Adaptive support ventilation (ASV) is an advanced closed-loop mode of mechanical ventilation (MV) that maintains an operator preset minute ventilation. ASV adjusts respiratory rates and pressure levels according to measured lung mechanics at each breath.1 In addition, ASV automatically switches between controlled and assisted ventilation according to the patient's status.2 Previous randomized controlled trials have tested the efficacy of ASV in patients after cardiothoracic surgery.3–5 In a study of fast-track cardiothoracic surgery patients, ASV compared with synchronized intermittent mandatory ventilation or traditional pressure support ventilation shortened the time to tracheal extubation.5 This was confirmed in another study of fast-track cardiothoracic surgery patients in which ASV was compared with pressure-regulated volume controlled ventilation.4 However, in a recent study of nonfast-track cardiothoracic surgery patients, ASV compared with traditional pressure support ventilation did not shorten the time to tracheal extubation.3
A lower operator set %-minute ventilation with ASV may allow for earlier and more frequent switches from controlled to assisted ventilation. Indeed, patients whose lungs are ventilated with lower minute volumes could be forced to breathe spontaneously sooner because arterial PCO2 thresholds for breathing are reached faster.6 Second, in the above-mentioned study of nonfast-track cardiothoracic surgery patients,3 patients were able to trigger the ventilator early in the weaning process, at least suggesting that a lower operator set %-minute could push patients toward longer periods of assisted ventilation and thereby earlier tracheal extubation.
In a randomized controlled trial of patients after planned and uncomplicated nonfast-track coronary artery bypass graft (CABG), we compared ASV using protocolized de-escalation and escalation of operator set %-minute ventilation (ASV-DE) with ASV using a fixed operator set %-minute ventilation (standard ASV). We hypothesized that ASV-DE reduces time to tracheal extubation compared with standard ASV.
Patients and Setting
Consecutive patients after elective and uncomplicated CABG admitted to the 28-bed intensive care unit (ICU) of the Academic Medical Center, Amsterdam, The Netherlands, were eligible for inclusion. The study protocol was approved by the local IRB, and preoperative written and signed informed consent was obtained from eligible patients programmed for surgery.
According to an open-label randomized controlled design, patients were assigned to receive MV with either ASV-DE or standard ASV.
Patients were included and randomized using sealed numbered envelopes on ICU arrival after surgery. We created a homogeneous group of patients after elective and uncomplicated CABG, i.e., without a history of chronic obstructive pulmonary disease or hemodynamic instability. Patients with a history of chronic obstructive pulmonary disease or a history of pulmonary surgery, and patients with an intraaortic balloon pump or inotropics and/or vasopressors at a more than usual rate (in milligrams per hour: dopamine 20, norepinephrine 0.5, dobutamine 25, or epinephrine [any rate]) on ICU arrival were excluded.
Cardiothoracic Surgery/Anesthesia Procedures
All patients in both groups were anesthetized according to our standard institutional protocol, starting with 1 or 2 mg lorazepam as premedication, followed by etomidate, sufentanil, and rocuronium for induction of anesthesia and facilitation of intubation. During the surgical procedure, sufentanil was used as analgesic, and sevoflurane plus propofol were used to maintain anesthesia. Muscle relaxants were not given during the surgical procedure. Morphine and midazolam could be administered at the end of the procedure.
Cardiopulmonary bypass was performed under moderate hypothermia (28°C–35°C), using a membrane oxygenator and nonpulsatile blood flow. At the end of anesthesia, all patients were transferred to the ICU with tracheal intubation. Anesthesiologists and surgeons at the operating room were blinded for inclusion or randomization of patients.
Unit policy comprised that a patient was cared for by a dedicated ICU nurse, responsible for 1 or 2 patients. Attending ICU nurses were constantly at the bedside, and changes in treatment according to the postoperative ICU protocol, based on observations by ICU nurses, were executed immediately.
The postoperative ICU protocol was similar for both study groups and involved fluid resuscitation with normal saline and starch solutions, blood transfusion to maintain hemoglobin concentration (≥5.0 mmol/L), norepinephrine in continuous infusion to achieve mean arterial blood pressure ≥70 mm Hg, and dobutamine and/or enoximone to achieve a cardiac index ≥2.5 L/min/m2 or a mixed venous oxygenation >60%.
Sedation and analgesics were given according to local protocol for postoperative cardiothoracic surgery patients. Propofol was given for sedation via continuous infusion. Infusion of propofol was stopped instantly when core temperature reached 35°C. The confusion assessment method for the ICU was used to screen for delirium, and if present, haloperidol was started. Acetaminophen (4 g/d) was started in all patients. The requirement for additional analgesia was assessed by attending ICU nurses. Morphine was given in boluses of 1 to 2 mg IV until patients were free of pain. The boluses were repeated as needed. Postoperative shivering, if present, was treated with meperidine (25 mg IV). Muscle relaxants were not given in the ICU.
All patients' lungs were ventilated by a Hamilton Galileo ventilator (software version GMP03.41f, GCP03.40a, GTP01.00; Hamilton Medical AG, Rhäzüns, Switzerland). Passive humidification of the ventilatory circuit was applied by means of an HME filter (Medisize Hygrovent S; Medisize, Hillegom, The Netherlands).
In both groups, the initial levels of fraction of inspired oxygen (FIO2) (50%) positive end-expiratory pressure (PEEP) (5 cm H2O), peak airway pressure (35 cm H2O), and %-minute ventilation (a theoretical value based on ideal body weight, 100%) were set by the attending ICU physician. Flow trigger sensitivity was set at 2 L/s; active patients could trigger the ventilator (i.e., actual minute ventilation could exceed set %-minute ventilation). An arterial blood gas analysis was performed 30 minutes after connection to the ICU ventilator, and 30 minutes after each modification of ventilator settings (except for FIO2), it was advised to perform an additional arterial blood gas analysis. FIO2 could be adjusted to maintain arterial oxygen saturation of ≥95%.
In both groups, patients were tracheally extubated after achieving general tracheal extubation criteria (i.e., responsive and cooperative, urine output >0.5 mL/kg/h, chest tube drainage <100 mL last hour, no uncontrolled arrhythmia, and having a core temperature >36.0°C and a respiratory frequency of >10 breaths per minute without machine-controlled breaths for at least 30 minutes). T-piece weaning was not used; patients were tracheally extubated when they reached the above-described extubation criteria.
ASV-DE Versus Standard ASV
With ASV-DE, as soon as body temperature reached 35.0°C with pH >7.25, irrespective of arterial PCO2, %-minute ventilation was decreased stepwise by 10% (de-escalation) until 70% of the theoretical value based on ideal body weight, only if pH declined <7.25%-minute ventilation was increased again (escalation) (Fig. 1). Indeed, by neglecting the PCO2 safety limits as defined for standard ASV, we created a span for de-escalation with ASV-DE.
With standard ASV, %-minute ventilation was only changed if PCO2 was <3.5 or >5.5 kPa. Indeed, settings with ASV were based on previously used safety limits to guarantee sufficient minute ventilation at all times.3
Collected data included the patient characteristics of gender, age, weight, and height, and the operation characteristics of number of bypasses, cardiopulmonary bypass time (pump time), and aortic clamp time. Intraoperative and ICU sedative and analgesic prescriptions; time from admission to ICU until reaching a central body temperature of 36.0°C; ventilation characteristics, tidal volume size, PEEP, inspiratory pressure (defined as the maximum airway pressure minus the level of PEEP) and respiratory rate, %-minute ventilation, and arterial blood gas data in time were collected. Respiratory data were collected by a data logger connected to the ventilator (Hamilton data logger, version 3.27.1; Hamilton Medical AG) and from our patient Data Management System (IMDsoft, Sassenheim, The Netherlands).
Outcome variables (see Definitions) were calculated for each patient. Primary end point was total duration of tracheal intubation; secondary end points were summed single assisted ventilation episodes, time to first single assisted ventilation episode, time to the assisted ventilation episode that was followed by tracheal extubation, and length of stay in the ICU.
Total duration of tracheal intubation was defined as the period from ICU admission until tracheal extubation, and a single assisted ventilation episode was defined as an episode of ≥20 minutes during which the patient was breathing at least 5 breaths per minute.
Opiate doses were all recalculated as morphine equipotent doses with the following formula: 10 mg morphine = 0.1 mg fentanyl = 0.01 mg sufentanil.7 Doses of benzodiazepines were similarly converted to equipotent doses of diazepam using the following formula: 5 mg midazolam = 10 mg diazepam = 50 mg oxazepam.8
The study was powered on total duration of tracheal intubation. Sample size assumptions were based on results of our previous study, i.e., a mean duration of ventilation of 16.4 hours in the ASV group.3 A reduction of approximately 10% was expected for the total duration of tracheal intubation. A sample size of 61 patients in each group was deemed to have 80% power to detect a difference in the duration of MV of 10%, assuming a common standard deviation of 3.3 hours, using a 2-sided t test with a 0.05 2-sided significance level.
Descriptive statistics were used to summarize patient characteristics. Categorical variables were compared between groups by χ2 tests. If normally distributed, continuous values were expressed as means ± SD; otherwise, medians and interquartile ranges were used. All analyses were performed in SPSS version 16.0 (SPSS, Inc., Chicago, IL).
We included 126 consecutive patients after elective and uncomplicated CABG: 63 patients were randomized to ASV-DE and 63 to standard ASV (Fig. 2). Of patients enrolled in the study, 2 patients were lost for analysis of the secondary end points because of data logger failures: 1 patient randomized to ASV-DE and 1 randomized to standard ASV.
Baseline, Perioperative, and ICU Characteristics
Groups were well balanced (Table 1). Arterial blood gas analyses on ICU admission were not different (data not shown). Core temperature on ICU admission was not different (35.5°C ± 1.1°C vs 35.7°C ± 0.6°C, ASV-DE versus standard ASV; P = 0.32). The number of patients with a temperature >36°C on ICU admission was also not different (27 [44%] vs 32 [51%], ASV-DE versus standard ASV; P = 0.24). There were no differences in time to rewarming to 36°C (2.1 ± 3.0 vs 1.7 ± 2.1 hours, ASV-DE versus standard ASV; P = 0.64). ICU survival was 100% for the 2 randomization groups.
In the ASV-DE group, mean %-minute ventilation at tracheal extubation was 92% ± 13% (14% were tracheally extubated at %-minute ventilation level of 70%, 77% at a level between 70% and 100%, and 9% at a level >100%). In the standard ASV group, mean %-minute ventilation at the time of tracheal extubation was 103% ± 10% (2% at a level <100%, 78% at a level of 100%, and 20% at a level >100%) (P < 0.05 versus ASV-DE).
Sedation and analgesic use was not different between randomization groups (Table 1). There were no patients who fulfilled the criteria for delirium, and haloperidol was never started.
Duration of MV and Assisted Ventilation Episodes
Duration of tracheal intubation was not different between groups (10.8 [6.5–16.1] vs 10.7 [6.6–13.9] hours, ASV-DE versus standard ASV; P = 0.32) (Fig. 3; Table 2). Neither time from admission to the first assisted breathing period (3.1 [2.0–6.7] vs 3.9 [2.1–7.5] hours; P = 0.49) nor the number of assisted ventilation episodes (78 [34–176] vs 57 [32–116] episodes; P = 0.20) was different. However, duration of assisted ventilation episodes that ended with tracheal extubation was longer with ASV-DE (2.5 [0.9–4.6] vs 1.4 [0.3–3.5] hours; P = 0.05).
In a per-protocol analysis in which only patients who reached ≤80%-minute ventilation before tracheal extubation were compared with patients in the standard ASV group, there were also no significant differences in time until extubation: 10.5 (8.0–16.0) vs 10.0 (6.0–13.0) hours (n = 16 vs n = 63). The choice for 80%-minute ventilation was arbitrary; however, we believed that 90%-minute ventilation was not clinically significant and with 70%-minute ventilation the number of patients would result in too few patients.
Ventilator and Ventilation Variables
Ventilator and ventilation variables are presented in Figure 4. There were no differences between groups regarding tidal volume, respiratory rate, arterial pH, PCO2, and PO2. The highest levels of arterial PCO2 were similar in the 2 randomization groups (5.9 [range, 5.2–6.4] vs 5.8 [range, 5.0–6.4] kPa, ASV-DE versus standard ASV; P = 0.82).
In this study of postoperative weaning of patients after planned and uncomplicated nonfast-track CABG, we found that ASV with protocolized de-escalation and escalation compared with standard ASV did not shorten duration of tracheal intubation. The time to the first assisted breathing period was also not different between groups. There was, however, a difference in the duration of the assisted breathing period ending with extubation.
MV could harm all patients, including those whose lungs are ventilated for only hours.9 Therefore, it is imperative to strive for shorter duration of MV and tracheal intubation at all times, including the weaning phase after surgery. In addition, controlled forms of MV could rapidly cause muscle atrophy of the diaphragm.10 To counteract this phenomenon, it is important to allow patients to use their diaphragm as soon as possible while still being mechanically ventilated. ASV allows for automatic switches between controlled ventilation and assisted ventilation, depending on the patient's activity. As such, ASV with protocolized de-escalation and escalation may improve outcome because there was a trend to shorter time until the first assisted breathing period, and more assisted ventilation episodes. Our study, however, was underpowered to show statistical difference regarding these secondary end points.
Although we hypothesized that protocolized de-escalation would prevent longer intubation times, our study showed otherwise. Of note, improved patient-ventilator synchrony with ASV could also lengthen duration of tracheal intubation. Indeed, this could be attributable to increased comfort, fewer alarms, and a gradual transmission from controlled to spontaneous ventilation thus not leading to apnea. Our study was not designed to test this hypothesis.
In contrast to our study, a significant reduction of time until tracheal extubation with ASV as compared with synchronized intermittent mandatory ventilation/pressure support was found in patients after fast-track cardiothoracic surgery.5 In this trial by Sulzer et al., initially ASV was set at 100%-minute ventilation (phase 1). When spontaneous breathing occurred, %-minute ventilation was reduced by 50% (phase 2), and if necessary again by 50% (phase 3). This weaning approach can be described as much more aggressive with respect to de-escalation, compared with our study. We chose to de-escalate stepwise until %-minute ventilation was 70%, as suggested on the Web site of the manufacturer.¶ Our stepwise approach and the minimum level of %-minute ventilation may have been a flaw.
In a more recent study in patients after fast-track cardiothoracic surgery, time to extubation was also significantly shorter with ASV as compared with pressure-regulated volume controlled with automode ventilation.4 In this trial by Gruber et al., weaning consisted of 3 phases: controlled ventilation (phase 1), assisted ventilation (phase 2), followed by a T-piece trial (phase 3) that ended with extubation. This trial did not use de-escalation. An important similarity between the trials by Sulzer et al. and Gruber et al., and in contrast to our trial, is that the former trials were both performed in fast-track cardiothoracic surgery patients, whereas we explicitly included nonfast-track patients.
There were no differences in arterial blood gas variables, including arterial pH and PCO2, which could be explained by the fact that patients in the ASV-DE group could adjust their minute ventilation when operator set %-minute ventilation was decreased (resulting in higher actual minute ventilation than the operator set %-minute ventilation). Indeed, time until the first assisted breathing period was shorter, and more assisted ventilation episodes were found in the ASV-DE group. It is also important to note that the highest levels of arterial PCO2 were not different between the 2 randomization groups, indicating that ASV-DE is at least as safe as standard ASV.
There are multiple reasons why we were unable to show a difference between standard ASV and ASV-DE, including standard of care in our setting and type of patients studied. In a study comparing SmartCare® (a knowledge-based weaning tool including an automatic gradual reduction of pressure support, automatic performance of spontaneous breathing trials, and generation of an incentive message when a breathing trial was successfully passed) with conventional weaning, Rose et al.11 found no differences regarding duration of MV. This finding was in sharp contrast to the results from a study by Lellouche et al.12 showing SmartCare to significantly reduce duration of MV. One important difference, however, between the control groups of the 2 studies was that duration of MV was shorter in the study by Rose et al. The shorter duration of MV could have masked any beneficial effect of the intervention in the first study, whereas it allowed for an important effect of the intervention in the second study. Differences in duration of MV could have resulted from differences in patient case mix and differences in standard care surrounding the studied patient populations in these 2 studies. We may have encountered a similar problem: in our study, duration of tracheal intubation was rather long compared with other trials of ASV. This may very well relate to the fact that we included nonfast-track patients instead of most other studies of weaning of cardiothoracic surgery patients. The rather long duration of MV may have precluded any effect of ASV-DE over standard ASV in our study.
Because this was an open-label, i.e., not blinded, randomized clinical trial, we could not exclude the possibility that patients randomized to the standard ASV group also benefited from early de-escalation. This could have minimized contrast between the study groups. To promote protocol adherence, nurses and physicians were able to assess only 1 of the 2 flowcharts (as presented in Fig. 1), for ASV-DE or standard ASV, depending on randomization group. We could not always prevent both flowcharts being available in the unit. Notably, however, we noticed a significant difference between the study groups regarding %-minute ventilation at the time of extubation and the period of assisted ventilation leading to tracheal extubation.
Apart from the fact that this was a single center study, which limits the generalizability of our conclusions, there are other limitations of the study. Sedation and analgesia requirements were not reported using specific scales. However, we did not gradually wean patients off of sedation, but stopped infusion of sedation completely when the core temperature was >35°C. Of note, sedation and analgesic requirements were the same in the 2 study groups. Another limitation is that we excluded patients with chronic obstructive pulmonary disease, also limiting generalizability.
Compared with a previous study of ASV by our group, overall weaning time in the present study was considerably shorter. Indeed, median time to tracheal extubation was 16.4 (12.5–20.8) hours in the previous study.3 The question must be raised whether tracheal extubation of cardiothoracic surgery patients is dependent on the ventilatory strategy alone, or (also) on factors independent of the ventilation strategy. The above-mentioned studies by Gruber et al.4 and Sulzer et al.5 certainly show that the ventilator strategy influences weaning time in these patients. One ventilatory strategy factor that could have influenced weaning time in our studies was the use of different levels of PEEP. Specifically, in our previous study of ASV, patients received 10 cm H2O PEEP in the first 4 hours after arrival in the ICU, and thereafter 5 cm H2O PEEP until tracheal extubation. In the present study, patients received 5 cm H2O PEEP throughout the complete weaning phase. This extra step in the weaning process could have accelerated weaning in the present study. In addition, this change in practice could have resulted in a change in use of sedatives because we continued sedatives for at least the first 4 hours, or as long as the higher level of PEEP was used, in the first study. This usually took longer than the time needed to reach a core temperature >35°C, which was the time to stop sedatives in the present study. Factors independent of ventilation strategy could also have a role. Both the surgical/anesthesiological team and the ICU team gained experience over time, whereas the local guidelines (apart from the advice on PEEP) of these teams as well as their composition did not change. Better understanding of the needs of patients after cardiothoracic surgery could have led to the use of less sedatives both intra- and postoperatively despite the fact that no formal protocol changes were implemented.13 Also, more experience with ASV in this particular patient group could have led to more confidence in earlier tracheal extubation in our department. Finally, better awareness of long weaning times in our institution could have led to a more proactive behavior with regard to tracheal extubation.14 Although we performed a randomized controlled trial, and as such all these factors should not have affected the primary outcome differently in the 2 study arms, one could certainly suggest that other factors than the ventilatory strategy have key roles in time until tracheal extubation in these patients.
In conclusion, compared with standard ASV, weaning of patients after nonfast-track CABG using ASV with protocolized de-escalation and escalation does not shorten time to tracheal extubation.
DAD helped design and conduct the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files. DPV helped conduct the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. JMB helped design the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. BAJMdM helped design the study. This author has seen the original study data and approved the final manuscript. AK helped conduct the study and analyze the data. This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. FP helped conduct the study. This author has seen the original study data and approved the final manuscript. MJS helped design the study, analyze the data, and write the manuscript. This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
¶ Hamilton Medical. Available at: http://www.hamilton-medical.com/. Accessed May 14, 2009.
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