Analgesic Efficacy of Free-opioid Anesthesia for Colorectal Surgery

Evaluation of the Analgesic Efficacy of Free Opioid Anesthesia for Patients Undergoing Colectomies and Rectal Resections: A Prospective, Randomized Controlled Clinical Trial

Objectives: To compare free-opioid anesthesia (the combination of epidural anesthesia, intravenous lidocaine, ketamine, propofol, and sevoflurane) and opioid anesthesia (fentanyl, propofol and sevoflurane) regarding intraoperative analgesic efficacy in colectomies and rectal resections at Viet Tiep Friendship Hospital. Methods: A prospective, randomized controlled clinical trial was performed on 98 patients who were anesthetized for colorectal surgery from December 2019 to November 2021. Patients were randomized into 2 groups: Group OA - Opioid anesthesia (n = 49): Intraoperative pain control by fentanyl; FOA group - Free-opioid anesthesia (n = 49): Intraoperative pain control by continuous infusion of lidocaine, bolus doses of ketamine combined with epidural levobupivacaine.

After being placed an epidural catheter and given a bolus dose of dexamethasone 0.1 mg/kg, patients was endotracheal anesthetized with propofol 1% 2-2.5 mg/kg, rocuronium 0.6 mg/kg. Intubation was implemented when TOF (Train Of Four)=0 and RE (Response Entropy), SE (State Entropy) ≤ 60. Patients in OA group received a bolus dose of fentanyl 2 µg/kg before induction of anesthesia while those in FOA group received bolus doses of lidocaine 1 mg/kg and ketamine 0.5 mg/kg. In FOA group, lidocaine 10% was sprayed on the patients glottis to facilitate intubation. For anesthesia maintenance, in group OA, a bolus dose of fentanyl 3 µg/kg was given 5 minutes before skin incision, and then a continuous infusion of fentanyl 2 µg/kg/h was maintained for intraoperative pain management; fentanyl 0.5 μg/kg was bolused when SPI (Surgical Pleth Index) > 50, 40 < SE < 60, TOF = 0 and the patient was hemodynamically stable. Propofol and fentanyl were discontinued at the start of skin closure. In FOA group, patients received intraoperative multimodal analgesia, in which an epidural bolus of 3 - 5 ml of levobupivacaine 0.1% was followed by a continuous infusion of 3 - 5 ml/h epidurally; in addition, intravenous infusion of lidocaine 1 mg/kg/hour and ketamine 0.25 mg/kg/h were maintained until the end of surgery. Patients were given a bolus of 3-5 ml levobupivacaine 0.1% epidurally and ketamine 0.25 mg/kg intravenously if SPI > 50, 40 < SE < 60, TOF = 0 and hemodynamics was stable. For all patients, anesthesia was maintained by volatile anesthetics (Sevoflurane or Desflurane) to ensure 40 < SE < 60, and rocuronium 0.2 mg/kg was repeated when TOF = 2 (the last injection of neuromuscular blockade was not given when the estimated duration from the point of injection to the point of abdominal closure is shorter than 20 minutes). Mechanical ventilation was provided with a tidal volume 6-8 ml/kg in the volume-controlled mode and respiratory rate at 10-12 breath/minute, FiO2 (Fraction of inspired oxygen)=50%. Peak airway pressure was maintained within the range of 12-16 cmH2O and EtCO2 (End-tidal Carbon dioxide) was kept from 35 to 40 mmHg with a fresh gas flow of 1.2 - 2 liters/minute. At the end of surgery, reversal of neuromuscular blockade was performed with neostigmine combined with atropine, and extubation was carried out when patients met the criteria. Postoperative pain management was implemented with patient-controlled epidural levobupivacaine 0.1% for 72 hours, and pain rescue with fentanyl 0.5 μg/kg.

Patients were randomized into 2 groups: Group OA - Opioid anesthesia (n = 49): Intraoperative pain control by fentanyl; FOA group - Free-opioid anesthesia (n = 49): Intraoperative pain control by continuous infusion of lidocaine, bolus doses of ketamine combined with epidural levobupivacaine.

The drugs were administered in 10 mL and 50 mL syringes labeled as ''loading'' or ''infusion'' respectively. All the drugs delivered in loading dose (intravenous lidocaine and ketamine, epidural levobupivacaine in FOA group; fentanyl and normal saline in OA group) were diluted in normal saline to 10 ml volume labeled indistinguishably as ''loading-1'' and ''loading-2'', "loading-3"…. Because the number of loading drugs in the FOA group was greater than in OA group, investigators added some 10 ml normal saline syringes in the OA group to make the number of "loading" syringes in the two groups equal, thereby ensuring complete blinding. The infusion drugs (lidocaine, ketamine and levobupivacaine in FOA group or normal saline in OA group) were prepared in 50 mL syringes and labeled as ''infusion-1'' and''infusion-2'' respectively. The patients and the anesthetists taking part in the procedures were not informed of the study protocol.

49 patients were injected bolus doses of lidocaine 1 mg/kg and ketamine 0.5 mg/kg before induction. Then intravenous propofol 1% 2-2.5 mg/kg, rocuronium 0.6 mg/kg were utilized for induction. For anesthesia maintenance, patients received intraoperative multimodal analgesia, in which an epidural bolus of 3 - 5 ml of levobupivacaine 0.1% was followed by a continuous infusion of 3 - 5 ml/h epidurally; in addition, intravenous infusion of lidocaine 1 mg/kg/hour and ketamine 0.25 mg/kg/h were maintained until the end of surgery. Patients were given a bolus of 3-5 ml levobupivacaine 0.1% epidurally and ketamine 0.25 mg/kg intravenously if SPI > 50, 40 < SE < 60, TOF = 0 and hemodynamics was stable. Postoperative pain management was implemented with patient-controlled epidural levobupivacaine 0.1% for 72 hours, and pain rescue with fentanyl 0.5 μg/kg.

49 patients received a bolus dose of fentanyl 2 µg/kg before induction of anesthesia. For anesthesia maintenance, in group OA, a bolus dose of fentanyl 3 µg/kg was given 5 minutes before skin incision, and then a continuous infusion of fentanyl 2 µg/kg/h was maintained for intraoperative pain management; fentanyl 0.5 μg/kg was bolused when SPI (Surgical Pleth Index) > 50, 40 < State Entropy (SE) < 60, Train of four (TOF) = 0 and the patient was hemodynamically stable. Propofol and fentanyl were discontinued at the start of skin closure. Postoperative pain management was implemented with patient-controlled epidural levobupivacaine 0.1% for 72 hours, and pain rescue with fentanyl 0.5 μg/kg.

Free opioid anesthesia (FOA) has been used in many countries around the world, making use of multimodal analgesia therapy which includes hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics and anti-inflammatory agents and sympathetic block in surgery. This method was demonstrated to contribute to enhanced recovery after surgery (ERAS). The use of long-acting local anesthetics also enhances postoperative pain relief. As a result, the concept of balanced anesthesia now has a change in three basic components: hypnotics, muscle relaxants and sympathomimetic inhibitors

Opioids have been used as one of three basic components of balanced anesthesia, including anesthetic drugs, pain relievers, and neuromuscular blockade agents (opioid anesthesia). Opioids not only facilitate deep anesthesia but also create the most favorable conditions for surgeries. Fentanyl is a potent opioid used to control pain, reduce the dose of sympathomimetic inhibitors and maintain hemodynamic stability. However, several common side effects of fentanyl are well known: nausea and vomiting, constipation, urinary retention, headache, pruritus, rash, histamine release, biliary spasm and respiratory depression, the most severe adverse effect

intraoperative alteration of Surgical Pleth Index (SPI). The Surgical Pleth Index (SPI) is an objective tool that can reflect nociception-antinociception balance and guide the use of intraoperative analgesics. The values of the SPI range from 0 to 100. During general anaesthesia, maintaining a value between 20 and 50 is generally recommended. When the SPI value is greater than 50 and exceeds 3-5 min, it routinely indicates that the noxious stimulation is too strong and that additional analgesic drugs are needed.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Non-invasive blood pressure was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The mean arterial blood pressure at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Heart rate was assessed every 5 minutes intraoperatively and recorded at some investigated time points. The heart rate at each time point was compared between the two groups.

Blood samples were collected in a heparin tube immediately before surgery (T0) and 1 hour after extubation. They were centrifuged, and then plasma was separated and stored at -70°C until being analyzed. IL-6 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Changes in IL-6 were recorded and compared between the two groups

Blood samples were collected in a heparin tube immediately before surgery (T0) and 1 hour after extubation. They were centrifuged, and then plasma was separated and stored at -70°C until being analyzed. IL-6 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Changes in IL-6 were recorded and compared between the two groups

Blood samples were collected in a heparin tube immediately before surgery (T0) and 1 hour after extubation. They were centrifuged, and then plasma was separated and stored at -70°C until being analyzed. IL-10 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Changes in IL-10 were recorded and compared between the two groups

Blood samples were collected in a heparin tube immediately before surgery (T0) and 1 hour after extubation. They were centrifuged, and then plasma was separated and stored at -70°C until being analyzed. IL-10 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Changes in IL-10 were recorded and compared between the two groups

Inclusion Criteria: Patients agreed to participate in the study. Patients aged ≥ 18 years old, Those who underwent elective colectomies or rectal resections, Those who were ASA (American Society of Anesthesiologists) classified as I - III, Those who were indicated for general endotracheal anesthesia from December 2019 to November 2021 at Viet Tiep Friendship Hospital Exclusion Criteria: Patients refused to participate in the study, Patients had BMI (Body Mass Index) ≥ 35; Pregnant or lactating or menstruating women; Those who had liver failure, renal failure, heart failure, history of chronic pain, alcohol or drug abuse, mental illnesses, allergies or contraindications to any studied medications. Those who were unable to assess pain or use of patient-controlled analgesia devices (PCA).

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request. Researchers could contact the corresponding author via email to ask for IPD.

The data is available only for research purposes and personal information of the participants need to be kept confidential

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