The MOF syndrome emerged two decades ago as a result of our ability to keep critically ill patients alive by advanced ICU technology. [1-3] Early clinical studies identified infection as being a prime inciting event. [2,3,21-23] Based on these observations, two infectious models of MOF were proposed: (1) insult forward arrow ARDS forward arrow pulmonary sepsis forward arrow MOF or (2) insult forwar arrow sepsis (principally intra-abdominal abscess) forward arrow ARDS/MOF. With these models in mind, researchers focused their attention on determining how a traumatic event sets the stage for infection and how infections mechanistically drive MOF. [16-19] As a result, throughout the 1980s, prevention, diagnosis and treatment of postinjury infections improved, but secondary infections remained a common MOF associated event. [36,37] The epidemiology of these infections appeared to change and in large part their continued high rate was owing to failure of local and systemic host defenses. Pneumonia remained clinically important, while intra-abdominal abscess became a less common event. Simultaneously, European reports of blunt trauma patients demonstrated that MOF could occur in the absence of infection. [24,25] Subsequently, alternative hypotheses were proposed suggesting trauma could induce a malignant systemic inflammatory response syndrome (SIRS) that precipitates MOF independent of infection (e.g., bacterial translocation, ischemia/reperfusion and "one-hit" and "two-hit" inflammatory models). [16-19] At the basic level, these proposed mechanisms are well documented and compelling. Unfortunately, we have not been able to translate this knowledge into the clinical practice. In part, we believe this is because of inadequate epidemiologic characterization of the MOF syndrome. 
We have focused our studies on trauma patients for several reasons. First, early postinjury SIRS appears to play a pivotal role in the ultimate pathogenesis of MOF and the mechanisms involved in early postinjury SIRS appear to be different from those involved in infection-driven SIRS. [30,38] Secondly, the inciting traumatic event can be identified and characterized independent of the resulting SIRS. Additionally, the early SIRS response can in turn be characterized independent of the outcome MOF. In other patient populations traditionally associated with MOF (e.g., gram-negative sepsis and intra-abdominal infection) these events are not temporally distinct. The inciting event is frequently diagnosed by the SIRS response and severe SIRS at diagnosis may overlap with the outcome variable MOF. [39-41] Additionally, trauma patients tend to be young and free of preexisting disease, while in other patient populations, advanced age and comorbidity are significant confounders. [31,32] Lastly, as a result of regionalized trauma care, major trauma patients are triaged to trauma centers where care is delivered by standardized protocols. This is invaluable not only when studying epidemiology, but also in the design of focused observational studies and ultimately interventional trials.
Interestingly, in a recent comprehensive study of trauma death in San Diego County, it was concluded that optimization of this regionalized trauma system lowered the incidence of sepsis and multiple organ failure.  Thirty-one (14%) of 224 in-hospital were owing to pneumonia or sepsis, which is lower than the 43 (21%) of 205 in-hospital deaths resulting from sepsis reported by Baker et al. in 1980.  Thus, if this comparison is valid, the incidence of MOF-related deaths is decreasing. However, this should not be construed to mean that the incidence of MOF is decreasing. In fact, the incidence of MOF appears to be increasing and the confusion arises because fewer MOF patients are dying. Given the different definitions and denominators used, this is a difficult issue to prove. However, in six recent studies (including ours), the incidence of MOF in high-risk trauma patients ranges from 14% to 42%, which is higher than the 7% reported by Fry et al. in 1980 and the 8% reported by Faist et al. in 1983. [11-15,22,24] This is an important trauma system issue. Severely injured patients who do not die early because of optimal initial management are admitted to ICUs where they receive expensive, high-acuity care. In the current study, 15% of trauma ICU patients who survived more than 48 hours, developed MOF. This cohort of patients required a mean of 19 days of mechanical ventilation and remained in our ICU for a mean of 26 days. Thus, from a resource perspective, MOF remains a significant problem.
The primary observation of the current study is that postinjury MOF appears to occur in at least two different patterns (i.e., early versus late). This concept is not new. In fact, in a 1975 report from Denver, Walker and Eiseman  noted that the pattern of postinjury ARDS was changing. Of 78 trauma patients requiring mechanical ventilation, 13 (17%) developed ARDS. Of these, nine had classic early onset ARDS (within 12 hours) and all survived. The remaining five patients developed late ARDS (more than 5 days), all were septic and all died of pulmonary insufficiency or bacteremic hypotension. The presentation was so disparate, the authors concluded that they were dealing with different diseases. In 1983, Faist et al.,  in an often-quoted Bavarian study, similarly noted two patterns of MOF. Of the 433 blunt polytrauma patients studied, 34 (8%) developed MOF. In 15 (44%), the onset was rapid (12 to 36 hours), apparently the result of combined severe multisystem trauma and shock. In the remaining 19 (56%), the onset was late (average 7.2 days) and uniformly associated with sepsis. Again in 1992, Waydhas et al.  from Munich, in a prospective study of 100 severe multisystem-injured patients (mean ISS = 37), noted that 45 developed organ failure within 2 days (primarily ARDS), and 14 evolved into MOF. A second peak of late MOF (predominated by liver failure) emerged in another 18 patients at 6 to 8 days. In nine (50%) of these late MOF patients, infections immediately preceded or coincided with onset of MOF. These findings are quite similar to our recent study of postinjury ventilator-associated pneumonias.  In this prospective study of 123 high-risk torso trauma patients (mean ISS = 36 +/- 2) who required more than 24 hours of mechanical ventilation, 28 patients (23%) developed MOF. In 14 (50%), the onset was early (less than or equal to3 days). Eleven of these patients developed pneumonias; in four cases, the onset was temporally associated with worsening MOF, while the remaining seven cases occurred late and had no significant impact on MOF scoring (i.e., they appeared to be "symptoms"). In the other 14 patients, the onset of MOF was late (more than 3 days). Nine of these patients developed pneumonia, and in eight,  the diagnosis of pneumonia was temporally associated with the onset of MOF (i.e., they appeared to be "triggers").
Collectively, the above studies corroborate our current study and are consistent with the hypothesis that MOF occurs as a result of a dysfunctional inflammatory response (see Figure 6). [19,41-47] Following major trauma, patients are resuscitated into an early state of hyperinflammation (i.e., SIRS). This can result in early MOF in the initial insult is massive ("one-hit" model) or if early secondary inflammatory insults occur ("two-hit" model). Alternatively, as time proceeds, negative feedback systems down-regulate early SIRS to limit potential autodestructive inflammation. This results in delayed immunosuppression, which is associated with major infectious complications. If this hypothesis is accurate, one strategy would be to limit early hyperinflammation. Our basic and clinical research studies suggest that the postinjury SIRS becomes activated as early as 6 to 12 hours postinjury. [48-54] Thus, anti-inflammatory interventions may need to be initiated quite early. Additionally, postinjury SIRS is complex and involves multiple effector cells with overlapping mediator cascades. Mild to moderate SIRS is most likely beneficial (i.e., it is the normal "injury stress response"), while severe SIRS is potentially harmful. Unfortunately, our current knowledge is limited in identifying which components should be modulated to achieve a favorable outcome. The recent problems with various anti-inflammatory strategies in large clinical studies for gram-negative sepsis, supports the need for observational studies in trauma. [48-50]
An alternative approach to modulating early hyperinflammation is to focus on delayed immunosuppression and the associated late infections. One crucial question is whether late infections cause ongoing MOF and thus contribute to mortality. The epidemiologic studies of Border et al.,  Marshall et al.,  and other provide compelling evidence to invoke the gut as the potential reservoir for pathogens in late MOF. Additionally, several gut-specific preventative strategies (e.g., early enteral feeding, immune-enhancing diets and selective gut decontamination) have been shown to reduce postinjury infections. [54-58] While the nutrition studies lack sufficient patient numbers to assess mortality as an outcome variable, there have been sufficiently large selective gut decontamination (SGD) trials to address this issue. Multiple studies have shown that SGD reduces major infections (principally pneumonia), but it does not consistently reduce mortality. [56,57] This has lead to the hypothesis that late infections are inconsequential symptoms of MOF.  The trauma-related SGD trials, however, may be flawed because they enrolled a large portion of head trauma patients whose mortality is not linked to sepsis-related MOF.  Therefore, we have two options with these existing studies: either we accept reduced infections as a reasonable goal or we need to perform epidemiologic studies to identify study candidates whose infections have attributable mortality and then enroll enough of these patients in new interventional trials to assess mortality as an endpoint. Another cogent issue is whether late MOF-associated "pneumonia" truly reflects active infection or are we just treating immuno-compromised hosts who are heavily colonized. Patients with late ARDS generally have signs of infections (e.g., low-grade fever, leukocytosis), chest roentgenographs that are heavily infiltrated and thus noninterpretable, and are likely to have endotracheal tube aspirate cultures positive as a result of prolonged intubation. In the last 4 years, we have been using bronchoalveolar lavage (BAL) to assist in this clinical dilemma.  In select patients with refractory ARDS, who have failed to respond to antibiotic therapy, we stop antibiotics and perform a BAL. In those patients whose clinical course does not deteriorate and the quantitative culture of the BAL fluid does not yield heavy growth, we treat with high-dose corticosteroids. We have observed dramatic improvement in over 80% of these patients.  Others observed similar success. [62,63] Perhaps more late MOF patients might benefit by this seemingly paradoxical therapy.
In conclusion, this study has documented that MOF remains a significant problem in our regionalized trauma system. Additionally, MOF appears to present in at least two patterns (i.e., early versus late). Better understanding of the relative roles of dysfunctional inflammation and infections in early MOF versus late MOF may facilitate the development of new strategies for the prevention and treatment of this morbid syndrome.
The authors express their sincere gratitude to Diane Blackmon for her excellent preparation of the manuscript.
Dr. Donald E. Fry (Albuquerque, New Mexico): I really appreciate the opportunity to discuss another fine presentation by Dr. Moore and his associates from Denver.
The issue of multiple organ failure is obviously one of considerable interest to everyone here that takes care of critically injured trauma patients. Unfortunately, the literature on this subject over the last 15 to 18 years is littered with different definitions, different criteria, dramatically different outcomes, very different observations by a whole host of very capable and qualified people.
It thus makes comparisons between these numerous reports virtually impossible. Everyone seems to use a different definition of what multiple organ failure is. The patient populations that are studied are different. The organs that are studied are indeed different.
So if I would take the liberty of comparing our own work of some 1,200 patients studied about 12 to 15 years ago with that of Dr. Moore's today, I find out that using our criteria compared to his criteria, that he's identifying twice as many multiple organ failure patients with half the mortality rate that we did about 15 years ago.
So one could reach a conclusion, if you just took things at face value, that multiple organ failure's not declining; it's increasing in frequency, since they saw it in 15% of the patients admitted in this series, but at only half the mortality rate.
Well, obviously, I don't believe that there's twice as many organ failure patients today, nor do I believe that there's half the mortality rate.
One of the things I would raise in this particular presentation that I'd like Dr. Moore to respond to is the use of heart failure as a criterion for organ dysfunction in these patients. The criteria that's been used is the utilization of inotropes. Inotropes are used for a host of different indications in the clinical arena, many times in patients that are having a severe systemic inflammatory response. The inotropes actually end up being used to deal with systemic vascular resistance problems and have absolutely nothing to do whatsoever with dysfunction or poorly functioning myocardium.
So I would really like Dr. Moore to assuage my concerns that he was dealing with peripheral vascular problems and that the heart was actually functioning very well, and accordingly he ended up with more organ failure patients than in fact really existed.
I've noticed that he's totally eliminated the issue of stress bleeding as a potential multiple organ failure expression, and I would be curious if Dr. Moore could address for us whether stress bleeding has in fact totally disappeared from the high altitude of Denver, and whether prophylaxis against that measure is indeed the cause for that?
I was interested to see the early and late multiple organ failure expressions, since I would have considered his late group actually to be early, and would have expected there to be an ultralate group that would have fell out some 14, 18, 21 days later, and that was clearly not seen in his group.
The patients that were identified in the early MOF group looked to me to be the patients that have had inadequate resuscitation, not because of care problems, but simply because of profound injury, inability to resuscitate. It would seem to me that those early 72-hour MOF patients were in fact patients that had severe shock and ischemia, and I'm not really surprised that there were a significant number of patients identified there.
On the other hand, the late MOF patients identified in this study only really had 27% of the patients have infection identified as a triggering event. I'm curious as to what was the frequency of the systemic inflammatory response syndrome in this group of patients. I think most of us, even those of us who advocated infection as the critical trigger in organ failure, no appreciate that it really is, I believe, the activation of the systemic inflammatory response syndrome, which may or may not be triggered by infection.
So I think a more meaningful observation. Fred, might be of those late organ failure patients, what number of those really did have SIRS.
Finally, I guess I continue to be troubled by why are we doing these kinds of studies, and I'd like for Dr. Moore to address that issue. When we all continue to use different criteria, we cannot correlate our information with each other. When we change the definitions, we can't longitudinally evaluate whether we're making improvements or not in the care.
I guess my final plea in this discussion is that we must come to some kind of a standard nomenclature in multiple organ failure if we're ever going to be able to make any sense out of this morass of data and publications. Thank you very much.
Dr. Philip Bosco (Granite Bay, California): I would just ask Dr. Moore what do you call a patient--a trauma patient--who has had bad shock, and has had the obligatory one or two blood volume transfusions, has ARDS, and 2 or 3 days later his or her bilirubin is eight or ten from blood transfusion? Is that multiple organ failure, sequential organ failure, or is that just a byproduct of blood transfusion?
Dr. Ronald J. Simon (Bronx, New York): I enjoyed your presentation very much. I just have one question. There's a rising interest in the lungs as a motor organ for multiorgan failure, and I just wonder how many of your patients with late organ failure had ARDS prior to their onset of multiorgan failure? Thank you.
Dr. H. Gill Cryer (Los Angeles, California): I'd like to amplify on the last question a little bit. Since the score is cumulative, it seems that what you may really have is two different rates of progression of the disease, both starting on the day of admission, rather than a group that develops it late and one that develops it earlier. In other words, the late group may actually start accumulating MOF points on day 1 but not accumulate enough points to meet the MOF threshold until day 7.
So, like the last questioner, is there evidence of a single organ dysfunction early on that progresses more slowly in the late MOF group?
If that is the case, did infection then lead to a progression toward a more severe syndrome?
Dr. Philip S. Barie (New York, New York): A very nice presentation, Fred. I enjoyed it. I have two questions, if I may.
First, you use a reasonable, if arbitrary, definition of multiple organ failure (MOF) and say that your patients either have it or they do not. We have been interested in quantitating MOF on a continuous basis rather than as an all or nothing phenomenon. If you change your cutoff point or look at a continuum of scores, does that influence your data?
Second, in your early patients who manifest MOF can you, at some point, discriminate outcomes relatively early on? Thank you.
Dr. Frederick A. Moore (closing): Dr. Fry, we aggressively resuscitate trauma patients at known risk for MOF. By 24 hours, virtually all the patients who are not going to die early (i.e., within 48 hours of admission) are hyperdynamic. At this juncture we curtail resuscitative efforts and persist only in patients who have evidence of a persistent or recurrent peripheral perfusion deficit. We do not intentionally maintain supernormal oxygen delivery beyond acute resuscitation nor do we attempt normalize systemic vascular resistance (SVR). We believe that a decreased SVR is the normal compensatory response in a severely injured patient who has been adequately resuscitated. We intentionally do not obtain organ dysfunctions scores until day 3 to distance ourselves from acute resuscitation efforts and at this time define heart failure as a cardiac index less than 3 on moderate dose of inotropes. Secondly, significant stress gastritis bleeding has disappeared. I cannot remember the last time a trauma patient at DGH needed operative intervention for this entity. In my experience, most high risk patients who are endoscoped early will have grade I to III gastric erosions. However, despite different prophylactic regimens, these do not progress to clinical bleeding. Compared to your experience in the late 1970s, the natural history of this entity has definitely changed. I believe this is because of better overall ICU care. We currently use sucralfate for prophylaxis because it has the least potential side effects. Along the same line, I believe the lack of a third peak of ultralate MOF is because of the changing epidemiology of postinjury intra-abdominal abscesses. Compared to your experience in the late 1970s, far fewer of our patients developed intra-abdominal abscesses. Additionally, they appeared to be diagnosed and treated earlier as a result of the availability of CAT scanning. Moreover their impact on triggering or worsening MOF was less important. Next, while I acknowledge that SIRS is a valuable concept, my problem with SIRS is that its definition is too sensitive. By the standard definition virtually all of our study patients had SIRS. A cogent issue is how to differentiate mild, moderate, and severe SIRS. Our medical colleagues, lead by Dr. Bone, in a recent consensus conference, quantitate the severity of SIRS by the presence or absence of organ dysfunctions. Thus by these criteria, all of our MOF patients have severe SIRS. Finally, the term MOF was coined by Dr. Ben Eiseman at Denver General Hospital in 1977. Since that time, MOF has been a focus of our surgery department's research efforts. Our scoring system was developed 10 years ago. It originally included eight organ dysfunctions; however, four were subsequently dropped because their definitions were subjective and they did not substantially contribute to identifying MOF. I believe that our revised score is as good as any currently available. I agree that a consensus conference, with surgical input, is badly needed.
Dr. Bosco, the scenario you describe is a bit atypical. Two to 3 days after a massive transfusion, the rise in bilirubin secondary to blood products would typically be in the range of only 2 to 3 mg/dL, although occasionally bilirubin will acutely rise above 5 if there was underlying liver disease or a transfusion reaction. On the other hand, liver failure in the MOF syndrome tends to present as a second peak in bilirubin beginning at 5 to 7 days postinjury.
Dr. Simon and Dr. Cryer, by our definition, patients develop MOF when their simultaneous organ dysfunction score exceeds a threshold. In both early and late MOF, the lung is frequently the first organ to fail. Presumably, the lungs are more vulnerable to systemic inflammation or our clinical tools to detect lung dysfunction are more sensitive. Nevertheless, patients rarely die of isolated lung failure. In late MOF, the lungs may indeed serve as a source of ongoing systemic inflammation. This is certainly true for a subset of ARDS patients who develop pneumonia.
Dr. Barie, we agree that defining MOF as a continuous variable from a statistical standpoint is better than defining it as a dicotomized variable. However, this is quite difficult to do since there is no gold standard for MOF. Additionally, the relative contribution of the various organ dysfunctions need to be quantitated. This will require a much larger data base. In regards to your second question, I assume the MOF score at early presentation would be predictive of death since 44% of these patients ultimately died. However, when we developed our MOF score we were not interested in predicting death, rather we were trying to describe the disease, which in turn could serve as an endpoint in our clinical studies.
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