Can Adequacy of Anesthesia Depth and Quality of Recovery be Influenced by the Level of Neuromuscular Blockade?: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Can Adequacy of Anesthesia Depth and Quality of Recovery be Influenced by the Level of Neuromuscular Blockade? (NCT02484651), a randomized phase 4 study. The primary outcome is BIS Signal Variability Using the Measured Standard Deviation During the Maintenance Phase of Anesthesia.

2. Clinical Question

The investigators hypothesized that maintaining deep blockade might suppress electromyographic activity and make BIS readings less variable. They also proposed that this approach could reduce the anesthetic drug doses needed to keep BIS within the target range. Those proposed effects are hypotheses, not established findings. The primary outcome reported in the registry record is BIS signal variability, not total propofol or remifentanil dose. The posted primary result therefore addresses the recorded measure of signal variability; it does not by itself answer every question raised in the trial’s rationale.

3. Trial Design

This was a phase 4 randomized controlled study with a parallel-group design. The registry record reports enrollment of 70 participants and two groups: standard clinical practice and deep neuromuscular blockade. The primary outcome results include 32 participants in the standard group and 31 in the deep-blockade group. Those outcome counts describe the reported analysis; reasons for any difference between enrollment and the outcome counts are not reported in the registry record.

Masking is listed as none, so the study is described as unmasked. The available record does not specify whether outcome processing or statistical analysis was blinded. The standard group received rocuronium for intubation, with neostigmine used for reversal if required. In the deep-blockade group, rocuronium was continued by infusion to maintain a deep block, with the description identifying sugammadex reversal. The record specifies PTC monitoring every 5 minutes for that group.

The primary outcome was the sample standard deviation of BIS readings during the maintenance phase of anesthesia. This phase was defined using BIS thresholds around loss of consciousness and stopping the propofol infusion, and its average duration was 130 minutes. Secondary outcomes listed in the record concern PQRS results at 15 and 40 minutes after surgery and PQRS satisfaction at day 3. Detailed results for those secondary outcomes are not reported in the registry record.

The registry record does not report the trial’s original sample-size justification, the allocation sequence method, or further details about concealment. Interim analyses and a prespecified statistical analysis plan are not reported in the registry record. These omissions limit assessment of the study’s planning and safeguards against bias beyond the design details explicitly recorded.

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.

Before assignment: 3 patients were excluded from the study after screening (signing the informed consent) but before randomization and assignment to the groups, due to: * 2 patients had their surgery postponed less than 2 hours before the schedule time * the scheduled surgical position of 1 patient was altered by the surgeon just before the start of the procedure.

Overall Study

Reasons for not completing this period:

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 BIS Signal Variability Using the Measured Standard Deviation During the Maintenance Phase of Anesthesia, measured over Maintenance of anesthesia, an average of 130 minutes.

The primary endpoint is the BIS signal’s sample standard deviation during maintenance of anesthesia. BIS is an EEG-derived index described in the record as ranging from 0 to 100: values near 100 represent an awake clinical state, while 0 denotes the maximal effect of an isoelectric EEG. The stated target range was 40 to 60. The endpoint is not the average BIS level; it is a measure of how much the recorded signal oscillated around its sample mean during the defined maintenance period.

A larger standard deviation means greater observed variation in the BIS signal over that period. The investigators used this measure because they hypothesized that deep neuromuscular blockade could suppress electromyographic activity and reduce apparent BIS variability. In general, a signal-variability measure can describe stability over time, but it does not by itself establish that the average signal was closer to a target or that anesthetic drug use was lower. Those are distinct questions and require their own reported outcomes.

The record reports a mean and standard deviation for each group’s endpoint values. The comparison is therefore a difference in group means of the variability measure, not a difference in the average BIS score itself. The primary outcome timeframe is maintenance of anesthesia, described as an average of 130 minutes. The specific number of BIS observations per participant is not reported in the registry record.

7. Results Posted in the Registry

• Deep NMB Group: mean 7.80 versus 7.60 on control; difference 0.20 (95% CI -0.59 to 0.99), standardized effect d = 0.13; z-test p = 0.620.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a two-sided t-test for the primary comparison. The recalculated result uses the posted group means, standard deviations, and participant counts to estimate an unadjusted difference in means. The two approaches address the same broad comparison, but their reported p-values are not identical: the registry reports 0.651, while the recalculation reports 0.62. The record does not explain the difference, so no specific cause should be assigned to it.

What does the mean difference represent?

The group means are 7.6 units for standard practice and 7.8 units for deep blockade. The recalculated mean difference is expressed as deep blockade minus standard practice, giving an estimate of 0.2 units. A positive value means the observed mean variability was higher in the deep-blockade group; a negative value would mean it was lower. This is an unadjusted comparison based on the posted summary statistics, not an adjusted estimate from a model incorporating participant characteristics or other covariates.

In general, a mean difference is a direct way to express the separation between two group averages on the endpoint’s original scale. It is useful to consider the estimate alongside its uncertainty: a small observed difference may be compatible with a wider range of true differences, particularly when the data are limited. The posted group standard deviations are 1.6 in each arm, and the recalculation uses a pooled standard deviation of 1.6. This pooled value supports a standardized effect estimate in the recalculation, but the clinical meaning of any standardized value depends on the endpoint and context.

How should the p-values be read?

In general, a p-value measures how unusual data at least as incompatible with a specified null model would be if that model and the test assumptions held. It is not the probability that the observed difference happened by chance, and it does not say how important the difference is. The registry’s p = 0.651 comes from its stated two-sided t-test. The recalculated p-value is unadjusted and is 0.62. The record labels the registry analysis as a superiority analysis. A superiority test evaluates evidence for a difference; a nonsignificant result does not demonstrate equivalence or prove that the groups have identical outcomes.

A two-sided test allows evidence in either direction to count against the null hypothesis. The t-test compares means while accounting for the variability and sample sizes in the groups. In general, its interpretation depends on assumptions about the observations and the distribution of the mean difference. The registry record does not report diagnostics for those assumptions, nor does it describe any alternative analysis. The primary outcome is based on repeated BIS signal measurements within a maintenance period, but the record does not specify how those repeated readings were reduced to participant-level values beyond describing the sample standard deviation.

Why does variability matter?

In general, standard deviation describes dispersion around a mean. Here it is used as the participant-level outcome representing fluctuations in BIS during maintenance. A lower participant-level value means less variability in that interval, whereas a higher value means more. Comparing the group means of these participant-level values addresses average variability across participants. It does not directly compare individual BIS readings as though every reading were an independent participant; the record’s endpoint description identifies a sample standard deviation per participant.

General statistical considerations include whether observations are independent across participants and whether the distribution of participant-level endpoint values is sufficiently compatible with the chosen mean-comparison method. The record does not report checks of distribution shape, outliers, or sensitivity analyses. These are not grounds to assume the method was invalid; they identify details that cannot be evaluated from the registry information.

What does the confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the observed data and the method’s assumptions. It conveys precision more directly than a p-value alone. The recalculated interval for the mean difference includes zero and extends to both negative and positive values. This indicates uncertainty about whether the underlying difference is below or above zero, as well as uncertainty about its magnitude. The interval is an unadjusted recalculation; it is not a confidence interval reported by the registry analysis, whose interval values are not reported in the registry record.

The recalculation uses the posted summaries and is not adjusted for other variables. It is consequently distinct from any analysis that might have used participant-level data or prespecified adjustments. Whether covariate adjustment was planned or conducted is not reported in the registry record. The distinction matters because a summary-statistic reanalysis cannot reproduce unreported modelling choices or account for participant-level features unavailable in the posted summaries.

Why can over-dispersion matter in general?

Over-dispersion is a general concern when observed variation is larger than a model assumes. If the analysis treats data as less variable than they are, uncertainty can be understated and statistical evidence can appear stronger than warranted. The reported primary analysis is a t-test on a continuous endpoint, not a count model, so over-dispersion in the count-data sense is not the central issue. More generally, the t-test’s estimate of uncertainty depends on how well its variance assumptions describe the participant-level outcome. The record does not report a separate assessment of variance structure or a robust alternative.

The sample-size illustrations are separate from the primary test result. They use the observed effect as a planning reference under stated assumptions and show how many participants per arm would correspond to selected power targets for selected fractions of that effect. They are not a retrospective measure of the trial’s probability of detecting an effect, and they do not establish what the original investigators planned. The original design assumptions and sample-size justification are not reported in the registry record.

10. Confidence Intervals and Precision

The recalculated confidence interval for the mean difference includes zero and extends in both directions. This means the data do not pin down the direction of the underlying difference with high precision: values consistent with a modest decrease as well as an increase are included. The interval’s endpoints are not reported to three or fewer decimal places in the posted comparison summary, so they are described by their relation to zero rather than reproduced with extra decimal places.

In general, a confidence interval is a range generated by a statistical procedure that, across repeated studies under its assumptions, would cover the target quantity at its stated confidence level. The confidence level for the recalculated interval is not specified in the comparison summary, so it should not be inferred. An interval conveys both the estimated effect and its uncertainty; it does not guarantee that every value in the interval is equally plausible, nor does it identify a clinically important threshold.

The group-level endpoint standard deviations are 1.6 units in both arms, and the analyzed counts are 32 and 31. Precision depends on the variability of the outcome and the number of observations, among other factors. The observed mean difference of 0.2 units is small relative to the reported group spread, but this comparison alone does not define a threshold for clinical importance. Such a threshold is not reported in the registry record.

The registry’s own analysis reports p = 0.651 but does not report a confidence interval for the group contrast. The recalculated interval is therefore useful as a summary-statistic illustration, not a substitute for an interval from the sponsor’s participant-level analysis. The interval includes zero, but that does not prove absence of an effect. It indicates that the posted data are compatible with more than one direction of difference under the recalculation’s assumptions.

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 sample-size illustrations report participants per arm, not a total across both groups and not total events. They use a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. These are planning assumptions for the illustrations; the trial’s original design assumptions and sample-size justification are not reported in the registry record.

For 100% of the observed effect, the illustration gives 1,005 participants per arm for 80% power and 1,345 participants per arm for 90% power. For 75% of the observed effect, the corresponding figures are 1,787 and 2,392 participants per arm. For 50% of the observed effect, they are 4,019 and 5,380 participants per arm.

In plain terms, the 80% power column describes the planned group size associated with an 80% chance of detecting the selected effect under the illustration’s assumptions, if that effect is truly present. The 90% column uses a higher target probability and therefore requires more participants for the same effect assumption. Smaller effects need more participants because they are harder to distinguish from ordinary sampling variation. This is not observed power: the figures are prospective planning illustrations based on the observed estimate, not a measure of the trial’s actual chance of finding a result.

Because the observed effect is uncertain, the illustrations should not be read as proof that those group sizes would be sufficient for every clinically relevant difference. Planning around a fraction of an observed effect is a way to explore sensitivity to effect size; it does not replace a design based on a prespecified meaningful difference and justified assumptions.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.200; pooled standard deviation σ = 1.600.
2. n = 2 × (1.96 + 0.842)² × 1.600² / 0.200² = 1,004.7, rounded up to 1,005 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
delta <- 0.2                      # observed difference in means
sigma <- 1.6                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2484651)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,005 (80% power), 1,345 (90% power)
 75% of observed effect: n per arm = 1,787 (80% power), 2,392 (90% power)
 50% of observed effect: n per arm = 4,019 (80% power), 5,380 (90% power)
power.t.test: 1005.6 
Simulated power at n = 1,005 per arm: 0.796 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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. Analyses Reported by the Sponsor

The registry’s own primary analysis is a two-sided t-test and reports p = 0.651 for the comparison. The recalculated unadjusted analysis from the posted group summaries gives a mean difference of 0.2 units and p = 0.62. The recalculation also gives a confidence interval that spans zero. These are related analyses of the same group comparison, but they are not identical outputs.

The sponsor’s result is the registry’s posted analysis. The recalculation is an unadjusted reconstruction from the group means, standard deviations, and analyzed counts, rather than a reproduction using participant-level data. The registry record does not explain why the two p-values differ, and the recalculation cannot establish which unreported analytic details might account for the difference. No discrepancy is flagged in the record, but the distinction between the official posted analysis and the summary-statistic recalculation remains important.

Both p-values indicate limited evidence against the no-difference null under their respective analyses. Neither should be treated as proof of equivalence or as a measure of clinical importance. The sponsor’s analysis takes precedence if a discrepancy is flagged; no such flag is present in this record.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and six analyses, while the available outcome information identifies the primary BIS variability outcome and two secondary PQRS outcome categories. The record does not report whether the investigators adjusted for multiple comparisons, how the six analyses relate to the listed measures, or whether a hierarchy was prespecified. A multiplicity strategy is not reported in the registry record.

In general, testing several outcomes or contrasts can increase the chance of at least one apparently notable result even when there is no underlying effect. Adjustment procedures or a prespecified hierarchy can address that issue, but whether either was used cannot be inferred from the number of analyses alone. The reported primary p-value should therefore be read as the result of its stated test, without assuming that it was adjusted or that it accounts for every other analysis.

The registry record does not report how missing primary outcome data were handled, whether all randomized participants were included in the analysis, or whether the analysis followed an intention-to-treat principle. The enrollment is 70, while the primary endpoint counts are 32 in the standard group and 31 in the deep-blockade group. Those figures do not explain the participant flow or indicate why the analyzed counts differ from enrollment. Reasons for missing data, exclusions, and the handling of incomplete BIS records are not reported in the registry record.

The record also does not report whether an interim analysis was planned or conducted, or whether a statistical analysis plan was finalized before results were examined. These details matter because prespecification helps readers distinguish planned analyses from decisions made after seeing the data. Their absence from the available record is not evidence that such procedures were or were not used; it means they cannot be assessed from the registry information.

Finally, the available description does not provide participant-level baseline characteristics, covariate-adjusted estimates, or sensitivity analyses. The primary comparison is therefore the unadjusted mean comparison reported by the registry and the separate recalculation from posted summaries. The robustness of the result to alternative analytic choices is not reported in the registry record.

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 non-serious adverse event terms

The serious adverse event figures are zero in the standard group and zero in the deep-blockade group. Each group has 35 participants listed as at risk for serious adverse events. The record also lists zero deaths in each group. These are the counts recorded for the reported safety categories; they do not establish that serious events are impossible or rule out uncommon risks.

In general, an observed count of zero means no event was recorded in the specified group and reporting period, not that the true event rate is necessarily zero. Interpretation also depends on how events were defined, how long participants were followed, and how completely events were collected. Detailed follow-up duration and event-ascertainment procedures are not reported in the registry record.

The registry lists other, non-serious adverse events in both groups, but the serious adverse event comparison is the focus. The absence of reported serious events should be read narrowly and alongside the study’s size and available follow-up information, rather than as a definitive safety conclusion.

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

The primary result shows similar observed mean BIS variability in the two groups: 7.6 units with standard practice and 7.8 units with deep blockade. The recalculated mean difference is 0.2 units, and the confidence interval includes zero. The registry’s two-sided test reports p = 0.651. Taken together, these statistics do not provide strong evidence of a difference in the primary endpoint in this study.

That is not the same as demonstrating that the strategies are equivalent, or that the true difference is exactly zero. The estimated contrast has uncertainty, and the interval includes values in both directions. Equivalence would require a defined margin and an analysis designed to assess whether the interval falls within that margin; neither is reported in the registry record. The study’s reported result should therefore be understood as an inconclusive comparison on the primary variability measure, rather than proof of sameness.

The endpoint concerns fluctuations in the BIS signal during maintenance of anesthesia. It does not directly establish whether BIS readings were more often within the target range of 40 to 60, whether the mean BIS differed, or whether propofol and remifentanil requirements changed. Although those drug requirements appear in the study rationale, their results are not reported in the registry record. The listed secondary PQRS outcomes also cannot be interpreted without their detailed results, which are not reported in the registry record.

The safety record lists no serious adverse events in either group among the participants at risk, and no deaths. Those observations are reassuring only in the limited descriptive sense that none were recorded; they cannot establish absence of risk. The available record does not support a broad conclusion about comparative safety.

Overall, the posted statistics characterize this trial’s measured endpoint and its uncertainty. They do not determine whether either approach should be used in clinical practice and are not medical advice. The result is specific to the trial population, outcome definition, monitoring, and analysis represented in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically interesting because its primary endpoint translates a mechanistic hypothesis into a measurable signal property. The investigators proposed that deep neuromuscular blockade could suppress electromyographic activity and reduce BIS variability. Rather than treating the BIS level itself as the outcome, the primary measure was the sample standard deviation during the maintenance phase. That choice makes clear why outcome definitions matter: variability, average level, time within a target range, and anesthetic dose are different statistical quantities.

The result also illustrates why effect estimates and uncertainty should be considered together. The group means are close, and the recalculated difference is 0.2 units, but the confidence interval crosses zero. A p-value alone would not show the range of estimates compatible with the data. Conversely, a nonsignificant test cannot be treated as proof of no effect or equivalence. The registry record does not report an equivalence margin, so that stronger interpretation is unavailable.

The planning illustrations expose another useful issue: a sample size depends on the effect a study is intended to detect. Their participant requirements rise when the assumed detectable effect is a smaller fraction of the observed effect, and they use explicit assumptions about significance level, allocation, and approximation. They are planning illustrations, not evidence about the trial’s actual power or original planning.

Finally, this record demonstrates the value of distinguishing an official analysis from a summary-statistic recalculation, and of noting what is not documented. The registry’s p-value and the recalculated p-value are not identical, while the record does not explain the difference. Details about missing data, multiplicity, and original sample-size planning are also unavailable. Transparent interpretation depends as much on these boundaries as on the reported point estimate.

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 available record does not describe participant characteristics, eligibility criteria, or the range of surgical procedures. Those details would help readers judge how closely the study population corresponds to other settings. The study is reported as unmasked, and the registry does not specify whether outcome processing or analysis was blinded. The potential influence of awareness of group assignment therefore cannot be assessed from the available information.

The primary endpoint is defined as a participant-level sample standard deviation of BIS during maintenance, but the record does not report the number or frequency of measurements used for each participant, data-quality rules, or how incomplete signal records were handled. It also does not report the distribution of the endpoint, diagnostic checks, or sensitivity analyses. These omissions limit independent assessment of the t-test assumptions and the robustness of the estimate.

Enrollment is listed as 70, while the primary endpoint results include 32 participants in one group and 31 in the other. The record does not provide a participant flow account, reasons for missing outcome data, or the analysis population definition. This prevents a clear assessment of attrition and its possible effect on the comparison.

The original sample-size justification, interim analyses, and detailed prespecified statistical plan are not reported in the registry record. Multiplicity handling and results for the listed secondary PQRS outcomes are also not available in the reported information. Finally, the comparison is unmasked and the outcome is a physiological signal measure; the result does not by itself answer broader questions about drug requirements, recovery, or clinical benefit.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Can Adequacy of Anesthesia Depth and Quality of Recovery be Influenced by the Level of Neuromuscular Blockade? — NCT02484651.
• Registry record last updated 2019-09-16; status last verified 2019-09.
• Results first posted 2019-09-16.
• 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

The registry describes a completed, phase 4 randomized parallel-group study comparing standard neuromuscular blockade with deep blockade during anesthesia. Masking is listed as none, and enrollment is 70. The primary endpoint is BIS signal variability, measured as the sample standard deviation during the maintenance phase of anesthesia.

Reported endpoint means are 7.6 units for the standard group and 7.8 units for the deep-blockade group, with analyzed counts of 32 and 31. The registry’s two-sided t-test reports p = 0.651. A separate unadjusted recalculation gives a mean difference of 0.2 units and p = 0.62; its confidence interval spans zero. The record also lists zero serious adverse events and zero deaths in each group.

Detailed results for the listed secondary outcomes, the original sample-size justification, and information about missing-data handling and multiplicity are not reported in the registry record. The primary comparison is therefore best read as an uncertain result for BIS signal variability, not as evidence of equivalence or as a complete account of the trial’s other questions.