Comparison of the effects of norepinephrine and phenylephrine on shivering and hypothermia in patients undergoing caesarean section under spinal anaesthesia at a tertiary hospital in China:a randomised, double-blind, controlled trial protocol

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • A fixed-rate prophylactic norepinephrine infusion will be compared with a fixed-rate prophylactic phenylephrine infusion.

  • Phenylephrine, a commonly used vasoactive drug, will serve as the control group.

  • Rectal temperature will be measured instead of nasopharyngeal temperature to prevent patient discomfort and data inaccuracies caused by breathing.

  • Our trial will not evaluate anxiety as a risk factor for shivering, due to personnel limitations.

Introduction

Spinal anaesthesia promotes systemic vasodilation in patients undergoing caesarean section, which inevitably leads to a redistribution of blood between the core and periphery, accompanied by a decrease in body temperature, resulting in shivering1 2 and hypothermia.3 4 Maternal shivering is a common occurrence, with an incidence rate as high as 60%, due to the body’s thermoregulatory centres compensating.5 The pathological and physiological mechanisms of perioperative shivering result from a combination of factors, including pain, disruption of reflex inhibitory mechanisms and decreased sympathetic activity. However, the primary cause is hypothermia.6 7 Shivering reduces maternal comfort and increases metabolic rate (shown as an increase in oxygen consumption and metabolic product carbon dioxide and even lactic acidosis) during the perioperative period. These effects can also affect the monitoring of ECG, blood pressure and blood oxygen saturation.8 Abnormal coagulation, delayed wound healing and increased infection are all complications of hypothermia.9

As a type of α-agonist, phenylephrine is a potent and fast-acting vasopressor that can better maintain the acid-base status of the fetus and has replaced ephedrine as the preferred vasopressor for hypotension during caesarean section.10 However, due to its unique pharmacological mechanism, phenylephrine administration is more prone to cause reflex bradycardia and decrease cardiac output.11 Norepinephrine is an α-adrenergic agonist that also has a weak β-agonist effect. It is the primary drug used to manage hypotension undergoing caesarean section under spinal anaesthesia.12–14 Norepinephrine is effective in maintaining blood pressure and neonatal safety during caesarean section, it is also less disruptive to heart rate (HR) and cardiac output than those of phenylephrine.15 Increasingly, more and more research is being performed focusing on exploring the possibility of norepinephrine replacing phenylephrine. Previous studies have compared the effects of phenylephrine and norepinephrine in improving hypotension, often using a single injection.12 16 17 This study will use continuous infusion of phenylephrine and norepinephrine at a fixed rate, which has the advantage of reducing haemodynamic fluctuations.18

Theoretically, vasoconstriction caused by vasoactive drugs can reduce the loss of core body temperature. A study found that prophylactic infusion of phenylephrine significantly improved maternal body temperature and reduced the incidence of shivering during caesarean section under spinal anaesthesia.19 Previous comparative studies on norepinephrine and phenylephrine have primarily focused on maintaining circulation and safety.20 The primary observation indicators were neonatal outcomes,21 bradycardia22 23 and hypotension.17 Then it is meaningful to compare the effects of norepinephrine and phenylephrine on shivering and hypothermia. The trial’s original intention was to observe the effects of equivalent doses of norepinephrine and phenylephrine on shivering and hypothermia in parturients undergoing caesarean section under spinal anaesthesia.

Objectives

The authors aim to conduct a randomised, double-blind, controlled trial to compare the effects of prophylactic infusion of equivalent doses of norepinephrine or phenylephrine on shivering and hypothermia in patients undergoing caesarean section under spinal anaesthesia.

Primary objective

The incidence of shivering.

Methods and analysis

Patients

The recruitment phase of this study will last for approximately 2 years, commencing in November 2023. The trial aims to recruit patients who are scheduled to undergo caesarean section, with an age range of 18–40 years. Relevant inclusion and exclusion criteria are listed below:

Inclusion criteria

  1. Aged from 18 to 40 years.

  2. American Society of Anesthesiologists class II or below.

  3. Singleton and full-term pregnancy.

  4. Willingness to participate in the study and undergo intraoperative temperature measurement.

Exclusion criteria

  1. Inability or refusal to give informed consent.

  2. Allergy to phenylephrine or norepinephrine.

  3. Known fetal abnormality.

  4. Mesenteric or peripheral vascular thrombosis.

  5. Suffering from severe vital organ diseases (such as heart, brain, liver and kidney).

  6. Current usage of monoamine oxidase inhibitors or tricyclic antidepressants.

  7. With fever (axillary temperature >37°C) or shivering.

  8. With any contraindication for spinal anaesthesia.

  9. Hypertensive disorders of pregnancy.

Patients who are unable to comply with the protocol, lack information on the primary outcomes, or experience severe complications during surgical anaesthesia will not be included in final analysis and statistical description. Additionally, patients have the right to decide whether to withdraw or continue based on their wishes and circumstances. For safety reasons, researchers may interrupt the trial. Any relevant causes and their final handling will be accurately recorded in the case report form.

Study design

This is a randomised, controlled clinical trial, which will enrol 240 patients undergoing caesarean section with spinal anaesthesia. Figure 1 displays the Consolidated Standard flow chart for reporting trials. A Standard Protocol Items24: Recommendations for Interventional Trials figure is included in figure 2 . Patients will be randomly assigned to either the phenylephrine or norepinephrine group.

Figure 1
Figure 1

Consolidated Standards of Reporting Trials flow diagram.

Figure 2
Figure 2

SPIRIT figure schedule of enrolment, interventions and assessments. SPIRIT, Standard Protocol Items: Recommendations for Interventional Trials.

Recruitment

Patients with a singleton full-term pregnancy who meet the eligibility criteria and voluntarily participate in this trial will be recruited into one of the groups at the obstetrical department of the Second People’s Hospital of Hefei. If possible damage occurs due to participation in this study, patients have the right to seek third-party judgement and receive corresponding compensation. The trial results will be kept strictly confidential. Patients who withdraw midway or refuse to cooperate with continuing the trial will be considered non-compliant with the protocol, and their data will not be included in statistical analysis.

Information consent

All pregnant women eligible for caesarean section under spinal anaesthesia will sign an informed consent form after fully understanding the methods and objectives of this trial, as well as the potential benefits and risks.

Randomisation, blinding and unblinding

Subjects will be randomly assigned in a 1:1 ratio with the SPSS V.16.0 software to receive phenylephrine or norepinephrine treatment. The paper pieces will br marked with grouping information placed in sequentially numbered envelopes. Both patients and anaesthesiologists will be unaware of the group assignment. Unblinding will be performed after the end of the trial or when patients experience adverse reactions that require treatment. To maintain independence and objectivity, an independent statistician who is blinded to participant allocation will be employed. Specific unblinding procedures, including the allocation time, sequence and identity verification process for unblinding participants, will be developed and approved by the ethics committee.

Study treatment

Patients who meet the inclusion criteria will be recruited until 240 cases. Phenylephrine (100 µg/mL) and norepinephrine (8 µg/mL) will be prepared by assistants who will not be involved in this trial. Patients will undergo routine sign monitoring after entering the operating room. After full lubrication with 2% lidocaine gel, a soft rectal temperature probe of a predetermined length will be inserted into the patient’s anus. Intravenous access will be secured using an 18G intravenous catheter. Within 15 min before surgery, a rapid intravenous infusion of 5 mL/kg lactate Ringer solution will be administered, and then the infusion will be continued at a rate of 6 mL/kg/hour. The ambient temperature in the operating room will be maintained at 22°C–24°C. A body blanket will be used when the patients enter the operating room. Active warming devices are not available in our institution but use of these devices may influence the overall incidence of hypothermia and shivering among the study participants.

Spinal anaesthesia will be implemented using 0.75% ropivacaine hydrochloride 12 mg at the L2–L3 or L3–L4 intervertebral space in a lateral decubitus position. The parturient will maintain a supine position on the left side at 15 degrees to displace the uterus to the left. The ‘study drug’ (containing phenylephrine or norepinephrine) is administered at a rate of 15 mL/hour starting from the intrathecal injection. The plane of midline sensory blockade will be checked by pinprick with blunt tipped needle, and the maximum sensory plane is generally reached within 20 min after spinal blockade. Circulatory parameters will be monitored every 3 min within the first 15 min after anaesthesia, and maternal rectal temperature will be recorded every 10 min throughout the surgical process. Ephedrine 6 mg will be used for treatment hypotension when the systolic blood pressure is below 90 mm Hg. Hypertension will be defined as an increase in mean arterial pressure (MAP) >20% from baseline.25 Once hypertension occurs, medication infusion will be stopped immediately until MAP returns to below the hypertension. Atropine 0.5 mg will be used and reused if necessary for bradycardia treatment when the HR <60 beats/min.

Shivering will be defined as muscle twitches in the face, chest, and extremities that last for 15 s. It will be classified according to commonly used grading criteria (none: no significant muscle tone; mild: slight muscle tone in the masseter; moderate: proximal muscle tremors; severe: whole body tremors).26 The incidence and severity of shivering will be assessed. Umbilical arterial blood will be collected for blood gas analysis from a segment of the umbilical cord that is double-clamped before the baby’s first breath. Treatment of moderate and severe tremors after delivery will be achieved with 5 mg of dezocine intravenously. The patient’s axillary temperature will continue to be monitored in the ward after surgery.

Trial outcomes

Primary outcome

The primary outcome of this trial is the incidence of shivering.

Secondary outcomes

Secondary outcome variables include the following:

  1. The severity of shivering.

  2. Rectal temperature.

  3. Umbilical artery blood pH value.

  4. The incidence of hypothermia (<36°C).

  5. Plasma clotting factor VIII activity, Fibrinogen, D-dimer.

Withdrawal or drop-out criteria

  1. The subject subjectively requests to withdraw from the trial.

  2. The subject fails to complete data collection.

  3. The occurrence of adverse events requires withdrawal from treatment.

  4. The subject’s intraoperative circulation is difficult to maintain or the pathological changes require withdrawal.

  5. The researcher believes that the subject is not suitable to continue.

Safety assessment

Adverse events occurring during the perioperative period, such as hypertension, drug extravasation, will be recorded and treated. Participants will receive free medical care for any adverse events, and all relevant information will be reported to the ethics committee.

Sample size calculation

Our previous study (unpublished) has shown that the incidence of shivering was 20% when treated with phenylephrine and 40% when treated with norepinephrine. The trial aims to recruit 240 eligible patients. This sample size will provide 90% power to show a reduction in the incidence of shivering between two groups at a two-sided alpha level of 0.05. We are also taking into account the 10% risk of failing to collect data or losing the case due to incompleteness. PASS software V.15.05 (USA) will be used to estimate the sample size in this trial.

Statistical methods

Stata V.14 software (USA) will be applied for data analysis. χ2 or Fisher’s exact test will be applied to analyse categorical variables expressed in proportion and percentage. Shapiro-Wilk test will be applied to analyse Continuous data presented as mean with SD or median and IQR. Unpaired Student’s t-test or Mann Whitney U test for parametric or non-parametric data will be applied for continuous and discrete variables. Repeated measures analysis of variance will be applied to compare core temperature within or between groups at any time point. The condition for significant difference is p<0.05.

Ethics and dissemination

Ethics approval and consent to participate

This clinical study will be conducted following the Declaration of Helsinki. It will be conducted in compliance with the protocol, Good Clinical Practice, designated standard operating procedures, and local laws and regulations relevant to the country of conduct. The protocol of this trial was approved by the Institutional Ethics Committee of The Second People’s Hospital of Hefei (ID: 2023-093).

Dissemination policy

The study data will be analysed and summarised after completion of the research. The research findings manuscript will then be submitted to a peer-reviewed journal for publication.

Data sharing

After publication, deidentified participant data (including data dictionaries), related documents (such as study protocol) and statistical analyses are available to external investigators who may wish to conduct secondary analyses or the meta-analyses.

Amendments to the protocol

The trial will strictly follow V.1.0 of the protocol. Any modifications to the protocol will be formally submitted to the Ethics Committee of The Second People’s Hospital of Hefei for review. The protocol will adhere to the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. Any deviations from the protocol will be documented and reported to the ethics committee.

Patient and public involvement

The design, implementation, reporting and dissemination plan of the study does not include patient and/or public opinions.

Data collection, monitoring and management

The pretrial results will serve as the baseline, and the data will be regularly summarised. If any data abnormalities are found during the trial, repeated measurements will be taken by other individuals or devices. Patients with significantly outlier data will be identified and timely discussions will be organised. The patient’s data will be input and encoded by two individuals (JB and YX), with dedicated personnel responsible for security and storage in duplicate (WT). Patient data will be stored on a password-protected computer and managed by the principal investigator (WT). Mid-term analysis will be conducted by the initiator, who has the right to access and make decisions based on the results. The experiment may be terminated based on these results.

Trial status

Recruitment began in November 2023 and is expected to conclude by December 2025. The protocol version is V.1.0. Any significant modifications to the plan will require resubmission of the ethics application to the committee.

Ethics statements

Patient consent for publication

Acknowledgments

The authors are deeply grateful for the support and contributions of patients, surgeons and nursing.

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