Alexander Wilmer

Early versus Late Parenteral Nutrition in Critically Ill Adults

BACKGROUND Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. METHODS In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. RESULTS Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P=0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about

Intensive Insulin Therapy in Mixed Medical/Surgical Intensive Care Units: Benefit Versus Harm

1,600) (P=0.04). CONCLUSIONS Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem program of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.).

Thrombocytopenia and prognosis in intensive care

Intensive insulin therapy (IIT) improves the outcome of prolonged critically ill patients, but concerns remain regarding potential harm and the optimal blood glucose level. These questions were addressed using the pooled dataset of two randomized controlled trials. Independent of parenteral glucose load, IIT reduced mortality from 23.6 to 20.4% in the intention-to-treat group (n = 2,748; P = 0.04) and from 37.9 to 30.1% among long stayers (n = 1,389; P = 0.002), with no difference among short stayers (8.9 vs. 10.4%; n = 1,359; P = 0.4). Compared with blood glucose of 110–150 mg/dl, mortality was higher with blood glucose >150 mg/dl (odds ratio 1.38 [95% CI 1.10–1.75]; P = 0.007) and lower with <110 mg/dl (0.77 [0.61–0.96]; P = 0.02). Only patients with diabetes (n = 407) showed no survival benefit of IIT. Prevention of kidney injury and critical illness polyneuropathy required blood glucose strictly <110 mg/day, but this level carried the highest risk of hypoglycemia. Within 24 h of hypoglycemia, three patients in the conventional and one in the IIT group died (P = 0.0004) without difference in hospital mortality. No new neurological problems occurred in survivors who experienced hypoglycemia in intensive care units (ICUs). We conclude that IIT reduces mortality of all medical/surgical ICU patients, except those with a prior history of diabetes, and does not cause harm. A blood glucose target <110 mg/day was most effective but also carried the highest risk of hypoglycemia.

Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013

Objective To study the incidence and prognosis of thrombocytopenia in adult intensive care unit (ICU) patients. Design Prospective observational cohort study. Setting The medical ICU of a university hospital and the combined medical-surgical ICU of a regional hospital. Patients All patients consecutively admitted during a 5-month period. Interventions Patient surveillance and data collection. Measurements and Main Results The primary outcome measure was ICU mortality. Data of 329 patients were analyzed. Overall ICU mortality rate was 19.5%. A total of 136 patients (41.3%) had at least one platelet count <150 × 109/L. These patients had higher Multiple Organ Dysfunction Score (MODS), Simplified Acute Physiology Score (SAPS) II, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores at admission, longer ICU stay (8 [4–16] days vs. 5 [2–9] days) (median [interquartile range]), and higher ICU mortality (crude odds ratio [OR], 5.0; 95% confidence interval [CI], 2.7–9.1) and hospital mortality than patients with daily platelet counts >150 × 109/L (p < .0005 for all comparisons). Bleeding incidence rose from 4.1% in nonthrombocytopenic patients to 21.4% in patients with minimal platelet counts between 101 × 109/L and 149 × 109/L (p = .0002) and to 52.6% in patients with minimal platelet counts <100 × 109/L (p < .0001). In all quartiles of admission APACHE II and SAPS II scores, a nadir platelet count <150 × 109/L was related with a substantially poorer vital prognosis. Similarly, a drop in platelet count to ≤50% of admission was associated with higher death rates (OR, 6.0; 95% CI, 3.0–12.0;p < .0001). In a logistic regression analysis with ICU mortality as the dependent variable, the occurrence of thrombocytopenia had more explanatory power than admission variables, including APACHE II, SAPS II, and MODS scores (adjusted OR, 4.2; 95% CI, 1.8–10.2). Conclusions Thrombocytopenia is common in ICUs and constitutes a simple and readily available risk marker for mortality, independent of and complementary to established severity of disease indices. Both a low nadir platelet count and a large fall of platelet count predict a poor vital outcome in adult ICU patients.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man

Acute‐on‐chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per‐protocol (PP) analysis (PP population n = 156). Up to 10 6‐8‐hour MARS sessions were scheduled. The main endpoint was 28‐day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28‐day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44‐1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure

BACKGROUND In animals, activation of 5-HT1 like receptors causes a relaxation of the gastric fundus through the activation of intrinsic inhibitory neurones. AIMS To investigate the effect of sumatriptan, an agonist at enteric neuronal 5-HT1receptors, on fasting fundus tone and sensitivity to gastric distension in man. METHODS A gastric barostat was used to study the effect of placebo and sumatriptan, 6 mg subcutaneously, on basal fundic tone in healthy subjects. In addition, stepwise isobaric and isovolumetric gastric distensions were performed and perception was measured before and after the administration of placebo and sumatriptan. RESULTS Placebo had no significant effects on gastric tone and on perception. Sumatriptan induced an immediate relaxation of the gastric fundus, reflected by an intragastric volume increase of 209 (39) ml (p<0.0005). After sumatriptan, intragastric pressures at the thresholds for perception or discomfort were not significantly altered. However, the intragastric volumes and the corresponding calculated wall tensions at perception and discomfort thresholds were significantly increased. CONCLUSIONS Administration of the 5-HT1 receptor agonist sumatriptan induces a relaxation of the gastric fundus in man, allowing larger intragastric volumes before thresholds for perception or discomfort are reached. The effects of sumatriptan on the gastric fundus may have therapeutic potential in the treatment of patients with functional dyspepsia.

Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study

IntroductionPatients with acute-on-chronic liver failure show an aggravated hyperdynamic circulation. We evaluated, in a controlled manner, potential changes in systemic haemodynamics induced by the molecular adsorbent recirculating system (MARS) and the Prometheus system liver detoxification devices in a group of patients with acute-on-chronic liver failure.MethodsEighteen patients (51.2 ± 2.3 years old; Child–Pugh score, 12.5 ± 0.2; Maddrey score, 63.1 ± 5.0; hepatic venous pressure gradient, 17.6 ± 0.9 mmHg) with biopsy-proven alcoholic cirrhosis and superimposed alcoholic hepatitis were either treated with standard medical therapy (SMT) combined with MARS (n = 6) or Prometheus (n = 6) or were treated with SMT alone (n = 6) on three consecutive days (6 hours/session). Liver tests, systemic haemodynamics and vasoactive substances were determined before and after each session.ResultsGroups were comparable for baseline haemodynamics and levels of vasoactive substances. Both MARS and Prometheus decreased serum bilirubin levels (P < 0.005 versus SMT), the Prometheus device being more effective than MARS (P = 0.002). Only MARS showed significant improvement in the mean arterial pressure (Δchange, +9 ± 2.4 mmHg versus -0.3 ± 2.4 mmHg with Prometheus and -5.2 ± 2.1 mmHg with SMT, P < 0.05) and in the systemic vascular resistance index (Δchange, +131.5 ± 46.2 dyne.s/cm5/m2 versus -92.8 ± 85.2 dyne.s/cm5/m2with Prometheus and -30.7 ± 32.5 dyne.s/cm5/m2 with SMT; P < 0.05), while the cardiac index and central filling remained constant. This circulatory improvement in the MARS group was paralleled by a decrease in plasma renin activity (P < 0.05), aldosterone (P < 0.03), norepinephrine (P < 0.05), vasopressin (P = 0.005) and nitrate/nitrite levels (P < 0.02).ConclusionThe MARS device, and not the Prometheus device, significantly attenuates the hyperdynamic circulation in acute-on-chronic liver failure, presumably by a difference in removal rate of certain vasoactive substances. These findings suggest conspicuous conceptual differences among the albumin dialysis devices.

Comparison of Premortem Clinical Diagnoses in Critically Ill Patients and Subsequent Autopsy Findings

Background ‘Acute-on-chronic liver failure’ (ACLF) is characterised in a more advanced stage by liver failure associated with multiple other end-organ failure. The global clinical characteristics of this entity remain, however, ill-defined. Objective To characterise and evaluate the clinicopathological features of patients with ACLF compared with patients with chronic decompensated cirrhosis (CHD) in a prospective, homogeneous cohort of patients with histologically proven alcoholic cirrhosis from 2002 to 2007. Results In total 250 patients were screened (ACLF (n=70, 28%) and CHD (n=180, 72%)). Alcoholic liver disease was observed in respectively 61/70 (87%) of patients with ACLF and 72/180 (40%) of patients with CHD. After exclusion of 31 patients, 102 patients were studied: 54 with ACLF (median age 51 years; Child–Pugh 12±2; in-hospital mortality 46% (25/54)) and 48 patients with CHD (median age 53 years; Child–Pugh 10±2; in-hospital mortality 10% (5/48)). In the patients with ACLF who survived the hospital stay, the difference in transplant-free survival compared with patients with CHD tended to attenuate with time. At admission the apparent infection of patient groups was comparable but during hospitalisation infection occurred more frequently in patients with ACLF (31/53 (58%)) than in those with CHD (12/47=26%) (p=0.007). Early signs of infection, positive systemic inflammatory response syndrome (SIRS) criteria at admission and ductular bilirubinostasis (p=0.04), were early features that predicted outcome in ACLF. Conclusion Patients with ACLF have a high short-term mortality but those who survived the acute exacerbation show a long-term outcome comparable to that of patients with CHD. Infection is the most common cause of mortality in these patients. Positive SIRS criteria and ductular bilirubinostasis are early markers of ACLF and might allow more rapid identification of high-risk patients.

Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis

OBJECTIVE To determine whether our practice of requesting an autopsy for patients who die in the medical intensive care unit (MICU) continues to be a valid approach to obtain clinically and educationally relevant findings. METHODS In this retrospective study conducted in an adult MICU population of a university hospital, the clinical diagnoses and postmortem major diagnoses of 100 patients who died in 1996 (autopsy rate of 93%) were compared. RESULTS Eighty-one percent of the clinical diagnoses were confirmed at autopsy. In 16%, autopsy findings revealed a major diagnosis that, if known before death, might have led to a change in therapy and prolonged survival (class I missed major diagnoses). The most frequent class I missed major diagnoses were fungal infection, cardiac tamponade, abdominal hemorrhage, and myocardial infarction. Another 10% of autopsies revealed a diagnosis that, if known before death, would probably not have led to a change in therapy (class II error). CONCLUSIONS Autopsy remains an important tool for education and quality control. In contrast with historical series of 1 to 2 decades ago, there is a clear shift in the type of class I missed major diagnoses toward opportunistic infections. Bedside-applicable techniques such as electrocardiography with supplemental posterior leads, echocardiography, and meticulous abdominal ultrasonography might improve the outcome in selected MICU patients.