Hormonal and metabolic responses to perioperative stress may contribute to the morbidity and mortality of cardiac surgical patients [1,2]. A high-dose opioid anaesthetic regimen may ‘blunt’ excessive metabolic and hormonal stress responses in this patient population. For example in a randomized trial of critically ill neonates undergoing open heart surgery, neo-nates who were assigned to deep intraoperative anaesthesia with high doses of sufentanil intraoperatively showed a decreased incidence of sepsis, metabolic acidosis, disseminated intravascular coagulation and fewer postoperative deaths than patients randomized to a halothane/morphine-based anaesthetic . Similarly, in adult patients undergoing coronary artery bypass grafting (CABG), high-dose opioid anaesthesia was associated with haemodynamic stability and a decrease in myocardial oxygen consumption .
However, clinical trials in adult cardiac surgery patients have not demonstrated a benefit of high-dose opioid anaesthesia. For example, a recent trial in adult patients undergoing CABG failed to demonstrate a beneficial effect of high-dose opioid anaesthesia on blunting cytokine release . In addition, delayed respiratory depression and prolonged emergence from anaesthesia has been associated with the use of high-dose opioid anaesthesia . This may be caused by a delayed recovery in respiratory function. For example, it has been shown that pulmonary dysfunction after cardiac surgery increases nosocomial infections, extrapulmonary organ dysfunction, prolonged intensive care unit (ICU) and hospital stay, as well as in-hospital deaths [6–8]. Therefore, a possible prolongation of postoperative respiratory recovery following high-dose opioid anaesthesia may significantly limit the intraoperative use of high-dose opioid regimens for cardiac anaesthesia. Nevertheless, the controversy regarding the use of high-dose opioid anaesthesia in cardiac surgery has not yet been resolved, and even recent clinical trials find advantages associated with the use of higher doses of opioids (e.g. decreased rate of myocardial infarction ).
The delay in postoperative respiratory recovery following high-dose intraoperative opioid anaesthesia may be related to the increased context-sensitive half-times (defined as time it takes for the plasma concentration to fall by half after cessation of continuous infusion) of many opioids when given over a prolonged duration [10,11]. In contrast, the short acting opioid remifentanil is characterized by a context-sensitive half-life of <4 min and a pharmakodynamic offset of <6 min . Remifentanil's methyl ester linkage makes the drug susceptible to metabolism by nonspecific circulating and tissue esterases. Therefore, its clearance is unaffected by changes in hepatic or renal function or by prolonged infusion time . Recently, several studies have investigated the intraoperative use of remifentanil for cardiac surgery, in particular whether a remifentanil-based anaesthetic may allow earlier extubation times, improve outcomes and cost [9,14,15]. In contrast, the effect of remifentanil on recovery of respiratory function after cardiac surgery remains largely unknown. We hypothesized that compared to a longer acting opioid, remifentanil's short context-sensitive half-life might be associated with a more rapid recovery of postoperative respiratory function despite using a high-dose opioid technique. Therefore, we randomized patients undergoing CABG to a high-dose intraoperative anaesthesia consisting of propofol/remifentanil or propofol/sufentanil and measured postoperative respiratory function, pulmonary complications, and both ICU and postoperative hospital length of stay.
After approval by the institutional review board and acquiring written informed consent from each individual, all consecutive ASA II and III patients undergoing isolated, elective primary CABG who met the study criteria were randomly assigned to a remifentanil- or sufentanil-based intraoperative anaesthetic technique. Randomization was performed using a computer-generated random number list designed to produce true randomization. All patients were blinded to their treatment group. A power analysis was based on an investigation by Nieuwenhuijs and colleagues . According to this study, opioids may alter the carbon dioxide (CO2) response (measured as change in minute ventilation over end-expiratory CO2 concentration) by 30%. Assuming α = 0.05 and β = 0.20, a sample size of 24 per group would be sufficient to reach statistical significance.
Exclusion criteria included a history of conges-tive heart failure, left ventricular ejection fraction <40%, chronic renal insufficiency (serum creatinine >1.5 mg dL−1 ), stroke, abnormal preoperative liver function tests, pulmonary hypertension (mean pulmonary artery pressure >25 mmHg based on the preoperative transthoracic echocardiogram ), chronic obstructive pulmonary disease (COPD) based on patients history, chronic alcohol abuse, ASA/NYHA classification >3 or emergency surgery. Patients were also excluded, if they required reoperation for haemorrhage, developed cardiac failure (inotropic support for over 48 h after the operation, intra- or postoperative placement of intra-aortic balloon pump or ventricular assist device) or acute renal failure (serum creatinine increase >1 mg dL−1 above baseline ) or any form of dialysis.
All patients had standard monitoring, including electrocardiography, radial arterial and central venous pressure monitoring, pulse oximetry, and measurement of inspiratory and expiratory CO2 concentrations. Pulmonary artery catheters and/or transesophageal echocardiography were used at the anaesthesiologist's discretion. Patients were premedicated with oral lorazepam 1–2 mg the night before surgery and received their usual cardiac medications. Patients who were randomized to the remifentanil group, received a remifentanil infusion of 1.5 μg kg−1 min−1 in combination with midazolam 50 μg kg−1 for induction of general anaesthesia. Muscle paralyzes was achieved with rocuronium bromide 1 mg kg−1 prior to tracheal intubation and subsequently repeated every hour if a twitch response was present after train of four stimulation (0.2 mg kg−1). Anaesthesiawas maintained throughout the operation with remifentanil (0.5–1.0 μg kg−1 min−1) and propofol (50 μg kg−1 min−1) infusions . Boluses of 0.5– 1 μg kg−1 remifentanil could be given as needed for intense stimulation (e.g. sternotomy). During the operation, mechanical ventilation (MV) was performed with pressure-controlled ventilation at 10 breaths min−1, tidal volumes of 10–12 mL kg−1 and a positive end-expiratory pressure setting of 5 cmH2O. The fraction of inspired oxygen (FiO2) was adjusted to maintain oxygen saturation by pulse oximetry >95%. End-tidal CO2 measurements were used to adjust the respiratory rate and tidal volumes to maintainan end-tidal CO2 between 30 and 35 mmHg. CABG was performed through a median sternotomy incision with saphenous vein, internal thoracic or radial arteries harvested as conduits. Prior to cardiopulmonary bypass (CPB), patients were anticoagulated with intravenous (i.v.) heparin (300 i.u. kg−1), and anticoagulation was monitored by measuring the activated clotting time (ACT >400 s). CPB was performed using an uncoated circuit with a prime volume of 1200 mL of crystalloids. Haemoglobin levels were maintained above 8g dL−1 throughout CPB. Myocardial protection was achieved with intermittent antegrade cardioplegia. Nonpulsatile CPB flow was maintained between 1.5 and 2L min−1 m−2 using a membrane oxygenator with mean perfusion pressures between 50 and 80 mmHg. Patients were not actively cooled, but their core temperature was allowed to drift to 34°C. During CPB, the lungs were not ventilated. After CPB, heparin was reversed with protamine and surgery was completed. Following the operation, patients were transferred to the ICU. The MV was weaned, once the following criteria were achieved: haemodynamic stability, a ratio of the arterial partial pressure of oxygen (PaO2) to FiO2 >300, body temperature >36.0°C, chest tube output <200 mL h−1 and reversal of muscle paralyses. The remifentanil infusion was gradually decreased to 0.1–0.025 μg kg−1 min−1 and weaning from MV was initiated according to a standardized protocol. Briefly, MV in the ICU was initiated with pressure-controlled ventilation at 10 breaths min−1, tidal volumes of 10–12 mL kg−1 and a positive end-expiratory pressure setting of 5 cmH2O. The FiO2 was adjusted to maintain oxygen saturation by pulse oximetry >95%. End-tidal CO2 measurements were used to adjust the respiratory rate and tidal volumes to maintainan end-tidal CO2 between 35 and 40 mmHg. Once awake and responding to commands, patients were changed to a pressure support ventilation mode. Respiratory mechanics were evaluated, and if acceptable (respiratory rate 10–28 breaths min−1, tidal volume > 5 mL kg−1, vital capacity (VC) > 10 mL kg−1, and negative inspiratory force ≤ 20 cmH2O), the patient was extubated. Over the next hour, while the remifentanil infusion was further decreased and discontinued, patient-controlled analgesia (PCA) providing i.v. piritramide (1.5 mg boluses), with a 10-min lockout interval and no background infusion or dose limit was initiated and maintained for 24 h. In addition, every patient received indomethacin per rectum (50 mg three times per day), starting upon arrival in the ICU until the third postoperative day .
Patients who were randomized to a sufentanil-based anaesthetic received equipotent doses of sufentanil, based on recent studies comparing sufentanil and remifentanil during cardiac surgery [14,21]. In short, 2 μg kg−1 of sufentanil was given for induction of general anaesthesia. Throughout the operation, sufentanil was given as an infusion of 20–40 ng kg−1 min−1. Boluses of 0.1–0.5μg kg−1 of sufentanil could be given as needed for intense stimulation (e.g. sternotomy). Other intraoperative medications (e.g. induction of anaesthesia with midazolam, propofol infusion throughout, paralytics, etc.), CPB techniques and surgical procedures were similar in both groups. The sufentanil infusion was discontinued upon skin closure. The protocol for weaning from MV was identical to the one used for patients receiving remifentanil. Similarly, piritramide via PCA was started as soon as the patient was awake.
In both groups, pain scores were monitored at rest with a visual analogue scale (VAS of 1–10; 1 representing no pain and 10 the worst pain). Pain scores were documented once the patient was awake, and for 72 h following extubation. Patients were discharged from the ICU once they did not require any inotropic support, had a stable hematocrit, had an oxygen saturation above 95% on nasal cannula and no complications occurred that would require further ICU support or monitoring (e.g. pneumothorax, ventricular tachycardia, major stroke, etc.). Patients were discharged from the hospital to their home or to a rehabilitation facility once they were weaned from supplemental oxygen therapy, could ambulate independently, all surgical tubes and drains were discontinued, and no signs of infections were present and no other complications would require a further hospital stay (e.g. problems with anticoagulation, dysrhythmias, etc.). Discharge decisions were at the discretion of the ICU-physicians and of the cardiac surgeons who agreed to the above discharge criteria and were blinded to the treatment group of the patient. Primary outcome parameters of pulmonary function in each group included CO2–response (slope of respiratory minute ventilation/end-expiratory CO2 [MV/etCO2]), forced expiratory volume in one second (FEV1), VC, functional residual capacity (FRC), and pulmonary complications (atelectasis, infiltrates) as documented by chest X-rays. All pulmonary function tests were performed in a seated position.
The CO2 response was assessed using a CO2 rebreathing technique by connecting the patient to a closed system that was pre-filled with 10 L of 100% oxygen . The increase in CO2 was measured with a main-stream capnometer system (Hewlett-Packard, Böblingen, Germany) and the change in minute ventilation was recorded with a volumeter (Draeger Volumeter; Bad Homburg, Germany). The CO2 sensitivity could thus be calculated as the relationship of change in minute ventilation over the end-tidal CO2 tension .
FRC was measured with an ultrasonic flowmeter using the nitrogen washout method . The ultrasonic flowmeter (Spiroson; Ecomedics, Dürnten, Switzerland) can be used to measure flow and molar mass of an inhaled or exhaled gas. By using 100% oxygen as a washout gas, and measurement of the end-expiratory nitrogen concentration, the FRC can be determined in mechanically ventilated or spontaneously breathing subjects . The ultrasonic flowmeter was also used to determine FEV1 and VC.
All pulmonary and ventilatory measurements were performed on the day before the surgery, immediately before extubation, 1, 24 and 72 h after extubation (time point 0–4, respectively) by a single member of the study team, blinded to the randomization. Chest X-rays were performed at 1 h prior and 1, 24 and 72 h after extubation. The absence or presence of atelectasis and infiltrates (‘yes’ or ‘no’ answer) were determined by a panel of three board certified radiologists. The radiologists were blinded to the patient's study group. The preoperative risk in all patients was assessed using the Tuman- and Parsonnet-risk scores prior to randomization [26,27]. In short, several different preoperative risk factors (e.g. low ejection fraction, renal failure, history of diabetes, etc.) were assessed and the patient's individual risk scores were calculated. Thus, baseline risk for perioperative complications could be compared in both treatment groups. Time to extubation was recorded in all patients as the time from the beginning of weaning until the patients were extubated.
All variables are displayed as odds, mean (± standard deviation), or medians (interquartile range), after assessing the outcome distribution (categorical, normal, non-normal) by normal-quartile plot of the residuals. Similarity of treatment groups was tested for patients' characteristics data, duration of anaesthesia, surgical times, ICU- and postoperative hospital length of stay, medical history, and risk scores using t-, Fisher-, Wilcoxon-, and χ2 tests. Adjustment for multiple testing was considered, but not needed here. Developments of pulmonary function tests were described by repeated measures multivariate analyses of variance (MANOVA) taking group, baseline measurement, time point (levels 1–4), and the interaction between group and time point, and baseline and time point as independent variables. The occurrence of atelectasis, and infiltrate by group and time was analyzed by logistic regression. Since atelectasis did not occur at the same times in both groups, occurrence of atelectasis was included in ANOVAs of pulmonary function with factors group, time and their interaction. The P < 0.05 were considered statistically significant. Adjustment for multiple tests by the Bonferroni–Holm procedure was considered.
A total of 59 patients were included into the study. Five patients who received a remifentanil-based anaesthetic, and four patients who received a sufentanil-based anaesthetic were excluded in the course of the study period (reoperation for bleeding: five patients; postoperative cardiac failure: two patients; intraoperative placement of an IABP: one patient; cerebrovascular accident: one patient). Thus, 25 patients remained in each treatment group who completed the study. No statistically significant difference between both groups were noted regarding patients' characteristics, duration of surgery, cross-clamp time, bypass time or risk scores (Table 1).
There were no differences between groups in pain scores measured prior to extubation and for 72 h afterwards. Mean pain scores were similar between groups (P = 0.89). In addition, the scores significantly decreased during the 72 h post-extubation in each group (P < 0.0001). Moreover, the recovery from pain was similar in both groups (P = 0.64; Table 2).
There were no differences between groups in the preoperative pulmonary function evaluation (CO2 response, FRC, VC, FEV1). Compared to preoperative values (0.90L min−1 mmHg−1), the CO2 response was dramatically decreased in both groups after the operation (P = 0.0034; Fig. 1a) and reached preoperative baseline values only at 72 h after extubation. However, the recovery was significantly faster in the remifentanil group (P = 0.018). In addition, the postoperative CO2 response was significantly less impaired in the remifentanil group, compared to sufentanil (mean difference 0.042L min−1 mmHg−1; P = 0.0063; Table 3). Compared to preoperative values (mean 2.6 L), the postoperative FRC was dramatically decreased in both the groups (mean 1.6 L; P = 0.0091) (Fig. 1b) and did not recover to preoperative values within 72 h after extubation (mean 1.9 L; P = 0.19). The FRC did not recover significantly faster in the remifentanil group (P = 0.72). Furthermore, there was no significant overall difference between the groups (P = 0.73; Table 3). VC was dramatically decreased in both the groups after the operation (mean 3.1 L before the operation to 0.8 L before extubation; P = 0.0029) (Fig. 1c) and did not recover to preoperative values within 72 h after extubation (mean 1.9 L; P = 0.10). The VC did not recover significantly faster in the remifentanil group (P = 0.65). Also, there was no significant overall difference between the groups (1.3 L vs. 1.2 L; P = 0.85; Table 3). Compared to preoperative values, the postoperative FEV1 was dramatically decreased in both groups (mean 2.1 L to 0.5 L; P = 0.0021; Fig. 1d). FEV1 recovered significantly to preoperative values within 72 h after extubation (mean 1.3 L; P = 0.049); however did not reach baseline levels again. There was no significant difference in the speed of recovery to preoperative values between groups (0.82 L vs. 0.81 L; P = 0.96). Also, there was no significant overall difference between the groups (P = 0.63; Table 3).
Taken together, the examination of pulmonary function in the present study demonstrates in both groups a dramatic decrease in all obtained pulmonary function tests following CABG. The postoperative recovery of lung function was still altered up to 3 days after surgery, and did not recover significantly in any group (exception: FEV1 values recovered significantly at 72 h in both groups). Differences between groups were observed for the CO2 response curve, suggesting that patients in the sufentanil group had a more depressed ventilatory response to CO2 throughout the study period. There was no significant difference between groups in lung function recovery over time for FEV1, VC and FRC.
The overall incidence of atelectasis (number of patients who developed atelectasis at any point of the study period) diagnosed by chest X-ray was 19 patients in the remifentanil group (76%), and 23 patients in the sufentanil group (92%). The incidence of atelectasis was significantly smaller in patients who were randomized to the remifentanil-based anaesthetic (time: P = 0.039; time-group interaction: P = 0.042) (Fig. 2). We excluded the possibility, that the incidence of atelectasis influenced the results of the MANOVA analysis in an univariate model (ANOVA). We found that the incidence of atelectasis did not mask the effects of the multivariate analysis. The overall incidence of pulmonary infiltrates (number of patients who developed a pulmonary infiltrate at any point of the study period) diagnosed by chest X-ray was two patients in the remifentanil group (8%), and three patients in the sufentanil group (12%). There was no difference in the occurrence of pulmonary infiltrates between groups at any time point. In addition, there was no difference between groups with regard to clinically significant adverse pulmonary complications. All patients could be extubated within 24 h after their arrival on the ICU. One patient in the remifentanil group, and one patient in the sufentanil group developed pneumonia, however, none of them required reinstitution of MV.
The time to extubation and ICU length of stay did not differ between groups. However, postoperative hospital length of stay was shorter in the remifentanil group, compared to patients who were randomized to intraoperative sufentanil (10 vs. 12 days (median), respectively; P = 0.03; Table 4).
Despite recent trends in cardiac anaesthesia emphasizing the possible advantages of balanced anaesthetic techniques, in which opioids are supplemented by volatile agents . There are recent reports suggesting the superiority of high-dose opioid techniques . However, delay in recovery of respiratory function after cardiac surgery may contribute to patients' morbidity and mortality [6–8,29]. We hypothesized that the intraoperative use of high doses of opioids with prolonged context-sensitive half-life may contribute to a delayed recovery of respiratory function in patients undergoing CABG surgery, whereas a high-dose short-acting opioid anaesthetic might decrease the stress response, but not affect postoperative respiratory function. In the present study, patients who were randomized to high doses of intraoperative remifentanil demonstrated better postoperative CO2 responsiveness, less atelectasis, and were discharged earlier from the hospital as compared to patients randomized to the longer acting opioid sufentanil. These data suggest that the intraoperative use of a high-dose opioid anaesthetic with a short context-sensitive half-life may be associated with an improved recovery of respiratory function when used in patients undergoing CABG surgery.
Although an effect of opioid on the resolution of atelectasis, CO2 sensitivity, and postoperative hospital length of stay was demonstrated, differences between groups regarding the spirometric lung function parameters, infiltrates, ICU length of stay or time to extubation were not observed. A previous randomized trial comparing high-dose remifentanil with fentanyl for fast-track coronary surgery demonstrated longer median times to extubation in subjects who received remifentanil than for those who received fentanyl (5.1 vs. 4.2 h, respectively) . In addition, two other trials failed to demonstrate earlier extubation times in patients who received remifentanil during cardiac surgery as compared to other opioids [14,31]. Most likely, other factors including the level of sedation , variability in postoperative critical care management , preoperative pulmonary function, or the use of fast-track cardiac anaesthesia techniques  may have influenced the timing of extubation to a greater extent than the pharmakokinetic properties of the opioid. Similarly in the present study, the observation that ICU length of stay was not affected by the randomization may reflect the impact of other confounding factors such as organizational procedures on a specific ICU (e.g. the routine of discharging all cardiac surgery patients who do well on the morning of the first postoperative day)  or the development of dysrhythmias . Such factors may have a greater impact on discharging a patient from an ICU than prolonged opioid effects. However, in the present investigation, one of the criteria to discharge patients from the hospital to their home or to a rehabilitation facility was the absence of supplemental oxygen therapy. This may be a possible explanation why patients in the remifentanil group were discharged earlier from the hospital.
Despite these considerations, one of the major concerns of prolonged opioid receptor occupancy is their effect on respiratory function, particularly respiratory depression . In the present study, impaired CO2 response was present almost throughout the whole study period in both treatment groups. However, CO2 responsiveness was more impaired in patients who were randomized to intraoperative sufentanil. A decrease in the CO2 responsiveness may be associated with a decreased minute ventilation, possibly predisposing patients to the development of atelectasis. However, it remains a possibility that other side effects of prolonged opioid effects (e.g. cognitive function or recovery of bowel function) may be the reason for the observed differences in postoperative hospital length of time. In fact, intraoperative opioids are known to delay postoperative recovery of bowel function  or the recovery of cognitive function in patients undergoing cardiac surgery . In addition, it is interesting that respiratory depression in the remifentanil group persisted for 3 days despite of the very short half-life of the drug. This suggests that there are additional factors than opioid receptor activation following cardiac surgery that may contribute to postoperative respiratory depression.
Although this study had enough power to demonstrate differences in some of the primary outcome parameters (i.e. differences in CO2 responsiveness caused by opioids) some limitations need to be pointed out. Initially, only a relatively small number of patients were randomized to each treatment group. In addition, the present investigation did not utilize a double-masked study design. In fact, the ICU nurses who were taking care of the patients were aware of the treatment group assignments. However, pulmonary technicians who obtained the measurements, the radiologists who interpreted the chest X-rays, the physicians in charge of extubating, transferring and discharging the patients as well as the patients themselves were blinded to the study group. Finally, there is some contradiction between the observed benefits associated with the use of remifentanil (better CO2 response, less atelectasis, shorter postoperative length of stay), yet no effect on other important variables were found (extubation time, ICU length of stay, other pulmonary function tests). This may be attributable to a lack of statistical power for some of the examined parameters. For example, as the occurrence of pulmonary infiltrates was much lower in both groups (5 of the 50 study patients, 10%) compared to atelectasis (42 of the 50 study patients, 82%), no statistical significant difference in the occurrence of pulmonary infiltrates could be demonstrated.
In conclusion, the present study demonstrates that postoperative respiratory function in patients undergoing CABG surgery is dramatically impaired during the postoperative period. A decrease in pulmonary function testing can still be demonstrated at the third postoperative day. Moreover, the present study potentially reveals differences in pulmonary function testing, respiratory complications and postoperative hospital length of stay between patients who were randomized to different opioids, suggesting that the use of high doses of intraoperative opioids with a prolonged context-sensitive half-life can further impair postoperative respiratory recovery. In contrast, if a high-dose opioid anaesthetic is chosen in order to dampen intraoperative stress responses to cardiac surgery, a short acting opioid like remifentanil may be associated with better respiratory recovery and shorter postoperative hospital length of stay.
Support was provided solely from institutional and/or departmental sources.
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