Effects of opioid-free anaesthesia compared with balanced general anaesthesia on nausea and vomiting after video-assisted thoracoscopic surgery: a single-centre randomised controlled trial

Abstract

Objectives

Opioid-free anaesthesia (OFA) has emerged as a promising approach for mitigating the adverse effects associated with opioids. The objective of this study was to evaluate the impact of OFA on postoperative nausea and vomiting (PONV) following video-assisted thoracic surgery.

Design

Single-centre randomised controlled trial.

Setting

Tertiary hospital in Shanghai, China.

Participants

Patients undergoing video-assisted thoracic surgery were recruited from September 2021 to June 2022.

Intervention

Patients were randomly allocated to OFA or traditional general anaesthesia with a 1:1 allocation ratio.

Primary and secondary outcome measures

The primary outcome measure was the incidence of PONV within 48 hours post-surgery, and the secondary outcomes included PONV severity, postoperative pain, haemodynamic changes during anaesthesia, and length of stay (LOS) in the recovery ward and hospital.

Results

A total of 86 and 88 patients were included in the OFA and control groups, respectively. Two patients were excluded because of severe adverse events including extreme bradycardia and epilepsy-like convulsion. The incidence and severity of PONV did not significantly differ between the two groups (29 patients (33.0%) in the control group and 22 patients (25.6%) in the OFA group; relative risk 0.78, 95% CI 0.49 to 1.23; p=0.285). Notably, the OFA approach used was associated with an increase in heart rate (89±17 vs 77±15 beats/min, t-test: p<0.001; U test: p<0.001) and diastolic blood pressure (87±17 vs 80±13 mm Hg, t-test: p=0.003; U test: p=0.004) after trachea intubation. Conversely, the control group exhibited more median hypotensive events per patient (mean 0.5±0.8 vs 1.0±2.0, t-test: p=0.02; median 0 (0–4) vs 0 (0–15), U test: p=0.02) during surgery. Postoperative pain scores, and LOS in the recovery ward and hospital did not significantly differ between the two groups.

Conclusions

Our study findings suggest that the implementation of OFA does not effectively reduce the incidence of PONV following thoracic surgery when compared with traditional total intravenous anaesthesia. The opioid-free strategy used in our study may be associated with severe adverse cardiovascular events.

Trial registration number

ChiCTR2100050738.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a randomised controlled trial investigating the role of opioid-free anaesthesia in postoperative nausea and vomiting after thoracic surgery, providing evidence for the use of opioid-free anaesthesia in thoracic surgery.

• This trial balanced the use of dexmedetomidine and patient-controlled analgesia after surgery while preventing the use of inhalational anaesthesia, to reduce the bias between the two groups.

• This was a single-centre trial with a limited sample size.

Introduction

Balanced anaesthesia has been well accepted to achieve unconsciousness, analgesia and immobility through the use of hypnotics, analgesics and neuromuscular blocking agents, respectively.^{1 2} Opioids have long been a cornerstone in perioperative pain management since the discovery of morphine, owing to their potent analgesic properties.³ However, the widespread use of opioids is not without drawbacks, as they can lead to respiratory depression, postoperative nausea and vomiting (PONV), constipation and so on.^{4 5} These potential opioid-related adverse drug events have been associated with delayed recovery after surgery, prolonged hospitalisation, increased healthcare costs and poorer patient outcomes.^6–8 The enhanced recovery after surgery (ERAS) protocol has gained significant acceptance in perioperative management across various surgical disciplines, including cardiac,⁹ thoracic,¹⁰ general^{11 12} and gynaecological surgeries.¹³ Key components of the ERAS pathways include opioid-sparing multimodal analgesia and the avoidance of long-acting opioids.¹⁴ Reducing opioid consumption has been linked to accelerated postoperative recovery and improved recovery quality.^{15 16}

In recent years, the use of opioids during general anaesthesia has come under scrutiny due to their numerous side effects and associated risks.¹⁷ As a result, there has been a growing interest in exploring alternatives such as opioid-free anaesthesia (OFA), which involves the implementation of regional analgesia and multimodal analgesic techniques that encompass the administration of intravenous lidocaine and dexmedetomidine.¹⁸ A meta-analysis comparing dexmedetomidine with remifentanil found that intraoperative dexmedetomidine was not only associated with lower postoperative pain scores but also maintained a more stable intraoperative blood pressure.¹⁹ Additionally, a study investigating opioid-free total intravenous anaesthesia with propofol, ketamine and dexmedetomidine reported a reduction in the incidence of PONV compared with the use of volatile anaesthetics and opioids in patients undergoing bariatric surgery.²⁰

Since the prevalence of PONV in surgical patients remains high even with the use of multiple antiemetics,²¹ several randomised controlled trials (RCTs) have demonstrated that the implementation of OFA techniques can effectively decrease the incidence of PONV, as indicated by two meta-analyses of RCTs.^{22 23} However, it is important to consider the heterogeneity of RCTs comparing OFA with traditional balanced anaesthesia using inhalational anaesthesia²⁰ or imbalanced use of dexmedetomidine,²⁴ which may be associated with PONV. Therefore, further investigation is warranted to explore the specific effects of OFA strategies on PONV.

In our centre, we have observed a high incidence of PONV following thoracic surgery, with an estimated incidence of about 40%. This elevated occurrence may be attributed to the administration of higher doses of opioids during these procedures. We hypothesised that OFA might be promising in reducing the incidence of PONV. Therefore, the present study aimed to explore the potential impact of OFA on PONV in the context of thoracic surgery. We also evaluate the haemodynamic response induced by the intubation of a double-lumen tube (DLT), which might be challenging without the use of opioids.

Methods

This was a single-centre RCT. The study is registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn; ChiCTR2100050738; first registered on 03/09/2021).

Participants

The patients who underwent elective video-assisted thoracoscopic surgery in our hospital were recruited between September 2021 and June 2022, and the first recruitment date was 6 September 2021. The inclusion criteria for patient selection were as follows: individuals aged 18–65 years, undergoing thoracoscopic lung resection under elective general anaesthesia (including lung wedge resection, segmentectomy, lobectomy and sleeve resection), American Society of Anesthesiologists classification of I–II, body mass index range of 18.5–25 kg/m², voluntarily participated in the study and provided informed consent.

On the other hand, patients were excluded from the study if they had hypersensitivity to any anaesthetics or other materials required during surgery; were pregnant or breast feeding; required outpatient or emergent surgery; had undergone transplantation or had a history of transplantation; exhibited tumour metastasis; presented with atrioventricular block, intraventricular block or Stokes-Adams syndrome; used long-term beta-blockers for more than 1 month or exhibited a heart rate (HR) lower than 50 beats per minute (bpm). Patients with dysfunction of the heart, lungs, liver, kidneys or other organs, as well as those with cognitive impairment that hindered effective communication, were also excluded. Furthermore, patients were withdrawn from the study if a severe adverse event occurred or if the anaesthesia providers identified any safety concerns.

Randomisation and blindness

The participants in the study were randomly assigned to either the OFA group or the control group in a 1:1 ratio using computer-generated random numbers after the approval of the Ethics Committee and before the recruitment of the first subject. A stratified blocked randomisation strategy was employed to keep the equal distribution of the two groups among three independent anaesthesiologists. The group allocation was concealed in envelopes and the allocation of the single subject was declared immediately before anaesthesia. The principal investigator, patients and outcome assessors were blinded to the groups.

Intervention

All patients routinely fasted for 6 hours prior to surgery. Once in the operating room, the patients were closely monitored using a three-lead ECG, non-invasive blood pressure cuff, continuous invasive arterial blood pressure monitoring and pulse oximetry (SpO₂).

The patients in the OFA group received an opioid-free strategy for anaesthesia induction and maintenance. The induction medications included a loading dose of dexmedetomidine (0.7 µg/kg over 10 min), dexamethasone (5 mg), midazolam (0.05 mg/kg), propofol (2–3 mg/kg), rocuronium (1 mg/kg), lidocaine (1.5 mg/kg) and magnesium sulfate (2.5 g), based on previous studies.^{20 22–25} The maintenance medications included propofol (4–6 mg/kg/hour), lidocaine (1.0 mg/kg/hour), dexmedetomidine (0.5 µg/kg/hour) and cisatracurium (0.05 mg/kg/hour).

On the other hand, patients in the control group received a conventional strategy with opioids for anaesthesia. The induction medications included a loading dose of dexmedetomidine (0.7 µg/kg over 10 min), dexamethasone (5 mg), midazolam (0.05 mg/kg), propofol (2–3 mg/kg), rocuronium (1 mg/kg) and sufentanil (0.5 µg/kg). The maintenance medications included propofol (4–6 mg/kg/hour), remifentanil (0.2 µg/kg/min), dexmedetomidine (0.5 µg/kg/hour) and cisatracurium (0.05 mg/kg/hour). In addition to the anaesthesia protocols, all patients received an ultrasound-guided paravertebral block at the T3 and T5 levels using 10 mL of 0.375% ropivacaine for each site in a lateral decubitus position immediately after induction of anaesthesia. For postoperative analgesia, a patient-controlled analgesia (PCA) pump was connected to all patients immediately after surgery. The PCA pump delivered a combination of 1.5 mg/kg nalbuphine and 3 µg/kg dexmedetomidine for pain control. During mechanical ventilation, a tidal volume of 6 mL/kg with a positive end-expiratory pressure of 5 cmH₂O was used for two-lung ventilation, while a tidal volume of 4 mL/kg with a positive end-expiratory pressure of 5 cmH₂O was used for one-lung ventilation. The respiratory frequency was adjusted to maintain an end-tidal carbon dioxide tension level between 35 and 45 cmH₂O as an indicator of appropriate ventilation.

During the induction period, patients will receive specific treatments based on their condition. If the systolic blood pressure (SBP) is higher than 180 mm Hg, nitroglycerin will be administered. For HRs above 100 bpm, esmolol will be used. If SBP falls below 85 mm Hg, ephedrine will be given, and for HR below 50 bpm, atropine will be used. The anaesthesiologists will adjust the dosage of propofol and remifentanil based on their expertise. Vasoactive medications will be administered as needed to regulate blood pressure and blood flow.

Outcomes

All patients were followed up on the first and second morning after surgery, by an anaesthetic nurse who was blinded to the grouping. The main focus of the study was to assess the incidence of PONV within 48 hours after surgery, which served as the primary outcome. Additionally, the severity of PONV measured by a Visual Analogue Scale (VAS) of 0–10, with an increment of 1, usage of rescue antiemetics in the ward, pain levels measured by a VAS of 0–10, with an increment of 1, utilisation of additional analgesics in the ward, maximum HR and invasive blood pressure within 3 min after trachea intubation, administration of vasoactive medication post-intubation, occurrences of hypotension and bradycardia, number of vasoactive medications used during surgery, duration of anaesthesia and surgery on the second day after surgery, length of stay in the recovery ward and hospital length of stay were all included as secondary outcomes. Furthermore, any other significant complications, such as bleeding events requiring a second surgery or intraoperative awareness, were also recorded. The data about anaesthesia recovery were not shown in the manuscript because the anaesthesia was recovered in the postoperative intensive care unit during the study period and additional sedatives might be used in the intensive care unit.

Statistical analysis

The sample size for the study was determined using the PASS V.11 software (Kaysville, Utah, USA). Based on the postoperative follow-up data from our centre over the past year, the estimated incidence of PONV after thoracic surgery was approximately 40%. We assumed that the use of OFA could reduce the incidence to 20%, considering previous research by An et al, who reported a reduction in PONV incidence from 41.7% to 4.3% with OFA.²⁵ To achieve a statistical power of 80% with a significance level (α) of 0.05 and a dropout rate of 10%, a sample size of 88 patients was required for each group.

Statistical analysis was conducted using IBM SPSS V.20.0. Categorical data were presented as numbers (percentages). Kolmogorov-Smirnov test was performed to assess the distribution of continuous data, and the continuous data with a normal distribution were expressed as mean±SD, while those with a non-normal distribution were presented as median (minimum, maximum) values. Χ² test was used for comparing categorical data, while Student’s t-test or Mann-Whitney U test was employed for comparing continuous data. A p value less than 0.05 was considered statistically significant.

Patient and public involvement

None.

Results

A total of 286 patients were eligible for the trial. Among them, 98 patients declined to participate, and 12 patients were excluded due to metastasis. Except for two patients in the OFA group who were later excluded, all other patients successfully completed the trial. One patient in the OFA group experienced severe bradycardia, with an HR dropping to 20 bpm before intubation. The infusion of dexmedetomidine had to be stopped temporarily, and chest compressions were administered for about half a minute. Another patient in the OFA group had an epilepsy-like convulsion during the anaesthesia induction period. The use of dexmedetomidine and lidocaine was terminated in these two patients, and they were then anaesthetised with traditional balanced anaesthesia strategy with sufentanil. The surgery was continued in these two patients and no adverse outcome was present after surgery. Hence, the final statistical analysis included 86 patients in the OFA group and 88 patients in the control group (figure 1).

Figure 1.

CONSORT flow diagram. CONSORT, Consolidated Standards of Reporting Trials; OFA, opioid-free anaesthesia.

The demographic data, baseline HR and blood pressure were comparable between the two groups. The risk score for PONV was also similar based on three baseline risk factors in the simplified Apfel PONV Prediction Scale²⁵: female gender, history of motion sickness or PONV, and non-smoking status (table 1). The types and sites of surgery were evenly distributed between the two groups. There were no significant differences in the total amount of propofol used, while the total amount of remifentanil during surgery in the control group was 1.45±0.7 mg. The average duration of anaesthesia was 164.9±46.9 min and 172.2±43.9 min (p=0.288), and the average duration of surgery was 126.0±45.3 min and 127.7±49.0 min in the OFA and control groups, respectively (p=0.804).

Table 1.

Demographic and baseline data of the participants

Parameters	OFA (n=86)	Control (n=88)	P value
Age (years)	52±11	51±9	0.468*
Male gender (%)	41 (47.7)	40 (45.5)	0.769†
Risk score of PONV			0.196†
0 (%)	2 (2.3)	0 (0)
1 (%)	34 (39.5)	27 (30.7)
2 (%)	50 (58.1)	60 (68.2)
3 (%)	0 (0)	1 (1.1)
ASA physical status (1/2)	39/47	46/42	0.361†
BMI (kg/m2)	23.4±2.8	22.9±2.4	0.192*
Baseline HR (bpm)	75±11	78±11	0.186*
Baseline SBP (mm Hg)	137±21	135±19	0.447*
Baseline DBP (mm Hg)	81±11	79±10	0.507*
Surgery type			0.458†
Lobectomy (%)	45 (52.3)	51 (58.0)
Segmentectomy (%)	28 (32.6)	29 (33.0)
Wedge resection (%)	13 (15.1)	8 (9.1)
Surgery site (left/right)	37/49	39/49	0.863†
Total propofol amount (mg)	808.8±343.7	892.9±314.9	0.094*
Total remifentanil amount (mg)	0	1.5±0.7*	–
Total dexmedetomidine amount (mg)	127.3±32.5	128.3±29.1	0.832*
Total lidocaine amount (mg)	273.3±66.8*	0	–*
Total anaesthesia duration (min)	165±47	172±44	0.288*
Total surgical duration (min)	126±45	128±49	0.804*

*Data shown as mean±SD and compared using Student’s t-test.

†Data shown as number or number (percentage) and compared using χ² test.

ASA, American Society of Anesthesiologists; BMI, body mass index; bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; OFA, opioid-free anaesthesia; PONV, postoperative nausea and vomiting; SBP, systolic blood pressure.

Within 48 hours after surgery, there were 22 patients with PONV in the OFA group and 29 patients in the control group with a relative risk of 0.78 (0.49, 1.23) (p=0.285). The incidence of PONV on the first and second days after surgery did not differ significantly between the two groups. Additionally, there were no significant differences in the severity of PONV or the use of rescue antiemetics within the 2-day postoperative period (table 2).

Table 2.

Incidence and severity of PONV within 48 hours after surgery

Parameters	OFA (n=86)	Control (n=88)	RR (95% CI)	P value
PONV (%)	22 (25.6)	29 (33.0)	0.78 (0.49, 1.23)	0.285*
PONV on the first day (%)	15 (17.4)	24 (27.3)	0.64 (0.36, 1.12)	0.120*
Severity of PONV on the first day	0 (0, 8)	0 (0, 8)		0.168*
Antiemetic medication on the first day (%)	8 (9.3)	5 (5.7)	1.64 (0.59, 4.61)	0.364*
PONV on the second day (%)	13 (15.1)	14 (15.9)	0.95 (0.48, 1.88)	0.885*
Severity of PONV on the second day	0 (0, 7)	0 (0, 9)		0.566*
Antiemetic medication on the second day (%)	2 (2.3)	5 (5.7)	0.41 (0.09, 1.78)	0.260*

*Data shown as mean±SD and compared using Student’s t-test.

OFA, opioid-free anaesthesia; PONV, postoperative nausea and vomiting; RR, relative risk.

As a secondary outcome, the VAS score for pain was similar between the two groups on the first and second day after surgery. The times of PCA and use of rescue analgesics seemed to be also comparable. There seem to be some haemodynamic changes before and after trachea intubation between the two groups. Before tracheal intubation, patients in the OFA group had higher HRs and lower SBP and diastolic blood pressure (DBP) compared with those in the control group. Following intubation, the OFA group experienced an increase in the highest HR and highest DBP compared with the control group. The highest SBP and the number of vasoactive medications were not significantly different between the two groups. Interestingly, hypotension and the need for vasoactive medications during surgery appeared to occur more frequently in the control group compared with the OFA group. The length of stay in both the recovery ward and the hospital after surgery did not differ statistically between the two groups (table 3). Notably, no correction was applied for multiple statistical analyses of these secondary outcomes.

Table 3.

Secondary outcomes

Parameters	OFA (n=86)	Control (n=88)	P value
Pain VAS score on the first day	0.7±1.8	1.0±2.1	0.243*
	0 (0, 8)	0 (0, 8)	0.168†
Pain VAS score on the second day	0.4±1.2	0.5±1.7	0.566*
	0 (0, 7)	0 (0, 9)	0.999†
PCA times	0.7±1.9	0.4±1.2	0.246*
	0 (0, 11)	0 (0, 7)	0.568†
Rescue analgesics (%)	10 (11.6)	16 (18.2)	0.225‡
Pre-intubation HR (bpm)	72±13	69±11	<0.001*
Pre-intubation SBP (mm Hg)	106±17	124±20	<0.001*
Pre-intubation DBP (mm Hg)	65±12	76±12	<0.001*
Post-intubation HR (bpm)	89±17	77±15	<0.001*
Post-intubation SBP (mm Hg)	141±29	133±23	0.056*
Post-intubation DBP (mm Hg)	87±17	80±13	0.003*
ΔHR >20% (%)	43 (50.0)	38 (43.2)	0.367‡
ΔSBP >20% (%)	56 (65.1)	12 (13.6)	<0.001‡
Vasoactive medication during induction (%)	10 (11.6)	4 (4.5)	0.086‡
Number of bradycardia events per patient during surgery	0.1±0.5	0.1±0.4	0.211*
	0 (0, 4)	0 (0, 2)	0.650†
Number of hypotension events per patient during surgery	0.5±0.8	1.0±2.0	0.020*
	0 (0, 4)	0 (0, 15)	0.021†
Incidence of vasoactive medication usage	0.1±0.5	0.1±0.4	0.211*
	0 (0, 4)	1 (0, 15)	0.015†
LOS in recovery ward (days)	1.0±0.1	1.0±0.1	0.987*
	1 (0, 1)	1 (0, 1)	>0.999†
LOS in hospital after surgery (days)	4.1±2.0	3.8±1.4	0.210*
	3 (2, 12)	3 (2, 11)	0.832†

*Data shown as mean±SD and compared using Student’s t-test.

†Data shown as median (minimum, maximum) and compared using Mann-Whitney U test.

‡Data shown as number (percentage) and compared using χ² test.

bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; LOS, length of stay; OFA, opioid-free anaesthesia; PCA, patient-controlled analgesia; SBP, systolic blood pressure; VAS, Visual Analogue Scale.

Discussion

The results of this randomised controlled clinical trial indicate that an opioid-free strategy does not reduce the incidence or severity of PONV compared with traditional opioid-based balanced anaesthesia. The incidence of acute kidney injury and the length of stay in the recovery ward or hospital were not affected by opioid administration. However, OFA was associated with higher haemodynamic fluctuations induced by tracheal intubation, while opioid-based balanced anaesthesia was linked to more instances of hypotension during surgery.

PONV remains a significant challenge for anaesthesiologists, as it can be difficult to prevent this distressing complication in certain high-risk patients. Given that nausea and vomiting are common side effects of opioids, an opioid-free approach has been proposed as a promising strategy to reduce PONV incidence. A meta-analysis has indicated strong evidence that OFA can lower the rate of PONV.²² In the context of thoracic surgery, one study reported a reduction in PONV incidence from 41.7% in the control group to 4.3% in the OFA group.²⁶ The patients in the opioid-free group were induced with dexmedetomidine, ketorolac, etomidate and cisatracurium, while those in the control group were induced with sufentanil, etomidate and cisatracurium. Anaesthesia was maintained with dexmedetomidine, sevoflurane and cisatracurium in the opioid-free group, and with remifentanil, sevoflurane and cisatracurium in the control group. Postoperative analgesia was not specified in this study. Therefore, the sample size of our current study was calculated based on an estimated 50% reduction in PONV incidence, from 40% to 20%. As a result, our data did not demonstrate any benefit of OFA in reducing the incidence of PONV. While at least two meta-analyses have shown a reduction in PONV rate with OFA, the included RCTs had relatively small sample sizes, and the varying surgical types, anaesthesia management and PONV risk among the recruited patients may contribute to different outcomes regarding the occurrence of PONV.^{23 26}

The strategy for OFA primarily involved using dexmedetomidine, lidocaine, magnesium or ketamine for anaesthesia induction and combining regional anaesthesia with inhalational anaesthetics or propofol, lidocaine and dexmedetomidine for anaesthesia maintenance.^{24 26–29} One major difference between our study and previous studies of OFA was the use of dexmedetomidine in the control group. Observational and clinical trials have suggested that dexmedetomidine may directly reduce the incidence of PONV,^{30 31} and the effect of the OFA strategy against PONV might be confounded by the use of dexmedetomidine. Thus, in our study, dexmedetomidine was used in both the pre-induction and intraoperative periods for both groups, including before intubation, during surgery and postoperatively, as we made efforts to ensure medication balance between the two groups. A meta-analysis indicated that dexmedetomidine prevented PONV as a secondary outcome in non-cardiac, non-neurosurgical populations.³² Another meta-analysis focused on thoracic surgery patients found that dexmedetomidine was associated with a significantly reduced incidence of PONV as the primary outcome.³³ Dexmedetomidine’s ability to reduce the incidence of PONV was attributed to several mechanisms.^{32 33} First, it may result in reduced opioid doses. Second, dexmedetomidine can decrease noradrenergic activity in the locus coeruleus, thereby preventing nausea and vomiting through the central nervous system. Third, dexmedetomidine might inhibit sympathetic activation during surgery, leading to the attenuation of systemic sympathetic activation and inflammation, which are associated with PONV pathogenesis. Therefore, dexmedetomidine may have contributed to the decreased incidence of PONV observed in the control group of our study.

The DLT is widely used for one-lung ventilation during thoracic surgery. However, the larger diameter of the DLT can lead to more pronounced sympathetic responses during intubation. Previous reports have indicated that the amount of remifentanil required for DLT intubation is approximately 30% higher than for intubation with single-lumen tubes.³⁴ Therefore, it may be challenging for the OFA strategy to effectively reduce sympathetic responses during DLT intubation. Our data showed that the highest HR and DBP were significantly higher in the OFA group, suggesting that the OFA strategy alone might not be sufficient to inhibit sympathetic responses during DLT intubation. The addition of opioids or other vasoactive medications may be necessary for intubation when using the OFA strategy in thoracic surgery. Interestingly, there were more hypotensive events and use of vasoactive drugs observed in the control group. We did not monitor anaesthesia depth using parameters such as bispectral index (BIS) due to the lack of support from medical insurance for anaesthesia depth monitors. The higher incidence of hypotension may indicate that the depth of anaesthesia was too deep without the guidance of BIS or other electroencephalographic monitors. Nevertheless, none of the patients developed acute kidney injury after surgery, suggesting that haemodynamic stability was well maintained through proper fluid management and the use of vasoactive medications.

The primary adverse effect of dexmedetomidine is bradycardia, which can sometimes be life-threatening. An RCT comparing OFA and standard balanced anaesthesia was prematurely terminated due to five cases of severe bradycardia.²⁷ In our study, we also observed one patient with severe bradycardia, and the anaesthesiologist had to perform chest compressions to prevent unexpected asystole. Therefore, it is important to exercise caution when using dexmedetomidine, as it has the potential to induce severe bradycardia and even asystole, and the opioid-free strategy used in our study may not be clinically recommended for widespread use. Another patient was excluded from recruitment due to epilepsy-like convulsions. Theoretically, dexmedetomidine may have beneficial effects in preventing excitotoxic neuronal damage and inhibiting seizure events.^{35 36} However, we were unable to determine the specific cause of the epilepsy-like convulsions.

There are several limitations to this trial. First, the sample size may not have been large enough to observe a statistical difference in the incidence of PONV between the OFA and control groups, as the actual incidence of PONV was lower than estimated in our study. The negative result might be induced by a type II error, and a proper sample size should be calculated in future studies. Second, the recovery time was not recorded in our study as all patients were transferred to the recovery ward for emergence, where it was controlled by the physicians in the thoracic department rather than the anaesthesiologists. Third, there was only one patient with three risk factors for PONV, so further investigation is needed to determine whether the OFA strategy can reduce the incidence of PONV in high-risk patients. Fourth, only patients younger than 65 years old were included in the study, so the generalisability of the findings was limited. Finally, no correction was applied for multiple statistical analyses of secondary outcomes, and the risk of type I error might be present when reading the secondary outcomes.

In conclusion, the current study findings suggest that OFA does not significantly reduce the incidence of PONV in lung surgery. As the same time, the absence of opioids may not be adequate to prevent the sympathetic responses triggered by the intubation of DLTs. However, the opioid-free technique of general anaesthesia used in this study may be associated with serious adverse events which may limit its clinical use.

Data availability statement

Data are available upon reasonable request. The data can be requested from the principle investigator with reasonable cause.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).

Ethics approval

This study involves human participants and was carried out in accordance with the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. The protocol was approved by the Ethics Committee of our hospital (CHEC2021-132, 26 August 2021). Participants gave informed consent to participate in the study before taking part.