ORIGINAL ARTICLE
Risk Factors for Apnea in Children Presenting With Out-of-Hospital Seizure Nichole Bosson, MD, MPH,*†‡ Daniel Khodabakhsh, MD,*†‡§ Amy H. Kaji, MD, PhD,*†‡ Jumie Lee, CPNP, MSN,*†‡ Benjamin Squire, MD, MPH,*†‡∥ and Marianne Gausche-Hill, MD*†‡ Objective: This study aimed to quantify risk factors for apnea in children 0 to 5 years of age with out-of-hospital seizure. Methods: This is a retrospective study of pediatric patients with seizure transported by paramedics to the pediatric emergency department (PED) of a tertiary center from July 2008 to June 2009. Patients with traumatic injury and those with another diagnosis after PED evaluation were excluded. We evaluated the effect of field diazepam and other potential risk factors on the occurrence of apnea, defined as the need for airway management, that is, bag-mask ventilation by paramedics or bag-mask ventilation or intubation by PED staff within 30 minutes of arrival. Results: There were 336 pediatric patients meeting inclusion criteria. The median age was 1.9 years (interquartile range,1.3–3.0 years); 193 patients (57%) were male. Fifty-four patients (16%) were treated with diazepam before PED arrival. There were 28 apneic events (8.3%). The adjusted relative risk for apnea given diazepam in the field by any route was 10.2 (95% confidence interval, 3.9–21.8; P < 0.0001), adjusted for age and seizure on arrival. Persistent seizure on PED arrival was also highly associated with apnea, with an adjusted relative risk of 15.8 (95% confidence interval, 6.5–28.9; P < 0.0001). Conclusions: Field treatment with diazepam and seizing at the time of PED arrival are associated with the occurrence of apnea in children 0 to 5 years of age with out-of-hospital seizure. Larger studies are needed to determine what other factors may contribute to this risk. Key Words: out of hospital, apnea, benzodiazepines, emergency medical services, seizures (Pediatr Emer Care 2014;30: 617–620)
S
eizure is a common chief complaint for pediatric patients in the out-of-hospital setting, accounting for approximately 15% of all emergency medical service (EMS) transports of pediatric patients in the United States.1 It is known that prolonged seizures can cause significant morbidity and mortality.2–4 Although many patients will require only supportive care, treatment is recommended for any seizure lasting more than 10 minutes.2 The sooner the seizure is treated, the more likely it is to be controlled.2 Parents and paramedics have the first opportunity to medically intervene. Initiating treatment for persistent seizures in the out-of-hospital setting is common practice in many EMS systems in the United States. Benzodiazepines are the antiepileptic drug of choice, and out-of-hospital administration of benzodiazepines has been shown to shorten overall seizure duration.5,6 Despite the relative safety and proven benefit of benzodiazepines for out-of-hospital treatment of seizure, respiratory depression From the *Department of Emergency Medicine, Harbor-UCLA Medical Center; and †Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance; ‡David Geffen School of Medicine at UCLA, Los Angeles; §International Medical Corps, Santa Monica; and ∥Huntington Memorial Hospital, Pasadena, CA. Disclosure: The authors declare no conflict of interest. Reprints: Nichole Bosson, MD, MPH, Harbor-UCLA Medical Center, 1000 W Carson St, Bldg D-9, Box 21, Torrance, CA 90502 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0749-5161
Pediatric Emergency Care • Volume 30, Number 9, September 2014
is a potential complication, especially in children.6 The risk of apnea after benzodiazepine administration for the treatment of pediatric seizures has been demonstrated in several studies.7–12 However, the rates of apnea in the studies have varied greatly, ranging from 0 to greater than 20% of treated patients.9,11,13–17 The wide range in reported rates of apnea is likely due, in part, to inclusion of children over a broad age range and variability in dosing of diazepam on a milligram-per-kilogram basis. This may be less than ideal because different factors may contribute to apnea at different ages, making risk-benefit analysis difficult for clinicians and out-ofhospital providers. There is limited knowledge, of what factors, beyond treatment with benzodiazepines, may predispose children to respiratory depression when treated for out-of-hospital seizure. Furthermore, the contribution of parental administered diazepam to the risk of apnea has not been clarified. We sought to identify risk factors for apnea in children 0 to 5 years of age, presenting with seizure. We evaluated the effect of both parental and EMS-administered diazepam as well as the contribution of other potential risk factors on the occurrence of apnea in this population. We hypothesized that younger age, prolonged seizure, current use of antiepileptic medication, or out-of-hospital treatment with benzodiazepines could be associated with apnea.
METHODS Study Design We conducted a single-center, retrospective, chart review of all pediatric patients with a diagnosis of seizure transported by paramedics to the pediatric emergency department (PED) at HarborUCLA Medical Center (HUMC) during a 1-year period from July 2008 to June 2009. Patients were identified by chief complaint from the base-hospital log of all paramedic transports to HUMC. The study was approved with waiver of informed consent by the institutional review board.
Population and Setting Harbor-UCLA Medical Center is a public teaching facility located in Los Angeles (LA) County serving a population of 1 million. Approximately 21,000 pediatric patients are treated annually. Children who arrive via the 911 system are transported by paramedic crews that consist of 2 paramedic-level emergency medical technicians stationed at local fire departments. Protocols in LA County support administration of benzodiazepines for seizure termination in any patient actively seizing with altered consciousness in the presence of paramedics. The dose may be repeated as needed with online medical control guidance until the seizure terminates. The average time from dispatch to hospital arrival for pediatric patients transported by paramedics in LA County is approximately 20 minutes, based on a previous study.18 Inclusion criteria were patients younger than 6 years transported by paramedics to the ED with the diagnosis of seizure. Patients with an out-of-hospital chief complaint of seizure but who were found to have another diagnosis on PED evaluation or whose primary complaint was traumatic injury were excluded. www.pec-online.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
617
Pediatric Emergency Care • Volume 30, Number 9, September 2014
Bosson et al
TABLE 1. Characteristics of Pediatric Patients Transported by EMS for Out-of-Hospital Seizure (n = 336) All Patients Characteristic Age Weight Sex Female Male Seizure disorder Seizing on ED arrival Prehospital medication received Any prehospital diazepam* Prehospital diazepam by EMS† Paramedic diazepam PR Paramedic diazepam IV Parental diazepam PR
Patients With Apnea
n (Median)
% (IQR)
n (Median)
% (IQR)
1.9 12.3
1.3–3.0 10.3–15.0
2.3 11.5
1.0–3.2 10.0–14.5
143 193 66 44
43 57 20 13
13 15 15 22
46 54 54 79
54 38 29 16 19
16 11 9 5 6
22 19 15 7 5
79 68 58 26 19
*Includes 3 patients treated by parents and EMS. † Includes 7 patients treated with both IV and PR diazepam.
Methods of Measurement Charts were reviewed by 2 investigators (DK, JL), not blinded to the purpose of the study, for the following study variables: paramedic-administered diazepam, route of administration, number of doses of medication administered, and total dose of medication administered. A third investigator (MGH) reviewed the data for accuracy and completeness. During the entire study period, diazepam was the benzodiazepine carried by paramedic units in LA County. Diazepam could be administered intravenously (IV) or per rectum (PR) at a dose of 0.1 mg/kg, titrated to seizure control. Of note, there was a protocol change at the start of the study period; the diazepam dose was reduced from 0.2 mg IV and 0.5 mg PR to 0.1 mg IVor PR. Paramedics used the Broselow tape to estimate patient weight for medication dosing. In addition, investigators extracted information on patient sex, age, weight, seizure on arrival to the ED (as a proxy for prolonged seizure duration), and history of a preexisting seizure disorder, defined by seizure disorder requiring chronic antiepileptic medication. A priori, it was determined that age and seizure on arrival to the ED would be important potential confounders, warranting adjustment, in a multivariable model. Age was coded as a continuous variable, whereas seizure on arrival to the ED was coded as a binary predictor. With the use of a standardized collection instrument, data were tabulated and entered into a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, Wash) and imported into SAS for analysis with SAS version 9.3 (SAS Corporation, Cary, NC). Outcome variables included the need for airway management for apnea defined as bag-mask ventilation by paramedics or bag-mask ventilation or intubation by ED staff within 30 minutes of arrival. Outcomes were abstracted and then confirmed by an agreement of 2 investigators, an emergency medicine (EM) physician (DK) and an EM physician with pediatric EM subspecialty training (MGH).
Analytical Methods The study outcomes (intubation or bag-mask ventilation) for each group were calculated as proportions with exact binomial confidence intervals. P values for unadjusted 2 2 tables were calculated using χ2 test, and relative risks (RRs) were calculated
618
www.pec-online.com
given the cohort design. Adjusted RRs were determined using multiple logistic regression and correcting odds ratios through methods described by Zhang and Yu.19
RESULTS There were 336 pediatric patients meeting inclusion criteria transported by paramedics during the study period. The median age was 1.9 years (interquartile range [IQR], 1.3–3.0 years), and 191 patients (57%) were male. Of the patients transported, 66 (20%) had a seizure disorder, and 96 (29%) were admitted to the hospital. Table 1 contains baseline characteristics of the study population. Fifty-four patients (16%) were treated with diazepam by paramedics or parents before PED arrival. Thirty-eight patients (11%) received diazepam by paramedics in the field, 19 patients (6%) received parental diazepam, and 3 patients (0.8%) were treated by both parents and EMS. In total, there were 28 apneic events (8.3%), 19 treated with diazepam and 9 not treated with diazepam. Twenty-five patients (7%) required intubation with a median time to intubation of 16 minutes (IQR, 11–20 minutes) from PED arrival. The unadjusted RR for apnea given diazepam in the field by any route was 19.2 (95% confidence interval [CI], 8.2–45.2; P < 0.001). The outcomes by route of administration are given in Table 2. Although 3 patients were treated with diazepam PR by both parents and paramedics and another 7 patients received both IVand PR diazepam by paramedics, analysis excluding such patients yielded similar results. Given the possibility of dosing errors after the change in diazepam dose initiated at the start of the study period, we compared apnea rates of children receiving the correct dose of diazepam with those of children who received doses greater than 20% above the correct dose by weight, including 6 patients (40%) treated with IV diazepam and 14 patients (50%) treated with PR diazepam. There was no difference in apnea rates by dose with this sensitivity analysis. The adjusted RR for apnea given diazepam in the field by any route was 10.2 (95% CI, 3.9–21.8; P < 0.0001), adjusted for age and seizure on PED arrival. In our exploratory univariate analysis of other potential risk factors for apnea, seizure on arrival to © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pediatric Emergency Care • Volume 30, Number 9, September 2014
Risk Factors for Apnea in Children
TABLE 2. Risk of Apnea in Pediatric Patients Treated for Out-of-Hospital Seizure by Route of Medication Administration Exposure Parental PR diazepam EMS diazepam any route* EMS IV diazepam EMS PR diazepam No field medications
n
Apnea Frequency
%
RR (95%CI)
P
19 38 16 29 281
5 19 7 15 5
26 50 44 52 2
14.8 (4.7–46.7) 28.1 (11.1–70.9) 24.6 (8.8–70.0) 29.1 (11.4–74.2) 1
Risk Factors for Apnea in Children Presenting With Out-of-Hospital Seizure Nichole Bosson, MD, MPH,*†‡ Daniel Khodabakhsh, MD,*†‡§ Amy H. Kaji, MD, PhD,*†‡ Jumie Lee, CPNP, MSN,*†‡ Benjamin Squire, MD, MPH,*†‡∥ and Marianne Gausche-Hill, MD*†‡ Objective: This study aimed to quantify risk factors for apnea in children 0 to 5 years of age with out-of-hospital seizure. Methods: This is a retrospective study of pediatric patients with seizure transported by paramedics to the pediatric emergency department (PED) of a tertiary center from July 2008 to June 2009. Patients with traumatic injury and those with another diagnosis after PED evaluation were excluded. We evaluated the effect of field diazepam and other potential risk factors on the occurrence of apnea, defined as the need for airway management, that is, bag-mask ventilation by paramedics or bag-mask ventilation or intubation by PED staff within 30 minutes of arrival. Results: There were 336 pediatric patients meeting inclusion criteria. The median age was 1.9 years (interquartile range,1.3–3.0 years); 193 patients (57%) were male. Fifty-four patients (16%) were treated with diazepam before PED arrival. There were 28 apneic events (8.3%). The adjusted relative risk for apnea given diazepam in the field by any route was 10.2 (95% confidence interval, 3.9–21.8; P < 0.0001), adjusted for age and seizure on arrival. Persistent seizure on PED arrival was also highly associated with apnea, with an adjusted relative risk of 15.8 (95% confidence interval, 6.5–28.9; P < 0.0001). Conclusions: Field treatment with diazepam and seizing at the time of PED arrival are associated with the occurrence of apnea in children 0 to 5 years of age with out-of-hospital seizure. Larger studies are needed to determine what other factors may contribute to this risk. Key Words: out of hospital, apnea, benzodiazepines, emergency medical services, seizures (Pediatr Emer Care 2014;30: 617–620)
S
eizure is a common chief complaint for pediatric patients in the out-of-hospital setting, accounting for approximately 15% of all emergency medical service (EMS) transports of pediatric patients in the United States.1 It is known that prolonged seizures can cause significant morbidity and mortality.2–4 Although many patients will require only supportive care, treatment is recommended for any seizure lasting more than 10 minutes.2 The sooner the seizure is treated, the more likely it is to be controlled.2 Parents and paramedics have the first opportunity to medically intervene. Initiating treatment for persistent seizures in the out-of-hospital setting is common practice in many EMS systems in the United States. Benzodiazepines are the antiepileptic drug of choice, and out-of-hospital administration of benzodiazepines has been shown to shorten overall seizure duration.5,6 Despite the relative safety and proven benefit of benzodiazepines for out-of-hospital treatment of seizure, respiratory depression From the *Department of Emergency Medicine, Harbor-UCLA Medical Center; and †Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance; ‡David Geffen School of Medicine at UCLA, Los Angeles; §International Medical Corps, Santa Monica; and ∥Huntington Memorial Hospital, Pasadena, CA. Disclosure: The authors declare no conflict of interest. Reprints: Nichole Bosson, MD, MPH, Harbor-UCLA Medical Center, 1000 W Carson St, Bldg D-9, Box 21, Torrance, CA 90502 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0749-5161
Pediatric Emergency Care • Volume 30, Number 9, September 2014
is a potential complication, especially in children.6 The risk of apnea after benzodiazepine administration for the treatment of pediatric seizures has been demonstrated in several studies.7–12 However, the rates of apnea in the studies have varied greatly, ranging from 0 to greater than 20% of treated patients.9,11,13–17 The wide range in reported rates of apnea is likely due, in part, to inclusion of children over a broad age range and variability in dosing of diazepam on a milligram-per-kilogram basis. This may be less than ideal because different factors may contribute to apnea at different ages, making risk-benefit analysis difficult for clinicians and out-ofhospital providers. There is limited knowledge, of what factors, beyond treatment with benzodiazepines, may predispose children to respiratory depression when treated for out-of-hospital seizure. Furthermore, the contribution of parental administered diazepam to the risk of apnea has not been clarified. We sought to identify risk factors for apnea in children 0 to 5 years of age, presenting with seizure. We evaluated the effect of both parental and EMS-administered diazepam as well as the contribution of other potential risk factors on the occurrence of apnea in this population. We hypothesized that younger age, prolonged seizure, current use of antiepileptic medication, or out-of-hospital treatment with benzodiazepines could be associated with apnea.
METHODS Study Design We conducted a single-center, retrospective, chart review of all pediatric patients with a diagnosis of seizure transported by paramedics to the pediatric emergency department (PED) at HarborUCLA Medical Center (HUMC) during a 1-year period from July 2008 to June 2009. Patients were identified by chief complaint from the base-hospital log of all paramedic transports to HUMC. The study was approved with waiver of informed consent by the institutional review board.
Population and Setting Harbor-UCLA Medical Center is a public teaching facility located in Los Angeles (LA) County serving a population of 1 million. Approximately 21,000 pediatric patients are treated annually. Children who arrive via the 911 system are transported by paramedic crews that consist of 2 paramedic-level emergency medical technicians stationed at local fire departments. Protocols in LA County support administration of benzodiazepines for seizure termination in any patient actively seizing with altered consciousness in the presence of paramedics. The dose may be repeated as needed with online medical control guidance until the seizure terminates. The average time from dispatch to hospital arrival for pediatric patients transported by paramedics in LA County is approximately 20 minutes, based on a previous study.18 Inclusion criteria were patients younger than 6 years transported by paramedics to the ED with the diagnosis of seizure. Patients with an out-of-hospital chief complaint of seizure but who were found to have another diagnosis on PED evaluation or whose primary complaint was traumatic injury were excluded. www.pec-online.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
617
Pediatric Emergency Care • Volume 30, Number 9, September 2014
Bosson et al
TABLE 1. Characteristics of Pediatric Patients Transported by EMS for Out-of-Hospital Seizure (n = 336) All Patients Characteristic Age Weight Sex Female Male Seizure disorder Seizing on ED arrival Prehospital medication received Any prehospital diazepam* Prehospital diazepam by EMS† Paramedic diazepam PR Paramedic diazepam IV Parental diazepam PR
Patients With Apnea
n (Median)
% (IQR)
n (Median)
% (IQR)
1.9 12.3
1.3–3.0 10.3–15.0
2.3 11.5
1.0–3.2 10.0–14.5
143 193 66 44
43 57 20 13
13 15 15 22
46 54 54 79
54 38 29 16 19
16 11 9 5 6
22 19 15 7 5
79 68 58 26 19
*Includes 3 patients treated by parents and EMS. † Includes 7 patients treated with both IV and PR diazepam.
Methods of Measurement Charts were reviewed by 2 investigators (DK, JL), not blinded to the purpose of the study, for the following study variables: paramedic-administered diazepam, route of administration, number of doses of medication administered, and total dose of medication administered. A third investigator (MGH) reviewed the data for accuracy and completeness. During the entire study period, diazepam was the benzodiazepine carried by paramedic units in LA County. Diazepam could be administered intravenously (IV) or per rectum (PR) at a dose of 0.1 mg/kg, titrated to seizure control. Of note, there was a protocol change at the start of the study period; the diazepam dose was reduced from 0.2 mg IV and 0.5 mg PR to 0.1 mg IVor PR. Paramedics used the Broselow tape to estimate patient weight for medication dosing. In addition, investigators extracted information on patient sex, age, weight, seizure on arrival to the ED (as a proxy for prolonged seizure duration), and history of a preexisting seizure disorder, defined by seizure disorder requiring chronic antiepileptic medication. A priori, it was determined that age and seizure on arrival to the ED would be important potential confounders, warranting adjustment, in a multivariable model. Age was coded as a continuous variable, whereas seizure on arrival to the ED was coded as a binary predictor. With the use of a standardized collection instrument, data were tabulated and entered into a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, Wash) and imported into SAS for analysis with SAS version 9.3 (SAS Corporation, Cary, NC). Outcome variables included the need for airway management for apnea defined as bag-mask ventilation by paramedics or bag-mask ventilation or intubation by ED staff within 30 minutes of arrival. Outcomes were abstracted and then confirmed by an agreement of 2 investigators, an emergency medicine (EM) physician (DK) and an EM physician with pediatric EM subspecialty training (MGH).
Analytical Methods The study outcomes (intubation or bag-mask ventilation) for each group were calculated as proportions with exact binomial confidence intervals. P values for unadjusted 2 2 tables were calculated using χ2 test, and relative risks (RRs) were calculated
618
www.pec-online.com
given the cohort design. Adjusted RRs were determined using multiple logistic regression and correcting odds ratios through methods described by Zhang and Yu.19
RESULTS There were 336 pediatric patients meeting inclusion criteria transported by paramedics during the study period. The median age was 1.9 years (interquartile range [IQR], 1.3–3.0 years), and 191 patients (57%) were male. Of the patients transported, 66 (20%) had a seizure disorder, and 96 (29%) were admitted to the hospital. Table 1 contains baseline characteristics of the study population. Fifty-four patients (16%) were treated with diazepam by paramedics or parents before PED arrival. Thirty-eight patients (11%) received diazepam by paramedics in the field, 19 patients (6%) received parental diazepam, and 3 patients (0.8%) were treated by both parents and EMS. In total, there were 28 apneic events (8.3%), 19 treated with diazepam and 9 not treated with diazepam. Twenty-five patients (7%) required intubation with a median time to intubation of 16 minutes (IQR, 11–20 minutes) from PED arrival. The unadjusted RR for apnea given diazepam in the field by any route was 19.2 (95% confidence interval [CI], 8.2–45.2; P < 0.001). The outcomes by route of administration are given in Table 2. Although 3 patients were treated with diazepam PR by both parents and paramedics and another 7 patients received both IVand PR diazepam by paramedics, analysis excluding such patients yielded similar results. Given the possibility of dosing errors after the change in diazepam dose initiated at the start of the study period, we compared apnea rates of children receiving the correct dose of diazepam with those of children who received doses greater than 20% above the correct dose by weight, including 6 patients (40%) treated with IV diazepam and 14 patients (50%) treated with PR diazepam. There was no difference in apnea rates by dose with this sensitivity analysis. The adjusted RR for apnea given diazepam in the field by any route was 10.2 (95% CI, 3.9–21.8; P < 0.0001), adjusted for age and seizure on PED arrival. In our exploratory univariate analysis of other potential risk factors for apnea, seizure on arrival to © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pediatric Emergency Care • Volume 30, Number 9, September 2014
Risk Factors for Apnea in Children
TABLE 2. Risk of Apnea in Pediatric Patients Treated for Out-of-Hospital Seizure by Route of Medication Administration Exposure Parental PR diazepam EMS diazepam any route* EMS IV diazepam EMS PR diazepam No field medications
n
Apnea Frequency
%
RR (95%CI)
P
19 38 16 29 281
5 19 7 15 5
26 50 44 52 2
14.8 (4.7–46.7) 28.1 (11.1–70.9) 24.6 (8.8–70.0) 29.1 (11.4–74.2) 1
