Glycopyrrolate Does Not Reduce the Incidence of Perioperative Adverse Events in Children with Upper Respiratory Tract Infections

Tait, Alan R. PhD; Burke, Constance BSN, RN; Voepel-Lewis, Terri MSN, RN; Chiravuri, Devi MD; Wagner, Deborah PharmD; Malviya, Shobha MD

Section Editor(s): Davis, Peter J.

doi: 10.1213/01.ane.0000243333.96141.40
Pediatric Anesthesia: Research Report

Two recent studies have identified copious secretions as an independent risk factor for perioperative adverse events in children who present for elective surgery in the presence of an upper respiratory tract infection (URI). We designed this study, therefore, to determine whether the administration of the anticholinergic drug, glycopyrrolate, to children with URIs would reduce the incidence of adverse perioperative respiratory events. One hundred thirty children (1 mo to 18 yr of age) who presented for elective surgery with a URI were randomized to receive either 0.01 mg/kg glycopyrrolate or placebo and were followed for the appearance and severity of any perioperative respiratory adverse events. The two groups were similar with respect to demographics, presenting URI symptoms, anesthetic management, and surgical procedure. In the intention-to-treat analysis, there were no statistical differences in the incidence or severity of perioperative respiratory adverse events between the glycopyrrolate and placebo groups (45.2% vs 37.5% respectively, P = NS). Furthermore, there were no differences in outcome between the two groups when children with congestion and secretions were analyzed separately (45.0% vs 37.0%, respectively). However, compared with the placebo group, children in the glycopyrrolate group had significantly shorter discharge times (83.9 min vs 111.4 min, P = 0.024), and significantly less postoperative nausea and vomiting (10.7% vs 33.3%, P = 0.005). These results suggest that glycopyrrolate, administered after induction of anesthesia to children with URIs, does not reduce the incidence of perioperative respiratory adverse events, and thus may not be clinically indicated for routine use in this population.

IMPLICATIONS: This study examines the effect of glycopyrrolate on perioperative adverse events in children presenting for elective surgery with an upper respiratory tract infection. Results showed that routine intraoperative administration of glycopyrrolate to these children seems to have no clinical benefit.

From the Department of Anesthesiology, University of Michigan Health System, Ann Arbor, Michigan.

Accepted for publication August 14, 2006.

Supported by the Department of Anesthesiology, University of Michigan.

Address correspondence and reprint requests to Alan R. Tait, PhD, Department of Anesthesiology, University of Michigan Health System, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Address e-mail to atait@umich.edu.

Article Outline

Several studies suggest that children who present for elective surgery while harboring an upper respiratory tract infection (URI) have an increased risk of adverse perioperative respiratory events (1–3). Although these events are typically mild and easily treated, they may be worrisome. Part of the concern regarding anesthetizing children with URIs is the presence of excess secretions and the potential for a sensitive or hyperreactive airway. Indeed, two large-scale studies have identified the presence of copious secretions and nasal congestion as independent risk factors for adverse events in children with URIs (1,3).

Perioperative control of excess secretions is typically achieved through careful suctioning under deep anesthesia and/or the use of anticholinergics such as glycopyrrolate or atropine. In one survey of pediatric anesthesiologists, approximately one-third reported using anticholinergics on a frequent basis for children with URIs (4). However, despite their use, there are no randomized studies to determine the effect of anticholinergics on perioperative adverse events in children with URIs. This randomized, double-blind study was therefore designed to test the hypothesis that, compared with placebo, administration of glycopyrrolate to children with URIs would reduce the incidence of secretion-related adverse events.

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METHODS

This study was approved by the University of Michigan institutional review committee, and informed consent was obtained from the parents or legal guardians of each child. The sample population consisted of ASA physical status I–III pediatric patients aged between 1 mo and 18 yr who presented for elective outpatient surgery with symptoms of a URI. Patients were excluded if they had any evidence of lower respiratory tract infection or if the anesthesiologist determined that proceeding with anesthesia would not be in the best interests of the child. Other exclusion criteria included ASA status >III, planned airway management with a facemask, emergent surgery, known hypersensitivity to glycopyrrolate, asthma, cardiovascular disease, or procedures requiring reversal of muscle relaxation with concomitant use of an anticholinergic drug. Children requiring total IV anesthesia were also excluded.

On the day of surgery, information was elicited from the parents with respect to their child's demographics, history of respiratory infection, allergies, presenting URI symptoms, and parental smoking habits. The diagnosis of a URI was based on previously defined criteria that required the presence of a minimum of two symptoms (nasal congestion, rhinorrhea, sore throat, malaise, fever <38°C, or nonproductive cough) plus confirmation by a parent (3). Anesthesia was induced with N2O/O2/sevoflurane and maintained with isoflurane. Children were randomized (using tables of random numbers) in a double-blind fashion to receive either 0.01 mg/kg of glycopyrrolate [maximum 0.6 mg (5)] or an equal volume of saline placebo administered immediately after anesthetic induction but before airway placement.

Monitoring included pulse oximetry, capnography, electrocardiography, heart rate, and arterial blood pressure. Subjects were observed for any episodes of perioperative respiratory events including cough, laryngospasm, bronchospasm, breath-holding, and oxygen desaturation. Each event was scored for severity (0 = no complication to 3 = most severe) on the basis of a previously published scale (3,6). Scores were established for each of five time-points (i.e., induction, placement of an endotracheal tube [ETT] or laryngeal mask airway [LMA], intraoperatively, removal of the airway, and in the postanesthesia recovery room), and a composite score (range 0–15) was obtained for each potential adverse event. Furthermore, parents were contacted by telephone 24 h after surgery and interviewed using a standard script to determine the incidence of any postoperative adverse events.

Sample size estimates were based on a previous study which suggested that the incidence of overall perioperative respiratory adverse events in children with URIs undergoing procedures requiring airway instrumentation under sevoflurane (induction) and isoflurane (maintenance) anesthesia was approximately 51% (3). Given this information, we believed that it would be important to detect a 50% reduction in the incidence of adverse respiratory events when using glycopyrrolate. To detect a difference of at least this size we required a sample of 56 per group (two sided, α = 0.05, β = 0.2).

Statistical analysis was performed using SPSS statistical software (SPSS, Chicago, IL) on an intention-to-treat basis (ITT). Parametric data such as age and duration of anesthesia and surgery were analyzed using unpaired t-tests. Nonparametric data were analyzed using Mann–Whitney U, χ2, and Fisher's exact tests, as appropriate. Data are presented as percentages or mean ± sd. Significance was accepted at the 5% level (P < 0.05).

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RESULTS

A diagram describing the participants' progress through the stages of the study is presented in Figure 1. Two hundred seven children were eligible for participation in this study. Thirty-five children who presented with respiratory symptoms had their surgery cancelled. Of these, 19 (54.3%) were cancelled because of a respiratory illness (8 by parents and 11 by the anesthesiologist or surgeon), 5 (14.3%) because the child was “sick” (as reported by the parent), 1 (2.9%) because of high fever, and 10 (28.6%) for other reasons. A total of 172 patients were thus approached for permission to participate in this study of which 42 declined. The remaining 130 children were randomized to receive either glycopyrrolate or placebo. However, of these, three children had their surgery cancelled after randomization, 10 experienced a change in anesthetic or airway management plan, and one received an anticholinergic as an adjunct to reversal of a muscle relaxant. Other protocol violations included an incorrect dose of glycopyrrolate, miscommunication by staff regarding drug administration, such that the drug was not given (in two), and in one case, the study drug leaked out of the syringe before administration.

The demographics of the study sample are described in Table 1 and show that there were no differences between groups with respect to gender, race/ethnicity, ASA status, parents' education, history of prematurity, parental smoking, surgical service, and surgery involving the airway. Furthermore, there were no differences in the presenting URI symptoms between groups, in the presenting phase of the URI (i.e., onset, middle, or end), or the seasons during which the children were recruited (Table 2). Anesthetic management was similar between the groups with respect to the induction and maintenance anesthetic drugs and the depth of anesthesia (i.e., awake versus deep) at the time of tube removal. The distribution of ETT and LMA use was also similar between the two groups. Children who received an ETT had a significantly more perioperative adverse events compared with those who received an LMA (49.4% vs 19.4%, P = 0.005); however, these differences in outcome were not different between the two groups.

The incidences of perioperative respiratory adverse events are described in Table 3. Based on the ITT analysis, there were no statistically significant differences in perioperative outcomes, although the relative risks of laryngospasm requiring succinylcholine and bronchospasm were approximately four- and twofold greater in the glycopyrrolate group, respectively. In addition, there were no statistical differences in the incidence and severity of adverse events at each of the five time-points between the glycopyrrolate and placebo groups. A per-protocol analysis of the data that excluded those children for whom there was a postrandomization protocol violation also showed no difference between the two groups with respect to the incidence of perioperative respiratory adverse events. For this analysis, the incidence of these events in the glycopyrrolate group was 46.4% as compared to 37.5% in the placebo group.

Given that the hypothesis of the study was to examine whether glycopyrrolate would reduce the incidence of secretion-related adverse events, the data were also analyzed to include only those children in whom one would expect an anticholinergic to be effective, i.e., those with nasal congestion and copious secretions. Further analysis of these children revealed no benefit of glycopyrrolate. In these children, the incidence of overall respiratory events in the glycopyrrolate group was 45.0% as compared to 37.0% in the placebo group. These values were virtually identical to those observed for the entire sample i.e., 45.2% and 37.5%, respectively. However, regardless of whether the child received glycopyrrolate or placebo, the presence of intraoperative secretions was associated with a significant increase in perioperative respiratory adverse events (46.7% vs 23.1%, P = 0.042).

Not surprisingly, there was more intraoperative tachycardia [defined as >150 bpm in infants, and >120 bpm in older children (7)] in the glycopyrrolate group when compared with that in the placebo group (68.3% vs 42.6% respectively, P = 0.008). Table 4 describes the incidence of postoperative outcomes between the two groups. As shown, children in the glycopyrrolate group experienced significantly more frequent parent-reported complications. Complications in this group included dehydration (one), flushed face (two), hyperactivity (two), wheezing (one), and dizziness (one). All complications were self-limiting. Children in the glycopyrrolate group did, however, experience less postoperative nausea and vomiting (PONV) and had significantly shorter discharge times compared with those in the placebo group.

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DISCUSSION

Data from two large-scale studies have implicated the presence of copious secretions as a risk factor for perioperative respiratory adverse events in children undergoing elective surgical procedures (1,3). Based on these data, it follows that administration of a drug that dries secretions may be important in decreasing the risk of perioperative complications in children with URIs. In practice, reduction of secretions may be achieved by careful suctioning under deep anesthesia and/or administration of an anticholinergic drug such as atropine or glycopyrrolate. Indeed, approximately one-third of surveyed members of the Society for Pediatric Anesthesia reported that they frequently used an anticholinergic drug in the management of the child with a URI (4). Results from the present study, however, suggest that this practice has no benefit. Indeed, children receiving glycopyrrolate experienced a slight increase in the incidence of postoperative adverse events compared with the placebo group.

Glycopyrrolate is a quaternary ammonium anticholinergic drug that is commonly used in anesthesia practice to reduce secretions, reduce the side effects associated with neuromuscular blockade reversal, and reduce gastric acidity (8,9). Glycopyrrolate has also been shown to be effective in reducing drooling in cognitively impaired children and adults (10). Furthermore, nebulized glycopyrrolate has been shown to be effective as a bronchodilator in patients with chronic obstructive pulmonary disease and asthma (11,12). Although atropine is used similarly in anesthesia practice, glycopyrrolate was chosen for this study because it is a known antisialogogue with fewer hemodynamic and other side effects (13). Despite these known effects, there are limited data with respect to the use of anticholinergic drugs to reduce perioperative respiratory complications in children with URIs.

The incidence of perioperative respiratory adverse events observed in this study was similar to that presented previously (3) and further supports the premise that, although children with URIs tend to have an increased risk of adverse respiratory outcomes, these are typically mild and easily managed. The hypothesis that glycopyrrolate, because of its antisialogogue properties, would reduce secretions and decrease the incidence of adverse events was not supported. Indeed, although children in the glycopyrrolate group experienced significantly more postoperative dry mouth, there was only minimal reduction in the observed subjective assessment of airway secretions perioperatively. The reasons for this are unclear. Studies examining the effect of the anticholinergic drug ipratropium on allergic and infectious nasal mucus production are equivocal. Although some studies have demonstrated a reduction in secretions after ipratropium administration (14,15), others have found no effect (16,17). In a study by Wolff and Kleinberg (18), glycopyrrolate given to healthy volunteers reduced both the salivary flow rate and the thickness of the residual mucosal saliva (a measure of residual mucosal wetness). In addition, salivary flow and residual mucosal thickness were affected to varying degrees depending on the sites within the oral cavity. This may help explain why many children in the glycopyrrolate group experienced postoperative dry mouth, although airway secretions were not seemingly altered. Of particular note in Wolff and Kleinberg's study is the fact that the amount of gingival crevicular fluid was not affected by glycopyrrolate. The reason for this is that gingival crevicular fluid is an inflammatory exudate that is not under neural control, and thus would not be expected to be affected by an anticholinergic drug. Because virus-associated secretions are, in part, inflammatory, this may help explain why glycopyrrolate had seemingly little effect on the amount of airway secretions in our study.

Increased airway reactivity in the presence of a URI has been implicated as a cause of bronchospasm and laryngospasm in children. Although not statistically significant, there were clinically relevant increases in the relative risks of laryngospasm (3.7) and bronchospasm (1.8) in children receiving glycopyrrolate, and more minor postdischarge complications. Anticholinergic drugs also increase the friability of mucous membranes and cause inspissation of secretions in addition to dry mouth (19). These side effects may thus, in part, explain the observed trend toward increased airway reactivity in children who received glycopyrrolate.

Elwood et al. (20) compared the efficacy of preemptive ipratropium, albuterol, or placebo in children with URIs. This study showed no differences in the incidence of postoperative complications in children who received either of these drugs compared with that in placebo group. This finding may have been partly related to patient selection, i.e., these were otherwise healthy children with mild URIs in whom anticholinergics or bronchodilators would not necessarily be expected to be of benefit. Similarly, in our study, one could argue that not all children with URIs would be expected to benefit from administration of an anticholinergic drug. However, when the data were analyzed to include only children who might benefit from glycopyrrolate, i.e., those with rhinorrhea and excess secretions, glycopyrrolate did not prove to be advantageous. Additionally, although a study by Stratelak et al. (21) showed that adult patients given glycopyrrolate as a premedicant had a significantly less sore throat than those who did not receive glycopyrrolate, our study revealed no such differences.

The reason why children in the glycopyrrolate group had shorter discharge times is unclear, but may have been related to the lower observed incidence of PONV in this group. Although we did not collect data on antiemetic use, the fact that the two groups were similar with respect to surgical procedure (particularly emetogenic procedures such as strabismus and tonsillectomy) suggests that any antiemetic prophylaxis would have been equally distributed between the groups. However, there are some data to suggest that glycopyrrolate may have some antiemetic properties. In a study by Ure et al. (22), women who were given glycopyrrolate before spinal anesthesia for cesarean section had a significant reduction in the incidence and severity of nausea. As an adjunct to the reversal of neuromuscular blockade, however, glycopyrrolate appears to have mixed effects on PONV (23,24).

It is unclear as to why a disproportionate number of protocol violations occurred in the glycopyrrolate group; however, comparison of the outcomes based on the ITT and per protocol analysis indicated that postrandomization protocol violations were not biased in favor of one group over the other. One concern, however, in any study that yields negative results, is that the sample was insufficiently powered to detect differences when they truly existed, i.e., β error. Although this study was sufficiently powered to detect what we believed to be an appropriate reduction in respiratory adverse events with glycopyrrolate, this effect size, in retrospect, was over-stated, and therefore, the potential for a β error cannot be discounted. Another consideration is that although the anesthesiologists responsible for the case were blinded to the group assignment, the appearance of certain clinical signs, e.g., tachycardia had the potential to unblind the group assignment. In any case, all observations were obtained from individuals with no vested interest in the study and, as such, any inadvertent unblinding should not have biased the reporting of outcome.

The routine use of anticholinergic drugs in pediatric practice has been called into question. In an editorial, Jöhr (19) argues that although these drugs are clearly indicated for certain situations (e.g., strabismus surgery), routine use cannot be justified in lieu of the potential side effects. Results of this study demonstrate that administration of glycopyrrolate after induction of anesthesia in children with URIs does not reduce the incidence of perioperative respiratory adverse events. Thus, although glycopyrrolate is relatively inexpensive, its administration to these children seems neither cost-effective nor necessary.

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REFERENCES

1. Parnis SJ, Barker DS, Van Der Walt JH. Clinical predictors of anaesthetic complications in children with respiratory tract infections. Paediatr Anaesth 2001;11:29–40.
2. Cohen MM, Cameron CB. Should you cancel the operation when a child has an upper respiratory tract infection? Anesth Analg 1991;72:282–8.
3. Tait AR, Malviya S, Voepel-Lewis T, et al. Risk factors for perioperative adverse respiratory events in children with upper respiratory tract infections. Anesthesiology 2001;95:299–306.
4. Tait AR, Reynolds PI, Gutstein HB. Factors that influence an anesthesiologist's decision to cancel elective surgery for the child with an upper respiratory tract infection. J Clin Anesth 1995;7:491–9.
5. Gunn V, Nechyba C, eds. Johns Hopkins Hospital: Harriet Lane handbook. 16th ed. Philadelphia, PA: Mosby, 2002.
6. Levy L, Pandit UA, Randel GI, et al. Upper respiratory tract infections and general anaesthesia in children. Peri-operative complications and oxygen saturation. Anaesthesia 1992;47:678–82.
7. Behrman R, Kliegman R, Jenson H, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia, PA: WB Saunders, 2003.
8. Warran P, Radford P, Manford M. Glycopyrrolate in children. Br J Anaesth 1981;53:1273–6.
9. Salem M, Wong A, Mani M, et al. Premedicant drugs and gastric juice pH and volume in pediatric patients. Anesthesiology 1976;44:216–19.
10. Stern L. Preliminary study of glycopyrrolate in the management of drooling. J Paediatr Child Health 1997;33:52–4.
11. Tzelepis G, Komanapolli S, Tyler D, et al. Comparison of nebulized glycopyrrolate and metaproteronol in chronic obstructive pulmonary disease. Eur Respir J 1996;9:100–3.
12. Gilman M, Meyer L, Carter J, Slovis C. Comparison of aerosolized glycopyrrolate and metaproteronol in acute asthma. Chest 1990;98:1095–8.
13. Desalu I, Kushimo O, Bode C. A comparative study of the hemodynamic effects of atropine and glycopyrrolate at induction of anaesthesia in children. West Afr J Med 2005;24: 115–19.
14. Kaiser H, Findlay S, Georgitis J, et al. The anticholinergic agent ipratropium bromide is useful in the treatment of rhinorrhea associated with perennial allergic rhinitis. Allergy Asthma Proc 1998;19:23–9.
15. Kim K, Kerwin E, Landwehr L, et al. Use of 0.06% ipratropium bromide nasal spray in children aged 2 to 5 years with rhinorrhea due to common cold or allergies. Ann Allergy Asthma Immunol 2005;94:73–9.
16. Gaffey M, Hayden F, Boyd J, Gwaltney JJ. Ipratropium bromide treatment of experimental rhinovirus infection. Antimicrob Agents Chemother 1988;32:1644–7.
17. Shusterman D, Murphy M, Walsh P, Balmes J. Cholinergic blockade does not alter the nasal congestive response to irritant provocation. Rhinology 2002;40:141–6.
18. Wolff M, Kleinberg I. The effect of ammonium glycopyrrolate (Robinul)-induced xerostomia on oral mucosal wetness and flow of gingival crevicular fluid in humans. Arch Oral Biol 1999;44:97–102.
19. Jöhr M. Is it time to question the routine use of anticholinergic agents in paediatric anaesthesia? Paediatr Anaesth 1999;9:99–101.
20. Elwood T, Morris W, Martin L, et al. Brochodilator premedication does not decrease respiratory adverse events in pediatric general anesthesia. Can J Anaesth 2003;50:277–84.
21. Stratelak P, White W, Wenzel D. The effect of glycopyrrolate premedication on postoperative sore throat. AANA J 1996;64: 545–8.
22. Ure D, James K, McNeill M, Booth J. Glycopyrrolate reduces nausea during spinal anesthesia for caesarean section without affecting neonatal outcome. Br J Anaesth 1999;82:277–9.
23. Joshi G, Garg S, Hailey A, Yu S. The effects of antagonizing residual neuromuscular blockade by neostigmine and glycopyrrolate on nausea and vomiting after ambulatory surgery. Anesth Analg 1999;89:628–31.
24. Chhibber A, Lustik S, Thakur R, et al. Effects of anticholinergics on postoperative vomiting, recovery, and hospital stay in children undergoing tonsillectomy with or without adenoidectomy. Anesthesiology 1999;90:697–700.
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