Joel M. Dulhunty

Continuous Infusion of Beta-Lactam Antibiotics in Severe Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial

BACKGROUND Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. METHODS This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. RESULTS Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). CONCLUSIONS Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis

RATIONALE Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing. OBJECTIVES To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. METHODS We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia. MEASUREMENTS AND MAIN RESULTS We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). CONCLUSIONS In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).

Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence

BACKGROUND Despite the proven benefits in hemorrhagic shock, blood transfusions have been linked to increased morbidity and mortality. The short-term adverse effects of blood transfusion in cardiac surgical patients are well documented but there are very few studies that adequately assess the long-term survival. This study was undertaken to evaluate the effects of transfusion on both short-term and long-term survival after cardiac surgery. METHODS Data from 5,342 patients who underwent a cardiac surgical procedure from January 2002 to December 2005 at our institution were reviewed. The effect of transfusion of packed red blood cells (PRBC) and other blood products was tested in a 2-level approach of transfusion (any) versus no transfusion, and also a 4-level approach of transfusion (PRBC, other blood products, and both blood and blood products) versus no transfusion. Long-term survival data of these patients were obtained. Cox proportional hazard models, Kaplan-Meier survival plots, and hazard functions were used to compare the groups. RESULTS A total of 3,013 of the 5,342 study patients (56.4%) received transfusion during or within 72 hours of their cardiac surgery. Median time to death was significantly lower for patients who received transfusions; 1.15 years for PRC and 0.83 years for any transfusion, compared with 4.68 years in the non-transfused group. The overall 30-day mortality was 1.7%, but in patients who received transfusions (3.6%) was significantly higher than the non-transfused group (0.3%, p<0.001). The 1-year mortality (overall 3.9%) in the transfused group (7.3%, p<0.001) was also significantly higher than that in the non-transfused group (1.3%). The 5-year mortality rate in the transfused group was more than double that in the non-transfused group (16% vs 7%). After correction for comorbidities and other factors, transfusion was still associated with a 66% increase in mortality. CONCLUSIONS This study suggests that blood or blood product transfusion during or after cardiac surgery is associated with increased short-term and long-term mortality. It reinforces the need for prospective randomized controlled studies for evaluation of restrictive transfusion triggers and objective clinical indicators for transfusion in the cardiac surgical patient population.

Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials

RATIONALE Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. OBJECTIVES In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. METHODS We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. MEASUREMENTS AND MAIN RESULTS We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. CONCLUSIONS Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.

Increased fluid resuscitation can lead to adverse outcomes in major-burn injured patients, but low mortality is achievable

BACKGROUND Excessive fluid resuscitation of large burn injuries has been associated with adverse outcomes. We reviewed our experience in patients with major-burn injury to assess the relationship between fluid, clinical outcome and cause of variance from expected resuscitation volumes as defined by the Parkland formula. METHODS Eighty patients with new burns > or =15% total body surface area (TBSA) admitted to the intensive care unit within 48 h of injury were included. RESULTS Mean fluid volume was 6.0+/-2.3 mL/kg/% TBSA at 24h. Bolus fluids for hypotension and oliguria explained 39% of excess variance from Parkland estimates and inaccurate burn size and weight assessment explained 9% of variance. Higher fluid volume was associated with pneumonia (adjusted odds ratio [AOR]=2.0; 95% confidence interval [CI] 1.2-3.4) and extremity compartment syndrome (AOR=7.9; 95% CI 2.4-26). Colloid use during the first 24h reduced the risk of extremity compartment syndrome (AOR=0.06; 95% CI 0.007-0.49) and renal failure (AOR=0.11; 95% CI 0.014-0.82). In-hospital mortality was low (10%) and not associated with >125% Parkland resuscitation (P=0.39). CONCLUSIONS Although fluid resuscitation in excess of the Parkland formula was associated with several adverse events, mortality was low. A multi-centre trial is needed to more specifically define the indications and volumes needed for burns fluid resuscitation and revise traditional formulae emphasising patient outcome. Improved training in burn size assessment is needed.

Continuous beta-lactam infusion in critically ill patients: the clinical evidence

There is controversy over whether traditional intermittent bolus dosing or continuous infusion of beta-lactam antibiotics is preferable in critically ill patients. No significant difference between these two dosing strategies in terms of patient outcomes has been shown yet. This is despite compelling in vitro and in vivo pharmacokinetic/pharmacodynamic (PK/PD) data. A lack of significance in clinical outcome studies may be due to several methodological flaws potentially masking the benefits of continuous infusion observed in preclinical studies. In this review, we explore the methodological shortcomings of the published clinical studies and describe the criteria that should be considered for performing a definitive clinical trial. We found that most trials utilized inconsistent antibiotic doses and recruited only small numbers of heterogeneous patient groups. The results of these trials suggest that continuous infusion of beta-lactam antibiotics may have variable efficacy in different patient groups. Patients who may benefit from continuous infusion are critically ill patients with a high level of illness severity. Thus, future trials should test the potential clinical advantages of continuous infusion in this patient population. To further ascertain whether benefits of continuous infusion in critically ill patients do exist, a large-scale, prospective, multinational trial with a robust design is required.

Vancomycin-associated Nephrotoxicity in the Critically Ill: A Retrospective Multivariate Regression Analysis*

Objectives:To evaluate the influence of vancomycin dose, serum trough concentration, and dosing strategy on the evolution of acute kidney injury in critically ill patients. Design:Retrospective, single-center, observational study. Setting:University Hospital ICU, Birmingham, UK. Patients:All critically ill patients receiving vancomycin from December 1, 2004, to August 31, 2009. Intervention:None. Measurements and Main Results:The prevalence of new onset nephrotoxicity was reported using Risk, Injury, Failure, Loss, End-stage renal disease criteria, and independent factors predictive of nephrotoxicity were identified using logistic regression analysis. Complete data were available for 1,430 patients. Concomitant vasoactive therapy (odds ratio = 1.633; p < 0.001), median serum vancomycin (odds ratio = 1.112; p < 0.001), and duration of therapy (odds ratio = 1.041; p ⩽ 0.001) were significant positive predictors of nephrotoxicity. Intermittent infusion was associated with a significantly greater risk of nephrotoxicity than continuous infusion (odds ratio = 8.204; p ⩽ 0.001). Conclusions:In a large dataset, higher serum vancomycin concentrations and greater duration of therapy are independently associated with increased odds of nephrotoxicity. Furthermore, continuous infusion is associated with a decreased likelihood of nephrotoxicity compared with intermittent infusion. This large dataset supports the use of continuous infusion of vancomycin in critically ill patients.

Malaria control in Central Malaita, Solomon Islands: 1. The use of insecticide-impregnated bed nets

The present study investigated the use of insecticide-impregnated bed nets by communities in central Malaita, Solomon Islands. Qualitative and quantitative data were collected by: (1) questionnaire administration to 124 care-givers of children aged 0-10 years of age; (2) 20 focus group discussions; (3) two structured observations of bed net re-impregnation, and (4) interviews with key informants. Ninety-four percent of all care-givers had bed nets, but only 62% had sufficient bed nets for all household members. Fifty-two percent used bed nets throughout the year and 70% of care-givers reported that all their children slept under bed nets. Although coastal householders considered malaria and mosquitoes more of a problem than inland householders, overall bed net compliance did not differ. Factors affecting bed net ownership were cost and community expectation of free bed nets. Bed net use was affected by four factors: (1) seasonality (99% used bed nets during the rainy season, 52% used them all year); (2) mosquito nuisance (59% of respondents reported that protection against mosquitoes was the main reason for using a bed net); (3) weather (68% of care-givers would not use a bed net if the weather was hot), and (4) low density of mosquitoes (respondents who used bed nets as protection against mosquito nuisance were more likely not to use bed nets when mosquitoes were few than those who used bed nets for malaria protection (odds ratio (OR), 3.9; 95% confidence interval (CI), 1.4-12.0). Protection against malaria was the main reason children slept under bed nets. Children from households where bed nets were used for malaria protection were more likely to sleep under bed nets than children from households where nets were used as protection from mosquitoes only (OR, 2.7; 95% CI, 1.3-5.9). Other factors that affected childrens bed net use were, age (users were significantly younger than non-users; chi(2)=7.9, degrees of freedom=1, P=0.005) and sufficiency of bed nets (OR, 2.0; 95% CI, 1. 3-7.0).

Temporal trends, risk factors and outcomes in albicans and non-albicans candidaemia: an international epidemiological study in four multidisciplinary intensive care units

This multicentre study (i) evaluated geographic and temporal changes in candidaemia ecology in the critically ill, (ii) identified risk factors associated with non-albicans candidaemia and (iii) examined the association of Candida ecology with mortality. A retrospective cohort study of patients who developed candidaemia in four general Intensive Care Units located in Australia, Greece, Belgium and Brazil was performed. Two hundred Candida organisms were identified by positive blood culture in 189 patients, including 112 Candida albicans (56.0%), 38 Candidaglabrata (19.0%), 21 Candidaparapsilosis (10.5%), 18 Candidatropicalis (9.0%), 6 Candidakrusei (3.0%), 1 Candidafamata (0.5%), 1 Candidazeylanoides (0.5%) and 3 non-differentiated Candida spp. (1.5%). No trend towards increased non-albicans species over the study period (P=0.68) or by geographic area (P=0.35) was demonstrated. Independent risk factors for non-albicans candidaemia included: female gender [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.13-3.86] and increased central venous catheter days (OR 1.16 per 5-day interval, 95% CI 1.05-1.28). Mortality in the non-albicans group was non-significantly higher than in the albicans group (65% vs. 53%; P=0.10). This study is unique in that a large number of intensive care candidaemias in four geographically diverse units have been studied.

Acquired hypernatraemia is an independent predictor of mortality in critically ill patients

This study reports the incidence and associated mortality of acquired hypernatraemia (Na > 150 mmol.l−1) in a general medical/surgical intensive care unit. Patients admitted over a 5‐year period with normal sodium values were eligible for inclusion; exclusions were made for burn/neurosurgical diagnoses and for hypertonic saline therapy. From 3475 admissions (3317 patients), 266 (7.7%) episodes of hypernatraemia were observed. Hospital mortality was 33.5% in the hypernatraemic group and 7.7% in the normonatraemic group (p < 0.001). Acquired hypernatraemia was an independent risk factor for in‐hospital mortality (OR 1.97, 95% CI 1.37–2.82, p < 0.001). Intermediate sodium levels (145–150 mmol.l−1) were associated with increased mortality (OR 1.42, 95% CI 1.02–1.98). Uncorrected sodium at discharge (p = 0.001) and peak sodium (p = 0.001) were better predictors of mortality than time to onset (p = 0.71) and duration of hypernatraemia (p = 1.0). Hypernatraemia avoidance is justified, but determinants of hypernatraemia and benefits of targeted treatment strategies require further elucidation.