Prolonged vs Intermittent Infusions of ß-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis.

Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Corrigendum to "Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis" [Crit Care Resusc 23(3) (2021) 273-284].

[This corrects the article DOI: 10.51893/2021.3.oa4.].

Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis.

Background: The ß-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of ß-lactam antibiotics in 7000 critically ill patients with sepsis. Objective: To describe a statistical analysis plan for the BLING III study. Methods: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. Results and conclusions: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. Trial registration:ClinicalTrials.gov Registry NCT03212990.

Protocol for an international, multicentre, prospective, observational study of nosocomial pneumonia in intensive care units: the PneumoINSPIRE study.

Background: Nosocomial pneumonia in the critical care setting is associated with increased morbidity, significant crude mortality rates and high health care costs. Ventilator-associated pneumonia represents about 80% of nosocomial pneumonia cases in intensive care units (ICUs). Wide variance in incidence of nosocomial pneumonia and diagnostic techniques used has been reported, while successful treatment remains complex and a matter of debate. Objective: To describe the epidemiology, diagnostic strategies and treatment modalities for nosocomial pneumonia in contemporary ICU settings across multiple countries around the world. Design, setting and patients: PneumoINSPIRE is a large, multinational, prospective cohort study of adult ICU patients diagnosed with nosocomial pneumonia. Participating ICUs from at least 20 countries will collect data on 10 or more consecutive ICU patients with nosocomial pneumonia. Site-specific information, including hospital policies on antibiotic therapy, will be recorded along with patient-specific data. Variables that will be explored include: aetiology and antimicrobial resistance patterns, treatment-related parameters (including time to initiation of antibiotic therapy, and empirical antibiotic choice, dose and escalation or de-escalation), pneumonia resolution, ICU and hospital mortality, and risk factors for unfavourable outcomes. The concordance of ventilator-associated pneumonia diagnosis with accepted definitions will also be assessed. Results and conclusions: PneumoINSPIRE will provide valuable information on current diagnostic and management practices relating to ICU nosocomial pneumonia, and identify research priorities in the field. Trial registration:ClinicalTrials.gov identifier NCT02793141.

Bacterial Profile, Multi-Drug Resistance and Seasonality Following Lower Limb Orthopaedic Surgery in Tropical and Subtropical Australian Hospitals: An Epidemiological Cohort Study.

We aimed to describe the epidemiology, multi-drug resistance and seasonal distribution of bacteria cultured within 12 months following lower limb orthopaedic surgery in tropical and subtropical Australian hospitals between 2010 and 2017. We collected data from four tropical and two subtropical hospitals. Categorical variables were examined using the Pearson Chi-squared test or Fisher's Exact test, and continuous variables with the Student t-test or Mann-Whitney U test. A Poisson regression model was used to examine the relationship between season, weather and the incidence of Staphylococcus and nonfermentative species. We found that at tropical sites, nonfermenters (Pseudomonas aeruginosa and Acinetobacter baumannii) were more common (28.7% vs. 21.6%, p = 0.018), and patients were more likely to culture multi-drug-resistant (MDR) nonfermenters (11.4% vs. 1.3%, p = 0.009) and MDR Staphylococcus aureus (35.9% vs. 24.6%, p = 0.006). At tropical sites, patients were more likely to be younger (65.9 years vs. 72.0, p = < 0.001), male (57.7% vs. 47.8%, p = 0.005), having knee surgery (45.3% vs. 34.5%, p = 0.002) and undergoing primary procedures (85.0% vs. 73.0%, p = < 0.001). Species were similar between seasons in both tropical and subtropical hospitals. Overall, we found that following lower limb orthopaedic surgery in tropical compared with subtropical Australia, patients were more likely to culture nonfermenters and some MDR species.

Modifiable risk factors for multidrug-resistant Gram-negative infection in critically ill burn patients: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to identify potentially modifiable risk factors for multidrug-resistant Gram-negative colonization or infection in critically ill burn patients. METHODS: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science and Central (Cochrane). Risk factors including antibiotic use and hospital interventions were summarized in a random-effects meta-analysis. Risk of publication bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation method and funnel plots. RESULTS: A total of 11 studies met the inclusion criteria. We identified several potentially modifiable risk factors and were able to grade their importance based on effect size. Related to prior antibiotic exposure, extended-spectrum cephalosporins (pooled odds ratio (OR) 7.00, 95% confidence interval (CI) 2.77-17.67), carbapenems (pooled OR 6.65, 95% CI 3.49-12.69), anti-pseudomonal penicillins (pooled OR 4.23, 95% CI 1.23-14.61) and aminoglycosides (pooled OR 4.20, 95% CI 2.10-8.39) were most significant. Related to hospital intervention, urinary catheters (pooled OR 11.76, 95% CI 5.03-27.51), arterial catheters (pooled OR 8.99, 95% CI 3.84-21.04), mechanical ventilation (pooled OR 5.49, 95% CI 2.59-11.63), central venous catheters (pooled OR 4.26, 95% CI 1.03-17.59), transfusion or blood product administration (pooled OR 4.19, 95% CI 1.48-11.89) and hydrotherapy (pooled OR 3.29, 95% CI 1.64-6.63) were most significant. CONCLUSION: Prior exposure to extended-spectrum cephalosporins and carbapenems, as well as the use of urinary catheters and arterial catheters pose the greatest threat for infection or colonization with multidrug-resistant Gram-negative organisms in the critically ill burn patient population.

A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis: BLING III.

BACKGROUND AND RATIONALE: ß-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis. DESIGN AND SETTING: The ß-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of ß-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021. PARTICIPANTS AND INTERVENTIONS: BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two ß-lactam antibiotics (piperacillin-tazobactam or meropenem) to receive the ß-lactam antibiotic by either continuous or intermittent infusion. MAIN OUTCOME MEASURES: The primary outcome is allcause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 after randomisation, new acquisition, colonisation or infection with a multiresistant organism or Clostridium difficile diarrhoea up to 14 days after randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation and duration of renal replacement therapy up to 90 days after randomisation. RESULTS AND CONCLUSIONS: The BLING III study will compare the effect on 90-day mortality of ß-lactam antibiotics administered via continuous versus intermittent infusion in 7000 critically ill patients with sepsis. TRIAL REGISTRATION: ClinicalTrials.gov Registry (NCT03213990).

Factors affecting the performance of public out-patient services.

Objective The delivery of public out-patient services is an essential part of complex healthcare systems, but the contribution of public out-patient services is often ill defined and poorly evaluated. The aim of this study was to identify and better understand those factors that may affect the performance of out-patient services to provide health service managers, clinicians and executives with a conceptual framework for future decision-making processes. Methods The present qualitative research involved five exploratory case studies. These case studies were conducted across two specialties at hospitals in the Metro North Hospital and Health Service in Queensland. Data were obtained from 38 interviews and 15 focus groups, and were analysed to identify common themes. Further analysis helped identify the most significant factors and build a conceptual framework for understanding the relationships between those factors and their effect on performance. Results Across both specialties there were 10 factors (scheduling, performance, service framework, categorisation or prioritisation of patients, internal and external stakeholders, resources, service demand, culture, system challenges and medical stakeholders) identified that may affect the performance of out-patient services. These factors were condensed into five core domains: culture, stakeholders, resources, demand and system reform. Conclusion Strategies to address the five core domains identified may provide a framework for sustainable improvement in the delivery of out-patient services. What is known about the topic? The provision of specialist out-patient services is an essential element of health service delivery. Access to specialist services in the public sector is challenging because of the escalating demand associated with an increasing and aging demographic. The factors that may affect the delivery of out-patient services need to be addressed for long-term sustainable improvement. What does this paper add? This paper provides a conceptual framework grounded in rigorous qualitative data analysis for understanding the internal and external factors that affect waiting times for specialist out-patient services. The results of this qualitative research indicate that there are five core domains that may influence waiting times in the public out-patient setting. When these domains are addressed at the strategic, tactical and operational levels, they have the potential to provide significant improvement in the delivery of out-patient services. What are the implications for practitioners? This paper guides the attention of relevant stakeholders towards the five core domains identified (culture, stakeholders, resources, demand and system reform) that influence the performance of waiting times at the operational, tactical and strategic levels within the public hospital setting.

Perceptions of pregnant women regarding antidepressant and anxiolytic medication use during pregnancy.

OBJECTIVE: The objective of this study was to explore attitudes and decision-making by pregnant women regarding antidepressant and anxiolytic use during pregnancy. METHOD: An observational study at an outer metropolitan hospital in Brisbane, Queensland. Pregnant women presenting for their first antenatal clinic visit were invited to complete a questionnaire. Participants were asked about current or previous antidepressant/anxiolytic use, influences on drug decision-making and the adequacy of information received. Perceptions were measured on a 7-point Likert scale. RESULTS: A total of 503 pregnant women were surveyed. The background prevalence of anxiety and depression was 30.0% (151), with 9.3% (47) respondents using antidepressant or anxiolytic medications during the current pregnancy. Of these 47 women, 68% ceased these medications during or while trying to become pregnant, most commonly due to potential side effects to the baby (16), health professional advice (8) and symptomatology that was under control (7). While the effect was modest, decision-making was most strongly influenced by general practitioners, family and the internet. CONCLUSIONS: Most women cease antidepressant/anxiolytic medication before and during pregnancy for reasons other than stability of condition. This study reveals an unmet need for accessible reliable information to guide pregnant women and their care providers.

Open cholecystectomy: Exposure and confidence of surgical trainees and new fellows.

BACKGROUND: The laparoscopic approach to cholecystectomy has overtaken open procedures in terms of frequency, despite open procedures playing an important role in certain clinical situations. This study explored exposure and confidence of Australasian surgical trainees and new fellows in performing an open versus laparoscopic cholecystectomy. MATERIALS AND METHODS: An online survey was disseminated via the Royal Australasian College of Surgeons to senior general surgery trainees (years 3-5 of surgical training) and new fellows (fellowship within the previous 5 years). The survey included questions regarding level of experience and confidence in performing an open cholecystectomy and converting from a laparoscopic to an open approach. RESULTS: A total of 135 participants responded; 58 (43%) were surgical trainees, 58 (43%) were fellows and 19 (14%) did not specify their level of training. Respondents who were involved in more than 20 open cholecystectomy procedures as an assistant or independent operator compared with those less exposed were more likely to feel confident to independently perform an elective open cholecystectomy (87.8% vs. 57.3%, P = 0.001), independently convert from a laparoscopic to open cholecystectomy (87.8% vs. 58.7%, P = 0.001) and independently perform an open cholecystectomy as a surgical consultant based on their level of exposure as a trainee (73.2% vs. 45.3%, P = 0.004). CONCLUSION: This study suggests the need to ensure surgical trainees are exposed to sufficient open cholecystectomies to enable confidence and skill with performing these procedures when indicated. Greater recognition of the need for exposure during training, including meaningful simulation, may assist.

Risk factors for multidrug-resistant Gram-negative infection in burn patients.

BACKGROUND: Infection with multidrug-resistant (MDR) Gram-negative organisms leads to poorer outcomes in the critically ill burn patient. The aim of this study was to identify the risk factors for MDR Gram-negative pathogen infection in critically ill burn patients admitted to a major tertiary referral intensive care unit (ICU) in Australia. METHODS: A retrospective case-control study of all adult burn patients admitted over a 7-year period was conducted. Twenty-one cases that cultured an MDR Gram-negative organism were matched with 21 controls of similar age, gender, burn size and ICU stay. Multivariable conditional logistic regression was used to individually assess risk factors after adjusting for Acute Burn Severity Index. Adjusted odds ratios (ORs) were reported. P-values < 0.25 were considered as potentially important risk factors. RESULTS: Factors increasing the risk of MDR Gram-negative infection included superficial partial thickness burn size (OR: 1.08; 95% confidence interval (CI): 1.01-1.16; P-value: 0.034), prior meropenem exposure (OR: 10.39; 95% CI: 0.96-112.00; P-value: 0.054), Gram-negative colonization on admission (OR: 9.23; 95% CI: 0.65-130.15; P-value: 0.10) and escharotomy (OR: 2.66; 95% CI: 0.52-13.65; P-value: 0.24). For cases, mean age was 41 (SD: 13) years, mean total body surface area burned was 47% (SD: 18) and mean days in ICU until MDR specimen collection was 17 (SD: 10) days. CONCLUSION: Prior meropenem exposure, Gram-negative colonization on admission, escharotomy and superficial partial thickness burn size may be potentially important factors for increasing the risk of MDR Gram-negative infection in the critically ill burn patient.

Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta-Analysis.

OBJECTIVE: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients. DESIGN: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies. INTERVENTIONS: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities. MEASUREMENTS AND MAIN RESULTS: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20-1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24-2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84-1.77). Subanalyses were conducted according to high (≥ 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results. CONCLUSIONS: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

Time to wait: a systematic review of strategies that affect out-patient waiting times.

Objective Out-patient waiting times pose a significant challenge for public patients in need of specialist evaluation and intervention. The aim of the present study was to identify and categorise effective strategies to reduce waiting times for specialist out-patient services with a focus on the Australian healthcare system. Methods A systematic review of major health databases was conducted using the key terms 'outpatient*' AND 'waiting time', 'process*' AND 'improvement in outpatient clinics'. Identified articles were assessed for their relevance by sequential review of the title, abstract and full text. References of the selected manuscripts were scanned for additional relevant articles. Selected articles were evaluated for consistent and emerging themes. Results In all, 152 articles were screened, of which 38 were included in the present review. Numerous strategies identified in the articles were consolidated into 26 consistent approaches. Three overarching themes were identified as significantly affecting waiting times: resource realignment, operational efficiency and process improvement. Conclusions Strategies to align resources, increase operational efficiency and improve processes provide a comprehensive approach that may reduce out-patient waiting times. What is known about the topic? Out-patient waiting times are a challenge in most countries that seek to provide universal access to health care for all citizens. Although there has been extensive research in this area, many patients still experience extensive delays accessing specialist care, particularly in the public health sector. The multiple factors that contribute to bottlenecks and inefficiencies in the referral process and affect patient waiting times are often poorly understood. What does this paper add? This paper reviews the published healthcare literature to identify strategies that affect specialist out-patient waiting times for patients. The findings suggest that there are numerous operational strategies that affect waiting times. These strategies may be categorised into three overarching themes (resource alignment, operational efficiencies and out-patient processes) that, when actioned in a coordinated approach, have the potential to significantly reduce out-patient waiting times. What are the implications for practitioners? This paper identifies evidence-based strategies for aligning resources, improving operational efficiency and streamlining processes, which may provide improvements to specialist out-patient waiting times for patients. Addressing the identified organisational, person-related, cultural and attitudinal factors will assist health system managers and health practitioners target the most appropriate improvement activities to reduce waiting times.

Changes in B-type Natriuretic Peptide and Related Hemodynamic Parameters Following a Fluid Challenge in Critically Ill Patients with Severe Sepsis or Septic Shock.

CONTEXT: Severe sepsis or septic shock. AIMS: The aim of this study is to examine the effect of a fluid challenge on the B-type natriuretic peptide (BNP) and the hemodynamic state. SETTINGS AND DESIGN: This observational study was conducted in an intensivist-led academic, mixed medical-surgical Intensive Care Unit. SUBJECTS AND METHODS: Focused transthoracic echocardiogram, plasma BNP, and hemodynamic measurements were recorded at baseline and following a 500 ml fluid challenge in thirty patients. Independent predictors of the percentage (%) change in stroke volume (SV) were sought. Next, these independent predictors were assessed for a relationship with the percentage change in BNP. STATISTICAL ANALYSIS USED: Multiple linear regressions, Wilcoxon rank-sum test, t-test, and Pearson's correlation were used. Data analysis was carried out using SAS. The 5% significance level was used. RESULTS: Using a multiple regression models, the percentage increase in SV was independently predicted by the percentage increase in mean arterial pressure, left ventricular end-diastolic volume/dimension (LVEDV/LVEDd), ejection fraction, and a decrease in Acute Physiology and Chronic Health Evaluation II score (P < 0.0001). Preload, measured using LVEDV1 (before the fluid challenge) was significantly larger in the fluid nonresponders (%SV increase <15%) vs. the responders (%SV increase ≥15%). Finally, the percentage change in BNP was positively correlated with left ventricular size at end diastole LVEDd, r = 0.4, P < 0.035). CONCLUSIONS: An increase in BNP soon after a fluid challenge may have some predictive utility of a large LVEDd, which in turn can be used to independently predict the SV response to a fluid challenge.

Association between augmented renal clearance and clinical outcomes in patients receiving ß-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial.

Augmented renal clearance (ARC) is known to influence ß-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive ß-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of ß-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

Should ß-lactam antibiotics be administered by continuous infusion in critically ill patients? A survey of Australia and New Zealand intensive care unit doctors and pharmacists.

Although there is a biological precedent for administration of ß-lactam antibiotics by continuous or extended infusion, there is no definitive evidence of a survival benefit compared with intermittent administration. The aim of this study was to explore clinician uncertainty with regard to the administration of ß-lactam antibiotics by continuous infusion. Doctors and pharmacists in Australian and New Zealand intensive care units (ICUs) were surveyed to investigate current ß-lactam antibiotic administration practices as well as the degree of uncertainty regarding the benefit of continuous infusion of two commonly used broad-spectrum ß-lactams, namely meropenem and piperacillin/tazobactam (TZP). There were 111 respondents to the survey. Intermittent infusion was reported as standard practice for meropenem (73.9%) and TZP (82.0%). A greater proportion of pharmacists compared with doctors believed continuous infusion to be more effective than intermittent administration (85.4% vs. 34.3%, respectively; P <0.001). Both groups reported uncertainty as to whether administration by continuous infusion resulted in better patient outcomes (65.9% and 74.6%, respectively; P = 0.85). Overall, 91.0% of respondents were prepared to enrol eligible patients into a definitive randomised controlled trial on ß-lactam antibiotic administration. In conclusion, there is equipoise among clinicians working in Australian and New Zealand ICUs as to whether administration by continuous infusion offers a survival benefit in critically ill patients.

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

RATIONALE: Optimization of ß-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 ß-lactam antibiotics. METHODS: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of ß-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 ß-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 ß-lactam administration was not independently associated with clinical cure. CONCLUSIONS: Compared with intermittent dosing, administration of ß-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality.

Antenatal and postnatal radiologic diagnosis of holocarboxylase synthetase deficiency: a systematic review.

BACKGROUND: Holocarboxylase synthetase deficiency results in impaired activation of enzymes implicated in glucose, fatty acid and amino acid metabolism. Antenatal imaging and postnatal imaging are useful in making the diagnosis. Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. Although biochemical assays are required for definitive diagnosis, certain radiologic features assist in the diagnosis of holocarboxylase synthetase deficiency. OBJECTIVE: To review evidence regarding radiologic diagnostic features of holocarboxylase synthetase deficiency in the antenatal and postnatal period. MATERIALS AND METHODS: A systematic review of all published cases of holocarboxylase synthetase deficiency identified by a search of Pubmed, Scopus and Web of Science. RESULTS: A total of 75 patients with holocarboxylase synthetase deficiency were identified from the systematic review, which screened 687 manuscripts. Most patients with imaging (19/22, 86%) had abnormal findings, the most common being subependymal cysts, ventriculomegaly and intraventricular hemorrhage. CONCLUSION: Although the radiologic features of subependymal cysts, ventriculomegaly, intraventricular hemorrhage and intrauterine growth restriction may be found in the setting of other pathologies, these findings should prompt consideration of holocarboxylase synthetase deficiency in at-risk children.

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

RATIONALE: Continuous infusion of ß-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 ß-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).