Abstract
Background:
Lidocaine and amiodarone are both included in the pediatric cardiac arrest guidelines as treatments of shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, although there is limited evidence to support this recommendation.
Methods:
In this cohort study from the Get With The Guidelines – Resuscitation registry, we included pediatric patients (≤18 years) with an in-hospital cardiac arrest between 2000 and 2018, who presented with an initial or subsequent shockable rhythm (ventricular fibrillation and pulseless ventricular tachycardia). Patients receiving amiodarone were matched to patients receiving lidocaine based on a propensity score, calculated from multiple patient, event, and hospital characteristics.
Results:
A total of 365 patients were available for the analysis, of which 180 (49%) patients were matched on the propensity score. The median age in the raw cohort was 6 (quartiles, 0.5–14) years, 164 (45%) patients were female, and 238 (65%) patients received an antiarrhythmic for an initial shockable rhythm. In the matched cohort, there were no statistically significant differences between patients receiving lidocaine compared to amiodarone in return of spontaneous circulation (RR, 0.99 [95%CI, 0.82–1.19]; p = 0.88), survival to 24 h (RR, 1.02 [95%CI, 0.76–1.38]; p = 0.88), survival to hospital discharge (RR, 1.01 [95%CI, 0.63–1.63]; p = 0.96), and favorable neurological outcome (RR, 0.65 [95%CI, 0.35–1.21]; p = 0.17). The results remained consistent in multiple sensitivity analyses.
Conclusions:
In children with cardiac arrest receiving antiarrhythmics for a shockable rhythm, there was no significant difference in clinical outcomes between those receiving lidocaine compared to amiodarone.
Keywords: Antiarrhythmics, Amiodarone, Lidocaine, Cardiac arrest, Heart arrest, Pediatrics
Introduction
In-hospital cardiac arrest (IHCA) occurs in over 7000 children each year in the US,1 with an in-hospital mortality reaching 60% in 2017.2 Ventricular fibrillation (VF) or pulseless ventricular tachycardia (PVT) is the presenting rhythm in about 10% of pediatric IHCA patients and the subsequent rhythm in about 15% of patients.3
Amiodarone and lidocaine are the most commonly used antiarrhythmic medications in the management of shock-refractory VF and PVT. In the 2005 and 2010 Pediatric Advanced Life Support (PALS) guidelines, published by the American Heart Association, amiodarone was recommended in preference to lidocaine as the first-line of antiarrhythmic.4,5 This recommendation was primarily based on smaller case-series6,7 and the adult literature.8,9
In 2014, investigators used data from a large IHCA registry in the US from 2000 to 2008 to compare the use of lidocaine or amiodarone to no antiarrhythmic medication for refractory VF and PVT.10 The authors found no significant difference in survival to hospital discharge for either medication, although lidocaine was independently associated with increased return of spontaneous circulation (ROSC). Based on this study, the 2015 PALS guidelines were revised with the statement “amiodarone or lidocaine are equally acceptable for the treatment of shock-refractory ventricular fibrillation or pulseless ventricular tachycardia in children”.11 However, the evidence for using lidocaine or amiodarone for refractory VF and PVT in pediatric IHCA remains limited.
In this study, to assist in the development of future guidelines, we compared outcomes in pediatric IHCA patients receiving amiodarone or lidocaine for an initial or subsequent rhythm of VF or PVT between 2000 and 2018.
Methods
Study design and data source
This was an analysis of prospectively collected data from the Get With The Guidelines®-Resuscitation (GWTG-R) registry. The GWTG-R registry is a large quality-improvement registry of IHCA patients in the US. The American Heart Association sponsors the registry and provides oversight of the data collection, analysis, and reporting process. At each participating site, trained research personnel abstract and enter information from all cardiac arrests without a do-not-resuscitate order into a database repository. A detailed description of the data collection process and quality control has been provided elsewhere.12,13 In the registry, cardiac arrest is defined as the loss of a palpable pulse or the presence of a pulse with inadequate perfusion, requiring chest compressions, defibrillation, or both, with a hospital-wide or unit-wide emergency response. Hospital-level data were obtained from the 2018 American Hospital Association Annual Survey and linked to the GWTG-R registry by the American Heart Association data management vendor (dataset version 10). IQVA is the data collection coordination center for the American Heart Association/American Stroke Association Get With The Guidelines® programs.
All participating institutions in the GWTG-R registry are required to comply with local regulatory and privacy guidelines. Because data are primarily used at the local site for quality-improvement, sites are granted a waiver of informed consent under the common rule.
Study population
The cohort included pediatric patients (≤18 years of age) with an index IHCA between January 1, 2000 and December 31, 2018. We only included patients presenting with an initial or subsequent pulseless shockable rhythm (VF or PVT) for which they received either amiodarone or lidocaine. We excluded patients receiving chest compressions for less than 2 min, patients receiving both amiodarone and lidocaine during the cardiac arrest, cardiac arrests occurring in the delivery room, and hospital visitors. For the primary analysis, we also excluded patients with missing data on the primary outcome and covariates. Patients with missing data were included after imputing missing values in a preplanned sensitivity analysis (see “Statistical Analysis”).
Exposure and outcomes
The use of amiodarone or lidocaine was defined as the administration of the medication at any time during the cardiac arrest independent of the number of defibrillation attempts. Timing and dosing of amiodarone and lidocaine are not available in the GWTG-R registry. The primary outcome was sustained ROSC, defined as the presence of a pulse and the cessation of chest compressions for at least 20 min, including the initiation of cardiopulmonary bypass or extracorporeal membrane oxygenation. The secondary outcomes included survival to 24-h after the cardiac arrest, survival to hospital discharge, and survival to hospital discharge with a favorable neurological outcome. Favorable neurological outcome was defined as a Pediatric Cerebral Performance Category (PCPC) score of 1 (normal or no cerebral disability) or 2 (mild cerebral disability)14 in accordance with the Utstein criteria.15
Statistical analysis
The goal of this study was to compare the use of amiodarone to lidocaine in pediatric IHCA patients presenting with VF or PVT. Because of the risk for resuscitation time bias16 and unmeasured confounding (e.g., the conversion to non-shockable rhythms, which have been associated with lower survival13), we did not compare the use of amiodarone or lidocaine to the use of no antiarrhythmic drug.
Descriptive statistics were used to summarize the study population. Continuous data are presented as medians with 1st and 3rd quartiles. Categorical data are presented as counts with frequencies.
To assess the adjusted association between the use of antiarrhythmics during cardiopulmonary resuscitation and outcomes, we used propensity score matching.17 The propensity score was calculated based on a multivariable logistic regression model. The use of antiarrhythmics was included as the dependent variable (with lidocaine as the reference category) and patient, event, and hospital characteristics were included as the independent variables (all variables presented in Table 1). Year of cardiac arrest was included in the model because the management (including the use of antiarrhythmics) and survival of cardiac arrest have changed over time.2 We did not adjust for the time to defibrillation due to the large amount of missing data for this variable and since time to defibrillation was recently found not to be associated with outcomes.18 All variables were prespecified based on clinical reasoning, prior publications, and availability in the registry.13,19–23
Table 1 -.
Patient characteristics in the full cohort.
| Lidocaine (n = 217) | Amiodarone (n = 148) | Standardized Differences | |
|---|---|---|---|
|
| |||
| Demographics | |||
| Sex | |||
| Male | 115 (53) | 86 (58) | −0.10 |
| Female | 102 (47) | 62 (42) | 0.10 |
| Age group | |||
| Neonate (<1 month) | 30 (14) | 17(11) | 0.07 |
| Infant (1 month to <1 year) | 41 (19) | 23 (16) | 0.09 |
| Child (1 year to <12 years) | 70 (32) | 47 (32) | 0.01 |
| Adolescent (≥12 years) | 76 (35) | 61 (41) | −0.13 |
| Illness category | |||
| Medical | |||
| Cardiac | 49 (23) | 39 (26) | −0.09 |
| Non-cardiac | 60 (28) | 46 (31) | −0.08 |
| Surgical | |||
| Cardiac | 75 (35) | 34 (23) | 0.26 |
| Non-cardiaca | 33 (15) | 29 (20) | −0.12 |
| Pre-existing conditionsb | |||
| Heart failure prior admission | 25 (12) | 18 (12) | −0.02 |
| Heart failure this admission | 41 (19) | 29 (20) | −0.02 |
| Hypotension | 66 (30) | 43 (29) | 0.03 |
| Respiratory insufficiency | 105 (48) | 73 (49) | −0.02 |
| Hepatic insufficiency | 7 (3) | 8 (5) | −0.11 |
| Renal insufficiency | 18(8) | 19 (13) | −0.15 |
| Metabolic abnormalities | 25 (12) | 36 (24) | −0.34 |
| Acute non-stroke CNS event | 17(8) | 18 (12) | −0.15 |
| Baseline depression in CNS | 30 (14) | 15 (10) | 0.11 |
| Metastatic malignancy | 7 (3) | 9 (6) | −0.14 |
| Pneumonia | 13(6) | 5 (3) | 0.12 |
| Septicemia | 21 (10) | 20 (14) | −0.12 |
| Location and Time of Event | |||
| Location | |||
| Emergency department | 11 (5) | 16(11) | −0.21 |
| Intensive care unit | 151 (70) | 112 (76) | −0.14 |
| Floor | |||
| Without telemetry | 15(7) | 7 (5) | 0.09 |
| With telemetry | 5 (2) | 3 (2) | 0.02 |
| Otherc | 35 (16) | 10(7) | 0.30 |
| Time of week | |||
| Weekendd | 54 (25) | 46 (31) | −0.14 |
| Weekday | 163 (75) | 102 (69) | <0.01 |
| Time of day | |||
| Nighttimee | 65 (30) | 46 (31) | −0.02 |
| Daytime | 152 (70) | 102 (69) | 0.02 |
| Year of cardiac arrest | |||
| 2000 – 2005 | 78 (36) | 20 (14) | 0.54 |
| 2006 – 2010 | 68 (31) | 41 (28) | 0.08 |
| 2011 – 2015 | 42 (19) | 46 (31) | −0.27 |
| 2016 – 2018 | 29 (13) | 41 (28) | −0.36 |
| Event Characteristics | |||
| Witnessed | |||
| Yes | 215 (99) | 139 (94) | 0.28 |
| No | 2(1) | 9 (6) | −0.28 |
| Monitored | |||
| Yes | 207 (95) | 141 (95) | 0.01 |
| No | 10(5) | 7 (5) | −0.01 |
| Interventions already in place | |||
| Vasoactive agents | 89 (41) | 67 (45) | −0.09 |
| Antiarrhythmics | 16(7) | 8 (5) | 0.08 |
| Arterial line | 84 (39) | 50 (34) | 0.10 |
| Mechanical ventilation | 157 (72) | 104 (70) | 0.05 |
| First pulseless rhythm | |||
| Ventricular fibrillation | 81 (37) | 37 (25) | 0.27 |
| Pulseless ventricular tachycardia | 69 (32) | 51 (34) | −0.06 |
| Asystole | 36 (17) | 20 (14) | 0.09 |
| Pulseless electrical activity | 31 (14) | 40 (27) | −0.32 |
| Sequence of shockable rhythm | |||
| Initial shockable | 150 (69) | 88 (59) | 0.20 |
| Subsequent shockable | 67 (31) | 60 (41) | −0.20 |
| Time to epinephrine | |||
| Early (<2min) | 100 (46) | 68 (46) | 0.01 |
| Not earlyf | 117 (54) | 80 (54) | −0.01 |
| Time to intubation | |||
| Early (<2min) | 4 (2) | 3 (2) | −0.01 |
| Not earlyf | 213 (98) | 145 (98) | 0.01 |
| Time to chest compressions (min) | 1 (1,1) | 1 (1, 1) | 0.11 |
| Hospital Characteristics | |||
| Number of pediatric beds | |||
| None | 16(7) | 22 (15) | −0.24 |
| 1–10 | 2(1) | 1 (1) | 0.03 |
| 11–25 | 16(7) | 12(8) | −0.03 |
| 26–50 | 12(6) | 11 (7) | −0.08 |
| ≥50 | 171 (79) | 102 (69) | 0.23 |
| Type of hospital | |||
| Primary pediatric | 139 (64) | 39 (26) | 0.82 |
| Primary adult | 78 (36) | 109 (74) | −0.82 |
| Teaching status | |||
| Major | 174 (80) | 104 (70) | 0.23 |
| Minor | 37 (17) | 43 (29) | −0.29 |
| Non-teaching | 6 (3) | 1 (1) | 0.16 |
| Geographic region | |||
| Northeast | 76 (35) | 27 (18) | 0.39 |
| South Atlantic | 53 (24) | 30 (20) | 0.10 |
| Midwest | 22 (10) | 38 (26) | −0.41 |
| South Central | 48 (22) | 29 (20) | 0.06 |
| West | 18(8) | 24 (16) | −0.24 |
CNS denotes central nervous system; GWTG-R denotes Get With The Guidelines-Resuscitation.
Including non-cardiac surgical patients, trauma patients, obstetric patients, and newborns.
Definitions have been provided elsewhere.
Including ambulatory or outpatient clinics, diagnostic or interventional areas, operating room, post-anesthesia recovery room, rehabilitation unit, and same-day surgical area.
Friday 11 PM to Monday 7 AM.
11:00 PM to 6:59 AM.
Provided >2 min or not provided.
Matching between patients receiving amiodarone to those receiving lidocaine was performed in a 1:1 ratio using an algorithm that optimized the number of matches within 0.2 standard deviations of the logit of the propensity score (Supplemental Fig. 1 in the Supplemental Material).24 The matched groups were compared using descriptive statistics and differences reported using standardized differences, with a difference between −0.1 and 0.1 signifying a negligible imbalance between the groups.25 Using the matched cohort, we performed modified Poisson regression26,27 and linear regression28 to assess the association between the use of amiodarone or lidocaine and outcomes. Generalized estimating equations (GEE) was used to account for the matching and clustering of patients within hospitals. Effect estimates from these analyses were reported as relative risk ratios (RR) and risk differences (RD) with 95% confidence intervals.
We performed four subgroup analyses for the primary outcome by adding interaction terms between the use of antiarrhythmics and prespecified variables to the modified Poisson regression model, including age group, year of cardiac arrest, sequence of shockable rhythm (initial vs subsequent), and illness category (cardiac vs non-cardiac).
We also performed six preplanned sensitivity analyses. First, to account for missing data on covariates and outcomes (Supplemental Table 1 in the Supplemental Material), we performed multiple imputations using the fully conditional specification method and assumed that the data were “missing at random”.29,30 A total of 20 imputed datasets were created.31 Second, to account for remaining imbalances between those receiving lidocaine and amiodarone, we used doubly robust methods for variables with a standardized difference less than −0.1 or above 0.1 by combining the use of propensity scores and modified Poisson regression, as described in detail elsewhere.32 Third, we repeated the primary analysis twice by only including patients who received at least one defibrillation or at least two defibrillations. We did not restrict the primary analysis to patients receiving a specific number of defibrillations, since the use of amiodarone or lidocaine may affect survival when provided early during the cardiac arrest,33 which could bias the results.34 Fourth, we repeated the analysis without including the initiation of cardiopulmonary bypass or extracorporeal membrane oxygenation in the definition of ROSC. Lastly, we accounted for alternate definitions of favorable neurological outcome, by performing the analysis with the outcome defined as (1) a discharge PCPC score of 1, 2, or no increase from baseline, (2) a discharge PCPC score of 1, 2, or 3, and (3) a discharge PCPC of 1, 2, 3, or no increase from baseline.35
All analyses were two-sided, with a significance level of p < 0.05. All secondary analyses should be considered exploratory as we did not adjust for multiple comparisons.36 SAS version 9.4 (SAS Institute, Cary, NC, USA) was used for all analyses.
Results
Patient characteristics
The study population included 365 patients, of which 217 (59%) patients received lidocaine and 148 (41%) patients received amiodarone (Fig. 1). The median age was 6 (quartiles, 0.5–14) years and 164 (45%) patients were female. There were 238 (65%) patients with an initial shockable rhythm and 127 (35%) patients with a subsequent shockable rhythm. Additional characteristics are provided in Table 1.
Fig. 1 -.
Inclusion and exclusion criteria for the primary analysis. Between 2000 and 2018, 12,601 pediatric patients with a pulseless cardiac arrest were registered in the Get With The Guidelines®-Resuscitation registry. A total of 365 patients were included for the propensity score matched analysis, of which 217 (59%) received lidocaine and 148 (41%) received amiodarone.
Unadjusted analyses
A total of 272 (75%) patients achieved ROSC in the raw cohort. In the unadjusted analysis, lidocaine was associated with an increase in ROSC compared to amiodarone (171/217 [79%] vs 101/148 [68%]; RR, 1.15 [95%CI, 1.01–1.31]; p = 0.03). Survival to 24 h occurred in 199 (55%) of patients. In the unadjusted analysis, lidocaine was associated with an increase in survival to 24 h compared to amiodarone (132/217 [61%] vs 67/148 [45%]; RR, 1.34 [95%CI, 1.09–1.65]; p = 0.004). A total of 124 (34%) patients survived to hospital discharge. Lidocaine was associated with an increase in survival to hospital discharge compared to amiodarone (84/216 [39%] vs 40/146 [27%]; RR, 1.42 [95%CI, 1.04–1.94]; p = 0.02). Data on neurological outcome were available in 327 (90%) patients, of whom 69 (21%) survived to hospital discharge with favorable neurological outcome. In this cohort, lidocaine was not associated with favorable neurological outcome compared to amiodarone (39/186 [21%] vs 30/141 [21%]; RR, 0.99 [95%CI, 0.65–1.50]; p > 0.99). Additional data are provided in Table 3.
Table 3 -.
Outcomes for the unadjusted analysis and propensity score-matched analysis.
| Outcomes | Unadjusted analysis |
Matched analysis |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lidocaine (N, %) | Amiodarone (N, %) | RR (95%CI) | RD (95%CI) | P-value | Lidocaine (N, %) | Amiodarone (N, %) | RR (95%CI) | RD (95%CI) | P-value | |
|
| ||||||||||
| Return of spontaneous circulation | 171/217 (78.8) | 101/148 (68.2) | 1.15 (1.01–1.31) | 10.6 (1.3–19.8) | 0.03 | 67/90 (74.4) | 68/90 (75.6) | 0.99 (0.82–1.19) | −1.1 (−15.3–13.1) | 0.88 |
| Survival to 24 h | 132/217 (60.8) | 67/148 (45.3) | 1.34 (1.09–1.65) | 15.5 (5.2–25.9) | 0.004 | 45/90 (50.0) | 44/90 (48.9) | 1.02 (0.76–1.38) | 1.1 (−13.6–15.9) | 0.88 |
| Survival to hospital discharge | 84/216 (38.9) | 40/146 (27.4) | 1.42 (1.04–1.94) | 11.5 (1.8–21.2) | 0.02 | 28/89 (31.5) | 28/90 (31.1) | 1.01 (0.63–1.63) | 0.4 (−14.5–15.2) | 0.96 |
| Favorable neurological outcome | 39/186 (21.0) | 30/141 (21.3) | 0.99 (0.65–1.50) | −0.3 (−9.3–8.6) | >0.99 | 12/78 (15.4) | 20/85 (23.5) | 0.65 (0.35–1.21) | −8.1 (−19.9–3.6) | 0.17 |
RR denotes relative risk; RD denotes risk difference.
Matched analysis
Of the 365 patients included in the raw cohort, 180 were matched based on the propensity score, with 90 (50%) patients receiving lidocaine and 90 (50%) patients receiving amiodarone (Supplemental Fig. 1 in the Supplemental Material). The groups were relatively well-matched overall (standardized difference between −0.1 and 0.1), although some imbalances remained for certain characteristics (Table 2).
Table 2 -.
Patient characteristics in the matched cohort.
| Lidocaine (n = 90) | Amiodarone (n = 90) | Standardized Differences | |
|---|---|---|---|
|
| |||
| Demographics | |||
| Sex | |||
| Male | 48 (53) | 48 (53) | <0.01 |
| Female | 42 (47) | 42 (47) | <0.01 |
| Age group | |||
| Neonate (<1 month) | 11 (12) | 10(11) | 0.04 |
| Infant (1 month to <1 year) | 13 (14) | 16 (18) | −0.09 |
| Child (1 year to <12 years) | 31 (34) | 30 (33) | 0.02 |
| Adolescent (≥12 years) | 35 (39) | 34 (38) | 0.02 |
| Illness category | |||
| Medical | |||
| Cardiac | 23 (26) | 24 (27) | −0.03 |
| Non-cardiac | 27 (30) | 28 (31) | −0.02 |
| Surgical | |||
| Cardiac | 21 (23) | 22 (24) | −0.03 |
| Non-cardiaca | 19 (21) | 16 (18) | 0.08 |
| Pre-existing conditionsb | |||
| Heart failure prior admission | 9(10) | 9(10) | <0.01 |
| Heart failure this admission | 14 (16) | 12 (13) | 0.06 |
| Hypotension | 30 (33) | 25 (28) | 0.12 |
| Respiratory insufficiency | 43 (48) | 43 (48) | <0.01 |
| Hepatic insufficiency | 5 (6) | 2 (2) | 0.17 |
| Renal insufficiency | 9(10) | 10(11) | −0.04 |
| Metabolic abnormalities | 13 (14) | 16 (18) | −0.09 |
| Acute non-stroke CNS event | 10(11) | 11 (12) | −0.04 |
| Baseline depression in CNS | 12 (13) | 10(11) | 0.07 |
| Metastatic malignancy | 3 (3) | 4 (4) | −0.06 |
| Pneumonia | 4(4) | 5 (6) | −0.05 |
| Septicemia | 11 (12) | 13 (14) | −0.07 |
| Location and Time of Event | |||
| Location | |||
| Emergency department | 8 (9) | 7 (8) | 0.04 |
| Intensive care unit | 67 (74) | 68 (76) | −0.03 |
| Floor | |||
| Without telemetry | 2 (2) | 5 (6) | −0.17 |
| With telemetry | 3 (3) | 2 (2) | 0.07 |
| Otherc | 10(11) | 8 (9) | 0.07 |
| Time of week | |||
| Weekendd | 26 (29) | 24 (27) | 0.05 |
| Weekday | 64 (71) | 66 (73) | <0.01 |
| Time of day | |||
| Nighttimee | 24 (27) | 25 (28) | −0.03 |
| Daytime | 66 (73) | 65 (72) | 0.03 |
| Year of cardiac arrest | |||
| 2000–2005 | 18 (20) | 16 (18) | 0.06 |
| 2006–2010 | 33 (37) | 34 (38) | −0.02 |
| 2011–2015 | 20 (22) | 22 (24) | −0.05 |
| 2016–2018 | 19 (21) | 18 (20) | 0.03 |
| Event Characteristics | |||
| Witnessed | |||
| Yes | 89 (99) | 88 (98) | 0.09 |
| No | 1 (1) | 2 (2) | −0.09 |
| Monitored | |||
| Yes | 86 (96) | 85 (94) | 0.05 |
| No | 4 (4) | 5 (6) | −0.05 |
| Interventions already in place | |||
| Vasoactive agents | 39 (43) | 39 (43) | <0.01 |
| Antiarrhythmics | 5 (6) | 7 (8) | −0.09 |
| Arterial line | 31 (34) | 28 (31) | 0.12 |
| Mechanical ventilation | 67 (74) | 62 (69) | 0.07 |
| First pulseless rhythm | |||
| Ventricular fibrillation | 29 (32) | 23 (26) | 0.15 |
| Pulseless ventricular tachycardia | 32 (36) | 35 (39) | −0.07 |
| Asystole | 13 (14) | 12 (13) | 0.03 |
| Pulseless electrical activity | 16 (18) | 20 (22) | −0.11 |
| Sequence of shockable rhythm | |||
| Initial shockable | 61 (68) | 58 (64) | 0.07 |
| Subsequent shockable | 29 (32) | 32 (36) | −0.07 |
| Time to epinephrine | |||
| Early (<2min) | 45 (50) | 44 (49) | 0.02 |
| Not earlyf | 45 (50) | 46 (51) | −0.02 |
| Time to intubation | |||
| Early (<2min) | 0 (0) | 1 (1) | −0.15 |
| Not earlyf | 90 (100) | 89 (99) | 0.15 |
| Time to chest compressions (min) | 1 (1,1) | 1 (1,1) | 0.13 |
| Hospital Characteristics | |||
| Number of pediatric beds | |||
| None | 12 (13) | 12 (13) | <0.01 |
| 1–10 | 1 (1) | 0 (0) | 0.15 |
| 11–25 | 9(10) | 7 (8) | 0.08 |
| 26–50 | 6(7) | 7 (8) | −0.04 |
| ≥50 | 62 (69) | 64 (71) | −0.05 |
| Type of hospital | |||
| Primary pediatric | 38 (42) | 34 (38) | 0.09 |
| Primary adult | 52 (58) | 56 (62) | −0.09 |
| Teaching status | |||
| Major | 67 (74) | 69 (77) | −0.05 |
| Minor | 22 (24) | 20 (22) | 0.05 |
| Non-teaching | 1 (1) | 1 (1) | <0.01 |
| Geographic region | |||
| Northeast | 25 (28) | 23 (26) | 0.05 |
| South Atlantic | 15(17) | 18 (20) | −0.09 |
| Midwest | 16 (18) | 15(17) | 0.03 |
| South Central | 20 (22) | 19 (21) | 0.03 |
| West | 14 (16) | 15(17) | −0.03 |
CNS denotes central nervous system; GWTG-R denotes Get With The Guidelines-Resuscitation.
Including non-cardiac surgical patients, trauma patients, obstetric patients, and newborns.
Definitions have been provided elsewhere.
Including ambulatory or outpatient clinics, diagnostic or interventional areas, operating room, post-anesthesia recovery room, rehabilitation unit, and same-day surgical area.
Friday 11 PM to Monday 7 AM.
11:00 PM to 6:59 AM.
Provided >2 min or not provided.
In the matched cohort, there were no statistically significant differences between patients receiving lidocaine compared to amiodarone in ROSC (67/90 [74%] vs 68/90 [76%]; RR, 0.99 [95% CI, 0.82–1.19]; p = 0.88), survival to 24 h (45/90 [50%] vs 44/90 [49%]; RR, 1.02 [95%CI, 0.76–1.38]; p = 0.88), survival to hospital discharge (28/89 [31%] vs 28/90 [31%]; RR, 1.01 [95%CI, 0.63–1.63]; p = 0.96), and favorable neurological outcome (12/78 [15%] vs 20/85 [24%]; RR, 0.65 [95%CI, 0.35–1.21]; p = 0.17). Additional data are provided in Table 3.
There were no statistically significant interactions between the use of antiarrhythmics and age group (p = 0.68), year of cardiac arrest (p = 0.66), sequence of shockable rhythm (p = 0.40), or illness category (p = 0.47). The results of these subgroup analyses are summarized in Fig. 2.
Fig. 2 -.
Subgroup analyses in the propensity-score matched cohort. Results are reported as risk ratios with 95% confidence intervals. The dashed vertical line (RR: 1.00) represents the risk ratio for no association.
Sensitivity analyses
Data were missing on at least 1 variable in 106 (23%) patients, with a median number of missing variables of 2 (quartiles, 1–3; mean, 2.1; standard deviation, 1.6). A total of 471 patients were included for the sensitivity analysis accounting for missing data and 234–246 patients were matched on the propensity score in the 20 imputed datasets. In this analysis, there were no statistically significant differences between patients receiving lidocaine compared to amiodarone in ROSC (RR, 1.11 [95%CI, 0.91–1.34; p = 0.32), survival to 24 h (RR, 1.18 [95%CI, 0.84–1.66; p = 0.34), survival to hospital discharge (RR, 1.25 [95%CI, 0.76–2.08; p = 0.38), and favorable neurological outcome (RR, 0.91 [95%CI, 0.44–1.88; p = 0.79).
The results from the remaining sensitivity analyses were consistent with the primary analysis as described in Supplemental Table 2 of the Supplemental Material.
Discussion
In this study, we used a large, IHCA registry in the US to compare outcomes in pediatric IHCA patients receiving amiodarone or lidocaine for a shockable rhythm. After matching patients on the propensity score, calculated from multiple patient, event, and hospital characteristics, we found no statistically significant differences between those receiving lidocaine compared to amiodarone in ROSC, survival to 24 h, survival to hospital discharge, and favorable neurological outcome. These results remained consistent in multiple subgroup and sensitivity analyses.
Amiodarone and lidocaine were developed as antiarrhythmic agents in the 1960s/1970s and have since been introduced as therapies for shock-refractory VF and PVT to facilitate successful defibrillation and reduce the risk of recurrent arrhythmias.37,38 The electrophysiological actions of these antiarrhythmics are complex and incompletely understood, but are primarily related to their effect on potassium, sodium, and calcium channels, which modifies the defibrillation threshold.39 From 2000 to 2014, the pediatric cardiac arrest guidelines favored amiodarone over lidocaine, whereas more recent updates to the guidelines have not provided a preference towards either medication, primarily due to the limited data in children and a lack of long-term data for adult cardiac arrests.40 The findings from our study support the current guidelines, however, the possibility remains that we were underpowered to detect clinically significant differences between groups given the small sample size.
Few studies have directly compared the use of lidocaine to amiodarone in cardiac arrest, particularly for hospitalized children, for whom only one observational study has been published.10,41 In that study, published in 2014, investigators used data from the GWTG-R registry between 2000 and 2009 to compare outcomes in pediatric patients receiving lidocaine or amiodarone compared to no antiarrhythmic for refractory VF and PVT.10,42 Contrary to our study, the previous authors found significantly higher rates of ROSC among patients receiving lidocaine compared to amiodarone (64% vs 44%; p = 0.002), although there was no significant difference in survival to hospital discharge. There are several potential reasons for the discrepant results between these studies. First, a corrigendum to the previous study was recently published, stating that both index and non-index events were included in the dataset, although the correlation between patients was not accounted for in the analysis, which may have led to overly narrow confidence intervals.42 Second, the previous study did not provide any adjusted comparison between the use of lidocaine and amiodarone, potentially leading to biased estimates. This potential for bias is also illustrated by the different results in the unadjusted and adjusted analyses for here (Table 3). Third, the main analysis in the previous study compared the use of lidocaine or amiodarone to no antiarrhythmic. Given that antiarrhythmic agents are recommended for refractory VF/PVT and because patients receiving neither lidocaine nor amiodarone are more likely to have a shorter duration of resuscitation, such a comparison could be biased. This bias is less likely to occur for a comparison of lidocaine to amiodarone, as these agents are likely given around the same point of time during resuscitation. Additional details regarding this concept have been provided elsewhere.16
A recent systematic review, commissioned by the International Liaison Committee on Resuscitation, identified two studies comparing the use of lidocaine to amiodarone in adult out-of-hospital cardiac arrest.41 In 2002, Dorian et al. randomized 347 patients to amiodarone or lidocaine.8 In that study, patients receiving amiodarone had a statistically significantly higher survival to hospital admission compared to those receiving lidocaine (p = 0.009). However, polysorbate 80 (which is the solvent for amiodarone) was added to the lidocaine solution as an emulsifier, which is known to cause hypotension,43,44 potentially leading to a harmful effect making this trial difficult to interpret. In a later study, published in 2016, Kudenchuk et al. randomized over 3000 patients to lidocaine, amiodarone, or placebo.45 Neither lidocaine nor amiodarone were found to be statistically significantly associated with survival to hospital discharge compared to placebo (23,7%, 24.4%, and 21.0%, respectively). There was also no statistically significant difference in survival between patients receiving lidocaine compared to those receiving amiodarone (p = 0.70). Given the differing etiologies of VF and PVT between pediatric IHCA and adult out-of-hospital cardiac arrest, the implications of these previous studies for pediatric IHCA remain unknown and the findings may not be generalizable to this patient population. This is especially true when considering that conditions in which amiodarone could have adverse effects may be common in pediatric IHCA, such as hypokalemia and QTc prolongation.46
The findings from our study should be interpreted in the context of some limitations. Although we used propensity score matching to reduce bias from potential confounding factors, there is still a possibility that unmeasured and residual confounding could have influenced our results. For example, despite our assumption that both agents were provided for the same indication, the timing of administration, sequence in relation to other interventions, and/or severity of illness among patients may have differed between those receiving amiodarone and lidocaine. There were some data to support this as many of the baseline characteristics were profoundly different for the two groups in the raw cohort of our study (Table 1). We may also have been underpowered to rule out a clinically relevant effect between groups in the propensity matched cohort as reflected by the very wide confidence intervals of our effect estimates, despite using 18 years of data from one of the largest IHCA registries worldwide. Lastly, the study addressed the use of lidocaine or amiodarone in patients with an IHCA and may not be generalizable to the out-of-hospital cardiac arrest population.
Conclusions
There were no statistically significant differences in ROSC, survival to 24 h, survival to hospital discharge, and favorable neurological outcome between children receiving amiodarone or lidocaine for shock-refractory VF and PVT. These findings support the current pediatric cardiac arrest guidelines, although the results were limited by the small sample size.
Supplementary Material
Acknowledgements
Mathias J. Holmberg and Lars W. Andersen were responsible for the data acquisition, performed the statistical analyses, and drafted the manuscript. All authors contributed to the design of the study, interpreted the results, and critically revised the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the submitted work.
There was no specific funding for this study. Dr Donnino is supported by grant K24-HL127101–04 and R01-HL136705–03 from the National Heart, Lung, and Blood Institute.
Footnotes
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.resuscitation.2019.12.033.
Conflicts of interest
The remaining authors have no conflicts of interest or sources of funding to declare.
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