Abstract
Background:
Supported by laboratory and clinical investigations of adult cardiopulmonary arrest, resuscitation guidelines recommend monitoring end-tidal carbon dioxide (ETCO2) as an indicator of CPR quality but note that “specific values to guide therapy have not been established in children.”
Methods:
This prospective observational cohort study was an NHLBI-funded ancillary study of children in the ICU-RESUScitation trial (NCT02837497). Hospitalized children (≤18 years of age and ≥37 weeks post-gestational age) who received chest compressions of any duration for cardiopulmonary arrest, had an endotracheal or tracheostomy tube at the start of CPR, and had evaluable intra-arrest ETCO2 data were included. The primary exposure was event-level average ETCO2 during the first 10 minutes of CPR (dichotomized as ≥20 mmHg vs. <20 mmHg based on adult literature). The primary outcome was survival to hospital discharge. Secondary outcomes were sustained return of spontaneous circulation (ROSC), survival to discharge with favorable neurologic outcome, and new morbidity among survivors. Poisson regression measured associations between ETCO2 and outcomes as well as the association between ETCO2 and other CPR characteristics: 1) invasively measured systolic and diastolic blood pressures and 2) CPR quality and chest compression mechanics metrics (i.e., time to CPR start; chest compression rate, depth, and fraction; ventilation rate).
Results:
Among 234 included patients, 133 (57%) had an event-level average ETCO2 ≥20 mmHg. After controlling for a priori covariates, average ETCO2 ≥20 mmHg was associated with higher incidence of survival to hospital discharge (86/133 (65%) versus 48/101 (48%); aRR 1.33, CI95 1.04 – 1.69, p=0.023) and ROSC (95/133 (71%) versus 59/101 (58%); aRR 1.22, CI95 1.00 – 1.49, p=0.046) compared with lower values. ETCO2 ≥20 mmHg was not associated with survival with favorable neurologic outcome or new morbidity among survivors. Average ETCO2 ≥20 mmHg was associated with higher systolic and diastolic blood pressures during CPR, lower CPR ventilation rates, and briefer pre-CPR arrest durations compared with lower values. Chest compression rate, depth, and fraction did not differ between ETCO2 groups.
Conclusions:
In this multicenter study of children with in-hospital cardiopulmonary arrest, ETCO2 ≥20 mmHg was associated with better outcomes and higher intra-arrest blood pressures, but not with chest compression quality metrics.
Keywords: heart arrest, cardiopulmonary resuscitation, carbon dioxide, pediatric intensive care units
INTRODUCTION
Cardiopulmonary resuscitation (CPR) quality is a known determinant of survival from cardiopulmonary arrest.1 Preclinical laboratory studies and clinical investigations of adult cardiopulmonary arrest have highlighted quantitative capnography (i.e., end-tidal carbon dioxide [ETCO2]) as a physiologic monitor that can be used to assess and titrate CPR technique.2–6 Supported by these data, a 2013 American Heart Association (AHA) Consensus Statement on CPR Quality endorsed targeting an ETCO2 ≥20 mmHg during CPR to improve outcomes.1 Subsequent iterations of pediatric and adult resuscitation guidelines recommended using ETCO2 as an indicator of CPR quality, but pediatric resuscitation guidelines note that “specific values to guide therapy have not been established in children.”7,8
As upwards of 70% of children with in-hospital cardiopulmonary arrests have advanced airways in place that can facilitate use of ETCO2 as a CPR monitor,9,10 establishing evidence-based ETCO2 targets is a practical means of broadly improving resuscitation quality and outcomes. While results from a prior single-center pediatric study found that in unadjusted analyses ETCO2 values were higher among patients who achieved return of spontaneous circulation (ROSC), results from another small multicenter study found no association between ETCO2 and outcomes.11,12 Therefore, in the decade since the 2013 Consensus Statement, minimal scientific progress has been made in this area.
To fill this knowledge gap, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded Collaborative Pediatric Critical Care Research Network (CPCCRN) and the National Heart, Lung, and Blood Institute (NHLBI) ICU-RESUScitation project (ICU-RESUS; NCT02837497) investigators prospectively designed an observational cohort study to evaluate the association between ETCO2 during pediatric CPR and 1) survival outcomes; 2) intra-arrest blood pressures; and 3) CPR mechanics and other CPR quality markers. For our primary analyses, we hypothesized that an event-level average ETCO2 ≥20 mmHg during pediatric inpatient CPR would be associated with higher incidence of survival to hospital discharge, higher intra-arrest blood pressures, and superior CPR mechanics and quality characteristics.
METHODS
Setting, Design, and Oversight
This prospective observational cohort study was an NHLBI-funded ancillary study of the ICU-RESUScitation project (ICU-RESUS; NCT02837497), entitled “Validation of Physiologic CPR Quality Using Non-inVasive Waveform Analytics (CPR-NOVA).” The parent study was a hybrid stepped-wedge cluster randomized trial evaluating a CPR quality improvement bundle comprised of physiologic-focused point-of-care CPR trainings and post-arrest debriefings.13 It was conducted across 10 clinical sites in the US (18 distinct ICUs). The institutional review boards of each site and of the University of Utah Data Coordinating Center (DCC) approved both the parent study and this ancillary investigation with a waiver of informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Subject Population
For the ICU-RESUS parent study, pediatric subjects (≤18 years of age and ≥37 weeks post-gestational age) with cardiopulmonary arrest requiring chest compressions of any duration in any of the participating ICUs were included. Subjects were excluded if, prior to the arrest, they: 1) had a terminal illness and were not expected to survive to discharge; 2) had a documented lack of commitment to aggressive ICU therapies; 3) had a determination of brain dead; or 4) had an out-of-hospital cardiopulmonary arrest associated with the current hospitalization.13 For this ancillary investigation, subjects were required to have an invasive airway (i.e., endotracheal tube or tracheostomy tube) in place at the onset of CPR, regardless of whether they were mechanically ventilated at the time. Subjects were excluded if they did not have at least one evaluable 30-second epoch of ETCO2 data.
Because the ICU-RESUS parent study and intervention focused on intra-arrest invasive arterial blood pressure waveform data, quantitative capnography waveforms were not collected on all patients with endotracheal or tracheostomy tubes initially (October 1, 2016 through May 5, 2019). Prospective collection of quantitative capnography on all patients with endotracheal or tracheostomy tubes commenced with the start of this CPR-NOVA ancillary investigation (May 6, 2019 through March 31, 2021). Prior to CPR-NOVA, a sub-sample of subjects had both invasive arterial line waveform data and ETCO2 waveforms collected and submitted (i.e., research coordinators transmitted both waveforms despite ICU-RESUS only requiring arterial line data). Both cohorts are included in these analyses.
Data Collection
The data collection and physiologic waveform analysis methods of the parent trial, and subsequent secondary studies, have been previously published.13–15 Briefly, trained research coordinators collected standardized cardiopulmonary arrest data elements,16 CPR quality mechanics data (e.g., compression depth, rate), and physiologic bedside monitor data (e.g., electrocardiogram, invasive arterial line, quantitative capnography) for index CPR events (i.e., the first event associated with the hospitalization). Baseline Pediatric Cerebral Performance Category (PCPC)17,18 and Functional Status Scale (FSS)19 scores were based on the patient’s pre-admission baseline and calculated based on review of documentation. For patients born during the current hospitalization or who had been hospitalized longer than 90 days at the time of the arrest, baseline PCPC and FSS were determined based on the patient’s status prior to the decompensation associated with the cardiopulmonary arrest. Abstraction of pre-arrest diagnoses (e.g., sepsis, pulmonary hypertension) was largely based on documentation of these diagnoses in the medical record. Explicitly defined diagnoses included respiratory insufficiency (presence of hypoxia or hypercarbia or requirement for invasive or non-invasive mechanical ventilation) and hypotension (systolic blood pressure [SBP] or diastolic blood pressure [DBP] <5th percentile for age or requirement for vasopressor/inotropic support [excluding dopamine ≤3 mcg/kg/minute] after intravascular volume expansion). The cause of arrest (hypotension, respiratory decompensation, arrhythmia, and/or cyanosis without respiratory decompensation) was based on documentation in the medical record rather than specific criteria with consultation with site principal investigators as needed. The Pediatric RISk of Mortality (PRISM-IV)20 score was calculated based on data collected between 2 and 6 hours pre-arrest and the Vasoactive-Inotrope Score (VIS)21 was calculated at 2 hours pre-arrest and 6 hours post-arrest.
Physiologic waveforms were de-identified locally and then transmitted to the University of Utah DCC for subsequent download and analysis by investigators at the Children’s Hospital of Philadelphia (CHOP). At CHOP, investigators reviewed each waveform for critical features such as: 1) the start of CPR; 2) interruptions in CPR; 3) periods of non-analyzable data; 4) periods of non-sustained ROSC; and 5) the end of the event. Custom MATLAB code (The MathWorks, Inc., Natick, MA) was utilized to determine SBP and DBP values. To ensure accurate determination of ETCO2 values and ventilation rates, capnographic waveforms were manually reviewed by investigators blinded to outcomes and other patient characteristics (RWM, KG, RMS). The peak of each capnographic waveform determined ETCO2 values, which were averaged over the course of 30-second data epochs.
Up to the first 10 minutes of hemodynamic and ETCO2 values during CPR were collected for each patient (up to twenty 30-second epochs). Epochs were considered evaluable if they had at least 7.5 seconds of CPR data, excluding periods of non-analyzable data or intermittent ROSC. The “event-level” average of each physiologic variable was the average of all evaluable epoch-level averages for a given patient.
Exposures, Outcomes, and Statistical Analyses
The primary exposure was whether the event-level average ETCO2 was ≥20 mmHg during the first 10 minutes of CPR. A secondary exposure was the percentage of 30-second epochs with average ETCO2 ≥20 mmHg. The primary outcome was survival to hospital discharge. Using observed parent trial screening and enrollment, we anticipated 280 evaluable events during the planning of this ancillary trial. Based on a power analysis using a t-test (parallel two-group design) of proportions with a two-sided alternative and type I error rate of 0.05, we expected more than 80% power to detect an absolute difference in survival to hospital discharge of 17% (33% to 50%) if the ETCO2 was ≥20 mmHg in 40–60% of patients. These estimates were informed by prior network publications.10,12,22
Secondary outcomes included ROSC, survival to discharge with favorable neurologic outcome (PCPC score of 1 – 3 or unchanged from baseline) and new morbidity among survivors (FSS score change ≥3 from baseline).17,19 Patients achieving return of circulation via venoarterial extracorporeal membrane oxygen support (extracorporeal CPR; E-CPR), were not classified as having ROSC. Intra-arrest physiologic variables included: 1) SBP and DBP (mmHg); 2) achievement of target SBP (≥60 mmHg for age <1 year or ≥80 mmHg for older children);13 and 3) achievement of target DBP (≥25 mmHg for age <1 year or ≥30 mmHg for older children).10,13,15 CPR mechanics and quality variables included: 1) chest compression depth (mm); 2) chest compression rate (min−1); 3) chest compression fraction (CCF; proportion of cardiopulmonary arrest event during which chest compressions are provided); 4) CPR ventilation rate (min−1); and 5) pre-CPR arrest duration (a marker of low- or no-flow time prior to initiation of CPR, defined as the time in seconds that a patient had an indication for CPR). Among patients surviving at least six hours following return of circulation (ROSC or E-CPR), proximate post-arrest outcomes included: 1) lactate (mmol/L);23 2) pH; 3) EEG background;24 and 4) VIS.25
Patient and event characteristics, as well as outcomes, were summarized by ETCO2 group. Additionally, intra-arrest physiologic measurements and CPR mechanics and quality measurements, as defined above, were summarized by ETCO2 group. Summaries reported were counts and percentages for categorical variables and median, first, and third quartiles for continuous variables. Associations of summarized variables with ETCO2 group were assessed with Fisher’s exact test for nominal variables, the Cochrane-Armitage trend test for ordinal variables (baseline and discharge PCPC scores), and the Wilcoxon rank-sum test for continuous variables.
The association of ETCO2 group with outcomes was evaluated with a Poisson regression model using generalized estimating equations to obtain robust error estimates. All models controlled for initial CPR rhythm (pulseless vs. non-pulseless [i.e., bradycardia with poor perfusion]), respiratory decompensation as an immediate cause of arrest, and arrhythmia as an immediate cause of arrest, covariates selected a priori due to their hypothesized association with ETCO2 group and survival.
Several exploratory analyses were conducted. First, we sought to evaluate ETCO2 as a continuous, rather than dichotomized exposure. We therefore constructed receiver operating characteristic (ROC) and spline curves to identify an alternative ETCO2 target / range. The optimal cutpoint from the ROC curve was determined by the Euclidean distance without consideration of covariables. To further visualize the relationship between the exposure and outcome, curves were created with natural cubic splines in logistic regression models, controlling for the same covariates as above. Internal knots for the splines were placed at the 10th, 50th, and 90th percentiles of the data. The number of internal knots was chosen to balance model fit and parsimony and was confirmed by assessment of the Bayesian Information Criterion. Second, scatterplots using epoch-level data were created to investigate the relationship of ETCO2 with: 1) SBP; 2) DBP; and 3) ventilation rate. Tests of association were based on univariable linear regression, with generalized estimating equations used to account for the use of multiple 30-second average values from a given CPR event. Third, to provide a useful bedside marker of probability of resuscitation success (i.e., probability of ROSC), the trend in ETCO2 over the first ten minutes of CPR were graphically depicted in patients with and without ROSC. The mean values were compared between patients with and without ROSC via mixed-effects linear regression modeling with an exponential temporal covariance structure to account for correlated observations. A random subject effect was also included to give a lower bound on the correlation between two different minutes of CPR for the same subject. Mixed-effects linear regression modeling assessed the difference in slope of change in ETCO2 between patients with and without ROSC, again using a temporal covariance structure. Lastly, we repeated the primary analyses with event-level ETCO2 <10 mmHg as an exploratory exposure.
Analyses were performed using SAS 9.4 (SAS Institute; Cary, NC). Reported p-values were based on a two-sided alternative and considered significant if less than 0.05.
RESULTS
Among the 1129 children experiencing an index cardiopulmonary arrest event in the parent ICU-RESUS trial, 824 (73%) had invasive mechanical ventilation in place at the start of CPR (532 prior to CPR-NOVA; 292 during CPR-NOVA) (Figure 1). Of these events with invasive mechanical ventilation, a total of 234 (28%) events were included in the final analytic cohort (96/532 (18%) prior to CPR-NOVA; 138/292 (47%) during CPR-NOVA). Table S1 compares patient characteristics across these two cohorts. Notably, pre-CPR-NOVA patients more frequently had pre-existing cardiac disease (p=0.028) and pre-arrest hypotension (p=0.002) and had higher pre-arrest PRISM scores (p=0.018) and VIS (p=0.04). However, absolute differences in survival to hospital discharge across ETCO2 groups (≥20 mmHg vs. <20 mmHg) did not differ between enrollment periods (Pre-CPR-NOVA enrollment period: 36/56 [64.3%] vs. 20/40 [50%]; p=0.21; during CPR-NOVA enrollment: 50/77 [64.9%] vs. 28/61 [45.9%]; p=0.038).
Figure 1: Patient Flow Diagram.
“Pre-NOVA” refers to patients enrolled in the ICU-RESUS parent study prior to prospective collection of ETCO2 waveform data for CPR-NOVA study (October 1, 2016 through May 5, 2019). “Intra-NOVA” refers to patients enrolled after the start of the CPR-NOVA ancillary investigation (May 6, 2019 through March 31, 2021).
Patient characteristics summarized by ETCO2 group are presented in Table 1. In terms of pre-existing conditions prior to CPR, subjects with event-level average ETCO2 ≥20 mmHg more frequently had respiratory insufficiency (p=0.004) and less frequently had hypotension (p=0.028). Event characteristics by ETCO2 group are presented in Table 2. Subjects with event-level average ETCO2 ≥20 mmHg more frequently had arrhythmia as the immediate cause of the cardiopulmonary arrest (p=0.034) and less frequently received epinephrine (p=0.002), calcium (p=0.017), and fluid boluses (p=0.046) during CPR. They received E-CPR less frequently than patients with lower ETCO2 (26/133 [19.5%] vs. 32/101 [31.7%]; p=0.046). Patient and event characteristics by survival to hospital discharge are presented in Tables S2 and S3, respectively.
Table 1: Patient Characteristics.
Comparison of patient characteristics between patients with average event-level ETCO2 ≥20 mmHg versus those with lower ETCO2 values. Analyses performed with Fisher’s exact test, Wilcoxon rank-sum test, or Cochrane-Armitage trend test.
| ETCO2 ≥20 mmHg (n = 133) | ETCO2 <20 mmHg (n= 101) | p | |
|---|---|---|---|
|
| |||
| Demographics | |||
| Age | 0.125 | ||
| ≤ 1 year | 75 (56.4%) | 67 (66.3%) | |
| 1 year - < 8 years | 34 (25.6%) | 15 (14.9%) | |
| 8 years - < 19 years | 24 (18.0%) | 19 (18.8%) | |
| Male | 69 (51.9%) | 48 (47.5%) | 0.598 |
| Pre-existing conditions | |||
| Respiratory insufficiency | 124 (93.2%) | 81 (80.2%) | 0.004 |
| Hypotension | 87 (65.4%) | 80 (79.2%) | 0.028 |
| Heart failure | 19 (14.3%) | 15 (14.9%) | 1.000 |
| Pneumonia | 17 (12.8%) | 6 (5.9%) | 0.119 |
| Sepsis | 25 (18.8%) | 12 (11.9%) | 0.205 |
| Trauma | 4 (3.0%) | 1 (1.0%) | 0.393 |
| Kidney disease/injury | 22 (16.5%) | 16 (15.8%) | 1.000 |
| Malignancy | 6 (4.5%) | 3 (3.0%) | 0.735 |
| Pulmonary hypertension | 26 (19.5%) | 18 (17.8%) | 0.866 |
| Congenital heart disease | 76 (57.1%) | 75 (74.3%) | 0.009 |
| Pre-event characteristics | |||
| Illness category | 0.083 | ||
| Medical cardiac | 33 (24.8%) | 32 (31.7%) | |
| Medical non-cardiac | 44 (33.1%) | 20 (19.8%) | |
| Surgical cardiac | 45 (33.8%) | 45 (44.6%) | |
| Surgical non-cardiac | 7 (5.3%) | 3 (3.0%) | |
| Trauma | 4 (3.0%) | 1 (1.0%) | |
| PRISM* | 7 [2, 12] | 7 [3, 12] | 0.679 |
| Vasoactive-inotrope score† | 1.5 [0, 8.0] | 2.5 [0, 10.0] | 0.246 |
| Baseline PCPC score‡ | 0.234 | ||
| 1 - Normal | 73 (54.9%) | 68 (67.3%) | |
| 2 - Mild disability | 29 (21.8%) | 9 (8.9%) | |
| 3 - Moderate disability | 14 (10.5%) | 14 (13.9%) | |
| 4 - Severe disability | 14 (10.5%) | 10 (9.9%) | |
| 5 - Coma/vegetative state | 3 (2.3%) | 0 (0.0%) | |
| Baseline FSS‡ | 6.0 [6.0,10.0] | 6.0 [6.0,9.0] | 0.092 |
ETCO2 indicates end-tidal carbon dioxide; FSS, Functional Status Scale; PCPC, Pediatric Cerebral Performance Category; PRISM, Pediatric RISk of Mortality score.
PRISM was evaluated 2 – 6 hours prior to the event.
Vasoactive inotrope score was evaluated 2 hours prior to the event and calculated from the following equation: dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + nitroprusside dose (μg/kg/min) + (10 × milrinone dose (μg/kg/min)) + (100 × epinephrine dose (μg/kg/min)) + (100 × norepinephrine dose (μg/kg/min)) +(100 × phenylephrine dose (μg/kg/min)) + vasopressin dose (munits/kg/hr).
Baseline PCPC and FSS represent subject status prior to the event leading to hospitalization.
Table 2: Cardiopulmonary Arrest Event Characteristics.
Comparison of cardiopulmonary arrest event characteristics between patients with average event-level ETCO2 ≥20 mmHg versus those with lower ETCO2 values. Analyses performed with Fisher's exact test or Wilcoxon rank-sum test.
| ETCO2 ≥20 mmHg (n = 133) | ETCO2 <20 mmHg (n= 101) | p | |
|---|---|---|---|
|
| |||
| Interventions in place prior to event* | |||
| Central venous catheter | 103 (77.4%) | 76 (75.2%) | 0.756 |
| Vasoactive infusion | 80 (60.2%) | 71 (70.3%) | 0.129 |
| Invasive mechanical ventilation | 123 (92.5%) | 89 (88.1%) | 0.268 |
| Non-invasive ventilation | 6 (4.5%) | 10 (9.9%) | 0.122 |
| Immediate cause(s) of event | |||
| Arrhythmia | 24 (18.0%) | 8 (7.9%) | 0.034 |
| Cyanosis without respiratory decompensation | 6 (4.5%) | 3 (3.0%) | 0.735 |
| Hypotension | 76 (57.1%) | 70 (69.3%) | 0.076 |
| Respiratory decompensation | 60 (45.1%) | 38 (37.6%) | 0.285 |
| Duration of CPR (minutes) | 7.0 [3, 22] | 11.0 [4, 36] | 0.052 |
| CPR timing† | 0.516 | ||
| Weekday | 80 (60.2%) | 57 (56.4%) | |
| Weeknight | 21 (15.8%) | 22 (21.8%) | |
| Weekend | 32 (24.1%) | 22 (21.8%) | |
| Medications during CPR | |||
| Epinephrine | 104 (78.2%) | 94 (93.1%) | 0.002 |
| Number of doses | 3 [1, 5] | 3.0 [1, 6] | 0.549 |
| Average interval between doses‡ | 5.0 [4.0, 7.3] | 5.0 [3.3, 8.0] | 0.575 |
| Time to first dose (minutes) | 1.0 [0, 2.0] | 1.0 [0, 2.0] | 0.423 |
| Atropine | 12 (9.0%) | 4 (4.0%) | 0.191 |
| Calcium | 52 (39.1%) | 56 (55.4%) | 0.017 |
| Sodium bicarbonate | 65 (48.9%) | 57 (56.4%) | 0.291 |
| Vasopressin | 6 (4.5%) | 4 (4.0%) | 1.000 |
| Amiodarone | 4 (3.0%) | 4 (4.0%) | 0.729 |
| Lidocaine | 4 (3.0%) | 2 (2.0%) | 0.701 |
| Fluid bolus | 26 (19.5%) | 32 (31.7%) | 0.046 |
| Extracorporeal CPR§ | 26 (19.5%) | 32 (31.7%) | 0.046 |
ETCO2 indicates end-tidal carbon dioxide; CPR, cardiopulmonary resuscitation.
Represents documented interventions in the pre-arrest period. Therefore, patients who were intubated in the peri-arrest period and had an endotracheal tube in place at the onset of CPR could appear in the “non-invasive ventilation” group and patients with a tracheostomy without ventilator support until the immediate pre-/peri-arrest period could be classified as receiving no pre-arrest ventilatory support.
Weekday is between 7 AM and 11 PM Monday - Friday; weeknight, after 11 PM Monday - Thursday; weekend, 11 PM on Friday through 7 AM on the following Monday.
(total duration of CPR in minutes – time to first epinephrine dose in minutes) / (total number of epinephrine doses – 1)
Successful cannulation onto extracorporeal membrane oxygenation support as the outcome of the CPR event
Intra-arrest physiologic and CPR quality metrics are compared across ETCO2 groups in Table 3. In events with event-level average ETCO2 ≥20 mmHg, intra-arrest SBP and DBP were higher than in events with ETCO2 <20 mmHg (SBP: 90.6 [75.1, 118.7] mmHg vs. 70.9 [55.5, 86.4] mmHg, p<0.001; DBP: 46.5 [37.9, 57.9] mmHg vs. 33.3 [26.8, 42.9] mmHg, p<0.001). Events with event-level average ETCO2 ≥20 mmHg were more likely to achieve a priori SBP targets (66/80 (82.5%) vs. 48/75 (65.8%); p=0.025) and DBP targets (76/80 (95.0%) vs. 61/75 (81.3%); p=0.011) compared with events with lower ETCO2 values.
Table 3: CPR Physiology and Quality.
Comparison of intra-arrest CPR physiology and quality measurements between patients with average event-level ETCO2 ≥20 mmHg versus those with lower ETCO2 values. Unless otherwise noted, values represent event-level averages during the first 10 minutes of CPR. Analyses performed with Fisher’s exact test or Wilcoxon rank-sum test.
| ETCO2 ≥20 mmHg | ETCO2 <20 mmHg | p | |
|---|---|---|---|
|
| |||
| Arterial BP data available | 80/133 (60.2%) | 75/101 (74.3%) | |
| CPR mechanics data available | 40/133 (30.1%) | 24/101 (23.8%) | |
| Intra-arrest Physiology | |||
| Average SBP (mmHg) | 90.6 [75.1, 118.7] | 70.9 [55.5, 86.4] | <0.001 |
| Average DBP (mmHg) | 46.5 [37.9, 57.9] | 33.3 [26.8, 42.9] | <0.001 |
| Target SBP* | 66/80 (82.5%) | 48/73 (65.8%) | 0.025 |
| Target DBP† | 76/80 (95.0%) | 61/75 (81.3%) | 0.011 |
| CPR Mechanics / Quality | |||
| Average CC rate (per minute)3 | 117.7 [108.8, 125.5] N=96 | 117.9 [109.5, 125.1] N=85 | 0.899 |
| Average CCF‡ | 0.97 [0.93, 1.00] N=96 | 0.96 [0.91, 0.99] N=85 | 0.091 |
| Average depth (mm) | 34.26 [24.75, 45.21] N=38 | 32.10 [21.82, 53.70] N=24 | 0.960 |
| Pre-CPR arrest duration (seconds)§ | 22.75 [0.45, 57.80] N=80 | 52.90 [15.50, 84.10] N=75 | 0.006 |
| Average ventilation rate (breaths/min) | 26.65 [19.96, 35.22] N=133 | 29.49 [24.11, 40.06] N=101 | 0.015 |
ETCO2 indicates end-tidal carbon dioxide; SBP, systolic blood pressure; DBP, diastolic blood pressure; CC, chest compression; CCF, chest compression fraction; CPR, cardiopulmonary resuscitation.
Average DBP ≥25 mmHg for patients <1 year old or ≥30 mmHg for patients ≥1 year old.
Average SBP ≥60 mmHg for subjects <1 year old or ≥80 mmHg for subjects ≥1 year old.
Calculated based on either arterial blood pressure waveform (prioritized when both available) or CPR quality-monitoring defibrillator.
Pre CPR arrest time: Duration (seconds) that a patient has a pulse pressure <10 mmHg and low SBP (<40 mmHg in infants < 1 year of age or <50 mmHg in older children).
Chest compression rate, depth, and fraction did not differ significantly between ETCO2 groups (Table 3). In events with event-level average ETCO2 ≥20 mmHg, pre-CPR arrest durations were shorter (22.8 [0.5, 57.8] sec vs. 52.9 [15.5, 84.1] sec, p=0.006) and CPR ventilation rates were lower (26.7 [20.0, 35.2] min−1 vs 29.5 [ 24.1, 40.1] min−1, p=0.015) compared with events with lower ETCO2 values.
Overall, the average ETCO2 across all events was 23.5 ± 11.94 mmHg; 133/234 (56.8%) patients had an event-level average ETCO2 ≥20 mmHg. More patients survived to hospital discharge when event-level average ETCO2 was ≥20 mmHg compared with lower ETCO2 values (86/133 [64.7%] vs. 48/101 [47.5%]; p=0.011). Multivariable outcome analyses are presented in Table 4. After adjusting for confounders, an ETCO2 ≥20 mmHg remained associated with higher relative risk of survival to hospital discharge (aRR 1.33, CI95 1.04 – 1.69, p=0.023) and ROSC (95/133 [71.4%] vs. 59/101 [58.4%]; aRR 1.22, CI95 1.00 – 1.49, p=0.046). The percentage of 30-second epochs achieving ETCO2 ≥20 mmHg was also associated with higher relative risk of survival to hospital discharge (aRR 1.03 per 10% increase in epochs achieving target, CI95 1.00 – 1.06, p=0.034) and ROSC (aRR 1.03 per 10% increase in epochs achieving target, CI95 1.01 – 1.06, p=0.006).
Table 4: Patient and Event Outcomes.
Association of intra-arrest ETCO2 classification with outcomes.
| Event Average ETCO2 ≥20 mmHg |
% CPR Epochs ETCO2 ≥20 mmHg |
Event Average ETCO2 <10 mmHg |
||||
|---|---|---|---|---|---|---|
| RR (CI95)* | p | RR (CI95)*† | p | RR (CI95)* | p | |
|
| ||||||
| PRIMARY OUTCOME | ||||||
| Survival to hospital discharge | 1.33 (1.04, 1.69) | 0.023 | 1.03 (1.00, 1.06) | 0.034 | 0.98 (0.59, 1.62) | 0.927 |
| SECONDARY OUTCOMES | ||||||
| Sustained ROSC‡ | 1.22 (1.00, 1.49) | 0.046 | 1.03 (1.01, 1.06) | 0.006 | 0.69 (0.39, 1.24) | 0.213 |
| Survival with favorable neurologic outcome§ | 1.23 (0.94, 1.59) | 0.128 | 1.02 (0.99, 1.05) | 0.180 | 0.92 (0.50, 1.69) | 0.788 |
| New morbidity|| | 1.09 (0.62, 1.89) | 0.772 | 1.01 (0.95, 1.08) | 0.690 | 0.91 (0.27, 3.09) | 0.877 |
ETCO2 indicates end-tidal carbon dioxide; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation.
Adjusted relative risk is based on Poisson regression with robust error estimates, controlling for initial rhythm (pulseless vs. non-pulseless), respiratory decompensation as an immediate cause of arrest, and arrhythmia as an immediate cause of arrest for a priori targets over the first 10 minutes of resuscitation.
RR is for an increase of 10 in percentage of CPR epochs achieving target ETCO2.
ROSC ≥ 20 minutes in duration, as defined by Utstein CPR reporting guidelines
Survival with favorable neurologic outcome is defined as a Pediatric Cerebral Performance Category (PCPC) score of 1–3 or no worse than baseline.
New morbidity is an increase in Functional Status Scale score ≥3.
Exploratory Analyses
Figure 2 depicts ROC and spline analyses of the relationship between ETCO2 and survival to hospital discharge. Analogous curves for ROSC are presented in Figure S1. The ROC analyses identified an optimal cutpoint for survival to hospital discharge of 19.64 mmHg (sensitivity 0.67, specificity 0.53; AUC 0.57 [CI95 0.5 – 0.65]). The optimal cutpoint for ROSC was 19.07 mmHg (sensitivity 0.69, specificity 0.53; AUC 0.62 [CI95 0.55 – 0.7]). Based on visual inspection of the spline curves and the close proximity of both cutpoints to the pre-specified ETCO2 threshold of 20 mmHg, alternative targets were not further evaluated.
Figure 2: Relationship Between ETCO2 and Survival to Hospital Discharge (Panel A: Receiver Operating Characteristic (ROC) Curve; Panel B: Probability Curves).
ROC curve: optimal cutpoint: ETCO2 19.6 mmHg (sensitivity: 0.67; specificity: 0.53; AUC: 0.571 [CI95 0.496, 0.647]). Probability curves were created with logistic regression and natural cubic splines, controlling for initial rhythm (pulseless vs. non-pulseless), and for respiratory decompensation and arrhythmia as the immediate causes of arrest.
The analyses using univariable linear regression to further evaluate the relationships between ETCO2 and 1) SBP, 2) DBP, and 3) CPR ventilation rate are presented in Figures S2 (Panel A: systolic BP; Panel B diastolic BP) and S3, respectively. ETCO2 was positively correlated with systolic BP (p<0.0001) and diastolic BP (p<0.001) and inversely correlated with ventilation rate (p=0.04).
The trend in ETCO2 over the first 10 minutes of CPR is graphically represented in Figure 3. There was a significant difference in both the mean ETCO2 (p<0.001) and the slope of ETCO2 change over time (effect size estimate: 0.74 (95% CI: 0.10, 1.38) mmHg/minute; p=0.023) among patients achieving ROSC vs. those who did not achieve ROSC (p=0.011).
Figure 3: Temporal Relationship Between ETCO2 During First 10 Minutes of CPR and Return of Spontaneous Circulation.
ROSC = solid line; No ROSC = dotted line. Comparisons between patients with and without ROSC performed with mixed-effects linear regression model with an exponential temporal covariance structure to account for correlated observations. Average ETCO2 over the first 10 minutes of CPR was higher in patients with ROSC vs. patients without ROSC (p<0.001) as determined by the main effect for ROSC in the model. The change in ETCO2 over time was greater in patients with ROSC vs. patients without ROSC (effect size estimate: 0.74 [95% CI 0.10, 1.38] mmHg; p=0.023) as determined by the interaction term between time (minutes) and ROSC. Error bars indicate standard error of the mean.
Tertiary post-arrest outcomes are presented in Table S4. Highest recorded lactate values in the first six hours post-arrest were significantly lower (5.7 [2.4,11.6] (mmol/L) vs. 7.5 [4.7,14.8] (mmol/L), p=0.01) in the ETCO2 ≥20 mmHg group compared with the lower ETCO2 group. There were no differences in lowest pH, EEG background patterns, or VIS.
Finally, an event-level average ETCO2 <10 mmHg was not associated with survival to hospital discharge or other outcomes (Table 4). Notably, among 21 of patients with event-level ETCO2 <10 mmHg, 20 (95%) achieved return of circulation (ROSC: 7; via E-CPR: 13), and 10 (48%) survived to hospital discharge. Of the 21 patients with event-level ETCO2 <10 mmHg, 12 (57%) had congenital heart disease and 6 (29%) had shunt-dependent or passive pulmonary blood flow.
DISCUSSION
In this multicenter cohort study of pediatric patients with in-hospital cardiopulmonary arrest who had an invasive airway in place at the start of CPR, average ETCO2 ≥20 mmHg during the first 10 minutes of CPR was associated with higher incidence and adjusted relative risk of both survival to hospital discharge and ROSC. To our knowledge, this the first multicenter pediatric clinical study providing evidence to support monitoring ETCO2 during CPR or provide an ETCO2 target for pediatric CPR. Events with an ETCO2 ≥20 mmHg during CPR were also more likely to achieve invasive arterial BP targets previously associated with higher incidence of neurologically favorable survival from pediatric cardiopulmonary arrest,10,15 providing important physiologic mechanistic data to support our primary findings.
There is a substantial body of preclinical laboratory data establishing that ETCO2 is highly correlated with pulmonary blood flow and cardiac output during CPR,26–29 and thus is a potentially effective non-invasive monitor of CPR quality. To that end, adult clinical investigations have established that ETCO2 values are generally higher among patients who achieve ROSC versus those who do not,6,30 that low ETCO2 is associated with mortality,3,4,6,31,32 and that CPR mechanics quality, namely chest compression depth, is correlated with ETCO2 levels during CPR.33 Though a single center pediatric study demonstrated an association between ETCO2 and ROSC,11 our study provides the first pediatric evidence to identify an association of ETCO2 with survival and demonstrates several significant findings suggesting that ETCO2 is associated with cardiac output during CPR. First, an ETCO2 ≥20 mmHg was associated with higher intra-arrest blood pressures during CPR, the primary driver of end organ perfusion. Importantly, events with an ETCO2 ≥20 mmHg were more likely to achieve DBP targets (≥25 mmHg in infants <1 year old, ≥30 mmHg in older children) that have previously been associated with improved neurologic survival after pediatric cardiopulmonary arrest.10,15 Second, lactate levels in the immediate post-arrest period were lower when target ETCO2 was achieved, despite similar pre-arrest PRISM and VIS scores between ETCO2 groups, suggesting that the higher ETCO2 values were associated with improved blood flow during CPR, and not simply a marker of differential pre-arrest illness. Finally, target ETCO2 values were associated with shorter pre-CPR arrest times, potentially suggesting that faster recognition of cardiopulmonary arrest (i.e., briefer periods of “no-flow”) allow for superior blood flow during CPR. However, in contrast to adult and pre-clinical studies,33–35 chest compression characteristics including rate, depth, and fraction did not differ between patients with ETCO2 ≥20 mmHg and those with lower ETCO2. Thus, the interventions that resuscitation teams should consider in response to a low ETCO2 require independent investigation.
In an attempt to provide an additional clinically useful metric for bedside providers to follow, we investigated if there was prognostic value in the change in ETCO2 values over time. Clinicians may appreciate temporal changes in ETCO2 more intuitively than the “average ETCO2” during CPR. In this study, we found that the change in ETCO2 during the first minutes of resuscitation is highly associated with the probability of resuscitation success (i.e., attaining ROSC). This may support the utility of using ETCO2 to inform treatment decisions. For example, failure of a low ETCO2 to improve in response to resuscitation strategies could potentially trigger rescue strategies such as E-CPR, which was more frequently used in the group with lower ETCO2 values.
Since the 2013 Consensus on Science Statement on CPR Quality, there has been a growing body of literature supporting the idea that rescuers should monitor and titrate the resuscitation effort according to a patient’s physiologic response, with many of these investigations focused on pediatric cardiopulmonary arrest. In large animal translational pediatric models, altering CPR technique (e.g., depth and rate of chest compressions) and vasopressor administration according to either invasive arterial blood pressure36,37 or ETCO234,35 is associated with better cardiopulmonary arrest outcomes. And while prospective clinical observational studies have established arterial DBP targets, similar data establishing the utility of ETCO2 had been lacking until now. As previously mentioned, prior work was limited by sample size12 or reliance on CPR quality monitoring defibrillators which are frequently not in place during the first critical minutes of the resuscitation.11 By leveraging the large physiologic waveform database of the ICU-RESUS trial, these data have begun to fill an important critical gap in the pediatric resuscitation knowledge base and have the potential to also improve patient-centric resuscitation algorithms.
Finally, the association between CPR ventilation rate and ETCO2 deserves brief comment. Similar to prior adult and pediatric investigations,12,33 we found that ETCO2 was inversely correlated with CPR ventilation rate (i.e., higher ventilation rates presumably led to lower ETCO2). As excessive ventilation can lead to increased intrathoracic pressure, increased right atrial pressure, decreased venous return, and thereby, reduced cardiac output,38,39 it is possible that either improved ventilation with preserved cardiac output or a reduction in cardiac output due to excessive ventilation is responsible for this inverse relationship. In our study, the median ventilation rate in both ETCO2 groups was within the current recommended range; however, 103/234 (44%) of events had event-level average ventilation rates exceeding 30 min−1, the upper rate of current AHA guideline recommendations.7 Ultimately, the complicated relationship between ventilation rate and other ventilation parameters and ETCO2 remains a fertile area for future scientific investigation.
This study has limitations. First, the observational study design precludes our ability to assign causation between higher ETCO2 levels and improved outcomes. Yet, our findings provide support to suggest a more direct mechanistic relationship between higher ETCO2 values and outcomes (e.g., improved intra-arrest blood pressures and lower lactates post-arrest). Second, these data were collected as part of the ICU-RESUS trial, which was conducted in a network of tertiary care hospitals with a documented interest in CPR quality and physiology.10,13 These characteristics, as well as the previously reported high-quality of CPR performed during the parent trial,13 must be considered in generalizing our findings across more diverse care environments. Third, all included patients had invasive airways at the start of CPR, and as such, whether our findings can be extrapolated to patients without invasive airways remains an unanswered question. Fourth, we limited our primary evaluation to the first 10 minutes of CPR. We did not investigate the relationship between outcomes and ETCO2 values after longer periods of CPR. However, we contend that by limiting our evaluation to the first 10 minutes, we are providing data that could lead to treatment adjustments that are more likely to affect resuscitation outcomes (e.g., early activation of E-CPR rescue). Finally, due to known limitations in the study of continuous capnography during CPR (obstruction from tracheal tube secretions, disconnection for various clinical reasons), we report data from 28% of patients that were eligible for inclusion, raising concerns regarding selection bias. While most of the patients included in this report are from the CPR-NOVA ancillary study, we did include the convenience sample of patients whose ETCO2 waveforms were transmitted with arterial line waveforms prior to CPR-NOVA to achieve enrollment goals based upon our a priori power calculation. Though there were several important patient characteristics that differed between groups, the absolute difference in survival between ETCO2 groups was similar across enrollment periods.
CONCLUSIONS
In this multicenter study, an ETCO2 ≥20 mmHg during CPR was associated with improved outcomes from pediatric in-hospital cardiopulmonary arrest, providing support for guideline recommendations that advise monitoring ETCO2 during CPR.
Supplementary Material
CLINICAL PERSPECTIVE.
What is new?
This prospective, multicenter study of children receiving cardiopulmonary resuscitation (CPR) in intensive care units is the first clinical study in children to demonstrate an association between end-tidal carbon dioxide (ETCO2) during CPR and survival to hospital discharge.
An average ETCO2 of at least 20 mmHg was associated with attaining return of spontaneous circulation and surviving to discharge.
What are the clinical implications?
These data offer support for CPR guideline recommendations to monitor ETCO2 as a gauge of pediatric CPR quality and offer a threshold of 20 mmHg for which clinicians can potentially aim.
Funding Sources:
This study was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD049934, UG1HD049981, UG1HD049983, UG1HD050096, UG1HD063108, UG1HD083166, UG1HD083170, and UG1HD083171) and National Heart, Lung, and Blood Institute (R01HL131544, R01HL147616, and K23HL148541) and by the Children’s Hospital of Philadelphia Research Institute Resuscitation Science Center.
Non-Standardized Abbreviations and Acronyms:
- AHA
American Heart Association
- CCF
chest compression fraction
- CPR
cardiopulmonary resuscitation
- CPR-NOVA
Validation of Physiologic CPR Quality Using Non-inVasive Waveform Analytics study
- DCC
data coordinating center
- DBP
diastolic blood pressure
- E-CPR
extracorporeal cardiopulmonary resuscitation
- ETCO2
end-tidal carbon dioxide
- FSS
Functional Status Scale
- ICU-RESUS
The ICU-RESUScitation Project clinical trial
- PCPC
Pediatric Cerebral Performance Category
- PRISM
Pediatric Risk of Mortality Score
- ROC
receiver operating characteristic
- ROSC
return of spontaneous circulation
- SBP
systolic blood pressure
- VIS
vasoactive-inotrope score
Footnotes
Disclosure Statement: None.
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