Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial.

IMPORTANCE: Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness. OBJECTIVE: To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2 days. INTERVENTIONS: Random allocation to receive a daily supplement of up to 100 g of IV amino acids or standard care. MAIN OUTCOMES AND MEASURES: Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function. RESULTS: 474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE II scores (20.2 ± 6.8 vs. 21.7 ± 7.6, P = 0.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P = 0.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21 AKI days per 10 patient ICU days, 95 % CI -0.27 to 1.04, P = 0.45). Amino acid therapy significantly improved eGFR (treatment group × time interaction, P = 0.004), with an early peak difference of 7.7 mL/min/1.73 m(2) (95 % CI 1.0-14.5 mL/min/1.73 m(2), P = 0.02) on study day 4. Daily urine output was also significantly increased (+300 mL/day, 95 % CI 145-455 mL, P = 0.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P = 0.062); however, this trend was not present after controlling for baseline imbalance (P = 0.21). CONCLUSION AND RELEVANCE: Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609001015235.

Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial.

IMPORTANCE: Systematic reviews suggest adult patients in intensive care units (ICUs) with relative contraindications to early enteral nutrition (EN) may benefit from parenteral nutrition (PN) provided within 24 hours of ICU admission. OBJECTIVE: To determine whether providing early PN to critically ill adults with relative contraindications to early EN alters outcomes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, single-blind clinical trial conducted between October 2006 and June 2011 in ICUs of 31 community and tertiary hospitals in Australia and New Zealand. Participants were critically ill adults with relative contraindications to early EN who were expected to remain in the ICU longer than 2 days. INTERVENTIONS: Random allocation to pragmatic standard care or early PN. MAIN OUTCOMES AND MEASURES: Day-60 mortality; quality of life, infections, and body composition. RESULTS: A total of 1372 patients were randomized (686 to standard care, 686 to early PN). Of 682 patients receiving standard care, 199 patients (29.2%) initially commenced EN, 186 patients (27.3%) initially commenced PN, and 278 patients (40.8%) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days (95% CI, 2.3 to 3.4). Patients receiving early PN commenced PN a mean of 44 minutes after enrollment (95% CI, 36 to 55). Day-60 mortality did not differ significantly (22.8% for standard care vs 21.5% for early PN; risk difference, -1.26%; 95% CI, -6.6 to 4.1; P = .60). Early PN patients rated day-60 quality of life (RAND-36 General Health Status) statistically, but not clinically meaningfully, higher (45.5 for standard care vs 49.8 for early PN; mean difference, 4.3; 95% CI, 0.95 to 7.58; P = .01). Early PN patients required fewer days of invasive ventilation (7.73 vs 7.26 days per 10 patient × ICU days, risk difference, -0.47; 95% CI, -0.82 to -0.11; P = .01) and, based on Subjective Global Assessment, experienced less muscle wasting (0.43 vs 0.27 score increase per week; mean difference, -0.16; 95% CI, -0.28 to -0.038; P = .01) and fat loss (0.44 vs 0.31 score increase per week; mean difference, -0.13; 95% CI, -0.25 to -0.01; P = .04). CONCLUSIONS AND RELEVANCE: The provision of early PN to critically ill adults with relative contraindications to early EN, compared with standard care, did not result in a difference in day-60 mortality. The early PN strategy resulted in significantly fewer days of invasive ventilation but not significantly shorter ICU or hospital stays. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN012605000704695.

Failure to report protocol violations in clinical trials: a threat to internal validity?

BACKGROUND: Excessive protocol violations (PV), which can be defined as preventable mistakes in study conduct, may result in patient harm and introduce errors into a clinical trial's results leading to flawed trial conclusions.The purpose of this project was to gain a better understanding of reported PVs, to describe current practice with regards to the use of methods for the reduction of PVs and to investigate relationships between clinical trial characteristics and PVs. METHODS: We reviewed 80 clinical trials conducted across a broad range of medical specialties published in four major general medical journals (The Lancet, NEJM, JAMA, BMJ). Eligible papers were identified using a PubMed search. For each included trial, two authors independently abstracted information on trial characteristics, PV reporting and PV rates and interventions used to reduce PVs. PVs were categorised into one of five distinct types: enrollment, randomisation, study intervention, patient compliance and data collection errors. Associations between PVs and study characteristics were investigated using logistic regression. RESULTS: Eighty clinical trials (20 from each journal) were identified from 101 consecutive PubMed abstracts. The median number of participants was 701 (range: 20 to 162, 367) and the median number of participating sites was 15 (range: 1 to 701). Nineteen percent (15/80) of included trials were single centre trials. The median study duration was 24 months (range: 5.81 - 127 months) and 74% (59/80) of included trials were primarily academic funded.Thirty two percent (26/80) of included trials failed to provide explicit reporting of any type of PV and none (0/80) of the trials provided explicit reporting of all five types of PVs. Larger clinical trials (more patients, more sites, longer duration, more complex management structure) were more likely to have more complete reporting of PV's.Only 9% (7/80) of trials reported the use of a specific study method to prevent PVs. Use of a run-in phase was the only method reported. CONCLUSIONS: PVs are under-reported. Although the CONSORT statement provides guidance on the reporting of PVs, reporting requirements are not explicit for all types of PVs. As a first step towards improved reporting by authors, we recommend the CONSORT statement highlight the importance of PVs by making reporting requirements more explicit.

Neurologic complications after off-pump coronary artery bypass grafting with and without aortic manipulation: meta-analysis of 11,398 cases from 8 studies.

OBJECTIVE: Neurologic complications after coronary artery bypass grafting remain a concern. Off-pump coronary artery bypass grafting is a surgical strategy proposed to decrease this risk. Use of an off-pump anaortic technique, which leaves the ascending aorta untouched, may result in further reductions. This systematic review of all published evidence compares neurologic complications after anaortic off-pump coronary artery bypass grafting versus that with aortic manipulation. METHODS: PubMed and Embase were searched up to August 2008. Experts were contacted, and reference lists of retrieved articles were hand searched. The search process was not limited to English-language sources. Observational studies comparing standard off-pump coronary artery bypass grafting technique with anaortic technique were eligible for inclusion if they reported neurologic complications (stroke and transient ischemic attack). Meta-analysis was conducted to assess differences between groups with regard to neurologic complications. RESULTS: Electronic search identified 1428 abstracts, which resulted in retrieval and detailed review of 331 full-text articles. Eight observational studies reported neurologic complications in 5619 anaortic off-pump coronary artery bypass grafting cases and 5779 cases with aortic manipulation. Postsurgical neurologic complications were significantly lower in anaortic off-pump coronary artery bypass grafting cases (odds ratio, 0.46; 95% confidence interval, 0.29-0.72; I(2) = 0.8%; P = .0008). CONCLUSIONS: Avoidance of aortic manipulation during off-pump coronary artery bypass grafting decreases neurologic complications relative to standard technique in which the ascending aorta is manipulated. In patients at high risk for stroke or transient ischemic attack, we recommend avoidance of aortic manipulation during off-pump coronary artery bypass grafting.

Early enteral nutrition reduces mortality in trauma patients requiring intensive care: a meta-analysis of randomised controlled trials.

INTRODUCTION: To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to adult trauma patients who require intensive care. MATERIALS AND METHODS: MEDLINE and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews was undertaken and academic and industry experts were contacted. Methodologically sound randomised controlled trials (RCTs) conducted in adult trauma patients requiring intensive care that compared the delivery of standard EN, provided within 24 h of injury, to standard care were included.The primary analysis was conducted on clinically meaningful patient-oriented outcomes, which included mortality, functional status and quality of life. Secondary analyses considered vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analysis was conducted using an analytical method known to minimise bias in the presence of sparse events. The impact of heterogeneity was assessed using the I2 metric. RESULTS: Three RCTs with 126 participants were found to be free from major flaws and were included in the primary analysis. The provision of early EN was associated with a significant reduction in mortality(OR = 0.20, 95% confidence interval 0.04­0.91, I2 = 0). No other outcomes could be pooled. A sensitivity analysis and a confirmatory analysis conducted using a different analytical method confirmed the presence of a mortality reduction. CONCLUSION: Although the detection of a statistically significant reduction in mortality is promising,overall trial quality was low and trial size was small. The results of this meta-analysis should be confirmed by the conduct of a large multi-center trial.

A systematic review of techniques and interventions for improving adherence to inclusion and exclusion criteria during enrolment into randomised controlled trials.

BACKGROUND: Enrolment of patients into a randomised controlled trial (RCT) in violation of key inclusion or exclusion criteria, may lead to excess avoidable harm. The purpose of this paper was to systematically identify and review techniques and interventions proven to prevent or avoid inappropriate enrolment of patients into RCTs. METHODS: EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, online abstract repositories, and conference websites were searched. Experts were contacted and bibliographies of retrieved papers hand-searched. The search cut-off date was 31 August 2009. RESULTS: No primary publications were found. We identified one study in the grey literature (conference abstracts and presentations) reporting the results of an evaluation of the effectiveness of an intervention designed to prevent or avoid inappropriate enrolment of patients into an RCT. In the context of a multicentre trial, use of a dummy enrolment run-in phase was shown to reduce enrolment errors significantly (P < 0.001), from 16.1% during the run-in phase to < 1% after trial initiation. CONCLUSIONS: Our systematic search yielded only one technique or intervention shown to improve adherence to eligibility criteria during enrolment into RCTs. Given the potential harm involved in recruiting patients into a clinical trial in violation of key eligibility criteria, future research is needed to better inform those conducting clinical trials of how best to prevent enrolment errors.

Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials.

PURPOSE: To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to critically ill patients. METHODS: Medline and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews were undertaken, and academic and industry experts were contacted. Methodologically sound randomised controlled trials (RCTs) conducted in critically ill patient populations that compared the delivery of standard EN, provided within 24 h of intensive care unit (ICU) admission or injury, to standard care were included. The primary analysis was conducted on clinically meaningful patient-oriented outcomes. Secondary analyses considered vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analyses were conducted using the odds ratio (OR) metric and a fixed effects model. The impact of heterogeneity was assessed using the I (2) metric. RESULTS: Six RCTs with 234 participants were analysed. The provision of early EN was associated with a significant reduction in mortality [OR = 0.34, 95% confidence interval (CI) 0.14-0.85] and pneumonia (OR = 0.31, 95% CI 0.12-0.78). There were no other significant differences in outcomes. A sensitivity analysis and a simulation exercise confirmed the presence of a mortality reduction. CONCLUSION: Although the detection of a statistically significant reduction in mortality is promising, overall trial quality was low, trial size was small, and the findings may be restricted to the patient groups enrolled into included trials. The results of this meta-analysis should be confirmed by the conduct of a large multi-centre trial enrolling diverse critically ill patient groups.

Evidence-based nutrition support in the intensive care unit: an update on reported trial quality.

PURPOSE OF REVIEW: Meta-epidemiological reviews report that trials of nutritional support in critical illness rarely fulfil basic quality requirements, with overall quality rated as 'worse than poor'. This update reviews recently published trials to determine whether current evidence meets or exceeds basic quality requirements. RECENT FINDINGS: Although recent trials were significantly more likely to report blinding, there is a concerning trend towards a decrease in overall trial quality. Many recent trials fail to report the use of 'any' of three key validity criteria: use of blinding, presentation of intention-to-treat analysis and the maintenance allocation concealment. SUMMARY: Future researchers must improve the quality with which trials are conducted and reported. Submitting a clinical trial to an approved registry prior to enrolling patients provides transparency of conduct. Investigators must ensure that an intention-to-treat analysis is reported, especially when a subset efficacy analysis is presented, even if the intention-to-treat analysis requires imputing missing data values. Investigators also need to improve reporting details concerning allocation concealment and blinding. Finally, until investigators, editors and reviewers embrace these measures, we strongly recommend that readers should become familiar with the appropriate evidence-based medicine users' guides so that they can base clinical decisions on valid studies.