While laparoscopic surgical procedures have various advantages over traditional open techniques, artificial pneumoperitoneum is associated with severe bradycardia and cardiac arrest. Dexmedetomidine, an imidazole derivative that selectively binds to α2-receptors and has sedative and analgesic properties, can cause hypotension and bradycardia. Our primary aim was to assess the association between dexmedetomidine use and intraoperative bradycardia during laparoscopic cholecystectomy.
We performed a systematic review with a meta-analysis and trial sequential analysis using the following PICOS: adult patients undergoing endotracheal intubation for laparoscopic cholecystectomy (P); intravenous dexmedetomidine before tracheal intubation (I); no intervention or placebo administration (C); intraoperative bradycardia (primary outcome), intraoperative hypotension, hemodynamics at intubation (systolic blood pressure, mean arterial pressure, heart rate), dose needed for induction of anesthesia, total anesthesia requirements (both hypnotics and opioids) throughout the procedure, and percentage of patients requiring postoperative analgesics and experiencing postoperative nausea and vomiting and/or shivering (O); randomized controlled trials (S).
Fifteen studies were included in the meta-analysis (980 patients). Compared to patients that did not receive dexmedetomidine, those who did had a higher risk of developing intraoperative bradycardia (RR: 2.81, 95% CI [1.34, 5.91]) and hypotension (1.66 [0.92, 2.98]); however, they required a lower dose of intraoperative anesthetics and had a lower incidence of postoperative nausea and vomiting. In the trial sequential analysis for bradycardia, the cumulative z-score crossed the monitoring boundary for harm at the tenth trial.
Patients undergoing laparoscopic cholecystectomy who receive dexmedetomidine during tracheal intubation are more likely to develop intraoperative bradycardia and hypotension.
Laparoscopic surgical procedures have various advantages over traditional open techniques, particularly in terms of early ambulation, decreased need for analgesia, and reduced hospital stay [
Several strategies have been employed to control this sympathetic response to pneumoperitoneum; among them, dexmedetomidine has shown promising results [
Therefore, we may infer that although dexmedetomidine could be useful for controlling sympathetic stimulation, administering it along with peritoneal insufflation could lead to severe intraoperative bradycardia.
It has been shown that compared with no dexmedetomidine or placebo, the use of dexmedetomidine for tracheal intubation is associated with an increased risk for intraoperative bradycardia in the general surgical population [
The secondary objectives of this study were to assess the association between dexmedetomidine use and hemodynamics at intubation (HR, MAP, systolic blood pressure [SBP]), the occurrence of intraoperative hypotension, intraoperative hypnotics and opioid consumption, and the occurrence of postoperative side effects (postoperative nausea and vomiting [PONV], shivering, and analgesic requirements).
We followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement guidelines to prepare this manuscript [
We performed a systematic review of the medical literature to screen for relevant articles. The search was performed in the following databases from inception until April 18, 2021 with no language restrictions: PubMed, Scopus, the Cochrane Central Register of Controlled Trials, EMBASE, and Google Scholar. The reference lists of the included studies were also examined. Details regarding the search strategy are available in
Two researchers (A.D.C. and F.G.) independently screened the titles and abstracts of the identified studies for inclusion. Each citation was reviewed, and the full text of any potentially relevant study was retrieved. All studies meeting the following PICOS (Population, Intervention, Comparison, Outcome) criteria were included in our analysis: adult (aged ≥ 18 years) patients undergoing endotracheal intubation for laparoscopic cholecystectomy (P); who received intravenous dexmedetomidine before tracheal intubation (I); compared to no intervention or any placebo (C); with data on the following: intraoperative bradycardia (primary outcome), intraoperative hypotension, hemodynamics at intubation (SBP, MAP, HR), dose needed for induction of anesthesia, total anesthesia requirements (both hypnotics and opioids) throughout the procedure, percentage of patients requiring postoperative analgesics, and percentage of patients experiencing PONV and postoperative shivering (O); and only RCTs were included (S).
After identifying those studies that met the inclusion criteria, two members of our team (M.I. and G.Z.) independently reviewed and assessed each of the included studies. Any disagreement regarding study selection or data extraction was resolved by discussion with a third author (A.D.C.). The following information was collected: first author; year; total number of patients per group; occurrence of intraoperative bradycardia (percent of patients) and hypotension (percent of patients); SBP, MAP, and HR at tracheal intubation; induction and intraoperative anesthetic type and dosage; analgesic requirement in the first 24 h; and PONV and shivering (percent of patients). If data were missing, a request was sent by e-mail to the corresponding author of the study. If no response was received after our initial request, a second request was sent seven days later. A third and last request was sent one week after the second request.
Two researchers (E.P. and N.R.) independently evaluated the quality of the included RCTs using the Risk of Bias (RoB) 2 Tool [
A meta-analysis of the data was performed using RevMan version 5.3 (The Cochrane Collaboration, 2020). The treatment effect for continuous outcomes is expressed as standardized mean difference (SMD) with 95% CIs when the outcome was expressed with different measurement techniques, or mean difference (MD) with 95% CIs when the outcome was derived from the same measurement technique. The treatment effect for dichotomous outcomes was expressed as risk ratios (RRs) with 95% CIs. Zero events were treated by applying a continuity correction adding one to each value.
To assess study heterogeneity, the chi-squared test and I2-statistic were used (considering I2 values as follows: low heterogeneity: < 25%, moderate heterogeneity: 25% to 50%, and high heterogeneity: > 50%) [
We performed the following pre-planned subgroup analyses on the main outcome.
We arbitrarily subdivided the dose of dexmedetomidine into a high dose (≥ 0.70 µg/kg), medium dose (0.40–0.69 µg/kg), and low dose (< 0.40 µg/kg) and evaluated the effects of these different dosing regimens on intraoperative bradycardia.
We evaluated whether the intraoperative use of dexmedetomidine continuous infusion affects the primary outcome.
We evaluated the effects of anticholinergic premedication on intraoperative bradycardia.
To investigate the robustness of our findings, we planned to perform the following sensitivity analyses: 1) only low risk of bias studies and 2) outcomes with a low heterogeneity (from 0 to 25%) with a random-effect model and by removing continuity correction.
A pre-specified trial sequential analysis (TSA) [
The search results are summarized in the PRISMA diagram (
The 15 included studies had a total of 519 patients randomized to the dexmedetomidine group and 461 randomized to the no intervention or placebo group. One study [
The dexmedetomidine bolus administered for tracheal intubation ranged from 1 µg/kg [
Two studies [
The primary and secondary outcomes are summarized in
Ten studies described the occurrence of intraoperative bradycardia [
In the TSA, the cumulative z-score crossed the monitoring boundary for harm at the tenth trial, yielding an effect that was both statistically and clinically significant (
Nine studies reported the incidence of intraoperative hypotension [
The MAP, SBP, and HR were reported in 11 [
Six studies reported the anesthesia requirements at anesthesia induction [
Only a few of the studies described the intraoperative opioid requirements [
We performed a meta-analysis of the five studies evaluating PONV, which revealed a lower risk of PONV for patients receiving dexmedetomidine (
Excluding the continuity correction did not change the effect estimation for any of the outcomes where the correction was applied (intraoperative bradycardia: RR 5.70, 95% CI [1.84, 17.76], P = 0.003, I2 = 0%; intraoperative hypotension: RR 1.96, 95% CI [0.99, 3.86], P = 0.05, I2 = 21%). Given that no meta-analysis with low heterogeneity was found and only two studies [
The Egger test was performed for intraoperative bradycardia HR and MAP outcomes, both of which included at least ten studies. Publication bias was not evident for any of the examined outcomes: intraoperative bradycardia (P = 0.755), MAP at intubation (P = 0.635), or HR outcomes (P = 0.124). For the other outcomes, notwithstanding the lack of clear asymmetry on visual inspection, a definite interpretation of the funnel plots was not possible due to the paucity of studies (Supplemental Data S5).
Subgroup analysis forest plots are available as supplementary material (
Five studies used a dexmedetomidine dose ≥ 0.70 µg/kg [
All studies except two [
None of the patients that received an anticholinergic drug at anesthesia induction developed bradycardia (RR: 1.86, 95% CI [0.52, 6.66], P = 0.34, I2 = 0%); however, the difference was not statistically significant among the groups (P = 0.46).
Our meta-analysis shows that premedication with dexmedetomidine for endotracheal intubation during laparoscopic cholecystectomy is associated with a higher risk of intraoperative bradycardia than placebo or no intervention. Moreover, patients receiving dexmedetomidine, despite requiring less anesthetics at anesthesia induction, developed lower blood pressure and HR during tracheal intubation, and experienced more frequent intraoperative hypotension but less frequent PONV.
Although laparoscopy is commonly considered a minimally invasive surgical approach, pneumoperitoneum is responsible for extensive perturbations of the patient’s physiology due to increased intra-abdominal pressure, cephalic displacement of the diaphragm with alterations in intrathoracic pressure, carbon dioxide accumulation, and marked hemodynamic response [
Given its potential impact on postoperative outcomes, sympathetic stimulus control during anesthesia is of paramount importance. Particularly, uncontrolled intraoperative tachycardia is associated with an increased risk of perioperative myocardial infarction [
However, blunting of the adrenergic response should be weighed against potential perioperative complications, such as bradycardia and hypotension. Our work suggests that dexmedetomidine administration may be associated with the occurrence of these hemodynamic alterations in approximately 5 out of every 100 patients.
While two previous meta-analyses evaluated the effects of dexmedetomidine administered during tracheal intubation [
Of note, Demiri et al. [
While the aforementioned studies were based on all surgical procedures (open or laparoscopic) [
Our study has a few limitations. First, although we focused only on laparoscopic cholecystectomy, which decreased clinical heterogeneity, we recognize that the heterogeneity associated with different anesthesia protocols and cut-off values for identifying some complications limits our conclusions. Second, to avoid increasing type I errors, we did not consider other potentially interesting outcomes (such as intraoperative hemodynamics).
In conclusion, patients undergoing laparoscopic cholecystectomy that receive dexmedetomidine during tracheal intubation are more likely to develop intraoperative bradycardia and hypotension. This effect may be attenuated by the administration of an anticholinergic agent.
None.
PN received royalties from Intersurgical for Helmet Next invention and speaking fees from Draeger, Intersurgical, Getinge, Philips, Resmed, MSD, Gilead and Novartis. The other authors have no other competing interests to declare.
Alessandro De Cassai (Conceptualization; Formal analysis; Investigation; Writing – original draft)
Nicolò Sella (Conceptualization; Writing – original draft)
Federico Geraldini (Conceptualization; Investigation; Writing – original draft)
Francesco Zarantonello (Conceptualization; Writing – original draft)
Tommaso Pettenuzzo (Conceptualization; Writing – original draft)
Laura Pasin (Conceptualization; Writing – original draft)
Margerita Iuzzolino (Conceptualization; Investigation; Writing – original draft)
Nicolò Rossini (Conceptualization; Writing – original draft)
Elisa Pesenti (Conceptualization; Writing – original draft)
Giovanni Zecchino (Conceptualization; Writing – original draft)
Marina Munari (Conceptualization; Writing – original draft)
Paolo Navalesi (Conceptualization; Supervision; Writing – review & editing)
Annalisa Boscolo (Conceptualization; Supervision; Writing – review & editing)
Search Strategy
Study characteristics
ROB2
Forest Plot
Funnel Plot
Grade
Subgroup+sensitivity
PRISMA flowchart of the study.
Risk of bias assessment. Overview of risk of bias assessment using RoB2 Tool.
Intraoperative bradycardia forest plot. Forest plot of intraoperative bradycardia.
Intraoperative bradycardia trial sequential analysis (TSA). Trial sequential analysis TSA of intraoperative bradycardia. The blue line represents cumulative evidence. The red horizontal lines represent monitoring boundaries for benefit (upper line), monitoring boundaries for harm (lower line), and futility boundaries (middle lines). The red vertical line corresponds to the required sample size.
Primary and Secondary Outcomes of the Studies Involved
Outcomes | N study | Mean (95% CI) | P value | I2 |
---|---|---|---|---|
Intraoperative bradycardia | 10 | RR 2.81 (1.34, 5.91) | 0.006 | 0% |
Intraoperative hypotension | 9 | RR 1.66 (0.92, 2.98) | 0.09 | 0% |
SBP | 5 | MD −18.54 (−34.01, −3.08) | 0.02 | 98% |
MAP | 11 | MD -9.42 (-14.30, -4.55) | < 0.001 | 95% |
HR | 13 | MD -16.30 (-21.48, -11.13) | < 0.001 | 95% |
Induction agents | 6 | SMD -2.68 (-4.06, -1.30) | < 0.001 | 96% |
Postoperative nausea/vomiting | 5 | RR 0.55 (0.38, 0.79) | 0.001 | 21% |
SBP: systolic blood pressure, MAP: mean arterial pressure, HR: heart rate. RR: relative risk, MD: mean difference, SMD: standardized mean difference.