This monocenter randomized controlled trial was performed in a German University Hospital between February 2016 and Mai 2017. It was approved by the appropriate Institutional Review Board (Ethikkommission der Ruhr-Universität Bochum, 4780-13) and registered at the Clinical Trials Registry (ref.: NCT03860129). Written informed consent was obtained from all patients prior to their inclusion in this study. Measurements complied with the ethical standards of the Declaration of Helsinki.
The MIRUS™ systems were kindly provided by the former marketeer (Pall Medical, Dreieich, Germany).
Study design and setting
We preoperatively enrolled ASA physical status classification I–III patients aged 18–80 years, who were scheduled for major surgery with an expected need for postoperative mechanical ventilation due to respiratory or hemodynamic problems (norepinephrine dose > 0.5 h−1, FiO2 > 0.5, PEEP > 10 mbar, body temperature < 36 °C). Exclusion criteria were ASA physical status classification IV, malignant hyperthermia, any neuromuscular diseases, increased intracranial pressure, autoimmune hepatitis, pregnancy, deafness, language barriers, involvement in other studies, refusal to give informed consent, and an expected tidal volume < 350 ml.
The closed envelop method was used to allocate patients at random to group ISO, SEVO, or DES.
General anesthesia was induced in the operating room with 0.2 µg kg−1 sufentanil and 2 mg kg−1 propofol to facilitate intubation with a cuffed tracheal tube. An epidural analgesia (ropivacaine 2 mg ml−1) was offered to patients without contraindications. Maintenance of anesthesia was with SEVO (1.0 MAC) and sufentanil. At the end of surgery, the SEVO application was stopped and patients obtained propofol (5 mg kg−1 h−1) for the transport from the operating room to the ICU.
Upon arrival in the ICU, patients were equipped with a multivariate electroencephalogram (Narcotrend®) to assess the depth of sedation. The RASS was additionally gathered by the nurses. After at least 1 h of propofol sedation (2.5 mg kg−1 h−1), patients were switched to VA sedation via MIRUS™. The patient’s expiratory VA concentration was monitored by MIRUS™ and automatically adjusted to maintain the target value 0.5 MAC. Sufentanil was administered by a syringe pump (5–30 µg h−1). The minimum VA sedation time was 2 h.
Lung protective mechanical ventilation (tidal volume 6–8 ml kg−1) was performed with a Puritan Bennett 840 ventilator (Covidien, Boulder, Co, USA) on a Bi-Level mode, which allows pressure control and pressure support ventilation. The pressure control mode was solely used until the criteria for a wake-up test were met (norepinephrine < 0.5 h−1, FiO2 < 0.5, PEEP < 10 mbar, body temperature > 36 °C). Then, the respiratory rate was halved, the pressure support mode used, and a spontaneous breathing trail performed (support 5–15 mbar, PEEP 5 mbar, FiO2 0.3). VA was still administered at 0.5 MAC. The sufentanil dose was not changed initially but reduced by 10 µg kg−1 h−1 if the patient did not start breathing within 30 min. An end-expiratory CO2 < 35 mmHg or > 14 breaths min−1 were treated with 5-µg sufentanil. As soon as patients breathed spontaneously (support 5 mbar), the rapid shallow breathing index was calculated (respiratory frequency divided by tidal volume). Once the index was < 105, the MAC was set to 0 with the exchanger within the breathing circuit (start of measuring awakening times). Decrement times from 0.5 to 0.25 MAC were recorded. The rapid shallow breathing index was again calculated immediately before extubation.
RASS was documented twice during propofol sedation, 5, 30, and 60 min after beginning of VA sedation, 60 min before the end and at the end of VA application, as well as after 5, 30, and 60 min in the post-sedation phase.
The Narcotrend® Index (NI), ventilation parameters, VA consumption, MAC, and expiratory VA concentration were continuously provided through the devices. The MAC fraction was evaluated using the formulas MAC1 = 1.47 vol% − (age·0.0071 vol%) for ISO, MAC1 = 2.31 vol% − (age·0.0106 vol%) for SEVO, and MAC1 = 8.43 vol% − (age·0.0428 vol%) for DES according to the manufacturer [7].
Blood gas analyses were performed upon ICU arrival, twice during VA sedation, and after the end of VA application to allow early adjustments of the set ventilator parameters.
A summary of the study design is pictured in Fig. 1.
Sample size calculation
Sample size calculation was conducted in g power (Heinrich-Heine-University, Dusseldorf, Germany) and is based on a pilot study investigating the VA consumption of MIRUS™ at 1.0 MAC during surgery [8]. Significantly different VA consumption rates of the three gases were reported with an estimated effect size of d = 3.56, which was transferred to the current study design. For an alpha of 0.05 and a power of 0.8, at least 3 patients per group were needed when analyzed via a univariate ANOVA. We enrolled 10 patients per group to detect effect sizes of at least d = 1.2, which displays a strong effect.
Statistical analysis
All variables were tested for normal distribution using the Kolmogorov–Smirnov test and each variables histogram. A non-parametric approach was chosen to analyze data consistently across groups and variables. All metric variables, except age, height and weight, which are displayed as mean ± 1 standard deviation, were presented as median [1st–3rd quartiles].
Differences across the 3 groups were tested for continuous variables with the Kruskal–Wallis test, which was further explored in case of a significant main effect ‘gas’ with the Mann–Whitney test. Age, height and weight were analyzed via a univariate ANOVA and further investigated with independent t-tests. Group-independent comparisons between propofol sedation and VA sedation were analyzed with the Wilcoxon test. Nominal data were analyzed via cross tables and the Chi2-test, or with Fishers exact test.
Effect sizes were calculated in case of significant results, meaning for direct group comparisons (Mann–Whitney tests) and for phase comparisons (Wilcoxon test). This was done via \(r = z/\sqrt {\text{Number of obersations}}\) with r = 0.1 (small effect), r = 0.3 (medium effect), and r = 0.5 (strong effect) [9].