OBJECTIVE:Creatine kinase and myoglobin are markers of muscular damage in rhabdomyolysis. Whereas myoglobin is considered to be the principal compound causing tubular damage, serum creatine kinase level is presently guiding therapeutic interventions in clinical practice to prevent acute renal failure. Because differences in elimination kinetics of these two compounds may influence therapeutic decisions, we studied elimination kinetics of myoglobin and creatine kinase in patients with rhabdomyolysis. DESIGN:Open, noncomparative study. SETTING:Intensive and intermediary care units in a university hospital. PATIENTS:A total of 13 consecutive patients with rhabdomyolysis whose baseline serum creatine kinase exceeded 5000 IU/L. Ten of 13 patients were treated with forced alkaline diuresis, and none were dialyzed. RESULTS:Myoglobin had faster elimination kinetics than creatine kinase (p <.01), and the average times to reach the 50% level of initial values were 12 hrs for myoglobin and 42 hrs for creatine kinase. Elimination of myoglobin was not affected by glomerular filtration rate. Compared with creatinine clearance (mean, 102 mL/min), myoglobin clearance was low (mean, 3 mL/min), both in patients with preserved renal function (n = 11) and in those with acute renal failure (n = 2). CONCLUSION:Serum myoglobin has faster elimination kinetics than creatine kinase in patients treated with forced alkaline diuresis for rhabdomyolysis. Considering the etiologic role of myoglobin, our data suggest that serum myoglobin level, rather than that of creatine kinase, should be used to guide therapy in patients with rhabdomyolysis.

The elimination of the piperacillin/tazobactam combination was studied in six patients with acute renal failure undergoing either continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 h. Piperacillin 4 g/tazobactam 0.5 g was given iv on three successive treatment periods and their concentrations in plasma, ultrafiltrate/dialysate and urine were determined for 12 h after each dose. The elimination half-life of piperacillin during CVVH (7.7 +/- 2.3 h; mean +/- s.d.) was significantly longer than during CVVHDF 1 L/h (6.7 +/- 1.9 h) or 2 L/h (6.1 +/- 2.0 h) (P < 0.05). Corresponding values for tazobactam were 13.9 +/- 3.9, 11.6 +/- 3.3 and 9.4 +/- 2.4 h, respectively (P < 0.05). Total piperacillin clearance during CVVH (3.89 +/- 1.23 L/h) was significantly lower than during CVVHDF 1 L/h (5.06 +/- 1.68 L/h) or 2 L/h (5.48 +/- 2.11 L/h) (P < 0.05). The corresponding tazobactam clearance values were 2.42 +/- 0.75, 3.13 +/- 0.66 and 3.75 +/- 1.43 L/h, respectively. The mean 12 h elimination of piperacillin and tazobactam in ultrafiltrate/dialysate was 29% and 37% during CVVH, 42% and 57% during CVVHDF (1 L/h), and 46% and 69% during CVVHDF (2 L/h). We recommend 8 hourly dosing of patients with renal failure on CVVH or CVVHDF with dialysis flow rates of 1 or 2 L/h treated with piperacillin 4 g/tazobactam 0.5 g.

The aim of this study was to assess the reliability of patient history in the identification of the drugs taken by patients who have an acute drug overdose. To this end, a prospective study involving 51 cases of acute, deliberate drug poisoning was carried out (patients with ethanol as the only apparent cause of intoxication were excluded). Information based on interviews with the patients and their companions or on circumstantial evidence (e.g., drug containers found) was compared with the results from drug analyses of various body fluids. The information obtained on admission was completely in accordance with the laboratory findings in only 27% of the cases. Minor discrepancies between the history and the results from drug analyses concerning the identity of the drugs taken were found in 55% of the cases. In 18% of the cases, the discrepancies were considered clinically important. Serious symptoms occurred in approximately 20% of the patients, but none of them were the result of incorrect information obtained on admission. All the patients survived. These results support the prevailing view that rapid identification of the drugs taken in overdose by means of comprehensive drug screens would have little effect on the treatment of most cases of acute poisoning. However, such assays would enable optimal treatment of many cases of acute poisoning by reducing the need for supervision and costly treatments and facilitating the identification of cases that would require prompt drug-specific treatment.

Meropenem elimination was studied in six patients with acute renal failure on continuous venovenous haemofiltration (CVVH) or continuous veno-venous haemodiafiltration (CVVHDF) 1 L/h and 2 L/h for 12 h. Meropenem 1 g was given iv over three dialysis periods, and plasma, ultrafiltrate/dialysate and urine concentrations of meropenem were determined. The half-life of meropenem was significantly longer (P < 0.05) during CVVH (7.5 +/- 2.0 h; mean +/- S.D.) than during CVVHDF 1 L/h (5.6 +/- 1.4 h) or 2 L/h (4.8 +/- 1.2 h). Meropenem clearance was 3.27 +/- 2.30 L/h, 4.72 +/- 2.69 L/h and 5.71 +/- 3.58 L/h in CVVH, CVVHDF 1 L/h and CVVHDF 2 L/h, respectively (P< 0.05 between CVVH and CVVHDF). Patients with renal failure on CVVHDF 1 or 2 L/h should be treated with meropenem 1 g bid; 500 mg tid may be enough for patients on CVVH.

Background and objectives: The optimal mode of treatment in spontaneous supratentorial intracerebral hemorrhage (SICH) is controversial.We assessed the value of hematoma evacuation in SICH in a case-control study.Methods: One hundred and forty-five patients with SICH without tumor or vascular abnormalities.Indication for surgery were made upon admission in 11 and after clinical deterioration in 13 patients.Assessed were age, sex.Glasgow Coma Scale (GCS), pupillary reaction on admission, localisation, etiology and hematoma volume, presence of ventricular blood, and Glasgow Outcome Scale on discharge.From further analysis patients > 80 years or with hematoma volume < 10 ml were excluded.Statistical analysis included: (i) a multiple regression model to determine prognostic factors; (ii) comparison between medical and surgical patients; (iii) matching the 24 evacuated with 24 medical patients according to those parameters retained from the regression model and additionally to other suspected factors influencing outcome; (iv) comparison between both groups to confirm comparability; and (v) testing for different outcome between the groups.Results: Prognostic factors were GCS, hematoma volume and location.All 24 evacuated patients could be matched to a medically treated patient regarding age, hematoma volume and location.GCS and pupillary reaction.Differences between both groups could not be detected.Outcome was not different between the medical and surgical group.Conclusions: Hematoma evacuation does not improve outcome in supratentorial spontaneous hemorrhages.Since mainly deteriorating patients were evacuated, the only effect of hematoma evacuation may be to stop deterioration rather than to improve overall outcome.

Several cases of poisoning with diltiazem have been described in the literature, but information about the pharmacokinetics of diltiazem in overdose is sparse. The authors report pharmacokinetic and clinical observations in a patient who ingested 7.2 g of slow-release dilitiazem. Grave, persistent hypotension was the overriding clinical manifestation, but the patient eventually survived with aggressive cardiovascular support. No serious conduction abnormalities were seen. Blood samples were taken repeatedly for 2-3 days for analysis of serum diltiazem and desacetyldiltiazem and desacetyldiltiazem concentrations. The serum diltiazem concentration measured in the first sample taken (16.5 h postingestion), 3,171 ng/ml, is one of the highest concentrations reported in a patient who survived. The half-life was 13.3 h for diltiazem and 10.5 h for desacetyldiltiazem. Charcoal hemoperfusion had no apparent effect on the elimination of either compound. The relatively long half-life of diltiazem may have resulted from rate-limiting absorption and probably does not indicate saturation of diltiazem metabolism. The patient was discharged with no apparent neurological or cardiological deficits.

The elimination of fluconazole was studied in six patients with acute renal failure undergoing continuous venovenous haemofiltration (CVVH) for 24 h, continuous venovenous haemodiafiltration (CVVHD) 1 L/h for 24 h and CVVHD 2 L/h for 24 h. Fluconazole 200 mg once daily was given intravenously on three successive days and the concentrations of fluconazole in serum, ultrafiltrate/dialysate and urine were determined for 24 h after each dose. The half-life of fluconazole in patients during CVVH (83.5 +/- 30.1 h; mean +/- S.D.) was significantly (P < 0.05) longer than that during CVVHD 1 L/h (30.4 +/- 5.0 h) or CVVHD 2 L/h (21.8 +/- 3.5 h). The total fluconazole clearance was 0.57 +/- 0.16 L/h, 1.50 +/- 0.24 L/h and 1.85 +/- 0.17 L/h in CVVH, CVVHD 1 L/h and CVVHD 2 L/h, respectively, and there was a significant difference (P < 0.05) between all these treatments. Daily renal excretion of fluconazole was minimal, ranging from 0.002 mg to 11.2 mg in different patients with different treatment modes. The methods tested increased the elimination of the unchanged drug 20- to 400-fold in patients with acute renal failure. Patients undergoing CVVHD therapy with a dialysis flow rates of 1 or 2 L/h should be treated with a daily dose of at least 200 mg of fluconazole to maintain therapeutic drug concentrations. However, in patients on CVVH therapy smaller doses of fluconazole may be enough.

Experimental evidence suggests that in addition to hypertension, serum lipids might also accelerate the decline in renal function. We tested this hypothesis in 2702 dyslipidemic middle-aged men without renal disease participating in the Helsinki Heart Study, a coronary primary prevention trial. The decline in renal function was estimated from linear regression slopes based on reciprocals of 10 serum creatinine determinations over the study period. Renal function deteriorated 3% on average during the 5-year study, and hypertension accelerated this change. Subjects with an elevated ratio of low- to high-density lipoprotein cholesterol ( > 4.4) had a 20% faster decline than those with a ratio less than 3.2. Both the contribution of the lipoprotein ratio and the protective effect of high-density lipoprotein cholesterol alone remained significant in multiple regression analyses. In the study of joint effects the contribution of lipids was confined to subjects with simultaneous elevation of blood pressure and lipids. The results suggest that in addition to hypertension, blood lipids also modify the decline in renal function.

Scintigraphy with indium-111 labelled antimyosin has an established role in the evaluation of cardiac muscle damage. This antibody has been shown to cross-react with myosin in skeletal muscle. We therefore studied the usefulness of this method for the detection of skeletal muscle lesions in rhabdomyolysis, myositis and hereditary muscular dystrophies. All nine patients with rhabdomyolysis had focal uptake of antimyosin antibody which correlated with the clinical findings of soft tissue damage. However, a number of symptomless lesions were also detected by immunoscintigraphy. In rhabdomyolysis the target to non-target uptake ratios varied from 1.3 to 7.6. Diffuse uptake of antibody in skeletal muscle was observed in all three patients with polymyositis-dermatomyositis and in 12 out of 13 patients with muscular dystrophies. In myositis the intensity of antibody accumulation correlated reasonably well with the magnitude of oedema detected by magnetic resonance imaging (MRI). Most patients with Becker type or non-X-chromosomal muscular dystrophies showed slight or moderate uptake of antibody, mainly in the lower extremities. In these patients more antibody accumulated in the calves than in the thighs, whereas the findings on MRI were more prominent in the thighs than in the calves, presumably because of the better preserved muscle bulk in the calves. We conclude that antimyosin scintigraphy can be used for the detection of muscle lesions not only in acquired muscle diseases but also in hereditary muscular disorders, and that immunoscintigraphy provides information on muscle disease activity not obtainable with MRI.

The study consisted of 89 consecutive patients (mean age = 41.5, range = 16-82, 64 men, 25 women) referred for renal biopsy because of clinical suspicion of renal parenchymal disease. Neither transplant kidneys nor tumour evaluation were included. A biopsy "gun" (Biopty) and 14 (2.0 mm) and 18 (1.2 mm) gauge needles were used with ultrasound guidance. Sixtyseven renal biopsies were guided using a freehand technique 42 using a fixed angle guide attachment. The mean glomerular yield was 9.4 glomeruli. Almost 25% of the 18 gauge needle biopsies (n = 57) had to be repeated and 29.3% of the 14 gauge needle biopsies (n = 75). The yield difference was not statistically significant (Chi-squared = 0.37, p = 0.54). There was no statistically significant difference between the distributions of failure to obtain a significant material for evaluation caused by the biopsy technique used (Chi-squared = 0.08, p = 0.78). When analysing cases of single successful pass the thinner needle produced 6.7 glomeruli (n = 36, SD = 5.08) and the thicker needle 13.8 glomeruli (n = 18, SD = 6.82). No serious complications occurred.

In countries where malaria is not endemic the diagnosis of the disease is often delayed or overlooked, particularly if the clinical symptoms are atypical and if automated cell analyzers are used instead of blood films for leucocyte differential counts. We report 2 cases of severe Plasmodium falciparum malaria with unusual clinical features: a 46-year-old man with an exceptionally long incubation period and a 22-year-old woman with presenting symptoms suggesting viral hepatitis. In both cases the diagnosis of malaria was unexpectedly made by observant laboratory technicians examining stained blood films for differential counts.

The serum protein binding of phenytoin, diazepam and propranolol was investigated in vitro in 32 elderly people with an age-related decrease in renal function by a pressure ultrafiltration method at 37 degrees C. The mean age of the patients was 88 +/- 1 years (mean +/- SE), and their mean 51Cr-EDTA clearance 46 +/- 4 ml/min. The main reason for hospitalization of these patients was their age. The free fraction of phenytoin correlated negatively with the serum albumin concentration, and that of propranolol with the alpha 1-acid glycoprotein (alpha 1-AGP) concentration. The free fraction of diazepam did not correlate with either of these binding proteins. In stepwise multiple regression analysis, the most significant variable for phenytoin free fraction was serum albumin concentration, with the serum urea concentration coming in second place. For the diazepam free fraction, the only significant variable was the serum urea level, although in the correlation matrix the correlation with creatinine was also significant. When the effect of serum albumin level was corrected mathematically, the urea level was the best determinant in regression analysis for both the phenytoin and diazepam free fractions. It can be concluded that an age-dependent decrease in renal function increases the free fraction of phenytoin and diazepam and is, together with hypoalbuminaemia, responsible for the increased free fraction of these drugs in the elderly. For propranolol the only important factor is the serum alpha 1-acid glycoprotein concentration.

The effect of acute renal disease on the serum free fraction of phenytoin, diazepam and propranolol was examined in vitro among 37 patients with acute renal insufficiency of varying etiology and 10 healthy control subjects, men and women equally. The free fractions were separated at 37 degrees C using a pressure ultrafiltration method. The free fraction of phenytoin varied from about 14% to 45% and that of diazepam from 2% to 10%. The free fraction did not correlate significantly with either the serum urea or creatinine concentrations or the creatinine clearance within the acutely uremic group. The free fractions of propranolol varied considerably in the uremic patients but did not correlate significantly with the above parameters either. The mean free fractions of propranolol in the acutely uremics (11.9 +/- 1.0%, mean +/- SE) and controls (8.9 +/- 0.5%) did not differ significantly. The free fractions of both phenytoin and diazepam had a significant inverse correlation with the serum albumin level and that of propranolol with the alpha 1-acid glycoprotein (alpha, AGP) level. The correlations were similar irrespective of the etiology of renal failure. In practice, the variable best predicting the phenytoin and diazepam free fractions in acute renal insufficiency is the serum albumin concentration, and for propranolol the serum alpha 1-AGP concentration.

The effect of chronic renal disease on the serum free fraction of phenytoin, diazepam and propranolol was examined in vitro among 60 conservatively treated patients with renal insufficiency of varying degree and different etiology, and in 10 patients with a nephrotic syndrome. The control group comprised 10 age and sex-matched healthy subjects. The free fractions were separated at 37 degrees C using a pressure ultrafiltration method. The highest free fractions of phenytoin and diazepam in uremic patients were 4 to 5-fold the normal. The free fractions were about twice the normal at a creatinine concentration of 800 mumol/l, and 2 to 4-fold at an urea concentration of 20-40 mmol/l. The creatinine and urea correlated with the free fractions of phenytoin and diazepam in a similar manner. The effect of a decreased serum albumin on the free fractions of these drugs was clear when its concentration was under 30 g/l. The creatinine and urea did not correlate with the free fraction of propranolol. However, after mathematically correcting the free fraction of propranolol to correspond to an alpha 1-acid glycoprotein (alpha 1-AGP) concentration of 0.9 g/l, it correlated significantly with creatinine and urea. The concentration of alpha 1-AGP was the most important determinant for the free fraction of propranolol. For practical purposes, the change in the free fractions of phenytoin and diazepam can be adequately predicted by the serum creatinine or urea and serum albumin levels. For propranolol the only parameter which needs to be analyzed is the serum alpha 1-AGP concentration.

The effect of total drug concentration on the free fraction was studied in vitro using sera of uremic and nonuremic subjects. Both therapeutic and toxic concentrations of radiolabeled phenytoin, diazepam, and propranolol were used. The free fraction was separated by a pressure ultrafiltration method at 37 degrees C and determined from 200-microliters aliquots of serum and the ultrafiltrate. Sera from 11 acutely uremic and 10 chronically uremic patients and from 10 healthy control subjects were used. Only slight increases in the free fraction were found over the concentration range studied in both nonuremic and uremic subjects. The concentration-dependent increases in the unbound fraction of phenytoin and diazepam were quite negligible compared with the two- to threefold increases caused by uremia itself. Thus, variation in total concentrations of phenytoin, diazepam, and propranolol does not change the free fractions to a clinically significant degree even in uremic patients with a compromised binding capacity.

The clinical methods most frequently used for serum free drug determinations are equilibrium dialysis and ultrafiltration. Both methods have usually been considered equal when comparisons have been made on normal sera. The purpose of the study was to develop a reliable and rapid method for serum free drug determinations especially for disease states where there is an increased free fraction. This modification of the pressure ultrafiltration method proved to meet these demands. The method was tested in vitro by adding radiolabelled phenytoin in different concentrations to normal and uraemic sera. The within-run and between-run variation coefficients were both under 5%. In comparison with equilibrium dialysis the values obtained by the ultrafiltration method were 0.65% lower (p less than 0.001, Student's paired t-test) in normal and 0.37% lower (non-significant) in uraemic sera. There are some theoretical grounds to presume that the results obtained by means of the pressure ultrafiltration method would better reflect the real values than those obtained by means of equilibrium dialysis.