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Effect of Oral Clonidine Premedication in Patients Undergoing Laparoscopic Surgery
Sunita Goel, Manju Sinha
 

Abstract
Laparoscopic surgery presents several challenges for the anaesthesiologist. The patient position required as well as the establishement of pneumoperitoneum has significant effects on the haemodynamics. Maximal haemodynamic changes are observed with the pneumoperitoneum and the patients in the Trendelenburg position.
In the last decade, the adrenergic alpha 2 agonist clonidine is being reconsidered for its sedative, analgesic, anaesthetic sparing effect, prolonging analgesic and motor blockade in clinical anaesthesiology, in addition to its classical antihypertensive and sympatholytic actions.
In our prospective, double blind controlled study of 100 patients of ASA grade I and II, we used oral clonidine as a premedicant. Patients were randomly assigned to two groups. One group received tablet clonidine 100 mg orally one hour prior surgery and the other group received placebo. All the patients were compared for their haemodynamic status intraoperatively and underwent major gynaecologic laparoscopic surgery.

 

Introduction

Clonidine can be used for premedication because it modulates haemodynamic changes during anaesthesia induction, both during and after surgery, improves myocardial perfusion during surgery, and decreases requirements for volatile anaesthetics and opioids during surgery.

Methods

We conducted a prospective double blind study of 100 patients of ASA I and II with written informed consent and approval of the Local Ethics Committee. All the patients underwent major laparoscopic surgery. The patients were divided in 2 groups of 50 patients each, one group was premedicated with 100 mg clonidine and the other group with a placebo. Preoperatively the patients were kept on liquid diet for 2 days and nil by mouth for the last 6-8 hours prior to surgery. No enema was given to any patient. All patients were premedicated orally with ranitidine 150 mg, metoclopramide 10 mg and with clonidine 100 mg or a placebo an hour prior to be taken for surgery.

Induction agent used was propofol 2 mg/kg and the muscle relaxant used was atracurium 0.8 mg/kg. Dexamethasone 4 mg was given i.v. during induction. Patients were intubated with 7.5 mm Portex endotracheal tube. Analgesics used for the surgery were fentanyl 2 mg/kg, pentazocine 30 mg intraoperatively and tramadol 100 mg post operatively in every patient. Diclofenac suppository 100 mg was inserted in all patients. Every patient was given 8 mg ondansetron along with neostigmine 0.05 mg/kg with glycopyrrolate 0.004 mg/kg for reversal. Anaesthesia was maintained by nitrous oxide in oxygen 50:50 with isoflurane as the inhalational agent (MAC 1).

We aimed to maintain a pulse rate of 60-70 beats/min and a systolic pressure of 110-120 mmHg and diastolic pressure of 70-80 mmHg by using beta-blockers or propofol intraoperatively.

Insufflation pressures, intraabdominal (intraperitoneal) with the Verres needle were kept at 20 mmHg till the insertion of the first port (blind port) and later reduced to 15 mmHg, which was maintained till the end of surgery.

Monitoring was done by pulse oximetry (SPO2), non-invasive blood pressure (NIBP), end tidal CO2 (ETCO2), temperature monitoring, agent monitor, NMT monitor, and spirometry with pressure and flow volume loops. (Datex Ohmeda Aestiva 7900 anaesthesia machine and Ohmeda Cardiocap 5 Monitor).

Exclusion criteria: Patients excluded from the study were diabetics and hypertensives and those with contraindications to the use of NSAIDs.

Material and Methods
Since Torchnil gave good results in RPL due to TORCH infections, we wanted to ascertain the antiviral activity of the individual herbs used in Cap. Torchnil. An assessment was done in vitro HIV culture for their reverse transcriptase and P24 inhibitory activity as compared to respective controls AZT and lamivudine.

The anti-HIV activity screening of the medicinal plants has been carried out by estimating virus-associated p24 antigen in the presence and absence of the plant extracts. The HIV was grown in HIV sensitive T cell lymphoma culture (H9 cell culture) and p24 is core antigen of HIV which can be used as one of the replication markers. The p24 inhibition was studied using p24 capture ELISA.6-8 The estimation of p24 was done with the help of p24 Capture ELISA kit purchased from ‘Zeptomatrix’. The assay was done in triplicates. With this we quantitated the virus associated p24 antigen in the presence and absence of the extracts and analyzed per cent inhibition.

Other screening assay performed was the Reverse Transcriptase (RT) inhibition in the presence and absence of the plant extracts. RT enzyme of HIV is the important unique enzyme, which performs the important part in HIV replication. The genes for HIV-RT, which are responsible for the drug resistance, undergo frequent mutations. During the HIV replication, HIV-RT uses HIV-RNA as a template for forming the complimentary DNA (cDNA) strand. The HIT-RT inhibition assay is based on the quantitation of the uptake of radio-labelled Thymidine in the cDNA. These individual plants were also studied for anti-HIV activity in vitro, which is assessed by testing inhibition of HIV 1 reverse transcriptase.9 These studies were carried out at Haffkin Institute for Training, Research and Testing, Mumbai.

Post market multicentric clinical research study of Torchnil in RPL

Mode of administration in patients: In all cases of RPL it is administered at a dose of one capsule twice daily during the pre conception period for three to six months followed by administration in same dose throughout pregnancy. Post marketing research of Cap. Torchnil has been done to find out its effectiveness and safety. This study covered the obstetricians in few cities in Maharashtra, viz. Mumbai, Navi Mumbai, Nashik and Nanded etc. Those obstetricians treating their RPL patients with Cap. Torchnil were given a common questionnaire and were requested to fill the same at their convenient time. 124 Doctors responded to the questionnaire. Qualifications of these practitioners are as following, MD (Ob and Gyn) 110; MBBS, DGO 5; MBBS, 7 and Ayurvedic practitioners, 2 (as given in Table 1).

Fig. 1
Fig. 2
Fig. 3

Results

The demographic data was comparable in both the groups as regarding to age, sex and weight of the patient. All patients were operated for major gynaecologic laparoscopic surgery like myomectomy or total laparoscopic hysterectomy. The average duration of surgery was 80 ± 24.36 mins in both the groups.
We observed that both the groups had parameters comparable at admission.
The clonidine group had statistically significant ‘P’< 0.005 low pulse rate, systolic and diastolic blood pressure on induction and 5, 10 mins post gas insufflation.
The haemodynamics at 30 mins, 60 mins and at extubation were almost comparable (Figs. 1, 2, and 3) (Table 1).


Discussion

Clonidine1 a centrally acting a-2 adrenergic agonist, was first introduced into clinical practice as an antihypertensive medication. The drug has been recently used for anaesthetic premedication,2 providing sedative, anxiolytic, and analgesic effects.

Clonidine attenuates hypertension,3 tachycardia, and norepinephrine release in response to stress induced by anaesthetic and surgical procedures, hence clonidine premedication may prevent perioperative myocardial ischaemia4 by improving myocardial oxygen balance.

Oral clonidine5 is well absorbed and used completely in the body. The pharmacological effect of clonidine appears in 1.5- 2 hours, with the peak level in 3 hours. The half life is approximately 8.5 ± 0.9 hours.

Clonidine is highly lipid soluble6 and easily crosses the blood brain barrier, interacting with alpha-adrenergic receptors at the spinal and supraspinal sites. Clonidine also causes a reduction of tonic sympathetic outflow and depression of blood pressure and heart rate.

Oral clonidine premmedication decreases the release of proinflammatory7 cytokines interleukin (IL) - 6, IL - 1b, and tumour necrosis factor–a, and stress hormones cortisol and adrenocorticotrophic hormone (ACTH).

Clonidine effects however, are not limited to the preoperative period. Clonidine has potent analgesic8,9 properties that reduce the MAC of volatile anaesthetics. It also decreases the requirement for IV anaesthetics and narcotics, as well as the requirement for volatile anaesthetics for surgery. Recovery from general anaesthesia is governed by pharmacodynamic and pharmacokinetic factors. Oral clonidine might delay recovery from anaesthesia.

Hypertension and tachycardia,3 accompanied by increased sympathetic nervous system activity, may lead to an imbalance between myocardial oxygen demand and supply.

The cardiovascular changes10 associated with laparoscopy, is an increase in systemic vascular resistance (SVR), mean arterial blood pressure (MAP) and myocardial filling pressures, accompanied by a fall in the cardiac index (CI). Catecholamine surges might reasonably be expected to cause an increase in SVR and MAP. Increasing intra-abdominal pressure from 10 mmHg to 20 mmHg is associated with a rise in norepinephrine and epinephrine secretion. The increase in SVR is not only related to mechanical factors as it outlasts the end of pneumoperitoneum. The humoral factors like catecholamines, prostaglandins, the renin- angiotensin system, especially vasopressin are potential mediators.

In our study, we have orally premedicated our patients with 100 mg clonidine. Table 1 shows the haemodynamic changes following premedication with clonidine. There is a significant fall in pulse rate in clonidine group at zero 5, 10 as compared to baseline (P < 0.05) which was not seen in the control group. There was a significant fall in the systolic blood pressure in the clonidine group and inter group comparison was significant (P > 0.05).

The haemodynamics were comparable at 30, 60 mins and at extubation of both the groups. Forty patients of the non- clonidine group required esmolol or propofol as infusion, intraoperatively to maintain the pressures within the constraints of the aim of the study. We administered a bolus dose of inj. esmolol 0.5 mg/kg over 30 seconds followed by an infusion of 200 mg/kg/min to stabilize the haemodynamics. The infusion of propofol was 3 mg/kg/hr. We did administer a bolus of esmolol 0.5 mg/kg for 2 patients in the clonidine group.

We had to administer glycopyrrolate 0.2 mg for 3 patients when there was bradycardia of 50/min or below in the clonidine group.

We observed that the anxiolysis in the clonidine group was better than in the placebo group.

The number of analgesics required in the placebo group was also higher than in the clonidine group, 20 of them were given ketorolac 30 mg, 10 were given hyocine 10 mg and midazolam 1 mg and 7 were given both of them, as an additional analgesic and anxiolytic post surgery. In contrast to 5 patients in the clonidine group who received ketorolac 30 mg.

We conclude that oral clonidine premedication provides a distinct advantage because of

  • Sedating properties
  • Decreased pressor response to laparoscopy and pneumoperitoneum
  • Maintenance of haemodynamic parameters
  • Analgesia sparing effect
  • Anxiolytic effect
  • No side effects other than bradycardia was observed which was easily treatable.
The only limitation is that it cannot be applied to patients presenting for emergency surgery.

We recommend the use of oral clonidine premedication for operative gynaecological laparoscopic surgeries.

References

  1. Kamibayashi T, Maze M. Clinical uses of a2- adrenergic agonists. Anesthesiology 2000; 93 : 1345-9.
  2. Higushi H, Adachi Y, Arimura S et al. Oral clonidine premedication reduces the awakening concentration of propofol. Anesth Analg 2002; 94 : 609-14.
  3. Nishina K, Mikawa K, Uesugi T et al. Efficacy of clonidine for prevention of perioperative myocardial ischaemia. Anesthesiology 2002; 96: vol 2.
  4. Ghignone M, Calvillo O, Quintin L. Anesthesia and hypertension: the effect of clonidine on perioperative hmodynamics an isoflurane requirements. Anesthesiology 1987; 67 : 3-10.
  5. Anaveka SN, Jarrot B, Toscano M, Loius WJ. Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects. Eur J Clinical Pharmacol 1982; 23 : 1147-52.
  6. Streibel HW, Koenigs D, Heil T. The role of clonidine in anesthesia. Anaesthetist 1993; Mar 42 : 3,131-41.
  7. Kim MH, Hahn TH. The effects of clonidine pretreatment on the peri-operative proinflammatory cytokines, cortisol, and ACTH responses in patients undergoing total abdominal hysterectomy. Anesth Analg 2000; 90 : 1441-4.
  8. Ghignone M, Quintin L, Duke PC, et al. Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology 1986; 64 : 36-42.
  9. Tanaka M, Nishikawa T. Effects of clonidine premedication on the pressor response to a adrenergic agonists. Br J Anaesth 1995; 75 : 593-7.
  10. Malley C, Cunningham AJ. Physiologic changes during Laparoscopy. Anesthesiology Clinics of North America. March 2001. Vol 19: Number 1.
 
 

ROUTINE USE OF IBUPROFEN AFTER HIP REPLACEMENT IS NOT JUSTIFIED

Routine postoperative ibuprofen as prophylaxis for ectopic bone formation after hip replacement surgery has no significant clinical benefits 6 to 12 months after surgery. Fransen and colleagues randomised 902 patients undergoing elective primary or revision total hip replacement surgery to 14 days’ treatment with ibuprofen (1200 mg daily) or matching placebo started within 24 hours of surgery. Despite a decreased risk of ectopic bone formation, ibuprofen made no significant difference to improvements in hip pain or physical function. It did, however, increase the risk of major bleeding complications.

BMJ, 2006; 333 : 519.

 
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