Glycopyrrolate during sevoflurane–remifentanil-based anaesthesia for cardiac catheterization of children with congenital heart disease

K. Reyntjens1,*, L. Foubert2, D. De Wolf3, G. Vanlerberghe4 and E. Mortier1

1 Department of Anaesthesiology, University Hospital Ghent, Ghent, Belgium. 2 Department of Anaesthesiology and CCM, OLV Hospital, Aalst, Belgium. 3 Department of Paediatric Cardiology, University Hospital Ghent, Ghent, Belgium. 4 Department of Anaesthesiology, H.H.R.M. Hospital, Menen, Belgium

* Corresponding author. E-mail: k.reyntjens{at}ugent.be

Accepted for publication August 31, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Remifentanil is recommended for use in procedures with painful intraoperative stimuli but minimal postoperative pain. However, bradycardia and hypotension are known side-effects. We evaluated haemodynamic effects of i.v. glycopyrrolate during remifentanil–sevoflurane anaesthesia for cardiac catheterization of children with congenital heart disease.

Methods. Forty-five children undergoing general anaesthesia with remifentanil and sevoflurane were randomly allocated to receive either saline, glycopyrrolate 6 µg kg–1 or glycopyrrolate 12 µg kg–1. After induction of anaesthesia with sevoflurane, i.v. placebo or glycopyrrolate was administered. An infusion of remifentanil at the rate of 0.15 µg kg–1min–1 was started, sevoflurane continued at 0.6 MAC and cisatracurium 0.2 mg kg–1 was given. Heart rate (HR) and non-invasive arterial pressures were monitored and noted every minute for the first 10 min and then every 2.5 min for subsequent maximum of 45 min.

Results. Baseline HR [mean (SD)] of 117 (20) beats min–1 decreased significantly from 12.5 min onwards after starting the remifentanil infusion in the control group [106 (18) at 12.5 min and 99 (16) beats min–1 at 45 min]. In the groups receiving glycopyrrolate, no significant decrease in HR was noticed. Glycopyrrolate at 12 µg kg–1 induced tachycardia between 5 and 9 min after administration. Systolic and diastolic arterial pressures decreased gradually, but there were no significant differences in the pressures between groups.

Conclusion. I.V. glycopyrrolate 6 µg kg–1 prevents bradycardia during general anaesthesia with remifentanil and sevoflurane for cardiac catheterization in children with congenital heart disease. Administering 12 µg kg–1 of glycopyrrolate temporarily induces tachycardia and offers no additional advantage.

Keywords: analgesics opioid, remifentanil ; children, congenital heart disease ; complications, bradycardia ; procedure, cardiac catheterization


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Cardiac catheterization in children with congenital heart disease can be performed under general anaesthesia. If a fast and stable recovery is ensured, the benefits of general anaesthesia i.e. better immobilization, and optimal control of haemodynamics and airway outweigh the advantages of monitored sedation. Remifentanil, a short acting µ-receptor opioid agonist, provides good intraoperative analgesia, predictable emergence and minimal risk of postoperative respiratory depression. It has a suitable pharmacological profile for cardiac catheterization, a procedure that is associated with variable and unpredictable procedural times, requirement of deep anaesthesia towards the end of the procedure (balloon dilatation of valvular or vascular stenosis) and minimal need for postoperative analgesia.

Vasodilatation and bradycardia associated with the use of remifentanil are possible drawbacks in a patient population in whom ventricular filling pressure and rate dependency of cardiac output are critical determinants of haemodynamic stability.1

The aim of this study was to investigate whether previously reported bradycardia during remifentanil–sevoflurane anaesthesia for cardiac catheterization can be prevented by administration of i.v. glycopyrrolate at induction of anaesthesia.2


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After institutional Ethics Committee approval and written informed consent from the parents, 45 children (ASA II or more, aged 1–36 months) with congenital heart disease and undergoing cardiac catheterization under general anaesthesia, were enrolled in a prospective, randomized, placebo-controlled, double-blind study. Using sealed envelopes, the patients were randomly allocated to one of the three groups by an anaesthetic nurse. For patients receiving glycopyrrolate, the dose was calculated according to body weight; Group G6 received glycopyrrolate 6 µg kg–1 and Group G12 received 12 µg kg–1 diluted to 2 ml with normal saline. In the placebo group (Group G0) 2 ml of normal saline was used. The anaesthetist was unaware of the group allocation. All children were fasted for at least 4 h before the procedure. Intake of clear fluids was allowed up to 3 h before induction of anaesthesia. Midazolam 0.3 mg kg–1 was administered rectally in the catheterization unit 20 min before induction of anaesthesia. The monitoring included ECG, non-invasive measurement of arterial pressure, capnography and pulse oximetry. In addition, inspiratory and expiratory gas concentrations (Capnomac, Ultima, Datex, Finland) were measured. After baseline measurements of haemodynamic variables, anaesthesia was induced with sevoflurane in decreasing doses (8–6–4–2 % in oxygen 100%) using a facemask. A 22 or 24 G cannula was inserted in a peripheral vein. After having obtained venous access the appropriate glycopyrrolate or placebo solution was administered i.v., and a remifentanil infusion was started at 0.15 µg kg–1 min–1. In addition cisatracurium 0.2 mg kg–1 was given and an i.v. infusion of glucose 5% at 5 ml kg–1 min–1 was started. Patient's trachea was intubated using an appropriately sized uncuffed tracheal tube (Mallinckrodt, Ireland) 4 min after the beginning of the remifentanil infusion, and the lungs were mechanically ventilated with oxygen–air, of 0.4, to maintain end-tidal carbon dioxide concentration between 4.5 and 5.5 kPa. Paracetamol 20 mg kg–1 was then given rectally and anaesthesia was maintained with sevoflurane (0.6 MAC, age adjusted, in oxygen–air) and remifentanil at 0.15 µg kg–1 min–1. For the first 10 min of the procedure heart rate (HR) and arterial pressure were monitored every minute. Thereafter, these parameters were measured every 2.5 min. Hypertension and hypotension were considered significant if systolic arterial pressure (SAP) differed by more than 20% from the baseline value for more than 1 min. Hypertension was planned to be treated with remifentanil bolus 0.2 µg kg–1, and hypotension with phenylephrine bolus 1 µg kg–1.

Statistical analysis was performed using repeated measures analysis of variance (ANOVA) with a Dunnett multiple comparisons post-hoc test for within-group evaluation. Differences between groups were analysed with a one-way ANOVA and a Bonferroni multiple comparisons test. P<0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Forty-five patients were enrolled in the study; 15 received placebo (Group G0), 15 received glycopyrrolate 6 µg kg–1 (Group G6), and the remaining 15 received glycopyrrolate 12 µg kg–1 (Group G12). Four procedures in Group G0, one in Group G6, and three in Group G12 lasted not longer than 45 min; consequently, the statistical analysis was limited to data until 45 min after induction of anaesthesia.

The groups were matched for patient characteristics and duration of procedure (Table 1). Induction of anaesthesia and tracheal intubation did not alter HR and mean arterial pressure (MAP) during the first 10 min of starting remifentanil infusion in the three groups, except for an increase in HR starting between 1 and 5 min following tracheal intubation in Group G12 (Table 2). In Group G0, HR decreased significantly from the baseline value from between 12.5 and 45 min. In contrast to the placebo group, HR was preserved in both the glycopyrrolate groups (Fig. 1); HR was significantly lower in Group G0 compared with Group G6 or Group G12 from 3 min after starting the remifentanil infusion (Fig. 1 and Table 2). No significant difference in HR between Group G6 and Group G12 was seen.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient characteristics, duration of procedure, type of procedure and pathology. Group G0, placebo; Group G6, glycopyrrolate 6 µg kg–1; Group G12, glycopyrrolate 12 µg kg–1. Data are given as numbers, mean (range) or mean (SD)

 

View this table:
[in this window]
[in a new window]
 
Table 2 Changes in heart rate (HR), systolic and diastolic arterial pressure. Group G0, placebo; Group G6, glycopyrrolate 6 µg kg–1; Group G12, glycopyrrolate 12 µg kg–1. SAP, systolic arterial pressure; DAP, diastolic arterial pressure. T0, sevoflurane 1 MAC, before infusion of remifentanil; T1–10, 1–10 min after starting remifentanil infusion; T4 coincides with tracheal intubation. n=15 in each group. Data are given as mean (SD).

 


View larger version (19K):
[in this window]
[in a new window]
 
Fig 1 Heart rate (HR) during remifentanil infusion in the three groups: Group G0, placebo; Group G6, glycopyrrolate 6 µg kg–1; Group G12, glycopyrrolate 12 µg kg–1. T0 is time period before starting remifentanil infusion, T12.5–T45 relate to 12.5–45 min after starting the infusion. Data are mean (SD). *P<0.05 vs T0; {dagger}P<0.05 vs both Group G6 and Group G12.

 
The MAP decreased significantly from 12.5 min after starting remifentanil in Group G12, and from 17.5 min in Group G0 and Group G6 (Fig. 2). There were no significant differences in systolic, diastolic, or MAP between any of the groups. Five patients needed treatment for hypotension (one in Group G0, two in Group G6, and two in Group G12). None of the patients was treated for hypertension. One patient in G12 needed anti-emetic treatment. We encountered no incidents of postoperative respiratory depression or hypoxia.



View larger version (43K):
[in this window]
[in a new window]
 
Fig 2 Changes in MAP during remifentanil infusion. Group G0, placebo; Group G6, glycopyrrolate 6 µg kg–1; Group G12, glycopyrrolate 12 µg kg–1. T0 is time period before starting remifentanil infusion, T12.5–T45 relate to 12.5–45 min after starting the infusion. Data are mean (SD) *P<0.05 vs T0; #P<0.05 vs T0; §P<0.05 vs T0, within each group.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
General anaesthesia for cardiac catheterization in children with congenital heart disease decreases the risk of respiratory depression, hypercapnia, and acidosis; these conditions can be detrimental in this patient population and can complicate interpretation of haemodynamic measurements that are necessary for decision making.3 The use of remifentanil during general anaesthesia for cardiac catheterization is associated with bradycardia.2 Although pre-treatment with glycopyrrolate can prevent bradycardia during halothane anaesthesia,4 its use in preventing opioid-induced bradycardia had not been studied so far.

The major finding of our study is that glycopyrrolate 6 or 12 µg kg–1 administered as an i.v. bolus after induction of anaesthesia, prevents bradycardia during remifentanil–sevoflurane anaesthesia for catheterization of children with congenital heart disease. In the placebo group, bradycardia occurred from 12.5 min after the start of the remifentanil infusion, whereas in both glycopyrrolate groups no bradycardia was noticed during 45 min of study period. Also, the HR changes were qualitatively similar in both the glycopyrrolate groups in this time course (Fig. 1), suggesting no benefit of using the higher dose. In quantitative terms, the higher dose of glycopyrrolate caused tachycardia 1 min after tracheal intubation and this was significant until 5 min after intubation. The clinical relevance of this tachycardia is uncertain as maximal mean HR was only 140 beats min–1 (Table 2). The time course of this HR increase coincided with the pressor response to tracheal intubation, which typically peaks at 1–2 min after laryngoscopy and usually subsides within 5–6 min, whereas tachycardia may persist for 10 min.5 Because the stress response to tracheal intubation was blunted in Group G0 and Group G6, and the anaesthetic regimen was the same in the three groups, the bolus effect of glycopyrrolate is a plausible explanation for the tachycardia seen in Group G12. Whereas a bolus of remifentanil can induce severe bradycardia and hypotension,5 6 even our technique of using low concentration–high flow continuous infusion of remifentanil induced bradycardia (Group G0). At the infusion rate set in our study, patients received a total of remifentanil 0.6 µg kg–1, in the time period of 4 min, before tracheal intubation; this dose is sufficient to prevent stress response.5 The addition of glycopyrrolate 6 µg kg–1 not only prevented bradycardia during induction of anaesthesia, but also kept HR virtually constant during 45-min study period.

We preferred giving glycopyrrolate by i.v. route as compared with the rectal route because the latter route can be associated with variable and/or incomplete gastrointestinal absorption.7 In a previous study in a similar population, rectal glycopyrrolate could not prevent bradycardia, albeit higher doses of remifentanil were used.2 After i.v. bolus, the mean distribution phase half-life of glycopyrrolate is 2.22 (1.26) min and mean elimination phase half life is 0.83 (0.27) h.7 Nevertheless, in the present study it protected against bradycardia for a prolonged period of time. It should also be noted that there is no linear relationship between the plasma level of glycopyrrolate and the HR response after i.v. administration.6 We preferred glycopyrrolate to atropine because the latter has central effects and leads to more prolonged impairment of parasympathetic nervous system control of HR than equipotent doses of glycopyrrolate.8

Although the use of glycopyrrolate efficiently prevented bradycardia, there was a significant, but clinically acceptable decrease in arterial pressure in all study groups. The decrease in MAP (between 15 and 20%) in this study was consistent with the findings of other studies in paediatric patients.2 9 10 In children undergoing general surgery, Chanavaz and colleagues studied the effect of atropine during remifentanil–sevoflurane anaesthesia using echocardiography.9 They described a reduction in cardiac index related to a decrease in HR in the placebo group and a decrease in stroke volume in atropine-treated patients, without changes in myocardial contractility. Although we did not study myocardial contractility in our study, the effect of remifentanil–sevoflurane on myocardial contractility is likely to be as small in our study as in the study by Chanavaz and colleagues. Because glycopyrrolate kept HR virtually unchanged in our patients, this raises the question whether the decrease in MAP in our patients was related to a decrease in preload and/or a decrease in afterload with this anaesthetic technique.

In conclusion, remifentanil–sevoflurane is a safe and feasible anaesthetic technique for paediatric cardiac catheterization, but is associated with bradycardia and a moderate degree of hypotension. We have shown that i.v. glycopyrrolate 6 µg kg–1 at induction of anaesthesia effectively prevents bradycardia, but not a moderate degree of hypotension.


    Acknowledgments
 
Support for this study was solely provided by departmental and institutional funding.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Beers R, Camporesi E. Remifentanil update: clinical science and utility. CNS Drugs 2004; 18: 1085–104[ISI][Medline]

2 Foubert L, Reyntjens K, De Wolf D, Suys B, Moerman A, Mortier E. Remifentanil infusion for cardiac catheterization in children with congenital heart disease. Acta Anaesth Scand 2002; 46: 355–60[CrossRef][ISI][Medline]

3 Donmez A, Kizilkan A, Berksun H, Varan B, Tokel K. One center's experience with remifentanil infusions for pediatric cardiac catheterization. J Cardiothor Vasc Anesth 2001; 15: 736–9[CrossRef][ISI][Medline]

4 Annila P, Rorarius M, Reikainen P, Oikkonen M, Baer G. Effect of pre-treatment with intravenous atropine or glycopyrrolate on cardiac arrhythmias during halothane anaesthesia for adenoidectomy in children. Br J Anaesth 1998; 80: 756–60[Abstract/Free Full Text]

5 Hall A, Thompson J, Leslie N, Fox A, Kumar N, Rowbotham D. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth 2000; 84: 100–2[Abstract]

6 Joo HS, Salasidis GC, Kataoka MT, et al. Comparison of bolus remifentanil versus bolus fentanyl for induction of anesthesia and tracheal intubation in patients with cardiac disease. J Cardiothor Vasc Anesth 2004; 18: 263–8[CrossRef][ISI][Medline]

7 Ali-Melkkila T, Kaila T, Kanto J. Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings. Acta Anaesth Scand 1989; 33: 513–7[ISI][Medline]

8 Parlow J, van Vlymen J, Odell M. The duration of impairment of autonomic control after anticholinergic drug administration in humans. Anesth Analg 1997; 84: 155–9[Abstract]

9 Chanavaz C, Tirel O, Wodey E, et al. Haemodynamic effects of remifentanil in children with and without intravenous atropine. An echocardiographic study. Br J Anaesth 2005; 94: 74–9[Abstract/Free Full Text]

10 Ross AK, Davis PJ, Dear GD, et al. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg 2001; 93: 1393–401[Abstract/Free Full Text]





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
95/5/680    most recent
aei254v1
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Reyntjens, K.
Articles by Mortier, E.
PubMed
PubMed Citation
Articles by Reyntjens, K.
Articles by Mortier, E.