A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children.

BACKGROUND: To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine. METHODS: Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed. RESULTS: Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient. CONCLUSION: The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.

The dilemma of immediate preoperative hypertension: to treat and operate, or to postpone surgery?

STUDY OBJECTIVE: To evaluate the efficacy and complications of immediate preoperative reduction of arterial blood pressure (BP) in patients with well-controlled hypertension but with diastolic blood pressure (DBP) between 110 and 130 mmHg on arrival at the operating room (OR). DESIGN: Prospective, randomized, large-sample study. SETTING: University-affiliated, 550-bed community hospital. PATIENTS: 989 patients with well-controlled hypertension, who were scheduled for surgery, and who had no previous myocardial infarction, unstable or severe angina pectoris, renal failure, pregnancy induced hypertension, left ventricular hypertrophy, previous coronary revascularization, aortic stenosis, preoperative dysrhythmias, conduction defects, or stroke. INTERVENTIONS: Patients with DBP between 110 and 130 mmHg were randomly allocated to two groups: 400 patients in the control group and 589 patients serving as the study group. The control group had their surgery postponed and they remained in hospital for BP control, and the study patients received 10 mg of nifedipine intranasally delivered. The patients were observed for cardiovascular and neurological complications during the intraoperative period and over the first three postoperative days. MEASUREMENTS AND MAIN RESULTS: The two groups were similar in age, gender, type of surgery, duration of anesthesia, and intraoperative fluid administration. There were no statistically significant differences in postoperative complications. The hospitalization time was considerable shorter in the study group than in the control group. CONCLUSIONS: Immediate preoperative reduction of DBP with intranasal nifedipine is safe in patients with well-controlled arterial hypertension but they presented with severe to very severe hypertension for patients in the OR. We were able to avoid unnecessary surgery postponement and attendant costs.

Association between hypophosphatemia and cardiac arrhythmias in the early stages of sepsis.

BACKGROUND: The purpose of this study was to evaluate a possible association between serum phosphate levels and the incidence of cardiac arrhythmias in the early stages of sepsis. METHODS: We conducted a prospective, controlled study in the General Intensive Care Unit (GICU) of a university hospital. Sixteen patients with sepsis, but without any previous cardiac disease, were studied during their first 24 h in the GICU. Patients were connected to a continuous ECG recording device. Blood samples for serum phosphate level determinations were drawn during the first 6 h after admission to the unit. RESULTS: Ten of 16 patients had 21 episodes of atrial and ventricular arrhythmias. These patients had higher mean Apache II scores (20.2+/-6.2) than the six patients without arrhythmias (13.2+/-1.7; P<0.05) and significantly lower mean phosphate levels (0.73+/-0.16 vs. 1.02+/-0.32 mmol/l; P<0.03). No association was found between serum phosphate levels and mortality among patients with arrhythmias, or when all survivors (with and without arrhythmia) were compared to all non-survivors. CONCLUSIONS: The results indicate that patients with sepsis and low serum phosphate levels are at a greater risk of developing cardiac arrhythmias. We suggest that phosphate supplementation in the early stages of sepsis may prevent cardiac arrhythmias.