Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz

The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ∼30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P < .001). Clopidogrel reduced both formation and elimination clearances of 8-OH EFV by 22% and 19%, respectively (P = .033 and .041). Other demographics and genotype of accessory CYP pathways did not predict EFV or metabolites PK. CYP2B6 genotype was the only significant predictor of EFV disposition. The developed model may serve as the foundation for further exploration of pharmacogenetic-based dosing of EFV

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background: End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods: This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results: In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion: Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background: The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods: In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results: Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89·6 per cent) compared with that in countries with a middle (753 of 1242, 60·6 per cent; odds ratio (OR) 0·17, 95 per cent c.i. 0·14 to 0·21, P < 0·001) or low (363 of 860, 42·2 per cent; OR 0·08, 0·07 to 0·10, P < 0·001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -9·4 (95 per cent c.i. -11·9 to -6·9) per cent; P < 0·001), but the relationship was reversed in low-HDI countries (+12·1 (+7·0 to +17·3) per cent; P < 0·001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0·60, 0·50 to 0·73; P < 0·001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion: Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries

Surgical site infection after gastrointestinal surgery in children: An international, multicentre, prospective cohort study

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Results Of 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda