Opioid-free anaesthesia based on paravertebral block for thoracotomic paediatric congenital cardiac surgery—effectiveness of postoperative analgesia: a protocol for a prospective, single-blinded, randomised controlled trial (OPTION trial)

Abstract

Background

Opioids were considered the main analgesics for pain management during and after cardiac surgery. There are many complications associated with the use of opioids. Paravertebral block (PVB) is injecting Anaesthetics into the paravertebral space. We designed a randomised controlled trial to investigate whether PVB-based opioid-free general Anaesthesia, as compared to traditional low-dose opioid-based fast-track anaesthesia, can reduce opioid consumption within 24 h after thoracotomy incision cardiac surgery with cardiopulmonary bypass (CPB) in paediatric patients.

Methods

This is a single-centre, single-blinded, randomised controlled trial with a 1:1 allocation ratio. Patients will be randomised into two groups (control group and PVB group); 20 children will be enrolled in this trial, with 10 subjects in each group. Block randomisation will be performed. Patients aged 1–6 years, with the diagnosis of atrial and/or ventricular septal deficient And scheduled for cardiac surgery via a right thoracotomic incision, will be eligible for enrolment. The primary outcome is opioid consumption during the first 24 h after surgery. The main secondary outcomes include the perioperative stress response, inflammatory level, and intraoperative haemodynamics.

Discussion

This is the first randomised clinical study investigating opioid-free anaesthesia based on PVB for paediatric congenital thoracotomy surgery with CPB. If the OPTION trial proves that opioid-free anaesthesia based on PVB is safe for children undergoing thoracotomic cardiac surgery, we would be glad to provide an OPTION for the perioperative management of these children, especially in the era of ERAS.

Trial registration

Chinese Clinical Trial Registry: ChiCTR2200066517 (www.chictr.org.cn), Registered on December 7, 2022.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-025-09067-3.

Background

Traditionally, opioids were considered the main analgesics for pain management during and after cardiac surgery (CS) based on a predictable haemodynamic profile [1–7]. However, opioids are associated with higher risks of ventilator-associated pneumonia and prolonged intubation, both of which have been correlated with higher mortality, longer intensive care unit (ICU) stay, and longer hospital stay [6, 8, 9].

The concept of enhanced recovery after surgery (ERAS) is gaining acceptance as a way to reduce hospital stays, improve surgical outcomes, and increase cost-effectiveness [10–13]. The crucial elements of the ERAS strategy in paediatrics undergoing CS include fast-track cardiac anaesthesia (FTCA), minimally invasive cardiac surgery (MICS), and multimodal analgesia (MA) [14]. Minimally invasive surgery was introduced in the 1950 s, but it was not until the 1990 s that minimal incisions were used for CS [15]. Benefits of MICS include decreased wound infection, increased patient satisfaction, less pain due to smaller incisions, and facilitating FTCA [16]. Although thoracotomies result in smaller incisions, they can cause significant pain due to muscle separation and intercostal nerve damage [17]. Proper pain management is crucial for CS patients to prevent serious untoward effects [17].

Regional nerve block, the targeted injection of local anaesthetics to block pain sensation to nerves that correspond to the site of surgical incision or manipulation, has a significant role in multimodal analgesia. Regional nerve blocks must account for nerve distribution in the surgical incision and drain sites [18–20]. Paravertebral block (PVB) is injecting anaesthetics into the paravertebral space [21]. PVB combined with general anaesthesia reduced perioperative narcotic use and pain scores in patients undergoing robotic mitral valve surgery [22]. When comparing PVB to thoracic epidural anaesthesia, patients undergoing minimally invasive direct coronary artery bypass grafting showed that PVB was effective in postoperative pain control with no significant changes in haemodynamics or respiratory parameters [23]. PVB decreased opioid administration, reduced the incidence of atrial fibrillation, and limited the influence on haemodynamic stability [24]. Paravertebral techniques have similar efficacy as thoracic epidural analgesia with fewer side effects, although hypotension has been reported.

Various individual components in the enhanced recovery after paediatric cardiac surgery, including minimal opioid initiatives for paediatric cardiac surgery and chest tube removal protocols, have been focused end points in efforts to improve efficiency and patient outcomes [25]. Opioid-free postoperative Analgesia has been recommended for more than 10 years [26, 27]. And by combining regional blocks with other agents such as nonsteroid anti-inflammatory agents, hypnotics, α−2 agonists, and other nonopioid agents, opioid-free anaesthesia (OFA) also can achieve stable haemodynamics during surgery. To our knowledge, the OFA based on PVB for thoracotomic paediatric cardiac surgery with CPB has not been reported.

We successfully implemented OFA by using PVB combined with general Anaesthesia in five children undergoing repair of the atrial or ventricular septal defect via thoracotomic incision. During the perioperative period, three children did not receive Any opioids. One child was empirically given a single dose of sufentanil before CPB without any opioids for postoperative analgesia. Another child was empirically given a small dosage of opioids for analgesia after the operation. The haemodynamics of these 5 children were stable perioperatively, including endotracheal intubation And extubation. The follow-up showed that all children had no moderate to severe pain within 24 h after the operation, confirming that PVB provided sufficient analgesia for the first postoperative day.

The results of previous studies showed that if unilateral PVB could be successfully implemented and combined with other anaesthetics, children undergoing cardiac surgery through lateral thoracotomic incision would be successfully anaesthetised without opioids. The new anaesthesia scheme can ensure haemodynamic stability throughout the perioperative period, including the first postoperative day; it can reduce postoperative mechanical ventilation time, ICU stay, and complications such as respiratory depression, nausea, and vomiting caused by opioids. In addition, it may save medical costs.

Study hypothesis

Primary hypothesis: PVB-based opioid-free general Anaesthesia, as compared to traditional low-dose opioid-based fast-track Anaesthesia, can reduce opioid consumption within 24 h after thoracotomy incision cardiac surgery with CPB in paediatric patients.

The mechanism of regional block in reducing perioperative opioid dosage is not clear. Therefore, we propose our secondary hypotheses: compared to children under traditional low-dose opioid anaesthesia: PVB-based OFA can achieve similar perioperative stress response and inflammatory levels while maintaining stable intraoperative haemodynamics. And other secondary hypotheses: compared to children under traditional low-dose opioid anaesthesia, PVB-based OFA can achieve the same analgesic effect, with a lower incidence of postoperative complications such as postoperative nausea and vomiting and postoperative respiratory depression. PVB-based OFA will not increase the postoperative mechanical ventilation time, postoperative ICU stay, and postoperative hospital stay.

Methods/design

Study design and setting

This is a single-centre, single-blinded, randomised controlled trial (RCT) with a 1:1 allocation ratio. The study is being conducted in Fuwai Yunnan Hospital, China. More than 1500 open-heart procedures were performed there each year. An independent data monitoring committee will evaluate safety during the trial. Study data will be securely stored in the study site and will be available to the principal investigator after completion of the study. A clinical research organisation will audit the trial conduct and ensure the accuracy of the data.

This study protocol is strictly in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting guideline which can be found in Supplement 1. The timing of interventions and data collection is detailed in Fig. 1. Individual data will not be granted to the public. An overall flow chart is provided in Fig. 2.

Fig. 1.

Schedule of the enrolment, interventions, and assessments. SI, skin incision; AI, anaesthesia induction; CPB, cardiopulmonary bypass; h, hours; m, minutes; FLACC, facial expression, legs, activity, cry, consolability

Fig. 2.

Flowchart of the included studies

Ethical approval and trial registration

The trial was approved by the Medical Ethics Committee of the Fuwai Yunnan Cardiovascular Hospital on August 15, 2022 (No. IRB2022-BG-029).

The trial has been registered prospectively with the Chinese Clinical Trials Registry: No. ChiCTR2200066517 (www.chictr.org.cn), registered on December 7, 2022.

Participant eligibility and consent

Trial site investigators will identify consecutive eligible patients from the following criteria. Eligible patients will receive written and oral information and will be included after investigators have obtained informed written consent from his/her parent or legal guardian.

Inclusion criteria

Patients will be eligible for enrolment if they meet all the following criteria:

1. Age between 1- And 6-year-old

2. Patients with the diagnosis of atrial septal deficient and/or ventricular septal deficient scheduled for cardiopulmonary bypass surgery via right thoracotomic incision

3. Inform consent signed by the parent or legal guardian

Exclusion criteria

Participants who meet any of the following criteria will be excluded:

1. Patients who were intubated, on mechanical circulatory support, or with intravenous inotropes before surgery

2. Emergency surgery or redo cardiac surgery

3. Body weight less than 6 kg or more than 30 kg

4. Diagnosed as severe pulmonary hypertension by preoperative echocardiography and/or cardiac catheterisation

5. Left ventricular ejection fraction less than 45% in most recent echocardiography before surgery

6. Allergic to ropivacaine or other regular anaesthetics, analgesics, or other medications regularly used in the study (including any drug mentioned in the following section “Study interventions”)

7. Preoperative platelet counts less than 100*10⁹/L or coagulopathy (defined as any of the following: prothrombin time more than 3 s above the upper normal limit; international normalised ratio > 1.5; activated partial thromboplastin time more than 10 s above the upper normal limit); bleeding tendency (including frequent gum bleeding, skin ecchymosis, and poor coagulation after the venous puncture)

8. Preoperatively using antiplatelets or anticoagulants

9. Diagnosed with scoliosis or any other contraindications to carry out PVB

Allocation and blinding

Patients enrolled in the study will be randomised into two groups (control group and PVB group). In order to ensure group comparability, block randomisation will be used. Randomisation will be done by investigators as close as possible to the surgery. Each patient will be given a unique patient number and a randomisation number will be computer generated. The investigator who is responsible for enrolment will visit the patients before surgery and get informed consent. Randomisation will be done once the patient enters the operation theatre; the enrolment number and the randomisation number of the patient will be written on the case report form (CRF).

The anaesthetists will be aware of patients’ group allocation because they will provide the intervention and be alert to the possible complications, but they will not be involved in postoperative treatment, follow-up or the analysis.

The patients, guardians, surgeons, ICU physicians, data collectors, and data analysts will not be aware of the trial grouping in the whole process; if patients are seriously ill or clinicians have any concerns about the treatment, unblinding will be taken. After unblinding, the patients will remain in the trial and be followed up. Any intraoperative event or deviation from the protocol will be recorded on the CRF.

Study interventions

Standard anaesthesia management

Upon arrival at the operation theatre, the patient will be sedated with inhalation of sevoflurane 6–8% and inserted a peripheral venous cannula. Intravenous induction includes dexamethasone (0.3 mg/kg), midazolam (0.02 mg/kg), penehyclidine hydrochloride (0.02 mg/kg), and cisatracurium (0.2 mg/kg).

Mechanical ventilation will start after endotracheal intubation to achieve An end-tidal carbon dioxide tension of 35–45 mmHg, with a limited inhaled oxygen concentration of 30–60% And a tidal volume of no more than 10 mL/kg during operation. Anaesthesia will be maintained with continuous infusion of propofol 0.2–5 mg/kg/h, dexmedetomidine 1 μg/kg/h, cisatracurium 0.2 mg/kg/h, And inhalational sevoflurane 1–3%.

Standard monitoring includes a 5-lead electrocardiogram, pulse oximeter, arterial blood pressure, central venous pressure, nasopharyngeal temperature, rectal/bladder temperature, and urine output.

Heparinisation for CPB will be based on a bolus dose of heparin 400 U/kg and maintenance of an activated clotting time > 410 s during CPB. In the PVB group, heparinisation is performed at least an hour after PVB. After systemic heparinisation, the ascending aorta, superior, and inferior vena cava will be cannulated. After aortic cross-clamping, cardioplegia will be perfused. Surgery will be performed under mild hypothermia (32–34 °C), with haemoglobin > 70 g/L during CPB. After weaning from CPB, modified ultrafiltration will be used And haemoglobin target will be around 100 g/L, and protamine will be titrated to reverse heparin.

After endotracheal intubation, the patient randomised into the PVB group will be placed in a lateral position and undergo the right T4 PVB. The sagittal in-plane method under ultrasound guidance will be recommended: the lower edge of the T4 spinous process on the right side is selected as the punction point, And the ultrasonic probe will be put about 2.5 cm away from the spine on the operation side. The direction of the probe is parallel to the spinal column and perpendicular to the skin. The position of the probe will be adjusted until the pleura and the superior costotransverse ligament can be distinguished, thus confirming the paravertebral space. After determining the position, inject the needle under the guidance of ultrasound to make it pass through the skin, external intercostal muscle, and intercostal intima successively until reaching the paravertebral space. After pumping back without fluid/blood And gas, inject 0.3% ropivacaine with a total amount of no more than 3 mg/kg. Pleural depression can be seen after injection. Other methods can also be used to apply PVB, such as sagittal out-of-plane method and horizontal (intercostal) in-plane or out-of-plane method. Patients randomised into the control group will not undergo PVB. In order to comply with the principle of blinding and avoiding unnecessary complications, skin puncture will be applied at a similar position in the control group.

In the control group, each dose of sufentanil 0.5 μg/kg iv. will be given before skin incision and aortic cannulation. In the PVB group, the patients will not receive any opioids during the operation; the sevoflurane concentration and propofol dosage will be titrated according to the depth of sedation and haemodynamic changes.

At the end of the surgery, subcutaneous infiltration Anaesthesia will be performed with 0.3% ropivacaine (total 1 mg/kg) at the surgical incision and the site of the drainage in the control group, while the PVB group patients will not receive subcutaneous infiltration anaesthesia.

Please refer to the Supplement 2 file for the definition of PVB failure, remedial intraoperative/postoperative analgesia plan as well, and institutional standard endotracheal extubation criteria.

Study outcomes and definitions

Primary outcome

The primary outcome of this trial is the opioid consumption during the first 24 h after surgery: the total amount of sufentanil and other opioids will be calculated as morphine equivalent dose (MED) divided by body weight.

Secondary outcomes

1. The incidence of excessive haemodynamic fluctuation after incising in both groups. Excessive haemodynamic fluctuation is defined as the fluctuation of mean arterial blood pressure value or heart rate greater than 20% after incision compared to baseline values.

2. Serum concentration of inflammation factors (IL-6, IL-8, IL-10) and stress hormones (cortisol, epinephrine, and norepinephrine).

   • Serum samples will be collected for measuring at these time points: 10 min after Anaesthesia induction, 10 min after skin incision, 10 min And 30 min after initiating CPB, 10 min after weaning from CPB, 4 h And 24 h postoperatively.

• (3)The FLACC scale will be recorded at 6, 12, 18, And 24 h postoperatively.
• (4)The first time FLACC ≥ 4 postoperatively.
• (5)The rate of opioid treatment for remedial analgesia between groups.
• (6)The rate of postoperative nausea and vomiting (PONV) during the 24 h postoperatively.
• (7)Length of hospital/ICU stay.
• (8)Length of endotracheal intubation.
• (9)The incidence of respiratory depression.

Respiratory depression is defined as: with no obvious upper respiratory tract obstruction: SpO₂ < 90% And lasts for more than 1 min, or respiratory rate < 8 times/min, or SpO₂ < 94% and respiratory rate < 10 times/min, or supplemental oxygen is needed to maintain SpO₂ > 94%.

Sample size estimation and statistical analyses

Sample size estimation

Sample size calculation is based on the primary outcome, which is the total consumption of opioids within 24 h after surgery. Referring to our pilot data, the total consumption of opioids within 24 h after surgery in the traditional low-dose opioid anaesthesia group (all opioids are converted into morphine equivalent dose MED, for example, 1 μg/kg sufentanil = 1 mg/kg MED) mean value was 1.02 ± 0.02 mg/kg MED, combined with published literature [28] And the experience of clinical experts, it is assumed that the total dose of postoperative 24 h opioids consumption in the PVB group will be reduced by 0.9 mg/kg MED on average, And the combined standard deviation is conservatively estimated as 0.5 mg/kg MED when the significance level of a statistical test is one-sided 0.025 And the power is 90%. The subjects will be randomly divided at a ratio of 1:1. Considering the maximum possible 10% dropout in the study, according to the statistical calculation, 8 children in each group will be needed. We thus conservatively chose 20 participants in this trial, with 10 subjects in each group. The corresponding sample size calculation formula is:

$$\eta =\frac{2{\left({\mu }_{1-\alpha },+,{\mu }_{1-\beta }\right)}^2{\sigma }^2}{{\left(x_T,-,x_C\right)}^2}$$ 1

In the formula, x_T corresponds to the dose of opioids in the PVB group within 24 h after surgery, while x_C represents the dose of opioids in the control group within the same period, μ_1−α means the (1 − α) quantile of standard normal distribution, α corresponds to the class I error of statistical test, α = 0.025, and β corresponds to the class II error level of the test, β = 0.1 (corresponding to the power of 90%).

Statistical analyses

A statistician with extensive experience in designing, conducting, and analyzing clinical trials will oversee this study. This individual will not participate in patient management, remain blinded to group allocation, and independently perform all statistical analyses. Multiple imputations will be used to deal with missing data. The primary outcome will be analysed by the intention-to-treat principle. All statistical analysis will be followed the intention-to-treat principles in which data from all subjects who undergo randomisation and receive related treatment. The per-protocol population will be used as sensitivity analysis.

Descriptive analyses: categorical variables will be expressed as counts And percentages, And continuous variables will be expressed as mean, standard deviation, maximum, and minimum values. Non-normally distributed variables will be expressed as median, 25th, And 75th quantiles. The normally distributed continuous variables will be compared by Student’s t-test (two groups) or variance analysis (multiple groups). The non-normally distributed continuous variables will be compared by the Wilcoxon rank sum test. Categorical variables will be presented as frequency and percentage and compared using the χ² test or Fisher’s exact test. Regression analysis will be used if the baseline characteristics show significant differences between the two groups.

Efficacy analyses: for the primary outcome (opioid dosage within 24 h after surgery), Student’s t-test will be used to compare the group differences. The two-sided 95% confidence intervals of the difference in total opioid dose within 24 h after surgery between groups will be estimated. By comparing the 95% confidence interval of the difference efficacy between two groups with 0 μg/kg to determine whether the optimal efficacy hypothesis is tenable. Results will be considered statistically significant if p < 0.05.

Data and safety monitoring board

The DSMB will consist of a cardiologist (chair), cardiac surgeon, independent statistician, cardiac anaesthesiologist interested in medical ethics and law, and clinical pharmacologist. No interim analysis will be performed. Recommendations to continue, modify, or terminate the study were made based on stopping rules and considering additional evidence related to DSMB. The process will be independent of investigators and the sponsor. The trial will be audited according to standard operating procedures by Fuwai Yunnan Hospital Clinical Research Programme Clinical Trial Support Unit internal monitoring committee.

Patient and public involvement

No patient or public entity were involved in designing the present study.

Protocol amendments

If there is any protocol revision after study enrolment, the sponsor and funder will be notified first, then the PI will notify the centre, and a copy of the revised protocol will be added to the Investigator Site File. Any deviations from the protocol will be fully documented using a breach report form.

Discussion

As far as we know, this is the first randomised clinical study powered to investigate the OFA based on PVB for thoracotomic paediatric congenital surgery with CPB. Postoperative pain control is essential for paediatric patients undergoing CS [1]. It is multifaceted and may result from various interventions, including sternotomy, thoracotomy, and chest drainage [2–4]. Adequate postoperative analgesia in children is crucial, not only for patients’ comfort, but also to improve respiratory status, attenuate the neuroendocrine response to stress, and prevent amplification of pain pathways. Traditionally, opioids were considered the main analgesic for pain management after CS based on a predictable haemodynamic profile [7]. However, opioids are associated with increased risks of ventilator-associated pneumonia And prolonged intubation, which have been correlated with higher mortality, longer ICU stays, And longer hospital stays. Opioid-free postoperative analgesia has been recommended for more than 10 years [25]. At present, studies that support the analgesic effectiveness of unilateral PVB in paediatrics undergoing MICS have a high degree of heterogeneity, inadequate randomisation, and lack of blinding. So far, the application of OFA based on PVB of thoracotomic paediatric congenital surgery with CPB has not been reported.

This study has several limitations. First, since PVB is not routinely applied in our institution for CPB surgery, concerning the safety issue, we only designed the OPTION trial single-blinded; the anaesthetists will be aware of the risks of PVB. However, all other staff will be blinded including surgeons, intensivists, patients, and follow-up staff. In the future, double-blinded trials are possible. Second, we may answer the question of postoperative analgesic effects of PVB-based opioid-free anaesthesia in these children; however, with a limited enrolment number, we may not target more clinical concerns, such as the safety issue when applying PVB in cardiac surgical patients, and all the secondary outcomes. Third, the implementation of PVB has the potential to fail. Although we designed remedial analgesic plans for both intraoperative and postoperative management and we a priori specify the intention-to-treat plan as our primary analysis, the failure in PVB may result in bias. Fourth, in the PVB group, we will postpone surgical incision and heparinization for concerns about bleeding and haematoma, thus will increase the overall theatre time for a single case.

If the OPTION trial proves that opioid-free anaesthesia based on PVB is safe for children undergoing thoracotomic cardiac surgery, we would be glad to provide an OPTION for the perioperative management of these children, especially in the era of ERAS.

Trial status

The study is currently recruiting patients. Recruitment began on April 10, 2023. We expect the study to be completed in August 2024.

Protocol version number: V1.3.

Protocol version date: 8 October 2021.

Strengths and limitations of this study

Strengths

This is the first randomised clinical study powered to investigate the analgesic effects of opioid-free anaesthesia based on PVB for thoracotomic paediatrics congenital surgery with CPB.

Limitations

1. In concern with the safety issue, we designed the current trial with single blinding; the anaesthetists will be aware of the risks of PVB and will not be blinded.

2. The sample size of this study may be enough to answer postoperative reduction in opioid consumption in paediatric thoracotomic cardiac surgery. But the number of enrolments may not be enough to answer safety issues such as potential complications that can used by PVB and all the secondary outcomes.

3. Implementing PVB has the potential to fail. Although remedial analgesic regimens were included in the study design, this may result in bias.

4. In the PVB group, we will postpone surgical incision and heparinization for concerns in bleeding and haematoma, thus will increase the overall theatre time for a single case.

Abbreviations

CPB

Cardiopulmonary bypass

ChiCTR

Chinese Clinical Trial Registry

CRF

Case report form

CS

Cardiac surgery

ERAS

Enhanced recovery after surgery

FLACC

Face legs activity cry consolability

FTCA

Fast-track cardiac anaesthesia

ICU

Intensive care unit

IL

Inflammation factors

MED

Morphine equivalent dose

MICS

Minimally invasive cardiac surgery

OFA

Opioid-free anaesthesia

PVB

Paravertebral block

RCT

Randomised controlled trial

SPIRIT

Standard Protocol Items: Recommendations for Interventional Trials

Authors’ contributions

ZZ, SS, and JS are joint first authors; they obtained the ethical approval, registered, and drafted the manuscript. YZ provided statistical expertise in clinical trial design and will conduct the statistical analysis. JG, ZD, JY, and FY will be involved in study implementation. YJ and KY are corresponding author; they designed the study and critically edited the manuscript. YJ served as the primary investigator and provided the funding. All authors participated, read, and approved the final manuscript.

Funding

This work was supported by Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project (No. FZX2019-06–01) grant number FZX2019-06-012022YFKY014 and Talent Trusteeship Program of Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences (No. 2024RCT-QN003), Yunnan Provincial Clinical Medicine Research Special Program (No. 202405AJ310003).

Data availability

During the study, the datasets used in the current study are available from the corresponding author on reasonable request. After the study, the results of this trial will be published in peer-reviewed journals and presented at national and/or international conferences.

Declarations

Ethics approval and consent to participate

The trial was approved by the Medical Ethics Committee of the Fuwai Yunnan Hospital on August 15, 2022 (No. IRB2022-BG-029). Eligible patients will receive written and oral information and will be included after investigators have obtained informed written consent from his/her parent or legal guardian.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.