The literature on emergency management of the pediatric

Original Article Incidence of Reflex Bradycardia and Effects of Pretreatment With Atropine Rebecca K. Fastle, MD and Mark G. Roback, MD Background: The American College of Emergency Physicians (ACEP) recommends atropine as adjunctive therapy to prevent reflex bradycardia prior to laryngoscopy/tracheal intubation (L/TI) in pediatric patients. Objective: To describe the incidence of reflex bradycardia and its relationship to the administration of atropine during L/TI in a Pediatric Emergency Department. Design/Methods: A retrospective cohort study was designed through review of records of all patients who received L/TI in the ED at an urban children s hospital from January 1997 to March 2001. Patients meeting inclusion criteria were placed into cohorts defined by whether they had received atropine prior to L/TI or not. Results: One hundred sixty-three patients received L/TI during the study period. One hundred forty-three patients met inclusion criteria. Sixty-eight patients received atropine (atropine group) prior to L/TI. Seventy-two percent of atropine group patients met ACEP criteria for atropine pretreatment. Seventy-five patients did not receive atropine pretreatment (no-atropine group). Forty-three percent of no-atropine group patients met ACEP criteria for pretreatment with atropine. The atropine group was younger [mean 22.5 vs. 36.4 months, P = 0.003, 95% CI ( 28.5, 0.70)], averaged the same number of intubation attempts [1.6 vs. 1.5, P = 0.941, 95% CI 0.1 ( 0.3,0.4)], and had normal or elevated HR for age prior to L/TI (mean 159 bpm). Hypoxia occurred more often in the atropine group [28% vs. 16%, P = 0.046, 95% CI for difference (0.3, 27.1)]. Bradycardia was noted in 6 patients during L/TI; 3 in the atropine group and 3 in the no-atropine group. Conclusion: Atropine is not routinely administered prior to L/TI in this pediatric ED. Pretreatment with atropine did not prevent bradycardia in all cases. These data suggest that use of atropine prior to L/TI may not be required for all pediatric patients. Some patients will experience bradycardia regardless of atropine pretreatment. Department of Pediatrics, Section of Emergency Medicine, University of Colorado Health Sciences Center and The Children s Hospital, Denver, CO. Presented APA-SPR, San Francisco, May 1999. Address correspondence and reprint requests to Rebecca K. Fastle, MD, Methodist Children s Hospital, Pediatric Emergency Department, 7700 Floyd Curl Drive, San Antonio, TX 78229. E-mail: rfastle@yahoo.com. Copyright n 2004 by Lippincott Williams & Wilkins ISSN: 0749-5161/04/2010-0651 Key Words: atropine, laryngoscopy/tracheal intubation, reflex bradycardia, pediatric rapid sequence intubation The literature on emergency management of the pediatric airway consistently recommends atropine for infants and children to prevent reflex bradycardia thought to be associated with laryngoscopy/tracheal intubation (L/TI). 1 4 The American College of Emergency Physicians (ACEP), the American Academy of Pediatrics (AAP), and the American Heart Association (AHA) currently recommend atropine premedication as part of rapid sequence intubation in the following patients: (1) all children younger than 1 year; (2) children receiving succinylcholine; (3) adolescents and adults receiving a second dose of succinylcholine; and (4) anyone with bradycardia at the time of intubation. 4,5 Infants and children have been reported to have a more pronounced vagal response to L/TI than adults. 6 8 Such responses may be caused by physiologic factors such as hypoxia, vagal stimulation during laryngoscopy, or pharmacologic agents. Profound bradycardia and even asystole have been documented after administration of the depolarizing neuromuscular blockade agent succinylcholine. 6 8 Although recommendations for the use of atropine to prevent reflex bradycardia during L/TI in the pediatric population are widespread, there is little information in the literature from actual emergency department (ED) rapid sequence intubations to support these recommendations. The purpose of this study was to investigate reflex bradycardia associated with L/TI in pediatric patients receiving rapid sequence intubation in the ED. We will compare our clinical use of atropine with ACEP guidelines. In addition, we will compare the incidence of bradycardia in patients who received atropine pretreatment with those who did not. METHODS Study Design A retrospective cohort study was designed and performed through review of medical records of all pediatric Pediatric Emergency Care Volume 20, Number 10, October 2004 651

Fastle and Roback Pediatric Emergency Care Volume 20, Number 10, October 2004 patients up to 19 years who received L/TI in the ED of a Regional Pediatric Level I Trauma Center from January 1997 to March 2001. Data were abstracted and recorded using a standardized data collection sheet. Patients who presented with bradycardia or cardiopulmonary arrest as well as those with known difficult airways who received intubation by anesthesiology or otolaryngology services were excluded. Those patients in which documentation in the record did not allow for calculation of change in heart rate (dhr) were also excluded. Patients were separated into 2 cohorts based on the presence (atropine) or absence (no-atropine) of atropine pretreatment. Atropine was dosed based on patient weight on all patients receiving intubation. Bradycardia was the primary outcome variable and rates of bradycardia in the cohort groups were compared. The ED resuscitation log, completed by a nurse whose only role during resuscitation was real-time documentation, was used to abstract data on changes in heart rate (HR), blood pressure, respiratory rate, oxygen saturation (as measured by pulse oximetry), additional interventions, and complications. Factors potentially contributing to bradycardia such as paralytic agent used, number of L/TI attempts, and oxygen saturation were obtained from the resuscitation log and recorded. When possible, participants in the care of patients receiving L/TI were queried shortly after the ED visit to clarify ambiguous or missing data abstracted from the record. Pre- and postintubation HRs were compared between groups. For each patient, change in HR (dhr = difference in HR before and after L/TI) was calculated. Bradycardia was defined as HR falling 2 standard deviations below normal for age as described by the AHA 9 or a decrease in HR during L/TI by >30% which was considered clinically significant. HR is documented in the resuscitation log immediately preceding and immediately after any intervention or change in patient status from timed, continuous cardiorespiratory monitor readings. Newborn to 3 months 85 205 3 months to 2 years 100 190 2 years to 10 years 60 140 >10 years 60 100 RESULTS Study Sample One hundred sixty-three patients received L/TI during the study period. A total of 20 cases were excluded: 8 patients were in cardiopulmonary arrest at the time of presentation, 2 patients had abnormal airways and received intubation by anesthesiology or otolaryngology, and 10 were excluded for incomplete medical records (Fig. 1). One hundred forty-three patients age 3 days to 19 years (median 12 months) were included in the final analysis. Sixty-eight patients (48%) received atropine prior to L/TI. Of the 68 patients in the atropine group, 49 (72%) met ACEP recommendations for atropine pretreatment. Thirty-two of the 75 patients (43%) in the no-atropine group met ACEP recommendations for atropine pretreatment (Fig. 1). The atropine patients were younger (mean age 22.5 vs. 36.4 months), averaged the same number of intubation attempts, and had normal or elevated HR for age prior to L/TI (mean HR 159). A total of 81/143 (57%) patients met ACEP criteria for atropine pretreatment. Of these patients, 49/81 (60%) received atropine pretreatment. Atropine patients had a statistically significant (P = 0.046) higher incidence of pre-l/ti hypoxia than those in the no-atropine group (28% vs. 16%) (Table 1). Six of 143 patients (4%) experienced bradycardia during L/TI. Three of these patients were in the atropine group and 3 in the no-atropine group. Three of the patients experiencing bradycardia during L/TI met ACEP recommended criteria for atropine pretreatment: 2 of these 3 received pretreatment with atropine. All bradycardic episodes resolved with bag mask ventilation or with endotracheal intubation. All patients were successfully intubated. Patients who met ACEP recommendations for atropine treatment prior to L/TI were considered separately. Table 2 summarizes the patients for whom atropine treatment prior to L/TI would be recommended based on current ACEP guidelines. Forty-nine of these 81 (60%) patients received atropine pretreatment. Patients who met ACEP criteria and Rates were compared using x 2 and confidence intervals for differences were calculated using large sample unpooled standard error estimate. Rate of hypoxia was compared between groups while adjusting for age using a logistic regression model. Hypoxia was defined as a pulse oximeter reading below 90% at an elevation of 5280 feet (Denver, CO). Nonnormally distributed continuous variables were compared using Wilcoxon rank sum tests. FIGURE 1. Flowchart of patients enrolled. 652 n 2004 Lippincott Williams & Wilkins

Pediatric Emergency Care Volume 20, Number 10, October 2004 TABLE 1. Group Comparisons by Age, Intubation Attempts, Adverse Events, and ACEP Criteria N = 143 Atropine (n = 68) No-Atropine (n = 75) P and Difference (95% CI) Age (mean) 22.5 months 36.4 months 0.003 13.9 ( 28.5, 0.70) L/TI attempts (mean) 1.6 1.5 0.941 0.1 ( 0.3, 0.4) Bradycardic events 3/68 (4%) 3/75 (4%) 0.888 0.5 ( 6.2, 7.1) Hypoxic events 19/68 (28%) 12/75 (16%) 0.046 12.7 (0.3, 27.1) No. patients meeting ACEP criteria for atropine pretreatment 49/68 (72%) 32/75 (42%) 0.001 29.3 (13.6, 45.1) received atropine were no different in terms of age, number of intubation attempts, and incidence of hypoxia than patients in the no-atropine group. Six patients experienced bradycardia in the study population. These patients were considered separately and are shown in Table 3. Three patients in the atropine group and 3 patients in the no-atropine group experienced bradycardia during L/TI. In each of the groups, 2/3 patients were hypoxic prior to the time they experienced bradycardia. Patients 2, 5, and 6 did not meet the AHA definition of bradycardia, however, they experienced a significant decrease in HR (>30%) from baseline which resolved with securing the airway. All 3 of these patients experienced hypoxia during L/TI. In all 6 cases, bradycardia resolved with successful endotracheal intubation and without further medical intervention. Of the 3 patients experiencing bradycardia in the atropine group, 2 met ACEP criteria. One of these patients was a 3-month-old with a subdural hematoma following nonaccidental trauma and the second was a 7-week-old with bronchiolitis. Pretreatment with atropine did not prevent bradycardia in these patients. Patient 3 in the no-atropine pretreatment group was an 11-month-old with croup. This patient met ACEP criteria for atropine pretreatment. This patient also became severely hypoxic during L/TI. Two patients experienced bradycardia without associated hypoxia. Patient 1 who had an apparent life-threatening event with apnea did not meet ACEP criteria for atropine pretreatment and did not receive atropine. Patient 4 with a subdural hematoma did meet ACEP criteria and did receive atropine prior to L/TI. Both patients experienced bradycardia, which resolved with tracheal intubation and no further interventions. Indications for L/TI varied. The top 4 indications for L/TI, which comprised 82% of patients enrolled, are noted in Table 4. The decision to use atropine premedication did not appear to be affected by patient diagnosis as the two groups were similarly divided in indications for intubation. In our study of 143 patients, 65 were intubated for respiratory failure associated with a primary respiratory illness. Of the 81 patients meeting ACEP criteria, 50 were intubated for impending respiratory failure from a primary respiratory illness. Sixty-two percent (31/50) of these patients were in the atropine pretreatment group. A total of 18 patients were intubated secondary to respiratory failure related to bronchiolitis. Eleven of these 18 received atropine. Of the patients experiencing bradycardia, only one had a documented infection with respiratory syncytial virus (RSV). This was a 7-week-old patient in the atropine pretreatment group. In this patient, atropine did not prevent bradycardia associated with L/TI. Succinylcholine was the paralytic agent used in 16 out of 143 patients. There were no episodes of bradycardia in patients receiving succinylcholine in our study group. DISCUSSION This study describes the clinical use of atropine and the incidence of bradycardia associated with L/TI in the ED of a Regional Pediatric Level I Trauma Center. When evaluating the utility of atropine, it is necessary to consider TABLE 2. Comparisons Between Groups of Patients Who Met ACEP Criteria for Atropine Treatment Prior to L/TI 81 Patients Met ACEP Criteria for Atropine Treatment Prior to L/TI Atropine Group, 49 (60%) No-Atropine Group, 32 (40%) Median age, months 1.4 9 0.76 Average no. L/TI 1.6 1.5 0.47 attempts/patient Bradycardia (%) 2 (4%) 1 (3%) 0.4 Hypoxia (%) 18 (37%) 7 (22%) 0.16 P n 2004 Lippincott Williams & Wilkins 653

Fastle and Roback Pediatric Emergency Care Volume 20, Number 10, October 2004 TABLE 3. Patients Experiencing Bradycardia Patient Reference Number Age, Months Atropine Y/N Meets ACEP Criteria for Atropine Pretreatment Hypoxia (Pulse Oximetry) No. L/TI Attempts Diagnosis Bradycardia (HR Before, During, and After L/TI) 1 13 N No >90% 3 Acute Life- 120, 60, 126 Threatening Event 2 15 N No 50% 2 Croup 208, 80, 189 3 11 N Yes 10% 2 Croup 176, 40, 124 4 3 Y Yes >90% 1 Nonaccidental Trauma/ 185, 66, 150 Subdural Hematoma 5 1.5 Y Yes 75% 2 RSV/Bronchiolitis 170, 80, 176 6 17 Y No 40% 2 Pneumothorax nephrotic syndrome 132, 90, 143 the pathophysiology behind the laryngeal reflex and other factors which may contribute to bradycardia associated with L/TI. The laryngeal reflex was first described almost 30 years ago by Johnson et al who clearly demonstrated that glucose solutions and cow s milk arrest respiration when introduced into the upper airway of newborn lambs. 10 The reflex is exaggerated under conditions of hypoxia and has been demonstrated to be particularly strong in newborn animals and infants. 10 Hypoxia can induce bradycardia via activation of peripheral arterial chemoreceptors. However, this occurs only during apnea, as input from pulmonary stretch receptors attenuates or reverses this mechanism. 10 12 This is the etiology behind the dramatic response to bag mask ventilation or successful intubation in patients with profound bradycardia during L/TI. Hypoxia was a relatively common adverse event experienced by patients in this study population. Overall, 31/ 143 (22%) of patients experienced some hypoxia. Sixty-one percent (19/31) of these patients were in the atropine pretreatment group. It is not immediately clear why most patients experiencing hypoxia fall into the atropine group as there does not appear to be a disproportionate representation of primary respiratory disease among these patients. The main difference between the two groups is reflected by patient age. Younger patients were more likely to receive pretreatment with atropine. Four out of six of the patients experiencing bradycardia during L/TI were hypoxic at the time they became bradycardic. Pediatric patients receiving L/TI for respiratory failure associated with RSV infection may have an exaggerated bradycardic response to L/TI. 13 The mechanism by which RSV infection reinforces the laryngeal reflex is not clear. Lindgren et al 13 speculated that RSV infection alters the sensitivity of the laryngeal chemoreceptors to the point that stimulation of these receptors may lead to prolonged or fatal apnea. In our study group of 143 patients, 18 were intubated for respiratory failure associated with bronchiolitis. Eleven of these 18 received atropine. Of the patients experiencing bradycardia, only one had clinical bronchiolitis and presumed infection with RSV. This was a 7-week-old patient in the atropine group. In this patient, atropine did not prevent the bradycardia associated with L/TI. However, this patient experienced hypoxia during L/TI which differs from other bronchiolitic patients in the study. In this patient, hypoxia may have been a more important risk factor for bradycardia with L/TI than infection with RSV. None of the 7 patients with bronchiolitis in the no-atropine group experienced bradycardia. All of these patients had normal or elevated HR and normal oxygen saturations immediately prior to L/TI. A variety of medications were used for rapid sequence intubation including sedatives, analgesics, paralytic agents, and adjuncts such as atropine. There were no significant differences between the cohorts and additional rapid sequence intubation pharmacologic agents. Dosing was based by weight on all patients and followed standard recommendations. No medicine dosing errors were identified in either cohort. Succinylcholine has been shown to cause bradycardia after the first administration in children and after the second and subsequent doses in adolescents and adults. 6 8,14 Atropine appears to be effective in preventing the bradycardia associated with the administration of succinylcholine TABLE 4. Most Common Indications for L/TI Indication Median Age, Months (N = 143) No. Patients (%) Atropine Group No-Atropine Group Respiratory 9 65 (45) 34/52% 31/48% disease Trauma/CHI 12 27 (19) 11/41% 16/59% Seizures 24 17 (12) 9/53% 8/47% Septic shock 1.5 9 (6) 4/45% 5/55% Other 16 25 (17.5) 10/40% 15/60% 654 n 2004 Lippincott Williams & Wilkins

Pediatric Emergency Care Volume 20, Number 10, October 2004 likely due to its effect on the sino-atrial node. 14 No patients receiving succinylcholine in this study experienced bradycardia. Eighty-one of 143 (56%) patients receiving L/TI met ACEP criteria for pretreatment with atropine. Thirty-two (40%) of these patients did not receive atropine. The only patient in this group that experienced bradycardia also had severe hypoxia at the time of L/TI. All of the patients in the no-atropine group who did not experience bradycardia had normal or increased HRs and were well oxygenated prior to L/TI. These data suggest that physiologic factors such as hypoxia may play a more important role in causing bradycardia than the vagal stimulation of L/TI. Also, not all patients appear to require atropine prior to L/TI to prevent reflex bradycardia. Furthermore, in patients with hypoxia prior to L/TI, atropine pretreatment was not always successful in preventing bradycardia. A continuous monitor or log of HRs was not documented in the records reviewed. This limits our study, as it is possible that brief decreases in HR during L/TI were not recorded. However, we have no reason to suspect that the quality of documentation varied systematically based on the indications for, or use of, atropine. In an effort to keep the medical record as complete as possible, interviews with ED staff were done shortly after most L/TI. In spite of this, there were 10 records that were incomplete and could not be used in the final analysis. The literature suggests that bradycardia during L/TI is multifactorial. This study was not able assess the actual effects of each variable associated with bradycardia in relation to atropine usage. This study is also limited by the fact that the principal investigator abstracted all data from the medical record and was not blinded to the study objective. For this reason, the potential for bias in data entry exists. The most important limitation to this study relates to the fact that bradycardia associated with L/TI is an uncommon event; occurring in only 4% of our study population. One reason for this low rate of bradycardia in our patient population is the fact that very few patients received succinylcholine prior to RSI. The low rate of bradycardia seen in patients receiving rocuronium further emphasizes our finding that reflex bradycardia is uncommon. A power calculation was performed using our baseline of 4% incidence of bradycardia. To detect a statistically significant (a = 0.05, b = 0.2) 50% decrease in the incidence of bradycardia with the use of atropine, 1238 patients would need to be enrolled in each arm of the study. For this reason, further prospective study of a much larger number of patients is warranted to identify which patients are truly at risk for bradycardia associated with L/TI and which patients may actually benefit from pretreatment with atropine. CONCLUSIONS Despite current recommendations, atropine is not routinely administered prior to laryngoscopy/tracheal intubation in our pediatric ED. Those patients who were younger and were hypoxic at the time of L/TI were more likely to receive atropine. Pretreatment with atropine did not prevent bradycardia in all cases. Physiologic factors such as hypoxia have a significant effect on HR and may play a more important role in causing bradycardia than the actual act of L/TI. These data suggest that the mandatory use of atropine prior to L/TI may not be required for all pediatric patients for whom it is currently recommended and that some patients will experience bradycardia associated with L/TI regardless of atropine pretreatment. REFERENCES 1. Yamamoto LG, Yim GK, Britten AG. Rapid sequence anesthesia induction for emergency intubation. Pediatr Emerg Care. 1990;6:200 213. 2. Tobias JD. Airway management for pediatric emergencies. Pediatr Ann. 1996;25:317 328. 3. McAllister JD, Gnauck KA. Rapid sequence intubation of the pediatric patient. Pediatr Clin North Am. 1999;46:1249 1284. 4. Silverman BK. Advanced PLS Course Manual. 2nd ed. Elk Grove Village, IL: Amer AP-ACEP; 1993:19 29. 5. PALS Provider Manual. American Academy of Pediatrics/American Heart Association; 2002:361. 6. Mazurek AJ, Rae B, Hann S, et al. Rocuronium versus succinylcholine: are they equally effective during rapid-sequence induction of anesthesia? Anesth Analg. 1998;87:1259 1262. 7. Cook DR. Can succinylcholine be abandoned? Anesth Analg. 2000; 90:S24 S28. 8. Gerardi MJ, Sacchetti AD, Cantor RM, et al. Rapid-sequence intubation of the pediatric patient. Ann Emerg Med. 1996;28:55 74. 9. PALS Course Manual. Dallas, TX: AHA; 1994;7.3. 10. Wennergren G, Milerad J, Hertzberg T. Laryngeal reflex. Acta Paediatr Suppl. 1993;389:53 56. 11. Wennergren G, Milerad J, Bjure J, et al. Hypoxia reinforces laryngeal reflex bradycardia in infants. Acta Paediatr Scand. 1989;78:11 17. 12. Mirakhur RK. Bradycardia with laryngeal spraying in children. Acta Anaesth Scand. 1982;26:130 132. 13. Lindgren C, Jing L, Graham B, et al. Respiratory syncytial virus infection reinforces reflex apnea in young lambs. Pediatr Res. 1992;31: 381 385. 14. Mathias JA, Evans-Prosser CDG, Churchill-Davidson HC. The role of the non-depolarizing drugs in the prevention of suxamethonium bradycardia. Br J Anaesth. 1970;42:609 613. n 2004 Lippincott Williams & Wilkins 655