Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02033629 |
| Other study ID # |
Anesth-JAN14 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 2014 |
| Est. completion date |
May 15, 2019 |
Study information
| Verified date |
March 2019 |
| Source |
Dammam University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The development of target effect-site controlled concentrations (TCI) of remifentanil have
gained increasing acceptance during cardiac surgery as regarding the resulting of hemodynamic
stability and early extubation. The use of low-dose opioid technique has been progressively
used nowadays because of its ceiling effect to attenuate cardiovascular responses to noxious
stimuli. We hypothesize that the use of low target remifentanil effect site concentrations
may provide comparable shorter times to tracheal extubation and hemodynamic stability to the
use of high remifentanil Ce during target-controlled propofol anesthesia for cardiac surgery.
Description:
Reducing the time to tracheal extubation and hence the duration of postoperative mechanical
ventilation could lessen postoperative complications, improve patients' outcome, shorten the
intensive care unit (ICU) stay, and reduce the cost of treatment.
Although high-dose opioid cardiac anesthesia has been shown to provide hemodynamic stability
and adequate depth of anesthesia in response to nociceptive stimulation, it may cause delayed
recovery and lengthening of the durations for postoperative ventilation support and (ICU
length of stay.
The pharmacokinetic-based drug infusion systems, target-controlled infusion (TCI), can
rapidly and easily enables changes and maintenance of a constant blood concentration of
intravenous anesthetic drugs. We demonstrated that, the use of a TCI of sufentanil at
effect-site concentrations (Ce) from 0.2 to 0.3 ng/mL during TCI of propofol anesthesia for
valve surgery shortened the times to clinical recovery and extubation.
Remifentanil, a short-acting opioid-receptor agonist with a context-sensitive half-time of 3
to 5 minutes allowing rapid emergence from anesthesia, even after an infusion of several
hours. Compared with sufentanil (0.03 to 0.04 µg/kg/min), the use of remifentanil (0.5 to 1.0
µg/kg/min) during propofol anesthesia improved recovery of pulmonary function and shortened
postoperative hospital length of stay after coronary artery bypass grafting (CABG).
Furthermore, a TCI of remifentanil at Ce of 1.5-5.0 ng/ml is more effective than a
constant-rate infusion in the inhibition of the stress response and the maintenance of the
cardiac autonomic nervous system balance during off-pump CABG. Similarly, the lowest
remifentanil Ce used in another study of explicit and implicit memory during cardiac surgery
under TCI propofol were 2 to 4 ng/ml.
Whereas, others used a wide range of remifentanil Ce from 2 to 10 ng/ml. However, the use of
higher remifentanil Ce of 7 ng/ml (equivalent to 0.3 ng/kg/min) was associated with longer
time to extubation than sufentanil Ce of 0.3 ng/ml (256 (92) vs. 161.9 (32.9) min,
respectively).This precludes the favorable unique pharmacokinetic characteristics of
remifentanil . Thus the use of low target controlled infusions of remifentanil could allow
faster time to extubation and reduce the overall cost of the anesthetics.
We hypothesize that using low remifentanil target-controlled Ce during TCI of propofol
anesthesia for cardiac surgery could decrease the time to tracheal extubation.
The subjects will be allocated randomly into the 3 groups by drawing sequentially numbered
sealed opaque envelopes that each contained a software-generated randomization code.
The patients will be monitored by a pulse oximeter, 5-lead electrocardiograph (leads II and
V5) with continuous ST-segment recording, radial mean arterial blood pressure (MAP)
measurements, end-tidal carbon dioxide measurements, a central venous catheter or pulmonary
artery catheter (according to the discretion of the attending anesthesiologist), and rectal
and nasopharyngeal temperature measurements. Significant ischemic responses defined as
reversible ST-segment changes from baseline, namely a ≥1-mV ST-segment depression or a ≥2-mV
ST segment elevation that lasted for ≥1 minute. Response entropy (RE) and state entropy (SE)
will be monitored by applying entropy electrodes (Datex-Ohmeda Division, Instrumentarium
Corporation, Helsinki, Finland) according to the manufacturer's recommendations.
An independent anesthesiologist who is not involved in collecting patient data will initiate
the remifentanil Ce (the model of Minto et al) according to the patient's randomization code
and is allowed to titrate the target propofol and remifentanil Ce and to administer
vasoactive medications as needed. After preoxygenation, anesthesia induction by simultaneous
target propofol and remifentanil infusions using the TCI system with syringe pumps
(Injectomat TIVA Agilia, Fresenius Kabi, France).
The target propofol Ce (model of Schnider et al 13) will be initiated at 1.0 µg/mL and
titrated stepwise by 0.5 µg/mL every 3 minutes until loss of consciousness and until an SE
<50 and a difference <10 between RE and SE (RE-SE) will be achieved. Cisatracurium, 0.2
mg/kg, will be given to facilitate tracheal intubation, and the lungs will ventilated with a
fraction of inspired oxygen of 0.5 to maintain normocapnia. The time from induction to
intubation will be recorded.
Anesthesia will be maintained by changing the propofol Ce at increments of 0.5 µg/mL (range,
1-4.5 µg/mL) every 3 minutes as necessary to maintain an SE <50, RE-SE difference <10, and
MAP and heart rate (HR) that are ≤20% of the baseline values. The remifentanil Ce will be
increased by a maximum of 3 increments of 0.5 ng/mL when the SE is >50, the RE-SE difference
is >10, and the MAP and HR are ≥20% of the baseline values despite a target propofol Ce >4.5
µg/mL. When the SE is <50 and the RE-SE difference is <10, the propofol Ce will be decreased
gradually to ≥1 µg/mL, followed by gradual decreases in remifentanil Ce by 0.5 ng/mL, until
the randomized Ce will be achieved. Based on our pilot study, the authors considered that
using 0.5-ng/mL increments in remifentanil Ce would obtund the entropy and hemodynamic
responses to noxious stimuli. The authors expected that 4 remifentanil Ce increments of 0.5
ng/mL would double the infusion rate in the Ce 1-ng/mL group to 2 ng/mL ([0.5 ng/mL x 4] + 1
ng/mL). The HR and MAP will kept within 20% of baseline values by achieving an adequate depth
of anesthesia (SE <50 and RE-SE difference <10), optimum analgesia, and the administration of
nitroglycerin, 0.05 mg, and esmolol, 20 mg. Cisatracurium, 1 to 3 µg/kg/min, was used to
maintain surgical relaxation. All patients will receive tranexamic acid, 50 mg/kg.
Light anesthesia is defined as an episode with SE values >50 and/or MAP and HR values >20%
above baseline that lasted for >3 consecutive minutes. The incidences of light anesthesia in
response to intubation, skin incision, sternotomy, maximal sternal spread, and sternal wire
placement will be recorded.
Hemodynamic control will be standardized according to the authors' protocol. Hypotension
(defined as >20% decrease in mean baseline MAP) will be treated with boluses of fluids,
phenylephrine 200 µg, ephedrine 5 mg, or epinephrine, 5 µg, as needed. Hypertension (defined
as >20% increase in mean baseline MAP) will be treated by deepening anesthesia and
administering doses of nitroglycerin, 0.05 mg, or labetalol, 20 mg. Tachycardia (defined as
>20% increase in mean baseline HR) will be treated with esmolol, 20 mg.
All operations will be performed by the same surgeons. Heparin, 300 IU/kg, will be given to
achieve an activated coagulation time >480 seconds. A standardized hypothermic
cardiopulmonary bypass (CPB) will be used. The target propofol Ce and remifentanil Ce will be
continued throughout surgery and CPB without any further adjustments because of CPB per se.
Before separation from CPB, all patients will be rewarmed to a rectal temperature of 36°C and
dobutamine, epinephrine, norepinephrine, and nitroglycerin will be used as needed. Heparin
will be neutralized with protamine sulfate.
The cisatracurium infusion will be discontinued and morphine 0.1 mg/kg will be administered
intravenously after surgical homeostasis is achieved. The target remifentanil Ce and propofol
Ce will be discontinued after skin closure.
The HR, MAP, and cardiac and systemic vascular resistance indices will be recorded before
(baseline) and 15 minutes after endotracheal intubation, 15 minutes after skin incision, 15
minutes after sternotomy, and 15 and 45 minutes after discontinuing CPB. Patients will be
transferred to the intensive care unit (ICU) in a ventilated state using the synchronized
intermittent mandatory mode or the pressure support mode.
Postoperative analgesia will be provided by intravenous paracetamol, lornoxicam, and
patient-controlled analgesia (PCA), morphine 1 mg, with a lockout interval of 8 minutes and a
maximum 4-hourly limit of 30 mg.
Extubation criteria included alertness, a train-of-four ratio ≥0.9, spontaneous breathing
with a tidal volume >5 mL/kg, respiratory rates >10 and <28 breaths/min, a maximum
inspiratory pressure ≤-20 cm H2O, stable hemodynamics without high doses of inotropic support
or severe arrhythmias, bleeding <100 mL/h, a core temperature >35.5°C, a urine output >0.5
mL/ kg/h, an arterial carbon dioxide tension ≤45 mmHg, an arterial oxygen tension >100 mmHg,
and a fraction of inspired oxygen <0.5. Blood samples will be drawn before CPB and 3, 12, 24,
and 48 hours after CPB to measure cardiac troponin I levels.
Intraoperative explicit awareness will be assessed on the second postoperative day by asking
the patients 3 simple questions in a standard interview: What was the last thing you remember
happening before you went to sleep? What is the first thing you remember happening on waking?
Did you dream or have any other experiences while you were asleep?
An independent investigator blinded to the study groups who is not involved in the patients'
management will collect the patient data.
Sample size calculation:
A priori power analysis of the published data showed that the normally distributed mean time
to tracheal extubation after remifentanil, 7 ng/mL, was 256 minutes (SD, 92 min). An a priori
power analysis indicated that a sample size of 23 for each group was sufficiently large to
detect 35% changes in the time to extubation after the administration of remifentanil Ce, 7
ng/mL, with a type-I error of 0.017 (0.05/3 possible comparisons) and a power of 90%. This
sample size was increased by 10% to compensate for patients dropping out during the study.
In view of our amending our protocol on 2015 to compare the low remifentanil Ce 1, 2, and 3
ng/ml rather than the earlier considered 3 higher concentrations (2, 5, and 7 ng/ml) because
of the noted significant haemodynamic compromise that required high use of
inotropes/vasopressors, this earlier considered sample size calculation can not be valid
anymore. Thus we recruited cases in a pilot study.
A pilot study showed that the normally distributed mean time to tracheal extubation after
remifentanil, 3 ng/mL, was 39 minutes (SD, 14.92 min). An a priori power analysis indicated
that a sample size of 21 for each group was sufficiently large to detect 15 min difference in
the time to extubation after the administration of remifentanil Ce, 3 ng/mL, with a type-I
error of 0.017 (0.05/3 possible comparisons) and a power of 90%. This sample size was
increased by 10% to account for patients dropping out during the study.
Statistical Analysis
The data will be tested for normality using the Kolmogorov-Smirnov test. Repeated-measures
analysis of variance will be used to analyze serial changes in the patient data at different
times. The Fisher exact test will be used for categorical data. Repeated measures analysis of
variance (ANOVA) will be used for continuous parametric variables and the differences will be
corrected by the post hoc Bonferroni test. The Kruskal-Wallis test will be performed for
intergroup comparisons for nonparametric values and post hoc pairwise comparisons were
performed using the Wilcoxon rank-sum t test. The data will expressed as means (SD), number
(percentage), or median [range]. A p value <0.05 is considered to represent statistical
significance.
