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Pneumoperitoneum in laparoscopic procedures is associated with hemodynamic response, due to the release of catecholamines and vasopressin. Magnesium and clonidine have been used to attenuate such hemodynamic responses by inhibiting release of these mediators. We conducted this randomized, double-blinded study to assess which of the two attenuates hemodynamic response better.
Ninety American Society of Anesthesiologists health status Classes I and II patients posted for elective laparoscopic cholecystectomy were randomized into three groups of thirty patients each. Group C received injection clonidine 1 μg/kg diluted in 10 mL normal saline over 10 min, prior to pneumoperitoneum. Group M received injection magnesium sulfate 50 mg/kg diluted in 10 mL normal saline over 10 min, prior to pneumoperitoneum. Group NS received 10 mL normal saline intravenously over 10 min, prior to pneumoperitoneum. Hemodynamic parameters were recorded before induction (baseline values), at the end of magnesium sulfate/clonidine/saline administration and before pneumoperitoneum (P0), 5 min (P5), 10 min (P10), 20 min (P20), 30 min (P30), and 40 min (P40) after pneumoperitoneum.
Systolic blood pressure, diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were all significantly higher in the normal saline group compared to magnesium and clonidine. On comparing patients in Group M and Group C, DBP, MAP, and HR were significantly lower in the magnesium group. Mean extubation time and time to response to verbal commands were significantly longer in the magnesium group.
Both magnesium and clonidine attenuated the hemodynamic response to pneumoperitoneum. However, magnesium 50 mg/kg, attenuated hemodynamic response better than clonidine 1 μg/kg.
Laparoscopic cholecystectomy is one of the most common laparoscopic surgeries performed worldwide. Pneumoperitoneum is commonly induced by carbon dioxide (CO2). Pneumoperitoneum, as well as hypercapnia due to CO2, is responsible for the adverse cardiovascular effects. An abrupt elevation of mean arterial pressure (MAP), systemic vascular resistance, and decreased cardiac output are commonly noted.[1,2] This vasopressor response is due to the release of both catecholamines[3,4] and vasopressin. The cardiac output will be further decreased by the reverse Trendelenburg position used in these surgeries. These events will be less tolerated, especially by patients with compromised cardiac function. Hence, attenuation of these vasopressor responses is of paramount importance to an anesthesiologist. Opioids, beta blockers, magnesium, and α2 agonists have been used for this purpose.
Magnesium has shown to block the release of catecholamines release from both adrenal medullae, as well as from nerve terminals. It has been used to attenuate intubation-induced vasopressor response. Magnesium also acts directly on blood vessels causing vasodilation, thus attenuating vasopressin-induced vasoconstriction.
Clonidine, a selective α2 agonist, decreases heart rate (HR) and arterial pressure. It has been used for attenuating vasopressor responses. We hypothesized that magnesium and clonidine can be used for attenuating the hemodynamic responses to pneumoperitoneum.
This study was undertaken after obtaining institutional Ethical Committee clearance, as well as informed consent from all patients. It was a randomized, double-blind study. The primary objective was to compare the effect of intravenous (IV) clonidine and magnesium sulfate on intraoperative hemodynamics during laparoscopic cholecystectomy. The secondary objective was to compare the effects of clonidine and magnesium sulfate on postoperative recovery, such as time for extubation and time to verbal response.
Ninety patients, aged 18–60 years, scheduled for elective laparoscopic cholecystectomy, belonging to American Society of Anesthesiologists (ASA) health status Classes I and II were included in the study. Patients were assigned randomly (computer-derived random number sequence) into three groups of thirty patients each: Group M (magnesium sulfate group), Group C (clonidine group), and Group NS (normal saline control group). The three groups were:
The drugs were prepared and administered by an anesthesiologist who was not involved with data collection or patient management. The patients, investigators, and the anesthesiologists were all blinded to the solution infused. Patients with hypermagnesemia, known allergy to magnesium sulfate and clonidine, hypertension, morbid obesity, and severe hepatic, renal, endocrine, and cardiac dysfunction were excluded from the study.
Premedication was with tablet ranitidine 150 mg and tablet ondansetron 8 mg orally at bedtime the night before surgery and on the day of surgery. Injection glycopyrrolate 0.2 mg intramuscular half an hour before shifting to OT. On arrival in the operation theater, monitors were attached (HR, noninvasive blood pressure, SpO2, electrocardiogram, and temperature) and baseline vital parameters were recorded. Preoxygenation was done for 3 min and patients received 1 µg/kg of fentanyl citrate intravenously. Propofol 2 mg/kg was used for induction and endotracheal intubation was facilitated by a muscle relaxant, vecuronium bromide 0.1 mg/kg.
The test drugs were infused over 10 min before creating pneumoperitoneum. Systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, and HR were recorded before induction (baseline values), at the end of magnesium sulfate/clonidine/saline administration and before pneumoperitoneum (P0), 5 min (P5), 10 min (P10), 20 min (P20), 30 min (P30), and 40 min (P40) after pneumoperitoneum. Pneumoperitoneum inflation pressures were maintained at 14 mm Hg. Maintenance of anesthesia was with nitrous oxide (50%), oxygen (50%), and isoflurane. IV fentanyl was given at a dose of 0.5 µg/kg when there were signs of inadequate analgesia (increase of MAP and HR 20% above baseline). Vecuronium 0.02 mg/kg was used for maintenance of muscle relaxation based on a train of four monitoring. Intermittent positive pressure ventilation was used and end-tidal CO2 (EtCO2) was maintained between 35 and 40 mm Hg. Patients were positioned in head up tilt of 15° with right lateral tilt. Intraoperative fluid requirements were as per Holliday-Segar formula. Hypotension (MAP <20% of baseline) was managed with fluid bolus or ephedrine 6 mg IV bradycardia (HR <50 bpm) was treated with atropine 0.6 mg IV. Neuromuscular blockade reversal was achieved at the conclusion of the surgery, with injection neostigmine and glycopyrrolate. Patients in whom laparoscopic cholecystectomy was converted to open procedure were excluded from the study.
Following times were noted down after tracheal extubation: (i) Time to tracheal extubation and (ii) time to response to verbal commands.
HR, MAP, SpO2, and EtCO2 were recorded throughout the surgical procedure at an interval of 10 min. Any other adverse events or side effects were recorded during the postoperative period.
The sample size was estimated based on the data provided in the study, “effects of magnesium sulfate and clonidine on propofol consumption, hemodynamics, and postoperative recovery.” Thirty in each group were recruited and estimated using the nMaster software (Department of biostatistics, CMC, Vellore, Tamil Nadu, India).
Analysis of variance was used to find the significance of study parameters between three or more groups of patients. Post hoc Tukey's test was used to find pair-wise significance and Student's t-test (two-tailed, dependent) was used to find the significance of study parameters on the continuous scale within each group. Chi-square/Fisher exact test was used to find the significance of study parameters on a categorical scale between two or more groups.
Table 1 shows demographic variables of the patients in the three groups. All three groups were comparable in respect to age, sex, body weight, ASA status, and duration of surgery. The baseline vitals were comparable between all the groups.
DBP of patients in Group NS was elevated significantly from P5 to P40 (P < 0.001) as compared to Group M and from P5 to P30 as compared to Group C. On comparing patients in Group M and Group C, DBP was significantly lower in M Group from P5 to P40 [Table 2].
SBP was significantly higher in Group NS when compared to both M and C from P5 to P40 (P < 0.001). Between M and C Groups, SBP was significantly lower at P5 (P < 0.001), but no difference from P10 to P40 [Table 3].
MAP was also significantly raised in NS Group from P5 to P40 as compared to both M and C Groups. However, on comparing MAP in Groups M and C, it was significantly lower in M Group at P5 (P = 0.035), P10 (P = 0.048), P30 (P = 0.027), and P40 (P = 0.05) [Table 4].
On comparing HR of patients in Group NS with Groups M and C, Group NS had significantly higher HR at P5 to P40 (P < 0.001). Moreover, HR was significantly lower in M Group as compared to C Group at all-time points (P < 0.001) [Table 5].
No significant episodes of hypotension or bradycardia were noted in any groups.
In clonidine group, the mean extubation time was 5.87 ± 0.95 min, in magnesium sulfate group 8.12 ± 1.59 min and in normal saline group 5.78 ± 0.99 min. Statistical evaluation between the groups showed statistically significant longer extubation times in magnesium sulfate group compared to clonidine or normal saline group. There was no significant difference in extubation times between clonidine and normal saline group [Table 6].
In clonidine group, the mean time to respond to verbal commands was 7.15 ± 1.05 min, in magnesium sulfate group 8.97 ± 1.69 min, and in normal saline group 7.07 ± 1.00 min. Statistically significant longer times were noted in magnesium sulfate group compared to clonidine or normal saline group. There was no significant difference in time to respond between clonidine and normal saline group [Table 7].
Pneumoperitoneum-induced cardiovascular changes include elevated arterial pressures with little or no change in HRs.[1,2] The role of magnesium and clonidine in attenuating hemodynamic responses to pneumoperitoneum have been studied earlier.[8,9] We did a randomized, double-blinded study to further confirm this finding.
Jee et al. found that magnesium sulfate at a dose of 50 mg/kg over 2–3 min prior to pneumoperitoneum, effectively attenuated the hemodynamic responses, without any episode of severe hypotension or bradycardia.
Kalra et al. compared magnesium sulfate (50 mg/kg) versus two doses of clonidine (1 µg/kg and 1.5 µg/kg) and concluded that clonidine at 1.5 µg/kg was most effective in attenuating hemodynamic response to pneumoperitoneum, with no difference between magnesium and clonidine 1 µg/kg. We used a similar dose of magnesium and compared it with 1 µg/kg clonidine. Both magnesium and clonidine group patients had a significant attenuation of hemodynamic responses as compared to normal saline. However, in our study, we noted that magnesium reduced DBP and MAP more than clonidine which was statistically significant.
Magnesium sulfate has shown to reduce the plasma catecholamines and vasopressin levels, thus contributing to its blunting effect on sympathoadrenal hemodynamic stress response. These effects of magnesium are noted at serum concentrations of 2–4 mmol/L.[13,14] However, in our study, the serum magnesium levels were not measured. In an earlier study, a dose of 50 mg/kg has been shown to achieve these levels. Magnesium has also been shown to have a vasodilator action, thus contributing to the reduction of blood pressure. Vasopressin concentrations raise in pneumoperitoneum due to increased compression of abdominal capacitance vessels with a consequent reduction in venous return to the heart.[15,16] Magnesium due to its vasodilator action might reduce vasopressin release. In our study, we noted that magnesium reduced arterial pressures more significantly as compared to both clonidine and the control group.
Clonidine, an α2 agonist, due to its central sympatholytic action, blunts the pressor response to pneumoperitoneum. Clonidine was used for this purpose in laparoscopic procedures by Aho et al. Clonidine was used orally at a dose of 150 µg, as a premedicant for blunting hemodynamic response in laparoscopic procedures.
A higher dose of IV clonidine (3 µg/kg) used by Altan et al. had a significant incidence of bradycardia and hypotension. We used a much lower dose of clonidine (1 µg/kg) and did not have any incidence of hypotension or bradycardia.
Kalra et al. used clonidine at doses of 1 µg/kg and 1.5 µg/kg and found that hemodynamic response was blunted more effectively with 1.5 µg/kg. We used clonidine at 1 µg/kg dose in view of the increased sedation seen with a higher dose of clonidine with a resultant prolonged recovery time. We noted that though clonidine 1 µg/kg attenuated hemodynamic response, magnesium blunted hemodynamic response more effectively.
In our study, patients receiving magnesium sulfate had significantly lower HRs as compared to both clonidine and normal saline. This is in contrast to earlier studies, where there was no significant difference in HRs between magnesium sulfate (50 mg/kg) and clonidine (1 µg/kg).
Magnesium sulfate has been shown to potentiate the neuromuscular blockade of non depolarizing relaxants and this was evident in our study too, with a prolonged time to extubation. Prolonged time to verbal response observed could be due to its central nervous system depressant action. Magnesium sulfate also has been known to produce general anesthesia and enhance the activity of local anesthetic drugs.
Both magnesium sulfate and clonidine effectively blunt the pressor response to pneumoperitoneum in laparoscopic cholecystectomy surgeries. However, magnesium sulfate at a dose of 50 mg/kg, blunts the hemodynamic response more effectively than clonidine 1 µg/kg.
There are no conflicts of interest.