Clinical trial NCT02964416
Conditions: Brain Neoplasm
Keywords: supratentorial craniotomy extubation response emergence tramadol
Sponsor: Aga Khan University
Start date: 2016-03-01; Completion date: 2018-12-01
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Several modalities have been studied to prevent coughing during emergence, including extubation in a deep plane of anesthesia but have proved to be unreliable. So far, no reliable method is recommended as standard of care. The advantages of administering tramadol includes a long duration of action, rapid recovery, limited depression of respiratory function and no effect on platelet makes it a safe medication to use for neurosurgical patients after craniotomy. The primary objective of the study is to observe the effect of single dose of tramadol (1mg/kg) administered 45 minutes before extubation on hemodynamic response (measurement of B.P and H.R) during extubation.

Detailed description:
Extubation after intracranial tumor surgery is desirable in order to make an early diagnosis of intracranial complications. Extubation however, may be associated with haemodynamic and metabolic changes e.g. agitation, increased oxygen consumption, catecholamine secretion, hypercapnia and systemic hypertension.

These changes cause cerebral hyperemia, intracranial hypertension leading to cerebral oedema or haemorrhage, thus it is important to have smooth extubation with minimal haemodynamic and metabolic effects.

Incidence of coughing on emergence from general anesthesia ranges from 38% to 96%. This may also result in postoperative intracranial hemorrhage, intracranial hypertension, cerebral edema or intraocular hypertension.This can be detrimental in neurosurgery.

Several modalities have been studied to prevent coughing during emergence, including extubation in a deep plane of anesthesia but have proved to be unreliable. So far, no reliable method is recommended as standard of care.

Tramadol, a synthetic opioid of the aminocyclohexanes group, is a centrally acting opioid analgesic that is used to treat moderate-to-severe pain and has an inhibitory effect on M1 and M3 muscarinic receptors. It also reduces the incidence of cough and improves extubation quality, and provides more stable haemodynamics during emergence. It neither causes respiratory depression, nor affects intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Other potential advantage of administering tramadol includes a long duration of action, rapid recovery, limited depression of respiratory function and no effect on platelets thus making it a safe medication to use for neurosurgical patients after craniotomy. The onset of effect following a single dose is 3 to 5 minutes with peak effect at 45 minutes.

Aim of doing this study is to observe the effect of a single dose of tramadol on quality of tracheal extubation as judged by incidence of coughing and haemodynamic changes at emergence from anesthesia.

OBJECTIVE:

Primary Objective: To observe the effect of single dose of tramadol (1mg/kg) administered 45 minutes before extubation on haemodynamic response (measurement of B.P and H.R) during extubation.

Secondary Objective: To measure the quality of emergence from general anaesthesia by measuring the frequency of cough, laryngospasm and episodes of desaturation.

OPERATIONAL DEFINITION:

Emergence Period: This will be defined as the time from the recovery of spontaneous breathing after giving reversal to tracheal extubation.

Quality of emergence: Good quality emergence will be defined as extubation not associated with coughing, bucking, tachycardia, hypertension, laryngospasm or bronchospasm.

Tachycardia and hypertension: Rise in heart rate and blood pressure more than 20% from baseline value.

Extubation response: Physiological response related to blood pressure and heart rate during extubation of trachea is called extubation response,

HYPOTHESIS:

Tramadol obtunds haemodynamic and cough response to extubation and thus results in good quality emergence after supratentorial craniotomy.

Arms: arm 1: Injection Tramadol 100mg diluted in 10 cc syringe (10mg/ml) to be given as 1mg/kg or (1ml/10kg) via intravenous route, once, at the time of dura closure arm 2: 0.9% Normal saline in 10 cc syringe,1ml/10kg via intravenous route, once at the time of dura closure
Interventions: intervention 1: Injection Tramadol intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: 0.9% Normal saline in 10 ml syringe

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page 
 
 
Title: Effect of single dose of tramadol on extubation response and quality of emergence 
following supratentorial intracranial surgery 
 
NCT number: NCT02964416 
 
Date of document: April 5 2016 
 
ERC: 2954- Ane- ERC-14  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol:  
Extubation after intracranial tumor surgery is desirable in order to make an early 
diagnosis of intracranial complications. Extubation however, may be associated with 
hemodynamic and metabolic changes e.g. agitation, increased oxygen consumption, 
catecholamine secretion, hypercapnia and systemic hypertension (1).  These changes 
cause cerebral hyperemia, intracranial hypertension leading to cerebral oedema or 
haemorrhage, thus it is important to have smooth extubation with minimal haemodyamic 
and metabolic effects. 
 
Incidence of coughing on emergence from general anesthesia ranges from 38% to 96%(2) 
This may also result in postoperative intracranial hemorrhage, intracranial hypertension, 
cerebral edema or intraocular hypertension (2). This can be detrimental in neurosurgery. 
 
Several modalities have been studied to prevent coughing during emergence, including 
extubation in a deep plane of anesthesia (3, 4) but have proved to be unreliable. So far, no 
reliable method is recommended as standard of care. 
Tramadol, a synthetic opioid of the aminocyclohexanol group, is a centrally acting opioid 
analgesic that is used to treat moderate-to-severe pain and has an inhibitory effect on M1 
and M3 muscarinic receptors. It also reduces the incidence of cough and improves 
extubation quality, and provides more stable hemodynamics during emergence (2). It 
neither causes respiratory depression, nor affects intracranial pressure (ICP) and cerebral 
perfusion pressure (CPP) (5). Other potential advantage of administering tramadol 
includes a long duration of action, rapid recovery, limited depression of respiratory 
function (6) and no effect on platelets (7) thus making it a safe medication to use for 
neurosurgical patients after craniotomy. The onset of effect following a single dose is 3 to 
5 minutes with peak effect at 45 minutes (8).  
 
Aim of doing this study is to observe the effect of a single dose of tramadol on quality of 
tracheal extubation as judged by incidence of coughing and hemodynamic changes at 
emergence from anesthesia. 
 
Methodology:  
 
This double-blind randomized controlled trial will be conducted over a period of two 
years, 2016 and 2017. A total of 80 patients will be recruited in the study after permission 
from the Ethics Review Committee of hospital. Power calculation will be based on 
hemodynamic response. Thirty-four subjects in each group will be recruited to achieve 
80% power to detect an absolute difference i.e. 10 mmHg and standard deviation of 10-
15 mmHg with 5% type I error. We plan to recruit 80 patients, to account for a 15% 
dropout rate.  Sample size estimation is based on a previous study (3).  
Patients will be recruited in the study during the preoperative anesthesia evaluation either 
at the preoperative clinic or after admission to the ward. After taking informed written 
consent, each medical record number will be sent to the Clinical Trials Unit (CTU), along 
with their expected date, day and timing of surgery. The CTU will randomly allocate the 
patients to one of the two groups, based on computer-generated allocation. After the 


patient will reach the preoperative area in the operating room (OR) an e-mail request will 
be generated to the CTU who would release the prepared study drug syringe and will 
send it to the principal investigator (PI). The syringe will contain either tramadol (volume 
10mg/ml in a 10 ml syringe) or placebo 0.9% normal saline in the same volume. Drugs 
for both groups will look alike so that patient, investigator, anesthetist administering the 
drugs or those making observations are all be blinded.  
Intraoperatively 
anesthesia 
care 
will 
be 
standardized. 
After 
application 
of 
electrocardiography (ECG), non-invasive blood pressure (NIBP) monitor and pulse 
oximeter, baseline heart rate (HR), invasive blood pressure (BP) and oxygen saturation 
(SpO2) will be recorded. Preoxygenation will be done for 3minutes with oxygen 
administered at a rate of 5 l/min via a breathing circuit. Anesthesia induction will be done 
with propofol (2 mg/kg) intravenously (IV) and fentanyl (2 μg/kg) IV followed by 
atracurium (0.6mg/kg) IV. Maintenance of anesthesia will be achieved with oxygen (O2), 
nitrous oxide (N2O) in 1:2 ratio, isoflurane (0.8–1%) and atracurium infusion (0.4 
mg/kg/hr-). Ventilation will be set at 8 ml/kg, volume controlled mode and respiratory 
rate adjusted to achieve a level of end-tidal carbon dioxide (ETCO2) of 29–30 mmHg. 
An arterial line will be inserted in radial artery for continuous invasive blood pressure 
monitoring, ECG, SpO2, capnography, inspiratory and expiratory concentrations of 
isoflurane minimum alveolar concentration (MAC) and N2O percentage, as well as 
neuromuscular block, will continuously be monitored. Paracetamol 1 gram will be 
infused over 20 min in all patients after induction. Top up fentanyl 20 μg boluses will be 
administered if either the patient’s HR or BP increased to 20 % above baseline and when 
other causes of tachycardia and hypertension are excluded. Atracurium infusion will be 
stopped 20 min before the end of surgery. Injection metoclopramide 10mg will be given 
in all patients at the time of closure of dura. 
Study drug (tramadol 1mg/kg or normal saline bolus) will be administered to the patients 
by the anesthetist 45 min before extubation i.e. approximately at the time of dural 
closure. Reversal of residual muscle relaxation will be achieved with neostigmine 
(0.05mg/kg) and glycopyrrolate (0.01mg/kg) intravenously and time will be noted when 
the patient will start breathing spontaneously. Patients will be extubated after resumption 
of adequate spontaneous breathing, following verbal commands and with stable vital 
signs. 
BP and HR will be recorded continuously from the arterial line, at 1 min before 
administration of  reversal drugs till 5 minutes after extubation, then intermittently at 10 
min interval for 30 min. Readings at 1, 2, 4 and 6 hours will be recorded postoperatively 
using noninvasive methods (CARESCAPE Monitor B650, GE Healthcare Ltd, Finland). 
Intravenous metoprolol 1mg bolus will be administered when hemodynamic values of BP 
and HR rose more than 20% from baseline values. 
Cough will be recorded as either “yes” or “no” at the following time points:  resumption 
of spontaneous breathing, when patients were able to respond to verbal commands, at the 
time of cuff deflation, at extubation and 2 min after extubation. Quality of tracheal 
extubation will be evaluated using a modified 5-point rating scale at the above-mentioned 
intervals, (5 = no coughing or straining; 4 = very smooth or minimal coughing; 3 = 
moderate coughing; 2 = marked coughing or straining; and 1 = poor extubation). [3]   
Any episode of bronchospasm, laryngospasm, or desaturation (oxygen saturation<92%) 
will also be noted during emergence and till 6 hours postoperatively. Sedation, PONV, 


any episode of convulsions and drop in GCS will also be noted at 2, 4 and 6 h 
postoperatively as secondary outcomes of quality of emergence. The study will end at 6 
hours post-extubation. 
Pain will be assessed for 6 h postoperatively using verbal rating scale (VRS) with 0 = no 
pain and 10 = worst pain. Sedation will be assessed as 0=no sedation, 1= mild sedation 
(eye-opening on verbal commands), 2= moderate sedation (eye-opening on painful 
stimulus), 3= deep sedation (not waking up on pain). All patients will be prescribed 
paracetamol one gram IV six hourly and tramadol 50mg IV as rescue analgesia in the 
first 6 hours post operatively. Anti- emetic prophylaxis will be given with each dose of 
tramadol.  
 
Statistical Analysis Plan:  
 
Statistical analysis will be performed using Statistical Packages for Social Science 
version 19 (SPSS Inc., Chicago, IL). Quantitative point estimate will be presented as 
mean and standard deviation and analysis by independent sample t-test and Mann-
Whitney U test after normality testing by Kolmogorov Smirnov test. Qualitative point 
estimates will be reported in term of frequency and percentage and analyzed by the chi-
square test or fisher exact test. Repeated measure ANOVA will be applied to compare 
mean, SBP, DBP and HR between groups (within/between subject effect).  P ≤ 0.05 will 
be considered significant. 
Data will be saved at primary investigator. Investigator will permit trial-related 
monitoring, audits and regulatory inspection by providing direct access to data. Decoding 
of the drugs will be done once the study is completed 
 
References: 
 
1. 
Mikawa K, Nishina K, Maekawa N, Obara H. Attenuation of cardiovascular 
responses to tracheal extubation: verapamil versus diltiazem. Anesth Analg. 
1996;82(6):1205-10. 
 
2. 
Lin BF, Ju DT, Cherng CH, Hung NK, Yeh CC, Chan SM, et al. Comparison 
between intraoperative fentanyl and tramadol to improve quality of emergence. Journal of 
neurosurgical anesthesiology. 2012;24(2):127-32. 
 
3. 
Valley RD, Ramza JT, Calhoun P, Freid EB, Bailey AG, Kopp VJ, et al. Tracheal 
extubation of deeply anesthetized pediatric patients: a comparison of isoflurane and 
sevoflurane. Anesth Analg. 1999;88(4):742-5. 
 
4. 
Neelakanta G, Miller J. Minimum alveolar concentration of isoflurane for tracheal 
extubation in deeply anesthetized children. Anesthesiology. 1994;80(4):811-3. 
 
5. 
Ferber J, Juniewicz H, Glogowska E, Wronski J, Abraszko R, Mierzwa J. 
Tramadol for postoperative analgesia in intracranial surgery. Its effect on ICP and CPP. 
Neurologia i neurochirurgia polska. 2000;34(6 Suppl):70-9. 
 


6. 
Sudheer PS, Logan SW, Terblanche C, Ateleanu B, Hall JE. Comparison of the 
analgesic efficacy and respiratory effects of morphine, tramadol and codeine after 
craniotomy. Anaesthesia. 2007;62(6):555-60. 
 
7. 
Rahimi SY, Alleyne CH, Vernier E, Witcher MR, Vender JR. Postoperative pain 
management with tramadol after craniotomy: evaluation and cost analysis. Journal of 
neurosurgery. 2010;112(2):268-72. 
 
8. 
Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after i.m. injection in 
comparison to i.v. infusion. International journal of clinical pharmacology and 
therapeutics. 1999;37(4):175-83.