We performed a retrospective, open-label, matched (1:1), single-centre study in a tertiary university medical centre (Dijon, France) between 2018 and 2019 (ClinicalTrials.gov Identifier: NCT02479529). The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. As the study was observational, and used existing, routinely collected data, informed consent was not required from the subjects. The present report was drafted in line with the STROBE statement .
The main inclusion criteria were as follows: age 18 or over, cardiac surgery with the use of cardiopulmonary bypass (CPB) (coronary artery bypass grafting (CABG), the surgical correction of valve disease (aortic, mitral), combined surgery (CABG and valve disease), aorta ascendant disease, and left ventricular assist device implantation). The main non-inclusion criteria were off pump cardiac surgery, preoperative painkiller use, gabapentin use, antidepressive therapy and preoperative cognitive dysfunction.
Maintenance or withdrawal of preoperative medications followed international guidelines. Anaesthesia and cardiopulmonary bypass procedures were standardised for all patients. At induction all patients received ketamine (0.3-0.5 mg kg-1). In the OA group, anaesthesia was induced with propofol (0.4–2 mg kg-1) and sufentanil (0.5 ng ml-1) until the loss of eyelash reflex. Sufentanil was continuously administered using the Schnider target-controlled infusion model. In the OFA group, anaesthesia was induced with dexamethasone (0.1 mg kg-1), lidocaine (1.5 mg kg-1 bolus 15 minutes before the start of propofol) and propofol (0.4–2 mg kg-1) until the loss of eyelash reflex. Lidocaine was continuously administered at 1.5 mg kg-1 h-1. In both group, tracheal intubation was facilitated with cisatracurium (0.15 mg kg-1). Sufentanil and lidocaine were stopped at the end of the surgery. In both groups, anaesthesia was maintained by target-controlled infusions of propofol (started at 2-4 ng ml-1). Titration of sedation was based on the bispectral index (Covidien, Boulder, CO, USA), and aimed to obtain a value between 40 and 60. Arterial hypertension (systolic arterial pressure > 140 mmHg) was treated with esmolol in case of tachycardia (heart rate >80 bpm) or urapidil/nicardipine in case of heart rate < 80 bpm.
Cardiopulmonary bypass with a heart-lung machine (Stockert Sorin S5 Heart Lung, Milan, Italy) was performed at a target blood flow of 2.4 l min-1m-2. The mean arterial blood pressure (MAP) was maintained at more than 65 mmHg by increasing the pump flow rate or, if then required, by administering a bolus of phenylephrine (100 mg) or norepinephrine (5 mg). The priming fluid of the CPB circuit contained 1500 ml crystalloids (Plasma-Lyte®; Baxter, Lessines, Belgium) and 5000 ui of heparin. After systemic heparinization (300 UI kg-1) to obtain a hemocron level of 400 sec, median sternotomy or thoracotomy, aortic and right auricular cannulations were started. Myocardial protection was ensured with multidose intermittent antegrade cold blood cardioplegia (via the aortic root every 15 minutes), or custodiol or Delnido. During aortic cross clamp, moderate hypothermia (32-34°C) was maintained. Normoglycemia (arterial blood glycemia < 10 mmol-1) was maintained using intravenous insulin (intravenous bolus of 5-10 ui) if necessary. Homologous red blood cell transfusions were given to patients with a haemoglobin value below 8 g dl-1. Heparin was reversed with protamine on a 1:1 ratio. All OA patients had loco-regional analgesia by serratus anterior plane block (thoracotomy, levobupivacaine 0.125 mg ml-1, 0.5 ml kg-1) or a parasternal continuous infusion of a local anaesthetic (sternotomy, levobupivacaine 0.125 mg ml-1 continuous infusion 8 ml h-1 during 48 hours). ICU management
At the end of surgery, all patients were sedated and the lungs were mechanically ventilated until haemodynamic stability and normothermia were obtained and blood loss was considered acceptable (less than 1 ml kg-1 h-1). Tracheal extubation was carried out according to the French guidelines . Patients were treated by physicians trained in postoperative cardiac surgical care, including a cardiologist. Circulatory support was guided by institutional protocols to achieve predefined end- points: mean arterial pressure more than 65 mmHg, cardiac index more than 2.2 l min-1 m-2, and urine output more than 0.5 ml kg-1 h-1.
Analgesia was standardized and comprised of intravenous paracetamol (1 g every 6 hours) and patient controlled morphine analgesia. Before extubation, all patients received 1 g of acetaminophen and titration of intravenous morphine with a bolus of 2 to 3 mg until a pain visual analogue scale below 3 was achieved. Then patient controlled analgesia morphine was set up with the following parameters: 1 mg bolus, refractory period of 7 min, maximum dose of 20 mg every 4 h and without continuous infusion. The use of complementary analgesics was left to the discretion of the physician. Complementary analgesia comprised the use of ketoprofen (50 mg), tramadol (50 mg), and nefopam (20 mg). Pain was assessed every 4 hours during the ICU stay by using the pain visual analogue scale. The patients’ electrocardiogram, pulse oxygen saturation and central venous blood pressure were continuously monitored. The scheduled blood tests included arterial/venous blood gas measurements on admission to the ICU, and then several times a day on request by the attending physician.
All data was continuously recorded in the institutional data base. The following variables were recorded: age, gender, body weight, height, personal medical history, ASA score, EuroSCORE2, Euroscore, type of cardiac surgery, the preoperative left ventricular ejection fraction, the duration of CPB, the duration of aortic clamping, the need for intraoperative blood transfusion, norepinephrine, dobutamine, the use of a antihypertensive agent (nicardipine, urapidil), the use of a short acting beta-blocker (esmolol), troponin values, creatinine value, time to extubation (hours), any occurrence of complications during the stay in the ICU or in the hospital, and the LOS in the ICU.
The primary endpoint was total cumulated morphine dose during the first 48 hours in milligrams. The secondary endpoints were: analgesic rescue, a composite endpoint of major adverse events (new onset of atrial fibrillation or flutter, second or third atrio-ventricular blockade, stroke, acute renal failure, confusion, reintubation, non-invasive ventilation support, and death in hospital), fluid expansion (ml), total propofol dose (mg), antihypertensive agent use, vasoplegic syndrome, catecholamine use, troponin Ic (ng ml-1), creatinine (mmol l-1), length of stay in ICU (in days), and length of stay in hospital (in days). The secondary composite endpoint was assessed during the hospital stay. All data was extracted from our institutional data base and collected by a physician (Alexandra Spitz) not working in the cardiac surgery anaesthesia-critical care department.
The trial was designed to investigate the potential superiority of OFA in terms of morphine consumption. According to the studies of Berthoud et al, we calculated that 55 patients per group would be able to demonstrate a difference of 10 mg of morphine consumption (with a mean consumption of 18 mg) with a power of 0.8 and an alpha risk of 0.05 [14, 15]. Based on known factors associated with postoperative pain and operative course, the database was matched (1:1) on age, body mass index, Euroscore 2, and type of surgery (sternotomy/thoracotomy) [16, 17]. The normality of the data distribution was assessed using the Shapiro-Wilk test. Data are expressed as the median (interquartile range). For comparisons of matched continuous variables, the Wilcoxon test was used. For comparisons of categorical variables, the Cochran-Mantel-Haenszel test with odds ratio (OR) . The threshold for statistical significance was set to p<0.05. Statistical analyses were performed with SPSS 24 (IBM, France).