Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.     

Disposition of aerosolized liposomal amphotericin B

Amphotericin B (AmB) is an important drug for the treatment of fungal infection, but toxicity limits the lung tissue doses which may be achieved through intravenous administration. Although incorporation of AmB in liposomes reduces these effects and increases the therapeutic index for intravenous administration, targeted delivery to lung tissues via inhaled liposomal AmB aerosol may be a more effective approach. Aerosolization of liposomal amphotericin B targets the lungs, the organs first infested by many fungi. Development of optimal aerosolized liposomal AmB therapies requires a better understanding of the effect that liposome surface charge has on lung clearance kinetics. In this work we evaluated the clearance kinetics and organ distribution of inhaled liposomal AmB in male Balb/C mice. Mice were exposed via nose only to AmB-containing liposomal aerosols having positive, negative, or neutral surface charge characteristics. The formulations were aerosolized using a Collison nebulizer. Groups of animals were euthanized at predetermined times and the lungs and other organs were analyzed for AmB. AmB was not detected in serum and other organs such as kidneys, liver, and brain. The disposition of neutral and positive liposomal amphotericin B in lungs followed biexponential kinetics. The alpha and beta phase half-lives for positive liposomes were 1.3 and 15.1 days, respectively, and 2.3 and 22 days for neutral liposomes. AmB delivered via negative liposomes exhibited monoexponential clearance with a half-life of 4.5 days. These results suggest that toxic side effects in nontarget tissues are minimal and may indicate a potential for long term protection against fungal infections.     

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.     

Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.     

Activity of liposomal amphotericin B against experimental cutaneous leishmaniasis

The polyene antibiotic amphotericin B is currently a second-line treatment for visceral leishmaniasis (VL) and mucocutaneous leishmaniasis. Lipid-amphotericin B formulations with lower toxicity than the parent drug that were developed for the treatment of systemic mycoses have proved to be an effective treatment for VL, especially AmBisome, a small unilamellar negatively charged liposome. In vitro, free amphotericin B was three to six times more active than the liposomal formulation AmBisome against both Leishmania major promastigotes in culture and amastigotes in murine macrophages. In a BALB/c L. major model of cutaneous infection, liposomal amphotericin B administered once a day on six alternate days by the intravenous route produced a dose-response effect between 6.25 and 50 mg/kg. Liposomal amphotericin B administered subcutaneously close to a lesion had no significant activity. Free drug was ineffective at nontoxic doses. The results suggest that liposomal amphotericin B may be useful in the treatment of cutaneous leishmaniasis.     

Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration

A prospective, randomized, double-blind and placebo-controlled study was conducted to assess the effectiveness of i.v. administration of 6% hydroxyethyle starch solution (HES) in preventing moderate and severe ovarian hyperstimulation syndrome (OHSS) in patients in an in-vitro fertilization programme. A total of 101 women who had serum oestradiol concentrations >1500 pg/ml and/or more than 10 follicles on day of human chorionic gonadotrophin (HCG) administration were recruited into two groups: HES group (n = 51) received 1000 ml 6% HES; and the placebo group (n = 50) received 1000 ml of sodium chloride 0.9% solution at the time shortly after embryo transfer. Follow-up examinations 7 +/- 1 and 14 +/- 1 days after embryo transfer included transvaginal ultrasound (diameters of each ovary and maximum cysts, number of cysts, ascites), blood tests (serum oestradiol, progesterone, beta-HCG, C-reactive protein, blood count, plasma proteins, electrolytes, kidney function tests) and evaluation of abdominal pain, nausea, diarrhoea, abdominal swelling and weight gain. Only one moderate OHSS developed in the HES group whereas seven moderate-severe cases were observed in the placebo group (P = 0.031). Furthermore, serum oestradiol concentration, leukocyte count, increase in abdominal circumference and weight gain 14 days after embryo transfer were significantly higher in the placebo group. There were no differences between the two groups in terms of age, oestradiol concentration and number of follicles at time of HCG injection. Administration of 6% HES prevents the development of moderate-severe OHSS in risk patients.     

Reversing oliguria in critically ill patients

Oliguria is a common occurrence in the ICU setting. In patients with preserved renal function, fluid challenges or low doses of diuretics are generally successful. In patients with oliguric renal failure, it is still essential to ensure adequate intravascular fluid volume, especially in critically ill patients. Loop diuretics remain the mainstay of treatment. When diuretic resistance is encountered, physicians should consider further optimization of hemodynamics, alternative loop diuretics, and combined drug therapy. In some cases, continuous renal replacement therapy can be very effective. Yet, while these interventions can help reduce the morbidity of severe volume overload, they have not been shown to improve mortality rates.     

Nutritional support of critically ill patients

Severe depletion of body protein stores can result from prolonged starvation or from hormonal and cytokine-mediated effects during critical illness. Recent advances in the understanding of cytokine actions have substantially refined the interpretation of the nutritional assessment of critically ill patients. In addition, the design of nutritional programs for hospitalized patients has changed considerably during the past decade. Although nutritional support of critically ill patients will not lead to positive nitrogen balance, nutrition can increase protein synthesis, enhance immune function, and beneficially modify the body's response to an illness.     

Human growth hormone kinetics in critically ill patients

Several studies have shown that exogenous human growth hormone (HGH) exerts an anabolic effect on protein metabolism in surgical patients with mild or moderate catabolism. However, contradictory results have been demonstrated in polytrauma patients where HGH did not improve protein metabolism. Aim of this study was to evaluate whether the pharmacokinetics of recombinant biosynthetic human GH (r-HGH) are altered in critically ill patients. After an overnight fast, r-HGH was infused at a rate of 460 micrograms/h/kg/bw during 120 min to five intensive care unit (ICU) patients. The patients were catabolic (nitrogen balance -11 +/- 0.5), showed normal liver function, and only one patient had a slightly impaired kidney function (creatinine > 1.5 mg/dl). Endogenous GH secretion was suppressed by continuous infusion of 50 micrograms/m2/h somatostatin. From plasma GH curves, elimination half life (t1/2kle), whole body clearance (Cltot) and steady state distribution space (DS) were calculated in an open two compartment model. Additionally, the effects of r-HGH infusion on plasma insulin, glucagon and amino acid concentrations were evaluated. T1/2kle was 19.6 +/- 2.3 min, Cltot 2.9 +/- 0.4 ml/kg/bw/min and DS 76.4 +/- 3.8 ml/kg/bw for 90 min. The plasma levels of total amino acids including the branched chain amino acids valine, leucine and isoleucine and of glutamine were significantly higher during r-HGH infusion than during the basal and somatostatin periods. In conclusion, the elimination of r-HGH in catabolic ICU patients is not different from that of healthy volunteers.     

Predictability of creatinine clearance estimates in critically ill patients

OBJECTIVES: a) To evaluate the predictive ability of different creatinine clearance methods as compared with the criterion standard, inulin clearance; and b) to determine which of the predictive methods yields the most accurate estimation of creatinine clearance. DESIGN: Prospective study. SETTING: Medical intensive care unit (ICU) of a university-affiliated tertiary care hospital. INTERVENTIONS: Glomerular filtration rate was measured by the criterion standard, inulin clearance. PATIENTS: Twenty mechanically ventilated adults. MEASUREMENTS: Renal function was assessed by the following procedures: inulin clearance using a standard protocol, 30-min creatinine clearance, 24-hr creatinine clearance, and creatinine clearance estimates by the Cockcroft-Gault equation. Ideal body weight, total body weight or lean body mass with actual serum creatinine or serum creatinine concentration corrected to 1 mg/dL (85 mumol/L) in cachectic patients were sequentially incorporated into the Cockcroft-Gault equation. RESULTS: The Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration, was the best predictor of inulin clearance with the smallest bias (9.7 +/- 8.6, 95% confidence interval 5.7 to 13.8). The bias encountered with the 30-min creatinine clearance was not different from that value with the 24-hr creatinine clearance (21.6 +/- 33.0, 95% confidence interval 6.2 to 37.1 vs. 25.4 +/- 28.3, 95% confidence interval 11.8 to 42.9). Good correlations existed between inulin clearance and the Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration (r2 = .81; p = .0001), as well as between inulin clearance and the Cockcroft-Gault equation, using the lower of ideal or total body weight and the higher of the actual serum creatinine concentration or corrected serum creatinine (r2 = .75; p = .0001). The 30-min creatinine clearance and the 24-hr creatinine clearance had poorer agreement with inulin clearance. The incorporation of a corrected serum creatinine value into the Cockcroft-Gault equation consistently led to better predictions and higher correlation coefficients. CONCLUSIONS: The utilization of the Cockcroft-Gault equation as used clinically (the lower of ideal or total body weight and the higher of actual serum creatinine or corrected serum creatinine concentration to 1 mg/dL [85 mumol/L]) results in more accurate predictions of glomerular filtration rate in the medical, critically ill patient than urine creatinine clearance measures. If creatinine clearance measures are used, the 30-min collection provided results not different from those results obtained with 24-hr urinary collections.     

A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d(L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9)/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38 degrees C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P < or = 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P < 0.01). Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5 x 10(9)/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB, 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P = 0.03) but a Kaplan-Meier analysis of time to differvescence of fever showed there was no significant difference between the arms. It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open-label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.     

Bone hyperresorption is prevalent in chronically critically ill patients

STUDY OBJECTIVE: Chronically critically ill (CCI) patients are primarily elderly people who have survived a life-threatening episode of sepsis but remain profoundly debilitated and ventilator dependent. The objective of this study was to determine the prevalence of bone hyperresorption and parathyroid hormone (PTH)-vitamin D axis abnormalities in these patients. DESIGN: Prevalence survey. SETTING: Respiratory care step-down unit (RCU) at a tertiary care teaching hospital. PATIENTS: Forty-nine ventilator-dependent CCI patients transferred from ICUs within the same institution. INTERVENTION: None. MEASUREMENTS AND RESULTS: N-telopeptide (NTx) levels in 24-h urine collections and serum intact PTH, 25-vitamin D, and 1,25-vitamin D levels were measured within 48 h of RCU admission. Patients were hospitalized a median of 30 days before RCU admission. Four patients (9%) had normal NTx and PTH levels. Forty-five patients (92%) had elevated urine NTx levels consistent with bone hyperresorption. Nineteen patients (42% of total patients) had elevated PTH levels consistent with predominant vitamin D deficiency, 4 patients (9%) had suppressed PTH levels consistent with predominant hyperresorption from immobilization, and 22 patients (49%) had normal PTH levels consistent with an overlap of both vitamin D deficiency and immobilization. There were no differences in vitamin D metabolites among these groups. CONCLUSIONS: CCI patients have a high prevalence of bone hyperresorption in which PTH levels may clarify the cause. Further studies will determine the efficacy and cost-effectiveness of routine NTx and PTH screening in these patients and the role of vitamin D and antiresorptive therapies.