Artikel Penelitian

A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl in Attenuating the Sympathetic Response to Direct Laringoscopy and Endotracheal Intubation
Suparto,* Olivia C. Flores,** Clarissa Angela A. Layusa**
*Fakultas Kedokteran Kristen Krida Wacana (UKRIDA) **University of the East Ramon Magsaysay Memorial Medical Center, Inc.

Abstract: Laryngoscopy and intubation is associated with increase in blood pressure and heart rate. This study aimed to demonstrate the efficacy of dexmedetomidine in attenuating this hemodynamic response. This was a randomized double-blind trial involving 56 patients for general anesthesia who were allocated to receive either dexmedetomidine I mcg/Kg and fentanyl 1 mcg/ Kg intravenously prior to anesthesia induction. All patients received incremental doses of propofol, atracurium and O2-sevoflurane. Systolic and diastolic blood pressures, heart rates, as well adverse events were monitored. There were a 13% decrease in SBP, 11% decrease in DBP, and 23% decrease in cardiac rate in the Dexmedetomidine group compared to a decrease of 19% SBP, 16% in DBP, and 6% in cardiac rate among those in the Fentanyl group. The decrease in the cardiac rates in the Dexmedetomidine group was significantly lower. Although SBP, DBP and cardiac rates increased with laryngoscopy and intubation, the circulatory response was attenuated in patients given Dexmedetomidine with mean increase of 25% and 29% in SBP and DBP respectively. The increase in both SBP and DBP in the Fentanyl group was 40%. The cardiac rates also increased from induction levels but the increase in the Dexmedetomidine group was significantly lower. The SBP, DBP, cardiac rate levels of patients given Dexmedetomidine at 60 seconds postintubation showed lower values than baseline, while the SBP, DBP and cardiac rates of subjects given Fentanyl exhibited sustained increase values that were greater than baseline. Bradycardia and hypotension were noted in the dexmedetomidine group with OR of 9.0 (95%CI: 1.026-78.94), and 1.5, (95%CI: 0.24-10.37) respectively. It was concluded that Dexmedetomidine at 1 mcg/Kg and Fentanyl at 1 mcg/Kg both produced lowering of blood pressures and cardiac rates, with significantly lower mean heart rates with Dexmedetomidine. Laryngoscopy and intubation produced less blood pressure increases in the Dexmedetomidine group and significantly lower cardiac rates. Dexmedetomidine reduced the amount of Propofol to produce unconsciousness. Keywords: dexmedetomidine, fentanyl, blood pressure, heart rate, direct laryngoscopy, endotracheal intubation

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A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl

Uji Coba Acak dalam Menentukan Efektivitas Dexmedetomidine terhadap Fentanyl dalam Menekan Respons Simpatis pada Laryngoskopi dan Intubasi Suparto,* Olivia C. Flores,** Clarissa Angela A. Layusa**
*Fakultas Kedokteran Kristen Krida Wacana (UKRIDA) **University of the East Ramon Magsaysay Memorial Medical Center, Inc.

Abstrak: Laringoskopi dan intubasi berhubungan dengan kenaikan tekanan darah dan denyut jantung. Studi ini bertujuan menunjukkan efektivitas dexmedetomidine dalam menumpulkan respon hemodinamik tersebut. Penelitian ini dilakukan secara acak, double-blind, melibatkan 56 pasien yang menjalani anestesi umum, yang terbagi menjadi dua kelompok dan masing-masing mendapatkan dexmedetomidine 1mcg/Kg atau fentanyl 1 mcg/Kg intravena sebelum dilakukan induksi anestesi. Semua pasien menerima dosis bertingkat dari propofol, atrakurium dan O2sevoflurane. Tekanan darah sistolik, diastolik, denyut jantung, dan efek samping dimonitor. Terdapat penurunan tekanan darah sistolik sebesar 13%, tekanan darah diastolik 11%, dan denyut jantung sebesar 23% pada grup Dexmedetomidine dibandingkan dengan penurunan tekanan darah sistolik sebesar 19%, tekanan darah diastolik 16%, dan denyut jantung 6% pada grup Fentanyl. Penurunan denyut jantung pada grup Dexmedetomidine secara signifikan lebih rendah. Meskipun tekanan darah sistolik, diastolik dan denyut jantung meningkat dengan laringoskopi dan intubasi, respons ini dilemahkan pada pasien-pasien yang diberikan Dexmedetomidine, dengan rata-rata kenaikan tekanan darah sistolik sebesar 25% dan diastolik sebesar 29%. Kenaikan tekanan darah sistolik dan diastolik pada grup Fentanyl sebesar 40%. Denyut jantung juga meningkat tetapi peningkatan pada grup Dexmedetomidine secara signifikan lebih rendah. Tekanan darah sistolik, diastolik dan denyut jantung 60 detik sesudah intubasi pada grup Dexmedetomidine menunjukkan tingkat yang lebih rendah dibandingkan awal, sedangkan pada grup Fentanyl menunjukkan nilai yang tetap meningkat dibandingkan awal. Bradikardi pada grup Dexmedetomidine terjadi dengan OR 9,0 (95%CI: 1,026-78,94) dan hipotensi terjadi dengan OR 1,5 (95%CI: 0,24-10,37). Sebagai kesimpulan, baik Dexmedetomidine 1 mcg/Kg maupun Fentanyl 1 mcg/Kg dapat menurunkan tekanan darah dan denyut jantung, namun denyut jantung rata-rata pada grup Dexmedetomidine secara signifikan lebih rendah. Laringoskopi dan intubasi pada grup Dexmedetomidine menunjukkan peningkatan tekanan darah lebih rendah dan denyut jantung yang secara signifikan. Dexmedetomidine mengurangi dosis Propofol dalam menurunkan kesadaran pasien. Kata kunci: dexmedetomidine, fentanyl, tekanan darah, denyut jantung, laringoskopi direk, intubasi endotrakeal.

Introduction Laryngoscopy and tracheal intubation are associated with a sympathetically mediated increase in blood pressure by 40-50% and heart rate by 20% that may be deleterious in patients with underlying cardiovascular and cerebrovascular disease.1,2 To ameliorate this pressor response, various methods have been tried including adrenergic blockers, vasodilators, calcium channel blockers, alpha 2 agonists, narcotics and inhalation anesthetics.1-14 One of the most studied drugs to attenuate the hemodynamic response to laryngoscopy and tracheal intubation during anesthetic induction is fentanyl.4-9 Fentanyl is a shortacting synthetic opioid agonist 75-125 times more potent than morphine. It has a rapid onset but has a distinct time

lag between the peak plasma fentanyl concentration and peak slowing on the EEG of around 3- 7 minutes. This reflects the delay in the attainment of a drug concentration in the plasma and the clinical effect.15,16 Yildiz M et al.17 investigated the effect of a single preinduction intravenous dose of dexmedetomidine (1 mcg/kg) on the cardiovascular response from laryngoscopy and endotracheal intubation, need for supplemental anesthetic agent, and perioperative hemodynamic stability. Their results showed that preoperative administration of single dose of dexmedetomidine resulted in progressive increase in sedation, blunted the hemodynamic responses during laryngoscopy, and reduced opioid and anesthetic requirements. Furthermore, dexmedetomidine decreased blood pressure and

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A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl heart rate as well as the recovery time after the operation.17 Dexmedetomidine is a relatively new, highly selective, short-acting central alpha 2 agonist. Activation of 2-receptors leads to: dose dependent sedation and anxiolysis, analgesia (supraspinal and spinal sites), decrease plasma catecholamines, centrally mediated bradycardia and hypotensive effects, diuresis from the inhibition of ADH release and antagonism of ADH tubular effects, and decongestion a and antisialogogue effects.18 Dexmedetomidine has increasingly gained popularity among anesthesiologists and intensive care physicians abroad as adjuvant to general and regional anesthesia techniques, and as a sedative. Its administration potentiates the effect of other sedative and hypnotic agents while causing minimal respiratory depression. It also reduce the sympathetic response-thus minimizing changes in blood pressure and heart rate-during critical moments such as larynb goscopy and intubation. However, bradycardia and hypotension may ensue.19,20 Now that this relatively new drug has been made available in our institution, the proponents of this study would like to test its purported favorable effects on blood pressure and cardiac rate during direct laryngoscopy and intubation. The study would like to determine the efficacy of dexmedetomidine in attenuating hemodynamic response to direct laryngoscopy and endotracheal intubation. Furthermore, it seeks to determine the differences in systolic and diastolic blood pressures and heart rates after laryngoscopy and endotracheal intubation between the patient groups given dexmedetomidine and fentanyl. Dexmedetomidine and fentanyls ability to decrease the anesthetic requirements was determined by comparing the amount of induction agent (propofol) needed to abolish the eyelash reflex. Finally, the authors aimed to compare the presence and degree of adverse events between the two drugs. Materials and Methods This is a randomized controlled trial to compare the hemodynamic effects of Fentanyl and Dexmedetomidine during direct laryngoscopy and intubation of the trachea. The anesthesiologists who did the direct laryngoscopy and intubation, the observers, and the data analysts, were all blinded as to the drug given to the patients. Ethics approval was obtained prior to the conduct of the study. Sample size was calculated with a power of 80% and a probability of 0.05 alpha error assuming a homogeneity of variance for both dexmedetomidine and fentanyl and an effect size equal to 20, yielded 28 for each group. The population comprised of surgical in-patients and out-patients of the UERMMMC Hospital from July to September 2008. All patients were to undergo general endotracheal anesthesia, aged 18 and above, with ASA risk I-III elective or emergency, and with voluntary, written, informed consent were included in the trial. Excluded were patients who were severely hypovolemic, those with anticipated dif128

ficult airway, patients diagnosed with 2nd-3rd heart block, and sinus bradycardia <50/min. Subjects who had longer than 30 seconds laryngoscopy, and/or multiple attempts at laryngoscopy/intubation were considered drop-outs, but would be included in the final analysis. Experimental Maneuver After a thorough pre-operative evaluation, an informed consent was obtained from each patient. Standard premedication with Nalbuphine (5-10 mg) and/or Hydroxyzine (25-50 mg) or Promethazine 25-50 mg IM were administered to the patients. Upon arrival at the operating room, allocation of subjects was made randomly with the aid of a randomized table contained in a sealed, opaque, individualized envelope. Patients were hooked to standard monitors such as NIBP, ECG, and pulse oximetry. Patients who belonged to the Dex group were given dexmedetomidine 1 mcg/Kg diluted with NSS to make 10 ml volume, administered slow IV for 10 minutes. On the other hand, those who belonged to the Fent group were given Fentanyl 1 mcg/Kg diluted with NSS also to make 10 mL volume, injected slow IV for 10 minutes. This was followed by Propofol 1% injection given in incremental dose until loss of eyelash reflex was attained. Sevoflurane at 0.5% was turned on and Atracurium 0.5 mg/Kg was given. Four minutes after atracurium injection, sevoflurane was increased to 2.5 vol % to deepen the anesthesia. Five minutes after Atracurium (expected onset of paralysis), the anesthesiologist commenced the direct laryngoscopy and intubation. As previously mentioned, more than 30 seconds attempt at laryngoscopy and intubation will be dropped out since hemodynamic responses from these stimuli are expected to increase markedly. Subjects with significant bradycardia (HR <50/min) during induction were to be given atropine 400 mcg IV. Subjects who developed significant hypotension (reduction of >20% from their usual BP or BP <90 mmHg systolic) during induction were first treated with fluid loading (10mL/Kg), lowered concentration of the inhalational gas, and/ or Ephedrine (510mg IV) if BP became worse or did not improve. Another observer unaware of the drug given took note of the blood pressures and cardiac rates of subjects at baseline, 15 minutes after injection of inducing agents (test drugs+ muscle relaxant), and 30 and 60 seconds after successful intubation. Other data noted were the total amount of propofol used per patient, and adverse events during and up to 4 hours after induction. Results The results were examined using the SPSS v.13. The BP and cardiac rates were analyzed with t-test assuming equality of variance between the two test drugs. P values <0.05 were considered significant. The odds ratio of the adverse events on the other hand were computed using MantelHaenszel estimate and verified further with the Pearson ChiMaj Kedokt Indon, Volum: 60, Nomor: 3, Maret 2010

A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl square test with p values of <0.05 considered significant association.
Table 1. Frequency of Demographic Characteristics Variable Age 18-34 35-51 52-68 69-85 Gender Male Female ASA Classification ASA I ASA II ASA III Dexmedetomidine Fentanyl

8 (29%) 10 (35%) 8 (29%) 2 (7%) 11 (40%) 17 (60%) 10 (36%) 16 (57%) 2 (7%)

6 (21%) 11(40%) 6 (21%) 5 (18%) 12 (43%) 16 (57%)

Dexmedetomidine group was significantly lower with p-value of 0.000. The systolic and diastolic blood pressures and heart rates increased in both groups after laryngoscopy and intubation. The mean increase in the systolic and diastolic pressures at 30 and 60 seconds post intubation in patients given either drug were similar and not statistically significant. On the other hand, the increase in heart rate at 30 sec and 60 sec from the start of laryngoscopy was significantly different between the two groups (p<0.05), with patients in the dexmedetomidine group exhibiting less tachycardia.
50
% Difference from baselini

10 (36%) 15 (54%) 3 (10%)

40 30 20 10 0 -10 -20 -30

Time

Table 2. Demographic Profile Dexmedetomidine Age Sex (M/F) (n) Weight 4516.24 11/12 60.1112.75 Fentanyl 49.6118.01 17/16 58.5411.96 P. value 0.319 0.636

BL

BL to 15 min 15 min to 30 30 sec to 60 sec sec

SBP (dex) DBP (dex) HR (dex) SBP (fen) DBP (fen) HR (fen)

Mean Presure (mmHg) / Heart Rate (bpm) Mean Presure (mmHg) / Heart Rate (bpm)

Table 1 and 2 show that there was adequate representation of subjects in both groups based on age, gender, and ASA class. The demographic data were similar, which showed no significant difference between the groups.
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Figure 4a. Difference in Systolic, Diastolic BP, and Heart rate from one Point in Time to the Previous Time, from Baseline to 60 Sec Post Intubation.

160 140 120 100 80 60 40 20 0 Base line 30 sec

SBP Dex DBP Dex HR Dex SBP Fen DBP Fen HR Fen

Mean pressures (mmHg) and heart rate (bpm)

140 120 100 80

SBP (Dex) DBP (Dex) HR (Dex) SBP (Fen)

60 40 20 0 BL 15 min T30 T60

DBP (Fen) HR (Fen)

Time from Baseline

160 140 120 100 80 60 40 20 0 SBP Dex DBP Dex HR Dex SBP Fen DBP Fen HR Fen

Relative Time

Figure 3. Comparison of Mean Systolic and Diastolic Pres sures and Heart Rates at Baseline, 15 Min PostInduction, 30 Sec and 60 Secs Post-Intubation

The baseline blood pressures and heart rates among the patients in both groups were comparable. Fifteen minutes after administration of the test drugs, the systolic and diastolic blood pressures as well as heart rates in both group decreased similarly. The decrease in the SBP in patients given Fentanyl was significantly lower with p-value of 0.04. On the other hand, the decrease in the heart rate in the

Time from Baseline Base line 60 sec *This difference between the 2 groups was statistically significant

Figure 4b. Difference in Systolic, Diastolic BP, and Heart Rate from one Point in Time to the Previous Time, from Baseline to 30 Secs and 60 Secs Postintubation

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A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl The SBP, DBP and heart rates in both groups all decreased after injection of the test drugs but only the change in heart rate in the Dexmedetomidine group was found to be statistically significant with p-value of 0.000. Thirty seconds after successful laryngoscopy and intubation, the SBP, DBP and heart rates similarly increased with slightly higher measurements in the Fentanyl group. SBP and DBP increased by 40% in the Fentanyl group compared to 25%-28% in the Dexmedetomidine group. However, this difference was not significant. Conversely, the cardiac rate in the Dexmedetomidine group at 30 seconds postintubation was 11% lower than baseline values. When compared to Fentanyl, the cardiac rate was 12% higher than baseline levels. This difference between the 2 groups was statistically significant with pvalue of 0.000. Sixty seconds after intubation, the Dexmedetomidine group had a decreased in the SBP by 5% and DBP by 10% from the 30- second postintubation levels. In the Fentanyl group, there was likewise a decrease in the SBP by 2% and DBP by 1% from the 30-second postintubation levels. The only significant change was seen in the much lower DBP in the Dexmedetomidine group (p-value 0.04). The heart rates in both groups increased, with a slightly greater increase in patients belonging to the Fentanyl group. Interestingly, the SBP, DBP, and heart rates of the patients in the Dexmedetomidine group at 60 seconds postintubation returned slightly lower than baseline values. In contrast, the mean SBP was 7%, DBP 12%, and heart rate 18% higher than baseline measurements in the Fentanyl group. This difference between the 2 groups was statistically significant.
Table 5. Propofol Requirements (in mg) N Dexmedetomidine Fentanyl 28 28 MeanSD 47.1422.25 86.0720.61 P- value 0.000 Table 6. Frequency of Bradycardia and Hypotension Among the Dexmedetomidine and Fentanyl Groups Bradycardia Yes No Hypotension Ye s No

Dexmedetomidine 7 (25%) 21 (75%) 3 (10.7%) 25 (89.3%) Fentanyl 1 (3.6%) 27 (96.4%) 2 (7.1%) 26 (92.9%) p-value (Pearson 0.022 0.639 Chi square) Odds ratio (Mantel9.0 1.560 Haenszel Estimate) 95% CI 95% CI (1.026, 78.943) (0.24, 10.137) p<0.05 is significant; Confidence Interval (CI) = 95%

The adverse events were noted to have occurred between the periods of induction to before laryngoscopy when there was minimal to no stimulus to the patients. None of the subjects were dropped out from the study. Discussion Laryngoscopy and intubation are two of the most consistent maneuvers that lead to significant increases in blood pressure and heart rate. This had been attributed to a sympathetic response as evidenced by an increase in the circulating catecholamine levels. These changes were reported to be greatest 60 seconds after intubation of the trachea that last for 5-10 minutes. 1 It is for these reasons that numerous studies had been undertaken to search for effective and safe drugs to attenuate this sympathetic response. The major findings in this study show that patients given either Dexmedetomidine 1 mcg/Kg or Fentanyl 1 mcg/Kg produced comparable lowering of DBP before direct laryngoscopy and intubation with a more significant lowering in the SBP of patients given Fentanyl. There was a 13% decrease in SBP, 11% decrease in DBP, and 23% decrease in cardiac rate in the Dexmedetomidine group compared to a decrease of 19% SBP, 16% in DBP, and 6% in cardiac rate among those in the Fentanyl group. The decrease in the cardiac rates in the Dexmedetomidine group was significantly lower. The results above are consistent with the study of Shehabi et al21 who claimed that Dexmedetomidine produced predictable falls in BP and cardiac rate in patients given Dexmedetomidine sedation in the ICU. Their results showed 16% (vs 13%) reduction in mean systolic blood pressure (SBP) and 21% (vs. 23%) reduction in heart rate. Although SBP, DBP and cardiac rates increased with laryngoscopy and intubation, the circulatory response was attenuated more in those patients given Dexmedetomidine with a mean increase of 25% and 29% in the SBP and DBP respectively. The increase in both SBP and DBP in the Fentanyl group was 40%, the same as the average reported increase in the blood pressures of patients as a manifestation of the sympathetic response.1,2 The cardiac rates also increased from induction levels but the increase in the Dexmedetomidine group was signifiMaj Kedokt Indon, Volum: 60, Nomor: 3, Maret 2010

Values are expressed as means SD; p<0.05 is significant.

The amount of propofol used was significantly less in the Dexmedetomidine group with p-value of 0.000. Bradycardia was significantly more common in the Dexmedetomidine group with p-value of 0.022. The odds of developing bradycardia is 9 times more likely to occur when Dexmedetomidine 1 mcg/Kg IV in 10 minutes is given. The lowest reading recorded was 43 (see Appendix 1). Alternatively, there is no significant difference in the occurrence of hypotension in the Dexmedetomidine and Fentanyl group. Statistically, the is no significat difference betwen the odds of developing hypotension with Dexmedetomidine at 1 mcg/Kg IV and Fentananyl 1 mcg/Kg IV .

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A Randomized Controlled Trial on the Effectiveness of Dexmedetomidine Versus Fentanyl cantly lower. When one would compare the effect of Dexmedetomidine on heart rate from baseline values, there was a reduction of 11 counts while the Fentanyl group showed an increase of 12 counts from baseline. This maybe secondary to the centrally-mediated bradycardic effect of Dexmedetomidine.18,19 This also validates the findings of Yildiz et al17 who reported that a single dose of dexmedetomidine 1 mcg/Kg given preoperatively produced blunting of the hemodynamic responses during laryngoscopy and decrease in heart rate, and findings of Feng et al,4 which showed that Fentanyl at 3 mcg/Kg attenuated BP changes but not tachycardia. The SBP, DBP, cardiac rate levels of patients given Dexmedetomidine at 60 seconds postintubation showed lower than baseline values, while the SBP, DBP and cardiac rates of subjects given Fentanyl exhibited sustained increase values that were greater than baseline measurements. This confirms that Dexmedetomidine produce a more favorable hemodynamic profile than Fentanyl. In contrast to the report of Shribman et al.1, the vital signs recorded in this study showed marked changes at 30 seconds postintubation with recovery at 60 seconds postintubation, compared to their results which showed greatest vital sign changes at 60 seconds after intubation of the trachea. The total amount used to produce loss of eyelash response to signal a state of unconsciousness was markedly lower in those patients administered Dexmedetomidine. This can be accounted for by the sedative effect of the drug as it acts on the locus ceruleus. This is a small neuronal nucleus in the upper brainstem which is an important modulator of wakefulness.22 The adverse events noted in this study were bradycardia in 7 patients who were treated with Atropine, and hypotension in 3 patients that were corrected with volume therapy and decreasing the concentration of the inhalational agent. These adverse events were all observed after administration of the test drug and induction agents (Propofol and Atracurium) up to the time prior to laryngoscopy. The odds for developing bradycadia with Dexmedetomidine at the dose used is 9.0 (95%CI: 1.026-78.94). Bradycardia is more likely to occur while hypotension similar in the Dexmedetomidine and Fentanyl group. This may reflect the centrally- mediated lowering of the cardiac rate and sympatholytic effect of Dexme-detomidine.15,23 Moreover, the additive effects of Propofol and the inhalational anesthetic may have contributed to the bradycardia and hypotension at the time when there was minimal to no-stimulus to the patients. Fentanyl is a commonly studied drug to blunt the circulatory effects of laryngoscopy and intubation. Several trials have tried varying doses from 2 mcg/Kg- 8 mcg/Kg given 1 minute to 10 minutes before intubation.2,16 In these trials, the Fentanyl dose found to be effective with minimal adverse effect is 2 mcg/Kg. The present study utilized a lower dose of Fentanyl at 1 mcg/Kg similar to the dose used by Uzmcgil et al, which showed good effect in preventing patient reaction with LMA insertion.24 The inadequate effect of Fentanyl to attenuate the hemodynamic response in this study maybe related to the lower dose used and longerthan-optimal time lag from drug administration to laryngoscopy. Conclusion Dexmedetomidine at 1 mcg/Kg and Fentanyl at 1 mcg/ Kg both produced lowering of blood pressures and cardiac rates, with significantly lower mean heart rates with Dexmedetomidine. Laryngoscopy and intubation produced less blood pressure increases in the Dexmedetomidine treated patients and significantly lower cardiac rates than those treated with Fentanyl. In addition, those given Dexmedetomidine showed return of hemodynamic parameters to baseline levels, while those given Fentanyl exhibited a sustained increase in blood pressure and cardiac rate well above baseline levels. Dexmedetomidine markedly reduced the amount of Propofol to produce unconsciousness. However, it can produce reversible lowering of heart rate prior to onset of physical stimulus like laryngoscopy and intubation. Recommendations For other investigators interested in pursuing this trial, the proponents of this study would like to recommend the following: Different dosages of Fentanyl be tried in search for the equipotent dose to 1 mcg/Kg of Dexmedetomidine. Lower Dexmedetomidine dose to decrease occurrence of adverse events. Look into the efficacy of preoperative atropine administration to prevent bradycardia with Dexmedetomidine 1 mcg/Kg. References
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