Ludwig Kramer

Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients.

ObjectivesTo investigate pharmacokinetics and metabolism of sodium citrate in critically ill patients. To determine the risk of citrate accumulation in the setting of liver dysfunction (cirrhosis, hepatorenal syndrome). DesignProspective cohort study. SettingIntensive Care Unit, Department of Medicine IV, University Hospital Vienna. PatientsConsecutive critically ill cirrhotic (n = 16) and noncirrhotic patients (n = 16). InterventionsInfusion of sodium citrate (0.5 mmol·kg−1·hr−1) and calcium chloride (0.17 mmol·kg−1·hr−1) for 2 hrs. Analysis of serial arterial blood samples. Measurements and Main ResultsTotal body clearance of citrate was normal in noncirrhotic critically ill patients but significantly reduced in cirrhotic patients (710 vs. 340 mL/min, p = .008). Citrate peak concentrations and concentration over time were increased by 65% and 114% in cirrhotic patients (p < .001), respectively; volumes of distribution were similar. Net metabolic changes were quantitatively similar, with pH and plasma bicarbonate concentrations increasing more slowly in cirrhotic patients. No citrate-related side effects were noted. Citrate clearance could not be predicted by standard liver function tests and was not appreciably influenced by renal function and Acute Physiology and Chronic Health Evaluation II scores. ConclusionsThis first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.

Early prediction of individual outcome after cardiopulmonary resuscitation

Prediction of individual outcome after cardiopulmonary resuscitation is of major medical, ethical, and socioeconomic interest but uncertain. We studied the early predictive potency of evoked potential recording after cardiac arrest in 66 resuscitated patients who returned to spontaneous circulation but were unconscious and mechanically ventilated. Detailed long-latency and short-latency sensory evoked potentials were recorded and neurological evaluations were done 4-48 h after admission to intensive care. In all 17 patients with favourable outcome (cerebral performance categories 1 and 2) the cortical evoked potential N70 peak, a reliable measure of cortical function, was detected between 74 and 116 ms. In 49 patients with bad outcome (categories 4 and 5) the N70 peak was absent in 35 or found with a delay between 121 and 171 ms in 14 (p < 0.05 vs favourable outcome). Thus the predictive ability was 100% with cutoff of 118 ms. To confirm reproducibility and validity, repeated tracings, and linked-earlobe referenced techniques were done and gave similar results. Early recording of long-latency evoked potentials after cardiopulmonary resuscitation is highly predictive of outcome.

Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment

Objective: To compare the prognostic ability of sensory evoked potentials in cardiac arrest survivors with the outcome predicted by a panel of experienced emergency physicians based on detailed prehospital, clinical, and laboratory data. Design: Inception cohort study. Setting: Medical intensive care unit and department of emergency medicine at a university hospital. Patients: A total of 162 unconscious, mechanically ventilated patients who survived ≥24 hrs after resuscitation from cardiac arrest. Interventions: Recording of sensory evoked potentials and outcome prediction after review of detailed clinical and laboratory data by emergency physicians within 24 hrs after cardiac arrest. Measurements and Main Results: At 6 months, the outcome of 36 patients was classified as favorable and 126 patients were rated as poor. After review of prehospital data, emergency physicians predicted favorable vs. poor outcome with a sensitivity of 70% and a specificity of 65%. After additional assessment of data 1 hr after cardiac arrest, the sensitivity of emergency physician predictions increased to 80%, whereas the specificity decreased to 48%. Outcome prediction by emergency physicians was most accurate after obtaining detailed patient data 24 hrs after cardiac arrest (sensitivity, 81%; specificity, 58%). In 35 of 36 patients with favorable outcomes, the cortical evoked potential N70 peak was detected between 72 and 128 msec. Of 113 patients with an N70 peak latency > 130 msec or an absent N70 peak, all except one had a poor outcome. By using a cutoff of 130 msec, the N70 peak latency alone had a sensitivity of 94% and a specificity of 97%. The predictive accuracy of the N70 peak latency was significantly higher than the clinical assessment 24 hrs after cardiac arrest (91% vs. 76%, p = .0003). Conclusion: In unconscious cardiac arrest survivors, a recording of long‐latency sensory evoked potentials is more accurate in predicting individual outcome than an emergency physician review of clinical data.

Subclinical impairment of brain function in chronic hepatitis C infection.

BACKGROUND/AIMS Central nervous system abnormalities such as fatigue and depression occur more frequently in chronic hepatitis C virus (HCV) infection than in many other causes of chronic liver disease. The finding that fatigue is unrelated to activity of hepatitis or mode of infection could indicate an independent effect of HCV on brain function. This study tested the hypothesis of a subclinical cognitive dysfunction in HCV-infected patients. METHODS One-hundred untreated HCV-RNA positive biopsy-proven patients were investigated by P300 event-related potentials, a sensitive electrophysiologic test of cognitive processing. Health-related quality of life and fatigue were assessed using the SF-36 questionnaire and the Fatigue Impact Scale, respectively. RESULTS Cognitive brain function was subclinically impaired in the cohort of HCV-infected patients as indicated by significantly prolonged P300 latencies (P=0.01 for comparison to matched healthy subjects) and reduced P300 amplitudes (P<0.001, respectively). Seventeen of the 100 HCV-infected patients had P300 latencies outside the age-adjusted normal range. Abnormal P300 characteristics were not related to the degree of histologic or biochemical activity of hepatitis, severity of fatigue or mental health impairment. CONCLUSIONS This study demonstrates that patients with HCV infection showed a slight but significant neurocognitive impairment, possibly indicating a further extrahepatic manifestation of chronic hepatitis C.

Incidence and prognosis of early hepatic dysfunction in critically ill patients : A prospective multicenter study

Objective:In critically ill patients, hepatic dysfunction is regarded as a late organ failure associated with poor prognosis. We investigated the incidence and prognostic implications of early hepatic dysfunction (serum bilirubin >2 mg/dL within 48 hrs of admission). Design:Prospective, multicenter cohort study. Setting:Thirty-two medical, surgical, and mixed intensive care units. Patients:A total of 38,036 adult patients admitted consecutively over a period of 4 yrs. Interventions:None. Measurements and Main Results:Excluding patients with preexisting cirrhosis (n = 691; 1.8%) and acute or acute-on-chronic hepatic failure (n = 108, 0.3%), we identified 4,146 patients (10.9%) with early hepatic dysfunction. These patients had different baseline characteristics, longer median intensive care unit stays (5 vs. 3 days; p < .001) and increased hospital mortality (30.4% vs. 16.4%; p < .001). Hepatic dysfunction was also associated with higher observed-to-expected mortality ratios (1.02 vs. 0.91; p < .001). Multiple logistic regression analysis showed an independent mortality risk of hepatic dysfunction (odds ratio, 1.86; 95% confidence interval, 1.71–2.03; p < .001), which exceeded the impact of all other organ dysfunctions. A case-control study further confirmed these results: Patients with early hepatic dysfunction exhibited significantly increased raw and risk-adjusted mortality compared with control subjects. Conclusions:Our results provide strong evidence that early hepatic dysfunction, occurring in 11% of critically ill patients, presents a specific and independent risk factor for poor prognosis.

Impaired subcortical and cortical sensory evoked potential pathways in septic patients.

ObjectiveSensory evoked potential (SEP) peak latencies were recorded in order to evaluate the incidence and severity of septic encephalopathy, testing the hypothesis that the occurrence of septic encephalopathy is more frequent than generally assumed. DesignProspective cohort study. SettingMedical intensive care unit of a university hospital. PatientsSixty-eight critically ill patients were studied within 48 hrs after the development of severe sepsis (n = 41) or septic shock (n = 27). InterventionsNone. Measurements and Main ResultsSeptic encephalopathy was defined as prolongation of SEP peak latencies beyond the upper limit of the reference range of subcortical (N13–N20 interpeak latency) and cortical SEP pathways (N20–N70 interpeak latency), as well as asymmetry of peak latencies marked by the presence of subclinical cerebral focal signs. Subcortical SEP pathways were impaired in 34% and cortical SEP pathways in 84% of all patients. The prolongation of the cortical SEP pathway correlated with the Acute Physiology and Chronic Health Evaluation III score (r = 0.23;p < .0001). SEP peak latencies did not differ in patients with severe sepsis compared with those with septic shock. Subclinical cerebral focal signs were present in 24% of the subcortical SEP pathways and in 6% of the cortical SEP pathways. ConclusionsSeptic encephalopathy occurs more frequently than generally assumed, and its severity is associated with the severity of illness. The impairment of subcortical and cortical SEP pathways was not different between patients with severe sepsis and those with septic shock.

Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin

BACKGROUND/AIMS A low serum ceruloplasmin level is considered a diagnostic test for Wilsons disease. To examine whether it is useful to detect presymptomatic patients with Wilsons disease, serum ceruloplasmin was determined by radial immunodiffusion (normal: 20-60 mg/dl) in all patients (n = 2867) admitted for evaluation of a liver disease in 1993 and 1994. METHODS Patients with levels lower than 20 mg/dl were further evaluated by determination of serum copper concentration, urine copper excretion and ophthalmological examination. If possible, a liver biopsy was performed and the hepatic copper content was determined by flame atomic absorption spectroscopy. RESULTS Seventeen patients had serum ceruloplasmin levels < 20 mg/dl. One had asymptomatic Wilsons disease (no Kayser-Fleischer rings or neurological symptoms). In the other 16 patients Wilsons disease was excluded. Based on elevated hepatic copper concentration, there were considered as heterozygous carriers of the WD gene. The remaining patients had various liver diseases (acute viral hepatitis in three, chronic hepatitis in two, drug-induced liver disease in three, alcoholic induced liver disease in two) or malabsorption (n = 3). CONCLUSIONS The positive predictive value of low serum ceruloplasmin was only 5.9%. Although helpful for identifying presymptomatic Wilsons disease, screening by determination of serum ceruloplasmin in unselected patients with clinical or laboratory evidence of liver disease is neither feasible nor cost effective.

Cyclosporine May Affect Improvement of Cognitive Brain Function After Successful Cardiac Transplantation

BACKGROUND The effects of cardiac transplantation on cognitive brain function are uncertain. METHODS AND RESULTS We measured cognitive brain function and quality of life in out-of-hospital cardiac transplant candidates (n = 55; ejection fraction, 19.9%; age, 54.8 years [means]). After transplantation, the patients were serially reevaluated at 4 months (n = 25) and at 12 months (n = 19). Brain function was measured objectively by cognitive P300 evoked potentials. Additionally, standard psychometric tests (Trail Making Test A, Mini-Mental State Examination, and Profile of Mood State test) were performed. Cognitive P300 evoked potentials were impaired in cardiac transplant candidates (359 ms, recorded at vertex) compared with 55 age- and sex-matched healthy subjects (345 ms, P < .01). Trail Making Test A was also abnormal (45 versus 31 seconds in 55 healthy subjects, P < .01). After transplantation, P300 measures were normalized at 4 months (345 ms, P < .05 versus before transplantation) but declined again at 12 months (352 ms, P = NS versus before transplantation). Stepwise multiple regression analysis revealed that cumulative cyclosporine dosage was the only predictor of individual cognitive brain function 4 months (753 mg/kg body wt, P < .05) and 12 months (2006 mg/kg body wt, P < .01) after transplantation, respectively. CONCLUSIONS Objective cognitive P300 auditory evoked potential measurements indicate that cognitive brain function is significantly impaired in patients suffering from stable end-stage heart failure. Successful cardiac transplantation is effective to fully normalize impaired brain function. Subsequent relative long-term decline of cognitive brain function after successful cardiac transplantation is strongly suggested to be related to cumulative cyclosporine neurotoxicity.

Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus)

ZusammenfassungDas durch MDMA (Ecstasy) ausgelöste fulminante Leberversagen weist — insbesondere exzessive Mortalität auf. Die notfallmäßige Lebertransplantation ist die einzige etablierte Behandungsform. Wir berichten über einen jungen Patienten mit kombinierter Ecstasy/Kokain-Intoxikation mit akutem Leberversagen, Rhabdomyolyse, Septuminfarkt und Multiorganversagen. Die Lebertransplantation wurde aufgrund des rezenten intravenösen Drogenkonsums trotz Erfüllung der Transplantationskriterien abgelehnt. Infolge massiver Hyperammoniämie (318 μmol/l) und refraktärer zerebraler Herniation begannen wir eine kontinuierliche extrakorporale Behandlung mit dem FPSA-Prometheus System, welches adsorptive und dialytische Toxinentfernung kombiniert. Nach rascher Normalisierung des Ammoniakwertes kam es innerhalb von 4 Tagen zu Einsetzen von Leberregeneration und vollständiger Rückbildung des Hirnödems. Der Patient konnte das Krankenhaus nach Rehabilitation mit geringgradigen neurologischen Folgeerscheinungen verlassen. Effiziente extrakorporale Detoxifikation kann durch eine rasche Normalisierung von Hyperammoniämie und Hirnödem bei Ecstasy/Kokaininduziertem akutem Leberversagen eine therapeutische Option darstellen.SummaryEcstasy-induced fulminant hepatic failure is associated with high mortality. If complicated by cerebral oedema, orthotopic liver transplantation is the only established treatment. We report a case of combined ecstasy/cocaine-induced fulminant hepatic failure presenting with severe rhabdomyolysis, myocardial infarction and multiorgan failure. Transplantation was declined by the transplant surgeons because of a history of intravenous drug abuse. As excessive hyperammonaemia (318 μmol/l) and refractory transtentorial herniation developed, treatment with a new liver detoxification device combining high-flux haemodialysis and adsorption (FPSA-Prometheus) was initiated. Within a few hours of treatment, ammonia levels normalised. Cerebral oedema was greatly reduced by day 4 and hepatic function gradually recovered. Following neurologic rehabilitation for ischaemic sequelae of herniation, the patient was discharged from hospital with only minimal deficits. In conclusion efficient extracorporeal detoxification may be an option for reversal of hyperammonaemia and refractory cerebral oedema in ecstasy/cocaine-induced acute liver failure.

Energy Metabolism in Acute Hepatic Failure

BACKGROUND Conflicting data are available concerning energy metabolism in liver disease. Changes should be most pronounced in acute hepatic failure in which loss of 85% of liver cell mass is reported. Metabolic rate could be decreased due to impairment in liver mass but may also be increased as a result of systemic-mediator actions. To clarify this issue we studied energy metabolism in acute hepatic failure. METHODS Energy metabolism was evaluated by indirect calorimetry in 12 patients with acute liver failure and 22 sex-, age-, and body size-matched healthy individuals. In controls and 5 patients, studies were performed in the postabsorptive state; the remaining 7 patients received glucose at a rate of 8 mumol/kg body weight.min to prevent hypoglycemia. RESULTS Resting energy expenditure was increased in acute liver failure compared with healthy controls (5.1 +/- 0.14 kJ.min-1 x 1.73 m-2 vs. 3.97 +/- 0.08 kJ.min-1 x 1.73 m-2; mean +/- SEM; P < 0.001). Respiratory quotient and oxidation rates for major fuels were not different between the total patient-group and controls. In patients without glucose supply, energy derived from fat was higher and from carbohydrate lower than in healthy controls and patients with glucose supply. CONCLUSIONS Energy expenditure is increased in acute liver failure. Altered substrate oxidation can be normalized by glucose supply.