Organ Dysfunction in the ICU: A Clinical Perspective

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1 Organ Dysfunction in the ICU: A Clinical Perspective Y.Sakr,C.Sponholz,andK.Reinhart Introduction Multiorgan dysfunction is a major cause of mortality in the intensive care unit (ICU) [1 3]. Sequential organ dysfunction syndrome was first described by Tilney et al. [4] in 1973 in a cohort of 18 patients after repair of ruptured abdominal aortic aneurysm and renal failure. The terms multiple organ failure syndrome (MOFS), multiple organ system failure (MOSF), and multiple organ failure (MOF) have since been used to describethissyndrome[5].uncontrolledinfectionswereinitiallythoughttobethe main cause of multiorgan dysfunction; however, massive activation of inflammatory mediators following other insults, such as severe trauma, may precipitate a similar condition. In 1992, the American College of Chest Physicians/Society of Critical Medicine (ACCP/SCCM) consensus conference [6] recommended definitions of sepsis and the proposed systemic inflammatory response syndrome (SIRS). The term multiple organ dysfunction syndrome was also proposed to describe this syndrome; however, firm definitions of organ dysfunction were not established. Several scoring systems have subsequently been developed to quantify organ dysfunction in ICU patients. In 2001, several North American and European intensive care societies revisited the definitions for sepsis and related conditions [7]. A staging system for sepsis, PIRO, which stratifies patients on the basis of their Predisposing conditions, the nature and extent of the insult (Infection), the nature and magnitude of the host Response, and the degree of Organ dysfunction, was proposed. The use of organ failure scores was encouraged to quantitatively describe organ dysfunction developing over the course of critical illness. The previous definitions of sepsis, severe sepsis, and septic shock were maintained essentially unchanged. Although much debate has focused on the non-specific nature of the SIRS criteria, no clear improvements could be offered. In fact, a number of additional criteria indicative of physiologic derangements were added to the four traditional SIRS criteria. These further non-specific alterations consist of clinical abnormalities (altered mental status, ileus) and biochemical evidence of involvement (procalcitonin [PCT], C-reactive protein [CRP], creatinine, or cytokines). Standard definitions for organ dysfunction are still lacking and several controversies regarding the best way to quantify organ dysfunction in the ICU remain unresolved [8]. The Epidemiology of Organ Dysfunction in the ICU Organ dysfunction is common in the ICU [1 3]. A large European, multicenter, observational study, Sepsis Occurrence in Acutely ill Patients (SOAP) [3], reported

2 Organ Dysfunction in the ICU: A Clinical Perspective 239 thatupto71%oficupatientshaveaconsiderabledegreeoforgandysfunction (sequential organ failure assessment [SOFA] score 8 2 for the corresponding organ); 81%ofwhichwaspresentonICUadmission.Sepsiscontributedto41%ofthe reported organ failures. MOF (failure of & 2 organs) occurred more in patients with sepsis (75 vs. 43%) compared with other ICU patients. The incidence of 2, 3, and & 4 organ failures was higher (38, 24, and 13 vs. 28, 12, and 4%, respectively), and all forms of organ failure were more common, in patients with sepsis compared with other ICU patients. In contrast, isolated single organ failure occurred more in patients with no sepsis (57 vs. 25%), with more renal (27 vs. 9%), respiratory (15 vs. 12%), and central nervous system (CNS) failure (11 vs. 2%) compared with patients with sepsis. Patients with no organ dysfunction on admission had ICU mortality ratesof6%whilethosewithfourormoreorganfailureshadmortalityratesof65%. Patients with severe sepsis had higher mortality rates (32 vs. 21%) compared to patients with organ failure without sepsis. Occurring alone or in combination, renal, respiratory, cardiovascular, and hepatic failure were associated with higher ICU mortality rates in patients with severe sepsis (41 vs. 23%; 35 vs. 26%; 42 vs. 34%; 45 vs. 28, respectively) compared to patients with no sepsis. The results of this multinational study underscore the common occurrence of organ dysfunction/failure in the ICU and its close relation to poor outcome in ICU patients. Sepsis appears to be an important associate of organ dysfunction in the ICU. The incidence of organ dysfunction/failure seems, unfortunately, not to be decreasing overtime, as seen when comparing the results of the SOAP study [3] with those with a similar cohort of ICU patients reported by Vincent et al [9] more than adecadeago. Quantifying Organ Dysfunction in the ICU Numerous physiological parameters and therapeutic interventions have been used to define multiple organ dysfunction [5]. The pulmonary, cardiovascular, renal, hepatic, hematologic, and central nervous systems were the organs most commonly considered in describing organ dysfunction/failure in the ICU. But other organs considered in this context included gastrointestinal, metabolic, endocrine, and immunologic function. As early as 1980, Fry et al. [10] proposed a system of four organ failures for surgical patients (pulmonary, hepatic, gastrointestinal, and renal failure). The sepsis severity score proposed by Stevens [11] comprised seven organ systems, each with five severity levels. Knaus et al. [12] defined organ system failure using a dichotomous score for five organ systems (cardiovascular, respiratory, renal, hematologic and neurologic failure). Goris et al. [13] proposed a score based on seven organ systems and three categories (0 = normal organ function, 1 = organ dysfunction, and 2=organ failure). In 1993, Fagon et al. [14] included infection in their organ dysfunction and infection model (ODIN). Other definitions were proposed by Hebert et al. [15], Pine et al. [16], Moore et al. [17] and Bernard et al. [18] One of the widely used organ dysfunction scores, the multiple organ dysfunction score (MODS) was proposed in 1995 by Marshall and collaborators [19] as an objective scale to measure the severity of MOF in critical illness. Descriptors of organ dysfunction were identified according to a systematic review of the literature and included PaO 2 /FiO 2 ratio for the respiratory system, serum creatinine concentration for the renal system, serum bilirubin concentration for the liver, platelet count for the hematologic system, and Glasgow coma scale (GCS) for the CNS. The cardiovas-

3 240 Y. Sakr, C. Sponholz, and K. Reinhart cular system was evaluated using the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure (CVP) to mean arterial pressure (MAP). The relative complexity of the cardiovascular component may be a drawback and is commonly modified using simple parameters such as heart rate, the use of inotropes, and serum lactate levels [20]. Nevertheless, this score was shown to successfully describe organ dysfunction in the ICU, was correlated strongly with the ultimate risk of ICU and hospital mortality rates [19], and reflected organ dysfunction development when measured sequentially in the ICU [19 21]. Another commonly used score was developed by a working group of the European Society of Intensive Care Medicine [9]: the SOFA score, comprising six organ systems, graded from 0 4 according to the degree of dysfunction failure. Organ systems considered in the SOFA score are: respiratory (PaO 2 /FiO 2 ), cardiovascular (blood pressure, vasoactive drugs), renal (creatinine and diuresis), hematological (platelet count), neurological (GCS) and liver (bilirubin). The reliability and accuracy of calculating the SOFA score among ICU physicians was shown to be good [22], probably due to its simplicity. It was further validated in various groups of critically ill patients [23 26]. Unlike the previous scores, which were established by consensus, the logistic organ dysfunction system (LOD) was developed by Le Gall et al. [27] using logistic regression techniques in a cohort of adult ICU patients. This score includes physiological variables of six organ systems GCS, PaO 2 /FiO 2 ratio, heart rate, blood pressure, serum urea, creatinine, urine output, white blood cell (WBC) count, bilirubin, platelet count, and prothrombin. The assignment of points in this score took into account both the relative severity among organ systems and the degree of severity within an organ system. Despite the complexity of this score, its prognostic value was not proven to be superior to the other scoring systems [28]. Oda et al. [29] developed the cellular injury score (CIS) as an index of cellular dysfunction in critically ill patients. CIS is derived from three parameters of intracellularmetabolism:arterialketonebodyratio,osmolalitygap,andbloodlactate. Each parameter is assigned 0 3 points according to arbitrarily defined cut off points. The usefulness of CIS in mortality prediction was reported in 157 patients withmof[29]andwasfoundtobecorrelatedandcomparabletothesofascorein terms of mortality prediction, in another study by the same authors [30]. This has not been investigated in a large cohort of unselected ICU patients. Similar scoring systems have been developed and validated in pediatric ICU patients including organ failure index [31] and pediatric logistic organ dysfunction (PELOD) [32] scores, comprising age specific criteria, adapted to the pediatric population. The Utility of Organ System Failure Scores Scoring systems for organ dysfunction/failure have been designed primarily as a descriptive tool, aimed at establishing standardized definitions to stratify and compare patients statuses in the ICU in terms of morbidity rather than mortality. The LODisoneexceptiontothis,asitwasdevelopedusingastatisticalprocedureto maximize its predictive value in terms of mortality prediction. Accordingly, organ dysfunction scores can also be used statistically to adjust analyses for baseline characteristics, to control for time dependent changes in matched cohort studies [33], to

4 Organ Dysfunction in the ICU: A Clinical Perspective 241 define subgroup analyses [34], and to directly compare organ dysfunction between groups as a secondary outcome in randomized trials [35, 36]. Organ dysfunction is a dynamic process; thus, sequential evaluation of organ dysfunction during the ICU stay may be helpful in tracing disease progression in the ICU and has been shown to be highly correlated to the subsequent outcome [20, 37]. As early as the 24 hours following ICU admission, changes in organ dysfunction as assessed by the SOFA score were found to predict eventual survival in severe sepsis [38]. The course of organ dysfunction/failure could also be useful in identifying patients who remain unresponsive despite appropriate treatment for several days, where intensive therapy may be considered futile [39]. In addition, as many of the components of the aforementioned scoring systems are readily affected by the various therapeutic maneuvers, they may be theoretically useful in the determination of therapeutic effects and setting therapeutic targets in the management of critically ill patients. Indeed, the severity of organ dysfunction is strongly correlated with outcome in critically ill patients [19, 27, 40, 41]. Interventions shown to have improved outcome exhibited similar favorable effects on organ function [42]. Accordingly, organ dysfunction scores can be used to predict outcome from critical illness [43]. Because comorbidities and baseline characteristics on ICU admission usually do not contribute to these scoring systems and may play a major role in determining the subsequentoutcomeintheicu,theperformanceoforgandysfunctionscoresintermsof outcome prediction may be inferior to that of severity scores such Acute Physiology and Chronic Health Evaluation (APACHE) II [44] and Simplified Acute Physiology Score (SAPS) II [45], that were designed primarily to efficiently predict outcome. It mayalsobeworthytonotethatthecontributionofeachorgandysfunctioninassociation with outcome seems not to be equal. The cardiovascular system has persistently been shown to have the highest impact followed by the renal, neurological, and respiratory systems [14, 27, 46, 47]. The correlation between organ failure and outcome may justify the use of the former as a surrogate end point for clinical studies. The relatively common occurrence of organ dysfunction in the ICU may permit a decrease in the sample size needed for future interventional studies, if organ dysfunction is used as the primary endpoint. However, the Food and Drug Administration (FDA) and the Retirement Medical Benefit Accounts (RMBA) have, until now, not accepted differences in organ dysfunction as primary endpoints in sepsis studies. Which Score is Best? The aforementioned organ dysfunction scores vary in the strategy of development (consensus vs. statistical techniques), characteristics of the validation-set, reason for development (descriptive vs. outcome prediction), data collection (admission values vs. sequential or summary of values all over the ICU stay), and weights of each organ system according to the utilized cut-off points. Several studies have evaluated the comparative prognostic value of the commonly used organ dysfunction scoring systems(table1).accordingtothecurrentevidence,thesescoresarequitesimilar in terms of outcome prediction.

5 242 Y. Sakr, C. Sponholz, and K. Reinhart Table 1. Studies comparing the predictive value of various organ dysfunction scores in terms of mortality prediction. Author n Setting Evaluated scores Main findings Oda et al [30] Timsit et al [28]* Tsai et al [24] Peres Bota et al [47] Petilla et al [48] Hantke et al [26] 47 General ICU SOFA and CIS SOFA and CIS similar discriminated poor outcome General ICU LOD and SOFA LOD and SOFA scores had good accuracy and internal consistency. No difference in discrimination between the two scores during the first week in the ICU 160 Critically ill patients with liver cirrhosis OSF, SOFA, and Child-Pugh score 949 General ICU APACHE II, MODS, and SOFA 520 General ICU APACHE III, SOFA, MODS and LOD 874 Surgical ICU APACHE II, MODS, and SOFA OSF and SOFA scores were closely correlated. Both OSF and SOFA scores displayed similarly excellent discriminative power compared to the Child-Pugh score. Outcome prediction of the APACHE II score was similar to the initial MODS and SOFA score in all patients and slightly worse in patients with shock. MODS and SOFA scores were similar in outcome prediction. Cardiovascular component of SOFA score performed better than that of MODS in outcome prediction. Highest outcome prediction with total maximum scores. Discriminative power was good and comparable between all organ dysfunction scoresandthatofapacheiii. SOFA, MODS and APACHE II scores similarly discriminated poor outcome. * Multicenter study; ICU: Intensive care unit; SOFA: Sequential Organ Failure Assessment; CIS: Cellular Injury Score; LOD: Logistic Organ Dysfunction; MODS: Multiple Organ Dysfunction score; APACHE: Acute Physiologic and Chronic Health Evaluation; SAPS: Simplified Acute Physiology Score; PELOD: Pediatric Logistic Organ Dysfunction; OSF: Organ System Failure Several criteria should be taken into consideration when judging the value of any scoring system in clinical practice. Reliability and validity are important issues that allow confident use of a scoring system in ICU patients with different case-mixes and baseline characteristics. Responsiveness is also an important criterion and signifies the ability of a scoring system to unmask temporal changes in organ dysfunction if measured sequentially. Dichotomous scores, such as the OSF score, may be less flexible in detecting such changes during the ICU stay. Simplicity and availabilityofthevariouscomponentsofthescoringsystemarealsocrucial.theuseofcomplex criteria, such as with the LOD, without any proven advantage for this complexity, may limit its widespread use in everyday practice. Likewise, using criteria that may not be available in all ICU patients, as in the cardiovascular component of MODS, may also be a practical limitation of its use.

6 Organ Dysfunction in the ICU: A Clinical Perspective 243 Dynamic measures of cellular response to insults such as apoptosis could be considered in the future to describe organ dysfunction at the cellular level [7].This could be particularly useful in developing therapies that target the injurious cellular processes. Conclusion Organ dysfunction is common in the ICU and is strongly correlated to outcome. Sepsis is associated with a significant degree of organ dysfunction and subsequently worse outcome. Despite the variability between various organ dysfunction scoring systems, their prognostic value seems to be similar in terms of mortality prediction. Thepresenceanduseofdifferentscoringsystemsmakesthecomparisonofdifferent descriptive and mortality predictive studies very difficult. This is of particular importance when these scores are used as entry characteristics, as criteria for stratified randomization, or as a surrogate end point for interventional or therapeutic studies in the ICU. Describing organ dysfunction in light of the PIRO system is promising. Further effort is required towards setting standard definitions that could have useful clinical and therapeutic utility. References 1. Deitch EA (1992) Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 216: de Mendonca A, Vincent JL, Suter PM, et al (2000) Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med 26: Vincent JL, Sakr Y, Sprung CL, et al (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34: Tilney NL, Bailey GL, Morgan AP (1973) Sequential system failure after rupture of abdominal aortic aneurysms: an unsolved problem in postoperative care. Ann Surg 178: Bertleff MJ, Bruining HA (1997) How should multiple organ dysfunction syndrome be assessed? A review of the variations in current scoring systems. Eur J Surg 163: American College of Chest Physicians/Society of Critical Care Medicine (1992) Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20: Levy MM, Fink MP, Marshall JC, et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31: Vincent JL, Wendon J, Groeneveld J, Marshall JC, Streat S, Carlet J (2003) The PIRO concept: O is for organ dysfunction. Crit Care 7: Vincent JL, Moreno R, Takala J, et al (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22: Fry DE, Pearlstein L, Fulton RL, Polk HC Jr (1980) Multiple system organ failure. The role of uncontrolled infection. Arch Surg 115: Stevens LE (1983) Gauging the severity of surgical sepsis. Arch Surg 118: Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) Prognosis in acute organ-system failure. Ann Surg 202: Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrere JS (1985) Multiple-organ failure. Generalized autodestructive inflammation? Arch Surg 120: Fagon JY, Chastre J, Novara A, Medioni P, Gibert C (1993) Characterization of intensive care unit patients using a model based on the presence or absence of organ dysfunctions and/or infection: the ODIN model. Intensive Care Med 19: Hebert PC, Drummond AJ, Singer J, Bernard GR, Russell JA (1993) A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. Chest 104:

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