502

Neuroanesthesia and Intensive Care Multiple organ dysfunction syndrome: a narrative review Purpose: To review multiple organ dysfunction syndrome w/d1 respect to: 1) clinicalmeasurement systems; 2) molecular mecha n/sins; and 3) therapeutic directions based upon molecular mecha n/sins. Methods: The Medline, Cochrane, and Best Evidence databases (1996 to 2000), conference proceedings, bibliographies of review articles were searched for relevant articles. Key index words were multiple organ failure, multiple system organ dysfunction, sepsis, septic shock, shock, systemic ir~ammatoU response syndrome. Outcomes prospectively defined were death and physiological reversal of end organ failure. Results: Multiple organ dysfunction/failure (MODS) is the most common cause for death in intensive care units. The recognition of this syndrome in the last 30 yr may be due to advances in early resuscitation unmasking these delayed sequelae in fllose that would have died previously. Multiple organ dysfunction occurs after shock of varied etiologies and may be the result of unbridled systemic ir~ammation. As yet, therapy directed to prevent or improve MODS has not dramatically altered outcomes. Conclusion: Multiple organ dysfunction may serve as useful mea sure of disease severity for risk adjustment and outcome marker for quality of care and therapy provided. Anesthesiologists treating shock palJents will note the subsequent development of MODS in the cdtical care unit and may be required to provide anesthetic sup port to these palJents.

Objectif : Passer en revue la documentation sur le syndrome de ddaillance multivisc&ale en regard : 7) des systemes de mesure clinique; 2) des mecanismes moleculaires et 3) des indications therapeutiques fond#es sur ces m#canismes. M#thode : On a consult# les bases de donn#es de Medline, Cochrane et Best Evidence (7996 a 2000), les actes de conf&ences, les biblio-

David J o h n s o n MD,* Irvin Mayers MD{

graphies d'articles de revues afin de trouver des articles pertinents. Les mots-cl#s ont #t# multiple organ failure, multiple system organ dysfunction, sepsis, septic shock, shock, systemic inflammatory response syndrome. L'#volution, en prospective, est la mort ou le renversement physiologique de la d#faillance organique. R#sultats : Le syndrome de d#fa#lance/d#ficience multivisc&ale (SDMV) est la cause la plus fr#quente de mort des malades a l'unit# des soins intensifs. La reconnaissance de ce syndrome au cours des 30 dernieres ann#es dent sans doute aux progres r#alis#s en r#animation pr#coce qui ont permis de d#voiler des s#quelles a retardement chez ceux qui seraient morts auparavant. La d#faillance muldvisc&ale survient apres un choc de causes d/verses et peut #tre le r#sultat d'une foudroyante inflammation g#n&alis#e. A cejour, le traitement visant pr#venir ou a r#duire la manifestation du SDMV n'en a pas beaucoup modifi# l'#volution. Conclusion : La d#faillance multivisc&ale peut servir de mesure utile de la s#v&it# d'une atteinte au moment de juger des risques et de marqueur de l'#volution en vue des soins de qualit# et d'une th&apie administrer. Les anesth#siologistes qui traitent des malades en choc devront noter l'#volution du SDMV a l'unit# des soins intens#s, car #s pourraient #tre appel#s a ,y foumir un soutien anesth#sique.

ULTIPLE o r g a n d y s f u n c t i o n syn d r o m e / f a i l u r e 0VIODS) is the u n w a n t ed o u t c o m e o f successful s h o c k resuscitation. Shock is defined as inade quate organ perfusion even after adequate fluid resusci ration often presenting as persistent h y p o t e n s i o n or need for vasoactive drugs to a u g m e n t b l o o d pressure. O n l y those patients n o t immediately dying from h e m orrhage or infection are alive long e n o u g h to d e m o n

M

From the Departments of Anesthesia, Medicine, Community Health and Epidemiology,* University of Saskatchewan, Saskatoon, Saskatchewan, and the Department of Medicine, t University of Alberta, Edmonton, Alberta, Canada. Address correspondence ra Dr. David Johnson, Department of Anesthesia, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, STN OW8, Canada. Phone: 306 655 1183; E mail: cujec@v wave.corn Acceued for publicaHon January 16, 2001.

Johnson etal.: MODS: A REVIEW

503

strate M O D S . T h e first case reports o f M O D S are only 25 yr old .1 3 As a s y n d r o m e , M O D S is d e f i n e d as altered o r g a n f u n c t i o n in the setting of sepsis, septic shock, or systemic i n f l a m m a t o r y r e s p o n s e s y n d r o m e . T h e affected o r g a n systems i n v o l v e d are: respiratory, cardiovascular, renal, hepatic, gastrointestinal, h e m a t o logical, e n d o c r i n e , and central nervous system. T h e g o a l o f this r e v i e w is a discussion o f M O D S w i t h respect to 1) clinical m e a s u r e m e n t systems; 2) m o l e c u l a r m e c h anisms; and 3) therapy based u p o n m o l e c u l a r m e c h a nisms. A t present, insufficient trials exist to w a r r a n t a

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F I G U R E 1 Illustrates the common physiological characteristics of multiple system organ failure and the variety of end organs/sys terns affected. Note that the changes induced are irrespective of the original etiology (i.e., infectious/non infectious). Individual patients vary to the extent of MODS depending on the balance of the specific injmy with their individual response.

systematic review w i t h g r a d e d r e c o m m e n d a t i o n s u p o n t h e t r e a t m e n t of H O D S . C o n s e q u e n t l y , this is a narra tive review. This review s h o u l d act as an u p d a t e for d i n ical anesthesiologists o n the possible p a t i e n t o u t c o m e s after their resuscitative care. W e anticipate t h a t anesthe siologists may in t h e f u t u r e a d m i n i s t e r m e d i a t o r t a r g e t ed anti i n f l a m m a t o r y t h e r a p y w h i c h may b e c o m e as r o u t i n e as perioperative antibiotics in patients w i t h H O D S . As yet, specific anesthetic c o n s i d e r a t i o n s for H O D S (other t h a n t h o s e c o n s i d e r a t i o n s for each iso lated organ) do n o t exist. T h e specific effects of anes thetics o n t h e i n f l a m m a t o r y r e s p o n s e (over and a b o v e t h e effects of the original disease process, stress, or surgery) have b e e n r e c e n t l y r e v i e w e d 4 and will n o t be s u m m a r i z e d here. R a t h e r t h a n a c o m p r e h e n s i v e listing o f b i o l o g i c a l c o m p o u n d s i n v o l v e d in i n f l a m m a t i o n , this r e v i e w focuses u p o n b i o l o g i c a l c o n c e p t s and their cur r e n t clinical implications. Clinical m e a s u r e m e n t systems A c o n s e n s u s c o n f e r e n c e by t h e A m e r i c a n C o l l e g e o f C h e s t Physicians and t h e S o c i e t y o f Critical C a r e H e d i c i n e in 1 9 9 2 p r o p o s e d t h a t t h e a c r o n y m H O D S b e a d o p t e d a n d d e f i n e d H O D S as t h e p r e s e n c e o f altered o r g a n f u n c t i o n in a severely ill p a t i e n t so t h a t h o m e o s t a s i s c a n n o t be m a i n t a i n e d w i t h o u t i n t e r v e n t i o n . 5 A variety o f m o r e specific d e f i n i t i o n s are u s e d t o classify o r g a n s as d y s f u n c t i o n a l u s i n g easily o b t a i n e d l a b o r a t o r y or p h y s i o l o g i c a l markers 1 (see T a b l e I). A variety o f m e c h a n i s m s can g e n e r a t e H O D S ( m e c h a n ical t i s s u e i n j u r y , m i c r o b i a l i n v a s i o n , e n d o t o x i n release, i s c h e m i a necrosis, i s c h e m i a r e p e r f u s i o n ) . 6 H O D S scoring systems can be classified using g e n eral p h y s i o l o g i c a l critical care s c o r e s i.e., A c u t e Physiological and Chronic Health Evaluation;

TABLE I Parameters and scores used in assessing organ dysfunction Parameter

SOFA?

Score

M O D S 1o

Score

L OD S 11

Score

Respirato U

PaO~/FiO~ and ventilation platelet number cell number bilirubin

0 to 4

PaOJFiO~

0 to 4

0 3 0 3

0 to 4

platelet number

0 to 4

PaO~/FiO~, ventilation and CPAP platelet, white blood

0 to 4

bilirubin

0 to 4

0 1

Cardiovascular

blood pressure and vasopressor use

0 to 4

0 to 4

Central nel~cous system Renal

Glascow Coma Scale

0 to 4

heart rate central venous pressure, blood pressure Glascow Coma Scale

bilirubin, prothrombin time heart rate and blood pressure

0 to 4

Glascow Coma Scale

0 5

Creatinine mine output Add worst daily scores

0 to 4

0 to 4

Creatinine urea urine output Add worst daily scores

0 5

Coagulation Hepatic

Aggregate score

0 to 24

Creatinine urine output Add worst daily scores

0 to 24

0 5

0 22

504

C A N A D I A N J O U R N A L OF A N E S T H E S I A

( A P A C H E ) , Simplified Acquired Physiological Score (SAPS), Mortality Probability M o d e l (MPM) 7 or spe cific organ score to describe dysfunction/failure (i.e., Multiple organ dysfunction score; M O D S ) , Sepsis related O r g a n Failure Assessment (SOFA), Logistic O r g a n Dysfunction System CLODS). T h e s p e c i f c organ dysfunction scores classify organs as failed (i.e., yes or no) 8 or dysfunctional using an ordinal scale (i.e., grad ed score). 9 11 The aggregate score quantitates severity in any one organ and the overall severity of organ dys function. T h e aggregate score can t h e n be interpreted as a likelihood of predicted mortality based u p o n the observed mortality in those study patients used to con s t m c t the original scoring system. Thus for the MOLDS score, an increase of one unit is scaled to reflect a change of mortality from 5% to 6%. As well, some organ dysfunction (cardiac, central nervous system) may have greater prognostic significance 12 and will provide m o r e prognostic insight. Ideally, scoring systems should be simple, d e m o n s t r a t e g o o d inter and intra observer reli ability, be generalizable over time and in different inten sive care units, a n d be i n d e p e n d e n t of t h e r a p y provided. 7 In setting an overall prevalence, it has been estimated that up to one half of the mortality in inten sive care units are attributable to M O D S . 13 14 Because organ failure is n o t h o m o g e n e o u s l y defined and scoring systems n o t standardized, the incidence of MOLDS, the specific cost for supportive care, and the attributable mortality for a patient u n d e r your care is n o t well defined.15 There exists no rationale to favour one scor ing system or another. As well, the scoring systems do n o t tell the clinician w h e n specific organ dysfunction is reversible or irreversible. Practically, a simple c o u n t or organs affected and the duration of the dysfunction will stratify mortality within b r o a d ranges b e t w e e n 60% to 98% d e p e n d i n g on age with dysfunction in three or m o r e organs for at least a week.16 A l t h o u g h scoring systems have b e e n traditionally used as a disease severity classification tool, they have value as m e a s u r e m e n t s of clinical o u t c o m e d u r i n g the process of care. 17The advantage of using M O D S as an o u t c o m e is t h a t it may be a less biased m e a s u r e m e n t o f

T A B L E II O u t l i n e s p o t e n t i a l uses o f m u l t i p l e o r g a n d y s f u n c t i o n s y n d r o m e scores Baseline severity assessment score Score at any one time Aggregate score over time

Admission severity of o r g a n failure Evolution over time of o r g a n failure Cumulative severity of o r g a n failure

C h a n g e in score C o m b i n e score with mortality

O r g a n failure attributable change Mortality adjusted severity of o r g a n failure

Score a g g r e g a t e d by institution

Quality of care performance marker

the original injury and s u b s e q u e n t care p r o v i d e d . In N o r t h America, w i t h d r a w a l o f t h e r a p y is c o m m o n . 1 8 D e a t h due to w i t h d r a w a l o f therapy may have i m p o r rant social and ethical d e t e r m i n a n t s t h a t overlay the b i o l o g i c a l d e t e r m i n a n t s of death. Differences in o u t comes may also be measured in those patients n o t dying and related to resource c o n s u m p t i o n . Table II outlines p o t e n t i a l uses o f M O D S scores. Molecular mechanisms In this section, we will review past and c u r r e n t t h e o ries a b o u t the causes o f M Q D S . T h e reader s h o u l d be sensitized to the fact t h a t past discarded or less p o p u lar theories were a d o p t e d and f o r m e d the basis of accepted clinical care. T h u s prior to basing t h e r a p y u p o n any new etiological theory, m o r e clinical evi dence t h a t is n o w available is required. Initially, the e t i o l o g y of M O D S was t h o u g h t to be u n c o n t r o l l e d infection. T h e t r e a t m e n t of sepsis or sep tic shock with antibiotics and source of infection con trol was c o n s i d e r e d the major t h e r a p e u t i c aim. 19 I n f e c t i o n as the sole e t i o l o g y is n o t in accord with the varied causes of M O D S 2 ° s u c h as pancreatitis, burns, major surgery, i s c h e m i a / r e p e r f u s i o n , and trauma. As well, in many patients an infectious a g e n t is n o t isolat ed.21 T h e i m p e t u s for considering a unifying h y p o t h e sis for M O D S is reinforced by the similarity in the n o t e d o r g a n disturbances (see Figure 1) and systemic physiological changes (hemodynamic, microvascular, and oxygen utilization). The unifying infectious etiology identified the g u t as a potential source of bacteria (host for 108 aerobes and 10 n anaerobes in the colon) or at least circulating prod ucts of bacteria. Decreased g u t perfusion and subse q u e n t damage to the mucosal and i m m u n o l o g i c a l g u t barriers may allow the translocation of e n d o g e n o u s bac teria or their products into the systemic circulation. This "second hit" a u g m e n t s the initial injury. 22 M o r e recently the intestinal mucosa is considered to be a n o t h e r source of inflammatory mediators activated by hypoperfused mucosa.2 3 M e a s u r e m e n t of intramucosal p H ( t o n o m e t r y ) can stratify m o r t a l i t y risk 24 b u t a t t e m p t s to a u g m e n t g u t perfusion are n o t considered to be useful therapy in altering M O D S o u t c o m e s in septic patients. 25'26 G u t sterilization in the prevention of ventilatory acquitted p n e u m o n i a is an extension of the concept of an e n d o g e n o u s g u t bacterial reservoir. H o w e v e r , for ventilatory acquitted p n e u m o n i a , the route of infection is considered to be o r a l / i n t e g u m e n t rather than systemic as in M O D S . 2 7 T h e widespread use of invasive cardiac m o n i t o r i n g reveals the association b e t w e e n indices of perfusion (cardiac output, systemic vascular resistance) and oxy

Johnson

etal.:

MODS: A REVIEW

505

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FIGURE 2 Illusuates the balance between insufficient inflamma tocf response leading to death and excessive (anti irfflammatocfor inflammatocf) leading to MODS. Survivalwithout MODS requires a balanced host response which is an additional considera tion in understanding the effect of disease insult.

gen c o n s u m p t i o n in patients with M O D S . e 8 Survivors have higher cardiac index, lower systemic vascular resis tance, and higher oxygen c o n s u m p t i o n than n o n sur vivors.29 Critical values are a cardiac index greater than 4.5 L.min 1. m 2, oxygen delivery index greater than 600 ml.min 1.m2, and oxygen c o n s u m p t i o n greater than 170 m l . m i n 1.m2.3° A l t h o u g h m a n y studies have demonstrated that survival is associated with attaining threshold critical values, attempts to enhance the hyper dynamic response with pharmacological agents (dobut amine, dopexamine) have n o t shown a consistent response in more than 18 r a n d o m i z e d control trials. 31 The dependency of oxygen c o n s u m p t i o n u p o n deliv ered oxygen may be an artifact of measurement. 32 A n o t h e r consideration for oxygen is the balance between tissue damaging oxidizing agents and their n e u t r a l i z a t i o n with anti oxidants. Reactive oxygen species are involved in the formation of reactive nitroge nous and ferric species and direct cellular destruction, and act as secondary messengers in the inflammatory cascade. 33 T h e b a l a n c e b e t w e e n reactive o x y g e n species/reactive n i t r o g e n o u s species may be i m p o r t a n t in d e t e r m i n i n g the progression of organ dysfunc tion.34 36 A significant p r o p o r t i o n of the increase in total oxygen c o n s u m p t i o n may be enhanced use by phagocytic cells.37 Finally, inflammation has become the most current etiological explanation of M O D S . Inflammation is the activation of circulating cells (leukocytes), the endotheli urn, the liver, and multiple mediator networks that are normally held in balance by corresponding anti inflam matory mediators. Chemotactic agents attract, adhesion

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FIGURE 3 Illusuates the variety of mediators and inflammatory products that are active in propagating the inflammatocf response. Neutrophils activated by tissue injmT both recruit other neu trophils (chemokines), bind to endothelial cells (adhesion mole cules), and produce cytokines to enhance the production of free radicals and proteolytic enzymes. This sustained inflammatocf state must be balanced by expression of anti inflammatocf cytokines and programmed cell death (apoptosis).58Both timing of expression and complexity of inflammatocf products underline the difficulty in therapeutic intervention.4

molecules focus, and cytotoxic agents assist these cells in driving the process. M O D S (see Figure 2) occurs w h e n either the host's inflammatory or anti inflammatory response to injury (or both) are excessive; death may occur if the host response to injury is either excessive or insufficient.a 8 In broad terms, following a noxious insult there is an initial response mediated by liver, neutrophils, macrophages and the endothelium. Hepatic inflammato ry proteins such as C reactive protein are opsonins of degraded proteins and nucleic acids derived from injured cells which would be potentially metabolized to more toxic substances, a° The macrophage response includes the release of a variety inflammatory mediators (e.g., T u r n o u t Necrosis Factor [TNF], I n t e r l e u k i n 1, Interleukin 6); these mediators then upregulate recep tots o n neutrophils (e.g., L Selectin) and endothelial cells (e.g., P Selectin, E Selectin, Intercellular Adhesion Molecule 1, Vascular Cell Adhesion Molecule 1 Cellular) and stimulate transmigration. Adhesion mole cules can be considered as aids to the retention of neu trophils as these large cells are transiently retained in the microvasculature by purely mechanical factors. 4° With transmigration other effector molecules (reactive free radical species, endopeptidases) are released that cause

506 organ damage and further recruit activated neutrophils to the site of injury. 41 Cytokines are important inflammatory mediators with the following actions: 1) directing a T lymphocyte response; E) inducing enzyme production in distant sites ( e.g., endothelium: nitric oxide, liver: C reactive pro rein); and 3) altering cell surface adhesion molecules. Cytokines can be broadly classified as: 1) growth factors (e.g., Transforming Growth Factor B); E) leukocyte chemotactic chemokines (e.g., Interleukin 8); 3) m o d u lators of lymphocyte function (e.g., Interleukin 4); and 4) modulators of inflammatory response (e.g., Interleukin 6 as a pro inflammatory mediator and Interleukin 10 as a anti inflammatory mediator). A large body of work has demonstrated that the clinical manifes tations of sepsis arise through the activation of a complex cascade of host derived mediator molecules .42 Indiscriminate injury from these mediators may be the underlying mechanism to M O D S . 43 The possible mech anisms of injury are: 1) excessive production of free rad icals: E) induction of elastase or endopeptidases: and 3) elevation of circulation soluble peptides that activate pro grammed cell death (apoptosis). However opposing this etiological concept is that the serum concentration of these pleiotropopic mediators do not always directly cor relate with mortality. 44 For example, an alternate poten tial mechanism for ischemia and reperfusion injury may be small vessel obstruction by microthombi. 45 The schema shown in Figure 3 is not all inclusive, b u t outlines various aspects of the inflammatory response in which the down regulation of mediators might be of benefit given their association with M O D S and death. 46The therapeutic challenge in attempting to modulate these pathways is that the number of media tors are numerous, their expression varies over the time of the illness, and their measurement using serum assays or biological assays may not be reflective of i n v i v o a c t i v ily. 42 As well, the modulating effects of overall health status 47 and genetic pleomorphism may significantly confound outcomes. For example there is differential organ expression of endothelial adhesion molecules in response to pro inflammatory cytokine signalling with such organs as the lung. 48 The production of hepatic inflammatory proteins such as fibrinogen is genetically modulated. 49 From an epidemiological perspective, postoperative septic patients that are high T N F produc ers have higher mortality and M O D S than low T N F producers, n° Knowledge of the individual inflammatory reaction to noxious stimuli may allow tailored therapy. Gene therapy using recombinant technology could potentially enhance an under expressed anti or pro inflammatory state. As well, targeting D N A or m R N A could block overproduction of specific proteins. 51

CANADIANJOURNAL OF ANESTHESIA Therapeutic directions based upon molecular mecha nisms The use of anti inflammatory agents for the sympto matic relief of infection dates back to the use of ASA to reduce fever. 52 One of the early randomized controlled clinical trials conducted to evaluate the effect of an anti inflammatory agent on the severity and incidence of sepsis in a high risk population 53 concluded that methylprednisilone was associated with a poorer out come and increased mortality rates when compared with placebo. Many other anti inflammatory agents, ranging from i v ibuprofen 54 to an inhibitor of the pro inflammatory cytokine T N F 55 have since been evaluat ed for the treatment of septic shock, but none have proved to be successful therapeutic interventions to date. When M O D S is established, extensive medical support is required until the excessive inflammatory response dampens. These supportive therapies may include mechanical ventilation (for acute lung injury), i v pressors or fuids (for cardiac failure), hemodialysis (for acute renal failure), total parenteral nutrition (for acute gut injury) or sedation (for acute brain dysfunc tion). It is hoped that early intervention with selective anti inflammatory therapy or with a combination of the appropriate agents at different times (according to the severity of M O D S ) will reduce inflammation, preserve organ function, and result in an increase in survival rates and a decrease in the utilization of hospital resources. O u r knowledge of the complex interactions that occur during an inflammatory response to infection is still lacking. Issues still to be addressed include how to achieve the appropriate balance between an inadequate response and an excessive one (both can lead to death!). For example, should the inflammatory response associ ated with hemorrhagic shock or gram negative bac teremia be down regulated to the same extent? In addition, how should patients who are diagnosed with M O D S at different times in the course of their illness be treated? Anti inflammatory therapy may be similar to other time sensitive treatments (e.g., thrombolysis for acute myocardial infarction and stroke), where only a finite window of time exists in which a specific treat ment will therapeutic. The theoretical intervention points for M © D S therapy directed at inflammation are: 1) cell adhesion retardation: E) inflammatory mediator reduction (translation/tran scfiption inhibition); 3) neutralizing (polyclonal or mon oclonal) antibodies directed at cytokine/ vasoactive / coagulation / complement mediators: 4) cytokine/ vasoactive / complement / coagulation mediator recep tot inhibitors: 5) anti inflammatory protein induction (preconditioning, substrates, products, or genes); and 6) anti oxidants and anti proteases. 51

Johnson etaL: MODS: A REVIEW Cloned proteins and m o n o c l o n a l antibodies are a m o n g the new therapeutic agents being developed that may regulate specific steps of the inflammatory response. Bedside tests to rapidly measure specific ele ments of the inflammatory cascade (e.g., Interleukin 6) are also u n d e r development. T u m o u r Necrosis Factor is detectable within 30 rain, Interleukin 1 within three hours and Interleukin 6 within six hours. 56 A recent meta analysis suggests polyclonal b u t n o t m o n o c l o n a l i m m u n o g l o b u l i n decreases mortality in sepsis. 5r The first d e m o n s t r a t i o n of a m o n o c l o n a l antibody in sepsis decreasing M O D S has j u s t been a n n o u n c e d (Press release American Thoracic Society Meeting T o r o n t o May 2000). Thus it may become possible to adjust anti inflammatory therapy in response to specific biochemi cal changes in the cascade. 58'59 The ultimate extension of this approach would see patients with M O D S receiv ing m o m e n t to m o m e n t titration of specific anti inflammatory agents, with the type and a m o u n t of medication administered based o n c o n t i n u o u s bedside measurements of inflammatory mediators. O u t c o m e s may relate to specific organ dysfunction rather than overall global mortality. Acknowledgements We would to acknowledge the staff at the Royal U n i v e r s i t y Hospital, Saskatoon and University Hospital, E d m o n t o n for the t h o u g h t f u l questioning which prompted this review. References 1 Tilney NL, Bailey GL, Morgan AP. Sequential system failure after rupture of abdominal aortic aneurysms: an unsolved problem in postoperative care. Ann Surg 1973; 178:117 22. 2 Polk HCJ~; Shields CL. Remote organ failure: a valid sign of occult intra abdominal infection. Surgery 1977; 81:310 3. 3 Fiseman B, BeaFt R, NoFton L. Multiple organ failure. Surgery Gynecology & Obstetrics 1977; 144:323 6. 4 M[ayeFsI, Johnson D. The nonspecific inflammatory response to injury. Can J Anaesth 1998; 45:871 9. 5 M[embevs of the American College of Chest Physicians/Society of CFitical CaFe Medicine Consensus ConfeFence Committee. American College of Chest Physicians/Society of Critical Care Consensus Conference: definitions of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864 74. 6 Papathanassoglou EDE, Moynihan JA, Ackerman MH. Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in the critically ill patients? A review and theoretical frame

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