Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial.

Importance: Latent cytomegalovirus (CMV) infection is present in more than half the adult population, and a viral reactivation (ie, when the virus becomes measurable in body fluids such as blood) can occur in up to one-third of these individuals during episodes of critical illness. Objective: To determine whether antiviral therapy is safe and effective for preventing CMV reactivation in a general population of critically ill patients. Design, Setting, and Participants: A single-center, open-label, randomized, controlled clinical trial recruited 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in the intensive care unit between January 1, 2012, and January 31, 2014. The mean baseline Acute Physiology and Chronic Health Evaluation II score of all patients was 17.6. Interventions: Patients were randomized to receive anti-CMV prophylaxis with valacyclovir hydrochloride (n = 34) or low-dose valganciclovir hydrochloride (n = 46) for up to 28 days to suppress viral reactivation, or to a control group with no intervention (n = 44). Main Outcomes and Measures: Time to first CMV reactivation in blood within the 28-day follow-up period following initiation of the study drug. Results: Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04-0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm. Other safety end points showed similar outcomes between groups. Conclusions and Relevance: Antiviral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reactivation in patients with critical illness. However, given the higher mortality, a large-scale trial would be needed to determine the clinical efficacy and safety of CMV suppression. Trial Registration: clinicaltrials.gov Identifier: NCT01503918.

Assessment of the performance of the Marsh model in effect site mode for target controlled infusion of propofol during the maintenance phase of general anaesthesia in an unselected population of neurosurgical patients.

BACKGROUND: Propofol target-controlled infusion (TCI) in effect site mode has become popular since it became commercially available. OBJECTIVE: We have performed a study to assess the pharmacokinetic performance of the Marsh model in effect site mode in an unselected group of patients during neurosurgery during the maintenance phase of anaesthesia. DESIGN: Fifty American Society of Anesthesiologists (ASA) physical status classes 1 to 3 adults underwent elective neurosurgery receiving propofol TCI using the Marsh model in effect site mode. Propofol dose titration and level of patient monitoring was determined by the attending anaesthesiologist. Arterial blood was sampled at regular intervals during the maintenance phase of anaesthesia and measured plasma propofol concentrations were compared with those estimated using TCI. SETTING: Large tertiary referral centre in Birmingham, UK, with a specialist neuroanaesthesia service. PATIENTS: Fifty ASA status I to III adult patients undergoing elective neurosurgery. MAIN OUTCOME MEASURES: Performance of Marsh model as assessed by median performance error (bias) and median absolute performance error (imprecision). RESULTS: Performance of the Marsh model showed a positive bias (median performance error) of 27.6%, and imprecision (median absolute performance error) of 29.4%. Analysis of pooled data demonstrated greatest bias in the early phase (15 to 30 min) of anaesthesia (mean prediction error of 51.6%). Analysis of covariates demonstrated that obesity (BMI >30 kg m(-2)) contributed around half of the bias detected (mean prediction error 47 vs. 23%, P < 0.001). Patients with advanced age and significant comorbidity (ASA physical status class >2) actually demonstrated significantly lower prediction errors. CONCLUSION: Pharmacokinetic analysis suggests that the performance of the Marsh model in effect site mode is poor in this broad patient population. The greatest bias demonstrated occurred in the early maintenance phase of anaesthesia. Of the covariates analysed, obesity contributed most significantly to an increased bias. Despite overall poor performance of the Marsh model, attending anaesthesiologists modified targeted propofol concentrations only 0.3 times per hour on average, using remifentanil dose modification nine times more frequently, with good surgical conditions in all patients.