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The most prominent contributions to multiple organ failure, multiple organ dysfunction syndrome, and systemic inflammatory response syndrome are described in this article. However, it is quite possible that there are others that have been missed. The problem of organ failure continues to perplex clinicians and scientists, and it contributes to fatal outcomes for patients with illnesses, infections, and injuries after operations. Although we know a fair bit about these problems, we frequently can do little about it. The best approach remains support to prevent failure.

Many potential therapeutic agents or drugs are evaluated in experimental animal laboratories, but in spite of interesting effects, they infrequently come into common clinical use. The reasons for this are reviewed. Agents studied previously and many being studied now are cited. Perhaps the biggest benefit of study of drugs in animals (other than for safety and toxicity) is to help us better understand the pathophysiology of disease.

Summary: BACKGROUND As care of the critically ill patient has improved and definitions of organ failure have changed, it has been observed that the incidence of organ failure and the mortality associated with organ failure appear to be decreasing. In addition, many early studies included large heterogeneous populations of both medical and surgical patients that may have influenced the incidence and outcome of organ failure. The purpose of this study is to establish the current incidence and mortality of organ failure in a homogenous population of critically ill trauma patients. METHODS All trauma patients admitted to the intensive care unit (ICU) at an urban Level I trauma center were prospectively studied. Patients were evaluated for the presence of organ failure using definitions proposed by Knaus and by Fry. Newer definitions of organ failure incorporating organ dysfunction and severity-of-illness scores were also obtained in all patients in an attempt to predict outcome. These included lung injury scores (acute respiratory distress syndrome scores), Acute Physiology and Chronic Health Evaluation (APACHE) II and III scores, Injury Severity Score (ISS), and multiple organ dysfunction scores. Primary outcomes assessed were death and the occurrence of organ failure by the various definitions. RESULTS Eight hundred sixty-nine trauma patients were admitted to the ICU and survived longer than 48 hours. Mean APACHE II and APACHE III scores at admission to the ICU and ISS were 12.2 +/- 22, 30.5 +/- 22.7, and 19 +/- 10, respectively. Single organ failure (SOF) occurred in 163 patients (18.7%) and multiple organ failure occurred in 44 patients (5.1%). All SOF was caused by respiratory failure. Respiratory failure occurred first in the majority of patients with multiple organ failure. Mortality was 4.3% with one organ system failure, 32% with two, 67% with three, and 90% when four organ systems failed. None of the patients with SOF died secondary to respiratory failure. Multiple stepwise regression analysis was performed to determine which of the following risk factors are associated with the occurrence of organ failure: mechanism of injury, lactate at 24 hours, ISS, APACHE II, APACHE III, acute respiratory distress syndrome score at admission, multiple organ dysfunction score at admission and total blood products transfused in 24 hours. Of these factors, APACHE III, lactate at 24 hours, and total blood products transfused in 24 hours were associated with the occurrence of organ failure. CONCLUSION The overall incidence of organ failure in a homogeneous trauma population appears to be lower than that reported in studies performed in heterogeneous patient populations in the 1980s. Mortality for SOF is low and appears to be related primarily to the patient's underlying injuries and not to organ failure. Mortality for two or three organ system failures is lower than reported 15 to 20 years ago. Mortality for patients with four or more organ system failures remains high, approaching 100%.

SIRS, MODS, and MOF are not diseases or even syndromes. They are simply clinical descriptors of people that are sick. They are symptoms and signs of various stages of illness progressing to death in the modern organ supporting ICU. They are catchy, popular acronyms but they cannot be treated specifically, and then only by support of organ functions. To help our patients and improve morbidity and mortality we must focus on specific diseases. Although ventilator associated pneumonia and pancreatitis may both produce an inflammatory response, cytokine-mediator activation and SIRS, they must each be treated in a different way. I believe that SIRS has led us astray.

The excitement of molecular biology and of genetic knowledge and their possibilities must be balanced against our limitations in using this information for the care of our patients. There is a great discrepancy between what we know and what we can do. There are many reasons for this. A major one is that science must simplify/reduce the variables in experimentation and then generalize in terms of a specific factor or effect, whereas patients are complex with variables that we do not yet understand completely. This powerful science is now teaching us about the genetic diversity in both susceptibility and outcome of disease, and the diversity in life experiences and antigen exposures. Clinicians have tried to lump together and treat in a similar way many diverse human diseases. This has not worked well. Pancreatitis and perforated diverticulitis both produce inflammation and sepsis, but they are different processes and may both lead to multiple organ failure. This lumping together has contributed to the failure of so-called magic bullets. There are new contributors to organ damage. Gender, lifestyle and prior disease differences also complicate the care of patients. Despite this, we are slowly and gradually improving the care of our surgical patients by careful pre-, intra- and postoperative support and better, simpler and safer operations.

Background: Giant paraesophageal hiatal hernia (GPEH) presents a risk of catastrophic complications that include massive bleeding, strangulation, and perforation and should be repaired. Controversy persists as to the surgical approach and whether an antireflux repair is required., Methods: This study reviews the experience with 100 patients with GPEH who underwent surgical repair between 1967 and 1999. Eighty patients underwent an elective operation, and 20 patients underwent an emergency procedure for complications of GPEH. The gastroesophageal junction was above the hiatus ("combined" hernia with sliding component) in 23 patients and in the abdomen in 77 patients, including 3 patients with a true parahiatal hernia., Results: A thoracic approach was used in 18 patients, mostly early in our experience; postoperative gastric volvulus requiring transabdominal repair developed in 2 patients. The remaining 82 patients underwent an abdominal repair, with temporary gastrostomy to prevent gastric displacement in 75 patients; the hernial sac was resected, and the hiatus was reconstructed in all of the patients. Thirty-five patients with reflux on preoperative work up underwent a fundoplication, with gastroplasty in 2 patients because of a short esophagus. No patient has experienced hernia recurrence. Whereas symptomatic relief was excellent in all patients with elective repair, mild reflux was present in 2 patients after emergency operation. There were no deaths among the patients who underwent elective operation; there were 2 hospital deaths among those patients who underwent emergency operation (10%)., Conclusions: GPEH should be repaired soon after recognition. Reflux should be evaluated before the operation, and if present, fundoplication should be part of the repair along with the reduction of the hernia, excision of the sac, gastropexy, and crural closure. These are best achieved with an abdominal approach.

Objective: To obtain further insight into the constitutional, phenotype-dependent changes of T-helper-1 and T-helper-2 signature lymphokine synthesis after trauma., Design: Prospective, descriptive study., Setting: Intensive care unit of a burn center in a community hospital., Patients: Ten patients 1, 3, 5, and 7 days after major burn injury and 15 healthy individuals., Interventions: Peripheral blood mononuclear cells were separated and incubated (5 hrs) for cytokine production induced by the accessory cell-independent stimulus of ionomycin and phorbol 12-myristate 13-acetate. After fixation and permeabilization, cell samples were immunofluorescently stained for cell surface antigens (CD4 and CD8), intracellular interferon (IFN)-gamma, and interleukin (IL)-4 synthesis. Results were correlated with corresponding enzyme-linked immunosorbent assay measurements of the culture supernatants., Measurements and Main Results: The phenotypic analysis of the composition of the helper (CD4) and suppressor/cytotoxic (CD8) T-cell subset demonstrated that patients suffering from major burns and healthy controls express these antigens in similar percentages. The ratio of CD4 positive to CD8 positive/CD16 negative T-cell subsets showed no significant changes after trauma compared with controls. The production of IL-4 was excessively up-regulated while the release of IFN-gamma was only slightly increased. The predominant cell source of IL-4 after burn trauma was the CD8+ cell with nearly five-fold increased production on day 5 (7.2+/-2.6%) vs. 1.5+/-0.4% in controls. While CD8+ cells are also capable of enhancing their IFN-gamma synthesis under stress by about 60% due to the significant participation of the naive CD45RA+ subset, the CD4+ IFN-gamma release remained largely unchanged. With this study, we demonstrated that in nonsurvivors the number of CD8+ IL-4-producing cells was significantly higher compared with controls; also, the number of IFN-gamma-releasing memory/effector CD45RO+ cells was lower compared with survivors., Conclusions: In previous experiments, we show that a shift to T(H)2 dominated phenotypes increases the risk for postburn infection. The current study confirms that major burns induce a significant shift of cytokine response in the T(H)2 direction and demonstrates that the CD8+, rather than the CD4+ phenotype, is present. Increased IL-4 production is associated with the T(H)2 lymphocyte. These diagnostic tests may help to differentiate patients with compensatory anti-inflammatory response syndrome and immunosuppression from those patients in the proinflammatory state associated with the systemic inflammatory response syndrome. The profile described in this article is associated with immunosuppression and may contraindicate attempts at anti-inflammatory therapy for sepsis.

The problems of inflammation and infection leading to organ dysfunction and failure continue to be the major problems after injury and operations and with intensive care for many diseases and problems. When SIRS goes to MODS and MOF, the mortality becomes high, ranging from 30-80% depending on the number of failed organs. In spite of this, there have been recent exciting discoveries and contributions to patient care. A reasonable question then is, are we making progress and if so, can we document it? Are the incidence and mortality of MOF decreasing? The literature comparing care over some years suggests a decrease in ICU mortality in patients with severe organ failure, a decrease in elective surgical mortality, and improvement in the results of care and outcome for trauma patients. Review of problems occurring in sick and injured patients indicates that certain problems are decreasing in frequency, such as renal failure and ARDS after trauma, stress gastrointestinal bleeding, and abdominal abscesses, and these should improve outcome. There are a number of exciting therapies that help certain patients but not everyone. These controversies challenge us to focus on where and when there are positive benefits. Risk factors for MOF are addressed to focus on early intervention. The possibilities of multiple therapeutic agents are described. Finally, we describe and emphasize our recommendation to strive to prevent MODS and SIRS.

The concept of multiple organ failure and related abnormalities was first developed in the 1970s. Multiple organ failure became evident when the support systems in intensive care units were able to keep patients alive long enough for multiple organ problems to develop in them. The high mortality of patients with multiple organ failure provided a focus for the problems that ultimately led to death for many patients in the intensive care unit. The frequency of infection, sepsis, or inflammation in producing multiple organ failure led to clinical trials of so-called magic bullets for the treatment of patients with sepsis. These trials have had either limited success or negative results, despite considerable evidence for efficacy or protection by such agents in experimental animals and in studies of normal human volunteers. I believe a major reason for these negative results has been the use of general entry criteria for the trials rather than the treatment of specific diseases or injuries.

Objective: Oxygen consumption (VO2I) and delivery (DO2I) indices have been stated to be superior to conventional parameters as endpoints for resuscitation. However, another interpretation of published data is that inability to increase VO2I/DO2I given adequate volume resuscitation reflects inadequate physiologic reserve and poor outcome., Design: Fifty-eight critically ill patients were randomized to two groups. In group 1 (27 patients) attempts were made to maintain VO2I > or = 150 or DO2I > or = 600 mL/min/m2. If DO2I was > 600, no attempt was made to increase VO2I even if it was < 150. Group 2 (31 patients) was resuscitated based on conventional parameters. Volume resuscitation protocols and goals for pulmonary capillary wedge pressure were the same in both groups. VO2I/DO2I were recorded in group 2, but physicians were blinded to this data. Age, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation (APACHE II) score were not different between groups., Main Results: Three patients in group 1 and two patients in group 2 died of organ failure (OF). One additional patient in group 2 died of refractory shock within 24 hours. Two of the patients in group 1 who died failed to meet VO2I/DO2I goals within 24 hours despite maximal resuscitation. Mortality was not different between the groups even with exclusion of the group 1 patients who failed to meet VO2I/DO2I goals (p = 0.66). After exclusion of the patient in group 2 who died of refractory shock, OF occurred in 18 of 27 (67%) in group 1 and in 22 of 30 (73%) in group 2 (p = 0.58). Length of ventilator support, intensive care unit stay, and hospital stay were not different between groups. When all patients were assessed, no difference was found in the incidence of OF between patients who attained the VO2I goal and those who did not. OF occurred in 20 of 34 (59%) patients who maintained a mean DO2I > or = 600 during the first 24 hours of the study and in 21 of 24 (88%) of those who did not (p < 0.02)., Conclusions: No difference was found in the incidence of OF or death in patients resuscitated based on oxygen transport parameters compared to conventional parameters. These data suggest that given adequate volume resuscitation, oxygen-based parameters are more useful as predictors of outcome than as endpoints for resuscitation.