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Tochie t al.BMCAnesthesiology 2022 22 2 https://doi.org/10.1186/s12871-022-01856-6 RESEARCH Open Access The efficacy and safety of an adapted opioid-free anesthesia regimen versus conventional general anesthesia in gynecological surgery for low-resource settings: a randomized pilot study 1* 1,2 3,4 Joel NoutakdieTochie , Roddy Stephan Bengono Bengono , Junette Mbengono Metogo , Raymond Ndikontar 1,, Serges Ngouatna , Ferdinand Ndom Ntock 3,4and Jacqueline Ze Minkande 1,5 Abstract Introduction: There is scarce data on the safety and efficacy of opioid-free anesthesia (OFA), in resource-limited settings due to the non-availability of dexmedetomidine, the reference OFA agent.We aimed to demonstrate the feasibility, efficacy and safety of a practical OFA protocol not containing dexmedetomidine, adapted for low-resource environments in very painful surgeries like gynecological surgery. Methods: We conducted a randomized pilot study on ASA I and II women undergoing elective gynecological surgery at a tertiary care hospital in Cameroon. Patients were matched in a ratio of 1:1 into an OFA and a conven- tional general anesthesia (CGA) group.The OFA protocol entailed the intravenous (IV) magnesium sulfate, lidocaine, ketamine, dexamethasone, propofol, and rocuronium, followed by isoflurane and a continuous infusion of a calibrated mixture of magnesium sulfate, ketamine and clonidine.The CGA protocol was IV dexamethasone, diazepam, fentanyl, propofol, and rocuronium, followed by isoflurane and reinjections of fentanyl propofol and a continuous infusion of normal saline as placebo.The primary endpoints were the success rate of OFA, isoflurane consumption and intraop- erative anesthetic complications.The secondary endpoints were postoperative pain intensity, postoperative compli- cations, patient satisfaction assessed using the QoR-40 questionnaire and the financial cost of anesthesia. Results: We enrolled a total of 36 women undergoing gynecological surgery; 18 in the OFA group and 18 in the CGA group.The success rate of OFA was 100% with significant lesser consumption of isoflurane in the OFA group, no signif- icant intraoperative complication and better intraoperative hemodynamic stability in the OFA group. Postoperatively, compared to the CGA group, the OFA group had statistically significantly less pain during the first 24 h, no morphine consumption for pain relief, had less hypoxemia during the first six hours, less paralytic ileus, less nausea and vomiting, no pruritus and better satisfaction.The mean financial cost of this adapted OFA protocol was statistically significant lesser than that of CGA. *Correspondence: joeltochie@gmail.com 1Department of Surgery and Sub-Specialties, Faculty of Medicine and Biomedical Sciences, University ofYaoundé 1,Yaoundé, Cameroon Full list of author information is available at the end of the article permitsuse,sharing,adaptation,distributionandreproductioninanymediumorformat,aslongasyougiveappropriatecredittothe originalauthor(s)andthesource,providealinktotheCreativeCommonslicence,andindicateifchangesweremade.Theimagesor otherthirdpartymaterialinthisarticleareincludedinthearticle’sCreativeCommonslicence,unlessindicatedotherwiseinacreditline regulationorexceedsthepermitteduse,youwillneedtoobtainpermissiondirectlyfromthecopyrightholder.Toviewacopyofthistory licence,visithttp://creativecommons.org/licenses/by/4.0/.TheCreativeCommonsPublicDomainDedicationwaiver(http://creativeco mmons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestatedinacreditlinetothedata.Tochie et al.BMCAnesthesiology2022 22 2 Page 2 of 13 Conclusion: This OFA regimen without dexmedetomidine for a low-resource setting has a promising success rate with few perioperative complications including mild intraoperative hemodynamic changes, decrease postoperative complications, pain, and opioid consumption in patients undergoing elective gynecology surgery. Trial registration: This study was registered at clinicaltrials.gov on 03/02/2021 under the registration number NCT04737473. Keywords: Opioid-free anesthesia, Adapted, Gynecological surgery, Efficacy, Safety, Cameroon Introduction 23] and severe acute and chronic postoperative at 40% For the last six decades, opioids have been a key com- [24]. Hence, the aforementioned benefits of OFA, make ponent of conventional general anesthesia (CGA) due to this anesthetic technique an attractive promising option for gynecological surgery [21]. However, the extent of the their analgesic effect, their hypnotic effect and their abil- ity to control the autonomic nervous system response to aforementioned benefits of OFA is questionable because surgical stress during CGA, with resultant hemodynamic dexmedetomidine, the reference OFA analgesic-sedative stability [1, 2]. However, recently, the principle underly- drug, recently used in a well-powered multicenter clinical ing the administration of opioids during CGA has been trial on 314 non-cardiac surgeries (including 18 gyneco- subjected to several opioid-related adverse effects like logical surgeries), was associated with more statistically postoperative respiratory depression [3], postoperative significant delayed extubation, prolonged PACU LOS, ileus (POI), postoperative nausea and vomiting (PONV) postoperative hypoxemia, and severe bradycardia war- [4], hyperalgesia [5], inflammation modulation, immune ranting early study termination [25]. Two other large depression especially in oncology surgery [6], poor post- well-powered recent studies [26, 27] conducted in high- operative analgesia, increased consumption of morphine income settings, comparing OFA (using dexmedeto- [7], pruritus, urinary retention [8] and postoperative midine) to CGA in laparoscopic gynecological surgery shivering [9]. These lead to undesirable delayed patient showed equivalent postoperative pain, postoperative opi- oid consumption, PONV, anti-emetic requirements [26, rehabilitation, prolonged length of hospital stay (LOS), increase cost of healthcare, poor patient satisfaction, not 27] with even more significant sedation scores and longer accepted in the current era of enhanced recovery after PACU LOS in the OFA group [27]. On the other hand, surgery (ERAS) [10]. In a bid to mitigate the aforemen- studies [28–31] carried out in low-and middle-income tioned opioid-related adverse effects in the perioperative countries above the Saharan region with some using period, an opioid-sparing anesthetic technique called dexmedetomidine in OFA for gynecological surgery are Opioid-Free Anesthesia (OFA) was recently developed in favour of better hemodynamic stability in addition to [11]. OFA is a technique of providing anesthesia by com- the aforementioned benefits of OFA. With an extensive bining intravenous administration of a combination of literature search, to the best of our knowledge, there is non-opioid agents to produce adequate intraoperative a dearth of comprehensive or reference data on the fea- analgesia, hypnosis, sympatholysis, and pain-free awak- sibility, safety and effectiveness of OFA in gynecological ening [12–14]. Some small sample-size clinical studies surgery in sub-Saharan Africa, the most poverty stricken limited to bariatric surgery and laparoscopic cholecys - region of the world and where dexmedetomidine is not tectomy have fairly demonstrated the superiority of OFA available due to its relatively high financial cost. Hence, over CGA in procuring several benefits such as better we propose this study to report on the feasibility, safety intraoperative analgesia, hypnosis, myorelaxation, hemo- and efficacy of an adapted OFA protocol not containing dynamics, bispectral index [14–16] with a reduction in dexmedetomidine in women undergoing gynecological postoperative pain [9, 15, 17], postoperative opioid con- surgery in a major referral Mother and Child Hospital in sumption [9, 17, 18], PONV [9, 17, 19], postoperative Cameroon. hypoxemia [9], higher postoperative patient satisfaction [9, 20] and shorter length of stay (LOS) in the postanes- Materials and methods thesia care unit (PACU) [20]. This manuscript adheres to the applicable 2010 CON- SORT guidelines for randomized controlled trials (sup- Gynecological surgery, including breast cancer sur- gery, leads to intense surgical stress, making gynecologi- plementary file 1). cal surgery particularly prone to intense postoperative pain, inflammation, marked shivering, severe PONV and Ethical considerations POI [21]. More specifically, following major gynecologi- Before the start of the study, the study protocol was cal surgery, PONV occur at incidences of 50—80% [22, approved by the Institutional Review Board of the FacultyTochie et al.BMCAnesthesiology2022 22 2 Page 3 of 13 of Medicine and Biomedical Sciences, University of Patients were matched for age, parity, comorbidities, Yaoundé I, Yaoundé, Cameroon (approval number: 223/ type of gynecological surgical procedure and ASA grade UYI/FMSB/VDRC/DAASR/CSD). This clinical trial was in a ratio of 1:1 to the OFA group and CGA group. Sim- registered at ClinicalTrials.gov; NCT04737473; February ple randomization was done by consecutive enrolment 03, 2021; principal investigator: Tochie JN (https://clini and encoding identifications of OFA cases on Mondays caltrials.gov/ct2/show/NCT04737473). and Wednesdays, followed by CGA cases on Tuesdays and Thursdays, until attainment of the minimum sam- Study design and study setting ple size. This randomization, determined by surgical This was a randomized controlled trial carried out at days of the week was chosen by the principal investiga - the Department of Anesthesiology and Intensive Care tor solely for this study and only the principal investiga- of the Yaoundé Gyneco-obstetric and Pediatric Hospi- tor knew the encoding concealment. At induction, only tal (YGOPH), Yaoundé, Cameroon between January 06, the principal investigator aided by a certified experienced 2020, to September 28, 2021 (21 months). The YGOPH external anesthesiologist and intensive care physician is a tertiary and University Teaching Hospital for the not involved in patient care were present in the operat - referral of mother and child illness in Yaoundé and its ing room and knew whether the patient was adminis- environs. The study was carried out precisely at the tered OFA or CGA. Thereafter, the certified experienced Anesthesiology unit and Intensive Care Unit (ICU) of the external anesthesiologist and intensive care physician YGOPH is run by four attending Anesthesiologist-Inten - not involved in patient care went out of the operating sive Care Physicians, 13 anesthesiologist-intensive care room. The surgical team and the rest of the anesthetist nurses and 16 state registered nurses. team both entered the operating room when the patient was administered maintenance anesthesia via an unla- Participant eligibility and sample size calculation beled infusion of either opioid-free analgesics (for the Eligible participants were adult non-pregnant women OFA group) or normal saline (for the CGA group). Apart aged≥18 years classified American Society of Anesthesi- from the principal investigator (JNT) and the certified ology (ASA) I and II, admitted to the study setting for an experienced external anesthesiologist and intensive care elective myomectomy, hysterectomy, ovarian cystectomy physician not involved in patient care, patients, surgeons or total mastectomy for benign pathologies and localized and the rest of the anesthetist and ICU teams were thus malignancies and who were able to follow instructions blinded to the OFA or CGA allocation. and comply with assessments. The exclusion criteria were history of allergy to any drug used for OFA or CGA; his- Anesthetic management tory of alcohol, opioid or drug abuse; chronic pain; psy- On arrival at the theater, all patients received standard chiatric illness; patients undergoing surgery with planned monitoring including ECG, pulse oximetry, non-invasive regional anesthesia of tissular infiltration of local anes- blood pressure and temperature. Thereafter, we began thesia, those with iatrogenic surgical complications such compensating any un-prescribed or undue clear oral as bowel, ureter or bladder injuries. The sample2size was fluid fasting by the patient for more than two hours with estimated using the formula: n=2(Zα+Z[1-β]) ×P×q/ Ringer Lactate Solution, followed by antibiotic prophy - d [32]. Zα is the standard normal variate equal to 1.96, laxis with intravenous (IV) amoxicillin-clavulanic acid the power was set at 80%, the level of significance (α) at 2 g, and then, pre-oxygenation. The anesthetic protocols 5%, the effect size is d and q is 1—P. P is the pre-study are as follows; estimate of the prevalence of gynecology surgery like hy- OFA was induced using an adapted French protocol terectomy at the Douala General Hospital of Cameroon by Beloeil H [34]; premedication with lidocaine 1.5 mg/ which is 14.54% [33]. A reduction of postoperative pain kg IV, magnesium sulfate 40 mg/kg (in 100 ml of saline by 40% will be considered significant for the effective- without exceeding 2.5 g), ketamine 25 mg IV and dexa - ness of the adapted OFA protocol. Hence, the minimum methasone 0.1 mg/kg IV. Induction of general anesthesia sample size calculated was 34 patients; we needed a mini- with propofol 1.5 mg/kg IV and rocuronium 0.1 mg/kg mum of 17 in the CGA group and 17 in the OFA group. IV. Anesthesia was maintained using isoflurane between 0.5–2%, and an electric pump syringe at 10–15 ml/h con- Participants’randomization and blinding taining a mixture of magnesium sulfate 40 mg/kg (with- Patient enrolment was done at the outpatient Anes- out exceeding a total dose of 2.5 g/24 h taking note of the thesiology unit solely by the principal investigator who induction dose), lidocaine 1.5 mg/kg, ketamine 0.25 mg, recruited all adult women ASA I and II who signed and clonidine 1 ug/kg. informed consent for an elective myomectomy, hys- CGA protocol consisted of premedication with diaz - terectomy, ovarian cystectomy or total mastectomy. epam 5  mg IV and dexamethasone 0.1  mg/kg IV. TheTochie et al.BMCAnesthesiology2022 22 2 Page 4 of 13 anesthesia was induced using fentanyl 3ug/kg IV, propo- POI was defined as an absence of flatus or stools within fol 2.5 mg/kg IV, and rocuronium 0.1 mg/kg IV. Anes- the first 48 h after extubation [34]. thesia was maintained using isoflurane between 0.5–2%, reinjections of one-quarter of the induction dose of fen- Postoperative phase tanyl every 20 – 30 min and one-quarter of the induction Due to the pilot nature of this study and the concern of dose of propofol as needed and a continuous infusion of post-anesthesia security, after surgery, all patients were normal saline via an electric pump syringe at 10–15 ml/h admitted to the ICU till hospital discharge for close mon- as placebo. itoring of any adverse effects of OFA and CGA. Analge- In both groups after induction of anesthesia, patients sics were administered based on the Numerical Rating were relayed to an anesthesia machine (MINDRAY scale (NRS), interpreted in Table 1. WATO EX65) where they were volume-controlled ven- tilated at the following parameters: tidal volume at 6 Outcomes or endpoints – 8 ml/kg, respiratory rate at 12 – 14 breaths/min, inspir- The primary outcomes were the failure of OFA (defined atory: expiratory fraction at 1: 2, positive end-expiratory as the intraoperative need to administer opioids for pressure at 2 – 4 cmH 0,2and end-tidal volume of car- adequate intraoperative analgesia) and the occurrence bon-dioxide (ETCO ) a2 30–50  mmHg. Intraoperative of intra-operative complications e.g. hypotension, high resuscitation consisted of compensating the fasted fluids, blood pressure, tachycardia and bradycardia. Other pri - administering hourly fluid maintenance, replenishing mary endpoints were the mean alveolar concentration fluid losses volume by volume with Ringer Lactate solu - (MAC in %) of isoflurane used in both groups. tion; blood transfusion when the amount of blood loss The secondary endpoints were pain intensity and authorized was exceeded; fluid bolus and reduction/ces- patient satisfaction within the first 48 h postoperation, sation of isoflurane in case of hypotension; administering as well as the occurrence of postoperative complications atropine 0.1 mg/kg IV in case of bradycardia; nicardipine until hospital discharge as detailed below: (1) pain inten- 1 – 2  mg bolus against high blood pressure. Approxi- sity (assessed using the Numerical Rating scale) and need mately 30 min before skin surgical closure, all patients for opioids for pain relief with the first 48 h of surgery; received IV paracetamol 1 g, IV tramadol 100 g and IV (2) patient satisfaction (assessed on the Quality of Recov- nefopam 20 mg. ery-40 [QoR-40] questionnaire in supplementary file 1) at 24 h and 48 h postoperation. The QoR-40 questionnaire Adverse effects is a universally or externally validated scale for the ass-ss These include any intra-operative undesirable effects of ment of patient satisfaction after major surgery based OFA or CGA such as hypotension, high blood pressure, on five criteria of recovery: physical comfort, emotional bradycardia, and tachycardia. Hypotension was defined state, physical independence, psychological support, and as a systolic blood pressure of less than 90 mmHg or a pain [28, 34]. The QoR-40 questionnaire is graded from mean arterial pressure of less than 65  mmHg. High 40 to 200, where QoR-40=40, QoR-40 between 41 and blood pressure was a systolic blood pressure greater than 159 and QoR-40≥160 indicate poor, moderate and good 140 mmHg and/or diastolic blood pressure greater than patient satisfaction; (3) the occurrence and number of 90 mmHg. A pulse less than 60 beats per minute was PONV episodes (managed by fluid hydration as well as termed bradycardia, whereas, a pulse greater than 99 anti-emetic; dexamethasone 4  mg IV bolus); (4) post - beats per minute was termed tachycardia. Adverse effects operative hypoxemia; (5) the need of endotracheal re- also included post-operative undesirable effects of OFA intubation with mechanical ventilation; (6) POI; (7) time or CGA such as postoperative hypoxemia and postop - between the end of OFA or CGA maintenance and extu - erative ileus (POI). Postoperative hypoxemia was defined bation; (8) hospital length of stay (max. 28 days) defined as therapeutic oxygen supplementation to maintain as the number of days after extubation before first hos- SpO2>95% within the first 48  h after extubation [34]. pital discharge; (9) other secondary endpoints: pruritus, Table 1 Numerical Rating scale interpretation Numerical Rating scale Meaning Management (NRS) ≤3 Mild pain Paracetamol 1 g/6 h IV 3 – 6 Moderate pain Paracetamol 1 g/6 h IV, diclofenac 75 mg/12 h IM (for 48 h) and tramadol 100 mg/8 h IV ≥7 Severe pain Paracetamol 1 g/6 h IV, diclofenac 75 mg/12 h IM (for 48 h) and tramadol 100 mg/8 h IV plus morphine at titrated dosesTochie et al.BMCAnesthesiolog2022 22 2 Page 5 of 13 need of oxygen postoperatively, time for the return of Baseline characteristics of the study population intestinal transit, mean time between the end of surgery The mean age of the women was 40.3±10.7  years and the first walk in hours, and mean total cost of drugs (range: 18 to 63 years). The OFA and CGA group were used for anesthesia (XAF). comparable in terms of mean age, mean parity, age, par- ity, comorbidities, types and indications of gynecologi- cal surgical procedure, mean systolic blood pressure, Follow‑up after discharge mean diastolic blood pressure, mean arterial pressure, Follow-up anesthesia visits at one, two, three and four mean oxygen peripheral saturation and ASA grade (all weeks after hospital discharge for clinical assessment p above 0.05) (See Table 2). in search of any potential complaint related to OFA or CGA. Any complaint/complication found was treated Primary endpoints accordingly. The success rate of OFA was 100% and no intraop- erative complication was observed in the OFA group Statistical analysis (Table  3). The intraoperative hemodynamics mainly evaluated using the variation in the mean arterial pres- Descriptive analysis was done using percentages of sure (MAP) showed more stable hemodynamics in the binary variables, mean (standard deviations) and median (interquartile range) for continuous variables. The pri- OFA group compared with the CGA group. Moreover, mary effect variable: the failure of OFA was analyzed and the MAP at one hour after the surgical incision was significantly more stable in the OFA group than in the intraoperative complications were analyzed as dichoto- CGA group (p=0.0026) as shown in Fig. 2. Isoflurane, mous variables (present/absent). Continuous variable the halogen gas partly used for maintenance anesthesia analysis was applied to secondary effect variables such as time between the end of OFA or CGA maintenance and in both the OFA and CGA groups was statistically con- sumed less in the OFA group compared with the CGA extubation, hospital length of stay, time for the return of group (p<0.001) (See Fig. 3). intestinal transit, mean time between the end of surgery and the first walk, and mean total cost of drugs used for anesthesia (XAF). Other secondary effect variables such Secondary endpoints as QoR-40 scale score, PONV, postoperative hypoxemia, Patients who underwent OFA were extubated faster than those who underwent CGA though statisti- need for endotracheal re-intubation, POI, pruritus and cally insignificant. Also, compared to the CGA group, need for oxygen postoperatively were analyzed as dichot- omous variables (present/absent). The distribution of the OFA group had lesser statistically significant pain data was assessed using the Kolmogorov-Smirnoff test. scores within the first 24 h post-operation (Fig. 4) and did not require morphine for postoperative pain relief; A comparison of categorical data between the OFA and had fewer hypoxemic episodes within the first six-hour CGA groups was performed using the Chi-square test and Fischer exact test. ANOVA test was performed for post-operation (Fig. 5) and required lesser oxygen post- repeated measures to assess postoperative pain reported operatively; had no POI; had lesser episodes of PONV; through the NRS at different time intervals (1st, 2 , 6th, had no pruritus; rehabilitated or began walking post- operatively faster after surgery; had good postopera- 12th, 24th and 48th hour) between the OFA and CGA groups. The threshold of statistical significance was set tive satisfaction compared with moderate postoperative at 0.05. All statistical analyses were performed using EPI satisfaction in the OFA group (all p<0.05). The mean INFO version 3.5.3 software. financial cost of OFA was statistically significantly lesser than the mean cost of CGA (46,500±2,573 XAF vs. 57,000±5,379 XAF; p<0.001) (See Table 4). Results A total of 50 women booked for elective gynecology sur- Follow‑up after discharge gery were approached. Fourteen were excluded: eight Patients in both the adapted OFA and CGA groups refused to consent; six were classified ASA IV due to two were followed up till four weeks after anesthesia with patients with a recent ischemic stroke (four months ago), no complications in both groups. two patients on recent chemotherapy (2 weeks ago) for breast cancer with abnormal hepatic function test and Discussion two patients on maintenance hemodialysis for end-stage This study showed that the proposed OFA technique renal. Hence, 36 participants were retained as the study without dexmedetomidine has a promising success rate population, yielding a response rate of 72%. Figure 1 illus-with few perioperative complications including mild trates a flow diagram for participant enrolment.Tochie et al.BMCAnesthesiolog2022 22 2 Page 6 of 13 Fig. 1 CONSORT 2010 flow diagram illustrating participants’enrollment intraoperative hemodynamic changes, decrease post- intraoperative complication and better intraoperative operative complications, pain, and opioid consumption hemodynamic stability in the OFA group. These findings in patients undergoing elective gynecology surgery in re-iterate previous reports from other clinical trials on low-resource settings. gynecological surgery [26, 28–31, 35–41] demonstrat - The primary endpoints of this clinical trial were to ing a 100% success rate for OFA with stable or better determine the failure of the adapted OFA protocol, hemodynamics and no intra-operative complications. intraoperative isoflurane consumption and the occur - By contrast, a multicentre French clinical trial on 314 rence of intraoperative complications. We found this non-cardiac surgeries (with 5.7% gynecological surgi - adapted OFA protocol had a 100% success rate with sig- cal procedures) reported more hypertension, hypoten- nificant lesser consumption of isoflurane, no significant sion and severe bradycardia (less than 45 beats/min)Tochie et al.BMCAnesthesiology 2022 22 2 Page 7 of 13 Table 2 Baseline characteristics of the study population Characteristics Total sample OFA group CGA group RR 95% CI p—value N=36 (%) N=18 (%) N=18 (%) Age (mean in years) 40.3±10.7 39.2±12.2 41.4±9.2 - - 0.6227 Parity 3.4±2.8 3.1±2.8 3.8±2.8 - - 0.4233 Past history - - 0.3456 None 32 (88.8) 15 (83.3) 17 (94.4) HIV 2 (5.6) 1 (5.6) 1 (5.6) Hypertension 2 (5.6) 2 (11.1) 0 (0) Type of surgery - - 0.0555 Myomectomy 17 (47.2) 5 (27.8) 12 (66.7) Ovarian cystectomy 8 (22.2) 7 (38.9) 1 (5.5) Hysterectomy 6 (16.7) 3 (16.7) 3 (16.7) Mastectomy 5 (13.9) 3 (16.7) 2 (11.1) Surgical Indications - - 0.1811 Mymectomy Fibroid – menometrorrh 13 (36.1) 6 (33.3) 7 (38.9) Fibroid – infertility 4 (11.1) 1 (5.6) 3 (16.7) Fibroid—pain 1 (2.8) 0 (0) 1 (5.6) Hysterectomy Localized cervical cancer 4 (11.1) 1 (5.6) 3 (16.7) Mastectomy Invasive ductal carcinoma 6 (16.7) 3 (16.7) 3 (16.7) Ovarian cystectomy Benign ovarian cyst 8 (22.2) 7 (38.9) 1 (5.6) Pre‑anaesthesia parameters Mean SBP (mmHg) 124.8±12.8 122±14.1 127.7±11.1 - - 0.1525 Median SBP (mmHg) 126 119.5 126 - - 0.1525 Mean DBP (mmHg) 77.4±10.8 76±11.4 78.8±10.2 - - 0.4957 Median DBP (mmHg) 80 78.5 81 - - 0.4957 Mean of MAP (mmHg) 89±29.9 82.8±40.9 95.3±9.1 - - 0.2168 Median MAP (mmHg) 93.5 93 96.5 - - 0.2168 Mean pulse (bpm) 84.6±13.4 82.9±15.1 86.2±11.7 - - 0.3110 Median pulse (bpm) 83 78.5 87 - - 0.3110 Mean SaO (2) 97.4±14.9 99.8±0.5 95.0±21.2 - - 0.5975 Median SaO (%) 100 100 100 - - 0.5975 2 Mean BMI (kg/m ) 2 25.7±5.1 23.9±5.7 27.5±3.6 3.6 0.37 – 6.83 0.0080 ASA 0.7 0.37 – 1.33 0.2443 I 23 (63.8) 13 (72.2) 10 (55.6) II 13 (36.1) 5 (27.8) 8 (44.4) ASA American Society of Anesthesiology, bpm Beats per minute, BMI Body mass index, CGA Conventional general anesthesia, CI Confidence interval, DPB Diastolic blood pressure, MAP Mean arterial pressure, menometrorrh Menometrorrhagia, OFA Opioid-free anesthesia, RR R2 ratio, SaO Oxygen peripheral saturation, SBP Systolic blood pressure during OFA which prompted the early termination of doses of 0.2– 0. 6ug/kg/h [30, 35, 37, 38] used by other the clinical trial [25]. Interestingly, all five cases of severe clinical trials on gynecology surgery where stable hemo - bradycardia occurred in prostatectomy, gastrectomy dynamics were observed. Although dexmedetomidine is and pancreatic surgery and none in gynecological sur - the reference OFA drug due to its α2-adrenergic anal - gical procedures. Moreover, this profound bradycardia gesic-sedative-hypnotic-sympatholytic properties, its occurred at a high dose of dexmedetomidine at 0.4 – 1.4 worldwide use is limited by its availability and relatively ug/kg/h which more than doubled dexmedetomidine high financial cost. As such, adapted OFA regimens notTochie et al.BMCAnesthesiology 2022 22 2 Page 8 of 13 Table 3 Intraoperative complications Intraoperative complication OFA group CGA group RR 95% CI P value N=18 N=18 Bradycardia 0 0 - - 0.5000 Hypotension 0 1 - - 0.5000 Tachycardia 0 4 - - 0.5000 High blood pressure 0 0 - 0.5000 CI Confidence interval, OR Risk ratio Fig. 2 Means of mean arterial pressures intraoperative variations between the OFA and CGA groups containing dexmedetomidine such as ketamine+lido- anti-inflammatory effect and an anti-hyperalgesic effect caine+profofol+atracurium [29] or ketamine+propo- than opioids. Our results concur with those of clinical studies on similar abdominal gynecological surgical pro- fol+magnesium sulfate+clonidine+rocuronium [40] or ketamine+lidocaine+dexamethasone+magnesium cedures [29, 35], laparocopic gynecological surgery [30, sulphate+clonidine+rocuronium like in the present 41] and mastectomies [28, 31, 39, 40] where significantly less postoperative pain, a net reduction of postopera- study have been used in gynecology surgery with stable peri-operative hemodynamic profiles and no intra-oper - tive opioid consumption and less rescue consumption of ative complications. This can be explained by the fact non-opioid analgesics like paracetamol, tramadol, pethi- that dexmedetomidine is a selective α2-adrenoreceptor dine and ketorolac. It is worth mentioning that despite agonist with marked dose-dependent cardiovascular our relatively small sample size statistically significant depressing effects [42]. differences in pain scores were still observed at 12 h and With regards to the secondary endpoints of this study, 24 h post-operation mainly in patients who underwent we found statistically significantly lesser postoperative mastectomy considering the severity in pain intensity of pain during the first 24  h post-operation in the OFA the latter. This finding of statistically significant differ- group compared to the CGA group. This was justified ences in pain intensity at 12 h and 24 h post-operation by no patient requiring morphine for postoperative pain concurs with those of Di Benedetto P et al. [40], Tripa- relief in the OFA group (0% vs. 33.3%; p=0.0095). This thy S et al. [28] and El-dein Aboalsoud RAH et al. [31] can be explained by the fact that the synergistic analge - on OFA vs. CGA for mastectomy in breast cancer with a sic effects of lidocaine [43, 44], dexamethasone, magne- similarly healthy ASA I and II small-sample population. sium sulphate [45], clonidine [46] and low-dose ketamine In the same vein, the advantage of ketamine in procur- [47] have been shown to have an overall greater anal- ing intra-operative and postoperative analgesia in OFA needs to particularly be spelled out. Ketamine analgesia gesic effect as well as an opioid-sparing property, anTochie et al.BMCAnesthesiology 2022 22 2 Page 9 of 13 Fig. 3 Intraoperative consumption of halogen gazes in the OFA and CGA groups Fig. 4 Postoperative pain intensity variations in the OFA and CGA groups. NRS=7 at 1 hour occurred only in mastectomies and hysterectomies. NRS was statistically different at 12 h and 24 h mainly in mastectomiesTochie et al.BMCAnesthesiology 2022 22 2 Page 10 of 13 Fig. 5 Means of postoperative peripheral oxygen saturation variations between the OFA and CGA groups Table 4 Secondary endpoints Variable OFA group CGA group RR 95% CI p – value N=18 (%) N=18 (%) Mean time between the end of maintenance anesthesia and extubation 13.61±6.55 17.67±6.25 - - 0.0705 in minutes (SD) Median time between the end of maintenance anesthesia and extubation 11 18.5 - - 0.0705 in minutes Need of morphine for postoperative pain relief 0 6 2.5 1.61–3.89 0.0095 Need of oxygen postoperatively 1 (5.6%) 12 (66.7%) 12 1.74–82.89 <0.001 Need of reintubation 0 (0%) 0 (0%) - - - Postoperative ileus 1 (5.6%) 15 (83.3%) 15 2.21–101.9 <0.001 Mean hours for return of intestinal transit (SD) 15.7±5.5 71±25 55.3 43.04–67.56 <0.001 Median hours for return of intestinal transit 17 74 - - <0.001 Postoperative nausea and vomiting 2 (11.1%) 9 (50%) 4.5 1.13–17.99 0.0137 Mean hour of occurrence of PONV (SD) 2.0±0.0 1.6±0.69 - - 0.3961 Mean hour of occurrence of PONV 2.0 2.0 - - 0.3961 Pruritus 0 (0%) 6 (33.3%) - - 0.0095 Mean time between the end of surgery and the first walk in hours (SD) 10.44±3.60 21.94±9.48 11.5 6.64 – 16.36 <0.001 Median time between the end of surgery and the first walk in hours 10 24 - - <0.001 Postoperative satisfaction at the 48 hour (mean QoR-40 score) 179.72±8.70 84.11±42.71 - - <0.001 (good satisfaction) (Moderate satisfaction) Mean length of hospital stay in days (SD) 5.06±0.42 5.22±0.65 - - 0.4328 Median length of hospital stay in days 5 5 - - 0.4328 Mean total cost of drugs used for anesthesia (XAF) 46,500±2,573 57,000±5,379 - - <0.001 CGA Conventional general anesthesia, CI Confidence interval, PONV Postoperative nausea and vomiting, OFA Opioid-free anesthesia, RR Risk ratio, SaO2 Oxygen peripheral saturation, QoR-40 Quality of Rehabilitation, SD Standard deviationTochie et al.BMCAnesthesiolog2022 22 2 Page 11 of 13 is obtained from its inhibitory central and peripheral rating scale for satisfaction. This reinforces evidence action on N-methyl-D-aspartic acid (NMDA) receptors of OFA as being safe and effective for gynecological involved in the transmission and modulation of acute surgery. As an expected side effect of opioids, there pain. In addition, ketamine used at low doses in OFA has were more cases of pruritus in the CGA group (6 vs. 0 an anti-inflammatory effect and anti-hyperalgesic effects cases; p=0.0095). The mean cost of anesthetic drugs exerted still via NMDA receptor antagonism leading was lesser in the OFA group (46,500±2,573 XAF vs. to good analgesia against both acute and chronic surgi- 57,000±5,379 XAF; p<0.001) as showcased in Table 4, cal pain [48]. Due to these aforementioned effects, it is hence, relatively cheaper and economic for resource- quite clear now that opioids intraoperative use can be limited settings. No statistically significant difference substituted by the intraoperative use of ketamine (even was seen with regards to the mean length of hospital without dexmedetomidine as an adjunct) in similar stay because it was a standard protocol to discharge all abdominal gynecology surgical procedures [29] and mas- postsurgical women with an uneventful postoperative tectomy [40] like in the current study. Compared to the course on day 05 post-operation. Overall, the benefits OFA group, the CGA had statistically significant more of this adapted OFA protocol cannot be overempha - postoperative hypoxemia during the 1 six hours war- sized due to a lessened economic burden on patients in ranting supplementary oxygen therapy (5.6% vs. 66.7%; resource-constrained settings but also due to the cur - p=0.0001). We attribute this finding to the lack of opi- rent global anesthesia era which promotes ERAS in oids in the OFA group which have a respiratory depress- gynecology surgery [10]. ing property compared to ketamine used in the adapted There are some limitations to the present study. OFA protocol which has a bronchodilator effect and no Firstly, its relatively small sample size (n=36) impli- respiratory depression effect [49]. This observation cor- cates the cautious generalizability of results to other roborates with those of previous clinical trials by El-deinlow-income settings. The main reason for this relatively Aboalsoud et al. [31]. on modified radical mastectomy small size over a wide enrollment period was due to with axillary for breast cancer surgery. By contrast, in the prevailing COVID-19 pandemic which reduced the the POFA trial on non-cardiac surgeries including 11.4% amount of elective gynecological surgical procedures gynecological surgical procedures, more postoperative performed at the study setting because of COVID-19 hypoxemia was observed in the OFA group (75% vs. 61%, preventive motives. Secondly, potential advantages of p=0.030) perhaps due to the additive sedative effects of OFA such postoperative opioid sparing in the geriat - dexmedetomidine, ketamine, propofol on the incidence ric population [51] and lesser respiratory depression of postoperative respiratory distress. in patients with pre-existing lung diseases [52] were Opioids are potent emetics via their direct action on not assessed. This is because the scope of study par- chemo-trigger zone receptors in the brainstem [50]. The ticipants was limited to ASA I and II patients for the result of this central stimulation during the perioperativesecurity or safety purpose of the pilot nature of this period leads to PONV, more common in major gyneco - randomized controlled trial, the first of its kind in a logical surgery, where PONV occurs at incidences of resource-limited setting. By applying this eligibility 50—80% [22, 23]. Hence, similar to previous studies on criterion, the study population retained without any gynecology surgery [28–30, 36–38, 40, 41] the frequency intentional selection bias were relatively young (mean of episodes of PONV was reduced in the OFA group age: 40.3±10.7 years) and healthy patients without pul- (p=0.0137). monary pathologies, precluding the assessment of the Lower rates of POI were seen in the OFA group com - aforementioned potential advantages of OFA. Several pared with the CGA group (5.6% vs. 83.3%; p<0.001) authors [29, 30, 38] working on OFA in gynecological and corroborates with findings on abdominal gyneco- surgery equally had a relatively young healthy ASA I logical surgery [29] and laparoscopic gynecology sur- and II study population as ours. Thirdly, the randomi - gery [41]. This was an expected finding that has been zation of patients was more of a pragmatic approach, correlated with the pharmacodynamic properties hence, might have flawed the study findings with allo- of opioids on the intestines: a reduction of peristal- cation bias. The strength of the study relies on its rebost tic movements [8]. Similar to other authors working methods using a clinical trial with adequate patient on both abdominal and laparoscopic gynecologi- follow-up up to four weeks post-operation to provide cal surgery [29, 30, 37, 38] as well as mastectomy [28, high-quality evidence on the efficacy and safety of OFA 31] patients in the OFA group demonstrated statisti- over CGA. Also, this proposed adapted OFA proto - cally significant quicker postoperative mobilization col not containing dexmedetomidine makes it simple, or recovery with better postoperative satisfaction practical and economical to implement in resource- assessed on either the QoR-40 questionnaire or verbal constrained environments.Tochie et al.BMCAnesthesiology 2022 22 2 Page 12 of 13 Conclusion Competing interests The authors declare that they have no competing interests. The current study findings suggest that the use of this adapted OFA protocol as an anesthetic technique in 1uthor details low-resource environments could have a promising suc- Department of Surgery and Sub-Specialties, Faculty of Medicine and Bio- medical Sciences, University ofYaoundé 1,Yaoundé, Cameroon. Department cess rate and mild hemodynamic changes with fewer of Anesthesiology and Critical Care Medicine, Sangmelima Reference Hospital, observed perioperative complications when compared Sangmelima, Cameroon. Department of Surgery and Sub-Specialties, Faculty with CGA. In addition, the use of this adapted OFA regi- of Medicine 4nd Pharmaceutical Sciences, University of Douala, Douala, men could be a safe and promising anesthetic technique/ Cameroon. Department of Anesthesiology and Critical Care Medicine, Douala General Hospital, Douala, Cameroon. Department of Anesthesiology regimen to decrease postoperative complications, pain, and Critical Care Medicine,Yaoundé Gyneco-Obstetric and Pediatric Hospital, Yaoundé, Cameroon. Department of Anesthesiology and Critical Care Medi- and opioid consumption in patients undergoing elective cine,Yaoundé Emergency Center,Yaoundé, Cameroon. gynecology surgery in resource-constraint settings. Received: 19 April 2022 Accepted: 4 October 2022 Abbreviations ASA: American Society Of Anesthesiology; CGA: Conventional General Anes- thesia; ERAS: Enhanced Recovery After Surgery; ETCO : EndTidalVolume Of Carbon-dioxide; ICU: Intensive Care Unit; IV: Intravenous; LOS: Length of Stay; References MAC: Mean Alveolar Concentration; NMDA: N-methyl-D-aspartic acid; NRS: 1. Prys-Roberts C, Kelman GR.The influence of drugs used in neuro- Numerical Rating Scale; PACU: Post-anesthesia Care Unit; POI: Postoperative leptanalgesia on cardiovascular and ventilatory function. Br J Anaesth. 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Combined • maximum visibility for your research: over 100M website views per year epidural-spinal opioid-free anaesthesia and analgesia for hysterectomy. Br J Anaesth. 1999;82(6):881–5. At BMC, research is always in progress. 37. Salem AM, Hafez MML, Eldin AS, Hagras AM. Opioid-Free Anesthesia for Laparoscopic Hysterectomy: Is it Appropriate? J Anest Inten Care Med. Learn more biomedcentral.com/submissions 2019;9(2):555757.