Editorial group: Cochrane Methodology Review Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, 2021.
Background Acute kidney injury is a serious complication that occurs in the context of an acute critical illness or during a postoperative period. Earlier detection of acute kidney injury may facilitate strategies to preserve renal function, prevent further disease progression and reduce mortality. Acute kidney injury diagnosis relies on a rise in serum creatinine levels and/or fall in urine output; however, creatinine is an imperfect marker of kidney function. There is interest in the performance of novel biomarkers used in conjunction with existing clinical assessment, such as NephroCheck® (Astute Medical, Inc., San Diego, CA, USA), ARCHITECT® urine neutrophil gelatinase-associated lipocalin (NGAL) (Abbott Laboratories, Abbott Park, IL, USA), and urine and plasma BioPorto NGAL (BioPorto Diagnostics A/S, Hellerup, Denmark) immunoassays. If reliable, these biomarkers may enable earlier identification of acute kidney injury and enhance management of those with a modifiable disease course. Objective The objective was to evaluate the role of biomarkers for assessing acute kidney injury in critically ill patients who are considered for admission to critical care. Data sources Major electronic databases, conference abstracts and ongoing studies were searched up to June 2019, with no date restrictions. MEDLINE, EMBASE, Health Technology Assessment Database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Web of Science, World Health Organization Global Index Medicus, EU Clinical Trials Register, International Clinical Trials Registry Platform and ClinicalTrials.gov were searched. Review methods A systematic review and meta-analysis were conducted to evaluate the performance of novel biomarkers for the detection of acute kidney injury and prediction of other relevant clinical outcomes. Random-effects models were adopted to combine evidence. A decision tree was developed to evaluate costs and quality-adjusted life-years accrued as a result of changes in short-term outcomes (up to 90 days), and a Markov model was used to extrapolate results over a lifetime time horizon. Results A total of 56 studies (17,967 participants), mainly prospective cohort studies, were selected for inclusion. No studies addressing the clinical impact of the use of biomarkers on patient outcomes, compared with standard care, were identified. The main sources of bias across studies were a lack of information on blinding and the optimal threshold for NGAL. For prediction studies, the reporting of statistical details was limited. Although the meta-analyses results showed the potential ability of these biomarkers to detect and predict acute kidney injury, there were limited data to establish any causal link with longer-term health outcomes and there were considerable clinical differences across studies. Cost-effectiveness results were highly uncertain, largely speculative and should be interpreted with caution in the light of the limited evidence base. To illustrate the current uncertainty, 15 scenario analyses were undertaken. Incremental quality-adjusted life-years were very low across all scenarios, ranging from positive to negative increments. Incremental costs were also small, in general, with some scenarios generating cost savings with tests dominant over standard care (cost savings with quality-adjusted life-year gains). However, other scenarios generated results whereby the candidate tests were more costly with fewer quality-adjusted life-years, and were thus dominated by standard care. Therefore, it was not possible to determine a plausible base-case incremental cost-effectiveness ratio for the tests, compared with standard care. Limitations Clinical effectiveness and cost-effectiveness results were hampered by the considerable heterogeneity across identified studies. Economic model predictions should also be interpreted cautiously because of the unknown impact of NGAL-guided treatment, and uncertain causal links between changes in acute kidney injury status and changes in health outcomes. Conclusions Current evidence is insufficient to make a full appraisal of the role and economic value of these biomarkers and to determine whether or not they provide cost-effective improvements in the clinical outcomes of acute kidney injury patients. Future work Future studies should evaluate the targeted use of biomarkers among specific patient populations and the clinical impact of their routine use on patient outcomes and management. Study registration This study is registered as PROSPERO CRD42019147039. Funding This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 7. See the NIHR Journals Library website for further project information.
Background Early and accurate acute kidney injury (AKI) detection may improve patient outcomes and reduce health service costs. This study evaluates the diagnostic accuracy and cost-effectiveness of NephroCheck and NGAL (urine and plasma) biomarker tests used alongside standard care, compared with standard care to detect AKI in hospitalised UK adults. Methods A 90-day decision tree and lifetime Markov cohort model predicted costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) from a UK NHS perspective. Test accuracy was informed by a meta-analysis of diagnostic accuracy studies. Clinical trial and observational data informed the link between AKI and health outcomes, health state probabilities, costs and utilities. Value of information (VOI) analysis informed future research priorities. Results Under base case assumptions, the biomarker tests were not cost-effective with ICERs of £105,965 (NephroCheck), £539,041 (NGAL urine BioPorto), £633,846 (NGAL plasma BioPorto) and £725,061 (NGAL urine ARCHITECT) per QALY gained compared to standard care. Results were uncertain, due to limited trial data, with probabilities of cost-effectiveness at £20,000 per QALY ranging from 0 to 99% and 0 to 56% for NephroCheck and NGAL tests respectively. The expected value of perfect information (EVPI) was £66 M, which demonstrated that additional research to resolve decision uncertainty is worthwhile. Conclusions Current evidence is inadequate to support the cost-effectiveness of general use of biomarker tests. Future research evaluating the clinical and cost-effectiveness of test guided implementation of protective care bundles is necessary. Improving the evidence base around the impact of tests on AKI staging, and of AKI staging on clinical outcomes would have the greatest impact on reducing decision uncertainty.
Background Convulsive status epilepticus is the most severe form of epilepsy and requires urgent treatment. We synthesised the current evidence on first-line treatments for controlling seizures in adults with convulsive status epilepticus before, or at, arrival at hospital. Methods We conducted a systematic review of randomised controlled trials (RCTs) assessing antiepileptic drugs offered to adults as first-line treatments. Major electronic databases were searched. Results Four RCTs (1234 adults) were included. None were conducted in the UK and none assessed the use of buccal or intranasal midazolam. Both intravenous lorazepam and intravenous diazepam administered by paramedics were more effective than placebo and, notably, intramuscular midazolam was non-inferior to intravenous lorazepam. Overall, median time to seizure cessation from drug administration varied from 2 to 15 min. Rates of respiratory depression among participants receiving active treatments ranged from 6.4 to 10.6%. Mortality ranged from 2 to 7.6% in active treatment groups and 6.2 to 15.5% in control groups. Conclusions Intravenous and intramuscular benzodiazepines are safe and effective in this clinical context. Further research is needed to establish the most clinically and cost-effective first-line treatment and preferable mode of administration. Head-to-head trials comparing buccal versus intranasal midazolam versus rectal diazepam would provide useful information to inform the management of the first stage of convulsive status epilepticus in adults, especially when intravenous or intramuscular access is not feasible. Approaches to improve adherence to clinical guidelines on the use of currently available benzodiazepines for the first-line treatment of convulsive status epilepticus should also be considered.
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