Study design overview

The present study is a prospective, single-centre, randomised, double-blinded, placebo-controlled two-arm trial in patients with delayed extubation after craniotomy.

Trial schematic diagram is shown in figure 1.

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Figure 1

Trial schematic diagram (ICU, intensive care unit; IV, intravenous; LOS, length of stay).

Study setting and population

The study setting is a neurosurgical ICU (30 beds) at the Beijing Tiantan Hospital (1100 beds), Capital Medical University, Beijing, China.

All patients after intracranial surgery with delayed extubation admitted to our ICU are screened daily for study eligibility.

Inclusion criteria are:

1. Age between 18–65 years;

2. Within 72 h after operation;

3. Awake and able to cope with the assessment of the visual analogue scale (VAS) pain score;

4. Ready for extubation after evaluation by the neurosurgeon and the ICU physician in charge.

Exclusion criteria are:

1. Operation relating to the medulla oblongata region;

2. Hepatic insufficiency;

3. Renal insufficiency;

4. Pregnant or lactating women;

5. Need continuous infusion of the vasopressor before the start of the study drug infusion;

6. Chronic opioid use over 3 months;

7. Known opioids allergy;

8. Readmitted to the ICU after randomisation to the study;

9. Enrolled in another trial.

The patient's endotracheal tube is extubated at the discretion of the neurosurgeon and the ICU physician in charge of the patient. The neurosurgeon and the ICU physician discuss the patient's status and evaluate the patient by a screen checklist (table 1).10 When the answers of all items in a checklist are “yes”, the patient is ready for extubation. At this time, a 24 h on-call study coordinator will be informed immediately, and the patient's eligibility for the study is evaluated and confirmed.

Randomisation, double-blind and allocation concealment

The study has a prospective, randomised, double-blinded, controlled parallel-group design. Randomisation is based on the computer-generated random digits table. The allocation sequence is sealed in numbered and opaque envelopes to ensure that the sequence is concealed. Enrolled patients are randomly assigned 1:1 to receive remifentanil (labelled as the Remi group) or placebo (labelled as the Saline group) infusion. Patients may be randomised into this study only once, unless they were discharged from the hospital and were readmitted beyond 180 days of the first enrolment. The study does not allow a cross-over and, if any occur, they will be reported as protocol violations.

Experimental drugs and placebos with the same character are prepared by a pharmacist. Patients and all study personnel except the investigative pharmacist are blind to treatment assignment. The details of the series are unknown to any of the investigators and are contained in a set of opaque and sealed envelopes, each bearing on the outside only the number.

Data collected at study entry

At baseline, data on the demographics, history of past illness characteristics and diagnosis of the patients are obtained. The surgical site, operation time, use of sedatives and analgesics during anaesthesia and ICU stay, time of mechanical ventilation, formulation and dose of postoperative patient-controlled-analgesia (PCA) pump, and time between end of operation and study drug infusion are recorded. Acute Physiology and Chronic Health Evaluation II score (APACHE II) is calculated.

Trial interventions

All patients are randomised 1:1 to receive remifentanil (Remi group) or placebo (Saline group) infusion. Patients in the Remi group receive an intravenous bolus dose of remifentanil 0.5 μg/kg over 60 s followed by a continuous infusion of 0.05 μg/kg/min for 20 min. Patients in the Saline group receive an intravenous infusion of 0.9% sodium chloride at a volume and rate equal to that of remifentanil. Study drugs are administered by using a syringe pump.

Immediately after drug infusion, the ICU physician evaluates the patient by using an extubation screen checklist shown in table 1. If the patient passes the evaluation, endotracheal extubation will be carried out immediately by registered ICU nurses. The patient will be labelled as “failing to pass extubation test after drug administration” if he or she does not pass the evaluation. The reason for test failure will be documented. The patient will be re-evaluated every hour thereafter, and data about extubation will be documented.

Vital signs, which include heart rate (HR), respiratory rate (RR), non-invasive BP and pulse oxygen saturation (SpO₂), are monitored continuously. VAS pain score is used to measure the pain intensity by the study investigator.25 Each patient is instructed and asked to point to a mark on a 10 cm horizontal line labelled with descriptors of pain intensity (‘No pain’ at the 0 cm point and ‘Extreme pain’ at the 10 cm point). VAS and vital signs (HR, RR, BP and SpO₂) are documented at four time points: before drug infusion (baseline), immediately before extubation, immediately to 3 min after extubation and 20 min after extubation.

Patients will be followed up until hospital discharge, death or 60 days after the trial intervention on a first come, first served basis. The following data are collected: incidence of reintubation within 72 h after extubation, incidence of reoperation due to intracranial haemorrhage or oedema within 72 h after extubation, LOS in the ICU and hospital, and mortality.

Adverse events management and emergency stop of the study drug

Patients are closely monitored during study drug infusion. Taking into account the potential adverse effects of remifentanil, experimental drugs must be terminated immediately when the following occur:

1. Unresponsive to calling and patting on the shoulder;

2. RR less than 8 respirations per minute and SpO₂ less than 92%;

3. HR less than 50 bpm after atropine in a 0.25 mg bolus;

4. Systolic BP less than 90 mm Hg;

5. Serious allergic reactions such as throat swelling, bronchospasm or skin rash.

These data will be documented and reported as adverse events.

Study end points

The primary end point of the present study is the incidence of severe pain during the periextubation period. Periextubation is defined as the period of time from immediately before extubation to 20 min after extubation. Severe pain is defined as one of the VAS pain scores is more than 5 cm.

Secondary end points include:

1. VAS pain score and vital signs (HR, RR, BP and SpO₂) during the periextubation period;

2. Incidence of failing to pass extubation evaluation after experimental drug infusion;

3. Incidence of reintubation within 72 h after extubation;

4. Incidence of reoperation due to intracranial haemorrhage or oedema within 72 h after extubation;

5. Incidence of adverse events during experimental drug infusion;

6. LOS in the ICU and hospital;

7. Mortality.

Current sample size justification

Primarily, we expect the incidence of severe pain during the periextubation period to decrease after remifentanil infusion in delayed extubation patients after craniotomy. Previous investigation showed that severe periextubation pain occurred in 45% of patients.8 It is expected that the incidence of severe pain would decrease to 30% after remifentanil infusion. Using the Power and Sample Size Calculation program, we will need to study 74 experimental participants and 74 control participants to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with a probability (power) of 0.8. The type I error probability with testing this null hypothesis is 0.05.

Statistical analysis

All analyses will be according to the intention-to-treat principle, that is, all randomised patients will be analysed in the groups to which they were originally allocated and will be blinded to treatment assignment.

Baseline characteristics will be summarised by univariate analyses. Categorical variables will be presented as numbers and percentages, and analysed by the χ² test. Continuous variables will be checked for normal distribution and presented as the mean and SD or median and IQR as appropriate. Comparison of continuous variables will be performed by using Student t test for normally distributed variables and the Mann-Whitney U test for non-normally distributed variables.

We use repeated measures of analysis of variance for comparing VAS pain score and vital signs (HR, RR, BP and SpO₂) across different time points (before drug infusion and during the periextubation period) between the two groups.

All tests of significance will be at the 5% significance level and two-sided. Analyses are conducted by using SPSS V.17.0.

Ethical aspects and informed consent

Patients with delayed extubation after craniotomy are often unable to provide consent before extubation. After the patient's eligibility for the study is confirmed, the ICU physician will introduce the family to the study coordinator. The physician will make sure the family knows the credentials of the study coordinator, and says that this person is going to discuss a research programme that is being conducted, and that this person is qualified to do so. The study coordinator will take the family to a place where they can talk confidentially. Every relevant aspect of the project will be described. The study coordinator will stop frequently, ask if there are any questions, and request that the family repeat back in their own words what is being discussed, to make sure they understand.

The study coordinator will explain that the patient may experience pain during extubation and, if so, the patient could become worse. The coordinator will say that a new opioid drug, remifentanil, provides adequate analgesia with minimal respiratory depression. He (or she) will explain that in a small percentage of patients, remifentanil could cause bradycardia, hypotension and respiratory depression. The potential advantages of using or not using remifentanil will be described. The study coordinator will be especially careful to assure the family that they are free to decline consent without consequences and that they can withdraw consent at any time without impact on treatment. Family members will be provided with contact information for the study coordinator, local coinvestigator and the local ethical committee. Written consent will be obtained in the presence of a witness.

A register is kept of all patients evaluated for inclusion and of patients who withdraw from the study. The latter are clinically followed up without their data being analysed in the study.

The study protocol and consent forms were approved on 1 November 2013 by the Institutional Review Board of the Beijing Tiantan Hospital Affiliated to Capital Medical University (approval number KY2013-002-01). The study was registered on 8 November 2013 at the Chinese Clinical Trial Registry (ChiCTR-PRC-13003879).

Dissemination plan

Results of the trial will be submitted to an international peer-reviewed journal. Results will also be presented at national and international conferences relevant to the subject fields.