Association of busulfan area under the curve with veno-occlusive disease following BMT.

Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.

Cardiopulmonary arrest following intravenous phenytoin loading.

Two patients, aged 44 and 68 years, presented with generalized seizures either witnessed or highly suspected. Both patients had laboratory-proven subtherapeutic anticonvulsant serum levels. The patients differed with regard to risk; one patient had existing cardiopulmonary disease, and the other was free of such risk factors except liver disease. An apparently appropriate dose of intravenous phenytoin was initiated in each case, and the patients were monitored appropriately and given supplemental oxygen. Bradycardia, hypotension, respiratory distress, and, ultimately, cardiopulmonary arrest occurred in both. The criteria proposed by Earnest et al. should be implemented for each seizure case that requires a decision on the urgent need for therapeutic anticonvulsant levels, whether by mechanical infusion, manual intravenous push, or oral loading. The mechanical infusion is the easiest method to standardize and monitor. The manual intravenous push has a greater possibility of inadvertent overdosage during some small time frame, as well as more local symptoms by some reports. Record et al. have recommended oral loading in selected patients. Careful consideration must be made of the choice of environment in which intravenous loading is done (e.g., emergency department, intensive care unit), as dictated by patient parameters, nursing staff levels, and planned disposition. The crucial factors contributing to the deterioration of both patients in the two cases presented were the concentration of phenytoin manually infused and the possibility that their high-risk status made them poor candidates for manual intravenous phenytoin. Dose and a hypersensitivity reaction were doubtful factors in these cases.