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Insertion of skull pin induces a significant increase in heart rate (HR), blood pressure (BP) and intracranial pressure. Alpha 2 agonist clonidine and intravenous (i.v.) lignocaine are effective in attenuating stress response. Local infiltration of pin site and scalp block with lignocaine are commonly used techniques for prevention of hemodynamic response to skull pin insertion. We compared the effectiveness of i.v. clonidine infusion and i.v. lignocaine infusion in suppressing the hemodynamic response to skull pin head holder insertion.
Randomized double blind study conducted with sample size - sixty patients, divided into two groups: Group C (n = 30) - clonidine i.v. dose 2 μg/kg; Group L (n = 30) - lignocaine i.v. dose 1.5 mg/kg.
All patients posted for elective craniotomy belonging to American Society of Anesthesiologists (ASA) 1 and 2, age group 18–70 were included in the study. ASA 3, 4; difficult airway; hypertensives; allergy to study drugs; ischemic heart disease; and arteriovenous malformations were excluded. Study drugs were administered 10 min prior to induction in 10 ml syringes with infusion pump over 10 min. Standard anesthesia protocol followed. HR, noninvasive BP, mean arterial pressure (MAP), and IBP were recorded at baseline (BL), after study drug (AD), 1 min after intubation (AI), 1 min prior to pin insertion -pre pin (PP), and 5 min after pin insertion (AP).
Descriptive and inferential statistical analysis – Student's t- and Chi-square/Fisher exact test were used (SAS 9.2, SPSS 15.0) P value described as *moderately significant (P value: 0.01 < P ≤ 0.05) **strongly significant (P value: P ≤ 0.01).
Groups were matched with respect to age (P = 0.7), gender distribution (P = 0.6), and weight (P = 0.67) There was no difference in BL HR in two groups. Significant difference in HR was noted after intubation P < 0.031 and pin insertion P < 0.001 stages with lower HR in Group C (76.03 ± 9.88) versus Group L (98 ± 60.89) MAP recordings showed no statistically significant difference in two groups at BL and after drug administration stages. A significant difference was seen in intubation (P < 0.014), very significant difference (P < 0.001) was noted in pre- and post-pin insertion stages with MAP was lower in Group C (76.03 ± 9.88) versus Group L (87.17 ± 8.90).
i.v. clonidine at dose of 2 μg/kg is a better drug in attenuating hemodynamic response to skull pin head holder insertion than i.v. lignocaine.
The brain is situated in a rigid cranial cavity with a limited capacity to compensate for changes in blood volume, intracranial pressure, and brain tissue.[1,2] Craniotomy incites noxious stimulus at various stages such as laryngoscopy, intubation, insertion of skull pin head holder, skin incision and extubation. Any noxious stimuli induce a sharp, sudden, and significant increase in heart rate (HR), blood pressure (BP), and intracranial pressure. Such sympathetic stimulation can be detrimental in patients with impaired cerebral autoregulation, cardiac patients, arterio-venous malformations, aneurysms, and intracranial space occupying lesions.[1,3,4] Anesthesiologists play a crucial role in controlling the response to noxious stimuli by means of modifying the depth of anesthesia.
In craniotomy, fixation of the head with pins is a necessary step to stabilize the head for adequate surgical exposure. These pins pass from the skin into the outer table of skull. The pin insertion induces a sympathetic as well as neuroendocrine response and necessitates the need for attenuation of this stress stimulus. Scalp block, pin site infiltration, and pharmacological methods have been tried and found effective in attenuation of the stress response.
Lignocaine and alpha 2 agonists are commonly used drugs in neuro-anesthesia for attenuating hemodynamic response to laryngoscopy and intubation. Lignocaine is routinely used for site infiltration or as intravenous (i.v.) bolus dose prior to intubation. Clonidine, an alpha 2 agonist, is used in preparations as oral tablets, i.v. bolus and also as an infusion for abolishing sympathetic response. In our study, we intended to use the same drugs as i.v. infusion and compare the effectiveness of these drugs in prevention of hemodynamic responses to skull pin head holder insertion.
The study was conducted at the Super Speciality Hospital attached to Bangalore Medical College and Research Institute. Institutional Ethical Clearance was obtained. The study was a prospective randomized double-blind study. As per power analysis - Based on outcome variable on BP for a two group study, with 90% statistical power, 5% level of significance, the sample of sixty was considered adequate (thirty in each group) to detect the difference of 20 mmHg with common standard deviation 15.
All patients posted for elective craniotomies belonging to American Society of Anesthesiologists Physical Status 1 and 2, in the age group of 18–70 years without any history of allergy to study drugs were included in the study. Patients not willing to take part in the study, emergency craniotomies, Glasgow coma scale <7, patients with a difficult airway, hypertension, ischemic heart disease, renal disease, aneurysm, and arteriovenous malformation were excluded from the study. Preanesthetic evaluation was done on the previous day of surgery. Patients were explained about the study and written informed consent for participation in the study was obtained.
On the day of surgery, i.v. line was secured in preoperative holdup area. Patients were randomly allocated to the study group by computer-generated random numbers. Sixty patients were divided into two groups: Group-C and Group-L, with a sample size of thirty each. Group C (n = 30) received i.v. clonidine 2 µg/kg, as infusion and Group L (n = 30) received i.v. lignocaine, 1.5 mg/kg as an infusion.[6,7] In the operation room, baseline readings of HR, noninvasive BP (NIBP), mean arterial pressure (MAP), and electrocardiogram and oxygen saturation were recorded. Study drugs were diluted to 10 ml with normal saline and administered in 10 ml syringes with syringe pump over 10 min. No interventions were made till study drugs were administered. After completion, drugs infusions were disconnected and were not used intra-operatively. All patients were administered injection fentanyl 2 µg/kg, induced with injection thiopentone 5 mg/kg, muscle relaxation achieved with injection vecuronium 0.1 mg/kg. Intubation was done when the train of four counts was 0 on neuromuscular monitor. Anesthesia was maintained with controlled ventilation with injection vecuronium, air-oxygen, and isoflurane on closed circuit. NIBP and MAPs were recorded every 3 min on Datex-Ohmeda monitor to avoid observer variation. Pin site infiltration and scalp block were avoided. Mayfield head holder was inserted in all cases. Monitor setting was changed to manual recording of NIBP and MAP at following instances - after drug administration (AD), after intubation (AI), 1 min prior to pin insertion-pre-pin (PP), and 5 min after pin insertion (AP). After recording the parameters of the study, intra-arterial line was placed, and the patient was positioned as per surgical procedure. Standard anesthesia protocol was followed in the management of cases. The increase of MAP >30 mmHg above baseline (BL) reading was considered as hypertension and a fall of MAP <20 mmHg was taken as hypotension. Rescue drug for hypertension was injection propofol in doses of 0.5 mg/kg boluses till MAP reached BL levels. Hypotension was managed with injection metaraminol 3 mg boluses and fluid bolus of 200 ml till BL levels were achieved. Bradycardia was managed with injection atropine 0.6 mg bolus. Patients who had profound hypotension or severe hypertension in spite of rescue medications were eliminated from the study and aggressive management as per protocol was carried out. After the study period, the patient was observed continuously as per standard anesthesia protocols. Depending on the requirements of surgery, anesthesia depth was altered with higher doses of opioids, propofol infusion, or thiopentone. Blood was transfused if necessary. Intra- and post-operative management were as per institutional practice. Use of above-mentioned drugs and changes would alter our observation of hemodynamics. Hence, our study recordings were restricted to pin insertion period only.
Results were tabulated and analyzed statistically as (1) demographic parameters – age, gender distribution, body weight (2) outcome variables - HR, MAP. HR and MAP were compared at following study intervals - Baseline (BB), after drug (AD), 1 min after intubation (AI), 1 min prior to pin insertion-prepin (PP), and 5 min after pin insertion (AP).
Student's t-test (two-tailed, independent) was used to find the significance of study parameters on a continuous scale between two groups (intergroup analysis) on metric parameters. Chi-square/Fisher exact test was used to find the significance of study parameters on categorical scale between two groups. Significance numbers were considered as below:
The statistical software SAS 9.2, SPSS 15.0, Stata 10.1, MedCalc 9.0.1, Systat 12.0 and R environment version 2.11.1 were used for the analysis of the data and Microsoft Word and Excel was used to generate graphs and tables.
Groups were matched with respect to age (P = 0.7), gender distribution (P = 0.6), and weight (P = 0.67). There was no difference in demographic parameters [Table 1].
HR variations are depicted in Table 2.
In Group C, the HR decreased from mean of 86.07 ± 16.45 to 78.13 ± 14.64. The HR remained below the BL levels at intubation, prepin insertion period, and also 5 min after pin insertion periods. This signifies the stability in HR variation achieved with injection clonidine.
In Group L, BL HR was 87.87 ± 16.69, after drug administration HR was maintained at the BL levels 87.87 ± 16.69. The HR showed an increase from baseline, after intubation, prior to and after pin insertion. Tachycardia or bradycardia was not recorded in any patient during the study period.
There was no difference in the BL HR in two groups. After study drug administration, there was difference noted in the HR within in the group as well as between the groups (P = 0.025). Very significant difference in the HR was noted between groups in prepin insertion and postpin insertion stages. Therefore, Group C had better control in HR than Group L.
MAP recordings with P values are discussed in Table 3.
The BL MAP was above 97 mmHg in both groups. In Group C, MAP remained at 90.53 ± 9.84 after drug administration. The MAP decreased by 9 mmHg at intubation and by 21 mmHg at postpin insertion from BL levels. The sympathetic stimulus-induced increase in BP was not seen in Group C.
In Group L, the MAP remained above 90 mmHg after drug administration and decreased only by 3 mmHg and 11 mmHg at intubation and post pin insertion period respectively. There was no statistically significant difference in two groups at BL and after drug administration stages. A significant difference was seen in intubation (P < 0.05), very significant difference was noted in pre- and post-pin insertion stages. Though in both groups, MAP was reduced from BL levels, difference was observed between groups in control of MAP at different stages in the study. Group C recorded a better control over BP than Group L.
Both groups did not need rescue drugs to manage hypotension or hypertension during study intervals as MAP was within the described range for hypotension and hypertension. No patient was excluded from the study. As the HR and MAP recordings were lesser in Group C than Group L at prior pin insertion and postpin insertion stages, clonidine at the dose of 2 µg/kg showed better control of hemodynamic response to skull pin head holder insertion.
Clonidine and lignocaine are commonly used drugs in anesthesia for attenuation of hemodynamic responses to laryngoscopy and intubation. Literature search revealed-lignocaine, a time-tested drug is commonly used for scalp block as infiltration; i.v. lignocaine is routinely used only as bolus dose 90 s prior to intubation. As there was a lack of studies using lignocaine as an infusion for attenuating pin insertion response and various studies, have compared scalp block versus i.v. clonidine, we chose to compare Lignocaine infusion with clonidine infusion. Our aim was to use drugs of different groups administered via the same route. Hence, two disparate drugs were selected.
Clonidine is a centrally acting antihypertensive drug with its selective alpha 2 receptor agonist action with selectivity of 220:1 for alpha 2: alpha 1 receptors. The beneficial effects of clonidine are dose-dependent analgesia, sedation, anxiolysis and reduced requirement of anesthetics and muscle relaxants.[2,5] Clonidine is available as oral, transdermal and i.v. preparations. Use of clonidine as parenteral or i.v. preparation is effective in attenuating stress response due to its ability to reduce systolic BP more than diastolic BP, maintenance of glomerular filtration, blunt reflex tachycardia for intubation, reduce vasomotor liability, and to reduce plasma cortisol levels.
Several studies have used oral preparation of clonidine in doses ranging from 3 to 5 µg/kg, 1 h prior to pin insertion and found effective control of BP and HR.[5,8,9,10] In one study conducted by Cormack and Costello, oral Clonidine in dose of 3 µg/kg significantly reduced the MAP from the baseline MAP of 126 mmHg to 80 mmHg after intubation (P < 0.001) and to 100 mmHg after pin insertion (P < 0.001). A similar finding was noted in our study too with MAP remaining at 86 mmHg postintubation and 76 ± 9 mmHg after pin insertion in Group C (P = 0.001). Similarly, HR was reduced from BL 70 beats/min(bpm) to 62 bpm and 68 bpm at prepin insertion and postpin insertion periods respectively. Our study recorded a steady fall in HR from 86 bpm to 76.8 and 76.03 bpm at prepin and after pin insertion periods. Ten percent fall in HR was noted in study by Cormack et al. and our study. Hence, clonidine at a dose of 2 µg/kg reduces the HR and BP response to pin insertion.
Chaudhry et al. used oral clonidine at 3 µg/kg 90 min before induction and recorded hemodynamics at various intervals throughout craniotomy procedure. The HR recorded in Clonidine group postintubation and postpositioning (pin insertion) was 83.18 and 73.82 respectively. In our study HR at postintubation and postpin insertion were 77 ± 10.83 and 76 ± 19.75 respectively. MAP recorded by Chaudhry et al. was 94.04 mmHg and 82 mmHg at postintubation and post positioning period; our study recorded 86.83 ± 9.71 and 76.03 ± 9.88 mmHg, respectively. Our study compares the control in HR and MAP similar to the findings of Chaudhry et al. though the slight difference in findings may be due to different route of administration.
In a study by Makwama et al., i.v. clonidine in dose of 2 µg/kg was used 10–15 min prior to induction. HR recorded at 1 min and 5 min after pin holder insertion were 84 ± 6 and 88.71, respectively. Results of HR variations of our study matched with findings of Makwama et al. MAP changes noted at 1 min and 5 min after pin holder insertion were 98.22 ± 5.9 and 109 ± 6.66, respectively. We noted 76.83 ± 9.75 and 76.03 ± 9.88 mmHg, respectively. Our study recorded 20% lower MAP than findings of Makwama et al. Though, the dose, route and timing of administration were comparable to our study, the fall in MAP was more than Makwama et al. This difference may be due to the difference in induction and anesthesia protocol followed.
Lignocaine is an amide local anesthetic with membrane stabilizing action. The decrease in HR and BP is due to its action on myocardium than on cerebral blood vessels. Hence, i.v. lignocaine is used for attenuating laryngoscopy and intubation response in neuro-anesthesia, lignocaine infiltration is routinely used for scalp block and incision site infiltration.
Literature search revealed lack of data on studies conducted with i.v. lignocaine infusion for attenuation of skull pin head holder insertion. Ours is the only study where i.v. 2% lignocaine was used as infusion for blunting hemodynamic response to pin insertion. However, there are umpteen numbers of studies supporting the use of i.v. bolus 2% lignocaine in the dose of 1.5 mg/kg for prevention of sympathetic response to laryngoscopy and endotracheal intubation.[6,7,11,12,13] Hence, we are justified in the safety and use of 2% lignocaine at dose of 1.5 mg/kg.
Chatterji et al. compared i.v. 2% lignocaine bolus at 2 mg/kg with oral clonidine at dose of 3 µg/kg for attenuation of hemodynamic response to laryngoscopy and intubation. i.v. lignocaine group recorded postintubation HR and MAP values of 99.14 ± 17.68 and 89.24 ± 10.14 respectively. Oral clonidine group recorded HR and MAP values of 77.97 ± 16.26 and 82.03 ± 2.59 respectively. Chatterji et al. concluded that oral clonidine was better than i.v. lignocaine in attenuating stress response to intubation. Our study too showed similar results with respect to HR and MAP at intubation and pin insertion periods. The use of i.v. lignocaine in our study prior to intubation proved beneficial in attenuating the laryngoscopy and intubation response in craniotomy cases. The effect also lasted till head holder insertion. However, the control over HR and BP was less effective than i.v. clonidine. This difference may be due to pharmacokinetic and pharmacokinetic properties of two drugs.
The study was restricted to postpin insertion period, though the study drugs have effect on the course of anesthesia throughout the procedure. The drugs lignocaine and clonidine continue to have the effect beyond the end point of the study. However, intraoperative use of mannitol, phenytoin, frusemide, and dexamethasone will alter the hemodynamics. Surgical blood loss, change in position will also add to continuous changes in the HR and BP. Several confounding factors were present throughout the craniotomy procedure which would alter hemodynamic and attributing the changes to drug used preoperatively would be difficult. In our study, neuroendocrine biomarkers, sedation scoring, requirement of anesthetic drugs, cerebral blood flow, cerebral blood volume, and intracranial pressures were not studied. These are the few limitations of our study.
There are no conflicts of interest.