Use of dexmedetomidine for prophylactic analgesia and sedation in delayed extubation patients after craniotomy: a study protocol and statistical analysis plan for a randomized controlled trial
Use of dexmedetomidine for prophylactic analgesia and sedation in delayed extubation patients after craniotomy: a study protocol and statistical analysis plan for a randomized controlled trial
Li-Hong Zhao 0
Zhong-Hua Shi 0
Ning-Ning Yin 0
Jian-Xin Zhou 0
0 Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University , No 6, Tiantan Xili, Dongcheng district, Beijing 100050 , China
Background: Pain and agitation are common in patients after craniotomy. They can result in tachycardia, hypertension, immunosuppression, increased catecholamine production and increased oxygen consumption. Dexmedetomidine, an alpha-2 agonist, provides adequate sedation without respiratory depression, while facilitating frequent neurological evaluation. Methods/design: The study is a prospective, randomized, double-blind, controlled, parallel-group design. Consecutive patients are randomly assigned to one of the two treatment study groups, labeled 'Dex group' or 'Saline group.' Dexmedetomidine group patients receive a continuous infusion of 0.6 g/kg/h (10 ug/ml). Placebo group patients receive a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. The mean percentages of time in optimal sedation, vital signs, various and adverse events, the percentage of patients requiring propofol for rescue to achieve/maintain targeted sedation (Sedation-Agitation Scale, SAS 3 to 4) and total dose of propofol required throughout the study drug infusion are collected. The percentage of patients requiring fentanyl for additional rescue to analgesia and total dose of fentanyl required are recorded. The effects of dexmedetomidine on hemodynamic and recovery responses during extubation are measured. Intensive care unit and hospital length of stay also are collected. Plasma levels of epinephrine, norepinephrine, dopamine, cortisol, neuron-specific enolase and S100-B are measured before infusion (T1), at two hours (T2), four hours (T3) and eight hours (T4) after infusion and at the end of infusion (T5) in 20 patients in each group. Discussion: The study has been initiated as planned in July 2012. One interim analysis advised continuation of the trial. The study will be completed in July 2013. Trial registration: ClinicalTrials (NCT): ChiCTR-PRC-12002903.
Dexmedetomidine; Analgesia; Sedation; Prophylactic; Delayed extubation; Craniotomy
Pain and agitation are major concerns in postoperative care
of neurosurgical patients. Several studies have shown that
moderate-to-severe postoperative pain is frequent
following craniotomy [1-7]. In a recent study by Mordhorst et al.
, 55% of patients had moderate or severe postoperative
pain in the first 24 hours following craniotomy. This study
had a similar result to the pilot study by De Benedittis et
al.  in which 60% of patients experienced postoperative
pain. Agitation is common in the ICU. It has been found
that there are multiple possible causes of agitation in the
ICU setting, including the presence of existing diseases,
pain, anxiety, delirium, dressing changes, invasive
procedures, nursing procedures, intubation, endotracheal tubes
and surgical incisions [8,9]. Pain and agitation can cause
tachycardia, hypertension, increased catecholamine
production, increased oxygen consumption and
immunosuppression [9,10]. Increased catecholamines have been shown
to contribute to myocardial ischemia, disturbed sleep and
catabolism . Hypertension can cause an increase in
brain edema or hemorrhage, which may give rise to brain
On the other hand, despite a greater awareness of pain
and agitation after craniotomy, clinicians remain
reluctant to administer analgesics and sedatives in patients
following craniotomy. The major concerns are the side
effects of these drugs, mainly that they reduce the
clinicians ability to monitor the level of consciousness and
that they induce respiratory depression .
Sedation goals for neurosurgical ICU patients are to
improve comfort, overcome anxiety and pain, facilitate
nursing care and mechanical ventilation, facilitate frequent
neurological assessments and provide sedation without
causing deleterious changes in intracranial pressure (ICP)
or cerebral perfusion pressure (CPP). An ideal sedative
agent in the ICU should be cheap, rapid in onset and
offset and without local and systemic adverse effects. There
is no sedative agent in use that has all these ideal
properties. However, dexmedetomidine, an alpha-2 agonist,
provides adequate sedation without respiratory depression,
while facilitating frequent neurological evaluation.
Dexmedetomidine, a potent and highly selective
alpha-2-adrenoceptor agonist, has been available in the
United States since the end of 1999 for use in humans
as a short-term (<24 hours) medication for sedation/
analgesia in the ICU in initially intubated and
mechanically ventilated patients .
Dexmedetomidine provides dose-dependent sedation,
anxiolysis and analgesia (involving spinal and supraspinal
sites) without respiratory depression . Although
alpha2-adrenoceptors are located throughout the body, they are
present in larger concentrations in vascular smooth
muscle and in key arousal areas of the central nervous
system (CNS), such as the locus ceruleus . Activation of
alpha-2-adrenoceptors in the CNS decreases centrally
mediated sympathetic activity and induces sedation [16,17].
Activation of presynaptic alpha-2-adrenoceptors in cortical
blood vessels decreases norepinephrine release, whereas
postsynaptic alpha-2-adrenoceptors may directly increase
vascular smooth muscle tone [15-17].
Sedation with dexmedetomidine differs from sedation
with other commonly used sedatives such as propofol or
midazolam. Dexmedetomidine may induce a sedative state
similar to physiologic sleep without respiratory depression
by acting on alpha-2 receptors in the locus ceruleus
[18-20], and patients may be aroused easily with
stimulation and are cooperative once aroused.
In addition to its sedative effects, dexmedetomidine
has significant analgesic qualities and may significantly
reduce concomitant opioid use. Analgesia with
dexmedetomidine is mediated primarily through interaction at
alpha-2a within the spinal cord, where drug activity
attenuates nociceptive signal transduction. The actual
mechanism of action appears to involve an interaction
with opioid receptors and, although dexmedetomidine
alone has been documented to reduce pain, the effect
when given jointly with opioids may be additive or
synergistic . Dexmedetomidine provides intense
analgesia during the postoperative period and reduces the
total number of post-surgical patients requiring opioids
with a corresponding reduction in opioid-associated
side effects .
Dexmedetomidine is accompanied by virtually no
respiratory depression at clinically relevant doses. Despite
profound sedative properties, dexmedetomidine is
associated with only limited respiratory effects, even when dosed
to plasma levels up to 15 times those normally achieved
during therapy, leading to a wide safety margin .
Hypercapnic arousal is preserved, and the apnea threshold is
actually decreased. Because dexmedetomidine has no
depressant effects on ventilation, its analgesic effect may
offer a significant advantage for patients at risk of
respiratory decompensation .
Hemodynamic effects of dexmedetomidine may result
from both peripheral and central mechanisms.
Dexmedetomidine is the pharmacologically active dextroisomer
of medetomidine . Stimulation of alpha-2
adrenoceptors by dexemedetomidine in pontine locus ceruleus
(LC) results in decreased firing of LC neurons secondary
to their hyperpolarization. It also has a sympatholytic
effect through decreases in the concentration of
norepinephrine. This, in turn, decreases the blood pressure (BP)
and the heart rate (HR) [24-27]. The initial response to
rapid dexmedetomidine infusion may be a transient
hypertension. However, the net effect of alpha-2 adrenoceptor
action is a significant reduction in circulating
catecholamines and a modest decrease in BP and heart rate HR.
Although hypotension has been described in patients
receiving dexmedetomidine, this physiological effect seems
to correlate with the use of a loading dose and/or
preexisting hypovolemia .
A meta-analysis including 24 trials showed that
dexmedetomidine did not appear to increase risk of
bradycardia. The risk of bradycardia was, however, significantly
higher in studies that used both a loading dose and high
maintenance doses (>0.7 ug/kg/h) than in studies that did
not use both. Risks of hypotension requiring interventions,
delirium, self-extubation, myocardial infarction,
hyperglycemia, atrial fibrillation and mortality were not
significantly different between dexmedetomidine and traditional
sedative and analgesic agents .
Dexmedetomidine could be a potentially useful
anesthetic adjuvant for neurosurgical patients . Two
studies have examined its use in patients undergoing
intracranial surgery [29,30]. Both studies showed that
the addition of dexmedetomidine improves
perioperative hemodynamic control. In these studies, the authors
controlled arterial blood pressure with a prescribed
incremental dosing of anesthetics. No patient in either
study required antihypertensive medications.
Dexmedetomidine does not have a significant effect on
intracranial pressure .
Dexmedetomidine also minimizes opioid induced
muscle rigidity, decreases post-operative shivering and
has hemodynamic stabilizing effects . The
medication is a unique sedative in that it does not cause
respiratory depression and the sedated patients are easily
aroused to perform a neurological examination or to
cooperate with procedures (for example, physiotherapy,
radiology imaging) without showing irritation [32,33].
Dexmedetomedine has been reported to provide
neuroprotective effects against ischemia in the CNS [34-38].
The S100B protein and the neuron-specific enolase (NSE)
are the most widely investigated of molecular markers in
patients with severe head injury, stroke or subarachnoid
hemorrhage (SAH). The concentration of these markers
has been shown to increase in the cerebrospinal fluid
(CSF) as well as in the serum [39-43]. In addition, in
patients with SAH the course of the S100B concentration
has been shown to correlate with neurologic deficits and
The aim of the present work is to evaluate the safety
and efficacy of dexmedetomidine for prophylactic
analgesia and sedation in delayed extubation patients after
craniotomy. The primary hypothesis is that prophylactic
use of dexmedetomidine will increase the percentage of
time in optimal sedation.
The present study is a prospective, single-center,
randomized, double-blind, placebo-controlled, two-arm trial
in patients with delayed extubation after craniotomy.
Study setting and population
The study setting is the neurosurgical ICU, Beijing
Tiantan Hospital, Capital Medical University, Beijing,
All patients after intracranial surgery with delayed
extubation admitted to our ICU are screened daily for
study eligibility. Patients are deemed eligible for this
study if they are 18-years-old, present with motor
responses to external stimuli in the Glasgow Coma Scale
(GCS-M) equal or higher than five in two hours (time
zero would be the time of ICU admission).
Exclusion criteria are:
Ethical aspects and informed consent
When a patient is identified as eligible for the study,
immediate contact will be made with the 24-hour on-call
study coordinator, who will confirm eligibility. Delayed
extubation patients after craniotomy are often unable to
provide consent until they improve. The attending
physician will introduce the family to the study coordinator.
The physician will make sure the family knows the
credentials of the study coordinator, and say that this
person is going to discuss a research program 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 there is a
possibility that the patient may experience pain, agitation,
and delirium,and, if so, the patient could become worse.
The coordinator will say that there is a new alpha-2
agonist that provides adequate sedation without
respiratory depression, while facilitating frequent neurological
evaluation. He will explain that in a small percentage
of patients, dexmedetomidine could cause bradycardia,
hypotension and respiratory depression. The potential
advantages of using or not using dexmedetomidine 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 co-investigator 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
analyzed in the study.
The study protocol and consent forms were approved
by the Institutional Review Board of Beijing Tiantan
Hospital Affiliated to Capital Medical University (approval
number KY2012-006-02) and by the Chinese Clinical Trial
Registry (ChiCTR-PRC-12002903). The Beijing Tiantan
Hospitals Institutional Review Board gave positive advice
for the addition of their ICU as the study site.
Data collected at study entry
At baseline, data on demographic characteristics and the
history of past illnesses of the patients are obtained. The
surgical site, operation time, intraoperative medication,
the input liquid quantity, and the amount of bleeding
and urine are recorded. The Acute Physiology and
Chronic Health Evaluation II score (APACHE II) and
Glasgow Coma Scale (GCS) are calculated.
Randomization, double-blind and allocation concealment
The study has a prospective, randomized, double-blind,
controlled, parallel-group design. Consecutive patients
are randomly assigned to one of the two treatment
study groups, labeled Dex group or Saline group.
Randomization is based on a computer generated
random digits table and follows a concealed process using
sealed and numbered envelopes that allocate the patient
to either of the two arms of the study. Patients may be
randomized into this study only once unless they were
discharged from the hospital and were re-admitted
beyond 180 days of the first enrollment. The study does
not allow cross-overs and, if any occur, they will be
reported as protocol violations.
Experimental drug and placebo 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.
All patients are randomized 1:1 to receive
dexmedetomidine or placebo infusion. Dexmedetomidine group
patients receive a continuous infusion of 0.6 g/kg/h (10
ug/ml). Placebo group patients receive a maintenance
infusion of 0.9% sodium chloride for injection at a volume and
rate equal to that of dexmedetomidine. The patients level
of sedation will be assessed using the Sedation-Agitation
Scale (SAS) per hour after starting the study drug infusion.
Any patient >5 on the SAS will be given rescue propofol
in 0.5 mg/kg bolus or infusion doses 0.5 to 2 mg/kg/h
until the attaining SAS 3 or 4. Fentanyl will be given in
0.05 mg increments to treat pain as needed.
The intervention must be emergency stopped when
the following occurs:
The percentage of patients requiring propofol for rescue
to achieve/maintain targeted sedation (SAS 3 or 4) and
total dose of propofol required throughout the study
drug infusion are collected. The percentage of patients
requiring fentanyl for additional rescue to analgesia and
total dose of fentanyl required are recorded.
Secondary endpoints also include vital signs and various
and adverse events. Vital signs are recorded every hour
throughout the procedure (BP, HR, respiratory rate (RR),
and SpO2) .Adverse events include hypotension,
hypertension, bradycardia, tachycardia, airway obstruction, apnea,
epilepsy, cerebral hemorrhage or infarction and
consciousness disorders (GCS-M <5).
The effects of dexmedetomidine on hemodynamic and
recovery responses during extubation are measured. BP,
HR, RR, and SpO2 are recorded one minute before
extubation, during extubation, and 1, 3, 5, 10 and 30
minutes after extubation. ICU and hospital length of stay
(LOS) are also collected.
Plasma levels of epinephrine, norepinephrine, dopamine,
cortisol, NSE and S100-B are measured before infusion
(T1), two hours (T2), four hours (T3) and eight hours
(T4) after infusion and end of infusion (T5) in 20 patients
Current sample size justification
Primarily, we expect the frequency of the patients
agitation to decrease and a reduction of pain after
dexmedetomidine infusion in delayed extubation patients after
craniotomy. In our previous studies, the baseline
frequency of agitation and pain in delayed extubation
patients after craniotomy was 30% and the mean
percentage of time in optimal sedation was 88%. It is
expected that the mean percentages of time in optimal
sedation would increase to 95% after dexmedetomidine
infusion. Using the Power and Sample Size Calculation
program, we will need to study 72 experimental subjects
and 72 control subjects 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.
All analyses will be according to the intention-to-treat
principle, that is, all randomized patients will be analyzed
in the groups to which they were originally allocated and
will be blinded to treatment assignment. Baseline
characteristics will be summarized by carrying out univariate
analyses. Categorical variables will be presented as
numbers and percents, percentages, and analyzed by the
2test. Continuous variables will be checked for normal
distribution and presented as mean and standard deviation
or median and interquartile range as appropriate.
Comparison of continuous variables will be performed using
Students t-test for normally distributed variables and the
MannWhitney U test for non-normally distributed
variables. Plasma levels of epinephrine, norepinephrine,
dopamine, cortisol, NSE and S100-, and BP, HR, RR and SpO2
will be analyzed by repeated measure analysis of variance
(ANOVA). All tests of significance will be at the 5%
significance level and two-sided. Analyses will be conducted
using SPSS 17.0.
A significant difference in the safety and/or efficacy
endpoints will provide important evidence for optimizing
intracranial surgery patient sedation. Also, a neutral
result will provide important insight, as this would mean
that more studies are needed to evaluate the safety and
efficacy of dexmedetomidine for prophylactic analgesia
and sedation in patients after craniotomy.
The study has been initiated as planned in July 2012. One
interim analysis advised continuation of the trial. The
study will be completed in July 2013.
APACHE II: Acute Physiology and Chronic Health Evaluation II score;
BP: blood pressure; CNS: central nervous system; CPP: cerebral perfusion
pressure; CSF: cerebrospinal fluid; GCS: Glasgow Coma Scale; GCS-M: motor
responses to external stimuli in GCS; HR: heart rate; ICP: intracranial pressure;
LC: locus ceruleus; NSE: neuron-specific enolase; RR: respiratory rate;
SAH: subarachnoid hemorrhage; SAS: Sedation-Agitation Scale;
SpO2: peripheral oxygen saturation.
LHZ and JXZ participated in the design of the study and drafted the
manuscript. ZHS and NNY participated in the design of the study. All authors
edited the manuscript and read and approved the final manuscript.
The study was funded by Beijing Health Bureau (No: 2009-3-28). The
sponsors had no role in the study design, data collection, data analysis, data
interpretation, or writing of the report. The authors wish to acknowledge the
support of John Boyd, professor, University of British Columbia, in revising
the manuscript for important intellectual content.
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