dexmedetomidine as an adjunct to anesthetic induction to attenuate hemodynamic response to endotracheal intubation in patients undergoing fast track cabg

α-2 adrenergic agonists decrease sympathetic tone[13,14] and pre-operative use of clonidine, an α-2 adrenergic agonist has been shown to blunt the hemodynamic responses to noxious stimul

Address for correspondence: Dr Özge Köner, Yeditepe Universitesi Hastanesi, Devlet yolu Ankara cad 102/104, 34752 Kozyatağı,’ İstanbul, Turkiye

E-mail: ozgekoner@superonline.com

Received: 23-02-09

Accepted: 13-08-09

ABSTRACT

limits the use of excessive fentanyl doses during anesthesia induction and to block the hemodynamic effects of intubation, an adjunct may often be necessary

α-2 adrenergic agonists decrease sympathetic tone[13,14] and pre-operative use of clonidine,

an α-2 adrenergic agonist has been shown

to blunt the hemodynamic responses to noxious stimulation and to prevent the overall hemodynamic variability.[15,16] It also reduces the need for anesthetics[15,17,18] and, therefore, can be used as an adjunct to general

INTRODUCTION Hypertension, arrhythmias and myocardial ischemia induced by endotracheal intubation are the results of a reflex increase in sympathetic and sympathoadrenal activity.[1] Opioids, local anesthetics, adrenergic blocking agents and vasodilating agents have been used

to attenuate this.[1-9] High-dose opioid is preferred to attenuate this response in cardiac surgery patients.[10] However, fast- track anesthesia with low-dose fentanyl has gained popularity in recent years.[11,12] This technique

Dexmedetomidine as an adjunct to anesthetic induction to attenuate hemodynamic response to

endotracheal intubation in patients undergoing fast-track CABG

Ferdi Menda, Özge Köner, Murat Sayın, Hatice Türe, Pınar İmer, Bora Aykaç

Department of Anesthesiology, Yeditepe University, Kozyatağı, İstanbul, Turkiye

During induction of general anesthesia hypertension and tachycardia caused by tracheal intubation may lead

to cardiac ischemia and arrhythmias In this prospective, randomized study, dexmedetomidine has been used

to attenuate the hemodynamic response to endotracheal intubation with low dose fentanyl and etomidate in patients undergoing myocardial revascularization receiving beta blocker treatment Thirty patients undergoing myocardial revascularization received in a double blind manner, either a saline placebo or a dexmedetomidine infusion (1 µg/kg) before the anesthesia induction Heart rate (HR) and blood pressure (BP) were monitored

at baseline, after placebo or dexmedetomidine infusion, after induction of general anesthesia, one, three and five minutes after endotracheal intubation In the dexmedetomidine (DEX) group systolic (SAP), diastolic (DAP) and mean arterial pressures (MAP) were lower at all times in comparison to baseline values; in the placebo (PLA) group SAP, DAP and MAP decreased after the induction of general anesthesia and five minutes after the intubation compared to baseline values This decrease was not significantly different between the groups After the induction of general anesthesia, the drop in HR was higher in DEX group compared to PLA group One minute after endotracheal intubation, HR significantly increased in PLA group while, it decreased

in the DEX group The incidence of tachycardia, hypotension and bradycardia was not different between the groups The incidence of hypertension requiring treatment was significantly greater in the PLA group It is concluded that dexmedetomidine can safely be used to attenuate the hemodynamic response to endotracheal intubation in patients undergoing myocardial revascularization receiving beta blockers.

Key words: Cardiac anesthesia, dexmedetomidine, fast track

DOI: 10.4103/0971-9784.58829 Original

Article

anesthetics Dexmedetomidine, a more specific and

selective α-2 adrenergic agonist than clonidine has

a shorter duration of action than clonidine[19,20] and

because of its sedative and analgesic properties it also

can be used as an adjunct to general anesthetics.[10,21]

There is a study relating to the effects of dexmedetomidine

on hemodynamic response to endotracheal intubation

in patients undergoing coronary artery bypass graft

(CABG), however, in this study dexmedetomidine has

been used with high dose fentanyl (30 µg/kg).[10] which

may interfere with the fast track protocol routinely used

in our center

This prospective, randomized, double blinded

study was planned to investigate the hemodynamic

effects of intravenous dexmedetomidine used as

anesthetic adjunct during induction of anesthesia We

hypothesized that, in combination with fentanyl 5 µg/kg,

intravenous dexmedetomidine infusion administered

prior to endotracheal intubation may attenuate the

hemodynamic response to intubation without causing

hemodynamic compromise

MATERIALS AND METHODS

After obtaining Ethics Committee approval, 30 patients

undergoing CABG were enrolled in this study The

exclusion criteria were - ejection fraction less than

40%, age more than 60 years and body mass index

(BMI) more than 30 kg/m2, left main coronary artery

occlusion more than 50%, valvular dysfunction,

preoperative medication with clonidine or

alphametyl-dopa, history suggestive of sensitivity to drugs used

during the study, preoperative left bundle branch block,

and severe systemic disorders (e.g insulin-dependent

diabetes mellitus, kidney or liver insufficiency, severe

respiratory disorder) Intubation attempt lasting longer

than 20 seconds was also considered as exclusion

criteria All patients were receiving oral metoprolol

(50 mg/day, if less than or equal to 70 kg, 100 mg/day,

if more than 70 kg) before the surgery for at least one

week All patients received their cardiac medications

two hours before surgery

The study was designed in a placebo controlled,

double blinded, randomized, prospective fashion The

patients were randomly seperated into two groups:

placebo (PLA, n1=15) and dexmedetomidine (DEX,

n2=15) by closed envelope method Pre-medication

consisted of midazolam 0.07 mg/kg given

intra-muscularly 30 minutes before the surgery Before arriving, at the operating room, a 16- gauge peripheral venous cannula was inserted into the right antecubital vein and according to study protocol all patients were prehydrated with 500 ml Lactated Ringer's solution In the operation room, monitoring of 12 leadelectrocardiogram (ECG) , invasive blood pressure obtained via the right radial artery catheter, urinary output, pulse oxymetry, neuromuscular block level via train of four (TOF) Watch (Organon TOF-Watch® SX, Ireland) was initiated All cannulations were performed under local anesthesia In all patients, baseline systolic arterial pressure (SAPt0), diastolic arterial pressure (DAP t0), mean arterial pressure (MAP t0) and baseline heart rate values (HR t0) were recorded after a three minute resting period following the insertion of the radial artery catheter The drug infusion (dexmedetomidine

or saline placebo similar in appearance) was then commenced in a double blinded fashion DEX group received a total dose of 1 µg/kg dexmedetomidine diluted in 100 ml sodium chloride (NaCl) solution in 15 minutes and the patients in PLA group received 100 ml NaCl solution in 15 minutes After a stabilization period

of 5 minutes, SAP t1, DAP t1, MAP t1 and heart rate (HR t1) were recorded All the hemodynamic measurements were made by yet another anesthesiologist who was blinded to the groups

A mixture of etomidate (0.3 mg/kg) and fentanyl (5 µg/ kg) was prepared for the induction of anesthesia This mixture was infused via an infusion pump in three minutes immediately after t1 hemodynamic recordings After the loss of eyelid reflex, rocuronium 1 mg/ kg was administered intravenously to facilitate endotracheal intubation Two minutes after administering the induction agents SAP t2, DAP t2, MAP t2 and HR t2 recordings were done and the trachea was intubated Each intubation was performed by an anesthesiologist and accomplished within 20 seconds Hemodynamic measurements were repeated after completion of administration of dexmedetomidine or placebo infusion and 1(t3), 3 (t4) and 5 (t5) minutes after the endotracheal intubation Table 1 shows the definition criteria and stepwise treatment of hypotension, hypertension, bradycardia and tachycardia

After the last recordings propofol 6-12 mg/kg/h and remifentanil 0.05-0.25 mcg/kg/min infusions were administered for maintenance of general anesthesia, troughout Three minutes after the beginning of total intravenous anesthesia a 7-F central venous catheter

was inserted into the right internal jugular vein

Nasogastric tubing, nasopharyngeal temperature

monitoring and urinary catheterization were performed

Ringer’s Lactate solution was infused at an approximate

rate of 5 ml/kg/h The total amount of intravenous

fluids given administered was limited to 1000 ml

prior to institution of cardiopulmonary bypass (CPB)

Controlled mechanical ventilation was adjusted to

maintain end-tidal carbon dioxide between 35-45

mmHg During hypothermic (32oC) CPB, propofol

(2-3 mg/kg/h) and remifentanil (0.05-0.10 µg/kg/min)

infusion was continued At the end of the surgery

patients were transferred to the surgical intensive care

unit with propofol and remifentanil infusion running

All data are presented as mean±SD (standard

deviation) Demographic data were analyzed by

Student’s t test Analysis of variance for repeated

measures (ANOVA) was used to analyze changes

over time When statistical significance was found,

the difference between two different data for each

variable was analyzed by Mann Whitney-U test

Inter-group comparisons for hemodynamic parameters were

made with Mann Whitney-U test To compare the

incidence of hypertension, hypotension, bradycardia

and tachycardia between the groups, Fisher’s exact

test was used, P<0.05 considered significant Power

analysis was carried out by statistical software Package

G Power 3.0® and while α=0.10, 1-β=0.80, d=0.8 and

allocation ratio n1/n2=1 the effective sample size was

30 for comparison of independent means

RESULTS

The groups were similar with respect to age, weight,

gender [Table 2] Post-operative mechanical ventilation time and intensive care unit stay were identical among the groups Postoperative mechanical ventilation time

was 240.7±37.9 min in PLA group and 244.7±41.5 min

in DEX group (P>0.05) Intensive care unit (ICU) stay was 1.3±0.5 days in PLA group and 1.3±0.4 days in DEX group (P>0.05).

Figures 1-4 show HR, MAP, SAP and DAP values of the two groups during the study In the DEX group (HR) was significantly lower than the baseline in all measurement times In the placebo group all the HR values, except for

t2, were higher than the baseline value In the placebo group, HR increased significantly after the intubation compared to baseline(P=0.03, mean difference of 6.8,

CI 95% (0.6-13)) (but not compared to the baseline), whereas it decreased in the DEX group at the same time

interval (P=0.004, mean difference of 10.0, CI 95%

3.8-16.3) Inter-group comparisons are shown in Figures 1-4

In DEX group, MAP was significantly lower compared to baseline values at all the measurement times, whereas in the placebo group only MAP t2 and t5 were significantly lower than the baseline value The decrease of MAP from baseline to t2 and to t5 was not different between the groups

In DEX group SAP was significantly lower throughout the study in comparison to the baseline values, whereas in the PLA group SAP significantly decreased compared to baseline only after induction of anesthesia and 5 minutes after intubation From baseline to t2 and to t5 the SAP decrease was similar in both groups

(P>0.05) In the PLA group SAP increased significantly

after the intubation compared to post-induction period

(P=0.008, mean difference of 24.6, CI 95% (7.4-41.9),

whereas it did not change significantly in DEX group after the intubation

In DEX group DAP was significantly lower compared to

Table 1: Hemodynamic criteria and stepwise treatment

of deviations throughout the operation

Deviation/Threshold Treatment

Hypertension

SAP≥20% above BL or

SAP>160 mmHg

Fentanyl (5 µg/kg)

- 3 min interval before next step

- GTN 50 mcg/min allowed meanwhile Repeat step 1 (3 min interval) Repeat step 1 (3 min interval) Rate (↑) of propofol by 1 mg/kg/h every one minute (after the study period) Hypotension

Either SAP≤30% below BL

and <90 mmHg or SAP<

80 mmHg

- Lactated ringer → CVP within 2 mmHg of BL

- Ephedrine (2.5 mg) allowed two times meanwhile

- Dopamine (5-15 µg/kg/min) Tachycardia (no hypertension)

HR>90 bpm

Esmolol in 0.5 mg/kg increments until effect

Bradycardia

HR<40 bpm Glycopyrolate in 0.2 mg increments

SAP: systolic arterial pressure, BL: baseline value, HR: heart rate,

GTN: glyceroltrinitrate, CVP: central venous pressure

Table 2: Demographic data recorded before the operation

PLA group (n=15) DEX group (n=15) P

Number of the grafts 2

3 4

3 9 3

3 10

n: sample size, HR: heart rate, PLA: placebo, DEX: dexmedetomidine

Figure 1: Changes in the heart rate observed in the two groups during the study

period *P<0.05 compared to baseline values †P<0.05 significant difference

between the groups

Figure 3: Changes in the systolic arterial pressure in the two groups during the

study period *P<0.05 compared to baseline values †P<0.05 significant difference

between the groups

Figure 2: Changes in the mean arterial pressure in the two groups during the

study period *P<0.05 compared to baseline values †P<0.05 significant difference

between the groups

Figure 4: Changes in the diastolic arterial pressure in the two groups during

the study period *P<0.05 compared to baseline values †P<0.05 significant

difference between the groups

baseline values at all the measurement times, while in

the PLA group only DAPt2 and DAPt5 were significantly

lower than the baseline value The decrease of DAPt2 and

DAPt5 from the baseline values (ΔDAPt0-t2 and ΔDAP

t0-t5) was not different between the two groups There

was a significant increase in DAP in the placebo group

after endotracheal intubation (P=0.03, mean difference

of 17, CI 95% (7- 26.9); whereas it did not change after

the intubation in the DEX group

The incidence of hypertension, hypotension, bradycardia

and tachycardia in two groups are shown in Table 3 The

incidence of tachycardia, hypotension and bradycardia

was not different among the two groups The incidence

of hypertension was significantly higher in PLA group

(P=0.036) In all patients hypotension was treated with

500 mL crystalloid fluid replacement and none of them

required ephedrine boluses during the induction period

Fluctuation of the invasive arterial blood pressure waveform guided the fluid therapy

DISCUSSION The decrease in the BP and stabilization in the placebo group after induction may be related to preoperative

Table 3: Incidence of hypotension, hypertension, bradycardia and tachycardia

P=0.499

P=0.036

P=1.000

P=0.195

DEX: dexmedetomidine

beta blocker therapy The heart rate, however, increased

following intubation in both groups, but there was no

difference in the number of patients having tachycardia

in the two groups (two vs five patients) In the study

group, there was a significant decrease in HR and BP

at all stages However, this change was acceptable and

desirable as no bradycardia was observed in any of the

patients and hypotension occurred in three patients

Myocardial ischemia might occur during the induction

– intubation sequence in patients with coronary artery

disease Intraoperative ischemia has been associated

with a high rate of perioperative myocardial infarction.[4]

Opioids, adrenergic blocking agents, vasodilating agents

and local anesthetics have been used to attenuate the

hemodynamic effects of endotracheal intubation In a

study, Lidocaine and nitroglycerin were found to be

ineffective in controlling the hemodynamic response

to laryngoscopy and intubation.[22]

Dexmedetomidine has analgesic and sedative effects[10,21]

in addition to blunting the hemodynamic response to

endotracheal intubation as shown in our study On the

other hand, dexmedetomidine has also been shown

to reduce the extent of myocardial ischemia during

cardiac surgery.[21] The above-mentioned properties of

dexmedetomidine may encourage anesthesiologists to

use it in addition to low dose fentanyl and etomidate

anesthetic induction to attenuate the hemodynamic

response

Jalonen et al,[10] used dexmedetomidine as an anesthetic

adjunct in CABG patients They used the high dose pure

opioid tecnique (30 µg/kg iv fentanyl) during cardiac

anesthesia induction Since high dose opioid use during

fast track cardiac anesthesia is abandoned.[11,12], this

study was planned with low dose fentanyl

Dexmedetomidine can lead to bradycardia and

hypotension.[23-28] Erkola et al, have shown in

their study that in patients undergoing abdominal

hysterectomy pre-medicated with dexmedetomidine,

bradycardia was more common than in those who were

premedicated with midazolam Alone [29] theoretically,

excessive hypotension and bradycardia induced by

dexmedetomidine could limit its use in patients with

ischemic heart disease in patients receiving beta blocker

therapymay be contra indicated But, in our study, the

incidence of hypotension was not any higher than that

observed in placebo group patients, and none of the

patients experienced bradycardia requiring treatment

Jalonen et al,[10] used dexmedetomidine as an anesthetic adjunct in CABG patients receiving beta blockade and reported that the intraoperative incidence of bradycardia requiring treatment was not more common in the dexmedetomidine group than in the placebo group The authors suggested that, with the beta-receptors already blocked, additional sympathetic blockade with dexmedetomidine did not appear to decrease the heart rate further The suggestion by Jalonen and coworkers appear relevant to our study as well

This study investigated the hemodynamic effects of dexmedetomidine during induction and intubation period, further studies investigating the myocardial protecting properties of dexmedetomidine during this stage of anesthesia may be needed to provide information about that aspect of the drug

We conclude that dexmedetomidine effectively blunts the hemodynamic response to endotracheal intubation

in patients undergoing myocardial re-vascularization and can be safely used at induction of general anesthesiain combination with fentanyl, even among patients receiving beta blockers

REFERENCES

1 Mikawa K, Nishina K, Maekawa N, Obara H Comparison of nicardipine, diltiazem and verapamil for controlling the cardiovascular responses

to tracheal intubation Br J Anaesth 1996;76:221-6.

2 Fassoulaki A, Kaniaris P Intranasal administration of nitroglycerine attenuates the pressor response to laryngoscopy and intubation of the trachea Br J Anaesth 1983;5:49-52.

3 Stoelting RK Attenuation of blood pressure response to laryngoscopy and tracheal intubation with sodium nitroprusside Anesth Analg 1979;58:116-9.

4 Mikawa K, Obara H, Kusunoki M The effect of nicardipine on the cardiovascular response to tracheal intubation Br J Anaesth 1990;64:240-2.

5 Charuluxananan S, Kyokong O, Somboonviboon W, Balmongkon B, Chaisomboonpan S Nicardipine versus lidocaine for attenuating the cardiovascular response to endotracheal intubation J Anesth 2000;14:77-81.

6 Martin DE, Rosenberg H, Aukburg SJ Low dose fentanyl blunts circulatory responses to tracheal intubation Anesth Analg 1982;6:680-4.

7 KO SH, Kim DC, Han YJ, Song HS Small dose fentanyl: optimal dose of injection for blunting the circulatory responses to tracheal intubation Anesth Analg 1998;86:658-61.

8 Cork RC, Weiss JL, Hameroff SR, Bentley J Fentanyl preloading for rapid sequence induction of anesthesia Anesth Analg 1984;63; 63:60-4.

9 Lev R, Rosen P Prophylactic lidocaine use preintubation: a review

J Emerg Med 1994;12:499-506.

10 Jalonen J, Hynynen M, Kuitunen A Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting Anesthesiology 1997;86:331-45.

11 Cheng DC Fast-track cardiac surgery: economic implications in postoperative care J Cardiothorac Vasc Anesth 1998;12:72-9

12 Engoren M, Luther G, Fenn-Buderer N A comparison of fentanyl,

sufentanil, and remifentanil for fast-track cardiac anesthesia Anesth

Analg 2001;93:859-64.

13 Maze M, Tranquilly W α-2 adrenoceptor agonists: Defining the role in

clinical anesthesia Anesthesiology 1991;74:581-605.

14 Aantaa R, Scheinin M α-2-adrenergic agents in anesthesiology Acta

Anaesthesiol Scand 1993;37:433-48.

15 Flacke JW, Bloor BC, Flacke WE, Wong D, Daza S, Stead SW Reduced

narcotic requirement by clonidine with improved hemodynamic and

adrenergic stability in patients undergoing coronary bypass surgery

Anesthesiology 1987;67:909-17.

16 Quintin L, Bonnet F, Macquin I Aortic surgery: Effect of clonidine

on intraoperative catecholaminergic and circulatory stability Acta

Anaesthesiol Scand 1990;34:132-7.

17 Kaukinen S, Pyykko Potentiation of halothane anaesthesia by clonidine

Acta Anaesthesiol Scand 1979;23:107-11.

18 Bloor BC, Flacke WE Reduction of halothane anesthetic requirements

by clonidine, an α-2 -adrenergic agonist Anest Analg 1982;61:741-5.

19 Virtanen R, Savola J, Nyman L Characterization of the selectivity,

specifity and potency of medetomidine as an α-2 adrenoceptor agonist

Eur J Pharmacol 1988;9-14.

20 Scheinin H, Virtanen R, MacDonald E, Lammintausta R Medetomidine-a

novel α-2-adrenoceptor agonist:A review of its pharmacological effects

Prog Neuro-Psychopharmacol Biol Psychiatry 1989;13:635-51.

21 Wijeysundera DN, Naik JS, Beattie WS α-2 adrenergic agonists to

prevent perioperative cardiovascular complications: a meta analysis

Am J Med 2003;114:742-52.

22 Singh H, Vichitvejpaisal P, Gaines GY, White PF Comparative effects of

lidocaine, esmolol and nitroglycerin in modifying the hemodynamic

response to laryngoscopy and intubation J Clin Anesth 1995;7:5-8.

23 Martin E, Ramsay G, Mantz J, Sum-Ping ST The role of the α-2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit J Intensive Care Med 2003;18:29-41.

24 Ben-Abraham R, Ogorek D, Weinbroum AA Dexmedetomidine: a promising agent for anesthesia and perioperative care Isr Med Assoc

J 2000;2:793-6.

25 Khan ZP, Ferguson CN, Jones RM α-2 and imidazoline receptor agonists: Their pharmacology and therapeutic role Anaesthesia 1999;54:146-65.

26 Lawrence CJ, De Lange S Effects of a single pre-operative dexmedetomidine dose on isoflurane requirements and peri-operative haemodynamic stability Anaesthesia 1997;52:736-44.

27 Scheinin H, Jaakola ML, Sjovall S, Ali-Melkkila T, Kaukinen S, Turunen

J, et al Intramuscular dexmedetomidine as premedication for

general anesthesia: A comparative multicenter study Anesthesiology 1993;78:1065-75.

28 Yildiz M, Tavlan A, Tuncer S, Reisli R, Yosunkaya A, Otelcioglu S Effect

of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation: perioperative haemodynamics and anaesthetic requirements Drugs R D 2006;7:43-52.

29 Erkola O, Korttila K, Aho M, Haasio J, Aantaa R Comparison of intramuscular dexmedetomidine and midazolam premedication for elective abdominal hysterectomy Anesth Analg 1994;79:646-53.

Cite this article as: Menda F, Köner Ö, Sayın M, Türe H, İmer P,

Aykaç B Dexmedetomidine as an adjunct to anesthetic induction to attenuate hemodynamic response to endotracheal intubation in patients undergoing fast-track CABG Ann Card Anaesth 2010;13:16-21.

Source of Support: Nil, Conflict of Interest: None declared.

content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use.