Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis.

UNLABELLED: It is unclear whether practice-related aspects of antimicrobial therapy contribute to the high mortality from septic shock among patients with cirrhosis. We examined the relationship between aspects of initial empiric antimicrobial therapy and mortality in patients with cirrhosis and septic shock. This was a nested cohort study within a large retrospective database of septic shock from 28 medical centers in Canada, the United States, and Saudi Arabia by the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group between 1996 and 2008. We examined the impact of initial empiric antimicrobial therapeutic variables on the hospital mortality of patients with cirrhosis and septic shock. Among 635 patients with cirrhosis and septic shock, the hospital mortality was 75.6%. Inappropriate initial empiric antimicrobial therapy was administered in 155 (24.4%) patients. The median time to appropriate antimicrobial administration was 7.3 hours (interquartile range, 3.2-18.3 hours). The use of inappropriate initial antimicrobials was associated with increased mortality (adjusted odds ratio [aOR], 9.5; 95% confidence interval [CI], 4.3-20.7], as was the delay in appropriate antimicrobials (aOR for each 1 hour increase, 1.1; 95% CI, 1.1-1.2). Among patients with eligible bacterial septic shock, a single rather than two or more appropriate antimicrobials was used in 226 (72.9%) patients and was also associated with higher mortality (aOR, 1.8; 95% CI, 1.0-3.3). These findings were consistent across various clinically relevant subgroups. CONCLUSION: In patients with cirrhosis and septic shock, inappropriate and delayed appropriate initial empiric antimicrobial therapy is associated with increased mortality. Monotherapy of bacterial septic shock is also associated with increased mortality. The process of selection and implementation of empiric antimicrobial therapy in this high-risk group should be restructured.

Etomidate and mortality in cirrhotic patients with septic shock.

BACKGROUND: Clinical effects and outcomes of a single dose etomidate prior to intubation in the intensive care setting is controversial. The aim of this study is to evaluate the association of a single dose effect of etomidate prior to intubation on the mortality of septic cirrhotic patients and the impact of the subsequent use of low dose hydrocortisone. METHODS: This is a nested-cohort study within a randomized double blind placebo controlled study evaluating the use of low dose hydrocortisone in cirrhotic septic patients. Cirrhotic septic patients ≥ 18 years were included in the study. Patients who received etomidate prior to intubation were compared to those who did not receive etomidate for all cause 28-day mortality as a primary outcome. RESULTS: Sixty two intubated patients out of the 75 patients randomized in the initial trial were eligible for this study. Twenty three of the 62 intubated patients received etomidate dose prior to intubation. Etomidate use was not associated with all cause 28-day mortality or hospital mortality but was associated with significantly higher ICU mortality (91% vs. 64% for etomidate and controls groups, respectively; p = 0.02). Etomidate patients who received subsequent doses of hydrocortisone required lower doses of vasopressors and had more vasopressor-free days but no improvement in mortality. CONCLUSIONS: In this group of septic cirrhotic patients with very high mortality, etomidate increased ICU mortality. Subsequent use of hydrocortisone appears to have no benefit beyond decreasing vasopressor requirements. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone.

Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial.

BACKGROUND: Recent studies have reported a high prevalence of relative adrenal insufficiency in patients with liver cirrhosis. However, the effect of corticosteroid replacement on mortality in this high-risk group remains unclear. We examined the effect of low-dose hydrocortisone in patients with cirrhosis who presented with septic shock. METHODS: We enrolled patients with cirrhosis and septic shock aged 18 years or older in a randomized double-blind placebo-controlled trial. Relative adrenal insufficiency was defined as a serum cortisol increase of less than 250 nmol/L or 9 µg/dL from baseline after stimulation with 250 µg of intravenous corticotropin. Patients were assigned to receive 50 mg of intravenous hydrocortisone or placebo every six hours until hemodynamic stability was achieved, followed by steroid tapering over eight days. The primary outcome was 28-day all-cause mortality. RESULTS: The trial was stopped for futility at interim analysis after 75 patients were enrolled. Relative adrenal insufficiency was diagnosed in 76% of patients. Compared with the placebo group (n = 36), patients in the hydrocortisone group (n = 39) had a significant reduction in vasopressor doses and higher rates of shock reversal (relative risk [RR] 1.58, 95% confidence interval [CI] 0.98-2.55, p = 0.05). Hydrocortisone use was not associated with a reduction in 28-day mortality (RR 1.17, 95% CI 0.92-1.49, p = 0.19) but was associated with an increase in shock relapse (RR 2.58, 95% CI 1.04-6.45, p = 0.03) and gastrointestinal bleeding (RR 3.00, 95% CI 1.08-8.36, p = 0.02). INTERPRETATION: Relative adrenal insufficiency was very common in patients with cirrhosis presenting with septic shock. Despite initial favourable effects on hemodynamic parameters, hydrocortisone therapy did not reduce mortality and was associated with an increase in adverse effects. (Current Controlled Trials registry no. ISRCTN99675218.).

Prevalence, Severity, and Prognostic Effect of Hepatopulmonary Syndrome in Liver Transplant Candidates.

BACKGROUND: Hepatopulmonary syndrome (HPS) is commonly encountered in the setting of end-stage liver disease (ESLD). Past studies have reported conflicting results in terms of demonstrating an association between HPS and mortality. The aim of this study was to determine the prevalence of HPS in patients with ESLD referred for assessment of transplantation suitability. In addition, we investigated survival rates in the setting of HPS, with and without liver transplantation. MATERIAL AND METHODS: The medical records of 524 consecutive patients with ESLD evaluated for potential liver transplantation were retrospectively reviewed. HPS was defined by a reduced partial pressure of oxygen or an elevated alveolar-arterial oxygen gradient and the presence of intrapulmonary vascular dilatation on contrast-enhanced echocardiography. RESULTS: In total, 57 subjects (12%) fulfilled the diagnostic criteria of HPS; 88% of these had mild to moderate HPS. For patients with HPS, the overall survival rates at 1 and 3 years were 95% and 92%, respectively. Liver transplants were received by 245 patients (53%), 26 of whom had HPS. For transplant recipients with HPS, the overall survival rates at 1 and 3 years were 96% and 91%, respectively, compared to 85% and 80% in subjects without HPS. Post-transplantation survival in patients with and without HPS did not differ significantly (HR=0.489, 95% CI: 0.153-1.564; p=0.228). CONCLUSIONS: This study demonstrated a high prevalence of IPVD and HPS among patients who were potential candidates for liver transplantation. HPS was mild to moderate in the majority of those affected and had no significant effect on overall survival.

Prevalence of portopulmonary hypertension among liver transplant candidates in a region highly endemic for viral hepatitis.

BACKGROUND: Portopulmonary hypertension (POPH) is rarely encountered in the setting of end-stage liver disease (ESLD) and, if severe, may preclude patients from undergoing liver transplantation. The aim of the present study was to determine the prevalence of POPH in the setting of ESLD for patients who were referred to King Abdulaziz Medical City-Riyadh (Riyadh, Saudi Arabia) for assessment for liver transplantation. MATERIAL/METHODS: The medical records of all patients evaluated for liver transplantation between 1993 and 2009 were retrospectively reviewed. Pulmonary hypertension (PH) was defined as an echocardiographically estimated right ventricular systolic pressure ≥40 mmHg and a mean pulmonary arterial pressure >25 mmHg measured using right heart catheterization. RESULTS: A total of 542 consecutive subjects with ESLD who underwent assessment for liver transplantation were identified; however, medical records for 18 were missing. The final cohort, therefore, consisted of 524 subjects with a mean (±SD) age of 49±13.9 years, 60% were male, and 70% had viral hepatitis. PH was detected by echocardiography in 64 (12%) of the 524 subjects. Hemodynamic data obtained from intraoperative right heart catheterization or as part of the pre-transplantation evaluation were available for 248 subjects, including 57 of the 64 who had echocardiographically defined PH. PH was confirmed in 30 subjects and ruled out in 27, and only 4 (0.76%) subjects fulfilled the criteria for POPH. CONCLUSIONS: The prevalence of POPH determined in the present study was lower than previously reported. Further prospective research is needed to confirm this finding and to explore possible clinical, genetic, and environmental factors that contribute to the low prevalence of POPH in regions highly endemic for viral hepatitis.

Modification and implementation of NCCN guidelines on hepatobiliary cancers in the Middle East and North Africa region.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers address hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Hepatocellular cancer incidence is higher in the Middle East and North Africa (MENA) region than in the West, and hepatitis B and C infections are particularly important; the incidence of gallbladder cancer is among the highest in the world. Regional problems include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities. Furthermore, costs associated with molecular and targeted therapies are an increasing concern. A committee was formed, consisting of leading specialists and decision-makers from the region, with each member being tasked to suggest modifications to the existing guidelines based on review of the literature and consultations with local colleagues. This committee met as a group, and then continued to discuss and debate the suggested modifications electronically. Several recommendations were finalized after vigorous debate. The final approved recommendations were then presented in April 2009 to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval. This project represents an effort to modify and implement the NCCN Guidelines on Hepatobiliary Cancers in the MENA region, while taking into consideration local differences in patient and disease characteristics. The hope is that this will form the basis of future local, regional, and international cooperation in guideline development and research.

External validation of a modified model of Acute Physiology and Chronic Health Evaluation (APACHE) II for orthotopic liver transplant patients.

INTRODUCTION: The purpose of the study was to validate the newly derived postoperative orthotopic liver transplantation (OLTX)-specific diagnostic weight for the Acute Physiology and Chronic Health Evaluation (APACHE) II mortality prediction system in independent databases. METHODS: Medical records of 174 liver transplantation patients admitted postoperatively to the adult intensive care units at King Fahad National Guard Hospital and the University of Wisconsin were reviewed, and data on age, sex, the underlying liver disease, APACHE II scores and the hospital outcome were collected. Predicted mortality was calculated using: 1) the original APACHE II diagnostic weight of postoperative other gastrointestinal surgery and 2) the newly derived OLTX-specific diagnostic category weight. Standardized mortality ratio and 95% confidence intervals were calculated. Calibration was evaluated with the Hosmer-Lemeshow goodness-of-fit C-statistic. Discrimination was tested by 2 x 2 classification matrices and by computing the areas under the receiver operating characteristic curves. Patient characteristics and outcome data were compared between the two hospitals. RESULTS: APACHE II significantly overestimated mortality when the original diagnostic weight was used, but provided a closer estimate of mortality with the OTLX-specific diagnostic weight. The C-statistic analysis showed better calibration for the new approach; discrimination was also improved. The performances of the prediction systems were similar in the two hospitals. The new model provided more accurate estimates of hospital mortality in each hospital. DISCUSSION: APACHE II provided an accurate estimate of mortality in liver transplant patients when the OLTX-specific diagnostic weight was used. With the new model, APACHE II can be used as a valid mortality prediction system in this group of patients.