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CTRI Number  CTRI/2012/05/002643 [Registered on: 10/05/2012] Trial Registered Retrospectively
Last Modified On: 23/06/2013
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug
Surgical/Anesthesia 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Comparative evaluation of the effect of Clonidine and Atenolol premedication on hemodynamic effects and Propofol dose requirement in patients undergoing ERCP under monitored anesthesia care: a double blind, randomized, placebo controlled study. 
Scientific Title of Study   Comparative evaluation of the effect of Clonidine and Atenolol premedication on hemodynamic effects and Propofol dose requirement in patients undergoing ERCP under monitored anesthesia care: a double blind, randomized, placebo controlled study. 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Devendra Gupta 
Designation  Associate Professor 
Affiliation  SGPGI, Lucknow 
Address  Dept of Anesthesiology, SGPGI, Rae Bareilly Road,

Lucknow
UTTAR PRADESH
226014
India 
Phone  8004904595  
Fax    
Email  dgupta@sgpgi.ac.in  
 
Details of Contact Person
Scientific Query
 
Name  Dr Devendra Gupta 
Designation  Associate Professor 
Affiliation  SGPGI, Lucknow 
Address  Dept of Anesthesiology, SGPGI, Rae Bareilly Road,

Lucknow
UTTAR PRADESH
226014
India 
Phone  8004904595  
Fax    
Email  dgupta@sgpgi.ac.in  
 
Details of Contact Person
Public Query
 
Name  Dr Devendra Gupta 
Designation  Associate Professor 
Affiliation  SGPGI, Lucknow 
Address  Dept of Anesthesiology, SGPGI, Rae Bareilly Road,

Lucknow
UTTAR PRADESH
226014
India 
Phone  8004904595  
Fax    
Email  dgupta@sgpgi.ac.in  
 
Source of Monetary or Material Support  
None 
 
Primary Sponsor  
Name  SGPGI 
Address  Rae Bareilly Road, Lucknow 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Devendra Gupta  ERCP Room; Dept of Anesthesilogy; Dept Of GAstroentrology; SGPGI  SGPGI, Rae barielly road
Lucknow
UTTAR PRADESH 
8004904595

dgupta@sgpgi.ac.in 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
SGPGI Institute Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Patients undergoing ERCP under monitored anaesthesia care at SGPGI, Lucknow 
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Atenolol 25mg  Route of administration: oral Dose 25mg single dose Half life: 6-7 hours  
Intervention  Clonidine (4 mck/kg)  Route of administration: Oral Dose 4 mcg/kg single dose Half life 12 hours  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  80.00 Year(s)
Gender  Both 
Details  > 18yrs,
Undergoing elective ERCP (diagnostic or therapeutic) under monitored anaesthesia care 
 
ExclusionCriteria 
Details  Consent not given
Patients already on Atenolol or Clonidine or on Cardiac Drugs.
Heart rate less 60 per min or Blood Pressure less than 100mgHG systolic.
Pregnant patients.
Emergency procedure.
ASA more than or equal to 4 patients
Patients requiring airway intervention or general anaesthesia.
Expected duration less than 30min or more than 2hours.
Patients with history of drug abuse or allergy to the drugs to be used.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Case Record Numbers 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
To evaluate the effectiveness of Atenolol and Clonidine premedication in preventing hemodynamic stress and myocardial injury in patients undergoing ERCP under sedation.   During procedure and 24 hours after procedure. 
 
Secondary Outcome  
Outcome  TimePoints 
1.To study the occurrence of adverse effects during ERCP.
2.To study the hemodynamic response to Buscopan administration.
3.To study the dose requirement of Propofol during the procedure and the effect of Atenolol and Clonidine premedication on it.
4.To assess the patient and operator satisfaction with procedures under sedation in our institution.
5.To evaluate the time of awakening and discharge to ward.
 
during procedure and 24 hours after the procedure 
 
Target Sample Size   Total Sample Size="114"
Sample Size from India="114" 
Phase of Trial   N/A 
Date of First Enrollment (India)   16/04/2012 
Date of First Enrollment (Global)  No Date Specified 
Estimated Duration of Trial   Years="0"
Months="4"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   under trial 
Brief Summary  

Endoscopic Retrograde Cholangio-Pancreatography (ERCP) has progressed from simple diagnostic procedures to difficult therapeutic, ones of increasing length and complexity. Anaesthesia is frequently required for greater patient comfort and operator satisfaction and demands clear understanding of the pathophysiology of the disease and the ERCP procedure itself.  Most of these procedures are performed in patients with ASA grade 3 or more. The hemodynamic stress of ERCP has been well described. Tachycardia, hypo/hypertension, ST segment changes, atrial and ventricular ectopics and fall in saturation have been seen during the procedure.[1] These changes are more common in the elderly patients; patients on whom the procedure is performed commonly. Studies have described occurrence of myocardial damage in the elderly undergoing ERCP, especially if the procedure is prolonged.[2] Butylscopolamine is commonly used to reduce gut motility and improve operating conditions. This also leads to tachycardia and ECG changes.[3] Atenolol and Clonidine have been used as premedication to provide hemodynamic stability in surgical patients.[4] They have, however, not been used in this setting. This study will assess the effect of single oral dose of Atenolol and Clonidine in patients undergoing ERCP under sedation. The incidence and prevention of myocardial ischemia in these patients will also be studied. Premedication with Atenolol or Clonidine is a simple intervention and this study proposes to highlight their effectiveness in preventing hemodynamic perturbations and myocardial injury during ERCP.

Drug Information

Clonidine

Description

Clonidine is a direct-acting α2 adrenergic agonist available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. Clonidine is available as tablets, as a transdermal patch, or as an injectable form.

Pharmacokinetics and Metabolism

Clonidine is well absorbed orally, and is nearly 100% bioavailable. It is highly lipid soluble and easily penetrates the CNS. The plasma level of Clonidine peaks in approximately 3 to 5 hours. The mean half life of the drug in plasma is about 12 hours. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.

Pharmacodynamics

Clonidine is thought to exert its hypotensive effect within the CNS by virtue of its conversion to α methyl norepinephrine, a potent α2 adrenergic agonist. It results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours.  Clonidine hydrochloride leads to a moderate reduction (15% to 20%) of cardiac output with no change in the peripheral resistance. Slowing of the pulse rate has been observed in most patients given Clonidine, but the drug does not alter normal haemodynamic response to exercise.

Indications

Clonidine has been found to be useful in the treatment of hypertension, alcohol, opiate, and nicotine withdrawal syndromes, attention-deficit/hyperactivity disorder (ADHD), and Tourette’s syndrome. In addition, Clonidine has also been used for migraine headaches and hot flashes associated with menopause.

Uses in Anaesthesia Practice

1) Anaesthetic Sparing Action

Per oral Clonidine has been shown to be an effective preanaesthetic medication to reduce anaesthetic requirement.[4] Per oral Clonidine has been shown to reduce the sleep dose of several I.V. inducing agents. The amount of opoids required for postoperative analgesia is reduced.

2) Adrenergic and Haemodynamic Stability[4]

Improved haemodynamic and adrenergic stability during surgery have been among the major advantages ascribed to Clonidine premedication. α2 agonist drugs are felt to act by reducing the overall tonic sympathetic action, while relatively preserving phasic sympathetic responses. This suggests that in situations where acute sympathetic responses are necessary, such as during sudden hypovolemia, appropriate compensatory mechanisms will be preserved. Similarly, sensitivity to boluses of vasodilator drugs is unchanged. On the other hand, Clonidine treated patients show exaggerated responses to vasopressors such as phenylephrine and ephedrine.

3) Analgesic Action

I.V. Clonidine has been shown to significantly reduce morphine requirements in relieving postoperative pain in placebo controlled double blind experiments.

4) Clonidine has been effective in decreasing secretions due to its antisialagogue effects.

5) Clonidine has been effective in attenuating the rise in intraocular pressure associated with laryngoscopy and tracheal intubation.

6) Other Effects in Anaesthesia

Clonidine 3-5µg/kg did not markedly depress the ventilator response to CO2 and did not potentiate morphine or Fentanyl induced respiratory depression. Clonidine 150 µg has also been found to effectively diminish postoperative shivering and oxygen consumption. α2 adrenergic agonists have also been used to block the occurrence of muscle rigidity after rapid administration of large doses of narcotics.

Side Effects as Premedication

The important perioperative side effects are bradycardia, hypotension and peri operative sedation. Clonidine should not be abruptly withdrawn but rather, slowly decreased over several days to avoid withdrawal symptoms. Treatment includes atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension.

 

Atenolol

Description

β-blockers are drugs that competitively and selectively block the action of catecholamines mediated via the β-receptors. Atenolol is a synthetic, β1-selective blocking agent. Atenolol is available as 25, 50 and 100 mg tablets for oral administration.

Pharmacokinetics and Metabolism

In man, absorption of an oral dose is rapid and consistent but incomplete. Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak blood levels are reached between 2-4 hours after ingestion. Atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Over 85% of an intravenous dose is excreted in urine within 24 hours compared with approximately 50% for an oral dose.

The elimination half-life of oral Atenolol is approximately 6 to 7 hours. A significant beta blocking effect of Atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours. Following oral doses of 50 mg or 100 mg, both β-blocking and antihypertensive effects persist for at least 24 hours.

Pharmacodynamics

a) Effect on Cardiovascular system: Atenolol has negative chronotopic and negative ionotropic effects which prevents the increase in heart rate, cardiac output and stroke volume along with a reduction in myocardial contractility. Atenolol, given as a single daily oral dose, is an effective antihypertensive agent providing 24-hour reduction of blood pressure.

b) Effect on Respiratory System: Blockade of β2 receptor site in the bronchi and bronchioles can lead to the development of increased airway resistance and bronchospasm. This action is very much decreased with a cardioselective β-blocker.

c) Effect on Metabolism: Atenolol can lead to an increase of plasma triglycerides and total cholesterol as well as to reduced high-density lipoprotein cholesterol values.

d) Anaesthesia and Major Surgery: It is not advisable to withdraw β-adrenoreceptor blocking drugs prior to surgery. However, care should be taken when using anaesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine.  Atenolol, like other β blockers, is a competitive inhibitor of β-receptor agonists and its effects on the heart can be reversed by administration of such agents like dobutamine or isoproterenol with caution.

Indications

Atenolol is used in the management of hypertension, angina pectoris, acute myocardial infarction and for the therapy of supraventricular and selected cases of ventricular arrythmias.

Side effect as premedication

a) Cardiovascular side effects: Atenolol can lead to bradycardia and hypotension. Abrupt cessation of chronic β-blocker therapy can lead to exacerbation of angina and in some cases sudden withdrawal may even cause myocardial infarction and death.

b) Respiratory side effects: Non-selective β-blockers like Propanolol block β2-Adrenergic receptors on the lungs and result in bronchospasm. This is less with β1-selective and those with intrinsic sympathomimetic activity.

c) Diabetes and Hypoglycemia: β blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses Atenolol does not potentiate insulin-induced hypoglycemia and does not delay recovery of blood glucose to normal levels.

 

References

1.      Kounis NG, Zavras GM, Papadaki PJ, Kouni SN, Batsolaki M, Gouvelou-Deligianni GV et al. Electrocardiographic changes in elderly patients during endoscopic retrograde cholangiopancreatography. Can J Gastroenterol. 2003 Sep;17(9):539-44.

2.      Fisher L, Fisher A, Thomson A. Cardiopulmonary complications of ERCP in older patients. Gastrointest Endosc. 2006 Jun;63(7):948-55.

3.      Christensen M, Reinert R, Rasmussen V, Schulze S, Rosenberg J. Factors that affect the variability in heart rate during endoscopic retrograde cholangiopancreatography. Eur J Surg. 2002;168(10):546-51.

4.      Gupta D, Srivastava S, Dubey RK, Prakash PS, Singh PK, Singh U. Comparative evaluation of atenolol and Clonidine premedication on cardiovascular response to nasal speculum insertion during trans-sphenoid surgery for resection of pituitary adenoma: A prospective, randomised, double-blind, controlled study. Indian J Anaesth. 2011;55(2):135–140.

 

 
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