DOI: https://doi.org/10.21203/rs.3.rs-19402/v1
Background: Dexmedetomidine(DEX) has proven to be an effective adjuvant to anesthetics owing to its sympatholytic, analgesic, and sedative properties. This study was designed to investigate the postoperative effects of continuous DEX infusion during gynecological laparoscopy and to evaluate the safety of this treatment.
Methods: Sixty patients undergoing selective gynecological laparoscopy with general anesthesia were randomly assigned into DEX group (group D )and normal saline group (group N). DEX was infused at 0.5ug/kg/h during anesthesia maintenance in group D while normal saline was infused at the same rate in group N. The primary outcome measures were heart rate and blood pressure at extubation, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24 and 48 hours after operation, NRS scores at 1, 2, 3 ,4, ,8,12,24 hours after surgery and OAA/S scores after extubation. The secondary outcome measures were time to extubation, propofol and remifentanil dosage during anesthesia, postoperative adverse events, and postoperative hospital stay.
Results: Systolic and diastolic blood pressures were lower in group D at extubation when compared with group N (P<0.05), but not different at the first postoperative hour or after. HR was lower both at extubation and the first postoperative hour in group D (P<0.05). NRS scores were lower in patients given DEX both at rest and movement at the first postoperative hour (P<0.05). Time to extubation and OAA/S scores after extubation were not different between groups. Postoperative respiratory depression, shivering and pruritus didn’t occur in this research. There were no significant differences in the incidence rate of postoperative adverse events or postoperative hospital stay between the groups.
Conclusions: Continuous infusion of DEX during gynecological laparoscopy provided better hemodynamic stability at extubation and the effects on HR continued until 1 hour after operation. DEX administration was associated with lower NRS scores at the first postoperative hour without excessive sedation. DEX is a useful and safe adjuvant for general anesthesia during gynecological laparoscopy.
Laparoscopy has many advantages, not the least of which is improved cosmesis. Laparoscopy has been confirmed to provide fewer postoperative complications and shorter hospitalization while the oncologic outcomes are not affected[1, 2]. General anesthesia is currently most commonly used for laparoscopic surgery[3–5], which helps eliminate the discomfort caused by the increased intra-abdominal pressure and peritoneal irritation during artificial pneumoperitoneum and special position[6]. Opioid-based general anesthesia is a classical anesthetic method to facilitate tracheal intubation and mechanical ventilation. Nowadays, various adjuvant drugs are applied in balanced anesthesia, one of which is dexmedetomidine(DEX), a highly selective a2-receptor agonist, which is able to induce a sleep-like state without respiratory depression[7, 8]. It has been confirmed that DEX infusion during anesthesia provided better hemodynamic stability during surgery and reduced the need for opioids, propofol and desflurane[9–12]. However, relatively few researches have been conducted as to the postoperative effects especially postoperative hemodynamic stability of this treatment, and the effect on time to extubation remains controversial[5, 10]. This study was designed to evaluate the postoperative effects of intraoperative DEX infusion during laparoscopic gynecological surgery. Hemodynamic parameters, OAA/S scores and NRS scores after anesthesia were analyzed. Propofol and remifentanil dosage, complications of general anesthesia and postoperative hospital stay were also recorded.
Participants selection
This randomized, double-blind, placebo-controlled, single-center clinical research was approved by Ethics Committee of Affiliated Hospital of Nantong University and all the participants have signed informed consents. This trial was performed between April 2019 to September 2019 and adheres to CONSORT guidelines. The ethical processes of the research conformed to the “Declaration of Helsinki”. The study was registered in chictr.org.cn on 11 March 2019 (registration number: ChiCTR1900021810), and the full trial protocol can be accessed at chictr.org.cn.
Sixty-one patients undergoing selective gynecological laparoscopy surgery with general anesthesia were enrolled in the study. Inclusion criteria were patients aged from 18-60 years old, American Society of Anesthesiology (ASA) status I-II. Exclusion criteria were pregnancy, malignant tumor, arrhythmia, hypertension, any kinds of medication, allergic to DEX or any drugs used during this study and other situations unsuitable for the research. Exclusion criteria during surgery were operation time less than 40min or more than 3 hours, changes of operative procedure and blood loss more than 400ml.
Study groups and randomization
Patients were randomly allocated to DEX group (group D) or normal saline group (group N) in a
1:1 ratio by random figure table provided by an independent statistician. The random numbers were placed in the envelopes and sealed, which were opened right before anesthesia induction. Study drugs were prepared by a nurse who was independent of data collection. The anesthesiologists and patients were blinded to treatment group allocation. DEX was infused at 0.5ug/kg/h in group D since induction of anesthesia and was stopped before skin suture. Patients in group N received normal saline infusion at the same rate.
Anesthesia methods
All patients were administered with a unified anesthetic induction: midazolam 2mg, propofol bolus of 1.5mg/kg, sufentanil bolus of 0.5ug/kg and cisatracurium 0.2mg/kg. Anesthesia was maintained with sevoflurane, propofol, remifentanil and cisatracurium. Infusion rate of propofol and remifentanil was adjusted according to bispectral index (BIS). Fluctuation range of blood pressure(BP) and heart rate(HR) was between ±20% of the basic value. Hypotension (systolic blood pressure decreased to 80% of the basic value or was lower than 90mmHg) was treated with ephedrine and bradycardia (HR decreased to 80% of the basic value or was lower than 50bpm) was treated with atropine. The BIS values was controlled between 40 and 60 and the end-tidal CO2 pressure was maintained at 35-45mmHg.Forced-air warming blankets were used during anesthesia. Azazetron was routinely used for all patients before extubation. Patients were given a patient-controlled intravenous analgesia (PCIA) pump with the formulation of sufentanil and azazetron once all the anesthetics were stopped.
Outcome measures
BP and HR were recorded before induction, at extubation (T0), 1(T1),2(T2),3(T3),4(T4),5(T5),6(T6),7(T7),8(T8),12(T9),24(T10), and 48(T11) hours after operation. NRS scores were recorded 1(T1), 2(T2), 3(T3) ,4(T4), ,8(T8),12(T9),24(T10) hours after operation. OAA/S scores were recorded at 10-min intervals for the first hour after extubation. Time to extubation (TE) was defined as the time from the cessation of all the anesthetics to extubation. Adverse events include hypertension, hypotension, tachycardia, bradycardia, respiratory depression, postoperative nausea and vomiting(PONV), shiver and pruritus.
Statistical analysis
Sample size was calculated according to preliminary data based on HR at the first hour after surgery, α = 0.05 , β = 0.20 and missing rate of 0.1. Minimum sample size was estimated 15 for each group, and we expanded the sample size to 30 for each group. Continuous data are presented as medians with 25–75% interquartile ranges. Continuous data were compared using Student’s t-test. For categorical data, Pearson’s chi-square test with Fisher’s exact test was used. A two-sided P value less than 0.05 was considered statistically significant.
Sixty-one patients were screened for eligibility, and one declined to participate. 60 patients were subsequently allocated to group N and group D. 2 patients were excluded for operation time less than 40min and 1 for operation time more than 3 hours in group N. 2 patients were excluded for operation time more than 3 hours in group D. 55 patients were statistically analyzed (Figure 1). There were no significant differences between the study groups regarding age, BMI, anesthesia time or basic BP and HR (Table 1). Anesthesia time was defined as the time from the induction of anesthesia to the cessation of all the anesthetics.
Differences were not significant between groups regarding to demographic and perioperative data (Table 1). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at extubation were 130[124.5,135] mmHg and 80[75,84.5] mmHg in group N, 120.5[114.5,125.25] mmHg and 67.5[62.5,73.25] mmHg in group D, and the differences were significant (P<0.05). Differences in SBP and DBP were not significant at the first postoperative hour or after (Figure 2). HR in group D were lower at extubation (61.5[57.5,65] bpm) and the first postoperative hour (66.5[61,72.75] bpm) when compared with group N (75[71,83] and 75[66.75,79.5] bpm, respectively) (P<0.05). Differences in HR were not significant at the second postoperative hour or after (Figure 2). Propofol dosage during anesthesia maintenance was 0.052[0.047,0.057]mg/kg/min in group N and 0.048[0.043,0.051]mg/kg/min in group D, remifentanil dosage was 0.14[0.13,0.16]ug/kg/min in group N and 0.12[0.11,0.14]ug/kg/min in group D, and the differences were significant (P<0.05). NRS scores at the first postoperative hour were 3[2,3] at rest and 3[3,4] at movement in group D, 3[3,4] and 4[4,5] in group N, and the differences were significant(P<0.05). NRS scores were similar at the second postoperative hour and after (Table 2). OAA/S scores were not different between groups (Table 2). Postoperative respiratory depression, shivering and pruritus didn’t occur in the two groups There were no significant differences in the incidence rate of postoperative adverse events between the groups (Table 3).
Figure 1. Trial consort flow diagram
Table 1. Patients demographic data and clinical characteristics
Figure 2. (a) Systolic blood pressure (SBP) at different time points. (b)Diastolic blood pressure (DBP) at different time points. (c) Heart rate (HR) at different time points, *P<0.05. BL: baseline, T0: extubation, T1-T8: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours after operation, respectively, T9: 12 hours after operation, T10: 24 hours after operation, T11: 48 hours after operation. Data are presented as mean (SD).
Table 2. NRS Scores and OAA/S Scores after sugery
Table3. Postoperative adverse events
DEX has long been used as a sedative for monitored anesthesia care(MAC) because of its sympatholytic effect, analgesic properties and lack of respiratory depression[13–15]. DEX improved both patient and anesthesiologist satisfaction and comfort during MAC procedure while requirements for midazolam and fentanyl were reduced[16]. In recent years, DEX also has been increasingly applied to general anesthesia as it helps attenuate sympathetic response and ensure intraoperative hemodynamic stability[17–19].
Bielka et al[5] conducted a trial about DEX infusion as an analgesic adjuvant during laparoscopic cholecystectomy, who came to a conclusion that intraoperative DEX infusion is effective for improving analgesia during and after operation and reduce postoperative morphine consumption. However, hemodynamic parameters were not observed in the study, and patient control analgesia (PCA) was not used, which might potentially increase probability of rescue analgesic use. In a clinical research during nasal surgery under inhaled maintenance anesthesia, DEX provided more stable hemodynamic changes during intraoperative emergence and higher global QoR-40 scores 24 hours after surgery[20], but hemodynamic parameters were not observed since 2 minutes after extubation. In this research, we recorded postoperative hemodynamic parameters hourly within 8 hours after surgery and evaluated the postoperative efficacy of intraoperative infusion of DEX through objective indexes.
The sympathetic activity decreases as plasma concentration of DEX increases[21], which results in a decrease in HR and BP during continuous infusion. In this research, BP and HR were lower in patients received DEX infusion at extubation and HR was lower in group D at the first postoperative hour, but the differences were not significant at the second hour or after, which indicated that the effect of sympathetic inhibition on BP and HR disappeared within 2 hours after operation. Patients accepted DEX infusion required less propofol and remifentanil for anesthesia maintenance, and this agrees with a former research by Yun Li et al, who also pointed out that DEX blunted surgical stress responses to an extent comparable to combined epidural and general anesthesia in patients undergoing open gastrectomy[22]. Time to extubation was similar between the groups, and this result is inconsistent with Bielka’s study[5], in which it was about 10 min shorter in DEX group while compared with normal saline group. We deduce that may be due to the higher dosage of intraoperative fentanyl used in normal saline group, while ultra-short-acting opioid remifentanil was infused for anesthesia maintenance in this research. Remifentanil undergoes very high clearance independent of organ function and infusion duration[23], and this also explains why respiratory depression was not observed in this study. A recent study also concluded that the co-administration of remifentanil and DEX infusion did not influence the arousability during general anesthesia[24]. NRS scores at the first postoperative hour were lower in group D both at rest and at movement. This is probably a consequence of the alleviation of remifentanil induced hyperalgesia[25], another property of DEX, but this effect didn’t make difference 2 hours after operation in this research. In a study during abdominal hysterectomy, intraoperative administration of DEX leaded to higher sedation scores immediately after extubation[26]. In this research, we assessed OAA/S scores at 10-min intervals for the first hour after extubation, and the results were not different between groups, thus we infer that DEX makes it smoothly through extubation and causes no excessive sedation afterwards. As warming blankets were used the whole course, shivering didn’t occur in the two groups. Pruritus didn’t happen in either group, and that may be due to the morphine-free anesthetic method[27] in this study. As to the incidence rate of hypertension, hypotension, tachycardia, bradycardia, and PONV, differences were not significant, and it confirms that intraoperative DEX infusion during general anesthesia will not increase the incidence of postoperative adverse events.
Continuous infusion of DEX during gynecological laparoscopy provided better hemodynamic stability at extubation and the effects on HR continued until 1 hour after operation. DEX administration was associated with lower NRS scores at the first postoperative hour without excessive sedation. DEX is a useful and safe adjuvant for general anesthesia during gynecological laparoscopy.
ASA:American Society of Anesthesiology; BIS:Bispectral index; BP:Blood pressure; DBP:Diastolic blood pressure; DEX:Dexmedetomidine; HR:Heart rate; MAC:Monitored anesthesia care; PCA:Patient-controlled analgesia; PCIA:Patient-controlled intravenous analgesia; PONV, postoperative nausea and vomiting; SBP:Systolic blood pressure;
Ethics approval and consent to participate
This study was carried out at Affiliated Hospital of Nantong University, PR China and was approved by Ethics Committee of Affiliated Hospital of Nantong University (Chairperson Prof. Zhangtao) on 23 February 2019, and all the patients have signed informed consents. The ethical processes of the study conformed to the “Declaration of Helsinki”.
Consent for publication
All authors have read and approved the content, and agree to submit for consideration for publication in this journal. This article has not been published elsewhere in whole or in part.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare that they have no competing interests
Funding
No funding support
Authors' contributions
B W made substantial contributions to the conception and design of the work, the acquisition, analysis, interpretation of data, drafting the work and substantively revising it. S L made substantial contributions to the acquisition, analysis of data and the drafting of the manuscript. Y G was involved in the conception and design of the work, data analysis and the drafting of the manuscript. X X was involved in data analysis and the drafting of the manuscript.
Acknowledgements
Not applicable