Nicardipine vs Esmolol Craniotomy Emergence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nicardipine vs Esmolol Craniotomy Emergence (NCT01951950), a randomized phase 1 study. The primary outcome is Failure of Drug to Control Systolic Blood Pressure (SBP) < 140 mmHg.

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-group Phase 1 trial with no masking. Nicardipine and esmolol were the two study interventions. The registry lists enrollment as 40, with 20 participants in each arm for the primary outcome. The trial status is completed. Its recorded start is 2013-09, and its primary completion is 2014-05.

The primary outcome was a binary count: participants with failure of drug to control SBP < 140 mmHg at 1 hour postoperatively. The posted results list 1 event in the nicardipine arm and 11 in the esmolol arm. The comparison is oriented as esmolol relative to nicardipine, with nicardipine designated as the control for the reported risk difference.

The record describes treatment as bolus dosing followed by infusion, with titration. The nicardipine description lists an initial infusion of 5 mg/hr and a maximum of 15 mg/hr; the esmolol description lists an initial infusion of 50 mcg/kg/min and a maximum of 200 mcg/kg/min. Both arm descriptions are truncated, so the complete dosing and decision rules are not reported in the registry record.

Allocation concealment, the randomization procedure, the setting, and the number of sites are not reported in the registry record. Nor are further details of participant eligibility, baseline characteristics, treatment adherence, or co-interventions reported. Those omissions limit how fully the trial conduct and the groups’ comparability can be assessed from the registry information.

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 Failure of Drug to Control Systolic Blood Pressure (SBP) < 140 mmHg, measured over 1 hour postoperatively.

The primary endpoint counts participants whose treatment failed to control systolic blood pressure below the stated threshold of 140 mmHg at 1 hour postoperatively. The registry labels the measure as the number of participants, making it a binary outcome: each participant is counted as having or not having the specified failure event. The record does not provide a more detailed operational definition of failure, such as how measurements across the postoperative period were combined.

This endpoint addresses the trial’s stated question about maintaining blood pressure within a goal range during emergence after craniotomy. The registry summary describes emergence hypertension as a concern in this population, particularly in the context of altered intracranial elastance. Counting participants who fail to meet the stated SBP goal provides a direct comparison of event frequency between the randomized treatment arms for the specified postoperative time point.

The measure is limited to the recorded endpoint and timeframe. It does not by itself describe the size or duration of blood pressure excursions, the number of measurements outside the goal, or later postoperative outcomes. Those details are not reported in the registry record. The endpoint should therefore be read as a count of participants meeting the registry’s failure definition, not as a complete account of blood pressure control or clinical outcomes.

7. Results Posted in the Registry

• Esmolol: 55.0% (11/20) versus 5.0% (1/20) on control; risk difference 50.0 percentage points (95% CI 26.2 to 73.8), risk ratio 11.00 (1.56–77.40); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is binary: a participant either contributes an event count for failure to control SBP < 140 mmHg at 1 hour postoperatively or does not. For a binary outcome, common ways to compare randomized groups include an absolute risk difference and relative measures such as a risk ratio or odds ratio. These measures answer related but different questions, so their numerical values are not interchangeable.

What does the risk difference mean?

The reported risk difference is 0.5 for esmolol relative to nicardipine. It compares the event probabilities on an absolute scale, with the nicardipine arm as the reference. The posted arm-level values are 0.05 for nicardipine and 0.55 for esmolol. The risk difference is therefore read as an absolute contrast in the probability of the specified event, not as a relative increase. Its confidence interval is 0.262 to 0.738.

How do relative measures differ?

The reported relative risk is 11.0: it compares the probability of an event in the esmolol arm with the probability in the nicardipine arm. Its confidence interval is 1.563 to 77.4. The reported odds ratio is 23.22, with a confidence interval from 2.585 to 208.6. An odds ratio compares odds rather than probabilities. When an event is not rare, an odds ratio can be farther from 1 than the corresponding relative risk, so it should not be read as though it were a risk ratio. The registry reports both measures but does not state why each was selected.

What does the p-value tell the reader?

The unadjusted p-value is < 0.001. In general, a p-value describes how unusual data at least as inconsistent with a specified null hypothesis would be if that null hypothesis and the test assumptions were true. It is not the probability that the null hypothesis is true, and it does not measure the probability that a treatment will produce a particular result in another study. The test used to obtain this p-value is not reported in the registry record. The label unadjusted indicates that the posted p-value is not presented as adjusted for multiple comparisons.

Why do the estimates differ in precision?

Each estimate is based on the same posted event counts but uses a different scale. The absolute and relative scales can give different impressions of magnitude. The intervals also depend on the chosen scale and estimation method. General statistical reasoning explains why limited event information can yield imprecise relative estimates: when the reference-group event count is low, plausible values for a ratio may span a wide range. The registry’s 1 event in the nicardipine arm and 11 in the esmolol arm are consistent with the wide interval reported for the relative risk and odds ratio.

Over-dispersion is a general concern when outcomes vary more than a simple model assumes, potentially making model-based uncertainty too narrow. The posted primary outcome is a participant-level binary count, and the registry record does not report a model, an over-dispersion assessment, or any adjustment for clustering. There is therefore no basis in the record to say that such methods were used or needed for this comparison.

The primary comparison is unadjusted in the posted results. Adjustment for baseline variables can sometimes improve precision or account for chance imbalance, but no covariate-adjusted estimate is reported. The registry lists zero analyses, while also presenting this comparison summary; any fuller analysis plan or additional analysis output is not reported in the registry record. The record does not specify the test, interval construction, missing-data handling, or analysis population used for the posted estimates. These omissions mean the numerical results can be described, but their exact computational details cannot be independently evaluated from the registry record.

General interpretation also distinguishes statistical evidence from clinical relevance. A small p-value can coexist with uncertainty about the exact effect magnitude, and a confidence interval does not determine whether an effect matters to patients or clinicians. The registry’s hypothesis and endpoint explain the intended comparison, but no threshold for clinical importance is reported. The estimates should be understood as statistical summaries of the observed primary endpoint in this trial, not as a complete judgment about the interventions.

10. Confidence Intervals and Precision

The 95% confidence interval for the risk difference is 0.262 to 0.738. In general, a confidence interval gives a range of values compatible with the data under the estimation procedure and its assumptions. It communicates uncertainty about the estimated contrast; it is not a guarantee that the true value lies within the particular interval, nor is it a range containing a fixed proportion of individual participant outcomes.

The reported relative risk is 11.0, with a 95% confidence interval from 1.563 to 77.4. The odds ratio is 23.22, with a 95% confidence interval from 2.585 to 208.6. Those intervals are wide, indicating that the precise magnitude of the relative contrast is uncertain. Both intervals exclude 1, the null value for a ratio. The risk-difference interval excludes 0, the null value for an absolute difference. These interval comparisons should be considered alongside the trial’s limited event information and the fact that the registry does not state the interval method.

The intervals describe statistical precision, not whether the observed contrast is clinically important. Their width also does not resolve concerns about generalizability, unmasked treatment, endpoint definition, or incomplete reporting. In particular, the lower and upper limits for a relative measure can look dramatic while still leaving substantial uncertainty about the size of the association. The posted figures support a difference in the observed event frequencies, while leaving the magnitude less precisely estimated than a single point estimate might suggest.

Precision is specific to the endpoint and time point. These intervals do not quantify uncertainty for blood pressure patterns outside 1 hour postoperatively, for other outcomes, or for a broader population. Further design and analysis details that might help readers assess the estimates are not reported in the registry record.

11. 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 events. They are illustrations based on fractions of the observed effect, rather than the original trial’s documented design calculation. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

For planning for 100% of the observed effect, the entries are 12 participants per arm for 80% power and 16 participants per arm for 90% power. For planning for 75% of the observed effect, the entries are 19 participants per arm for 80% power and 25 participants per arm for 90% power. For planning for 50% of the observed effect, the entries are 36 participants per arm for 80% power and 47 participants per arm for 90% power.

In plain language, the 80% power column gives the illustrative participants per arm for a design with an 80% chance of detecting the specified effect under the listed assumptions, if that effect and the model assumptions hold. The 90% power column expresses the corresponding planning target for 90% power. These are design calculations for hypothetical future studies, not observed power for this completed trial.

The entries increase as the effect to be detected becomes smaller: a smaller effect generally requires more participants to distinguish it from random variation at the same planned power and significance level. The figures depend on the assumptions and the observed effect used as the starting point. They should not be interpreted as a recommendation or as evidence that a future study would reproduce this trial’s result.

12. 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 = 0.050; treatment proportion p₁ = 0.550; average p̄ = 0.300.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6481 = 1.2702.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5431 = 0.4571.
4. n = (1.2702 + 0.4571)² / (0.5000)² = 11.9, rounded up to 12 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 <- 0.05                          # control proportion
p1 <- 0.55                          # 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(1951950)
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 = 12 (80% power), 16 (90% power)
 75% of observed effect: n per arm = 19 (80% power), 25 (90% power)
 50% of observed effect: n per arm = 36 (80% power), 47 (90% power)
power.prop.test: 11.9 
Simulated power at n = 12 per arm: 0.828 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and zero secondary outcomes posted. It reports an unadjusted p-value for the primary comparison, but a plan for handling multiple comparisons is not reported in the registry record. With no secondary outcomes posted, the available record does not establish whether additional outcomes or analyses were considered elsewhere or how any multiplicity would have been addressed.

The registry lists zero analyses while providing a comparison summary for the primary outcome. A fuller statistical analysis plan, including the test used and any planned covariate adjustment, is not reported in the registry record. It is therefore not possible to determine whether the posted analysis follows a prespecified plan or whether other analyses were conducted but not entered in the registry.

Missing-data methods and the number of participants with unavailable endpoint measurements are not reported in the registry record. The posted primary outcome lists 20 participants in each arm, but that alone does not establish whether any enrolled participants were excluded, whether every randomized participant was analyzed, or how missing measurements were handled. Imputation, sensitivity analyses, and rules for defining the analysis population are not reported in the registry record.

The record does not state whether the analysis followed intention-to-treat, per-protocol, or another population definition. It also does not provide participant flow or reasons for any exclusions. These details matter because decisions about incomplete observations and analysis populations can affect interpretation of an estimated treatment contrast. Their absence does not show that data were missing or that exclusions occurred; it means those matters cannot be assessed from the registry record.

14. Safety Results

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

Other (non-serious) adverse events

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

The adverse-event entries list 26 participants at risk in each arm. For serious adverse events, the number affected is 0 in both the nicardipine and esmolol groups. For other adverse events, the number affected is also 0 in both groups. No serious adverse-event terms are listed. These counts should be read as registry entries, not as proof that no unrecorded events occurred.

The listed at-risk counts of 26 per arm differ from the 20 participants per arm listed for the primary outcome. The record does not explain the difference or describe the safety analysis population, so the counts should not be reconciled by assumption. The registry reports no death count for either arm; deaths are not reported in the registry record.

The adverse-event information does not include further detail about event definitions, collection methods, follow-up duration, severity categories, or whether events were judged related to treatment. Those details are not reported in the registry record. Zero affected counts in the posted fields therefore provide limited information about safety and should not be interpreted as establishing the absence of risk.

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

The posted primary result shows that failure to control SBP < 140 mmHg at 1 hour postoperatively was recorded for 1 participant in the nicardipine arm and 11 participants in the esmolol arm. The reported unadjusted risk difference is 0.5 for esmolol relative to nicardipine, with a 95% confidence interval from 0.262 to 0.738 and an unadjusted p-value of < 0.001. This is evidence of a difference in the observed event frequencies for this trial’s endpoint and timeframe.

The result does not establish the exact size of a treatment effect with high precision. The confidence intervals for the relative risk and odds ratio are broad, and the registry’s analysis methods and detailed endpoint rules are not reported. Nor does the primary outcome establish what happened to blood pressure outside the stated measurement period, whether participants experienced other outcomes, or whether one intervention is preferable in a broader clinical context.

The registry summary gives a rationale focused on emergence hypertension after craniotomy and states a hypothesis favoring nicardipine. The posted outcome addresses a specific measure of blood pressure control, not morbidity, mortality, or overall clinical benefit. Those broader outcomes are not reported as secondary results in the registry. The safety entries also have reporting limitations, including an unexplained at-risk count and death counts that are not reported in the registry record.

Randomization and the between-arm comparison are relevant strengths for interpreting the reported contrast, but the trial is Phase 1, unmasked, and has 20 participants per arm listed for the primary endpoint. The results should be interpreted in light of those features and the limited registry detail. They describe the trial’s observed data; they do not guarantee the same event frequencies in other participants, settings, or treatment circumstances.

16. Why This Trial Matters Statistically

This trial illustrates why the scale of a binary treatment comparison matters. The registry reports an absolute risk difference alongside a relative risk and an odds ratio. The absolute measure conveys the contrast in event probabilities, while the relative measures describe the contrast on ratio scales. Reading all three together helps avoid treating an odds ratio as though it were a risk difference or a relative risk.

It also shows how a clear difference in observed counts can coexist with uncertainty about effect magnitude. The intervals for the relative measures are wide, so the point estimates should not be mistaken for precise values. A p-value below the stated threshold is not a substitute for examining confidence intervals, outcome definitions, or the design and analysis details.

The trial’s context makes the endpoint and timing central to interpretation. The outcome is failure to control SBP below 140 mmHg at 1 hour postoperatively, not a general measure of every aspect of care after craniotomy. A statistical comparison is only as broadly meaningful as the population, intervention, comparator, outcome, and timeframe it represents.

Finally, this record highlights the importance of reporting. Details about randomization, missing data, analysis populations, the statistical test, and safety-event collection are not reported in the registry record. Without those details, readers can describe the posted estimates but have less information for evaluating how they were produced and how well they apply beyond the trial. The lesson is methodological: interpret an estimate together with its scale, precision, endpoint, and reporting context.

17. 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 primary outcome comparison is based on 20 participants per arm, with 1 event in the nicardipine arm and 11 in the esmolol arm. This is a limited amount of information for estimating a binary outcome, particularly for relative measures whose confidence intervals are wide. The trial is registered as Phase 1, and the registry does not report its original sample-size justification or design assumptions.

The trial was unmasked. The record does not explain whether outcome assessment was standardized or whether anyone assessing the endpoint was unaware of treatment assignment. The randomization procedure and allocation concealment are also not reported in the registry record. These reporting gaps constrain assessment of possible bias, without establishing that bias occurred.

The endpoint is limited to failure to control SBP < 140 mmHg at 1 hour postoperatively. A more detailed definition of the event and the way measurements were assessed is not reported. Longer-term blood pressure outcomes, secondary outcomes, and broader clinical outcomes are not posted. Participant eligibility and baseline characteristics are also not reported, limiting assessment of the population represented.

The registry’s treatment descriptions are truncated, and the complete dosing instructions are not reported. The safety entries list 26 participants at risk in each arm, whereas the primary outcome lists 20 per arm; the registry does not explain the distinction. Death counts are not reported in the registry record. Missing-data methods, participant flow, analysis population, and the statistical test are also not reported, leaving important aspects of conduct and analysis unclear.

The recorded start and primary-completion dates give month-level timing only. The number of sites and the study setting are not reported in the registry record. Taken together, these limitations mean the posted results can be interpreted as a specific trial comparison, but its precision, implementation, and applicability cannot be fully evaluated from the registry information alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Nicardipine vs Esmolol Craniotomy Emergence — NCT01951950.
• Registry record last updated 2014-08-29; status last verified 2014-08.
• Results first posted 2014-08-29.
• 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.

21. Record Summary

NCT01951950 is a completed randomized, unmasked, parallel-group Phase 1 trial sponsored by Northwestern University. It compared nicardipine with esmolol for emergence hypertension after craniotomy in the context of brain tumors. The registry lists enrollment of 40, a start of 2013-09, and primary completion in 2014-05.

The primary endpoint was failure of drug to control SBP < 140 mmHg at 1 hour postoperatively. The posted counts are 1 event among 20 participants in the nicardipine arm and 11 among 20 in the esmolol arm. The unadjusted risk difference for esmolol relative to nicardipine is 0.5, with a 95% confidence interval from 0.262 to 0.738; the unadjusted p-value is < 0.001.

The registry lists no secondary outcomes and zero analyses. Adverse-event entries list zero affected participants for serious and other adverse events in each group, with deaths not reported in the registry record. Several design, analysis, endpoint, and safety details are not reported in the registry record.