Statistically significant differences versus convincing evidence of real treatment effects: an analysis of the false positive risk for single-centre trials in anaesthesia.

BACKGROUND: The American Statistical Association has highlighted problems with null hypothesis significance testing and outlined alternative approaches that may 'supplement or even replace P-values'. One alternative is to report the false positive risk (FPR), which quantifies the chance the null hypothesis is true when the result is statistically significant. METHODS: We reviewed single-centre, randomised trials in 10 anaesthesia journals over 6 yr where differences in a primary binary outcome were statistically significant. We calculated a Bayes factor by two methods (Gunel, Kass). From the Bayes factor we calculated the FPR for different prior beliefs for a real treatment effect. Prior beliefs were quantified by assigning pretest probabilities to the null and alternative hypotheses. RESULTS: For equal pretest probabilities of 0.5, the median (inter-quartile range [IQR]) FPR was 6% (1-22%) by the Gunel method and 6% (1-19%) by the Kass method. One in five trials had an FPR ≥20%. For trials reporting P-values 0.01-0.05, the median (IQR) FPR was 25% (16-30%) by the Gunel method and 20% (16-25%) by the Kass method. More than 90% of trials reporting P-values 0.01-0.05 required a pretest probability >0.5 to achieve an FPR of 5%. The median (IQR) difference in the FPR calculated by the two methods was 0% (0-2%). CONCLUSIONS: Our findings suggest that a substantial proportion of single-centre trials in anaesthesia reporting statistically significant differences provide limited evidence of real treatment effects, or, alternatively, required an implausibly high prior belief in a real treatment effect. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42023350783).

Incidence of postoperative delirium in surgical patients: An observational retrospective cohort study.

SummaryPerioperative neurocognitive disorders including postoperative delirium (POD) are common complications of anaesthesia and surgery, associated with morbidity, mortality and a large economic cost. Currently, limited data are available on the incidence of POD in the New Zealand population. The objective of this study was to utilise New Zealand national level datasets to identify the incidence of POD. Our primary outcome was defined as a diagnosis of delirium via ICD 9/10 coding within seven days of surgery. We also analysed demographic, anaesthetic and surgical characteristics. All adult patients undergoing any surgical intervention under sedation, regional, general or neuraxial anaesthesia were included, and patients who received surgical intervention under local anaesthetic infiltration alone were excluded. We reviewed ten years of patient admissions from 2007 to 2016. Our sample size was 2,249,910 patients. The incidence of POD was 1.9%, much lower than previously observed, potentially indicating significant under-reporting of POD in this national level database. With acknowledgement of the limitations of potential undercoding and under-reporting, we found that the incidence of POD was higher with increasing age, male sex, general anaesthesia, Maori ethnicity, increasing comorbidity, surgical severity and emergency surgery. A diagnosis of POD was associated with increased mortality and hospital length of stay. Our results highlight potential risk factors of POD and disparities in health outcomes in New Zealand. Additionally, these findings suggest systemic under-reporting of POD in national level datasets.

Using the Delphi process to determine the minimum clinically important effect size for the Balanced-2 randomised controlled trial.

BACKGROUND: The sample size calculation is an important step in designing randomised controlled trials. For a trial comparing a control and an intervention group, where the outcome is binary, the sample size calculation requires choosing values for the anticipated event rates in both the control and intervention groups (the effect size), and the error rates. The Difference ELicitation in TriAls guidance recommends that the effect size should be both realistic, and clinically important to stakeholder groups. Overestimating the effect size leads to sample sizes that are too small to reliably detect the true population effect size, which in turn results in low achieved power. In this study, we use the Delphi approach to gain consensus on what the minimum clinically important effect size is for Balanced-2, a randomised controlled trial comparing processed electroencephalogram-guided 'light' to 'deep' general anaesthesia on the incidence of postoperative delirium in older adults undergoing major surgery. METHODS: Delphi rounds were conducted using electronic surveys. Surveys were administered to two stakeholder groups: specialist anaesthetists from a general adult department in Auckland City Hospital, New Zealand (Group 1), and specialist anaesthetists with expertise in clinical research, identified from the Australian and New Zealand College of Anaesthetist's Clinical Trials Network (Group 2). A total of 187 anaesthetists were invited to participate (81 from Group 1 and 106 from Group 2). Results from each Delphi round were summarised and presented in subsequent rounds until consensus was reached (>70% agreement). RESULTS: The overall response rate for the first Delphi survey was 47% (88/187). The median minimum clinically important effect size was 5.0% (interquartile range: 5.0-10.0) for both stakeholder groups. The overall response rate for the second Delphi survey was 51% (95/187). Consensus was reached after the second round, as 74% of respondents in Group 1 and 82% of respondents in Group 2 agreed with the median effect size. The combined minimum clinically important effect size across both groups was 5.0% (interquartile range: 3.0-6.5). CONCLUSIONS: This study demonstrates that surveying stakeholder groups using a Delphi process is a simple way of defining a minimum clinically important effect size, which aids the sample size calculation and determines whether a randomised study is feasible.

Processed electroencephalography-guided general anaesthesia to reduce postoperative delirium: a systematic review and meta-analysis.

BACKGROUND: Postoperative delirium (POD) is the most common serious postoperative complication in older adults. It has uncertain aetiology, limited preventative strategies, and poor long-term outcomes. This updated systematic review and meta-analysis aimed to estimate the effect of processed electroencephalography (pEEG)-guided general anaesthesia during surgery on POD incidence. METHODS: We performed a systematic review and meta-analysis by searching OVID MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases. Studies of adult patients having general anaesthesia for any surgery where pEEG was used and POD was an outcome measure were included. Full-text reports of RCTs published from database inception until August 28, 2021, were included. Trials were excluded if sedation rather than general anaesthesia was administered, or the setting was intensive care. The primary outcome was POD assessed by validated tools. The study was prospectively registered with PROSPERO. RESULTS: Nine studies, which included 4648 eligible subjects, were identified. The incidence of POD in the pEEG-guided general anaesthesia or lighter pEEG target group was 19.0% (440/2310) compared with 23.3% (545/2338) in the usual care or deeper pEEG target group (pooled odds ratio=0.78; 95% confidence interval, 0.60-1.00; P=0.054). Significant heterogeneity was detected (I2=53%). CONCLUSIONS: Our primary analysis demonstrated a highly sensitive result with a pooled analysis of trials in which the intervention group adhered to manufacturer's recommended guidelines, showing reduced incidence of POD with pEEG guidance. High clinical heterogeneity limits inferences from this and any future meta-analyses. CLINICAL TRIAL REGISTRATION: CRD42020199404 (PROSPERO).

Towards a national perioperative outcomes registry: A survey of perioperative electronic medical record utilisation to support quality assurance and research at Australian and New Zealand College of Anaesthetists Clinical Trials Network hospitals in Australia.

In Australia, 2.7 million surgical procedures are performed annually. Historically, a lack of perioperative data standardisation and infrastructure has limited pooling of routinely collected data across institutions. We surveyed Australian and New Zealand College of Anaesthetists (ANZCA) Clinical Trials Network hospitals to investigate current and potential uses of perioperative electronic medical record data for research and quality assurance.A targeted survey was sent to 131 ANZCA Clinical Trials Network-affiliated hospitals in Australia. The primary aim was to map current electronic data collection methods and data utilisation in six domains of the perioperative pathway.The survey response rate was 32%. Electronic data recording in the six domains ranged from 19% to 85%. Where electronic data exist, the ability of anaesthesiology departments to export them for analysis ranged from 27% to 100%. The proportion of departments with access to data exports that are regularly exporting the data for quality assurance or research ranged from 13% to 58%.The existence of a perioperative electronic medical record does not automatically lead to the data being used to measure and improve clinical outcomes. The first barrier is clinician access to data exports. Even when this barrier is overcome, a large gap remains between the proportion of departments able to access data exports and those using the data regularly to inform and improve clinical practice. We believe this gap can be addressed by establishing a national perioperative outcomes registry to lead high-quality multicentre registry research and quality assurance in Australia.

Protocol for the MAnagement of Systolic blood pressure during Thrombectomy by Endovascular Route for acute ischemic STROKE randomized clinical trial: The MASTERSTROKE trial.

REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12619001274167p. RATIONALE: Cerebral blood flow is blood pressure-dependent when cerebral autoregulation is impaired. Cerebral ischemia and anesthetic drugs impair cerebral autoregulation. In ischemic stroke patients treated with endovascular thrombectomy, induced hypertension is a plausible intervention to increase blood flow in the ischemic penumbra until reperfusion is achieved. This could potentially reduce final infarct size and improve functional recovery. AIM: To test if patients with large vessel occlusion stroke treated with endovascular thrombectomy will benefit from induced hypertension. DESIGN: Prospective, randomized, parallel group, open label, multicenter clinical trial with blinded assessment of outcomes. PROCEDURES: Patients with anterior circulation stroke treated with endovascular thrombectomy with general anesthesia within 6 h of symptom onset, and patients with 'wake up' stroke or presenting within 6 to 24 h with potentially salvageable tissue on computed tomography perfusion scanning, are included. Participants are randomized to a systolic blood pressure target of 140 mmHg or 170 mmHg from procedure initiation until recanalization. Methods to maintain the blood pressure are at the discretion of the procedural anesthesiologist. STUDY OUTCOMES: The primary efficacy outcome is improvement in disability measured by modified Rankin Scale score at 90 days. The primary safety outcome is all-cause mortality at 90 days. ANALYSIS: The Mann-Whitney U test will be used to test the ordinal shift in the seven-category modified Rankin Scale score. All-cause mortality will be estimated using the Kaplan-Meier method and compared using a log-rank test.

General Anesthesia Versus Conscious Sedation in Endovascular Thrombectomy for Stroke: A Meta-analysis of 4 Randomized Controlled Trials.

BACKGROUND: In ischemic stroke patients, studies have suggested that clinical outcomes following endovascular thrombectomy are worse after general anesthesia (GA) compared with conscious sedation (CS). Most data are from observational trials, which are prone to measure and unmeasure confounding. We performed a systematic review and meta-analysis of thrombectomy trials where patients were randomized to GA or CS, and compared efficacy and safety outcomes. METHODS: The Medline, Embase, and Cochrane databases were searched for randomized controlled trials comparing GA to CS in endovascular thrombectomy. Efficacy outcomes included successful recanalization (Thrombolysis in Cerebral Infarction score of 2b to 3), and good functional outcome, defined as a modified Rankin Scale score of 0 to 2 at 3 months. Safety outcomes included intracerebral hemorrhage and 3-month mortality. RESULTS: Four studies were identified and included in the random effects meta-analysis. Patients treated with GA achieved a higher proportion of successful recanalization (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.26-3.62; P=0.005) and good functional outcome (OR: 1.71, 95% CI: 1.13-2.59; P=0.01). For every 7.9 patients receiving GA, one more achieved good functional outcome compared with those receiving CS. There were no significant differences in intracerebral hemorrhage (OR: 0.61, 95% CI: 0.20-1.85; P=0.38) or 3-month mortality (OR: 0.62, 95% CI: 0.33-1.17; P=0.14) between GA and CS patients. CONCLUSIONS: In centers with high quality, specialized neuroanesthesia care, GA treated thrombectomy patients had superior recanalization rates and better functional outcome at 3 months than patients receiving CS.

Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors.

Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.

Development and Validation of a Multivariate Prediction Model of Perioperative Mortality in Neurosurgery: The New Zealand Neurosurgical Risk Tool (NZRISK-NEURO).

BACKGROUND: Multivariate risk prediction models individualize prediction of adverse outcomes, assisting perioperative decision-making. There are currently no models specifically designed for the neurosurgical population. OBJECTIVE: To develop and validate a neurosurgical risk prediction model, with 30-d, 1-yr, and 2-yr mortality endpoints. METHODS: We accessed information on all adults in New Zealand who underwent neurosurgery or spinal surgery between July 1, 2011, and June 30, 2016, from an administrative database. Our dataset comprised of 18 375 participants, split randomly into derivation (75%) and validation (25%) datasets. Previously established covariates tested included American Society of Anesthesiologists physical status grade (ASA-PS), surgical acuity, operative severity, cancer status, and age. Exploratory covariates included anatomical site, gender, diabetes, trauma, ethnicity, and socioeconomic status. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct 30-d, 1-yr, and 2-yr mortality models. RESULTS: Our final models included 8 covariates: age, ASA-PS grade, surgical acuity, cancer status, anatomical site, diabetes, ethnicity, and trauma. The area under the receiver operating curve for the 30-d, 1-yr, and 2-yr mortality models was 0.90, 0.91, and 0.91 indicating excellent discrimination, respectively. Calibration also showed excellent performance with McFadden's pseudo R2 statistics of 0.28, 0.37, and 0.41 and calibration plot slopes of 0.93, 0.95, and 0.94, respectively. The strongest predictors of mortality were ASA-PS 4 and 5 (30 d) and cancer (1 and 2 yr). CONCLUSION: NZRISK-NEURO is a robust multivariate calculator created specifically for neurosurgery, enabling physicians to generate data-driven individualized risk estimates, assisting shared decision-making and perioperative planning.

Systematic review and meta-analysis of the perioperative use of vasoactive drugs on postoperative outcomes after major abdominal surgery.

BACKGROUND: The perioperative use of vasoactive drugs is ubiquitous in clinical anaesthesia; yet, the drugs, doses, and haemodynamic targets used are highly variable. Our objectives were to determine whether the perioperative administration of vasoactive drugs reduces mortality, morbidity, and length of stay in adult patients (aged 16 yr or older) undergoing major abdominal surgery. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for peer-reviewed RCTs with no language or date restrictions. Studies that assessed the intraoperative use of vasoactive drugs were included. Title, abstract, and full-text screening was performed. Risk of bias for each outcome measure was conducted. We calculated the risk ratio (RR) using the Mantel-Haenszel random-effects model with corresponding 95% confidence interval (CI) for dichotomous outcomes, and mean difference using the inverse variance random-effects model with corresponding 95% CI for continuous outcomes. RESULTS: Twenty-six studies (5561 participants) were included. There was no difference in mortality at the longest follow-up with an RR of 0.84 (95% CI: 0.63-1.12; P=0.23). The intervention significantly reduced the number of patients with one or more postoperative complications; RR: 0.76 (95% CI: 0.66-0.88; P=0.0002). Hospital length of stay was reduced by 0.91 days in the intervention group. CONCLUSIONS: This review is limited by the quality and sample size of individual studies, and the heterogeneity of the settings, interventions, and outcome measures. Perioperative administration of vasoactive drugs may reduce postoperative complications and hospital length of stay in adult patients having major abdominal surgery.

Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder.

BACKGROUND: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity. METHODS: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine. RESULTS: Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation. CONCLUSIONS: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.

Retrospective analysis of the 13-year trend in acute and elective surgery for patients aged 60 years and over at Auckland City Hospital, New Zealand.

BACKGROUND: As the worldwide population has aged, the number of surgical procedures performed on older patients has increased. It is not known whether this increase has been proportional to growth in the elderly population. The aim of this study was to assess the population-adjusted incidence of acute and elective general and orthopaedic surgery in older patients at a tertiary hospital in New Zealand. METHODS: This was a retrospective study using routinely collected electronic data from Auckland District Health Board (DHB) and New Zealand Ministry of Health databases. Population estimates and numbers of general surgical and orthopaedic procedures from 2004 to 2016 were obtained. Annual age-specific incidence rates of surgical procedures were calculated and trends analysed using negative binomial regression. RESULTS: The incidence of elective surgery increased by 5.35% annually from 2004 to 2016. The rate of increase is lower in the Maori population (2.14%) compared with other ethnic groups (4.22%-5.62%). The incidence of acute surgery in those aged 70 years and above decreased from 2004 to 2016. The European and other ethnic group had the highest rate of acute surgery, and higher rates of elective surgery than Pacific and Asian peoples. CONCLUSION: The increasing number of elective general surgical and orthopaedic procedures performed on older patients in Auckland DHB is beyond what is expected for population growth alone. This has significant implication for clinicians, healthcare providers and governmental institutions. Ethnic differences are evident and warrants further attention as these may reflect disparities in access to surgery.

Simultaneous EEG/fMRI recorded during ketamine infusion in patients with major depressive disorder.

A single subanaesthetic dose of ketamine rapidly alleviates the symptoms of major depressive disorder (MDD). However, few studies have investigated the acute effects of ketamine on the BOLD pharmacological magnetic resonance imaging (phMRI) response and EEG spectra. In a randomised, double-blind, active placebo-controlled crossover trial, resting-state simultaneous EEG/fMRI was collected during infusion of ketamine or active placebo (remifentanil) in 30 participants with MDD. Montgomery-Asberg depression rating scale scores showed a significant antidepressant effect of ketamine compared to placebo (69% response rate). phMRI analyses showed BOLD signal increases in the anterior cingulate and medial prefrontal cortices and sensitivity of the decrease in subgenual anterior cingulate cortex (sgACC) BOLD signal to noise correction. EEG spectral analysis showed increased theta, high beta, low and high gamma power, and decreased delta, alpha, and low beta power with differing time-courses. Low beta and high gamma power time courses explained significant variance in the BOLD signal. Interestingly, the variance explained by high gamma power was significantly associated with non-response to ketamine, but significant associations were not found for other neurophysiological markers when noise correction was implemented. The results suggest that the decrease in sgACC BOLD signal is potentially noise and unrelated to ketamine's antidepressant effect, highlighting the importance of noise correction and multiple temporal regressors for phMRI analyses. The lack of effects significantly associated with antidepressant response suggests the phMRI methodology employed was unable to detect such effects, the effect sizes are relatively small, or that other processes, e.g. neural plasticity, underlie ketamine's antidepressant effect.

A single-centre, randomised controlled feasibility pilot trial comparing performance of direct laryngoscopy versus videolaryngoscopy for endotracheal intubation in surgical patients.

INTRODUCTION: Most trials comparing effectiveness of laryngoscopy technique use surrogate endpoints. Intubation success is a more appropriate endpoint for comparing effectiveness of techniques or devices. A large pragmatic clinical trial powered for intubation success has not yet been performed. METHODS: We tested the feasibility of a randomised controlled trial to compare the performance of direct laryngoscopy versus videolaryngoscopy for endotracheal intubation. The trial was conducted in the Department of Adult and Emergency Anaesthesia at the Auckland City Hospital, New Zealand. Patients over 18 years who required endotracheal intubation and were not known or predicted to be difficult to bag-mask ventilate were eligible for the study. Patients were excluded if they required rapid sequence induction, fibreoptic intubation or were unable to consent due to language barriers or cognitive impairment.Patients were permuted block randomised in groups of 8 to either direct laryngoscopy (DL) or videolaryngoscopy (VL) for the technique of endotracheal intubation. Patients were blinded to laryngoscopic technique; the duty anaesthetist, outcome assessors and statistician were unblinded.Feasibility was assessed on recruitment rate, adherence to group assignment and data completeness. Primary outcome was first-pass success rate, with secondary outcomes of time to intubation (seconds), Intubation Difficulty Score and complication rate. RESULTS: One hundred and six patients were randomised and 100 patient results were analysed. Completed data from patients randomised to the DL group (n = 49) was compared with those in the VL group (n = 51). Group adherence and data completeness were 100% and 97%, respectively. First-pass success rate was 83.7% in the direct laryngoscopy group and 72.5% in the videolaryngoscopy group (p = 0.18). Median time to intubation was significantly shorter for direct laryngoscopy when compared to videolaryngoscopy (34 s v 43 s, p = 0.038). Complications included mucosal trauma and airway bleeding which are recognised complications of endotracheal intubation. CONCLUSION: A large, pragmatic, multicentre, randomised controlled trial comparing the relative effectiveness of direct laryngoscopy and indirect videolaryngoscopy is feasible. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12615001267549.

The five-minute prebreathe in evaluating carbon dioxide absorption in a closed-circuit rebreather: a randomized single-blind study.

INTRODUCTION: Closed-circuit underwater rebreather apparatus (CCR) recycles expired gas through a carbon dioxide (CO2) 'scrubber'. Prior to diving, users perform a five-minute 'prebreathe' during which they self-check for symptoms of hypercapnia that might indicate a failure in the scrubber. There is doubt that this strategy is valid. METHODS: Thirty divers were block-randomized to breathe for five minutes on a circuit in two of the following three conditions: normal scrubber, partly-failed scrubber, and absent scrubber. Subjects were blind to trial allocation and instructed to terminate the prebreathe on suspicion of hypercapnia. RESULTS: Early termination was seen in 0/20, 2/20, and 15/20 of the normal, partly-failed, and absent absorber conditions, respectively. Subjects in the absent group experienced a steady, uncontrolled rise in inspired (PICO2) and end-tidal CO2 (PETCO2). Seven subjects exhibited little or no increase in minute volume yet reported dyspnoea at termination, suggesting a biochemically-mediated stimulus to terminate. This was consistent with results in the partly-failed condition (which resulted in a plateaued mean PICO2 near 20 mmHg), where a small increase in ventilation typically compensated for the inspired CO2 increase. Consequently, mean PETCO2 did not change and in the absence of a hypercapnic biochemical stimulus, subjects were very insensitive to this condition. CONCLUSIONS: While prebreathes are useful to evaluate other primary functions, the five-minute prebreathe is insensitive for CO2 scrubber faults in a rebreather. Partly-failed conditions are dangerous because most will not be detected at the surface, even though they may become very important at depth.