The University of Michigan Institutional Review Board determined that this retrospective observational study that included data acquired prospectively for quality assurance (QA) purposes (HUM00163494) was exempt from regulation. The records of consecutive adults (age ≥ 18 years) who underwent a complete brain death evaluation from July 2016 through September 2022 were reviewed. Patients were identified on the basis of an institutional brain death registry, which includes all patients who have undergone a complete brain death evaluation. Baseline characteristics, including primary diagnosis, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (P/F ratio) measured before the apnea test, presence of ARDS based on the Berlin criteria [11], ventilator settings before the apnea test, vasopressor requirement, coronavirus disease 2019 (COVID-19) status, use of venovenous (VV) or venoarterial (VA) extracorporeal membrane oxygenation (ECMO), and organ donor status, were extracted from institutional medical records. Variables related to the apnea test, such as technique (oxygen insufflation vs. conventional mechanical ventilation), duration of the test, and peak arterial partial pressure of carbon dioxide (pCO2) were reviewed.

Brain death evaluation was performed in concordance with institutional policy. In 2016, following the acquisition of a fleet of Dräger Evita Infinity V500 ventilator machines, which provide an option to turn off the apnea backup, and clinical experience outside the brain death evaluation process, institutional policy was modified to allow performance of the apnea test on conventional mechanical ventilation. A postapproval neurocritical care QA project was initiated to monitor the use of this technique. Between July 2016 through December 2018, all apnea tests conducted on mechanical ventilation were supervised by neurointensivists who monitored ventilator scalars and reported any spontaneous or artifactual respiratory effort. Based on the results of this QA assessment, routine neurointensivist monitoring of apnea tests conducted on mechanical ventilation was discontinued in 2019, although the presence of a physician continued to be a requirement of the longstanding institutional protocol. The protocol also requires that details of any patient instability, artifactual respiration, or evidence of spontaneous respiration be included in brain death documentation within the medical record. Choice of apnea test technique was at the discretion of the attending physician. Preoxygenation was performed for ≥ 10 min before the apnea test. The target duration of the test was 10 min, at which point arterial blood gas analysis was performed. The test was terminated sooner in the presence of spontaneous respiratory effort or cardiopulmonary instability, defined as an oxygen saturation (SpO2) level < 90%, mean arterial pressure (MAP) < 65 mm Hg despite titration of vasopressor, systolic blood pressure < 90 mm Hg despite titration of vasopressor, or new cardiac arrhythmia. A decision to terminate the apnea test for severe patient instability was at the discretion of the physician supervising the test. When the apnea test was terminated for cardiopulmonary instability, arterial blood gas testing was performed before resumption of machine-initiated ventilation. Institutional criteria for an adequate respiratory stimulus were pCO2 ≥ 60 mm Hg with a ≥ 20-mm Hg rise from baseline. Apnea tests on mechanical ventilation were performed with Dräger Evita Infinity V500 machines in pressure support mode with the apnea backup turned off. The process to turn off the apnea backup in this and other commonly used conventional ventilators is presented in Table 1. Pressure support was turned to zero and variable PEEP, appropriate to the individual patient, was used. Apnea tests with oxygen insufflation were performed with disconnection from the ventilator, insertion of oxygen tubing into the ETT, and oxygen flow at 4–6 L/min. Patients who could not undergo or successfully complete apnea testing required a confirmatory test for the determination of brain death.

The primary outcome of interest was successful completion of the apnea test. The secondary outcome of interest was the occurrence of any complications attributable to apnea testing, including but not limited to institutional criteria for discontinuation: oxygen desaturation (SpO2 < 90%), hypotension (MAP < 65 mm Hg) despite titration of vasopressors, pneumothorax, new cardiac arrhythmia, and cardiac arrest. We also examined the occurrence of autotriggering events (with flow trigger at 2 L/min) and any description of artifactual waveforms that resembled spontaneous respiratory effort.

Descriptive analysis was performed with proportions and percentages for categorical variables and medians with interquartile ranges (IQRs) for continuous variables. The statistical significance of associations between variables and outcomes of interest was assessed with the χ2 test or Fischer exact test for categorical variables and the Mann–Whitney U-test for continuous variables. Multivariate analysis was performed with patient instability of any cause as the binary response variable and the following predictor variables: age, cause of brain death, P/F ratio, vasopressor requirement, use of ECMO, and apnea test technique. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated for independent predictors of the outcome. The threshold for statistical significance was p < 0.05.