Nicolas V. Christou

Multiple Organ Dysfunction Score: A reliable descriptor of a complex clinical outcome

OBJECTIVE To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness. DESIGN Systematic literature review; prospective cohort study. SETTING Surgical intensive care unit (ICU) of a tertiary-level teaching hospital. PATIENTS All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of < 5%, whereas a value of 4 represented marked functional derangement and an ICU mortality rate of > or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices. CONCLUSIONS This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)

Surgery Decreases Long-term Mortality, Morbidity, and Health Care Use in Morbidly Obese Patients

Objective:This study tested the hypothesis that weight-reduction (bariatric) surgery reduces long-term mortality in morbidly obese patients. Background:Obesity is a significant cause of morbidity and mortality. The impact of surgically induced, long-term weight loss on this mortality is unknown. Methods:We used an observational 2-cohort study. The treatment cohort (n = 1035) included patients having undergone bariatric surgery at the McGill University Health Centre between 1986 and 2002. The control group (n = 5746) included age- and gender-matched severely obese patients who had not undergone weight-reduction surgery identified from the Quebec provincial health insurance database. Subjects with medical conditions (other then morbid obesity) at cohort-inception into the study were excluded. The cohorts were followed for a maximum of 5 years from inception. Results:The cohorts were well matched for age, gender, and duration of follow-up. Bariatric surgery resulted in significant reduction in mean percent excess weight loss (67.1%, P < 0.001). Bariatric surgery patients had significant risk reductions for developing cardiovascular, cancer, endocrine, infectious, psychiatric, and mental disorders compared with controls, with the exception of hematologic (no difference) and digestive diseases (increased rates in the bariatric cohort). The mortality rate in the bariatric surgery cohort was 0.68% compared with 6.17% in controls (relative risk 0.11, 95% confidence interval 0.04–0.27), which translates to a reduction in the relative risk of death by 89%. Conclusions:This study shows that weight-loss surgery significantly decreases overall mortality as well as the development of new health-related conditions in morbidly obese patients.

Weight gain after short- and long-limb gastric bypass in patients followed for longer than 10 years.

Objective:To complete a long-term (>10 years) follow-up of patients undergoing isolated roux-en-Y gastric bypass for severe obesity. Background:Long-term results of gastric bypass in patients followed for longer than 10 years is not reported in the literature. Methods:Accurate weights were recorded on 228 of 272 (83.8%) of patients at a mean of 11.4 years (range, 4.7–14.9 years) after surgery. Results were documented on an individual basis for both long- and short-limb gastric bypass and compared with results at the nadir BMI and % excess weight loss (%EWL) at 5 years and >10 years post surgery. Results:There was a significant (P < 0.0001) increase in BMI in both morbidly obese (BMI < 50 kg/m2) and super obese patients (BMI > 50 kg/m2) from the nadir to 5 years and from 5 to 10 years. The super obese lost more rapidly from time zero and gained more rapidly after reaching the lowest weight at approximately 2 years than the morbidly obese patients. There was no difference in results between the long- and short-limb operations. There was a significant increase in failures and decrease in excellent results at 10 years when compared with 5 years. The failure rate when all patients are followed for at least 10 years was 20.4% for morbidly obese patients and 34.9% for super obese patients. Conclusions:The gastric bypass limb length does not impact long-term weight loss. Significant weight gain occurs continuously in patients after reaching the nadir weight following gastric bypass. Despite this weight gain, the long-term mortality remains low at 3.1%.

The gastrointestinal tract. The "undrained abscess" of multiple organ failure.

ObjectiveThis study determined the association between proximal gastrointestinal (GI) colonization and the development of intensive care unit (ICU)-acquired infection and multiple organ failure (MOF) in a population of critically ill surgical patients. Summary Background DataICU-acquired infection in association with progressive organ system dysfunction is an important cause of morbidity and mortality in critical surgical illness. Oropharyngeal and gastric colonization with the characteristic infecting species is common, but its association with ICU morbidity is poorly defined. MethodsA prospective cohort study of 41 surgical ICU patients was undertaken. Specimens of gastric and upper small bowel fluid were obtained for quantitative culture; the severity of organ dysfunction was quantitated by a numeric score. ResultsOne or more episodes of ICU-acquired infection developed in 33 patients and involved at least one organism concomitantly cultured from the upper GI tract in all but 3. The most common organisms causing ICU-acquired infection—Candida, Streptococcus faecalis, Pseudomonas, and coagulase-negative Staphylococci–were also the most common species colonizing the proximal GI tract. Gut colonization correlated with the development of invasive infection within 1 week of culture for Pseudomonas (90% vs. 13% in noncolonized patients, p < 0.0001) or Staphylococcus epidermidis (80% vs. 6%, p < 0.0001); a weaker association was seen for colonization with Candida. Infections associated with GI colonization Included pneumonia (16 patients); wound infection (12 patients), urinary tract infection (11 patients), recurrent (tertiary) peritonitis (11 patients), and bacteremia (10 patients). ICU mortality was greater for patients colonized with Pseudomonas (70% vs. 26%, p = 0.03); organ dysfunction was most marked in patients colonized with one or more of the following: Candida, Pseudomonas, or S. epidermidis. ConclusionsThe upper GI tract is an Important reservoir of the organisms causing ICU-acquired infection. Pathologic GI colonization is associated with the development of MOF in the critically ill surgical patient.

Multiple organ dysfunction syndrome: exploring the paradigm of complex nonlinear systems.

Objectives The objectives of this article are to introduce and explore a novel paradigm based on complex nonlinear systems, and to evaluate its application to critical care research regarding the systemic host response and multiple organ dysfunction syndrome (MODS). Data Sources Published original work, review articles, scientific abstracts and books, as well as our personal files. Study Selection Studies were selected for their relevance to the applications of nonlinear complex systems, to critical care medicine, and to the concepts presented. Data Extraction We extracted all applicable data. Data Synthesis Following a brief review of MODS, an introduction to complex nonlinear systems is presented, including clear concepts, definitions, and properties. By examining the multiple, nonlinear, interrelated, and variable interactions between the metabolic, neural, endocrine, immune, and inflammatory systems; data regarding interconnected antibody networks; and the redundant, nonlinear, interdependent nature of the inflammatory response, we present the hypothesis that the systemic host response to trauma, shock, or sepsis must be evaluated as a complex nonlinear system. This model provides a new explanation for the failure of trials using various antimediator therapies in the treatment of patients with sepsis and MODS. Understanding the host response as a complex nonlinear system offers innovative means of studying critical care patients, specifically by suggesting a greater focus on systemic properties. We hypothesize that analysis of variability and connectivity of individual variables offer a novel means of evaluating and differentiating the systemic properties of a complex nonlinear system. Current applications of evaluating variability and connectivity are discussed, and insights regarding future research are offered. Conclusion The paradigm offered by the study of complex nonlinear systems suggests new insights to pursue research to evaluate, monitor, and treat patients with MODS.

Results of a multicenter trial comparing imipenem/cilastatin to tobramycin/clindamycin for intra-abdominal infections.

We designed a multicenter study to compare tobramycin/clindamycin to imipenem/cilastatin for intra-abdominal infections. We included the Acute Physiology and Chronic Health Evaluation (APACHE II) index of severity and excluded patients without established infection. Two hundred ninety patients were enrolled, of whom 162 were evaluable. Using logistic regression to analyze both outcome at the abdominal site of infection and outcome as mortality, we found a significant correlation for both with APACHE II score (p less than 0.0001 for both). Next we analyzed the residual effect of treatment assignment and found a significant improvement in outcome for imipenem/cilastatin-treated patients (p = 0.043). The differences in outcome were explained by a higher failure rate for patients with gram-negative organisms for tobramycin/clindamycin-treated patients (p = 0.018). This was reflected in a significantly higher incidence of fasciitis requiring reoperation and prosthetic fascial replacement. Maximum peak tobramycin levels were analyzed for 63 tobramycin/clindamycin patients harboring gram-negative organisms. For failures the maximum peak was 6.4 +/- 1.9 micrograms/mL, and time to maximum peak was 4.6 +/- 5.2 days. For successes the maximum peak was 6.1 +/- 1.7 micrograms/mL, occurring at 3.8 +/- 2.6 days. This study supports inclusion of severity scoring in statistical analyses of outcome results and supports the notion that imipenem/cilastatin therapy improves outcome at the intra-abdominal site of infection as compared to a conventionally prescribed amino-glycoside-based regimen.

Ertapenem Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections: Results of a Double-Blind, Randomized Comparative Phase III Trial

ObjectiveTo examine the clinical efficacy and safety of ertapenem, a novel &bgr;-lactam agent with wide activity against common pathogens encountered in intraabdominal infection. Summary Background DataErtapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections. MethodsThis prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections. ResultsSix hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam. ConclusionsIn this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.

Bariatric surgery reduces cancer risk in morbidly obese patients

BACKGROUND To assess the effect of bariatric surgery on the cancer risk of patients with morbid obesity because evidence is mounting of an association between obesity and cancer. METHODS We performed an observational 2-cohort study. The treatment cohort (n = 1035) included patients who had undergone bariatric surgery from 1986 to 2002. The control group (n = 5746) included age- and gender-matched morbidly obese patients who had not undergone weight-reduction surgery and who were identified from a single-payor administrative database. The subjects with physician or hospital visits for a cancer-related diagnosis or treatment within the 6 months previous to the beginning of the study were excluded. The cohorts were followed up for a maximum of 5 years from study inception. RESULTS Bariatric surgery resulted in a significant reduction in the mean percentage of excess weight loss (67.1%, P <.001). The surgery patients had significantly fewer physician/hospital visits for all cancer diagnoses (n = 21, 2.0%) compared with the controls (n = 487, 8.45%; relative risk .22, 95% confidence interval .143-.347; P = .001). The physician/hospital visits for common cancers such as breast cancer were significantly reduced in the surgery group (P = .001). For all other cancers, the physician/hospital visits showed a trend toward being lower in the surgery group. Because of the low frequencies, statistical significance could not be demonstrated for individual cancer diagnoses. CONCLUSION The data suggest that bariatric surgery improves the cancer outcomes in some morbidly obese patients.

Iron Absorption and Therapy after Gastric Bypass

Background: Iron deficiency anemia is a common complication of gastric bypass. The authors assessed the value of taking vitamin C with oral iron in correcting deficiencies in iron stores and anemia postoperatively. Materials and Methods: Iron absorption tests were performed on 55 patients 3.2 ± 2.0 years after isolated gastric bypass to identify those at higher risk for the late development of anemia. Twenty-nine of this group agreed to a therapeutic trial of iron alone or with vitamin C over a 2-month period. All 55 patients were followed up for 27.1 ± 1.0 months following the study. Results: The iron absorption test identified patients with low iron stores, as indicated by low serum ferritin, and those with sufficient absorption surface to benefit from oral iron. The addition of vitamin C appears to enhance the therapeutic effect of iron by correcting ferritin deficits (P < 0.01) and anemia (P < 0.05). Differences in intestine length bypassed by the operation (10 vs. 100 cm) did not affect late ferritin and hemoglobin values. Conclusion: This study suggests but does not prove that the addition of vitamin C to iron therapy after gastric bypass is more effective in restoring ferritin and hemoglobin than iron alone. These results are in contrast with the outcome 22.8 months later, when ∼50% of study patients were again anemic. Closer follow-up of patients is urgently needed.

Estimating mortality risk in preoperative patients using immunologic, nutritional, and acute-phase response variables.

We measured the delayed type hypersensitivity (DTH) skin test response, along with additional variables of host immunocompetence in 245 preoperative patients to determine which variables are associated with septic-related deaths following operation. Of the 14 deaths (5.7%), 12 were related to sepsis and in 2 sepsis was contributory. The DTH response (p less than 0.00001), age (p less than 0.0002), serum albumin (p less than 0.003), hemoglobin (p less than 0.02), and total hemolytic complement (p less than 0.03), were significantly different between those who died and those who lived. By logistic regression analysis, only the DTH skin test response (log likelihood = 41.7, improvement X2 = 6.24, p less than 0.012) and the serum albumin (log likelihood = 44.8, improvement X2 = 17.7, p less than 0.001) were significantly and independently associated with the deaths. The resultant probability of mortality calculation equation was tested in a separate validation group of 519 patients (mortality = 5%) and yielded a good predictive capability as assessed by (1) X2 = 0.08 between observed and expected deaths, NS; (2) Goodman-Kruskall G statistic = 0.673) Receiver-Operating-Characteristic (ROC) curve analysis with an area under the ROC curve, Az = 0.79 +/- 0.05. We conclude that a reduced immune response (DTH skin test anergy) plus a nutritional deficit and/or acute-phase response change are both associated with increased septic-related deaths in elective surgical patients.