Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study

BMJ

Aug 1998

DOI: 10.1136/bmj.317.7155.379

Citations:72

Influential Citations:2

Interventional (Human) Studies

High RoB

Enhanced Details

Methods

Prospective randomized phase II trial; neutropenic cancer patients with pulmonary infiltrates or refractory fever of unknown origin during broad-spectrum antibiotics; 51 patients randomized (24 to glucose arm; 27 to intralipid arm); stratified by presence of refractory fever of unknown origin or pneumonia and underlying malignancy; non-blinded; ethics committee approval and informed consent; trial designed with power to detect differences in serum creatinine/creatinine clearance; stopped early for patient safety.

Intervention

Amphotericin B 0.75 mg/kg/day for eight days, then every other day. Regimen A: amphotericin B in glucose 5% solution (10 mg/mL) infused intravenously. Regimen B: amphotericin B in intralipid 20%—amphotericin B dissolved in glucose 5% (10 mg/mL) then mixed with 250 mL intralipid 20% and infused intravenously; infusion duration 1–4 hours; identical dose and schedule in both regimens; no dose escalation.

Results

Amphotericin B in intralipid did not reduce toxicity compared with amphotericin B in glucose 5%. No significant difference in renal function between arms (creatinine/BUN rose in both); cumulative potassium requirement was lower in the intralipid arm, but this was confounded by differences in diuretic use. Pulmonary toxicity was more frequent and often more severe in the intralipid group (pulmonary symptoms in 17/27 intralipid vs 11/24 glucose; grade 3–4 acute dyspnea in 11 intralipid vs 4 glucose; other pulmonary events higher in intralipid). Some patients discontinued early due to pulmonary events. Authors conclude amphotericin B in intralipid is not an acceptable delivery method for neutropenic cancer patients; intralipid should be regarded as chemically incompatible with amphotericin B; no demonstrated efficacy advantage. Trial terminated early for safety; regimen not recommended.

Limitations

Pulmonary toxicity assessment not standardized (blood gases/O2 saturation not routinely measured; bedside tests only during distress); imbalance in pneumonia baseline between arms may bias toxicity interpretation; early termination and small sample size reduce power; non-blinded infusions; confounding factors (e.g., diuretic use) affect interpretation of electrolyte changes.

Abstract

Abstract Objective : To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients. Design : Single centre stratified, randomised non-blinded phase II study. Setting : University hospital providing tertiary clinical care. Subjects : 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27). Interventions : Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion. Main outcome measures : Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute). Results : Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05). Conclusions : Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs. show less