Awakening in Spine Surgery: A Comparison Between Clinical Signs and Bispectral Index: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Awakening in Spine Surgery: A Comparison Between Clinical Signs and Bispectral Index (NCT02174913), a randomized na study. The primary outcome is Extubation Time.

2. Clinical Question

This is a focused comparison of two ways to guide propofol infusion in a specific operative context. It asks about extubation timing after surgery, not every aspect of recovery, the quality of neurophysiologic monitoring, or longer-term outcomes. The registry also lists total propofol dosage as a secondary outcome, which can inform the description of drug use but is not the primary question.

3. Trial Design

The registry identifies NCT02174913 as a completed, randomized, triple-masked, parallel-group study sponsored by Mahidol University. The listed phase is NA. Enrollment is recorded as 34. The record lists a start date of 2014-05 and a primary completion date of 2016-02. These registration details describe the study structure and status; they do not specify the exact conduct dates for each participant.

Participants were assigned to one of two parallel approaches. In the BIS arm, BIS guided target controlled infusion of propofol, with a stated BIS range of 40-60 throughout the operation. In the clinical-signs arm, heart rate, blood pressure and movement guided the infusion. Fentanyl was used for analgesia and atracurium for tracheal intubation in both arm descriptions. The registry does not report the randomization sequence method, allocation concealment procedure, or which roles were masked under the triple-masking designation.

The primary outcome is extubation time, expressed as a mean and standard deviation for each arm, with awakening time defined as the period from the end of the operation to endotracheal extubation. Its recorded timeframe is 4 hr. Total propofol dosage is the one posted secondary outcome, expressed in mg from start of anesthesia to finish of the operation. The registry lists 34 enrolled participants and reports 17.0 for each arm in the posted outcome summaries.

The registry record does not report the original sample-size justification, the details of the analysis population, or a statistical analysis plan. It lists no reported analyses. These omissions limit what can be inferred about the trial's intended estimand and analysis procedures, even though the record contains arm-level outcome summaries and unadjusted comparisons.

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.

Population: 40 patients met the inclusion criteria; however, three patients in each group were discontinued from the study due to protocol violation.

6. Primary Endpoint

The registry lists the primary outcome as Extubation Time, measured over 4 hr.

Extubation time is the primary endpoint. The registry defines it as awakening time from the end of the operation to endotracheal extubation, measured in minutes, with a timeframe of 4 hr. The posted summaries report the mean and standard deviation for each arm. This endpoint addresses the timing of an observable event after surgery and provides a direct way to compare the two methods used to guide propofol infusion.

As a continuous measure, extubation time is summarized by a group mean, which describes the average recorded time in that arm, and a standard deviation, which describes the spread of individual observations around that average. These summaries convey different aspects of the outcome: similar means can coexist with substantial variability among participants. The arm-level means are 16.3 for BIS and 16.6 for clinical signs; the corresponding standard deviations are 9.7 and 8.9.

The endpoint has a defined clinical event and time origin, but it is not a complete measure of awakening or recovery. It does not, on its own, capture other dimensions such as alertness, comfort, complications, or subsequent recovery. Those outcomes are not the primary endpoint described in the registry record. The endpoint definition also does not report how extubation decisions were standardized or whether any observations were unavailable. Those details are not reported in the registry record.

Interpreting the endpoint therefore requires attention to both the mean difference and its uncertainty, as well as to the limited scope of what extubation timing represents. A comparison in this measure answers the registered question about elapsed time to extubation; it should not be generalized automatically to other outcomes or settings.

7. Results Posted in the Registry

• Clinical Signs: mean 16.60 versus 16.30 on control; difference 0.30 (95% CI -5.96 to 6.56), standardized effect d = 0.03; z-test p = 0.925.

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.

Total Propofol Dosage

• 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:
  • Clinical Signs: mean 2,340 versus 2,146 on control; difference 194.00 (95% CI -338.42 to 726.42), standardized effect d = 0.24; z-test p = 0.475.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Clinical Signs and the control. The interval gives the range of effects that remain compatible with the data.

Total propofol dosage is the one posted secondary endpoint. Its summaries and unadjusted comparison describe a mean dosage contrast, while the primary endpoint concerns elapsed time to extubation. The two outcomes address related but distinct aspects of the anesthetic approach: one concerns the recorded amount of propofol during the operation, and the other concerns timing after the operation. Neither outcome can stand in for the other, and a pattern in one does not determine the result in the other.

Read together, the posted results do not give a precise account of either the primary extubation-time contrast or the secondary dosage contrast. The confidence intervals for both include zero and permit differences in either direction. The record does not report analyses that combine the outcomes or formally test whether changes in dosage relate to changes in extubation timing. Any connection between the two should therefore be treated as a question for further analysis, not as an established mechanism or finding.

Secondary outcomes generally carry less confirmatory weight than a prespecified primary outcome, especially when several outcomes or analyses are considered. In general, examining multiple outcomes increases the opportunity for chance findings unless the analysis plan addresses that multiplicity. The record identifies one secondary outcome and lists no reported analyses, but does not describe whether other outcomes were assessed, how the secondary outcome was selected, or whether a multiplicity strategy was planned. The unadjusted result should be viewed as descriptive evidence rather than an independent confirmatory conclusion.

The secondary endpoint can still be informative: it records an outcome that may help characterize how the assigned infusion-guidance strategies were used. But a point estimate alone is not enough to determine the direction or size of a reliable difference. Its uncertainty, the limited enrollment, and the absence of detail about the analysis plan all matter when weighing it alongside the primary result.

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

• Total Propofol Dosage

9. Statistical Interpretation

10. Statistical Methods Explained

The posted outcomes are continuous measurements summarized by means and standard deviations. The primary measure, extubation time, is recorded in minutes. The secondary measure, total propofol dosage, is recorded in mg. A mean is the arithmetic average of recorded values within an arm. A standard deviation describes how dispersed those values are around the mean; it is not the uncertainty around the mean itself. The registry provides arm-level means and standard deviations for both outcomes.

What does the mean difference represent?

The mean difference compares the average in one arm with the average in the other. For the primary outcome, the posted estimate is 0.3 min for clinical signs relative to BIS. For total propofol dosage, it is 194.0 mg for clinical signs relative to BIS. The sign depends on the stated ordering: a positive estimate means the clinical-signs average is higher than the BIS average, while a negative estimate would mean it is lower. A mean difference is measured in the same units as its outcome and does not describe how every participant's result compares with another participant's.

What does a confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the observed data under the method used to construct it. It conveys uncertainty around the point estimate, rather than guaranteeing that the true value lies within the displayed endpoints. A narrow interval indicates greater precision than a wide interval, all else being equal. For the primary comparison, the interval is -5.958 to 6.558 min; for dosage, it is -338.4 to 726.4 mg. Each includes zero, while the breadth of each interval shows that the posted estimate is not highly precise.

How should the p-value be read?

The unadjusted p-value is 0.925 for extubation time and 0.475 for total propofol dosage. 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 null hypothesis is true, nor does it measure the size or clinical importance of a difference. A p-value also does not replace the estimate and confidence interval: the estimate describes direction and magnitude, while the interval describes uncertainty. The registry record does not report a multiplicity adjustment or a sponsor-reported analysis, so these values should be read as unadjusted posted comparisons.

Why do the standard deviations matter?

In general, the variability of observations affects the precision of a comparison of means. When participant outcomes vary considerably within arms, the arm averages may be estimated less precisely, particularly when the groups are small. The posted standard deviations for extubation time are 9.7 and 8.9 min. For total propofol dosage, they are 742.0 and 839.0 mg. Those values describe observed dispersion, not evidence that any particular participant's outcome is typical or that the outcome distribution follows a specific shape. The registry record does not report distributional diagnostics.

What does randomization contribute?

In general, random assignment aims to make the groups comparable on average with respect to measured and unmeasured baseline factors, so that outcome differences can be interpreted as contrasts between assigned strategies if the trial is conducted and analyzed appropriately. Randomization does not ensure that the groups will be identical, especially in a study with limited enrollment. The record identifies the study as randomized but does not report the sequence generation or concealment method. It also does not report enough information to assess adherence, crossover, exclusions, or whether analyses followed assigned groups.

What is not documented?

The record lists no reported analyses and does not describe a formal statistical analysis plan. It does not report covariate adjustment, the analysis population, how missing outcome values were handled, or whether any interim analyses occurred. Those details cannot be inferred from the arm summaries. General statistical interpretation therefore rests on the posted unadjusted mean comparisons and their confidence intervals, while the specific procedures behind them remain unreported in the registry record.

11. Confidence Intervals and Precision

Precision concerns how tightly the data locate the estimated difference. For extubation time, the mean difference is 0.3 min, with a confidence interval from -5.958 to 6.558 min. The range crosses zero and includes both negative and positive differences. Thus, the observed estimate is close to zero, but the interval also permits differences in either direction that are larger than that point estimate. The result is not precise enough to establish that the underlying mean difference is negligible.

The arm summaries provide context for this uncertainty. The BIS mean is 16.3 min with a standard deviation of 9.7, while the clinical-signs mean is 16.6 min with a standard deviation of 8.9. Each arm summary is based on 17.0 participants. The standard deviations reflect variation among recorded observations; the confidence interval reflects uncertainty in the estimated contrast. They are related, but they are not interchangeable measures.

For total propofol dosage, the estimated difference is 194.0 mg, and the confidence interval ranges from -338.4 to 726.4 mg. It likewise includes zero and covers a broad range of possible differences in either direction. The interval should be considered alongside the reported group means and standard deviations, rather than interpreted only through the point estimate or p-value.

In general, a confidence interval is a measure of statistical uncertainty under its calculation method and assumptions, not a guarantee about the true value. Neither outcome interval establishes equivalence, and neither identifies which values would be clinically important. The registry record does not report a clinically meaningful difference threshold. The intervals therefore describe statistical precision, while the importance of the differences cannot be determined from the registered summaries alone.

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 illustrations are for participants per arm, not total events. Both posted outcomes are continuous measures, so the displayed figures correspond to participants per arm. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to a stated fraction of the observed effect. The registry record does not report the trial's own original sample-size assumptions or justification.

The 80% power column gives the illustrative number of participants per arm that would be needed, under those assumptions, for an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column describes the corresponding planning target for a 90% chance. These are design calculations, not outcomes from the completed trial. They are not observed power.

For extubation time, planning for 100% of the observed effect gives 15,114 participants per arm for 80% power and 20,233 for 90% power. Planning for 75% of the observed effect gives 26,869 per arm for 80% power and 35,970 for 90% power. For total propofol dosage, the corresponding 100% row gives 262 per arm for 80% power and 351 for 90% power. The calculations use the observed estimates as planning inputs, so they should not be mistaken for the trial's prespecified design.

Smaller effects require more participants to detect at the same power and significance level, because they are harder to distinguish from random variation. The illustrations are conditional on their stated assumptions and do not show what would happen under other allocation schemes, analysis methods, or outcome variability. The curve should be read in the same way as the tabulated planning values: as a relationship between the effect targeted and the number of participants per arm under the stated calculation, not as a summary of what the completed trial achieved.

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

Worked calculation for this trial

1. Observed difference Δ = 0.300; pooled standard deviation σ = 9.309.
2. n = 2 × (1.96 + 0.842)² × 9.309² / 0.300² = 15,113.5, rounded up to 15,114 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 <- 0.300000000000001                      # observed difference in means
sigma <- 9.30859817588019                     # 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(2174913)
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 = 15,114 (80% power), 20,233 (90% power)
 75% of observed effect: n per arm = 26,869 (80% power), 35,970 (90% power)
 50% of observed effect: n per arm = 60,454 (80% power), 80,931 (90% power)
power.t.test: 15114.4 
Simulated power at n = 15,114 per arm: 0.802 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary endpoint and one posted secondary endpoint, and it lists no reported analyses. It does not state whether the trial protocol or analysis plan included additional endpoints, subgroup comparisons, repeated measurements, or interim looks at the data. It also does not report whether any formal adjustment for multiple testing was planned or applied. These details are not reported in the registry record.

In general, multiplicity arises when several statistical questions are examined. Testing multiple outcomes or comparisons can increase the chance that at least one result appears notable by chance, even when each individual test uses the same nominal threshold. A prespecified primary endpoint helps identify the principal question, but it does not by itself resolve how secondary outcomes should be interpreted. Because no multiplicity strategy is described, the posted p-values should be treated as unadjusted and exploratory for interpretation of the secondary outcome.

Missing-data handling is also not described. The record provides arm summaries with 17.0 participants in each arm, but it does not report whether all randomized participants contributed primary and secondary outcome data, whether any observations were missing, or how missing values were handled. A summary count alone does not establish the analysis population or show whether exclusions occurred after randomization. The registry record does not report the number or reasons for any missing observations.

The record does not specify whether the analysis followed intention-to-treat principles, used a per-protocol population, or used another definition. It also does not provide details about treatment adherence, crossovers, protocol deviations, covariate adjustment, or sensitivity analyses. These omissions matter because analytic choices can affect both estimates and their uncertainty, particularly in a randomized study with limited enrollment. They do not establish that the analysis was inappropriate; they mean that the registry summary does not permit those features to be evaluated.

Consequently, interpretation should distinguish what is directly recorded—the arm summaries and unadjusted comparisons—from what would require additional documentation. A protocol, analysis plan, or fuller results report would be needed to assess prespecification, missingness, and the handling of multiple outcomes. None of those details should be inferred from the posted outcome values alone.

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.

The registry reports no serious adverse events among the 17 participants at risk in the BIS arm and none among the 17 participants at risk in the clinical-signs arm. It also reports no other adverse events in either arm and no deaths in either arm. These are the posted safety figures for the study record.

Zero reported events does not mean that an event is impossible, nor does it show that the approaches have identical safety profiles. In general, when a study has limited enrollment, uncommon events may not occur in the observed participants even if they can occur in a wider population. The record's event counts describe what was reported during this study, not the full range of possible risks.

The registry does not provide serious-event terms, because no serious events are listed, and it does not give additional detail about event definitions, surveillance procedures, timing, or causal attribution. It also does not report a narrative explaining how adverse events were collected. The absence of reported events should therefore be read narrowly as zero recorded serious and other adverse events and zero deaths in the listed arm summaries, rather than as evidence establishing safety beyond this trial.

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

The results describe a randomized comparison of BIS-guided and clinical-sign-guided target controlled infusion of propofol among patients having spine surgery with neurophysiologic monitoring. The primary endpoint is the time from the end of surgery to endotracheal extubation. The posted means are close, and the estimated difference is small relative to the uncertainty represented by its confidence interval. The interval includes zero and allows differences in either direction.

That pattern means the registry results do not provide a precise estimate of the primary contrast. It does not establish that the approaches are equivalent, that there is no difference, or that one approach is superior. Equivalence or non-inferiority would require a defined margin and an analysis designed for that purpose; these are not reported in the registry record. The unadjusted p-value is not a measure of the probability that either approach is effective or ineffective.

The secondary dosage outcome likewise has an uncertain estimated contrast. It offers descriptive information about the recorded mean propofol amounts but does not, by itself, establish a reliable difference. Nor does it establish that dosage is a cause of any observed extubation timing. The record does not report a joint analysis relating these endpoints.

The study's randomized, parallel design is relevant to the comparison, but the registry summary does not describe all methods needed to judge the validity or scope of the estimates. The specific randomization procedures, masking roles, analysis population, missing-data handling, and statistical plan are not reported. Enrollment and the posted arm summaries also limit how much can be learned about uncommon outcomes or subtle differences.

These results apply to the registered comparison and outcomes, in the population described as spine surgery patients having neurophysiologic monitoring. They should not be extended automatically to other procedures, patient groups, anesthesia regimens, or recovery outcomes. The record supports a careful account of the observed averages and their uncertainty; it does not support medical advice or a broad conclusion about which method should be used.

17. Why This Trial Matters Statistically

This trial is statistically informative as an example of why a point estimate, its uncertainty, and the study design need to be considered together. The primary estimate is close to zero, but its confidence interval is wide enough to include differences in either direction. Reading only the mean difference would understate uncertainty; reading only the p-value would discard information about the range of plausible contrasts.

The randomized parallel design addresses a focused methodological question: whether guiding target controlled infusion of propofol using BIS rather than clinical signs is associated with a different mean extubation time in the described operative setting. The two arms share the listed use of fentanyl and atracurium, while the guidance method differs. This makes clear why precise descriptions of the intervention and comparator matter when interpreting an outcome contrast.

The record also illustrates the distinction between a primary result and a secondary result. Extubation time is the primary endpoint, while total propofol dosage is secondary. Although both can help characterize the comparison, an unadjusted secondary result should not be treated as a separate definitive confirmation. A documented analysis plan would help readers understand how the outcomes were prioritized and how multiplicity was addressed.

Finally, planning illustrations based on observed effects are not a substitute for the original design rationale and do not reveal the trial's observed power. Their large variation across targeted effect fractions emphasizes that sample-size calculations depend on what difference is considered worth detecting and on the assumptions used. The original design assumptions are not reported in the registry record. In this study, uncertainty and incomplete reporting are central parts of the statistical interpretation, not details to set aside.

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 registry summary has important limitations for interpreting this specific trial. Although it identifies a randomized, triple-masked, parallel design, it does not say how the random sequence was generated or concealed, or who was masked. The term triple-masked alone does not identify which participants or study personnel were unaware of assignment. These missing details limit assessment of how assignment and masking were implemented.

The registry does not report detailed eligibility criteria, baseline characteristics, adherence, protocol deviations, or crossovers. It also does not describe how extubation decisions were standardized across participants or how the 4 hr timeframe was applied in practice. Such details could help establish how consistently the endpoint was measured and whether the two groups were comparable in relevant features, but they cannot be inferred from the outcome summaries.

The analysis population, missing-data approach, statistical analysis plan, and original sample-size justification are not reported. No analyses are listed. As a result, it is not possible to determine from the registry record whether the posted comparisons were prespecified, adjusted for covariates, or based on all randomized participants. The registry provides arm summaries and unadjusted comparisons, but not enough procedural detail to reconstruct the analysis or assess its sensitivity to alternative choices.

Enrollment is recorded as 34, with 17.0 participants per arm in the outcome summaries. The confidence intervals are broad, and the record provides no threshold for a clinically important difference. Therefore, even the direction and clinical relevance of possible differences cannot be settled from these statistics alone. Safety summaries report zero events, but do not describe surveillance, event definitions, or follow-up beyond the posted summaries.

These are limitations of what the registry record documents, not proof that the study lacked procedures or that the conduct was deficient. Additional protocol and results information would be required to resolve them.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Awakening in Spine Surgery: A Comparison Between Clinical Signs and Bispectral Index — NCT02174913.
• Registry record last updated 2020-07-13; status last verified 2020-06.
• Results first posted 2020-07-13.
• 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

NCT02174913 is a completed randomized, triple-masked, parallel-group study sponsored by Mahidol University. The registry lists enrollment of 34 and a study start of 2014-05, with primary completion in 2016-02. The listed phase is NA. The population described is patients having spine surgery with neurophysiologic monitoring.

The comparison is BIS-guided versus clinical-sign-guided target controlled infusion of propofol. BIS is maintained at 40-60 in the BIS arm; heart rate, blood pressure and movement guide infusion in the clinical-signs arm. The primary endpoint is extubation time, defined as awakening time from the end of the operation to endotracheal extubation. Total propofol dosage is the posted secondary outcome.

The primary mean difference is 0.3 min, with a confidence interval from -5.958 to 6.558 min and an unadjusted p-value of 0.925. The secondary dosage comparison is also uncertain. The registry reports no serious adverse events, other adverse events, or deaths in either arm. Important design and analysis details, including the original sample-size rationale and missing-data procedures, are not reported in the registry record.