We performed a retrospective and single-centre study in a tertiary university hospital (Bordeaux, France) from November 2018 to February 2020.
The OFA protocol has been implemented in our institution from February 2018. After an initial period of several months, to guarantee good communication between every care provider and the compliance to the OFA protocol, we have started to recruit patients from November 2018. Thus, from November 2018 to February 2020 we have included retrospectively from our database 40 consecutive patients undergoing on-pump cardiac surgery and receiving an OFA.[19,20] Data of these 40 OFA patients were compared to 40 other patients operated during the same period but receiving an OBA. During the study period (from November 2018 to February 2020), a total of 2108 consecutive patients underwent on-pump cardiac surgery. To prevent temporal bias, we took into account the temporal effect and obtained homogenous groups in time, sampling cases evenly in time across the recruitment period. Hence, 40 OBA patients were recruited and included in the analysis at the same pace. These 40 OBA patients were selected weekly (week recruitment period block), with a ratio of 1:1, from our database. OBA patients were selected identifying patients undergoing similar cardiac surgical procedure with equivalent cardiopulmonary bypass duration as patients in the OFA group. If for one week several patients responded to these criteria, we decided arbitrarily to include the first patient meeting such criteria in order to follow a chronological rational. Patients undergoing off-pump cardiac surgery and/or with pre-operative hemodynamic instability and/or with atrio-ventricular block grade 2 or 3 and/or hypersensitivity to opioids were excluded.
Upon arrival in the operating room, routine monitoring (five lead-ECG, pulse oximeter, non-invasive arterial pressure) was instituted. A peripheral venous catheter and an arterial catheter were inserted under local anesthesia. After induction of anesthesia, hemodynamic monitoring was completed by inserting a triple lumen central venous catheter in the right internal jugular vein to infuse drugs and to monitor the central venous pressure. Anesthesia management is summarized in the supplementary material (additional files Table 1).
As previously published by our team, anesthesia in the OBA group was based on propofol and remifentanil both simultaneously administered via target-controlled infusion (TCI) using the Schnider's and the Minto's models, respectively. The induction of anesthesia was ensured with a target effect-site concentration of propofol between 2.0 and 4.0 μg.ml− 1 and remifentanil between 3.0 and 10.0 ng ml− 1. For the maintenance of anesthesia target effect-site concentrations of propofol and remifentanil were adapted to maintain bispectral index (Covidien, Boulder, CO, USA) value between 40 and 60 and to maintain a Mean Arterial Pressure (MAP) between 60 and 85 throughout all the surgical procedure, respectively. A 0.10–0.15 mg.kg− 1 bolus dose of morphine was given intravenously 30 min before the anticipated end of surgery for postoperative analgesia. In these patients, the intraoperative use of ketamine (IV bolus 0.3 mg.kg− 1 at the induction followed by continuous infusion 0.25 mg.kg− 1.h− 1) and/or lidocaine (1.5 mg.kg− 1 bolus followed by continuous infusion 1.5 mg.kg− 1.h− 1) and/or magnesium sulfate (3 g over 15 min at the induction) was left at the discretion of the attending anaesthetist.
In the OFA group, a pre-induction mixture of intravenous boluses of dexmedetomidine (0.3–0.6 μg.kg− 1 over 15 min), magnesium sulfate (3 g over 15 min), dexamethasone (0.1 mg.kg− 1) and lidocaine (1.5 mg.kg− 1) was given over 15 min. A bolus of ketamine (0.3 mg.kg− 1) was followed by continuous infusion (0.25 mg.kg− 1.h− 1), which was stopped at wound closure. Then, the anesthesia was induced by intravenous anaesthesia with TCI of propofol (2 to 4 μg. mL− 1). The maintenance of anesthesia was ensured by propofol administered via TCI using the Schnider's target effect-site concentrations adapted to bispectral index values between 40 and 60. After the induction, a continuous infusion of dexmedetomidine (0.1 to 0.5 μg.kg− 1.h− 1) and lidocaine (1.5 mg.kg− 1.h− 1) were started. The continuous infusion of dexmedetomidine was adapted to MAP values. If MAP was below 55 mmHg during surgery, dexmedetomidine was completely discontinued. Conversely, if MAP was higher than 90 mmHg and BIS between the target values, dexmedetomidine was increased up to 0.5 μg.kg− 1.h− 1. When hypertension persisted despite these maximal doses, urapidil or nicardipine were given.
In both groups, no regional anesthesia was performed and the tracheal intubation was facilitated with neuromuscular blockade using cisatracurium bolus 0.15 mg.kg− 1 followed by a continuous infusion of 0.1 mg.kg− 1.h− 1 until aortic unclamping. Cardiopulmonary bypass (CPB) was conducted with a heart-lung machine (Stockert Sorin S5 Heart Lung, Milan, Italy) with a target blood flow of 2.4 L.min− 1.m− 2 or more if SvO2 was less than 70%. During CPB, the MAP was maintained above 55 mmHg increasing the pump flow rate, reducing propofol target if BIS was below 40, discontinuing dexmedetomidine infusion in the OFA group or decreasing remifentanil up to 2 ng. mL− 1 in the OBA group if BIS was above 40 or administrating vasoactive drugs (ephedrine, norepinephrine) if hypotension persisted. The CPB circuit was primed with 900 à 1200 ml of crystalloids (Plasma-Lyte®; Baxter, Lessines, Belgium) and 5000 UI of heparin. After systemic heparinization (300 UI.kg− 1) to reach an activated cephalin time above 420 s, median sternotomy was performed then aortic and right auricular cannulations were started. Perioperative hyperglycemia above 10 mmol. L− 1 was treated by intravenous insulin as elsewhere detailed. Homologous red blood cell transfusions were guided by physiological parameters such as SvO2 and haemoglobin level when less than 7.5 g.dL− 1. Heparin was reversed with protamine at a 1:1 ratio.
In absence of counter-indication, all patients in each group received 30 min before the end of surgery, nefopam (IV bolus 20 mg followed by an infusion of 100 mg over 24 h) and paracetamol (1 g followed by 1 g every 6 h). Remifentanil, ketamine, lidocaine and dexmedetomidine were stopped at the end of the surgical dressing. Only propofol was continued in all patients during the intensive care unit (ICU) transfer.
Upon arrival in ICU, postoperative sedation was ensured with a continuous propofol infusion. Propofol infusion was stopped and patients extubated once blood loss was considered acceptable (less than 1 ml. kg− 1.h− 1), chest x-ray ruled out complications, a hemodynamic stability, a normothermia and no residual neuromuscular blockade (train-of-four ratio measured at the adductor pollicis muscle > 90%) were obtained. The scheduled blood tests on admission to the ICU included arterial blood gas measurements and hypersensitivity cardiac troponin I (hs-cTnI) between 12 and 24 h after surgery. Pain was assessed as early as possible after the ICU arrival using a numerical pain rating scale (NPRS). Initial analgesia consisted of morphine titration with a bolus of 3 mg if NPRS was greater than 3. Then, morphine patient-controlled analgesia was started as follow: 1 mg bolus, refractory period of 7 min, maximum dose of 20 mg every 4 h without continuous infusion. Then, pain was assessed at least every 2 h by nurses during the ICU stay using the NPRS. Intravenous rescue analgesia was given if NPRS score was > 3 and was left to the discretion of the attending physician and included ketoprofen (50–100 mg every 8 h) and/or tramadol (50–100 mg every 6 h) and/or ketamine boluses (10–20 mg) and/or oral oxycodone (5–10 mg maximum 6 per day). Non-invasive ventilation indications were high-risk patients (obesity, chronic obstructive pulmonary disease), atelectasis, hypoxemia, hypercapnia, obstructive sleep apnea without personal equipment and acute respiratory failure. Patients were discharged from ICU at the discretion of their attending physician. The following variables were continuously recorded in the institutional database:[19,20] age, gender, body weight, height, personal medical history and medicines, Euro-SCORE II, type of cardiac surgery, the preoperative left ventricular ejection fraction, the duration of CPB, intraoperative blood transfusion, norepinephrine, dobutamine or milrinone, antihypertensive agent (nicardipine, urapidil), atropine, creatinine value, time to extubation (hours), arrythmias or conduction blockade and any other occurrence of complications during the ICU or in-hospital stay, and the length of stay (LOS) in the ICU and hospital.
The primary endpoint was the total amount of opioid consumed in its equivalent of intravenous morphine during the first 48 postoperative hours and included intravenous morphine given at the end of surgery, the titration dose, the morphine administered via a patient-controlled analgesia, the dose of oral oxycodone prescribed postoperatively on the surgical ward with the following conversion ratios: oral morphine/oxycodone 2:1 and oral morphine/IV morphine 1:3 and the tramadol dose with the following conversion ratio: tramadol/IV morphine 1:15. The secondary endpoints were the intraoperative fluid expansion, intraoperative vasoactive agent administration, median maximal values of NPRS at rest and during coughing within the first post-operative 48-h, analgesia rescue requirement and the rate of non-invasive ventilation support, new onset of atrial fibrillation, and postoperative delirium defined as episode of confusion in nursing or medical observation. Secondary outcomes included also postoperative stroke and/or seizure, the incidence acute kidney injury defined as a Kidney Disease: Improving Global Outcomes stage 2 or 3, the postoperative level of hs-cTnI, ICU and hospital length of stay, and the hospital mortality rate. All data were collected from our institutional informatic database by a physician who was not involved in the care of the study patients.
The Shapiro-Wilks normality test was used to assess the normality of quantitative outcomes. In case of normality, quantitative variables were expressed as mean (SD) and a Student test was used to compare the OBA group with the OFA groups. If non normality was assumed, these variables were presented as interquartile range (IQR) and were compared using a Mann-Whitney-Wilcoxon test. Categorical outcomes were expressed as number (percentage) and were compared using a Chi-Square test or Fischer's Exact tests (when the expected values in one of the cells of the contingency table was less than 5). Statistical analyses were conducted using GraphPad Prism version 8.4.3 (GraphPad Software, San Diego, California, USA). For all the statistical tests, a 0.05 significance level was used to claim a statistically significant effect and all reported p values are from 2-sided tests. The sample size was determined from a preliminary retrospective analysis including 18 patients treated using an OBA protocol but no included in the final analysis. In these patients, the mean dose of morphine sulfate equivalents consumed during the first 48 postoperative hours was 21 ± 8 mg. Considering a 30% decrease in patients treated with an OFA protocol as clinically relevant, a sample size of 35 patients per group provided 90% power with a two-sided type I error of 0.05 to show this difference. Taking into account an anticipated loss-to-follow-up rate of 10%, a total of 40 patients per group was planned.
This retrospective observational study was conducted in accordance with the ethical standards of the declaration of Helsinki and relevant guidelines and regulations. In accordance with French law, this study was approved by our ethics committee (Comité d'Ethique du Centre Hospitalier Universitaire de Bordeaux-Groupe Publication) on August 13, 2020 (reference number GP – CE2020–33 by Chair Dr. Thibaud Haaser). The design of the study complies with the general data protection regulation n ° 2016/679/EU of April 27, 2016 and falls within the framework of article 65–2 of the Data Protection Act n ° 78–17 of January 6, 1978 modified 2018. Consequently, it does not require a declaration to the national supervisory authority. Because the current study was a retrospective observational trial with patients treated according to our hospital standard of care, our ethics committee (Comité d'Ethique du Centre Hospitalier Universiataire de Bordeaux-Groupe Publication) granted an authorisation to waive written informed consent from patients. In addition, the other conditions relating to the right to privacy and the protection of personal health data were approved by the data protection officer and the study was recorded in the processing register under the reference CHUBX2020RE0260. All data were collected and analyzed confidentially assigning an identification number to each patient.
BMC Anesthesiol. 2021;21(166) © 2021 BioMed Central, Ltd.