Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.

Treatment of advanced breast cancer with vinorelbine and docetaxel with or without human granulocyte colony-stimulating factor.

PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m(2) on days 1 and 15 and docetaxel 30 mg/m(2) on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 microg/kg/d was given. RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient. CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.

Similar metabolic responses to standardized total parenteral nutrition of septic and nonseptic critically ill patients.

BACKGROUND: Nutritional support is an important link between the response to injury and recovery in critical illness. OBJECTIVE: Our goal was to evaluate energy and substrate metabolism in septic and nonseptic critically ill patients in the resting state and during the administration of standardized total parenteral nutrition. DESIGN: This was a prospective, clinical cohort study of 25 consecutively admitted critically ill patients either with (n = 14) or without (n = 11) sepsis who received total parenteral nutrition. Resting energy expenditure was measured on days 0, 2, and 7 by indirect calorimetry. Energy and substrate balances were calculated on days 2 and 7. RESULTS: Resting energy expenditure was not significantly different between septic and nonseptic patients on day 0 (2.65 +/- 0.49 and 2.36 +/- 0.56 kJ x min(-1) x m(-2), respectively). Energy balances were positive for both groups on days 2 (0.68 +/- 0.4 and 0.74 +/- 0.6 kJ x min(-1) x m(-2), respectively; NS) and 7 (0.65 +/- 0.3 and 0.78 +/- 0.5 kJ x min(-1) x m(-2), respectively; NS). Substrate balances were not significantly different between groups on days 0, 2, and 7. Resting energy expenditure on day 0 was negatively correlated with the severity of illness in septic patients only (r = -0.58, P < 0.05). CONCLUSIONS: Metabolic changes were not significantly different between septic and nonseptic critically ill patients during the administration of standardized total parenteral nutrition. A disease-specific macronutrient composition of total parenteral nutrition formulas does not seem to be necessary in either septic or nonseptic critically ill patients.

Fat elimination in acute renal failure: long-chain vs medium-chain triglycerides.

Elimination and hydrolysis of fat emulsions containing long-chain (LCT; Intralipid) or long- and medium-chain triglycerides (MCT; Lipofundin MCT) were compared in seven patients with acute renal failure (ARF) and six healthy control subjects. In control subjects, clearance of MCT was slightly higher than that of LCT (1.93 +/- 0.34 vs 1.55 +/- 0.3 mL.kg body wt-1.min-1, P less than 0.05). The rise in plasma triglycerides was similar and the release of free fatty acids was higher during MCT (P less than 0.02). In ARF, clearance of both LCT and MCT was equally reduced (0.53 +/- 0.12 vs 0.59 +/- 0.14 mL.kg body wt-1.min-1, P less than 0.01 vs control subjects). Again, the rise in triglycerides was comparable. Free fatty acid release was higher during MCT but lower than in control subjects. Plasma concentrations of glucose and lactate were not affected in control subjects but increased during both LCT and MCT in ARF. Thus elimination of both LCT and MCT is profoundly decreased in ARF. The impaired lipolysis in ARF cannot be circumvented by the use of MCT.

Energy metabolism in acute and chronic renal failure.

Energy metabolism was measured by indirect calorimetry in 86 patients with various forms of renal failure and in 24 control subjects. In patients with acute renal failure with sepsis, oxygen consumption, carbon dioxide production, and resting energy expenditure were increased (P less than 0.05). In other groups with renal failure (acute renal failure without sepsis, chronic renal failure with conservative treatment or hemodialysis, and severe untreated azotemia) these indices were not different from those of control subjects. Urea nitrogen appearance was decreased in patients with chronic renal failure undergoing conservative treatment, in those with severe untreated azotemia, and in hemodialysis patients (P less than 0.05). We conclude that renal failure has no influence on energy expenditure as long as septicemia is absent. Reduced urea nitrogen appearance rates in chronic renal failure are due to a reduced energy and protein intake. Wasting is a consequence of decreased food intake but not of hypermetabolism in chronic renal failure.

Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine.

BACKGROUND: The effects of food restriction on energy metabolism have been under investigation for more than a century. Data obtained are conflicting and research has failed to provide conclusive results. OBJECTIVE: The objective of this study was to test the hypothesis that in lean subjects under normal living conditions, short-term starvation leads to an increase in serum concentrations of catecholamines and thus to an increase in resting energy expenditure. DESIGN: Resting energy expenditure, measured by indirect calorimetry, and hormone and substrate concentrations were measured in 11 healthy, lean subjects on days 1, 2, 3, and 4 of an 84-h starvation period. RESULTS: Resting energy expenditure increased significantly from 3.97 +/- 0.9 kJ/min on day 1 to 4.53 +/- 0.9 kJ/min on day 3 (P < 0.05). The increase in resting energy expenditure was associated with an increase in the norepinephrine concentration from 1716. +/- 574 pmol/L on day 1 to 3728 +/- 1636 pmol/L on day 4 (P < 0.05). Serum glucose decreased from 4.9 +/- 0.5 to 3.5 +/- 0.5 mmol/L (P < 0.05), whereas insulin did not change significantly. CONCLUSIONS: Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.

Prevention of upper gastrointestinal bleeding in long-term ventilated patients. Sucralfate versus ranitidine.

Thirty-two long-term ventilated patients were randomly selected for a study of the efficacy of sucralfate (1 g six times per day via gastric tube) versus ranitidine (six 50-mg to six 100-mg doses per day intravenously) for the prevention of upper gastrointestinal bleeding. The patients of the two treatment groups (each 16) were comparable with respect to diseases precipitating acute respiratory failure and risk factors of bleeding, e.g., renal failure, thrombopenia, coagulopathy, and anticoagulant treatment. Mean duration of mechanical ventilation was 7.4 in sucralfate- and 7.7 days in ranitidine-treated patients. During mechanical ventilation, macroscopically visible bleeding developed in three of the sucralfate-treated (18.7 percent) and seven of the ranitidine-treated (43.7 percent) patients. Until the end of the study, only three of the sucralfate-treated but nine of the ranitidine-treated (56.2 percent) patients bled; the difference between the two treatment groups was at all times significant (p less than 0.05). Packed red blood cells had to be administered to the three bleeding patients in the sucralfate group and to seven bleeding in the ranitidine group. Therefore it seems that sucralfate prevented mostly minor bleeding. The high bleeding rate during ranitidine treatment was presumably due to the high number of pH-nonresponders, as almost 30 percent of the gastric aspirates of this group had a pH less than 5. During treatment no difference was found in positive blood culture specimens and bronchial secretions between the two groups. However, nosocomial pneumonia developed in two ranitidine-treated patients, whereas that complication developed in none of the sucralfate-treated patients. In long-term ventilated patients, sucralfate prevented minor upper gastrointestinal bleeding significantly better than ranitidine. However, this does not imply that major upper gastrointestinal bleeding can be prevented by either sucralfate or ranitidine in these patients.

Energy and substrate metabolism in patients with chronic extensive graft-versus-host disease.

BACKGROUND: Allogeneic stem cell transplantation is frequently complicated by graft-versus-host disease (GVHD). Weight loss is one of the characteristic features of GVHD. The etiology of weight loss in GVHD is not completely understood. METHODS: We measured resting energy expenditure (REE) and substrate oxidation rates by indirect calorimetry in patients with stable chronic extensive GVHD under immunosuppressive therapy (n=13) and sex-, age-, height-, and weight-matched healthy controls (n=13) in order to evaluate metabolic changes in these patients. Measurements were done on day 518+/-261 after allogeneic stem cell transplantation in the postabsorptive state. Serum concentrations of glucagon, norepinephrine, tumor necrosis factor-alpha, interleukin-6, and free fatty acids were determined. RESULTS: Patients showed a maximum weight loss of 22% during their course of GVHD; nevertheless, they regained 15% of total body weight (TBW) during successful treatment of GVHD. Indirect calorimetry showed an increase in REE per kilogram of TBW (patients, 21.8+/-3.1 kcal/kg TBW/day; controls, 19.9+/-2 kcal/kg TBW/day; P<0.05). Respiratory quotient (patients, 0.79+/-0.04, controls, 0.86+/-0.04; P<0.005) and non-protein respiratory quotient (0.78+/-0.05 and 0.87+/-0.05, respectively; P<0.005) were decreased in patients. GVHD patients had elevated serum glucagon and norepinephrine concentrations, whereas tumor necrosis factor-alpha and interleukin-6 were in the normal range. CONCLUSIONS: Patients with chronic extensive GVHD show an increase in REE and alterations in fat and carbohydrate oxidation rates. These changes seem to be the result of increased action of glucagon and norepinephrine.

Fatal encephalitis in a patient with chronic graft-versus-host disease.

A 32-year-old male patient with chronic myelocytic leukemia in accelerated phase received a bone marrow allograft from his 42-year-old HLA/MLC-identical sister. He recovered from acute graft-versus-host disease (GVHD) grade III-IV of skin, liver and gut, but chronic GVHD of progressive onset developed. On day 556 post-graft severe thrombocytopenia was resistant to prednisolone, cyclophosphamide and high dose immunoglobulin. Splenectomy was followed by a normalization of platelet counts. The subsequent clinical course was characterized by progressive muscular atrophy and weight loss. Dysphagia, dysarthria, cachexia and ultimately recurrent pneumonic episodes ensued. The cachectic patient developed a highly abnormal breathing pattern with hypoventilation and intermittent apnea requiring mechanical ventilation. Auditory evoked potentials revealed a considerable dysfunction of the brainstem. The patient died on day 1120 post-graft from pneumonia, aggravated by thoracic muscular insufficiency. Postmortem examination revealed diffuse predominantly lymphoid perivascular infiltration in meninges and CNS tissue; proliferation of activated microglial cells expressing the HLA-DR antigen was prominent in the brainstem. These histologic changes are similar to those observed in the CNS in experimental GVHD. We suggest that this case represents the first documentation of CNS involvement in chronic GVHD.

Diagnosis of gallbladder perforation in acute acalculous cholecystitis in critically ill patients.

In the presence of ascites ultrasound is not appropriate to distinguish between gallbladder perforation and acute acalculous cholecystitis. However, the correct and early diagnosis of gallbladder perforation is important for the treatment and prognosis. We report 4 critically ill patients with ascites. All patients had evidence of gallbladder perforation by ultrasound and underwent cholecystectomy: 2 patients had gallbladder perforation, but 2 had acalculous cholecystitis without perforation. Markedly elevated serum alkaline phosphatase was the only discriminating finding indicating gallbladder perforation.

Influence of fluid replacement on extravascular lung water (EVLW) in patients with diabetic ketoacidosis.

Fluid replacement is a major issue in the treatment of patients with diabetic ketoacidosis. During this therapy, development of pulmonary edema has been reported and attributed to an increase in pulmonary microvascular pressure and a decrease in colloid-osmotic pressure (COP). Because clinically apparent pulmonary edema is associated with an increase in extravascular lung water (EVLW) and impairment of pulmonary gas exchange, we studied the effect of fluid replacement on EVLW, COP, pulmonary hemodynamics and gas exchange parameters in 8 patients with diabetic ketoacidosis (blood glucose greater than 300 mg/dl, pH less than 7.1). EVLW was estimated by the thermal-dye technique. All variables were successively determined upon admission (A), after initial fluid replacement (IFR), when glucose had fallen below 180 mg/dl, after 8 h of intravenous glucose treatment (G), and after 24 h of total parenteral nutrition (TPN). Despite a total net fluid intake of 6.0 +/- 1.61, a significant decrease (p less than 0.001) in COP from 29.6 +/- 5.5 at A to 18.8 +/- 2.2 mmHg after TPE and a significant increase (p less than 0.001) in PCWP from 4 +/- 2 at A to 10 +/- 3 mmHg after TPE, EVLW remained almost unchanged. EVLW was 5.1 +/- 2.8 at A, 5.3 +/- 2.1 after IFR, 4.8 +/- 1.4 after G, and 5.3 +/- 1.7 ml/kg after TPN. However, PaO2 decreased from 137 +/- 17 at A to 87 +/- 10 mmHg after TPE (p less than 0.001), while Qs/Qt increased significantly (p less than 0.05). The alterations in gas exchange may be indicative of pulmonary dysfunction but as they were not associated with accumulation of EVLW, they may as well reflect the compensation of metabolic derangements in diabetic ketoacidosis.

Evoked potentials in severe herpes simplex encephalitis.

Diagnostic and prognostic value of evoked potentials (EP) were studied in 5 patients with severe herpes simplex encephalitis (HSE). Latency of the third negative cortical N70 peak, elicited by median nerve stimulation, was prolonged in 3 survivors with Glasgow coma score of less than or equal to 6 (115 vs 71 ms in controls, p less than 0.05), but normal after improvement of the acute disease. N70 right to left interhemisphere difference was increased initially in the 4 survivors (26 vs 3 ms in controls, p less than 0.05) indicating focal brain involvement, a crucial finding in HSE. The first cortical N20 peak was preserved in all survivors even during deep coma where evaluation of brain function is difficult. Auditory brainstem EP were normal in all patients and useful to exclude brainstem death. In severe HSE, somatosensory long-latency EP are an effective monitor of the level of impaired consciousness and can detect brain focal signs. Short-latency N20 components may be predictive of the outcome.

Outcome prediction for patients with cirrhosis of the liver in a medical ICU: a comparison of the APACHE scores and liver-specific scoringsystems.

OBJECTIVE: To find the most adequate prognostic scoring system for predicting ICU-outcome in patients with decompensated liver cirrhosis in a medical intensive care unit (ICU). DESIGN: Retrospective analysis of patients' records over a 10-year period. SETTING: A medical ICU at the university medical center of Vienna. PATIENTS AND PARTICIPANTS: 94% (n = 198) of all patients with cirrhosis admitted to our medical ICU throughout the 10-year study period. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: From data obtained at admission and at 48 h after admission, scores were calculated using the following scoring systems: Acute Physiology and Chronic Health Evaluation (APACHE) II and III, Scale for Composite Clinical and Laboratory Index Scoring (CCLI), Mayo Risk Score, and Child's Classification. Statistical analysis for the prognostic variables was performed using the chi-square test, t-test, Youden index, and area under a receiver operating characteristic (ROC) curve. APACHE III was found to be the most reliable outcome predictor at admission and after 48 h for patients with decompensated liver cirrhosis (AUC = 0.75 and 0.8, respectively). CONCLUSIONS: To predict the outcome for patients with decompensated cirrhosis of the liver admitted to a medical ICU liver failure alone is not decisive. Liver-specific scoring systems (Mayo Risk Score, CCLI) are adequate, but the APACHE II and III proved to be more powerful, because they include additional physiologic parameters and therefore also take into account additional complications associated with this liver disorder.

Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.

To determine the therapeutic effect of the carinitine palmitoyltransferase I (CPT-I) inhibitor, etomoxir, eight hospitalized obese non-insulin-dependent diabetes mellitus (NIDDM) patients were studied (body mass index [BMI], 28.7 +/- 1.3 kg/m2; age, 54 +/- 8 years [means +/- SE]) at baseline (placebo = t1), and after oral etomoxir (50 mg/d = t2, 100 mg = 3, 150 mg = t4, 200 mg = t5, placebo = t6). Fasting blood glucose (mmol/L), triglycerides (mmol/L), cholesterol (mmol/L), free fatty acids (mumol/L), beta-hydroxybutyrate (mumol/L), and alanine aminotransferase (GPT, U/L) were determined (t1 to t6), as were glucose utilization (M value; indirect calorimetry) and hepatic glucose production during a 10 mU/kg.min euglycemic clamp (t1 and t4). A dose-dependent decrease was induced by etomoxir in fasting blood glucose (t1 to t5: 9.5 +/- 0.7, 8.7 +/- 1.0, 8.3 +/- 1.1 [P v t1 less than .05], 7.8 +/- 0.9, [P v t1 less than .01], 7.9 +/- 1.1 [P v t1 less than .05]), which was reversible in t6 (9.9 +/- 1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (-54%, P v t1 less than .01), cholesterol (-24%, P v t1 less than .05), and beta-hydroxybutyrate (-44%, P v t2 less than .01), while free fatty acids increased by 52% (P v t1 less than .05), as did GPT (t1: 17 +/- 3; t5: 32 +/- 7 U/L [P v t1 less than .01]).(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term energy balance in patients with infections: carbohydrate-based versus fat-based diets.

The effects of a carbohydrate-based diet (50% carbohydrate calories, 30% fat calories, 20% protein calories) versus a fat-based diet (28% carbohydrate calories, 55% fat calories, 17% protein calories) on oxidation rates of carbohydrate, fat, and protein were assessed in 12 patients with infections by indirect calorimetry and estimation of urea nitrogen production rate. The diets were given continuously for 18 hours in a randomized cross-over study on 2 consecutive days. Energy supply (kcal/d) was adjusted individually to meet the energy expenditure measured on the preceding day after an overnight fast and was 1,647 +/- 129 (SEM) for the carbohydrate-based diet and 1,655 +/- 131 for the fat-based diet. Oxidation rates (kcal/d) for carbohydrate (carbohydrate-based diet, 525 +/- 70; fat-based diet, 363 +/- 84) were different between the diets (P less than .05), whereas no difference could be found for fat (carbohydrate-based diet, 820 +/- 117; fat-based diet, 968 +/- 136) and protein (carbohydrate-based diet, 252 +/- 29; fat-based diet, 236 +/- 23). However, during carbohydrate-based feeding, carbohydrate balance (288 +/- 93 kcal/d) and fat balance (-327 +/- 107 kcal/d) were significantly different from zero (P less than .05), indicating continuous oxidation of endogenous fat and storage of administered glucose. During the fat-based diet, carbohydrate and fat balances were not different from zero. A correlation between energy and substrate balances was not seen during either diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of oxygen-consumption by use of reverse Fick-principle and indirect calorimetry in critically ill patients.

Oxygen consumption was measured simultaneously by the reverse Fick-principle (V02FICK) and by indirect calorimetry ("Metabolic Measurement Cart Horizon") (V02MMC) in 31 critically ill patients; 24 men and 7 women. Seventeen patients were breathing spontaneously, 14 patients were on mechanical ventilation. The fractional inspiratory oxygen concentration (FI02) in ventilated patients ranged from 0.21 to 0.4 (mean 0.302). Total oxygen consumption as measured by indirect calorimetry was 286.7 +/- 59.7 ml/min (mean +/- SD), and measured by reverse Fick-principle 258.9 +/- 52.2 ml/min (mean +/- SD). The coefficient of correlation between the two methods was r = 0.873. The absolute difference of oxygen consumption between reverse Fick-method and indirect calorimetry was 11.3%. Regression analysis according to Theil revealed a similar regression between spontaneously breathing and mechanically ventilated patients for the studied FI02 values below 0.4. It is concluded that indirect calorimetry is a reliable method for measuring oxygen consumption in spontaneously breathing as well as mechanically ventilated critically ill patients.

Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system.

OBJECTIVE: The mortality of patients with liver cirrhosis admitted to an intensive care unit (ICU) has been found to be high. This study was performed to assess the physiological and laboratory parameters which are able to identify on ICU admission the cirrhotic patients who are most likely to die. DESIGN: Prospective clinical trial. METHODS: Two groups of patients were analysed. Group A consisted of 196 consecutive cirrhotic patients admitted to our medical ICU for various reasons. For the detection of independent outcome predictors, we used a multiple logistic regression model. Based on these variables, the 'intensive care cirrhosis outcome (ICCO) score' was calculated. The ability to discriminate between survivors and non-survivors was determined by receiver operating characteristic curves, and the area under the curve was calculated. Group B consisted of 70 consecutive cirrhotic patients for prospective validation of the ICCO score. RESULTS: Applying multiple logistic regression analysis, bilirubin, cholesterol, creatinine clearance and lactate were found to be independently associated with the hospital mortality. The ICCO score was 0.3707 + (0.0773 x bilirubin (mg/dl)) - (0.00849 x cholesterol (mg/dl)) -(0.0155 x creatinine clearance (ml/min)) + (0.1351 x lactate (mmol/l)), giving an area under a receiver operating characteristic curve of 0.9. Increasing score values were associated with an increase in mortality. All patients with an ICCO score > +2.6 died. CONCLUSIONS: Application of the ICCO score is rapid and available at the patient's bedside, and its application is simple and reproducible. In cirrhotic patients, the ICCO score has a high ability to discriminate between survivors and non-survivors. The ICCO score may facilitate estimation on ICU admission of the prognosis of critically ill cirrhotic patients.

Treatment of Candida albicans fungaemia with fluconazole.

Sixty-five patients with Candida albicans fungaemia, admitted to intensive care units, were treated intravenously with fluconazole. All patients had at least one blood culture which was positive for C. albicans. The first group of 34 consecutive patients received fluconazole at a dose of 5 mg/kg bodyweight/day and the subsequent 31 patients received 10 mg/kg/day. Thirty patients in each group were evaluated. The clinical response rate was 60% in the 5 mg/kg once daily group and 83% in the group which received 10 mg/kg/day. Eradication of C. albicans from the blood was achieved in all but two patients in the 5 mg/kg group and in all patients in the 10 mg/kg group. As regards other sites of infection, eradication was achieved in only nine of 25 cases from the 5 mg/kg group and in 11 of 23 cases from the 10 mg/kg group. Death related to fungal infection occurred in eight patients receiving 5 mg/kg/day and in one patient receiving 10 mg/kg/day. Fluconazole was reasonably well tolerated. Raised concentrations of liver enzymes were observed in 14 patients. Other adverse effects were fatigue, nausea, gastric pain, sleepiness and epileptic seizure. In conclusion, fluconazole at a dose of 10 mg/kg/day would seem to be an effective and safe drug for the management of C. albicans fungaemia.

Acute renal failure in the elderly 1975-1990.

Two hundred and forty-two elderly patients (> 65 years) with acute renal failure (ARF) treated at a predominantly medical intensive care unit between 1975 and 1990 were retrospectively analyzed for underlying diseases, severity of disease (as evaluated by the rate of ventilated patients, septicemia and APACHE II score, respectively), causes of ARF, acute and chronic risk factors for the development of ARF, complications during treatment and outcome. Overall mortality was 61%; 28 patients (12%) died in spite of resolution of ARF so actually, 49% of the patients died in ARF. Outcome was comparable to other age groups with overall mortality being 57% in patients < 18 years and 59% in those 19-65 years. Moreover, within the group of elderlies mortality did not increase with age and was 60% in those aged 65-68 and 54% in those aged > 80 years, respectively. The need for renal replacement therapy, plasma creatinine > 6 mg/dl, anuria, BUN > 120 mg/dl, ventilator dependency and the presence of septicemia all negatively affected outcome. During the years 1975 to 1990 mortality decreased from > 70% to < 50% (p < 0.02). This improvement of survival was seen in spite of an increase in the severity of disease (1975-1982: 20% ventilated patients, 24% with septicemia, 1983-1990 51% and 40%, respectively, p < 0.01). We conclude that age per se is not an important determinant of survival in patients with ARF and that prognosis has improved considerably during the last 15 years and this was seen in spite of an increase in the severity of disease. It is not justified to withhold therapy in elderly patients acquiring ARF.

[Clinical experiences with high-dose methotrexate]. / Klinische Erfahrungen mit hochdosiertem Methotrexat.

40 patients with various forms of malignant disease, who had already been subjected to conventional regimens of treatment, were treated between 1976 and 1981 at the Department of Chemotherapy, Vienna University, with high-dose methotrexate (MTX) as sole therapeutic agent. 18 patients received MTX in moderately high doses of 250 mg/m2 to 750 mg/m2 at 10-day intervals. 19 patients were treated with high doses of 5 to 15 g MTX at 10-day intervals. In 2 cases of severe malignant non-Hodgkin's lymphoma one patient received 2 X 1 g MTX with an interval of 19 days between doses and the other received a single dose of 5 g MTX by infusion. One patient with alveolar soft part cell sarcoma was given ultra-high therapy, with a cumulative dose of 205 g. None of the patients in the group given moderately high-dose MTX therapy, whereas three in the high-dose group had an objective remission. Objective remission was obtained neither in the two lymphoma patients nor in the ultra-high-dose treated case. Complications such as leucopenia and/or thrombopenia were found in 9%, reversible transaminase activity increases in 45%, as well as a decrease in creatinine clearance in 10% of the cases. Irreversible severe kidney insufficiency was found in none of the cases. One patient with lymphoma died as a result of severe toxic epidermiolysis with involvement of the gastrointestinal mucosa, whilst the other suffered from pulmonary complications in the form of the respiratory distress syndrome. On the basis of our experience the use of high-dose MTX therapy as an alternative method following trials of all conventional regimens is not recommended.