Etomidate Versus Ketamine for Emergency Endotracheal Intubation: a Prospective Randomized Clinical Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Etomidate Versus Ketamine for Emergency Endotracheal Intubation: a Prospective Randomized Clinical Trial (NCT02643381), a randomized phase 4 study. The primary outcome is Survival at Day 7.

2. Clinical Question

3. Trial Design

This was a Phase 4, randomized, parallel-group clinical trial with no masking. Participants were assigned to receive etomidate or ketamine immediately before emergency endotracheal intubation. The registry record lists University of Texas Southwestern Medical Center as the sponsor and reports enrollment of 801 participants. The posted arm counts were 396 for etomidate and 395 for ketamine.

The trial status is completed. The recorded start date is 2016-06-06 and the primary completion date is 2020-12-01. The listed conditions are cardiopulmonary arrest and respiratory arrest. The record also identifies emergency endotracheal intubation and mechanical ventilation among the interventions, while the arm descriptions specify the assigned medication before intubation.

Random allocation is intended to make the groups comparable, on average, with respect to both measured and unmeasured characteristics. It does not guarantee that the groups will be identical. Because masking was listed as none, the trial was open-label. The record does not describe allocation concealment, adherence to assigned treatment, crossovers, or whether outcome assessment was blinded; those details are not reported in the registry record.

The primary outcome was survival at Day 7. The registry record also lists secondary outcomes concerning survival at Day 28, organ failure scores, durations of mechanical ventilation and catecholamine therapy, ICU length of stay, new diagnosis of adrenal insufficiency, and intubation attempts. Numerical results in the posted outcome details include Day 28 survival and new adrenal insufficiency. Results for the other listed secondary outcomes are not reported in the registry record. The protocol’s full statistical plan and the rationale used to determine the original enrollment target are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Survival at Day 7, measured over Day 7.

The primary endpoint counts participants who were alive at Day 7 following emergency endotracheal intubation. It is a binary outcome at the participant level: each participant either met the survival definition at that time point or did not. The posted totals therefore give both the number meeting the definition and the number of participants in each randomized arm.

Survival is used as an outcome because it is a direct measure of whether participants were alive at a defined time after the procedure. A fixed follow-up point gives the two groups a common time horizon for comparison. In this trial, the primary time point was Day 7; Day 28 survival was listed as a secondary outcome. The registry definition states that survival is the number of participants who survived at Day 7 following emergency endotracheal intubation.

As a general statistical point, a binary endpoint makes it possible to compare the proportion of participants meeting the outcome in each arm. Such a comparison does not describe the timing or circumstances of events within the follow-up period, and it does not explain the mechanism behind any difference. The endpoint’s role is to quantify the stated outcome at the specified time. The registry record does not report additional details about endpoint adjudication or how participants with unavailable Day 7 status were handled.

7. Results Posted in the Registry

• Ketamine: 85.1% (336/395) versus 77.3% (306/396) on control; risk difference 7.8 percentage points (95% CI 2.4 to 13.2), risk ratio 1.10 (1.03–1.18); unadjusted two-proportion z-test p = 0.005.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Survival at Day 28

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Ketamine: 66.8% (264/395) versus 64.1% (254/396) on control; risk difference 2.7 percentage points (95% CI -3.9 to 9.3), risk ratio 1.04 (0.94–1.15); unadjusted two-proportion z-test p = 0.426.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ketamine and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With New Diagnosis of Adrenal Insufficiency

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Ketamine: 1.0% (4/395) versus 2.8% (11/396) on control; risk difference -1.8 percentage points (95% CI -3.7 to 0.1), risk ratio 0.36 (0.12–1.14); unadjusted two-proportion z-test p = 0.069.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ketamine and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the clinical picture beyond survival at Day 7. They include later survival, organ failure scores, durations of respiratory support and catecholamine therapy, ICU length of stay, adrenal insufficiency, and the number of intubation attempts. These outcomes describe different aspects of participants’ courses and are not interchangeable measures of the primary endpoint.

The posted numerical secondary comparisons do not give a uniform inferential pattern that can be read as a single confirmation of the primary result. They concern separate outcomes, have their own uncertainty, and should be interpreted in their own terms. A secondary result that is not statistically distinguishable from no difference does not negate the primary comparison; nor does a secondary result in a particular direction independently establish a broader treatment effect.

General: Secondary outcomes are often useful for describing a trial and identifying questions for further study, but they usually carry less confirmatory weight than a prespecified primary endpoint. When several outcomes are examined, the chance of observing at least one apparently notable result can rise. A multiplicity strategy, outcome hierarchy, or clear distinction between confirmatory and exploratory analyses helps readers assess that risk. Such a strategy is not reported in the registry record.

The registry record lists seven secondary outcomes, but detailed numerical results are not available for every listed measure in the posted information. Results for the other listed secondary outcomes are not reported in the registry record. The record also does not describe whether all secondary outcomes were analyzed according to a prespecified plan or how missing observations were handled. As a result, the secondary findings are best treated as supplementary evidence rather than as a set of independent tests that can settle the primary question.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Survival at Day 28
• Sequential Organ Failure Assessment (SOFA) Scores
• Duration of Mechanical Ventilation
• Duration of Catecholamine Therapy
• Length of Stay in ICU
• Number of Participants With New Diagnosis of Adrenal Insufficiency
• Number of Attempts Necessary to Intubate

9. Statistical Interpretation

10. Statistical Methods Explained

General: A randomized parallel-group trial assigns participants to distinct treatment arms and compares outcomes between those groups. The primary comparison is between participants assigned to etomidate and those assigned to ketamine. Since survival at Day 7 is a count of participants meeting a yes-or-no outcome definition, the posted summaries can be expressed as counts and as a difference between the groups’ event proportions.

What does a risk difference describe?

General: A risk difference subtracts the event proportion in one group from the event proportion in the other. It is an absolute contrast, expressed on the probability scale, rather than a ratio of the groups. A positive or negative sign depends on the order of subtraction and on which outcome is counted. For this trial, the posted comparison is framed as ketamine relative to etomidate and the event is survival, so the positive direction indicates more observed survival in the ketamine arm. The calculation uses the counts and group sizes in the posted results.

The posted primary comparison reports a risk difference and a confidence interval, as well as an unadjusted p-value. These are related but not interchangeable quantities. The estimate gives the observed contrast; the interval communicates uncertainty about that contrast; and the p-value assesses compatibility with a no-difference model under the statistical test used. The registry record does not name the test or give a fuller analysis specification, so the method behind the p-value cannot be evaluated from the record alone.

What does the p-value tell the reader?

General: A p-value measures how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. A small p-value is evidence against that model, but it does not say how likely the null hypothesis is, how likely the result is to repeat, or whether an effect is important for a particular decision. It also does not account automatically for the number of outcomes or analyses considered. The primary unadjusted p-value is 0.005. The registry record does not report whether the primary comparison was adjusted for any other analyses.

How should the confidence interval be read?

General: A confidence interval is a range of effect values generated by a method that has a stated long-run coverage property when its assumptions hold. It gives a sense of both the direction and precision of an estimate. For a risk difference, zero represents no difference between the two event proportions. An interval that stays on one side of zero is consistent with a directional difference under the interval method; an interval spanning zero includes no difference among the values compatible with the data at that confidence level. The primary interval does not cross zero, while the posted intervals for the two secondary comparisons described in the results do cross zero.

The registry record does not report the confidence level or the full statistical procedure used to construct the intervals. The intervals should therefore be read as the posted uncertainty summaries, not as a substitute for a complete statistical analysis plan. The estimates are unadjusted comparisons based on the posted group summaries. No adjusted estimates or model-based results are listed in the registry record.

Why does the outcome type matter?

General: Binary outcomes have only two states under the stated definition, so the event count and the number at risk determine the observed event proportion. This differs from continuous outcomes, where the distribution of measurements and their spread are central, or time-to-event outcomes, where event timing and censoring are important. Day 7 survival is presented as a participant count, not as a time-to-event estimate. The record does not describe censoring methods or a survival-curve analysis for this endpoint.

The arm sizes are close but not exactly equal. A risk difference uses each arm’s own event count and denominator. The fact that the groups were randomized supports comparison, but the posted counts do not establish whether every randomized participant had complete outcome data or was included in a particular analysis population. The analysis population and missing-outcome handling are not reported in the registry record.

What does unadjusted mean?

General: An unadjusted comparison uses the observed outcome summaries without statistical correction for other variables or for multiple comparisons. Adjustment can serve different purposes, such as accounting for prespecified baseline factors or controlling the chance of false-positive findings across multiple tests. The term unadjusted does not itself mean that the comparison is invalid; it means that no such correction is reflected in the posted p-value. The registry record does not report a covariate-adjusted primary analysis or a plan for multiplicity.

The trial record includes other outcomes, and a result on the primary endpoint is not a statistical guarantee that every secondary outcome will have the same pattern. Each outcome has its own event frequency, estimate, and uncertainty. General: when multiple outcomes are examined, the chance of at least one apparently unusual result can increase if no adjustment or hierarchy is used. Because the registry record does not report how secondary analyses were planned or interpreted, their p-values deserve more caution than a single prespecified primary comparison.

11. Confidence Intervals and Precision

The primary survival comparison has a positive risk-difference estimate, and the posted confidence interval lies entirely above zero. This indicates that the data are compatible with a range of positive differences rather than a range that includes no difference under the interval method. The interval’s width represents uncertainty: narrower intervals generally indicate more precise estimates, while wider intervals leave greater uncertainty about the size of the contrast. The registry record does not report the confidence level or the method used to construct the interval.

Precision should not be judged only by whether an interval crosses zero. A confidence interval conveys both direction and plausible magnitude, whereas a p-value compresses evidence into a measure of compatibility with a null model. The primary comparison’s p-value is 0.005, but that value does not quantify the size of the survival contrast or resolve its generalizability.

The secondary intervals are less conclusive about direction because they include no difference. This does not establish that the groups were equivalent on those outcomes; it means the data do not exclude no difference under the posted intervals. General: demonstrating equivalence or non-inferiority requires a prespecified margin and an analysis designed for that purpose. Such a margin or framework is not reported in the registry record.

More generally, precision depends on the amount of information in the data, the frequency of the outcome, and the analysis method. The arm counts and event totals are available, but the record does not provide details about missing outcome observations or the precision goals used when the trial was originally designed. Interpretation should therefore combine the observed counts with the interval, while recognizing that the registry record does not provide a complete account of the analysis choices.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants and not total events. The planning illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers effects set at 100%, 75%, and 50% of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record; these planning figures are a separate illustration based on the observed effect.

The 80% power column describes the number of participants per arm that the planning calculation associates with an 80% chance of detecting the stated effect under the listed assumptions, if that effect and those assumptions hold. The 90% power column gives the corresponding planning target for a 90% chance. These are design probabilities under a statistical model, not guarantees about a future study or a measure of what happened in this completed trial.

The rows planning for 75% or 50% of the observed effect use smaller target effects than the row planning for 100% of the observed effect. Smaller effects are harder to distinguish from random variation, so the planning calculations require more participants per arm. This sensitivity matters because the observed effect can be an uncertain basis for planning another study; a smaller assumed effect leads to a larger projected enrollment requirement.

The displayed planning calculations are not observed power. They do not tell whether the completed trial had a particular probability of finding a result after its outcomes were observed. They are illustrations of how the target effect and chosen planning assumptions change the required sample size. The registry record does not report the trial’s original design calculation, any planned interim analyses, or whether enrollment targets changed during conduct.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.773; treatment proportion p₁ = 0.851; average p̄ = 0.812.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5529 = 1.0837.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5502 = 0.4630.
4. n = (1.0837 + 0.4630)² / (0.0779)² = 394.2, rounded up to 395 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.772727272727273                          # control proportion
p1 <- 0.850632911392405                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2643381)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 395 (80% power), 528 (90% power)
 75% of observed effect: n per arm = 730 (80% power), 976 (90% power)
 50% of observed effect: n per arm = 1,702 (80% power), 2,278 (90% power)
power.prop.test: 394.2 
Simulated power at n = 395 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity plan for the primary and secondary outcomes. It does not state whether there was a formal hierarchy, whether some secondary outcomes were designated exploratory, or whether any adjustment was used to control the chance of false-positive findings across multiple comparisons. The posted p-values are described as unadjusted. In the absence of a reported plan, they should not be interpreted as if they were corrected for the full set of outcomes or analyses.

General: Testing multiple outcomes can increase the overall chance of obtaining at least one small p-value even when there is no underlying difference for any outcome. Adjustment methods or a prespecified testing sequence can address this issue, but they may change how evidence is interpreted. A p-value for an individual secondary outcome does not by itself account for other tests. This is one reason secondary results generally carry less confirmatory weight when the analysis strategy is unclear.

Missing-data methods are also not reported in the registry record. The posted arm counts identify the group sizes and outcome counts, but do not explain whether any participants lacked an outcome measurement, how such cases were treated, or whether sensitivity analyses were performed. The analysis population is not reported in the registry record. It is therefore not possible to determine from the record whether the comparison followed an intention-to-treat approach, a per-protocol approach, or another population definition.

The record does not report a full statistical analysis plan, including the planned test for the primary endpoint, covariate adjustment, rules for handling protocol deviations, or the timing of any planned interim analyses. These omissions do not change the posted counts and p-value, but they limit assessment of whether the analysis followed prespecified procedures and how robust the conclusions are to alternative choices.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: aspiration (2.0%), oral/ dental trauma (1.0%), bleeding (0.8%).

The registry record reports serious adverse events for 10 of 396 participants in the etomidate arm and 9 of 395 participants in the ketamine arm. It reports zero other adverse events in each arm. The listed serious adverse-event terms include aspiration at 2.0%, oral/dental trauma at 1.0%, and bleeding at 0.8%. These figures describe the safety information posted in the registry; the record does not give enough detail to establish whether each event was considered related to a study medication or the procedure.

Deaths are listed separately: 142 in the etomidate arm and 131 in the ketamine arm. Those counts should not be treated as a direct comparison of adverse-event risk without knowing the registry’s definitions, follow-up, and analysis method. In particular, the primary endpoint is survival at Day 7, whereas the safety listing reports deaths without specifying in this summary that they refer to the same time point. The registry record does not report an adjusted safety comparison or further detail on event ascertainment. Event counts alone do not establish causation or provide a complete account of safety.

16. What the Result Does, and Does Not, Mean

The primary data show higher observed Day 7 survival counts in the ketamine arm than in the etomidate arm, and the posted unadjusted comparison is statistically distinguishable from no difference by its reported p-value and confidence interval. That is a description of the randomized groups in this trial. It is not a guarantee that the same contrast would occur in every setting, nor does it identify the mechanism responsible for the observed difference.

A statistically notable result is not the same as proof of a treatment effect in all relevant populations. Randomization supports a fair comparison on average, but readers also need to consider trial conduct, outcome completeness, analysis choices, and how closely future patients and settings resemble those in the trial. The registry record does not report detailed eligibility criteria, the analysis population, missing-data handling, or the full statistical plan, so those aspects cannot be assessed from the posted record.

The secondary findings answer distinct questions and have their own uncertainty. They should not be combined informally into a single verdict about all outcomes. Their interpretation is further limited because the registry record does not report a multiplicity plan, and numerical details are not available for every listed secondary outcome.

The safety counts also require careful interpretation. A count of events does not establish that a medication caused an event, and the record does not provide details sufficient to compare event risk in a way that accounts for event definitions, timing, or attribution. The reported deaths are a separate set of counts and should not be substituted for the primary Day 7 survival analysis.

In general, a trial result is one contribution to an evidence base. The posted findings quantify an observed comparison, along with uncertainty, for the enrolled participants and defined endpoints. They do not alone establish broader applicability, explain individual outcomes, or settle questions that were not measured or reported.

17. Why This Trial Matters Statistically

This trial offers a clear example of how a randomized comparison can be read through an absolute outcome contrast. The primary endpoint is a participant count at a defined time, and the arm denominators make the comparison interpretable as survival proportions as well as raw counts. The risk difference expresses the contrast on an absolute scale, while its confidence interval conveys uncertainty around the estimate.

The trial also illustrates why a p-value should not be read alone. The primary result’s p-value is 0.005, but the estimate and interval are needed to understand direction and precision. Secondary comparisons have different levels of uncertainty, and their interpretation depends on whether outcomes and analyses were prespecified and whether multiplicity was addressed. Those planning and analysis details are not reported in the registry record.

Another statistical lesson is the distinction between a trial’s original design and a retrospective planning illustration. The planning figures based on fractions of the observed effect show that smaller target effects require larger participant counts under the stated assumptions. They do not reveal the rationale for the completed trial’s enrollment target and are not a measure of observed power.

Finally, a completed randomized trial can still have reporting limits. Details about missing data, analysis populations, outcome ascertainment, and the analysis plan affect how fully readers can evaluate its results. Naming these gaps is part of interpreting the evidence: it distinguishes what the posted statistics establish from what remains uncertain.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The trial was open-label, with masking listed as none. Awareness of assignment can influence care or assessment in some settings, particularly for outcomes involving clinical judgment. The primary outcome of survival is comparatively direct, but the registry record does not describe whether outcome assessment was blinded or how survival status was verified.

The record does not report detailed eligibility criteria or participant characteristics. This makes it difficult to assess how closely the enrolled group represents other populations requiring emergency intubation. Although the listed conditions include cardiopulmonary arrest and respiratory arrest, the registry record does not provide further detail about the clinical mix of participants.

Important analysis details are not reported in the registry record, including the original sample-size justification, the full statistical analysis plan, the analysis population, missing-data methods, and any multiplicity strategy. Numerical results are not available for every listed secondary outcome. These gaps limit evaluation of prespecification, robustness, and the extent to which the posted secondary findings were exploratory.

The safety information is also limited in the posted record. Event counts are available, but attribution, timing, definitions, and the method used to compare safety outcomes are not described in the registry record reported. The death counts are listed separately and should not be assumed to represent the primary endpoint’s follow-up window. These limitations concern interpretation of the registry record and do not alter the reported outcome counts.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Etomidate Versus Ketamine for Emergency Endotracheal Intubation: a Prospective Randomized Clinical Trial — NCT02643381.
• Registry record last updated 2021-12-15; status last verified 2021-11.
• Results first posted 2021-12-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

NCT02643381 is a completed Phase 4 randomized, open-label, parallel-group trial of etomidate versus ketamine immediately before emergency endotracheal intubation. Enrollment was 801 participants, with 396 assigned to etomidate and 395 to ketamine. The primary endpoint was survival at Day 7. The posted counts were 306 and 336, respectively, and the unadjusted comparison reported p = 0.005.

The registry record lists seven secondary outcomes and provides detailed numerical comparisons for Day 28 survival and new diagnosis of adrenal insufficiency. It also posts serious and other adverse-event counts. The original sample-size justification, complete analysis plan, multiplicity approach, analysis population, and missing-data methods are not reported in the registry record. The results should therefore be read as posted outcome comparisons with those reporting limitations in mind.