Multiple Organ Dysfunction During Resuscitation Is Not Postinjury Multiple Organ Failure

PAPER Multiple Organ Dysfunction During Resuscitation Is Not Postinjury Multiple Organ Failure

David J. Ciesla, MD; Ernest E. Moore, MD; Jeffrey L. Johnson, MD; Angela Sauaia, MD, PhD; Clay C. Cothren, MD; John B. Moore, MD; Jon M. Burch, MD

Hypothesis: Multiple organ dysfunction (MOD) within Main Outcome Measures: Development of postinjury 48 hours of injury is a reversible physiologic response MODasdefinedbyaDenverMOFscoreof4orhigherwithin to tissue injury and resuscitation. 48 hours of injury and MOF as defined by a Denver MOF score of 4 or higher more than 48 hours after injury. Design: A prospective 10-year inception cohort study ending September 2003. Results: Postinjury MOD and MOF were diagnosed in 209 (16%) and 300 (23%) patients, respectively. Age, In- Setting: Regional academic level I trauma center. jury Severity Score, and 12-hour blood transfusion re- quirements were significantly higher among patients who Patients: One thousand two hundred seventy-seven con- developed MOD and MOF. Of the 209 patients who de- secutive trauma patients at risk for postinjury multiple veloped MOD, 134 (64%) progressively developed MOF organ failure (MOF). Inclusion criteria were being 16 years while 75 (36%) had MOD resolve within 48 hours. and older, being admitted to the trauma intensive care unit, having an Injury Severity Score higher than 15, and Conclusion: Multiple organ dysfunction during resus- surviving more than 48 hours after injury. Isolated head citation is a reversible response to severe injury and of- injuries were excluded. ten resolves during the resuscitation period.

Interventions: None. Arch Surg. 2004;139:590-595

OSTINJURY MULTIPLE ORGAN organ dysfunction during this period re- failure (MOF) is a leading flects reversible derangements induced by cause of late postinjury the inciting event or incomplete resusci- deaths and morbidity de- tation. spite more than 25 years of Cryer et al8 have recently ques- intensiveP study.1-3 The etiology is pro- tioned this rationale in a study of pa- posed to be a result of uncontrolled sys- tients at high risk of developing postin- temic inflammation leading to secondary jury MOF where it was concluded the organ injury and dysfunction.4 Clinical MOF was established within 24 hours of manifestations can range from a mild sys- injury. Recognizing differences in study de- temic inflammatory response to overt or- sign, this article prompted us to reevalu- gan failure. The initial magnitude of the ate our definitions of postinjury MOF. We postinjury inflammatory response is de- undertook this study to define the rela- pendent on the amount of tissue injury, tionship between multiple organ dysfunc- the degree of shock, and the presence of tion (MOD) that occurs during resuscita- host factors such as age and comorbid dis- tion and MOF that persists beyond the ease. We developed an MOF scale in 1987 resuscitation period. We hypothesized that as a descriptive end point for clinical stud- organ dysfunction during resuscitation is ies.5 A slightly modified scale (the Den- not postinjury MOF. ver MOF scale) has since been used in gen- erating predictive models of postinjury METHODS MOF based on early physiologic re- 1,6,7 Trauma patients admitted to the Rocky Moun- From the Denver Health sponses to injury and resuscitation. Our tain Regional Trauma Center surgical inten- Medical Center and the definition of MOF did not include organ sive care unit at Denver Health Medical Cen- University of Colorado Health dysfunction scores obtained within 48 ter, Denver, Colo, were studied prospectively Sciences Center; Denver. hours of injury because it was thought that from 1992 until September 2003. The Denver

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Dysfunction Grade 0 Grade 1 Grade 2 Grade 3

Pulmonary PaO2/F1O2 ratio Ͼ208 208-165 165-83 Ͻ83 Renal creatinine level, mg/dL Ͻ1.8 1.8-2.5 2.5-5.0 Ͼ5.0 Hepatic total bilirubin level, Ͻ2.0 2.0-4.0 4.0-8.0 Ͼ8.0 mg/dL Cardiac No inotropes and cardiac index Minimal inotropes or cardiac index Moderate inotropes High inotropes Ͼ3.0 L/min per meter squared Ͼ3.0 L/min per meter squared

SI conversion factors: To convert renal creatinine to micromoles per liter, multiply by 88.4; total bilirubin to micromoles per liter, multiply by 17.1.

Health Medical Center is a state-designated level I trauma center verified by the American College of Surgeons Committee 700 All Cases MOF Cases on Trauma, Chicago, Ill. Inclusion criteria were having an In- 600 jury Severity Score (ISS) higher than 15, surviving more than 48 hours after injury, being admitted to the surgical intensive 500 care unit within 24 hours of injury, and being 16 years and older. 400 Patients with isolated head injuries were excluded. Daily physiologic and laboratory data were collected through surgical in- 300 No. of Cases tensive care unit day 10, and clinical events were recorded there- 200 after until death or hospital discharge. The data collection and storage processes were in compliance with Health Insurance 100 Portability and Accountability Act of 1996 regulations and were 0 approved by our institutional review board. The database was 16-24 25-40 >40 maintained on an IBM-compatible computer using Microsoft ISS Access 97 (Microsoft Corp, Redmond, Wash). Organ dysfunction was defined using the Denver MOF scor- Figure 1. Distribution of study patients according to Injury Severity Score ing system.9 In brief, 4 organ systems (pulmonary, hepatic, re- (ISS). White bars represent the total number of patients in each ISS group. Black bars represent the number of multiple organ failure (MOF) cases in nal, and cardiac) were evaluated daily throughout the pa- each ISS group. Multiple organ failure occurred in 72 patients (17%) with tient’s intensive care unit stay and organ dysfunction was graded ISSs of 16 to 24, 184 patients (29%) with ISSs of 25 to 40, and 119 patients on a scale from 0 to 3 (Table 1). The pulmonary score was (57%) with ISSs higher than 40. simplified to assign a dysfunction grade based on the partial pressure of carbon dioxide–fraction of inspired carbon dioxide ratio.10 The values that determine the division points have been adjusted for altitude by multiplication of the value by the Table 2. Characteristics of Patients With and ratio of atmospheric pressure in Denver to that at sea level (630 Without Multiple Organ Failure (MOF)* mm Hg:760 mm Hg). The MOF or MOD score was calculated as the sum of the simultaneously obtained individual organ MOF Score scores on each hospital day. Single organ failure was defined Ͻ4 Ն4 as an organ failure grade greater than 0, and MOF was defined (n = 902) (n = 375) as a total score of 4 or higher. Postinjury day 0 was defined as the first 24 hours following injury. An MOF score within 48 Men 71 74 hours of injury was defined as MOD. For patients who died be- Age, mean ± SD, y 35.5 ± 15.4 41.8 ± 18.1† fore postinjury day 10, the MOF score on the day of death was Older than 55 y 10 21 Blunt mechanism 82 84 carried out to day 10. Injury Severity Score, mean ± SD 27.2 ± 9.7 34.4 ± 13.2† Statistical analyses were performed using SAS for Win- Injury Severity Score Ͼ25 48 70 dows (SAS Institute, Cary, NC). Categorical variables were 12-h RBC count, mean ± SD 0.16 ± 0.87 0.68 ± 1.93† ␹2 compared using a test with the Yates correction for conti- Received Ͼ0 U of blood 6 22† nuity or the Fisher exact test when expected cell values were Mortality rate 2 24† smaller than 5. For continuous variables with normal distribution, analysis of variance or t tests (with the appropriate Abbreviation: RBC, red blood cell. modification when the assumption of equal variances did not *Values expressed as percentages unless otherwise indicated. hold) were used. Continuous variables without a normal dis- †PϽ.05. tribution were analyzed using the Wilcoxon Two-Sample Test. PϽ.05 was considered significant. The predictive power of the initial organ dysfunction for subsequent MOF was of 37.3±16.5. The mortality rate was 9% (110 patients). evaluated by calculating its sensitivity, specificity, and predic- Three hundred seventy-five patients (29%) had at least tive value. 1 daily MOD score of 4 or higher. The distribution of MOD scores 4 or higher according to ISS is shown in Figure 1. RESULTS Seventy-two (17%) of 430 patients with ISSs between 16 and 25 had at least 1 MOD score of 4 or higher. Char- Data were collected on 1277 patients during a 10-year acteristics of patients who developed an MOD score of 4 period ending September 2003; 921 (72%) were men, and or higher are compared with those who did not in the mean age±SD was 37.3±16.5 years. Blunt mecha- Table 2. Patients who developed an MOD score of 4 or nisms accounted for 72% of injuries with an overall ISS higher during the study period were older, more se-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 200 All Cases Table 5. Effects of Varying Resuscitation Time Limit on New Cases 180 Multiple Organ Failure (MOF) at 96 Hours Postinjury*

160 Resuscitation Time Limit, h 140 Ͻ24 Ͻ48 Ͻ72 120 MOD and MOF96 38 110 140 100 MOD only 29 99 126 80 MOF96 only 203 131 101 No. of Patients 60 Neither MOD nor MOF96 1007 937 910 Sensitivity, % 16 46 58 40 Specificity, % 97 90 88 20 Positive predictive value, % 57 53 53

0 Negative predictive value, % 83 88 90 012345678910 Postinjury Day Abbreviation: MOD, multiple organ dysfunction. *MOD denotes an MOF score of 4 or higher occurring within the Figure 2. Distribution of the onset and prevalence of multiple organ resuscitation time specified in the table. MOF96 denotes an MOF score of 4 dysfunction and multiple organ failure (MOF) according to postinjury day. or higher present on or after 96 hours postinjury. Values are expressed as White bars represent the total number of patients with an MOF score of 4 or number of patients unless otherwise indicated. higher. Black bars represent the number of new cases with an MOF score of 4 or higher. Our previous work defined the resuscitation period limit as 48 hours postinjury. To distinguish MOF during the Table 3. Contingency Table of Multiple Organ Dysfunction resuscitation period from the postresuscitation period, (MOD) vs Multiple Organ Failure (MOF) at 48 Hours* we use the term MOD to denote an MOF score of 4 or higher occurring within the resuscitation period and MOF MOF No MOF Total to denote an MOF score of 4 or higher occurring after MOD 134 75 209 the resuscitation period. Table 3 presents the relation- No MOD 166 902 1068 ship between MOD and MOF using this definition in a Total 300 977 1277 2ϫ2 contingency table. Although ␹2 analysis shows a Ͻ *Values are expressed as number of patients. strong relationship between MOD and MOF (P .001), the sensitivity or proportion of patients with MOF that had antecedent MOD was only 45%, and the positive pre- Table 4. Effects of Varying the Resuscitation Time Limit dictive value or the proportion of patients with MOD that on Multiple Organ Dysfunction (MOD) progressed to MOF was only 64%. Table 4 presents the and Multiple Organ Failure (MOF)* effect of varying the resuscitation time limit by 24-hour increments from 24 hours to 96 hours. The sensitivity Postinjury Time, h and the negative predictive value increased while the specificity and positive predictive value decreased as the re- 24 48 72 96 suscitation time was extended. MOD and MOF 49 134 152 156 The trends in Table 4 are not unexpected because MOD only 18 75 114 134 increasing the resuscitation time allows larger numbers MOF only 308 166 109 85 Neither MOD nor MOF 902 902 902 902 of patients with MOD and decreases the number of pa- Sensitivity, % 14 45 58 65 tients with MOF. Alternatively, Table 5 compares the Specificity, % 98 92 89 87 effects of increasing the resuscitation time on the pres- Positive predictive value, % 73 64 57 54 ence of MOF on or after postinjury day 3. In this table, Negative predictive value, % 75 84 89 91 MOD denotes an MOF score of 4 or higher occurring within the resuscitation time specified in the table, while *Values are expressed as number of patients unless otherwise indicated. Forty-eight hours postinjury is the standard time limit. MOF96 denotes an MOF score of 4 or higher present on or after 96 hours postinjury. The sensitivity increased and the specificity decreased as the defined resuscitation time verely injured, and received more blood in the first 12 was extended. However, there was no change in posi- hours following injury. Mortality was also higher among tive and negative predictive values as the resuscitation patients with an MOD score of 4 or higher. time was extended. The temporal distribution of the onset and preva- Results from Table 4 and Table 5 demonstrate that lence of MOF according to postinjury day is shown in a significant proportion of patients with MOD will have Figure 2. The onset is defined as the day on which the the condition resolve within 72 to 96 hours following in- first MOF score of 4 or higher occurs. The onset oc- jury. To examine this further, we followed the course of curred within 48 hours in 209 patients (56%) who de- MOF in patients who developed an MOF score of 4 or veloped an MOF score of 4 or higher. The purpose of this higher within 48 hours of injury through postinjury day study was to define the relationship between organ dys- 10. Figure 3 shows the prevalence of MOF according function that occurs during resuscitation and organ fail- to postinjury day in patients who developed MOD within ure that persists once resuscitation has been completed. 48 hours of injury. Of the 209 patients who developed

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 an MOF score of 4 or higher within 48 hours of injury, 250 75 (36%) had MOD resolve within 72 hours and 93 (44%) had MOD resolve within 96 hours. Finally, we compared the characteristics of pa- 200 tients who developed MOD that progressed to MOF with those with MOD that had resolved within 48 hours 150 following injury. Table 6 shows that there were no dif- 100 ferences in sex, age, or ISSs between the 2 groups. Pa- No. of Cases tients who progressed from having MOD to having

MOF tended to receive more units of blood during the 50 first 12 hours of resuscitation than the patients whose MOD resolved within 48 hours (P=.059), although the 0 proportion of patients receiving 1 or more units of MOD2345678910 blood during the first 12 hours was not different. Mor- Postinjury Day tality was higher among patients in whom MOD pro- Figure 3. Distribution of patients with multiple organ dysfunction (MOD) that gressed to MOF. progressed to multiple organ failure (MOF) according to postinjury day. The black bar represents the total number of patients who developed MOD within 48 hours of injury; white bars, the number of patients with MOD and COMMENT persistent MOF. The working definition of MOF that we developed pre- viously did not include MOD scores obtained during the first 48 hours following injury because organ dysfunc- Table 6. Characteristics of Patients With Multiple tion during this period was thought to reflect the host Organ Dysfunction (MOD) Who Did and Did Not Develop Multiple Organ Failure (MOF)* response to injury and effects of incomplete resuscitation.5 As a result, we were potentially ignoring a popu- MOF lation of patients with MOF that resolved within 48 hours. In this study, we considered an MOF score of 4 or higher No Yes at any time during the first 10 days following injury to (n = 75) (n = 134) define postinjury MOF. The onset of MOF occurred within Men 80 73 48 hours of injury in 209 patients (56%) who developed Age, mean ± SD, y 39.3 ± 16.5 42.4 ± 17.6 an MOD score of 4 or higher during the study period. Older than 55 15 23 8 Blunt mechanism 85 88 Cryer et al found similar results in a study of high-risk Injury Severity Score, mean ± SD 34.9 ± 12.6 36.5 ± 14.4 patients where 67% of those with a maximum daily MOF Injury Severity Score Ͼ25 69 77 score of 3 or higher had an MOF score higher than 0 12-h RBC count, mean ± SD 0.53 ± 1.09 1.05 ± 2.80 within 24 hours of injury. While we do not consider MOF Received Ͼ0 U of blood 24 24 scores lower than 4 to represent MOF, the study by Cryer Mortality rate 11 31† et al illustrates the finding that organ dysfunction after injury often begins early in the hospital course of the se- Abbreviation: RBC, red blood cell. *Values are expressed as percentages unless otherwise indicated. verely injured patient. †PϽ.05. Risk factors for postinjury MOF include age, injury severity, degree of shock, and blood transfusion.6,11 Although the risk of postinjury MOF increases with in- the literature. However, most strategies attempt to meet jury severity, a significant proportion of patients who de- resuscitation goals within 24 hours of injury. In this study, velop MOF have moderate injuries (ISS, 16-25).12 In this we defined resuscitation periods according to postin- study, we found that 72 (17%) of 430 patients with an jury days. We varied the time limits for resuscitation in ISS indicating moderate injury developed an MOF score 24-hour increments and found that moving the limit closer of 4 or higher within 10 days of injury. In contrast, 303 to injury decreases the proportion of patients who de- (36%) of 847 patients with an ISS of 25 or higher devel- velop MOD during the resuscitation period and in- oped an MOF score of 4 or higher within 10 days of increases the proportion of MOF following resuscitation. jury. This risk is increased to 46% if more than6Uof Since the total number of patients with an MOF score of blood are transfused during the first 12 hours of resus- 4 or higher remains constant, the net result is an in- citation.6 Nonetheless, patients with moderate injuries crease in sensitivity and negative predictive value with a account for 34% of the population at risk and 17% of the concomitant decrease in specificity and positive predic- cases of MOF. tive value. Specificity and negative predictive value re- Organ dysfunction during resuscitation does not in- main high because the majority of the patients (902 [71%] variably progress to MOF beyond the resuscitation pe- of 1277 patients) had daily MOF scores lower than 4 at riod. The difficulty then is to distinguish between tran- all times during the first 10 days following injury. Al- sient organ dysfunction that occurs as a result of injury though the value of MOD for predicting MOF (positive and resuscitation from durable organ failure that per- predictive value) was highest for the 24-hour time limit, sists once shock is reversed and homeostasis is reestab- the sensitivity was only 14%. If used as a predictive test, lished. Defining the end point of complete resuscitation a patient with MOD during the first 24 hours has a 75% based on clinical parameters continues to be debated in probability of developing MOF. However, only 14% of

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 patients with MOF will have had MOD during the first REFERENCES 24 hours following injury. Thus, a screening test for MOF based only on an MOF score of 4 or higher within 24 hours 1. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reas- of injury would miss the 76% of MOF cases where onset sessment. J Trauma. 1995;38:185-193. occurs after 24 hours. 2. Durham RM, Moran JJ, Mazuski JE, et al. Multiple organ failure in trauma pa- One problem with this method is that the predic- tients. J Trauma. 2003;55:608-616. tive power of the initial organ dysfunction for subse- 3. Nast-Kolb D, Aufmkolk M, Rucholtz S, et al. Multiple organ failure still a major quent MOF relies on a variable time definition that af- cause of morbidity but not mortality in blunt multiple trauma. J Trauma. 2001; 51:835-841. fects both the resuscitation and postresuscitation periods 4. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury mul- simultaneously. As an alternative, we considered the ef- tiple organ failure. Surg Clin North Am. 1995;75:257-277. fect of varying the resuscitation time limit on predicting 5. Moore FA, Moore EE, Poggetti R, et al. Gut bacterial translocation via the portal the presence of MOF at or after 96 hours from injury. vein: a clinical perspective with major torso trauma. J Trauma. 1991;31:629- Results are similar in that sensitivity increases and speci- 636. 6. Sauaia A, Moore FA, Moore EE, et al. Early predictors of postinjury multiple or- ficity decreases as the resuscitation time is extended and gan failure. Arch Surg. 1994;129:39-45. the negative predictive value remains relatively high. How- 7. Sauaia A, Moore FA, Moore EE, Lezotte DC. Early risk factors for postinjury mul- ever, the positive predictive value remains relatively con- tiple organ failure. World J Surg. 1996;20:392-400. stant near 50%. This illustrates that MOD will resolve in 8. Cryer HG, Leong K, McArthur DL, et al. Multiple organ failure: by the time you predict it, it’s already there. J Trauma. 1999;46:597-604. half of the patients within 96 hours of injury. 9. Sauaia A, Moore FA, Moore EE, et al. Multiple organ failure can be predicted as Of the 209 patients with MOD, 121 (58%) had im- early as 12 hours after injury. J Trauma. 1998;45:291-301. proved before the second postinjury day and 75 (36%) 10. Offner PJ, Moore EE. Lung injury severity scoring in the era of lung protective remained free of MOF until postinjury day 10. Forty- mechanical ventilation: the PaO2/FIO2 ratio. J Trauma. 2003;55:285-289. seven patients who initially improved worsened at some 11. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620-624. point before postinjury day 10. Thus, although almost 12. Moore FA, Sauaia A, Moore EE, et al. Postinjury multiple organ failure: a bimo- 60% of patients with MOD improve by the second dal phenomenon. J Trauma. 1996;40:501-510. postinjury day, many develop MOF within 10 days. This may represent the resolution of MOD and subsequent development of late MOF owing to a second insult such DISCUSSION as pneumonia or sepsis. Alternatively, this may reflect a Donald E. Fry, MD, Albuquerque, NM: I want to thank the deficiency in the MOF scale where a patient with organ association for the invitation to address a subject about which dysfunction falls below the MOF threshold. Patients I have been writing for 25 years. I’m not convinced that I know with MOD that resolved within 48 hours did not differ in any more today than I did 25 years ago. Could we have my dis- sex, age, injury severity, or blood transfusion require- cussion slide, please? ments in the first 12 hours following injury. Further I’d like to distill the data down into one very usable slide. study is needed to delineate risk factors that are associ- I do want to congratulate the Denver group again on continu- ated with the progression of MOF beyond the resuscita- ing to pursue this subject, because I think it is an extraordi- tion period. narily interesting one. The data are intriguing, the numbers are In summary, MOD that develops during the first 48 large, and the description of the population is excellent. My hours following injury often resolves during the resus- only problem is that I come up with a 180-degree opposite conclusion. Let me amplify if I may. citation period. Moreover, organ dysfunction during re- They have identified early MODs within the first 48 hours suscitation is not a prerequisite for subsequent develop- as occurring in 209 patients. That means that of the popula- ment of MOF. While a strong relationship between tion of 1277 patients, 1068 did not develop MODs. They have transient organ dysfunction and postinjury MOF exists, identified the 288 patients (23%) that developed multiple or- organ dysfunction during resuscitation likely repre- gan failure longitudinally across the entire study. Of those 288 sents a manifestation of the postinjury hyperinflamma- patients, 134 were in the early MODs group. We see that 64% tory response. The findings in this study support our prior of the early MOD patients, in fact, develop multiple organ fail- definitions of postinjury MOF with respect to time of on- ure; if you didn’t have early MODs, only 14% developed organ ␹2 set.12 We submit that MOD that occurs within 48 hours failure. I did a hand-calculated in the back of the room and of injury represents reversible physiologic responses to came up with 180; that is still a P value very, very much less than .001. At lunchtime, I tried to find a ␹2 table on the Inter- injury and resuscitation that have the potential for reso- net and was unsuccessful, but I would certainly agree that that lution once resuscitation is complete. is a highly statistically significant variable. So I would say to the opposite of what has been presented, that a 64% probability of early MOD equaling ultimately MOF is pretty good. I’ll Accepted for publication January 22, 2004. take 64% to the racetrack everyday. This paper was presented at the 111th Scientific Ses- So I actually would suggest that early organ dysfunction sion of the Western Surgical Association; November 10, 2003; is in fact a very significant variable in predicting that a patient Tucson, Ariz; and is published after peer review and revi- is going to have organ failure for the balance of their course sion. The discussions that follow this article are based on and would suggest that their data actually supports very nicely that of Dr Cryer’s, which seemed to have stimulated this study. the originally submitted manuscript and not the revised Now, obviously 154 patients did not have early MODs and manuscript. 154 patients had other variables that were clearly responsible Corresponding author: David J. Ciesla, MD, Depart- for these patients developing organ failure. Let me recount a ment of Surgery, Denver Health Medical Center, 777 Ban- few of those variables. Age; injury severity; shock; volume re- nock St, Denver, CO 80204 (e-mail: [email protected]). suscitation; blood transfusions; specific injury of long bone, head

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 injury or soft tissue, head injury patients were all excluded from of the patients with early organ dysfunction did not develop this study; infection and sepsis; the integrity of the host; pre- organ failure. Therefore, that group might be relegated to what existing disease; intrinsic host defense; hyperalbuminemia, might be considered hazardous therapy to prevent a process whether it’s acquired or whether it’s intrinsic second to mal- that will not evolve. If we embark on manipulating the im- nutrition or underlying disease; nutritional support interven- mune system in these patients, there is going to be a calcu- tions; oxygenation; blood sugar control; temperature control; lated risk. In summary, we appreciate your perspective. As you and others. know, we have promoted the concept, as well as others, that If I’ve learned anything about sepsis and organ failure over multiple organ failure is fundamentally deranged inflamma- 25 years, it is that there is no silver bullet. We must abandon tion and the stage is set within that first 24-hour period. the concept of looking for a single variable or a single marker Basil A. Pruitt, Jr, MD, San Antonio, Tex: I was won- to invariably predict. Nothing will invariably predict. So it cer- dering if the different trajectories reflect different physiologic tainly would be my observation to amplify further on remarks reserve within the 3 groups, ie, are the patients with early MOD I made this morning, that we need complexity theory or chaos those who are sensitive to volume overload, and are the pa- theory analysis of the multiple variables that we involved in these tients with later MOD/MOF those with greater reserve who tol- patients. I would surely argue that the evidence for early dys- erate volume loading longer until the edema fluid is resorbed function being a major contributor is apparent to me, but it is and then manifest a Denver score of 3 or more? If the maxi- not the only variable to be sure, so I guess I would ask the ques- mum Denver score is 12, did you find a correlation between tion of our essayists if they could show me the wisdom that I total Denver score and the ultimate fate of these patients? have failed to appreciate in evaluating their manuscript. I would Dr Moore: Dr Pruitt also provides an interesting perspec- like to see the evidence that it doesn’t predict organ failure be- tive; his platform is that we have created MOF in trauma/burn cause to my analysis it clearly does, and I would certainly love care because of overzealous resuscitation and, in fact, I think to see a multicenter longitudinal study with high- he is absolutely correct that we need to reconfigure early re- performance computational science applied to a vast number suscitation. In this analysis, I don’t think we can answer whether of patients to help us try to ultimately answer this very com- cardiac reserve is pivotal in determining trajectory, but cer- plex question. tainly age is an independent risk and for organ failure it may Dr Moore: Thank you, Dr Fry. We have similarly struggled well be their relative intolerance to injudicial fluid loading. for 25 years to understand this disease, as you know, and we David H. Wisner, MD, Sacramento, Calif: Gene, I won- seem to spar about every other year based on a differing per- der if what you are seeing here is just a result of the use of what spective. We agree this is a very complex arena. But today we really is a multiple organ failure score for both of your defini- are addressing a relatively simple aspect. The LA County ex- tions. The score you are using for MODs is something derived perience reported by Gill Cryer indicated that if you are going to define multiple organ failure down the line, and you sort of to study MOF, it is already established on the first day of in- arbitrarily used it as the same score for multiple organ dys- jury. Organ dysfunction within that first 48 hours is a risk fac- function. I wonder if you used different kinds of physiologic tor for multiple organ failure consistent with the central mecha- scores the correlation might be somewhat better. nistic role of the hyperinflammatory state. What concerns us Dr Moore: We haven’t dissected out the individual com- is targeting that group exclusively for therapy because 53% of ponents to see their correlation but as you are suggesting, an the patients who ultimately developed multiple organ failure injury score principally related to cardiac and pulmonary dys- did not have dysfunction within the first 48 hours. Therefore, function within the first 48 hours may be quite different than we would neglect the majority of the patients in whom inter- a change in bilirubin or creatinine. Thank you for your sug- vention may have an impact. Furthermore, more than a third gestion.

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