Intranasal Versus Intravenous Ketamine for Procedural Sedation in Children With Non-operative Fractures: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Intranasal Versus Intravenous Ketamine for Procedural Sedation in Children With Non-operative Fractures (NCT03781817), a randomized phase 4 study. The primary outcome is Number of Participants Who Achieved Adequate Sedation..

2. Clinical Question

The primary endpoint is a binary outcome: each participant either met the adequate-sedation threshold within the stated timeframe or did not. The posted counts show that all 17 participants in the intravenous group achieved the threshold, compared with 4 of 23 in the intranasal group. These observed counts describe the trial participants; they do not establish how the result would generalize to other settings or populations.

3. Trial Design

The registry record identifies this as a randomized, phase 4, parallel-group trial with quadruple masking. Its stated enrollment was 40. The record gives a start date of 2019-09-09 and a primary completion date of 2022-01-21, and lists the trial status as terminated. The sponsor was the University of Alabama at Birmingham. The reason for termination is not reported in the registry record.

The two groups received different ketamine routes with normal saline by the other route: intravenous ketamine plus intranasal normal saline, or intranasal ketamine plus intravenous normal saline. This arrangement is consistent with masking both routes, but the registry record does not describe who was masked, how masking was maintained, or whether it was assessed. The randomization sequence and allocation-concealment procedures are also not reported in the registry record.

The posted primary outcome is the number of participants achieving adequate sedation, assessed from induction up to 10 minutes. The record defines adequate sedation as a Modified Ramsay Sedation score of at least 4. It also lists secondary outcomes concerning non-serious adverse events, duration of sedation using the Modified Ramsay Sedation Scale, and emergency department stay.

The posted primary counts are 17 of 17 for intravenous ketamine and 4 of 23 for intranasal ketamine. The registry record does not explain why the posted group counts differ from a balanced allocation, whether all randomized participants were included in each outcome analysis, or how any missing observations were handled. A protocol, planned sample-size rationale, and reasons for stopping the trial are not reported in the registry record. The stated enrollment is a trial record value, not a substitute for an explanation of the analysis population.

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 Number of Participants Who Achieved Adequate Sedation., measured over Induction up to 10 minutes.

The primary endpoint counts participants who achieved a Modified Ramsay Sedation score of at least 4 during induction up to 10 minutes. The registry record describes the scale as ranging from 0 to 6, with higher scores indicating deeper sedation; a score of at least 4 was set as satisfactory for deep sedation. The endpoint therefore turns a measured sedation level into a yes-or-no classification against a prespecified clinical threshold.

A threshold-based endpoint can be easier to interpret than a score alone: it directly describes how many participants crossed the level designated as adequate. It also discards information about scores within each category and about how far a participant’s score lies above or below the threshold. The registry record does not report the individual scores or the distribution of scores, so those features cannot be examined.

The endpoint is suited to the stated non-inferiority question only when interpreted against a prespecified non-inferiority margin and an appropriate analysis. The margin, confidence level and formal primary analysis are not reported in the registry record. The observed count difference is consequently informative about the posted participants, but it does not by itself establish the planned non-inferiority conclusion.

7. Results Posted in the Registry

• Intranasal Ketamine: 17.4% (4/23) versus 100.0% (17/17) on control; risk difference -82.6 percentage points (95% CI -98.1 to -67.1), risk ratio 0.17 (0.07–0.42); unadjusted two-proportion z-test p = <0.001.

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.

Duration of Sedation Using Modified Ramsay Sedation Scale.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Intranasal Ketamine: mean 101.21 versus 65.71 on control; difference 35.50 (95% CI 9.08 to 61.92), standardized effect d = 0.79; z-test p = 0.008.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Intranasal Ketamine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Duration of Emergency Department Stay.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Intranasal Ketamine: mean 312.40 versus 325.65 on control; difference -13.25 (95% CI -70.19 to 43.69), standardized effect d = -0.16; z-test p = 0.648.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Intranasal Ketamine and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the description beyond whether the sedation threshold was reached. They include non-serious adverse events, duration of sedation, and emergency department stay. The two duration outcomes measure different spans of time: sedation duration runs from induction to discharge from sedation by the emergency physician, while emergency department stay runs from arrival to the discharge order. Their numerical results are reported separately and should not be treated as interchangeable measures.

Across these outcomes, the posted results do not present a single consistent pattern that can be collapsed into one overall conclusion. Sedation duration differs between the groups in the unadjusted comparison, while the emergency department stay comparison is imprecise and includes values on either side of zero. These measures do not directly answer the primary question about reaching adequate sedation within 10 minutes. A longer or shorter duration, on its own, cannot establish whether the sedation threshold was achieved.

Secondary findings carry less inferential weight when they are unadjusted and when the statistical plan for handling multiple outcomes is not reported. Testing or estimating several outcomes creates more opportunities for chance findings, and a prespecified multiplicity strategy can change how results should be interpreted. The registry record does not report such a strategy or formal analyses for the duration outcomes. Their estimates are therefore best treated as descriptive and exploratory, rather than as confirmatory evidence that resolves the primary result or the trial’s non-inferiority aim.

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

• Percentage of Participants With Non-serious Adverse Events.
• Duration of Sedation Using Modified Ramsay Sedation Scale.
• Duration of Emergency Department Stay.

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: a participant either achieved the defined sedation threshold within the stated timeframe or did not. The arm counts are the most direct description of this outcome. An unadjusted risk difference compares the observed proportions between groups, with the order defined as intranasal relative to intravenous ketamine. A negative value means the observed proportion was lower in the intranasal group. The posted risk difference is -0.826.

What does the risk difference describe?

The risk difference expresses the absolute separation between the observed group proportions. It is useful because it stays on the probability scale and directly reflects the difference in the frequency of the endpoint. It does not adjust for covariates, and it is not a guarantee that the same separation would occur in other participants or settings. The associated 95% confidence interval runs from -0.981 to -0.671. Its limits describe the range of values compatible with the unadjusted method and observed counts, subject to that method’s assumptions.

How does the relative risk add context?

The relative risk compares the observed probability in the intranasal group with that in the intravenous group. The posted relative risk is 0.174, with a 95% confidence interval from 0.071 to 0.424. A relative measure gives a comparison in proportional rather than absolute terms; it should be read alongside the group counts and risk difference. With small groups and a sparse outcome pattern, relative measures can be especially sensitive to the observed counts. Neither measure supplies the missing non-inferiority margin or formal testing plan.

What does the p-value address?

The primary unadjusted p-value is p < 0.001. In general, a p-value describes how unusual data at least as discrepant as those observed would be under a specified null model. It does not give the probability that a hypothesis is true, measure clinical importance, or establish that the trial met a non-inferiority objective. The registry record does not report a formal primary analysis or the full statistical plan, so the unadjusted value should be interpreted as a summary of the observed comparison rather than a complete account of the planned inferential procedure.

How should continuous outcomes be read?

For the two posted duration outcomes, the registry gives group means and standard deviations. A mean is a measure of the group’s average, while a standard deviation describes variation among participant values around that average. The comparison is a mean difference, calculated as intranasal minus intravenous. Its confidence interval represents uncertainty in that mean difference under the unadjusted method. These comparisons do not account for possible skewness, outliers, or other distributional features because the individual observations are not reported.

The registry record lists no reported analyses for these secondary outcomes. The displayed unadjusted comparisons are recalculated from the posted summary statistics, not reported adjusted or covariate-controlled analyses. Such recalculations summarize the posted group data but cannot reproduce analyses that might have used individual-level data or a different prespecified model. No discrepancy is flagged for the posted comparisons.

What are the planning illustrations?

The sample-size illustrations are based on the observed effect, not on the trial’s own design rationale. They assume a two-sided significance level of 0.05, equal allocation between groups, a normal approximation, and an effect to detect set to a stated fraction of the observed effect. The entries are participants per arm for the stated power and effect scenario. They are planning illustrations, not observed power, and they do not explain the trial’s enrollment or termination. A planning calculation based on an observed effect is particularly uncertain when the trial is small, since the observed effect itself may be imprecise.

For general interpretation, over-dispersion means variability greater than assumed by a statistical model; if present, it can make model-based uncertainty too small. The posted duration outcomes include standard deviations, but the registry record does not describe a distributional assessment or a model for over-dispersion. The registry also does not report an interim-analysis plan, missing-data method, or prespecified analysis populations. These omissions limit assessment of whether the posted comparisons match the original analysis plan.

11. Confidence Intervals and Precision

For the primary risk difference, the posted 95% confidence interval extends from -0.981 to -0.671. The entire interval is below zero, so the unadjusted comparison is inconsistent with equal observed probabilities under the method used. The interval remains broad: it includes a range of negative differences rather than identifying one exact magnitude. The relative risk interval, from 0.071 to 0.424, likewise communicates uncertainty about the relative comparison. Confidence intervals are not guarantees that the true value lies within the interval; they describe the behavior of the method across repeated applications under its assumptions.

The precision of both estimates is constrained by the small posted group counts and by the binary endpoint. The primary counts include one group in which every posted participant met the threshold and another in which only 4 of 23 did. That pattern is striking, but limited observations do not remove uncertainty about the population effect. The registry record does not report missing-data handling, the analysis population, or a formal primary model, so the intervals cannot address uncertainty arising from those choices.

For the continuous secondary outcomes, the confidence interval for sedation duration is 9.083 to 61.92 minutes for the mean difference, and the interval for emergency department stay is -70.19 to 43.69 minutes. The first interval is entirely positive; the second spans values on both sides of zero. These intervals are unadjusted and should be interpreted as estimates of mean differences, not as proof of equivalence or absence of an effect. They also do not capture uncertainty from multiple outcome testing or unreported analytic choices.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary endpoint and several secondary outcomes, but it does not report how the statistical plan handled multiple outcomes or comparisons. When many outcomes are examined, the chance of observing an apparently unusual result by chance can increase. In general, a multiplicity plan specifies which outcomes are confirmatory and whether any adjustment or testing sequence is used. Without that plan, unadjusted secondary p-values should not be interpreted as if they were protected from multiple testing.

The registry record does not report missing-data procedures, the number of participants excluded from any outcome analysis, or the population used for each analysis. It also does not specify whether analyses followed intention-to-treat, per-protocol, or another population definition. These details matter in randomized trials, and are especially relevant to a non-inferiority question, where different analysis populations can affect interpretation. The posted arm counts describe the results available in the record but do not establish how missing or excluded observations were treated.

The record does not report an interim-analysis plan, stopping rule, or the reason the trial was terminated. It also does not report a formal primary statistical analysis or the non-inferiority margin. These are distinct uncertainties: multiplicity concerns the interpretation of multiple results, while missing-data and analysis-population details concern which observations enter an estimate. Neither can be resolved from the posted outcome counts alone. The secondary comparisons should consequently be read as unadjusted summaries, and the primary counts as the observed result rather than a fully documented non-inferiority analysis.

13. 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 non-serious adverse event terms

The posted serious adverse event counts are zero in the intravenous group and zero in the intranasal group. The posted death counts are also zero in both groups. These are counts observed in the trial record; they do not show that the risk of a serious event is absent. With the posted group sizes, uncommon events may not occur during a trial even when they remain possible, and the record does not provide a confidence interval for these safety counts.

The registry lists a secondary outcome concerning non-serious adverse events. The posted other adverse event counts are 1 in the intravenous group and 3 in the intranasal group. Serious and non-serious events are different categories and should not be combined. The registry record provides no serious-event terms and does not give further detail about event types, timing, severity definitions, or relatedness. These limited counts support a description of what was recorded, not a broad comparative safety conclusion.

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

The posted primary result shows that the adequate-sedation threshold was reached by all 17 participants in the intravenous ketamine group and by 4 of 23 participants in the intranasal ketamine group. The unadjusted risk difference and relative risk both indicate a lower observed frequency of threshold achievement in the intranasal group. This is a description of the randomized participants and the outcome counts recorded for them.

The result does not, by itself, establish the trial’s intended non-inferiority conclusion. A non-inferiority conclusion requires a prespecified margin and a suitable analysis; neither is reported in the registry record. A small p-value for a comparison against no difference does not replace that framework. The registry record also does not report the formal primary analysis, missing-data handling or analysis population, all of which would help readers assess how the result was obtained.

Nor does this trial alone establish what would happen in other settings, among children with different fracture or clinical characteristics, or under different sedation procedures. The registry record’s eligibility detail is limited, and the reason for termination is not reported. The secondary outcomes add context about duration and adverse events but are unadjusted and do not change the definition of the primary endpoint.

The appropriate statistical reading is therefore bounded: the posted counts show a substantial observed separation in adequate-sedation achievement, with uncertainty expressed by the confidence intervals. They are not a treatment recommendation, a guarantee about individual outcomes, or a complete answer to the stated non-inferiority question.

15. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between a clinical objective and the analysis needed to support it. The stated objective was non-inferiority, but the registry record does not report the non-inferiority margin or formal primary analysis. A conventional comparison of observed proportions can describe the direction and size of the result, yet it cannot establish whether a prespecified non-inferiority criterion was met. Keeping those questions separate is important when interpreting trials with non-inferiority aims.

The posted data also illustrate why effect estimates and uncertainty belong together. The observed group counts show a pronounced difference in threshold achievement, while the confidence intervals still span a range of possible effect sizes. Readers should consider both the magnitude of the estimate and its precision, rather than relying on a p-value alone.

Finally, the record highlights the importance of reporting analysis populations, missing-data procedures, multiplicity plans, and the reasons for trial termination. These are not administrative details: they determine how fully readers can assess the evidence and whether secondary findings are confirmatory or exploratory. The trial’s results are therefore informative as posted, but the incomplete reporting of its statistical plan limits the strength of conclusions that can be drawn.

16. 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 registry record leaves several trial-specific details unreported. It does not give the reason for termination, the planned sample-size justification, or the non-inferiority margin. Without the margin and a formal primary analysis, readers cannot determine from the record whether the intended non-inferiority criterion was met. The stated enrollment and posted results do not explain the decision to stop or the rationale for the group sizes.

The record does not describe the randomization sequence, allocation concealment, who was masked, or whether masking was assessed. Although both routes included normal saline by the other route, practical details of administration and masking are not reported. Eligibility criteria beyond the broad description of children with non-operative fractures are also not reported, which constrains assessment of the population to which these results may apply.

Analysis populations, missing-data methods, exclusions, and outcome-specific denominators are not explained. Nor does the record report an interim-analysis plan, a multiplicity strategy, or formal analyses for the secondary duration outcomes. The posted confidence intervals and comparisons therefore do not account for every possible analytic choice. The limited event counts also provide little detail about the types and timing of adverse events. These reporting gaps do not alter the posted counts, but they limit how comprehensively those counts can be evaluated.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Intranasal Versus Intravenous Ketamine for Procedural Sedation in Children With Non-operative Fractures — NCT03781817.
• Registry record last updated 2023-04-20; status last verified 2023-04.
• Results first posted 2023-04-20.
• 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.

20. Record Summary

The registry record describes a randomized, quadruple-masked, parallel phase 4 trial comparing intranasal with intravenous ketamine for procedural sedation in children with non-operative fractures. Stated enrollment was 40. The listed status is terminated; the start date is 2019-09-09 and the primary completion date is 2022-01-21. The reason for termination is not reported in the registry record.

The primary endpoint was achievement of a Modified Ramsay Sedation score of at least 4 during induction up to 10 minutes. The posted counts were 17 of 17 in the intravenous group and 4 of 23 in the intranasal group. Secondary outcomes concerned non-serious adverse events, sedation duration and emergency department stay. The registry record does not report the non-inferiority margin, formal primary analysis, analysis populations, missing-data approach, or multiplicity plan.