Low Dose Dexmedetomidine Attenuates Hemodynamic Response to Skull Pin Holder Application.

BACKGROUND: The application of skull pin holder elicits an adverse hemodynamic response that can be deleterious; there are many drugs that have been used to attenuate this response. We have conducted this study to evaluate the efficacy of intravenous (i.v.) dexmedetomidine on attenuation of hemodynamic responses to skull pin head holder application and to compare the effectiveness of two doses of i.v. dexmedetomidine (1 μg/kg and 0.5 μg/kg bolus).
MATERIALS AND METHODS: Ninety American Society of Anesthesiologists physical Status I-III patients undergoing craniotomy were randomized into three groups of thirty each. After intubation, patients in Group A received 1 μg/kg of i.v. dexmedetomidine, Group B received 0.5 μg/kg of i.v. dexmedetomidine, whereas Group C received an equivalent quantity of normal saline. Hemodynamic parameters were monitored regularly after skull pin insertion.
RESULTS: There was no significant difference in the monitored hemodynamic parameters among the three groups from baseline until intubation. Heart rate (HR) and mean arterial pressure (MAP) increased significantly at skull pin insertion and subsequent points in Group C, whereas the values decreased in Groups A and B (P < 0.05). Patients in Group A showed a higher and sustained attenuation of MAP. Patients in Group C had a higher incidence of tachycardia and hypertension requiring additional measures to attenuate the response.
CONCLUSIONS: Dexmedetomidine in either dosage (1 μg/kg or 0.5 μg/kg) was effective in attenuating hemodynamic response to skull pin insertion. Dexmedetomidine in doses of 0.5 μg/kg was as effective in attenuating the HR and MAP response to skull pin insertion as compared to a dose of 1 μg/kg.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

In patients undergoing neurosurgical procedures, the head is stabilized by means of fixation of head frames or head holders. These head frames have pins that are inserted deep into pericranium through skin and galea aponeurotica. Despite the fact that these head frames are fixed under general anesthesia; they produce intense sympathetic response resulting in an increase in the intracranial pressure (ICP).[1] This increase in the arterial blood pressures increases cerebral blood flow and subsequently the ICP.[2] Patients with abnormal intracranial pathology have an abnormal cerebral autoregulation and thus more prone for increased ICP when the systemic arterial pressure increases.[3] Interventions that reduce sympathetic tone improves neurological outcome, treatment with agents that reduce the release of norepinephrine in the brain may provide protection against the damaging effect of cerebral ischemia.[4] Various methods such as intravenous (i.v.) alfentanil,[5] subanesthetic doses of ketamine,[6] fentanyl, and sufentanil have been administered before the skull pin insertion.[7] Other techniques included oral gabapentin,[8] pin site infiltration with local anesthetic,[9] and scalp block[10] been used to blunt the hemodynamic responses to scalp pin insertion with variable success. Dexmedetomidine decreases the central nervous system sympathetic outflow in a dose-dependent manner. Dexmedetomidine in doses of 1 µg/kg infusion over 10 min before induction has been used to attenuate the hemodynamic response to skull pin application.[1112] However, this dose occasionally is known to cause bradycardia and hypotension. We have proposed a hypothesis that a reduced dose of 0.5 µg/kg may be as effective in attenuating hemodynamic responses to skull pin head holder with fewer adverse events.

MATERIALS AND METHODS

This is prospective, randomized placebo-controlled study, conducted over a period of 18 months, after obtaining clearance from the Institutional Ethical Committee and informed consent from the patient. Patients aged 18–60 years, with the American Society of Anesthesiologists physical status I–III, undergoing the elective neurosurgical procedure under general anesthesia and requiring the application of skull pins were included in the study. Patients undergoing intracranial aneurysm surgery, those having significant cardiac (shock, bradycardia, severe heart failure, acute myocardial infarction, or conduction defects), respiratory (acute respiratory failure or acute respiratory distress syndrome), renal (acute or chronic renal dysfunction/failure), hepatic disease (acute hepatitis/severe liver disease), or taking medication that can affect hemodynamic parameters were excluded from the study.

All the patients underwent anesthetic evaluation a day before surgery. Routine preoperative laboratory investigations were done. Patients were fasted for 8 h before surgery. On arrival at operating room, i.v. line accessed with 16-gauge cannula and 0.9% normal saline infusion initiated. Baseline heart rate (HR), blood pressure, and oxygen saturation were recorded. Patients were randomly allocated to one of the three groups using the computer-generated table of random numbers. Patients in each group were stipulated to receive either dexmedetomidine or placebo. Group A received i.v. dexmedetomidine at 1 µg/kg, Group B received i.v. dexmedetomidine at 0.5 µg/kg, and Group C received 0.9% saline infusion as placebo. The test drugs were infused over 10 min subsequent to intubation.

After preoxygenation for 5 min, patients were induced with fentanyl 2 µg/kg and of propofol until the loss of verbal response. Vecuronium of 0.1 mg/kg was used for muscle relaxation; mask ventilation was continued for 3 min. Subsequently, patients were intubated with the appropriate sized oral endotracheal cuffed tube. Anesthesia was maintained after intubation with isoflurane in O2/air mixture (FIO2 =0.4) ventilation controlled to target an end-tidal carbon dioxide between 30 and 32 mmHg. Radial artery was cannulated with a 20-gauge catheter for continuous invasive arterial blood pressure monitoring. The subclavian vein was cannulated with a 7-Fr polyurethane double-lumen central venous catheter and fluids infused to maintain central venous pressures (CVPs) between 8 and 10 cm of water.

Dexmedetomidine of different doses or placebo was diluted by an independent investigator. The test drug infusion was initiated by the attending anesthesiologist who was blinded to the test drug after all invasive monitoring lines were in place. The pin insertion sites were marked by the neurosurgeon, and each pin site was infiltrated with 2 ml 0.25% bupivacaine each 8 min after starting infusion of the study drug. The patients head was fixed on a Sugita frame head holder with four point pins by applying constant pressure on the scalp until the pins were firmly tightened 10 min after the start of study infusion.

The outcome variables HR, systolic, diastolic, and mean arterial pressures (MAP) were recorded at the following time intervals Bl baseline value, In immediately after intubation, T0 at pin insertion, and T0.5, T1, T2, T4, T10, T15, T30 – 0.5, 1, 2, 4, 8, 10, 15, and 30 min after pin insertion, respectively.

Intraoperative bradycardia of >20% fall from baseline was treated with i.v. atropine. An increase in the HR from baseline by more than 20% was treated with fentanyl 1 µg/kg bolus. If tachycardia persisted i.v. esmolol 5 mg incremental doses every 5 min was given. MAP <30% from baseline was treated by reducing inspired isoflurane concentration to 0.5% after ensuring CVP to be between 8 and 10 cm water. If hypotension still persisted, it was treated with i.v. ephedrine 6 mg. MAPs more than 30% from baseline and were treated by increasing the inspired concentration of isoflurane to 1.5%, and if persisting, fentanyl (1 µg/kg bolus) was repeated once. Propofol infusion was started and titrated to the desired response if hypertension persisted, despite the other measures.

Statistical analysis

Descriptive statistical analysis has been carried out in the present study. Results on continuous measurements are presented as mean ± standard deviation, and results on categorical measurements are presented in number (%). One-way ANOVA test was used to find the significance of study parameters on categorical scale between the three groups. Independent sample t-test was used to find the significance of study parameters on continuous scale within the group (intragroup analysis) on metric parameters. The significance is assessed at 5% level of significance. P < 0.05 was considered statistically significant.

The sample size was based on the previous study.[10] According to statistical power analysis, 27 patients per treatment group were needed to get an 80% power in detecting a 10% difference between treatment groups with 5% type I error. Assuming a few dropouts, the final sample size was set at 90 patients, thirty patients per group [Figure 1]. The Statistical software SPSS software, version 18 (IBM, USA) was used for the analysis of the data, and Microsoft Word and Excel has been used to generate graphs and tables.

Figure 1

Consort flow diagram of study subjects.

RESULTS

No statistically significant difference was observed in groups regarding demographic parameters [Table 1]. There were no significant differences in the means of HR and MAP among the three groups at baseline and intubation. At the point of skull pin insertion and at T0.5, T1, T2, T4, T10, T15, T30, the means of HR, and MAP were higher in Group C as compared to Groups A and B, with statistical significant values obtained at all monitoring points for HR and up to 15 min for MAP [Table 2].

Table 1

Patients characteristics

Table 2

The means of individual hemodynamic parameters at baseline, intubation, 0, 0.5, 1, 2, 4, 10, 15, and 30 min after skull pin insertion

As compared to the values at intubation, HR and MAP increased at skull pin insertion and at subsequent points in Group C, whereas the values decreased in Group A and Group B. This attenuation in the values as compared to those at intubation was more pronounced in Groups A than B [Figures 2 and 3].

Figure 2

Heart rate variation between the groups.

Figure 3

Mean arterial pressure variation between the groups.

Comparing between the two doses of dexmedetomidine used in the study (1 µg/kg in Group A and 0.5 µg/kg in Group B), the responses were similar in both the groups with respect to HR. Statistically, significant difference between the groups was obtained at T0.5, T2, T4 for MAP; with cases in Group A showing higher and sustained attenuation in hemodynamic variables as compared to cases in Group B [Table 2].

A significantly higher percentage of cases in Group C developed intraoperative tachycardia and hypertension necessitating additional measures as compared to dexmedetomidine Groups A and B. There were no differences between the two doses of dexmedetomidine in terms of significant intraoperative hemodynamic variations necessitating additional measures [Table 3]. Only one case each in Groups A and B developed tachycardia and subsequently received fentanyl bolus, 17 cases (56.7%) in Group C had to be administered fentanyl to treat tachycardia (P < 0.001). While only one case in Groups A and B developed tachycardia which responded adequately to fentanyl bolus and did not require any further measures. Seven patients (23.3%) of the cases in Group C did not respond adequately to fentanyl and additionally required i.v. esmolol (P < 0.05). There was no significant difference between the groups in terms of frequency of bradycardia and therein necessity of atropine administration.

Table 3

The use of fentanyl/esmolol to treat tachycardia and fentanyl/isoflurane to treat hypertension during the study

DISCUSSION

We conducted this prospective, randomized, double-blind, placebo-controlled study to examine whether an addition of demedetomidine to a commonly administered balanced anesthetic regimen improves global hemodynamic stability during skull pin application in patients undergoing craniotomy. The control of hemodynamic parameters during neurosurgical procedures is of great concern so as to ensure optimal cerebral perfusion pressure. Anesthesia maintained at adequate depths via inhalation, or narcotic agents cannot often reliably ablate the response to various surgical stimuli leading to raised ICP and ultimately reducing cerebral perfusion pressure in susceptible patients.[13] The prevention and hemodynamic control of response to nociceptive stimuli are extremely important to preserve brain homeostasis in neurosurgical patients.

Dexmedetomidine, an α2 adrenoreceptor agonist, is gaining popularity in neuroanesthesia because its sympatholytic and antinociceptive properties that may improve hemodynamic stability at critical moments of surgery.[14] Dexmedetomidine reduces the hemodynamic response and plays a role in brain protection.[15] A recent meta-analysis suggested that, among patients undergoing craniocerebral operation receiving dexmedetomidine, hemodynamics was more stable, and there was a higher survival rate compared with patients in the control groups.[16] The use of dexmedetomidine did not increase the incidence of hypotension or bradycardia, common side effects of the drug.[16] Anesthetic technique was standardized in this study; the dexmedetomidine infusion was timed such that the peak effect of the drug would coincide with the time of pin application.

There are only a few studies in literature have evaluated dexmedetomidine to reduce the hemodynamic response during skull pin application.[10111718] To the best of our knowledge, this is the first study in the literature comparing two different doses of dexmedetomidine in a prospective randomized manner for assessing the stress response to skull pin insertion. Dexmedetomidine (1 µg/kg over 10 min) attenuated the hemodynamic response to pin application.[10] Dexmedetomidine 1 µg/kg has been found to be comparable to local infiltration of lignocaine at pin application sites to attenuate the hemodynamic response associated with skull pin application. However, the use of dexmedetomidine was also associated with significantly higher incidence of hypotension and bradycardia. They concluded that further studies may be required to formulate a dosage of dexmedetomidine which will attenuate the hemodynamic response without causing significant hypotension or bradycardia.[10] We have compared the standard recommended dose 1 µg/kg over 10 min of dexmedetomidine, and a reduced dose of 0.5 µg/kg over 10 min to reduce the hemodynamic response to skull pin insertion. El Dawlatly et al. found that both dexmedetomidine 0.25 µg/kg over 10 min and lignocaine were equally effective in attenuating the hemodynamic response to pin application. The combination of low-dose dexmedetomidine infusion and local lignocaine infiltration maximally attenuated the hemodynamic response. There were no episodes of hypotension and bradycardia requiring rescue medication in concurrence to the findings our study.[18] The use of bispectral index monitor would have been ideal to assess depth of anesthesia during skull pin application; this could not be used due to nonavailability at the time when the study was initiated, and this would be the limitation of this study.

The hemodynamics were stable in the dexmedetomidine groups compared to the control group where significant number of patients required fentanyl, esmolol, or increase in isoflurane concentration to treat the tachycardia and hypertension during the skull pin application.

CONCLUSION

We found that dexmedetomidine in doses of 0.5 μg/kg was effective in attenuating the HR and MAP response to skull pin insertion as compared to a dose of 1 μg/kg. We conclude that although the standard 1 μg/kg of dexmedetomidine showed a sustained response, dexmedetomidine in a dose of 0.5 μg/kg is as effective in reducing the hemodynamic response to skull pin application.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.