The effect of pre-operative intravenous clonidine infusion on patient hemodynamics in those undergoing laparoscopic cholecystectomy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.148840
Context: Laparoscopic cholecystectomy is one of the most common laparoscopic procedures done. Laparoscopy involves pneumoperitoneum and its subsequent effects. It involves changes in cardiorespiratory system. Earlier studies have documented usefulness of Clonidine in this context. Aims: (1) Evaluation of hemodynamic changes in patients undergoing laparoscopic cholecystectomy receiving pre-operative clonidine infusion. (2) Effect of intravenous clonidine on post-operative analgesia measured in time duration for first rescue analgesic. Settings and Design: This was a prospective, randomized, double blind study. It was conducted at a single specialty high volume tertiary care center. Subjects and Methods: The study took place at a tertiary specialty institute from July 2012 to September 2012. It involved 60 cases randomized into 2 groups by simple randomization. Statistical Analysis Used: The statistical analysis for the inter group hemodynamic parameters and numerical data was done using paired t-test, while categorical data was analyzed by Chi-square test. P ≤ 0.005 was considered to be significant. Results: Clonidine group of patients had significantly lower systolic, diastolic and mean arterial blood pressures with significantly lower heart rate and also statistically significant prolongation of post-operative analgesia and sedation. Conclusions: Clonidine pre-operatively given as infusion in dose of 4 mcg/kg in laparoscopic surgeries, provides a stable hemodynamic state with minimal additional drug requirement and good post-operative analgesia. Keywords: Analgesia, clonidine, laparoscopy, pneumoperitoneum
Laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum is followed in many centers and such cases are usually treated on day care basis. Pneumoperitoneum alters homeostasis with changes in cardiovascular, pulmonary and stress response. Cardiovascular alterations include increase in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MABP). [1] These effects are primarily due to hypercarbia leading to sympathetic overdrive, release of catecholamines, cortisol, renin-angiotensin-aldosterone and vasopressin, in turn causing increase in systemic vascular resistance (SVR) and pulmonary vascular resistance and hence hemodynamic instability. [2] Furthermore, the reverse trendelenburg position used for cholecystectomy further alters baroreceptor mechanism leading to high blood pressures. Clonidine, an alpha 2 agonist has previously been tried orally as a pre-medicant in laparoscopic cholecystectomy surgeries as it inhibits the central sympathetic outflow, thus decreasing HR and blood pressure due to reduction in SVR and cardiac output. Clonidine sensitizes brainstem vasomotor center to inhibition by baroreflexes and also blunts stress response to surgical stimuli. This may help to reduce the narcotic and anesthetic dose. [3] This study intends the use of intravenous clonidine infusion pre-operatively in a dose of 4 μg/kg. The objectives of the study were as follows:
With institutional review board approval and after informed consent of the patients, 60 patients were included in the study to the effect so that the power of the study could be more than 80%. Patients were grouped as, group C receiving injection clonidine intravenous infusion 4 μg/kg in 50 ml NS over 15 min in recovery room under observation while group P received NS intravenous infusion 50 ml over 15 min. The inclusion criteria for the study were: American Society of Anesthesiologists (ASA) grade I and II patients, adults aged 18-50 years, both males and females, body mass index (BMI) between 20 and 30. Patients with cardiorespiratory disease, hypertension, ischemic heart disease, mental depression or any medication that might interfere with clonidine action such as tricyclic antidepressants, monoamine oxidase inhibitors, hypersensitivity or allergy for the drug were excluded; so also surgical duration was limited to 2 h. Intra-operative all cases receiving either nitroglycerine, labetalol or any other antihypertensive were noted and excluded. All patients were loaded with 500 ml of NS to prevent sudden hypotension. Bradycardia or hypotension more than 20% of the baseline was immediately treated with injection atropine 0.6 mg and injection ephedrine 3 mg aliquots respectively. Anesthesia was protocolled as pre-oxygenation with 100% oxygen for 5 min, Iv induction with propofol 2 μg/kg, fentanyl 2 μg/kg and atracurium 0.5 mg/kg intubating dose, intubated with Portex® endotracheal tube, maintained on O 2 (50%):N 2 O (50%) and dial concentration of sevoflurane adjusted accordingly. Routine intra-operative monitoring was done and reversal with injection neostigmine 0.04 mg/kg and glycopyrrolate 10 mcg/kg injection paracetamol 1 g 30-45 min after induction was given as analgesic. Capnography monitoring in the post-intubation period was carried out and accordingly paCO 2 levels maintained between 35 and 45 mmHg. Parameters assessed were baseline: HR, SBP, DBP, MABP, saturation of oxygen SpO 2 ; pre-induction. HR, SBP, DBP, MABP, SpO 2 , end tidal carbon dioxide (et CO 2 ), respiratory rate (RR); post-intubation, at regular intervals 10, 15, 30, 45, 60, 75, 90, 105 and 120 min and on extubation. In the post-operative period when visual analog scale (VAS) score dropped to or below value of 3, the patient received a rescue dose of analgesic in form of injection diclofenac 75 mg given intramuscular. In such a case, the time to first rescue analgesic was noted in minutes. The level of sedation in the same period was gauged as per the Ramsay scale. The other thing to be noted was the dial concentration of sevoflurane during the intra-operative period. Any >20% deviation in the HR or the MABP from the baseline was treated immediately. Bradycardia was treated with injection atropine 0.6 mg. Hypotension was treated with fluids with or without injection ephedrine. Hypertension was treated with nitroglycerine drip. The abdominal pressures during insufflation was not let to exceed 14 mmHg with a flow rate of CO 2 2 L/min maximum and position of reverse trendelenburg not exceeding 30 with left tilt. Statistical Analysis Used The statistical analysis for the inter group hemodynamic parameters and numerical data was performed by using paired t-test, while categorical data was analyzed by Chi-square test. P ≤ 0.005 was considered to be significant. The SPSS software was used to do the analysis.
The statistical analysis for all the hemodynamic parameters could not be done beyond 90 min as fewer cases lasted that long. Three cases from group P were excluded as they showed exaggerated hypertensive response or tachycardia requiring nitroglycerine infusion or labetalol. The demographic data that is age, sex, ASA grades, weight, height, BMI and surgical duration matched for both groups [Table 1].
There was no significant difference in pre-drug hemodynamic parameters for both groups. The HR varied significantly (P = 0.001) in both groups during pre-induction, intubation and on 5 min after intubation, other parameters did not vary. However, at 10, 15, 30, 45, 60, 75 and 90 min along with HR, the SBP, DBP and MABP varied significantly (P = 0.001). The SpO 2 remained same in both the groups. The post extubation VAS scores differed significantly (P = 0.000) with scores being higher in group P which co-related with the time of first rescue analgesic being less in group P. The patients in group C were more sedated (P = 0.000) compared with group P, but never did score exceed 2. The RR and end-tidal CO 2 did not vary in both groups throughout the surgery. Finally, the dial concentration of sevoflurane did differ significantly in both groups, concentrations being less in group C (P = 0.000). The mean time duration required for first analgesic dose in clonidine group was 33 ± 8.6 min compared to 5 ± 2 min in the control arm (P < 0.001). During the study none of the patient had any drug related adverse reaction. There was no mortality in the study.
Many studies have confirmed that CO 2 pnemoperitoneum during laparoscopy causes significant hemodynamic changes such as increase in MABP, SVR and decrease in cardiac output. [4],[5],[6] While preloading can improve venous return and hence cardiac output, the rest of the aforementioned sequelae require some kind of therapeutic intervention. [1] Various hypotensive drugs such as nitroglycerine, labetalol an α2 agonist and others such as opioids, inhalational agents have been used in past with varied results. Many of these agents have significant side-effects. Clonidine a selective alpha 2 agonist along with its hypotensive effection, causes sedation, analgesia and prevents shivering. Oral clonidine in dose of 150 ug pre-operatively given does have promising results however the bio-availability being 90%, it takes 2-4 h for its peak effect. When given intravenously however, it takes 30-45 min to peak and hence was chosen to give as infusion prior so that the effect is achieved by the time pneumoperitonem was created. Although dose ranging from 1 to 8 mcg/kg intravenous were used in different studies, [4] until date no particular minimum effective and maximum tolerable dose is noted anywhere. Tripathi et al. [4] in their study noted no significant difference in hemodynamics, intubation and extubation response with 1 mcg/kg dose while 2 mcg/kg dose ad significant effect with no much post-operative analgesia. Surprisingly, Joris et al. [1] in their study used clonidine in a dose of 8 mcg/kg with stable hemodynamics. In our study, with 4 mcg/kg clonidine, there was statistically significant difference in HR, SBP, DBP and MABP (P = 0.001) intra-operatively in clonidine group compared to those who received placebo. Thus, clonidine provided stable intra-operative hemodynamic condition. Only one patient had bradycardia which required atropine. No event of hypotension requiring intervention was noted. This suggests the safety of clonidine at this dose. Furthermore, clonidine at 4 mcg/kg did attenuate intubation and extubation response.
The sedation score was comparatively higher in group C as to group P. It could be taken to our advantage that the patients slept comfortably post-operatively. At the used dose of clonidine sedation score never exceeded three; that is no intervention was required to maintain airway or oxygenation. In this study, the RR was deliberately not standardized so as to maintain a stable etCO 2 levels ranging from 35 to 45 mmHg by. In both groups there was no significant difference in intra-operative ventilator frequency used. There was a significant difference in the time required for first analgesic dose (P = 0.001) in clonidine group when compared with placebo. The duration increased to almost 45 min post-operatively in patients who had received clonidine. The only disadvantage of this study was that patients required continuous monitoring pre-operatively during the infusion thus extending their stay inside the OT complex. Another proven drawback of clonidine is that the use of this drug in patients with hypertension and on beta blockers is still a query owing to its potential to cause severe bradycardia. There was no significant adverse reaction to clonidine use and there was no mortality. We conclude that clonidine is fairly safe to use at intravenous dosage of 4 mcg/kg. It definitely provides a stable hemodynamic state with minimal additional drug requirement and good post-operative analgesia.
The authors are gratefully acknowledged Asian Institute of Gastroenterology, Hyderabad - 500 082.
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