Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus

Abstract

Objective: To quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT).

Methods: We evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness.

Results: Of 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery.

Conclusions: Endotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus.

Trial registration information: ClinicalTrials.gov Identifier: NCT01960075.

© 2021 American Academy of Neurology.

Figures

Figure 1. Time to Intubation

One hundred seventeen (24.5%) patients met the prespecified analysis endpoint of endotracheal intubation within 120 minutes of Established Status Epilepticus Treatment Trial (ESETT) study drug initiation (inset, red line), after which events were censored (y-axis signifies the proportion of participants free of endotracheal intubation). This prespecified time point captured treatment events proximal to the measured covariates while capturing 84.2% of the 139 patients undergoing endotracheal intubation over the 24 hours during which events were recorded.

Figure 2. Individual or Combinations of Baseline Vital Signs Do Not Differentiate Which Patients Undergo Subsequent ETI

(A) Individual baseline vital signs are shown as overlapping violin plots for variables including heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and oxygen saturation (Sao2). Violin plots depict symmetric kernel densities around a common vertical axis, where the kernel density estimated the probability density function at each point, providing a continuous analog of the univariate histogram. (B) Multivariable combinations of baseline vital signs are displayed as colored contour plots depicting clusters of 3 vital signs (x, y, and color) represented 2-dimensionally as individual patients (black dots). There is nearly complete overlap in baseline vital signs between the population of patients managed with and without subsequent intubation, with differences driven primary by individual patient outliers presenting with the combination of multiple baseline vital sign abnormalities (e.g., tachypnea, tachycardia, and a third abnormal vital sign; black circles) or the rare and isolated occurrence of profound hypoxia (red circle). Contour lines computed with Delaunay triangulation separated distinct bivariate combinations of standardized vital signs, assigning a color for the representative value of a third standardized vital sign for the subpopulation of patients between contour lines. All vital signs are standardized as age-specific z scores. ETI = endotracheal intubation.

Figure 3. Site-Specific Variation and Rate of ETI

(A, funnel plot) Risk of endotracheal intubation (ETI) includes outliers when adjusted for site enrollment volume. (B) Risk of intubation was significantly lower in pediatric patients than adults but not significantly different when adults or children specifically presented to a center with dedicated pediatric, dedicated adult, or mixed population. (C and D) Among (C) pediatric sites or (D) adult and general emergency department (ED) sites enrolling at least 15 participants, a wide range of site-specific intubation rates were evident, but there was no clear site-specific association between the rate of intubation and the distribution of total weight-standardized lorazepam (LZP) equivalents, intensive care unit (ICU), length of stay (LOS), or hospital LOS. Distributions are shown as violin plots of equal area; white lines represent medians, and shaded boxes represent interquartile ranges. To examine associations between weight-based dosing and site-specific intubation rates, this exploratory analysis restricted the analysis of high-enrolling pediatric ED sites to individuals weighing

Figure 4. Age and Length of Stay Vary According to the Reason for ETI

(A and B) Reason for endotracheal intubation (ETI) varied across age groups. Respiratory depression was the most commonly cited reason among patients 2 to 17 years of age (10%, n = 45) but the least commonly cited reason among patients >65 years of age (2%, n = 17). Decreased level of consciousness (LOC) and continued seizure activity were more commonly cited as reasons for endotracheal intubation among patients 18 to 65 or >65 years of age compared with patients 2 to 17 years of age. Patients intubated due to continued seizure activity (median 46 years, interquartile range [IQR] 17–65 years, p = 0.002) or decreased LOC (median 42 years, IQR 7–64 years, p = 0.05) were significantly older (B) than patients intubated due to respiratory depression (median age 11 years, IQR 5–55 years). In addition, hospital length of stay was longer (C) for patients intubated due to continued seizure activity (median 7 days, IQR 3–12 days, p = 0.04) than patients intubated due to respiratory depression (median length of stay 4 days, IQR 2–6.25 days).