />
29
30<br />
pregnant and postpartum admissions to the <strong>in</strong>tensive<br />
care unit: a systematic review<br />
W. Pollock<br />
L. Rose<br />
C.L. Dennis<br />
School of Nurs<strong>in</strong>g<br />
and Midwifery, La Trobe<br />
University/Mercy Hospital<br />
for Women, Heidelberg,<br />
Australia<br />
PURPOSE: To determ<strong>in</strong>e the <strong>in</strong>cidence and characteristics of pregnant and<br />
postpartum women requir<strong>in</strong>g admission to an <strong>in</strong>tensive care unit (ICU).<br />
METhOdS: Medl<strong>in</strong>e, PubMed, EMBASE and CINAHL databases (1990-2008)<br />
were systematically searched for reports of women admitted to the ICU<br />
either pregnant or up to 6 weeks postpartum. Two reviewers <strong>in</strong>dependently<br />
determ<strong>in</strong>ed study eligibility and abstracted data.<br />
RESULTS: A total of 40 eligible studies report<strong>in</strong>g outcomes for 7,887 women<br />
were analysed. All studies were retrospective with the majority report<strong>in</strong>g<br />
data from a s<strong>in</strong>gle centre. The <strong>in</strong>cidence of ICU admission ranged<br />
from 0.7 to 13.5 per 1,000 deliveries. Pregnant or postpartum women accounted<br />
for 0.4-16.0% of ICU admissions <strong>in</strong> study centres. Hypertensive<br />
disorders of pregnancy were the most prevalent <strong>in</strong>dication for ICU admission<br />
[median 0.9 cases per 1,000 deliveries (range 0.2-6.7)]. There was<br />
no difference <strong>in</strong> the profile of ICU admission <strong>in</strong> develop<strong>in</strong>g compared to<br />
developed countries, except for the significantly higher maternal mortality<br />
rate <strong>in</strong> develop<strong>in</strong>g countries (median 3.3 vs. 14.0%, p = 0.002). Studies<br />
report<strong>in</strong>g patient outcomes subsequent to ICU admission are lack<strong>in</strong>g.<br />
COnCLUSIOnS: ICU admission of pregnant and postpartum women occurs<br />
<strong>in</strong>frequently, with obstetric conditions responsible for the majority of ICU<br />
admissions. The ICU admission profile of women was similar <strong>in</strong> developed<br />
and develop<strong>in</strong>g countries; however, the maternal mortality rate rema<strong>in</strong>s<br />
higher for ICUs <strong>in</strong> develop<strong>in</strong>g countries, support<strong>in</strong>g the need for ongo<strong>in</strong>g<br />
service delivery improvements. More studies are required to determ<strong>in</strong>e<br />
the impact of ICU admission for pregnant and postpartum women.<br />
Intensive Care Med 2010;36(9):1465-74
the rAge axis <strong>in</strong> systemic <strong>in</strong>flammation,<br />
acute lung <strong>in</strong>jury and myocardial dysfunction:<br />
an important therapeutic target?<br />
B.C. Creagh-Brown<br />
G.J. Qu<strong>in</strong>lan<br />
T.W. Evans<br />
A. Burke-Gaffney<br />
Unit of Critical Care,<br />
Respiratory Science, National<br />
Heart and Lung Institute<br />
Division, Faculty of Medic<strong>in</strong>e,<br />
Imperial College, London, UK<br />
bACkGROUnd: The sepsis syndromes, frequently complicated by pulmonary<br />
and cardiac dysfunction, rema<strong>in</strong> a major cause of death amongst the<br />
critically ill. Targeted therapies aimed at ameliorat<strong>in</strong>g the systemic <strong>in</strong>flammation<br />
that characterises the sepsis syndromes have largely yielded disappo<strong>in</strong>t<strong>in</strong>g<br />
results <strong>in</strong> cl<strong>in</strong>ical trials. Whilst there are many potential reasons<br />
for lack of success of cl<strong>in</strong>ical trials, one possibility is that the pathways targeted,<br />
to date, are only modifiable very early <strong>in</strong> the course of the illness.<br />
More recent approaches have therefore attempted to identify pathways<br />
that could offer a wider therapeutic w<strong>in</strong>dow, such as the receptor for advanced<br />
glycation end-products (RAGE) and its ligands.<br />
PURPOSE: The objectives of this study were to review the evidence support<strong>in</strong>g<br />
the role of the RAGE axis <strong>in</strong> systemic <strong>in</strong>flammation and associated<br />
acute lung <strong>in</strong>jury and myocardial dysfunction, to explore some of<br />
the problems and conflicts that these RAGE studies have raised and to<br />
consider strategies by which they might be resolved.<br />
METhOdS: MEDLINE was searched (1990-2010) and relevant literature<br />
collected and reviewed.<br />
RESULTS And COnCLUSIOn: RAGE is an <strong>in</strong>flammation-perpetuat<strong>in</strong>g receptor<br />
with a diverse range of ligands. Evidence support<strong>in</strong>g a role of the<br />
RAGE axis <strong>in</strong> the pathogenesis of systemic <strong>in</strong>flammation, ALI and myocardial<br />
dysfunction is compell<strong>in</strong>g with numerous animal experiments show<strong>in</strong>g<br />
the beneficial effects of <strong>in</strong>hibit<strong>in</strong>g the RAGE axis. Despite a number<br />
of unanswered questions that need to be further addressed, the potential<br />
for <strong>in</strong>hibit<strong>in</strong>g RAGE-mediated <strong>in</strong>flammation <strong>in</strong> humans undoubtedly<br />
exists.<br />
Intensive Care Med 2010;36(10):1644-56<br />
31
32<br />
Do chronic liver disease scor<strong>in</strong>g systems predict<br />
outcomes <strong>in</strong> trauma patients with liver disease?<br />
A comparison of meLD and Ctp<br />
M.J. Seamon<br />
M.J. Franco<br />
S.P. Stawicki<br />
B.P. Smith<br />
H. Kulp<br />
A.J. Goldberg<br />
T.A. Santora<br />
J.P. Gaughan<br />
Division of Trauma<br />
and Surgical Critical Care<br />
(MJS, HK, AJG, TAS),<br />
Department of Surgery;<br />
Biostatistics Consult<strong>in</strong>g<br />
Center (JPG), Temple<br />
University School<br />
of Medic<strong>in</strong>e; Department<br />
of Surgery (MJF, BPS),<br />
Temple University Hospital,<br />
Philadelphia, PA; Division<br />
of Critical Care, Trauma,<br />
and Burn (SPS), Department<br />
of Surgery, Ohio State<br />
University Medical Center,<br />
Columbus, OH<br />
bACkGROUnd: Although the Child-Turcotte-Pugh (CTP) score is an established<br />
outcome prediction tool for patients with liver disease, the Model<br />
for End-Stage Liver Disease (MELD) score has recently supplanted CTP for<br />
patients await<strong>in</strong>g transplantation. Currently, data regard<strong>in</strong>g the use of<br />
CTP <strong>in</strong> trauma is limited, whereas MELD rema<strong>in</strong>s unstudied. We compared<br />
MELD and CTP to determ<strong>in</strong>e which scor<strong>in</strong>g system is a better cl<strong>in</strong>ical outcome<br />
predictor after trauma.<br />
METhOdS: A review of trauma admissions dur<strong>in</strong>g 2003-2008 revealed 68<br />
patients with chronic liver disease. S<strong>in</strong>gle and multiple variable analyses<br />
determ<strong>in</strong>ed predictors of hepatic complications and survival. MELD and<br />
CTP were compared us<strong>in</strong>g odds ratios and area under the receiver operat<strong>in</strong>g<br />
curve (AUC) analyses. A p value ≤ 0.05 was significant.<br />
RESULTS: The mean MELD and CTP scores of the population were 13.1 ± 6.0<br />
and 8.3 ± 1.8, respectively (mean ± SD). Overall, 73.5% had one or more<br />
complications and 29.4% died. When survivors were compared with nonsurvivors,<br />
no difference <strong>in</strong> mean MELD scores was found, although mean<br />
CTP score (survivors, 7.7 ± 1.5; nonsurvivors, 9.4 ± 1.9; p = 0.001) and class<br />
(“C” survivors, 12.1%; “C” nonsurvivors, 56.3%; p = 0.002) were different,<br />
with survival relat<strong>in</strong>g to liver disease severity. Odds ratios and AUC determ<strong>in</strong>ed<br />
that MELD was not predictive of hepatic complications or hospital<br />
survival (p > 0.05), although both CTP score and class were predictive<br />
(p < 0.05; AUC > 0.70).<br />
COnCLUSIOn: Trauma patients suffer<strong>in</strong>g from cirrhosis can be expected<br />
to have poorer than predicted outcomes us<strong>in</strong>g traditional trauma scor<strong>in</strong>g<br />
systems, regardless of <strong>in</strong>jury severity. Scor<strong>in</strong>g systems for chronic liver<br />
disease offer a more effective alternative. We compared two scor<strong>in</strong>g systems,<br />
MELD and CTP, and determ<strong>in</strong>ed that CTP was the better predictor of<br />
hepatic complications and survival <strong>in</strong> our study population.<br />
j Trauma 2010;69(3):568-73
Use of recomb<strong>in</strong>ant factor viia <strong>in</strong> Us military casualties<br />
for a five-year period<br />
C.E. Wade<br />
B.J. Eastridge<br />
J.A. Jones<br />
S.A. West<br />
P.C. Sp<strong>in</strong>ella<br />
J.G. Perk<strong>in</strong>s<br />
M.A. Dubick<br />
L.H. Blackbourne<br />
J.B. Holcomb<br />
Center for Translational Injury<br />
Research and Department<br />
of Surgery, University<br />
of Texas Health Science<br />
Center, Houston, TX, USA<br />
bACkGROUnd: Two prospective randomized trauma trials have shown<br />
recomb<strong>in</strong>ant factor VIIa (rFVIIa) to be safe and to decrease transfusion<br />
requirements. rFVIIa is presently used <strong>in</strong> 22% of massively transfused civilian<br />
trauma patients. The US Military has used rFVIIa <strong>in</strong> combat trauma<br />
patients for five years, and two small studies of massively transfused patients<br />
described an association with improved outcomes. This study was<br />
undertaken to assess how deployed physicians are us<strong>in</strong>g rFVIIa and its<br />
impact on casualty outcomes.<br />
METhOdS: US combat casualties (n = 2,050) receiv<strong>in</strong>g any blood transfusion<br />
from 2003 to 2009 were reviewed to compare patients receiv<strong>in</strong>g rFVI-<br />
Ia (n = 506) with those who did not (n = 1,544). Propensity-score match<strong>in</strong>g<br />
(primary analysis) and multivariable logistic regression were used to compare<br />
outcomes. Differences were determ<strong>in</strong>ed at p < 0.05.<br />
RESULTS: Twenty-five percent of patients received rFVIIa. Significant differences<br />
were noted between groups <strong>in</strong> <strong>in</strong>dices of <strong>in</strong>jury severity (Injury<br />
Severity Score, Abbreviated Injury Scale score, and Glasgow Coma Scale<br />
score), admission physiology (systolic blood pressure, diastolic blood pressure,<br />
heart rate, temperature, base deficit, hemoglob<strong>in</strong>, and <strong>in</strong>ternational<br />
normalization ratio), and use of blood products, <strong>in</strong>dicat<strong>in</strong>g that patients<br />
treated with rFVIIa were more severely <strong>in</strong>jured, <strong>in</strong> shock, and coagulopathic.<br />
For propensity-score match<strong>in</strong>g, factors associated with death were<br />
used: Injury Severity Score, Glasgow Coma Scale score, heart rate, systolic<br />
blood pressure, diastolic blood pressure, Hgb, and total packed red blood<br />
cell. A total of 266 patients per group were matched; 52% of the rFVIIa<br />
group. After pair<strong>in</strong>g, there were no significant differences <strong>in</strong> any of the<br />
demographics, <strong>in</strong>clud<strong>in</strong>g <strong>in</strong>cidence of massive transfusion (53% vs. 51%).<br />
There was no difference <strong>in</strong> the rate of complications (21% vs. 21%) or<br />
mortality (14% vs. 20%) for patients not treated or receiv<strong>in</strong>g rFVIIa, respectively.<br />
COnCLUSIOn: In military casualties, rFVIIa is used <strong>in</strong> the most severely<br />
<strong>in</strong>jured patients based on physician selection rather than on guidel<strong>in</strong>e<br />
criteria. Use of rFVIIa is not associated with an improvement <strong>in</strong> survival or<br />
an <strong>in</strong>crease <strong>in</strong> complications. The undetected bias of physician selection of<br />
patients for treatment with rFVIIa, likely, has an impact on case match<strong>in</strong>g<br />
to achieve equivalence similar to that of randomized control studies. This<br />
<strong>in</strong>ability to match populations, thus, prevents def<strong>in</strong>itive <strong>in</strong>terpretation of<br />
this study and others studies of similar design. This problem emphasizes<br />
the need to develop entry criteria to identify patients who could potentially<br />
benefit from use of rFVIIa and the need to subsequently perform<br />
efficacy studies.<br />
j Trauma 2010;69(2):353-9<br />
33
34<br />
prolonged prothromb<strong>in</strong> time after recomb<strong>in</strong>ant<br />
activated factor vii therapy <strong>in</strong> critically bleed<strong>in</strong>g<br />
trauma patients is associated with adverse outcomes<br />
N.R. McMull<strong>in</strong><br />
C.E. Wade<br />
J.B. Holcomb<br />
T.G. Nielsen<br />
R. Rossa<strong>in</strong>t<br />
B. Riou<br />
S.B. Rizoli<br />
Y. Kluger<br />
P.I. Choong<br />
B. Warren<br />
B.J. Tortella<br />
K.D. Boffard<br />
NovoSeven Trauma Study<br />
Group<br />
US Army Institute of Surgical<br />
Research, BAMC-Fort Sam<br />
Houston, TX, USA<br />
bACkGROUnd: In trauma patients with significant hemorrhage, it is<br />
hypothesized that failure to normalize prothromb<strong>in</strong> time (PT) after recomb<strong>in</strong>ant<br />
activated factor VII (rFVIIa) treatment predicts poor cl<strong>in</strong>ical<br />
outcomes and potentially <strong>in</strong>dicates a need for additional therapeutic <strong>in</strong>terventions.<br />
METhOdS: To assess the value of PT to predict outcomes after rFVIIa or<br />
placebo therapy, we performed a post hoc analysis of data from 169 severely<br />
<strong>in</strong>jured, critically bleed<strong>in</strong>g trauma patients who had 1-hour postdose<br />
PT measurements from two randomized cl<strong>in</strong>ical trials. Basel<strong>in</strong>e characteristics<br />
and outcome parameters were compared between subjects<br />
with 1-hour postdose PT ≥ 18 seconds and PT < 18 seconds.<br />
RESULTS: In rFVIIa-treated subjects, prolonged postdose PT values ≥ 18<br />
seconds were associated with significantly higher 24-hour mortality<br />
(60% vs. 3%; p < 0.001) and 30-day mortality, <strong>in</strong>creased <strong>in</strong>cidence of massive<br />
transfusion, and fewer <strong>in</strong>tensive care unit-free days compared with<br />
postdose PT values < 18 seconds. Recomb<strong>in</strong>ant rFVIIa-treated subjects with<br />
postdose PT ≥ 18 seconds had significantly lower basel<strong>in</strong>e hemoglob<strong>in</strong> levels,<br />
fibr<strong>in</strong>ogen levels, and platelet counts than subjects with postdose PT<br />
values < 18 seconds even though they received similar amounts of blood<br />
products before rFVIIa dos<strong>in</strong>g. Placebo-treated subjects with postdose<br />
PT ≥ 18 seconds had significantly <strong>in</strong>creased <strong>in</strong>cidence of massive transfusion,<br />
significantly decreased <strong>in</strong>tensive care unit-free days, and significantly<br />
lower levels of fibr<strong>in</strong>ogen and platelets at basel<strong>in</strong>e compared with<br />
subjects with postdose PT values < 18 seconds.<br />
COnCLUSIOnS: The presence of prolonged PT after rFVIIa or placebo<br />
therapy was associated with poor cl<strong>in</strong>ical outcomes. Because subjects with<br />
postdos<strong>in</strong>g PT ≥ 18 seconds had low levels of hemoglob<strong>in</strong>, fibr<strong>in</strong>ogen,<br />
and platelets, this group may benefit from additional blood component<br />
therapy.<br />
j Trauma 2010;69(1):60-9
the effect of acute traumatic bra<strong>in</strong> <strong>in</strong>jury<br />
on the performance of shock <strong>in</strong>dex<br />
C.G. McMahon<br />
R. Kenny<br />
K. Bennett<br />
R. Little<br />
E. Kirkman<br />
Department of Emergency<br />
Medic<strong>in</strong>e (CGMM); Tr<strong>in</strong>ity<br />
College, St. James’s Hospital,<br />
Dubl<strong>in</strong>, Ireland; Department<br />
of Geriartic Medic<strong>in</strong>e (RK);<br />
Institute of Neuroscience,<br />
Tr<strong>in</strong>ity College, Dubl<strong>in</strong>,<br />
Ireland; Department<br />
of Pharmacology &<br />
Therapeutics (KB); Tr<strong>in</strong>ity<br />
Medical School, Tr<strong>in</strong>ity<br />
College, Dubl<strong>in</strong>, Ireland;<br />
Manchester University (RL);<br />
Manchester, United K<strong>in</strong>gdom;<br />
and Surgical Sciences,<br />
Trauma, Biomedical Sciences<br />
(EK): Salisbury, UK<br />
bACkGROUnd: Shock <strong>in</strong>dex (SI) is recognized to be a more reliable early<br />
<strong>in</strong>dicator of hemorrhage than traditional vital signs. Acute traumatic<br />
bra<strong>in</strong> <strong>in</strong>jury (TBI) can be associated with autonomic uncoupl<strong>in</strong>g and may<br />
therefore alter the reliability of SI <strong>in</strong> patients with comb<strong>in</strong>ed TBI and peripheral<br />
hemorrhage. The aim of this study was to evaluate the performance<br />
of SI when acute TBI of mild and moderate severity were associated<br />
with progressive simple hemorrhage.<br />
METhOdS: This study was undertaken <strong>in</strong> a laboratory sett<strong>in</strong>g. Brian <strong>in</strong>jury<br />
was <strong>in</strong>duced us<strong>in</strong>g the lateral fluid percussion model <strong>in</strong> anesthetized rats.<br />
The fluid percussion device delivered an applied cortical pressure of 1.2<br />
atm and 1.8 atm, produc<strong>in</strong>g mild and moderate TBI, respectively. Control<br />
animals underwent identical procedures but with no applied cortical<br />
pressure. Hemorrhage was <strong>in</strong>duced 10 m<strong>in</strong>utes after bra<strong>in</strong> <strong>in</strong>jury, at<br />
a rate of 2% of blood volume per m<strong>in</strong>ute until 40% blood volume was<br />
withdrawn.<br />
RESULTS: The SI response to <strong>in</strong>creas<strong>in</strong>g volume of hemorrhage was unaltered<br />
when control and mild TBI groups were compared (test of <strong>in</strong>teraction<br />
p = 0.39). There was a 50% mortality rate observed 20 to 60 m<strong>in</strong>utes<br />
after hemorrhage <strong>in</strong> the moderate TBI group. The SI response to<br />
hemorrhage <strong>in</strong> the moderate TBI group compared with the control group<br />
became significantly different at 40% blood volume loss (test of <strong>in</strong>teraction<br />
p = 0.048). Comparison of the SI response with hemorrhage between<br />
survivors and nonsurvivors of moderate TBI revealed a significant difference<br />
(p = 0.007). SI was markedly attenuated <strong>in</strong> the presence of <strong>in</strong>creas<strong>in</strong>g<br />
hemorrhage <strong>in</strong> the nonsurvivor subgroup of moderate TBI.<br />
COnCLUSIOnS: SI significantly underestimated underly<strong>in</strong>g hemorrhage<br />
<strong>in</strong> the presence of acute TBI of moderate severity where attenuation of<br />
the biphasic heart rate and blood pressure response was also most pronounced.<br />
j Trauma 2010;69(5):1169-75<br />
35
36<br />
plasma superoxide dismutase activity and mortality<br />
<strong>in</strong> patients with septic<br />
M.O. Guerreiro<br />
F. Petronilho<br />
M. Andrades<br />
L. Constant<strong>in</strong>o<br />
F.G. M<strong>in</strong>a<br />
J.C. Moreira<br />
F.D. Pizzol<br />
C. Ritter<br />
Laboratório de Fisiopatologia<br />
Experimental (MOG, FP, LC,<br />
FGM, FDP, CR), Universidade<br />
do Extremo Sul Catar<strong>in</strong>ense,<br />
Criciúma, SC, Brazil;<br />
Programa de Pós Graduação<br />
em Ciências Biológicas<br />
(FP, MA, JCFM), Bioquímica,<br />
Universidade Federal do Rio<br />
Grande do Sul; Programa<br />
de Pós Graduação em<br />
Ciências Médicas (MOG),<br />
Universidade Federal do Rio<br />
Grande do Sul, Porto Alegre,<br />
RS, Brazil<br />
bACkGROUnd: The aim of this study was to determ<strong>in</strong>e whether plasma<br />
superoxide dismutase (SOD) activity, <strong>in</strong> comparison with other oxidative<br />
parameters, is associated with mortality <strong>in</strong> humans with septic.<br />
METhOdS: We conducted a prospective observational study <strong>in</strong>clud<strong>in</strong>g<br />
96 patients with septic. Blood samples were collected immediately after<br />
study <strong>in</strong>clusion and 24 hours after. We then determ<strong>in</strong>ed plasma levels of<br />
thiobarbituric acid reactive species, prote<strong>in</strong> carbonyls, SOD, and catalase<br />
activities.<br />
RESULTS: Plasma carbonyls and SOD activity, but not plasma thiobarbituric<br />
acid reactive species and catalase activity, were significantly higher <strong>in</strong><br />
non-survivors. SOD activity significantly correlated with Acute Physiology<br />
and Chronic Health Evaluation II and Multiple Organ Dysfunction Score. In<br />
addition, SOD activity presented similar area under the receiver operator<br />
characteristic curve when compared with Acute Physiology and Chronic<br />
Health Evaluation II to predict mortality. A dim<strong>in</strong>ution of 25% or more on<br />
SOD activity between D1 and D2 was associated with a better outcome.<br />
COnCLUSIOn: Our data provide some new <strong>in</strong>formation on the use of plasma<br />
SOD activity as a biomarker <strong>in</strong> human sepsis.<br />
j Trauma 2010;69(6):E102-6
<strong>in</strong>flammatory alterations <strong>in</strong> a novel comb<strong>in</strong>ation model<br />
of blunt chest trauma and hemorrhagic shock<br />
D.H. Seitz<br />
M. Perl<br />
U.C. Liener<br />
B. Tauchmann<br />
S.T. Braumüller<br />
U.B. Brückner<br />
F. Gebhard<br />
M.W. Knöferl<br />
Department of Trauma<br />
Surgery, Hand, Plastic<br />
and Reconstructive Surgery<br />
(DHS, MP, UCL, BT, STB, FG,<br />
MWK) and Division<br />
of Surgical Research (UBB),<br />
University of Ulm, Ulm,<br />
Germany<br />
bACkGROUnd: Chest trauma frequently occurs <strong>in</strong> severely <strong>in</strong>jured patients<br />
and is often associated with hemorrhagic shock. Immune dysfunction<br />
contributes to the adverse outcome of multiple <strong>in</strong>juries. The aims<br />
of this study were to establish a comb<strong>in</strong>ed model of lung contusion and<br />
hemorrhage and to evaluate the cardiopulmonary and immunologic response.<br />
METhOdS: Male mice were subjected to sham procedure, chest trauma,<br />
hemorrhage (35 ± 5 mm Hg, 60 m<strong>in</strong>utes), or the comb<strong>in</strong>ation. Respiratory<br />
rate, heart rate, and blood pressure were monitored. Plasma, Kupffer<br />
cells, blood monocytes, splenocytes, and splenic macrophages were isolated<br />
after 20 hours. Tumor necrosis factor-alpha (TNF-alpha), <strong>in</strong>terleuk<strong>in</strong><br />
(IL)-6, 10, 12, 18, and macrophage <strong>in</strong>flammatory prote<strong>in</strong>-2 levels <strong>in</strong> plasma<br />
and culture supernatants were determ<strong>in</strong>ed.<br />
RESULTS: Heart rate and blood pressure dropped <strong>in</strong> all groups, and after<br />
chest trauma and the double hit, these values rema<strong>in</strong>ed reduced until the<br />
end of observation. Blood pressure was lower after the double hit than<br />
after the s<strong>in</strong>gle hits. Plasma and Kupffer cell TNF-alpha concentrations<br />
were <strong>in</strong>creased after lung contusion but not further enhanced by subsequent<br />
hemorrhage. Peripheral blood mononuclear cell (PBMC) TNF-alpha<br />
and IL-6 release were suppressed after the comb<strong>in</strong>ed <strong>in</strong>sult. IL-18 concentrations<br />
were <strong>in</strong>creased <strong>in</strong> PBMC supernatants after chest trauma and <strong>in</strong><br />
splenic macrophage supernatants of all groups.<br />
COnCLUSIOnS: Although physiologic readouts were selectively altered <strong>in</strong><br />
response to the s<strong>in</strong>gle or double hits, the comb<strong>in</strong>ation did not uniformly<br />
augment the changes <strong>in</strong> <strong>in</strong>flammation. Our results suggest that the lead<strong>in</strong>g<br />
<strong>in</strong>sult regard<strong>in</strong>g the immunologic response is lung contusion, support<strong>in</strong>g<br />
the concept that lung contusion represents an important prognostic<br />
factor <strong>in</strong> multiple <strong>in</strong>juries.<br />
j Trauma 2011;70(1):189-96<br />
37
38<br />
Liver ischemia/reperfusion <strong>in</strong>jury:<br />
processes <strong>in</strong> <strong>in</strong>flammatory networks--a review<br />
M. Abu-Amara<br />
S.Y. Yang<br />
N. Tapuria<br />
B. Fuller<br />
B. Davidson<br />
A. Seifalian<br />
Liver Transplantation<br />
and Hepatobiliary Unit,<br />
Royal Free Hospital,<br />
London, UK<br />
Liver ischemia/reperfusion (IR) <strong>in</strong>jury is typified by an <strong>in</strong>flammatory response.<br />
Understand<strong>in</strong>g the cellular and molecular events underp<strong>in</strong>n<strong>in</strong>g this<br />
<strong>in</strong>flammation is fundamental to develop<strong>in</strong>g therapeutic strategies. Great<br />
strides have been made <strong>in</strong> this respect recently. Liver IR <strong>in</strong>volves a complex<br />
web of <strong>in</strong>teractions between the various cellular and humoral contributors<br />
to the <strong>in</strong>flammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils,<br />
and hepatocytes are central cellular players. Various cytok<strong>in</strong>es,<br />
chemok<strong>in</strong>es, and complement prote<strong>in</strong>s form the communication system<br />
between the cellular components. The contribution of the danger-associated<br />
molecular patterns and pattern recognition receptors to the pathophysiology<br />
of liver IR <strong>in</strong>jury are slowly be<strong>in</strong>g elucidated. Our knowledge<br />
on the role of mitochondria <strong>in</strong> generat<strong>in</strong>g reactive oxygen and nitrogen<br />
species, <strong>in</strong> contribut<strong>in</strong>g to ionic disturbances, and <strong>in</strong> <strong>in</strong>itiat<strong>in</strong>g the mitochondrial<br />
permeability transition with subsequent cellular death <strong>in</strong> liver<br />
IR <strong>in</strong>jury is cont<strong>in</strong>uously be<strong>in</strong>g expanded. Here, we discuss recent f<strong>in</strong>d<strong>in</strong>gs<br />
perta<strong>in</strong><strong>in</strong>g to the aforementioned factors of liver IR, and we highlight<br />
areas with gaps <strong>in</strong> our knowledge, necessitat<strong>in</strong>g further research.<br />
Liver Transpl 2010;16(9):1016-32
Criteria for diagnos<strong>in</strong>g benign portal ve<strong>in</strong> thrombosis<br />
<strong>in</strong> the assessment of patients with cirrhosis<br />
and hepatocellular carc<strong>in</strong>oma for liver transplantation<br />
F. Piscaglia<br />
A. Gianstefani<br />
M. Ravaioli<br />
R. Golfieri<br />
A. Cappelli<br />
E. Giampalma<br />
E. Sagr<strong>in</strong>i<br />
G. Imbriaco<br />
A.D. P<strong>in</strong>na<br />
L. Bolondi<br />
Bologna Liver Transplant<br />
Group<br />
Division of Internal Medic<strong>in</strong>e,<br />
Department of Digestive<br />
Disease and Internal<br />
Medic<strong>in</strong>e, St. Orsola-Malpighi<br />
University Hospital, Bologna,<br />
Italy<br />
Malignant portal ve<strong>in</strong> thrombosis is a contra<strong>in</strong>dication for liver transplantation.<br />
Patients with cirrhosis and early hepatocellular carc<strong>in</strong>oma (HCC)<br />
may have either malignant or benign (fibr<strong>in</strong> clot) portal ve<strong>in</strong> thrombosis.<br />
The aim of this study was to assess prospectively whether well-def<strong>in</strong>ed<br />
diagnostic criteria would enable the nature of portal ve<strong>in</strong> thrombosis to<br />
be established <strong>in</strong> patients with HCC under consideration for liver transplantation.<br />
Benign portal ve<strong>in</strong> thrombosis was diagnosed by the application<br />
of the follow<strong>in</strong>g criteria: lack of vascularization of the thrombus on<br />
contrast-enhanced ultrasound and on computed tomography or magnetic<br />
resonance imag<strong>in</strong>g, absence of mass-form<strong>in</strong>g features of the thrombus,<br />
absence of disruption of the walls of ve<strong>in</strong>s, and, if uncerta<strong>in</strong>ty persisted,<br />
biopsy of the thrombus for histological exam<strong>in</strong>ation. Patients who did not<br />
fulfill the criteria for benign thrombosis were not placed on the transplantation<br />
list. In this study, all patients evaluated at our center dur<strong>in</strong>g<br />
2001-2007 with a diagnosis of HCC <strong>in</strong> whom portal ve<strong>in</strong> thrombosis was<br />
concurrently or subsequently diagnosed were discussed by a multidiscipl<strong>in</strong>ary<br />
group to determ<strong>in</strong>e their suitability for liver transplantation. The<br />
outcomes for 33 patients who met the entry criteria of the study were as<br />
follows: <strong>in</strong> 14 patients who were placed on the transplantation list and<br />
underwent liver transplantation, no malignant thrombosis was detected<br />
when liver explants were exam<strong>in</strong>ed histologically; 5 patients who were<br />
placed on the transplantation list either rema<strong>in</strong>ed on the list or died from<br />
causes unrelated to HCC; <strong>in</strong> 9 patients, liver transplantation was contra<strong>in</strong>dicated<br />
on account of a strong suspicion, or confirmation, of the presence<br />
of malignant portal ve<strong>in</strong> thrombosis; and 5 patients who were <strong>in</strong>itially<br />
placed on the transplantation list were subsequently removed from it on<br />
account of progression of HCC <strong>in</strong> the absence of evidence of neoplastic<br />
<strong>in</strong>volvement of thrombosis. In conclusion, for a patient with HCC and portal<br />
ve<strong>in</strong> thrombosis, appropriate <strong>in</strong>vestigations can establish whether the<br />
thrombosis is benign; patients with HCC and benign portal ve<strong>in</strong> thrombosis<br />
are candidates for liver transplantation.<br />
Liver Transpl 2010;16(5):658-67<br />
39
40<br />
recurrent preeclampsia: the effect of weight change<br />
between pregnancies<br />
D. Mostello<br />
J. Jen Chang<br />
J. Allen<br />
L. Luehr<br />
J. Shyken<br />
T. Leet<br />
Division of Maternal-Fetal<br />
Medic<strong>in</strong>e, Department<br />
of Obstetrics, Gynecology,<br />
and Women’s Health,<br />
and School of Public Health,<br />
Sa<strong>in</strong>t Louis University School<br />
of Medic<strong>in</strong>e, St. Louis, MO,<br />
USA<br />
ObjECTIvE: To estimate whether the risk of recurrent preeclampsia is affected<br />
by <strong>in</strong>terpregnancy change <strong>in</strong> body mass <strong>in</strong>dex (BMI).<br />
METhOdS: We conducted a population-based cohort study us<strong>in</strong>g Missouri<br />
maternally l<strong>in</strong>ked birth certificates for 17,773 women whose first<br />
pregnancies were complicated by preeclampsia. The women were placed<br />
<strong>in</strong>to three groups: those who decreased their BMIs, those who ma<strong>in</strong>ta<strong>in</strong>ed<br />
their BMIs, and those who <strong>in</strong>creased their BMIs between their first two<br />
pregnancies. The primary outcome was recurrent preeclampsia <strong>in</strong> the second<br />
pregnancy. Adjusted risk ratios and 95% confidence <strong>in</strong>tervals were<br />
calculated us<strong>in</strong>g Poisson regression analysis.<br />
RESULTS: The overall rate of recurrent preeclampsia <strong>in</strong> women who decreased<br />
their BMIs between pregnancies was 12.8% (risk ratio 0.70, confidence<br />
<strong>in</strong>terval 0.60-0.81) compared with 14.8% if BMI was ma<strong>in</strong>ta<strong>in</strong>ed and<br />
18.5% <strong>in</strong> those who <strong>in</strong>creased their BMIs (risk ratio 1.29, confidence <strong>in</strong>terval<br />
1.20-1.38). With<strong>in</strong> the normal weight, overweight, and obese weight<br />
categories, women who decreased BMI between pregnancies were less<br />
likely to experience recurrent preeclampsia. Women <strong>in</strong> all weight categories<br />
who <strong>in</strong>creased their BMIs between pregnancies were more likely to<br />
experience recurrent preeclampsia.<br />
COnCLUSIOn: Interpregnancy weight reduction decreases the risk of recurrent<br />
preeclampsia and should be encouraged <strong>in</strong> women who experience<br />
preeclampsia.<br />
Obstet Gynecol 2010;116(3):667-72
Fresh-frozen plasma transfusion strategy <strong>in</strong> trauma<br />
with massive and ongo<strong>in</strong>g bleed<strong>in</strong>g.<br />
Common (sense) and sensibility<br />
A.M. Ho<br />
P.W. Dion<br />
J.H. Yeung<br />
C.S. Ng<br />
M.K. Karmakar<br />
L.A. Critchley<br />
T.H. Ra<strong>in</strong>er<br />
C.W. Cheung<br />
B.A. Tay<br />
Department of Anaesthesia<br />
and Intensive Care, Pr<strong>in</strong>ce<br />
of Wales Hospital,<br />
The Ch<strong>in</strong>ese University<br />
of Hong Kong, Shat<strong>in</strong>, NT,<br />
Hong Kong<br />
Dur<strong>in</strong>g trauma resuscitation <strong>in</strong>volv<strong>in</strong>g massive transfusion, the best freshfrozen<br />
plasma to packed red blood cells ratio is unknown. No randomised<br />
controlled trial (RCT) is available on this subject, although there are plenty<br />
of observational studies suggest<strong>in</strong>g that the ratio should be about 1:1.<br />
This ratio also makes more physiological sense, and we suggest that <strong>in</strong><br />
patients with massive and ongo<strong>in</strong>g bleed<strong>in</strong>g, it is a sensible strategy with<br />
which to start resuscitation.<br />
Resuscitation 2010;81(9):1079-81<br />
41
42<br />
extracorporeal membrane oxygenation <strong>in</strong> severe trauma<br />
patients with bleed<strong>in</strong>g shock<br />
M. Arlt<br />
A. Philipp<br />
S. Voelkel<br />
L. Rupprecht<br />
T. Mueller<br />
M. Hilker<br />
B.M. Graf<br />
C. Schmid<br />
Department<br />
of Anesthesiology,<br />
University Hospital<br />
Regensburg, Germany<br />
AIM Of ThE STUdy: Death to trauma is caused by disastrous <strong>in</strong>juries on<br />
scene, bleed<strong>in</strong>g shock or acute respiratory failure (ARDS) <strong>in</strong>duced by trauma<br />
and massive blood transfusion. Extracorporeal membrane oxygenation<br />
(ECMO) can be effective <strong>in</strong> severe cardiopulmonary failure, but preexist<strong>in</strong>g<br />
bleed<strong>in</strong>g is still a contra<strong>in</strong>dication for its use. We report our first<br />
experiences <strong>in</strong> application of <strong>in</strong>itially hepar<strong>in</strong>-free ECMO <strong>in</strong> severe trauma<br />
patients with resistant cardiopulmonary failure and coexist<strong>in</strong>g bleed<strong>in</strong>g<br />
shock retrospectively and describe blood coagulation management on<br />
ECMO.<br />
METhOdS: From June 2006 to June 2009 we treated adult trauma patients<br />
(n = 10, mean age: 32 ± 14 years, mean ISS score 73 ± 4) with percutaneous<br />
veno-venous (v-v) ECMO for pulmonary failure (n = 7) and with venoarterial<br />
(v-a) ECMO <strong>in</strong> cardiopulmonary failure (n = 3). Diagnosis <strong>in</strong>cluded<br />
polytrauma (n = 9) and open chest trauma (n = 1). We used a new m<strong>in</strong>iaturised<br />
ECMO device (PLS-Set, MAQUET Cardiopulmonary AG, Hech<strong>in</strong>gen,<br />
Germany) and performed <strong>in</strong>itially hepar<strong>in</strong>-free ECMO.<br />
RESULTS: Prior to ECMO median oxygenation ratio (OR) was 47 (36-90)<br />
mmHg, median paCO was 67 (36-89) mmHg and median norep<strong>in</strong>ephr<strong>in</strong>e<br />
2<br />
demand was 3.0 (1.0-13.5) mg/h. Cardiopulmonary failure was treated effectively<br />
with ECMO and systemic gas exchange and blood flow improved<br />
rapidly with<strong>in</strong> 2 h on ECMO <strong>in</strong> all patients (median OR 69 (52-263) mmHg,<br />
median paCO 41 (22-85) mmHg. 60% of our patients had recovered com-<br />
2<br />
pletely.<br />
COnCLUSIOnS: Initially hepar<strong>in</strong>-free ECMO support can improve therapy<br />
and outcome even <strong>in</strong> disastrous trauma patients with coexist<strong>in</strong>g bleed<strong>in</strong>g<br />
shock.<br />
Resuscitation 2010;81(7):804-9
ons formation under restrictive reperfusion<br />
does not affect organ dysfunction early after<br />
hemorrhage and trauma<br />
C. Zifko<br />
A.V. Kozlov<br />
A. Postl<br />
H. Redl<br />
S. Bahrami<br />
Ludwig Boltzmann Institute<br />
for Experimental and Cl<strong>in</strong>ical<br />
Traumatology <strong>in</strong> AUVA<br />
Research Center, Vienna,<br />
Austria<br />
Reactive oxygen species have been implicated <strong>in</strong> the pathophysiology of<br />
early reperfusion. We aimed to determ<strong>in</strong>e 1) reactive oxygen and nitrogen<br />
species (RONS) formation <strong>in</strong> organs of rats and 2) its pathophysiological<br />
relevance dur<strong>in</strong>g a phase of restrictive reperfusion after hemorrhagic/<br />
traumatic shock (HTS). Fifty-seven male Sprague-Dawley rats were subjected<br />
to a cl<strong>in</strong>ically relevant HTS model, featur<strong>in</strong>g laparotomy, bleed<strong>in</strong>g,<br />
and a phase of restrictive reperfusion. The RONS scavenger 1-hydroxy-3carboxy-2,2,5,5-tetramethyl-pyrrolid<strong>in</strong>e<br />
hydrochloride (cont<strong>in</strong>uous i.v. <strong>in</strong>fusion)<br />
and electron paramagnetic resonance spectroscopy were applied<br />
for RONS (primarily superoxide and peroxynitrite) detection. Compared<br />
with sham-operated animals, the organ-specific distribution of RONS<br />
changed dur<strong>in</strong>g restrictive reperfusion after HTS. Reactive oxygen and<br />
nitrogen species formation <strong>in</strong>creased dur<strong>in</strong>g restrictive reperfusion <strong>in</strong><br />
red blood cells and ileum only but decreased <strong>in</strong> the kidney and rema<strong>in</strong>ed<br />
unchanged <strong>in</strong> other organs. Hemorrhagic traumatic shock followed by<br />
restrictive reperfusion resulted <strong>in</strong> metabolic acidosis, dysfunction of liver<br />
and kidney, and <strong>in</strong>creased oxidative burst capacity <strong>in</strong> circulat<strong>in</strong>g cells.<br />
Plasma RONS correlated with shock severity and organ dysfunction. However,<br />
RONS scaveng<strong>in</strong>g neither affected organ dysfunction nor oxidative<br />
burst capacity nor myeloperoxidase activity <strong>in</strong> lung when compared with<br />
the shock controls. In summary, a phase of restrictive reperfusion does not<br />
<strong>in</strong>crease RONS formation <strong>in</strong> most organs except <strong>in</strong> <strong>in</strong>test<strong>in</strong>e and red blood<br />
cells. Moreover, scaveng<strong>in</strong>g of RONS does not affect the early organ dysfunction<br />
manifested at the end of a phase of restrictive reperfusion.<br />
Shock 2010;34(4):384-9<br />
43
Aggiornamenti <strong>in</strong> Rianimazione e Terapia Intensiva è una rivista periodica che pubblica articoli brevi, case reports ed<br />
abstracts dalla letteratura <strong>in</strong>ternazionale riguardanti tutti gli aspetti legati all’epidemiologia, all’eziologia, alla patofisiologia,<br />
alla diagnosi e al trattamento delle malattie acute e dei traumi.<br />
Gli articoli scientifici orig<strong>in</strong>ali dovranno essere accompagnati da una dichiarazione firmata dal primo Autore, nella quale<br />
si attesti che i contributi sono <strong>in</strong>editi, non sottoposti contemporaneamente ad altra rivista, ed il loro contenuto conforme<br />
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La loro accettazione è subord<strong>in</strong>ata al parere conclusivo del Direttore Scientifico che si riserva <strong>in</strong>oltre il diritto di richiedere agli<br />
Autori la documentazione dei casi e dei protocolli di ricerca, qualora lo ritenga opportuno.<br />
norme generali<br />
Testo: <strong>in</strong> l<strong>in</strong>gua italiana e corredato di: titolo del lavoro (<strong>in</strong> italiano ed <strong>in</strong> <strong>in</strong>glese); parole chiave (<strong>in</strong> italiano ed <strong>in</strong> <strong>in</strong>glese);<br />
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pubblicati dopo revisione fatta dalla Redazione che però decl<strong>in</strong>a ogni responsabilità per eventuali <strong>in</strong>esattezze<br />
sia del dattiloscritto che delle <strong>in</strong>dicazioni relative a figure e tabelle.<br />
Nella prima pag<strong>in</strong>a devono comparire: il titolo (conciso, <strong>in</strong> italiano ed <strong>in</strong>glese); le parole chiave <strong>in</strong> italiano ed <strong>in</strong>glese ; i nomi<br />
degli Autori e l’Istituto o Ente di appartenenza; la rubrica cui si <strong>in</strong>tende dest<strong>in</strong>are il lavoro (decisione che è comunque subord<strong>in</strong>ata<br />
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compariranno la bibliografia, le didascalie di tabelle e figure e l’eventuale menzione del Congresso al quale i dati dell’articolo<br />
siano stati comunicati (tutti o <strong>in</strong> parte). Tabelle: devono essere contenute nel numero (evitando di presentare lo stesso<br />
dato <strong>in</strong> più forme) e numerate progressivamente. figure: vanno riprodotte <strong>in</strong> foto o digitale e numerate con eventuale<br />
<strong>in</strong>dicazione dell’orientamento. I grafici ed i disegni possono essere <strong>in</strong> fotocopia, purché di buona qualità. bibliografia: va<br />
limitata alle voci essenziali identificate nel testo con numeri arabi ed elencate al term<strong>in</strong>e del dattiloscritto nell’ord<strong>in</strong>e <strong>in</strong> cui<br />
sono state citate, avvalendosi delle abbreviazioni <strong>in</strong>ternazionali.Esempi di corretta citazione bibliografica per:<br />
Articoli e riviste:<br />
Bianchi M, Laurà G, Recalcati D. Il trattamento chirurgico delle rigidità acquisite del g<strong>in</strong>occhio. M<strong>in</strong>erva Ortopedica<br />
1985;36:431-438.<br />
Libri: Tajana GF. Il condrone. Milano: Edizioni Mediamix 1991.<br />
Capitoli di libri o atti di Congressi:<br />
Krmpotic-Nemanic J, Kostovis I, Rudan P. Ag<strong>in</strong>g changes of the form and <strong>in</strong>frastructure of the external nose and its importance<br />
<strong>in</strong> rh<strong>in</strong>oplasty. In: Conly J, Dick<strong>in</strong>son JT, eds. Plastic and Reconstructive Surgery of the Face and Neck. New York: Grune and<br />
Stratton 1972, p. 84.<br />
R<strong>in</strong>graziamenti, <strong>in</strong>dicazioni di grants o borse di studio, vanno citati al term<strong>in</strong>e della bibliografia. Le note,<br />
contraddist<strong>in</strong>te da asterischi o simboli equivalenti, compariranno nel testo a piè di pag<strong>in</strong>a. Term<strong>in</strong>i matematici, formule,<br />
abbreviazioni, unità e misure devono conformarsi agli standards riportati <strong>in</strong> Science 1954;120:1078. I farmaci vanno <strong>in</strong>dicati<br />
col nome chimico.<br />
Solo se <strong>in</strong>evitabile potranno essere citati col nome commerciale (scrivendo <strong>in</strong> maiuscolo la lettera <strong>in</strong>iziale del prodotto).<br />
norme specifiche per le s<strong>in</strong>gole rubriche<br />
Articoli orig<strong>in</strong>ali brevi: comprendono brevi lavori (non più di 3 cartelle di testo) che offrono un contributo nuovo o frutto<br />
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seguenti parti: <strong>in</strong>troduzione, materiale e metodo, risultati, discussione e conclusioni. Nella sezione Obiettivi va s<strong>in</strong>tetizzato<br />
con chiarezza l’obiettivo (o gli obiettivi) del lavoro, vale a dire l’ipotesi che si è <strong>in</strong>teso verificare; nei Metodi va riportato il<br />
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cieco …), il tipo di trattamento e il tipo di analisi statistica impiegata. Nella sezione Risultati vanno riportati i risultati dello<br />
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implicazioni cl<strong>in</strong>iche. Sono ammesse 2 tabelle o figure e una dec<strong>in</strong>a di voci bibliografiche.<br />
Casi cl<strong>in</strong>ici: vengono accettati dal Comitato di Redazione solo lavori di <strong>in</strong>teresse didattico e segnalazioni rare. La presentazione<br />
comprende l’esposizione del caso ed una discussione diagnosticodifferenziale. Il testo deve essere conciso e corredato, se<br />
necessario, di 1-2 figure o tabelle e di pochi riferimenti bibliografici essenziali. Il riassunto è di circa 50 parole.<br />
Gli scritti di cui si fa richiesta di pubblicazione vanno <strong>in</strong>dirizzati (<strong>in</strong> orig<strong>in</strong>ale o per E-mail) a: Pac<strong>in</strong>i <strong>Editore</strong> SpA - Ufficio<br />
Editoriale, via Gherardesca, 56121 Ospedaletto (PI) - c.a. Lucia Castelli - Tel. 050 3130224 - E-mail: lcastelli@<br />
pac<strong>in</strong>ieditore.it.
albunorm<br />
RIASSUnTO dELLE CARATTERISTIChE dEL PROdOTTO<br />
1. dEnOMInAZIOnE dEL MEdICInALE<br />
Albunorm 20% “200 g/l, soluzione per <strong>in</strong>fusione”.<br />
2. COMPOSIZIOnE QUALITATIvA E QUAnTITATIvA<br />
Albunorm 20% è una soluzione contenente 200 g/l di prote<strong>in</strong>a totale di cui almeno il 96% è album<strong>in</strong>a umana.<br />
Un flacone da 50 ml contiene 10 g di album<strong>in</strong>a umana.<br />
Un flacone da 100 ml contiene 20 g di album<strong>in</strong>a umana.<br />
Eccipienti:<br />
– Sodio (144-160 mmol/l);<br />
– Albunorm 20% è una soluzione iperoncotica.<br />
Per l’elenco completo degli eccipienti, vedere paragrafo 6.1.<br />
3. fORMA fARMACEUTICA<br />
Soluzione per <strong>in</strong>fusione.<br />
La soluzione è un liquido chiaro, leggermente viscoso, con colorazione gialla, ambra o verde.<br />
4. InfORMAZIOnI CLInIChE<br />
4.1 Indicazioni terapeutiche<br />
Re<strong>in</strong>tegro e mantenimento del volume del sangue circolante <strong>in</strong> presenza di chiara ipovolemia, e dove l’uso di un colloide<br />
risulta appropriato.<br />
Di norma la scelta dell’album<strong>in</strong>a al posto del colloide artificiale dipenderà dalle condizioni cl<strong>in</strong>iche <strong>in</strong>dividuali del paziente,<br />
<strong>in</strong> relazione alle raccomandazioni ufficiali.<br />
4.2 Posologia e modo di somm<strong>in</strong>istrazione<br />
La concentrazione della preparazione a base di album<strong>in</strong>a, il dosaggio e la velocità di <strong>in</strong>fusione, devono essere adattate<br />
alle condizioni <strong>in</strong>dividuali di ciascun paziente.<br />
Posologia<br />
Il regime di somm<strong>in</strong>istrazione dipende dalla costituzione del paziente, dalla gravità del trauma o della malattia, e dalla<br />
entità delle perdite di fluidi e prote<strong>in</strong>e.<br />
Per la determ<strong>in</strong>azione della dose necessaria si devono effettuare misurazioni circa l’adeguatezza del volume circolante e<br />
non dei livelli di album<strong>in</strong>a nel sangue.<br />
Nel caso fosse necessaria la somm<strong>in</strong>istrazione di album<strong>in</strong>a umana, la funzionalità emod<strong>in</strong>amica deve essere regolarmente<br />
monitorata; ciò può comprendere:<br />
– pressione arteriosa e frequenza del polso;<br />
– pressione venosa centrale;<br />
– pressione arteriosa polmonare;<br />
– analisi delle ur<strong>in</strong>e;<br />
– elettroliti;<br />
– ematocrito/ emoglob<strong>in</strong>a.<br />
Metodo di somm<strong>in</strong>istrazione<br />
L’album<strong>in</strong>a umana può essere <strong>in</strong>fusa direttamente per via endovenosa o può anche essere diluita <strong>in</strong> una soluzione<br />
isotonica (ad es. glucosio al 5% o cloruro di sodio allo 0,9%).<br />
La velocità di <strong>in</strong>fusione deve essere adeguata alle condizioni <strong>in</strong>dividuali ed alle <strong>in</strong>dicazioni.<br />
In corso di plasmaferesi la velocità di <strong>in</strong>fusione deve essere adattata alla velocità della procedura.<br />
4.3 Contro<strong>in</strong>dicazioni<br />
Ipersensibilità a preparazioni di album<strong>in</strong>a o ad uno qualsiasi degli eccipienti.<br />
4.4 Avvertenze speciali e precauzioni di impiego<br />
In presenza di reazioni allergiche o di tipo anafilattico, l’<strong>in</strong>fusione deve essere immediatamente sospesa. In caso di shock,<br />
seguire il trattamento consigliato dalle l<strong>in</strong>ee guida per la terapia dello shock.<br />
Quando si somm<strong>in</strong>istra album<strong>in</strong>a, deve essere prestata particolare attenzione a tutte quelle condizioni <strong>in</strong> cui l’ipervolemia<br />
e le sue conseguenze o l’emodiluizione possono rappresentare un rischio specifico per il paziente.<br />
Esempi di tali condizioni sono:<br />
– <strong>in</strong>sufficienza cardiaca scompensata;<br />
– ipertensione;<br />
– varici esofagee;<br />
– edema polmonare;
– diatesi emorragica;<br />
– anemia grave;<br />
– anuria renale e post-renale.<br />
In uno studio retrospettivo sul follow-up di pazienti critici con trauma cranico, la rianimazione volemica con album<strong>in</strong>a è<br />
stata associata ad un più alto tasso di mortalità rispetto alla rianimazione volemica con l’utilizzo di soluzione fisiologica.<br />
Mentre i meccanismi alla base di questa differenza osservata nella mortalità non sono chiari, si consiglia cautela nell’uso<br />
di album<strong>in</strong>a <strong>in</strong> pazienti con gravi traumi cranici.<br />
L’effetto colloido-osmotico dell’album<strong>in</strong>a umana al 20 o 25% è approssimativamente 4 volte superiore a quello del<br />
plasma umano. Pertanto, quando si somm<strong>in</strong>istra album<strong>in</strong>a concentrata, bisogna prestare attenzione ed assicurare al<br />
paziente una adeguata idratazione. I pazienti devono essere accuratamente monitorati al f<strong>in</strong>e di evitare un sovraccarico<br />
circolatorio e iperidratazione.<br />
Le soluzioni di album<strong>in</strong>a umana al 20-25% hanno una concentrazione elettrolitica m<strong>in</strong>ore di quella delle soluzioni al<br />
4-5%. Quando viene somm<strong>in</strong>istrata album<strong>in</strong>a, deve essere monitorato lo stato elettrolitico del paziente (vedere paragrafo<br />
4.2) e si devono attuare <strong>in</strong>terventi opportuni per ristabilire o mantenere l’equilibrio elettrolitico normale.<br />
Le soluzioni di album<strong>in</strong>a non devono essere diluite con acqua per preparazioni <strong>in</strong>iettabili perché ciò potrebbe causare<br />
una emolisi nei pazienti riceventi.<br />
Se devono essere somm<strong>in</strong>istrati volumi relativamente più elevati, sono necessari controlli della coagulazione e<br />
dell’ematocrito. Si deve <strong>in</strong>oltre assicurare una adeguata sostituzione degli altri componenti ematici (fattori della<br />
coagulazione, elettroliti, piastr<strong>in</strong>e ed eritrociti).<br />
Si può <strong>in</strong>oltre verificare una ipervolemia se il dosaggio e la velocità di somm<strong>in</strong>istrazione non sono adeguate alla funzione<br />
circolatoria del paziente. L’<strong>in</strong>fusione deve essere <strong>in</strong>terrotta immediatamente ai primi s<strong>in</strong>tomi cl<strong>in</strong>ici di sovraccarico<br />
cardiovascolare (cefalea, dispnea, congestione giugulare), o di aumento della pressione arteriosa, o della pressione venosa<br />
ed edema polmonare.<br />
L’esperienza sull’uso di Albunorm 20% nei bamb<strong>in</strong>i è limitata; perciò il prodotto deve essere somm<strong>in</strong>istrato <strong>in</strong> questi<br />
soggetti solo nel caso <strong>in</strong> cui i benefici siano nettamente superiori ai potenziali rischi.<br />
Questo medic<strong>in</strong>ale contiene 7,2-8 mmol di sodio per ogni flacone da 50 ml e 14,4-16 mmol di sodio <strong>in</strong> quelli da 100 ml<br />
di album<strong>in</strong>a umana <strong>in</strong> soluzione. Questo deve essere tenuto <strong>in</strong> considerazione nei pazienti sottoposti ad una dieta a basso<br />
tenore di sodio.<br />
Questo medic<strong>in</strong>ale contiene 1 mmol di potassio nel flacone da 100 ml di album<strong>in</strong>a umana <strong>in</strong> soluzione. Questo deve<br />
essere tenuto <strong>in</strong> considerazione nei pazienti con ridotta funzionalità renale o sottoposti ad una dieta a basso tenore di<br />
potassio.<br />
Le misure standard per la prevenzione delle <strong>in</strong>fezioni causate dall’utilizzo di medic<strong>in</strong>ali derivati da sangue o plasma<br />
umano comprendono la selezione dei donatori, lo screen<strong>in</strong>g delle donazioni <strong>in</strong>dividuali e dei pool di plasma per<br />
marker specifici di <strong>in</strong>fezione e l’utilizzo di procedure nella fase di produzione atte all’<strong>in</strong>attivazione/rimozione di<br />
virus.<br />
Nonostante ciò, quando si somm<strong>in</strong>istrano specialità medic<strong>in</strong>ali preparate da sangue o plasma umano, non può essere<br />
totalmente escluso il rischio di trasmissione di agenti <strong>in</strong>fettivi.<br />
Ciò si applica anche a virus emergenti o di natura sconosciuta e ad altri agenti patogeni.<br />
Non ci sono segnalazioni di <strong>in</strong>fezioni virali trasmesse a seguito di somm<strong>in</strong>istrazione di album<strong>in</strong>a preparata <strong>in</strong> accordo alle<br />
specifiche della Farmacopea Europea.<br />
È vivamente raccomandato, ogni volta che si somm<strong>in</strong>istra Albunorm 20% al paziente, di trascrivere il nome ed il numero<br />
di lotto del prodotto al f<strong>in</strong>e di stabilire un legame tra paziente e lotto del prodotto.<br />
4.5 Interazioni con altri medic<strong>in</strong>ali ed altre forme di <strong>in</strong>terazione<br />
Non sono note specifiche <strong>in</strong>terazioni dell’album<strong>in</strong>a umana con altri farmaci.<br />
4.6 Gravidanza e allattamento<br />
La sicurezza di Albunorm 20% per l’uso <strong>in</strong> gravidanza non è stata valutata <strong>in</strong> studi cl<strong>in</strong>ici specifici. Tuttavia, l’esperienza<br />
cl<strong>in</strong>ica con album<strong>in</strong>a sembra comunque <strong>in</strong>dicare l’assenza di effetti dannosi durante la gravidanza, sul feto o sul<br />
neonato.<br />
Non sono stati condotti studi di tossicità riproduttiva negli animali con Albunorm 20%.<br />
Ad ogni modo, l’album<strong>in</strong>a umana è un normale componente del sangue umano.<br />
4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macch<strong>in</strong>ari<br />
Albunorm 20% non altera la capacità di guidare veicoli o di usare macch<strong>in</strong>ari.<br />
4.8 Effetti <strong>in</strong>desiderati<br />
Raramente si verificano reazioni lievi come rossore, orticaria, febbre e nausea.<br />
Queste reazioni di solito scompaiono rapidamente, riducendo la velocità di <strong>in</strong>fusione o con la sospensione dell’<strong>in</strong>fusione.<br />
Molto raramente si possono verificare reazioni più gravi, quali shock. Nel caso di reazioni gravi, l’<strong>in</strong>fusione deve essere<br />
<strong>in</strong>terrotta e si deve <strong>in</strong>iziare un trattamento appropriato.<br />
Le seguenti reazioni avverse sono state osservate durante la fase post-market<strong>in</strong>g con soluzioni di album<strong>in</strong>a umana e<br />
pertanto potrebbero verificarsi anche con Albunorm 20%.
Sistema-Organo-Classe Reazioni (frequenza sconosciuta)*<br />
Disturbi del Sistema Immunitario Shock anafilattico, reazione anafilattica, ipersensibilità<br />
Disturbi psichiatrici Stato confusionale<br />
Patologie del sistema nervoso Cefalea<br />
Patologie cardiache Tachicardia<br />
Bradicardia<br />
Patologie vascolari Ipotensione<br />
Ipertensione<br />
Vampate<br />
Patologie respiratorie, toraciche e mediast<strong>in</strong>iche Dispnea<br />
Patologie gastro<strong>in</strong>test<strong>in</strong>ali Nausea<br />
Patologie della cute e del tessuto sottocutaneo Orticaria<br />
Edema angioneurotico<br />
Rash eritematoso<br />
Iperidrosi<br />
Patologie sistemiche e condizioni relative alla sede di<br />
somm<strong>in</strong>istrazione<br />
* Non può essere determ<strong>in</strong>ata sulla base dei dati disponibili.<br />
Febbre<br />
Brividi<br />
Per <strong>in</strong>formazioni sulla sicurezza relativa agli agenti trasmissibili, vedere il paragrafo 4.4.<br />
4.9 Sovradosaggio<br />
Il sovradosaggio e una velocità di <strong>in</strong>fusione troppo elevata possono <strong>in</strong>durre ipervolemia.<br />
L’<strong>in</strong>fusione deve essere immediatamente <strong>in</strong>terrotta ai primi s<strong>in</strong>tomi cl<strong>in</strong>ici di sovraccarico circolatorio (cefalea, dispnea,<br />
congestione giugulare) o per aumento della pressione arteriosa, della pressione venosa centrale o di edema polmonare,<br />
e devono essere valutati attentamente i parametri emod<strong>in</strong>amici del paziente.<br />
5. PROPRIETÀ fARMACOLOGIChE<br />
5.1 Proprietà farmacod<strong>in</strong>amiche<br />
Categoria farmacoterapeutica: succedanei del sangue e frazioni proteiche plasmatiche.<br />
Codice ATC: B05AA01.<br />
L’album<strong>in</strong>a umana rappresenta quantitativamente più della metà delle prote<strong>in</strong>e totali plasmatiche e rappresenta circa il<br />
10% del risultato della attività di s<strong>in</strong>tesi proteica del fegato.<br />
Dati fisico-chimici<br />
L’album<strong>in</strong>a umana al 20% o 25% ha un corrispettivo effetto iperoncotico rispetto al plasma umano.<br />
Una delle più importanti funzioni fisiologiche dell’album<strong>in</strong>a è data dal suo contributo alla pressione oncotica del sangue<br />
ed alla sua funzione di trasporto.<br />
L’album<strong>in</strong>a stabilizza il volume ematico circolante ed è un trasportatore di ormoni, enzimi, farmaci, toss<strong>in</strong>e ecc.<br />
5.2 Proprietà farmacoc<strong>in</strong>etiche<br />
In condizioni normali la concentrazione totale dell’album<strong>in</strong>a è di 4-5g/kg di peso corporeo, di questi il 40-50% è presente<br />
nello spazio <strong>in</strong>travascolare ed il 55-60% <strong>in</strong> quello extravascolare.<br />
In casi particolari, come ad esempio nelle ustioni gravi o durante uno shock settico, l’<strong>in</strong>cremento della permeabilità<br />
capillare aumenta la capacità di diffusione della album<strong>in</strong>a e si può avere pertanto una sua anomala distribuzione.<br />
In condizioni normali l’emivita dell’album<strong>in</strong>a è <strong>in</strong> media di 19 giorni. L’equilibrio tra la s<strong>in</strong>tesi e la sua elim<strong>in</strong>azione è<br />
mantenuto normalmente da un meccanismo a feed-back.<br />
L’elim<strong>in</strong>azione avviene per la maggior parte <strong>in</strong> sede <strong>in</strong>tracellulare ad opera delle proteasi lisosomiali.<br />
Nei soggetti sani, meno del 10% dell’album<strong>in</strong>a <strong>in</strong>fusa lascia lo spazio <strong>in</strong>travascolare durante le prime due ore che<br />
seguono l’<strong>in</strong>fusione. Nei pazienti tuttavia è frequente una notevole variabilità della risposta volemica. In alcuni pazienti,<br />
<strong>in</strong>fatti, il volume plasmatico può aumentare per alcune ore. Comunque, <strong>in</strong> pazienti critici, l’album<strong>in</strong>a può diffondere nello<br />
spazio extra vascolare <strong>in</strong> quantità consistente con una velocità non prevedibile.<br />
5.3 dati precl<strong>in</strong>ici di sicurezza<br />
L’album<strong>in</strong>a umana è un normale costituente del plasma umano, ed ha le sue stesse proprietà fisiologiche.<br />
Negli animali, i test di tossicità <strong>in</strong> s<strong>in</strong>gola dose hanno scarsa rilevanza cl<strong>in</strong>ica e non permettono la determ<strong>in</strong>azione della<br />
dose tossica e della dose letale, né di stabilire un rapporto dose-effetto.<br />
Studi di tossicità a dosi ripetute non sono praticabili nei modelli animali a causa della formazione di anticorpi contro le<br />
prote<strong>in</strong>e eterologhe.<br />
F<strong>in</strong>ora l’album<strong>in</strong>a non è stata associata a embrio-feto tossicità e ad un potenziale rischio mutageno od oncogeno.<br />
Nei modelli animali non sono stati descritti s<strong>in</strong>tomi di tossicità acuta.
6. InfORMAZIOnI fARMACEUTIChE<br />
6.1 Elenco degli eccipienti<br />
Sodio cloruro 5,7 g/l<br />
Acetiltriptofano 3,9 g/l<br />
Acido caprilico 2,3 g/l<br />
Acqua per preparazioni <strong>in</strong>iettabili qba 1000 ml<br />
Elettroliti:<br />
Sodio 144-160 mmol/l<br />
6.2 Incompatibilità<br />
L’album<strong>in</strong>a umana soluzione non deve essere <strong>in</strong>iettata con altri farmaci, sangue <strong>in</strong>tero, concentrato di emazie e acqua<br />
per preparazioni <strong>in</strong>iettabili.<br />
6.3 Periodo di validità<br />
2 anni<br />
Dopo l’apertura del flacone, il contenuto deve essere usato immediatamente.<br />
6.4 Precauzioni particolari per la conservazione<br />
Non conservare a temperature superiori ai 25°C.<br />
Conservare i flaconi nella confezione orig<strong>in</strong>ale per proteggerli dalla luce.<br />
Non congelare.<br />
6.5 natura e contenuto del contenitore<br />
Soluzione per <strong>in</strong>fusione, 50 ml <strong>in</strong> flacone (vetro tipo II) provvisto di tappo (gomma bromobutilica).<br />
Confezione da 1 flacone.<br />
Confezione da 10 flaconi.<br />
Soluzione per <strong>in</strong>fusione, 100 ml <strong>in</strong> flacone (vetro tipo II) provvisto di tappo (gomma bromobutilica).<br />
Confezione da 1 flacone.<br />
Confezione da 10 flaconi.<br />
È possibile che non tutte le confezioni siano commercializzate.<br />
6.6 Precauzioni particolari per lo smaltimento e la manipolazione<br />
Il prodotto può essere somm<strong>in</strong>istrato per via endovenosa o può anche essere diluito <strong>in</strong> una soluzione isotonica (ad es.<br />
glucosio 5% o cloruro di sodio 0,9%).<br />
L’album<strong>in</strong>a <strong>in</strong> soluzione non deve essere diluita con acqua per preparazioni <strong>in</strong>iettabili, questo potrebbe causare una<br />
emolisi nei soggetti riceventi.<br />
Nella somm<strong>in</strong>istrazione di grossi volumi, si raccomanda di scaldare l’album<strong>in</strong>a umana a temperatura ambiente prima<br />
dell’<strong>in</strong>fusione.<br />
Non usare soluzioni torbide o con depositi. Questo può <strong>in</strong>dicare che la prote<strong>in</strong>a è <strong>in</strong>stabile o che la soluzione è stata<br />
contam<strong>in</strong>ata.<br />
Una volta che il contenitore della soluzione è stato aperto, il contenuto deve essere usato immediatamente.<br />
Il medic<strong>in</strong>ale non utilizzato ed i rifiuti derivati da tale medic<strong>in</strong>ale devono essere smaltiti <strong>in</strong> conformità alla normativa locale<br />
vigente.<br />
7. TITOLARE dELL’AUTORIZZAZIOnE ALL’IMMISSIOnE In COMMERCIO<br />
Octapharma Ltd. The Zenith Build<strong>in</strong>g 26 Spr<strong>in</strong>g Gardens Manchester M21AB UK.<br />
Rappresentante Legale: Octapharma Italy S.p.A. Via Cisanello 145 56100 Pisa.<br />
8. nUMERO(I) dELL’AUTORIZZAZIOnE ALL’IMMISSIOnE In COMMERCIO<br />
Albunorm 20% Confezione da 1 flacone da 50 ml AIC n°: 039187063.<br />
Albunorm 20% Confezione da 10 flaconi da 50 ml AIC n°: 039187075.<br />
Albunorm 20% Confezione da 1 flacone da 100 ml AIC n°: 039187087.<br />
Albunorm 20% Confezione da 10 flaconi da 100 ml AIC n°: 039187099.<br />
9. dATA dELLA PRIMA AUTORIZZAZIOnE/ RInnOvO dELL’ AUTORIZZAZIOnE<br />
Ottobre 2009.<br />
10. dATA dI REvISIOnE dEL TESTO<br />
Maggio 2011.