Hypertonic Resuscitation Following Traumatic Injury: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Hypertonic Resuscitation Following Traumatic Injury (NCT00316017), a randomized phase 3 study. The primary outcome is 28 Day Survival.

2. Clinical Question

3. Trial Design

The registry identifies NCT00316017 as a phase 3, randomized, quadruple-masked, parallel-group study titled Hypertonic Resuscitation Following Traumatic Injury. It lists the University of Washington as sponsor and traumatic shock as the condition. The registered study objective was to determine whether hypertonic saline, with or without dextran, could improve overall survival in people with traumatic injury and shock.

Three fluids were compared: 7.5% hypertonic saline/6% Dextran-70 (HSD), 7.5% hypertonic saline (HS), and 0.9% normal saline. The registry reports enrollment of 895. The study started in 2006-05, reached primary completion in 2009-08, and has a status of terminated. The reason for termination is not reported in the registry record. The original planned enrollment and the trial’s original sample-size justification are not reported in the registry record.

The primary outcome was 28-day survival, measured from Emergency Department arrival. The primary analysis population was per protocol: it included only people who received the study fluid per randomization, defined as the study fluid having been connected to the patient’s IV. The posted group sizes for this outcome are 220 for HSD, 256 for HS, and 376 for normal saline. These are the outcome analysis denominators and should not be treated as evidence that every randomized participant was included in the primary analysis.

The registry also lists secondary outcomes covering respiratory distress syndrome-free survival, multiple organ dysfunction, infection, blood products, fluid use, ventilator-free days, and time alive outside the ICU or hospital. It lists 22 outcome measures and 21 posted secondary outcomes. The primary outcome’s posted sponsor analysis is a test for proportions across all three groups. The registry does not report the complete statistical plan or the details of masking procedures.

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: 895 subjects were randomized. 852 subjects completed the study. Randomization was performed when the outer study fluid bag wrapper was removed in the presence of a patient. To ensure there was no bias, a secondary intention to treat analysis was also performed which included all randomized patients even if the fluid was not administered.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per protocol, analysis was done on only those subjects who received the study fluid per randomization; this was defined as that the study fluid had been connected to the patient's IV.

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 28 Day Survival, measured over 28 days from time of Emergency Department (ED) arrival.

The primary endpoint is the number of participants surviving through 28 days from the time of Emergency Department arrival. It is a binary outcome: each participant either survived through the specified period or did not. The registry defines the primary population per protocol, including participants whose assigned study fluid was connected to the patient’s IV.

Survival is directly relevant to the trial’s stated objective of assessing overall survival after traumatic injury with shock. A binary outcome also allows the groups to be compared by the proportion surviving, rather than only by the raw count, because the numbers analyzed in the groups differ. For this outcome, the registry records 164 participants in the HSD group, 187 in the HS group, and 279 in the normal-saline group as surviving. The respective analysis denominators are 220, 256, and 376.

The registry’s definition uses 28 days from Emergency Department arrival. It also explains that the day of the episode is counted as Day 0, so the 28-day period runs from Day 0 through Day 28, with a maximum possible value of 29 for measures expressed as days. That counting convention is relevant to day-based secondary outcomes; the primary outcome itself is reported as survival through the stated follow-up period.

The endpoint does not by itself describe the timing or cause of deaths, nor does it capture every aspect of recovery. Those details are not reported in the registry record for the primary outcome. Its interpretation is therefore specific to survival status through the registered follow-up period and the per-protocol population.

7. Results Posted in the Registry

• 7.5% Hypertonic Saline (HS): 73.0% (187/256) versus 74.5% (164/220) on control; risk difference -1.5 percentage points (95% CI -9.4 to 6.4), risk ratio 0.98 (0.88–1.09); unadjusted two-proportion z-test p = 0.711.
• 0.9% Normal Saline: 74.2% (279/376) versus 74.5% (164/220) on control; risk difference -0.3 percentage points (95% CI -7.6 to 6.9), risk ratio 1.00 (0.90–1.10); unadjusted two-proportion z-test p = 0.926.

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.

Adult Respiratory Distress Syndrome(ARDS)-Free Survival Through Day 28

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • 7.5% Hypertonic Saline (HS): 66.4% (170/256) versus 66.8% (147/220) on control; risk difference -0.4 percentage points (95% CI -8.9 to 8.1), risk ratio 0.99 (0.87–1.13); unadjusted two-proportion z-test p = 0.924.
  • 0.9% Normal Saline: 65.4% (246/376) versus 66.8% (147/220) on control; risk difference -1.4 percentage points (95% CI -9.3 to 6.5), risk ratio 0.98 (0.87–1.10); unadjusted two-proportion z-test p = 0.729.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 7.5% Hypertonic Saline (HS) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 0.9% Normal Saline and the control. The interval gives the range of effects that remain compatible with the data.

Worst Multiple Organ Dysfunction Score (MODS) Mean Through Day 28

• 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:
  • 7.5% Hypertonic Saline (HS): mean 9.30 versus 8.70 on control; difference 0.60 (95% CI -1.15 to 2.35), standardized effect d = 0.06; z-test p = 0.501.
  • 0.9% Normal Saline: mean 8.80 versus 8.70 on control; difference 0.10 (95% CI -1.52 to 1.72), standardized effect d = 0.01; z-test p = 0.904.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 7.5% Hypertonic Saline (HS) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 0.9% Normal Saline and the control. The interval gives the range of effects that remain compatible with the data.

Presence of Nosocomial Infection Through Day 28

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • 7.5% Hypertonic Saline (HS): 24.6% (63/256) versus 23.6% (52/220) on control; risk difference 1.0 percentage points (95% CI -6.7 to 8.7), risk ratio 1.04 (0.76–1.43); unadjusted two-proportion z-test p = 0.805.
  • 0.9% Normal Saline: 23.7% (89/376) versus 23.6% (52/220) on control; risk difference 0.0 percentage points (95% CI -7.0 to 7.1), risk ratio 1.00 (0.74–1.35); unadjusted two-proportion z-test p = 0.993.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 7.5% Hypertonic Saline (HS) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 0.9% Normal Saline and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists 21 posted secondary outcomes, spanning respiratory distress syndrome-free survival, organ dysfunction, infection, use of blood products and fluids, ventilation, and time alive outside the ICU or hospital. The detailed numerical results available for ARDS-free survival, MODS, and nosocomial infection show estimates near zero for the pairwise contrasts against HSD, with confidence intervals that include zero. The sponsor’s overall tests for these outcomes are p = 0.94, p = 0.73, and p = 0.8, respectively.

At a broad level, these reported secondary results do not provide a contrasting pattern that overturns the primary survival result. They are supportive context rather than independent confirmation of a specific treatment effect. The registry lists other secondary outcomes, but their numerical results are not reported in the registry record in the outcome details used for these comparisons; no conclusions about their direction or size should be inferred from their titles alone.

Secondary outcomes are often useful for describing other dimensions of illness and care, but interpreting many outcomes creates a multiplicity problem. In general, the more comparisons examined, the greater the chance of finding an apparently unusual result by chance. The registry does not report a correction or prespecified hierarchy for secondary testing. The reported secondary p-values should therefore be treated as unadjusted evidence, not as a collection of independent confirmatory tests. They also do not change the meaning of the primary endpoint or establish the effects of the fluids on outcomes that are not numerically reported.

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

• Adult Respiratory Distress Syndrome(ARDS)-Free Survival Through Day 28
• Worst Multiple Organ Dysfunction Score (MODS) Mean Through Day 28
• Presence of Nosocomial Infection Through Day 28
• Packed Red Blood Cells (PRBC) First 24 Hours
• Total Fluids First 24 Hours
• Ventilator-free Days Through Day 28
• Days Alive Out of the Intensive Care Unit (ICU) Through Day 28
• Days Alive Out of the Hospital Through Day 28

9. Statistical Interpretation

10. Statistical Methods Explained

Statistical methods help separate the observed group summaries from the uncertainty around comparisons. The registry reports counts for the binary primary endpoint, a sponsor-reported overall test, and pairwise recalculations based on the posted summaries. These quantities answer related questions, but they should not be treated as interchangeable.

What does the overall test assess?

The sponsor used a test for proportions across the three primary-outcome groups and reported p = 0.91. In general, an overall test asks whether the outcome proportions differ somewhere among the groups; it does not identify which particular pair differs. The reported p-value is a measure of how compatible the observed group pattern is with the test’s null hypothesis, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference.

The recalculations compare HS with HSD and normal saline with HSD separately. Each reports a risk difference: the difference between the observed outcome proportions in the two groups, expressed on the probability scale. For survival, the estimates are -0.015 for HS versus HSD and -0.003 for normal saline versus HSD. The sign indicates the direction of the contrast as defined in the recalculation. The point estimate is only one part of the result; the interval around it conveys the uncertainty in that estimate.

Why report confidence intervals?

In general, a confidence interval describes a range of values reasonably compatible with the data and the method used to calculate the interval. A narrow interval indicates greater precision than a wide interval. An interval that includes zero for a risk difference means that the data do not distinguish the comparison from no difference at the stated confidence level. It does not prove that the groups are identical. Both primary pairwise intervals include zero and extend to values on either side, so the direction and size of a possible difference remain uncertain.

The recalculated pairwise p-values are unadjusted. In general, testing several outcomes or comparisons increases the chance that at least one result may appear unusual by chance alone. Methods for addressing this issue can include prespecified adjustment strategies, but the registry does not report whether or how such a strategy was used. The sponsor’s reported overall test remains distinct from the separate recalculated pairwise tests.

How do the other outcome types differ?

The registry reports ARDS-free survival and nosocomial infection as binary outcomes, with participant counts by group. Their sponsor analyses use tests for proportions. The MODS outcome is a mean score, with standard deviations reported for each group, and the sponsor used ANOVA. In general, ANOVA compares group means while accounting for within-group variation. A standard deviation describes how spread out individual values are around a group mean; it is not the same as the uncertainty in the mean or a confidence interval for a group difference.

The recalculated MODS pairwise comparisons report mean differences and confidence intervals. The HS versus HSD estimate is 0.6, with a 95% confidence interval from -1.149 to 2.349. The normal-saline versus HSD estimate is 0.1, with a 95% confidence interval from -1.524 to 1.724. Both intervals include zero. The reported overall ANOVA p-value is 0.73; it tests for an overall difference among group means and does not establish which pair, if any, differs.

What does the analysis population mean?

The primary outcome analysis was per protocol, limited to participants whose study fluid was connected to the patient’s IV in accordance with randomization. In general, an intention-to-treat analysis retains participants in their assigned groups regardless of treatment receipt, preserving the randomized assignment as the basis of comparison. A per-protocol analysis instead focuses on participants meeting a protocol-defined treatment condition. The registry does not report whether an intention-to-treat analysis was also performed or how missing primary-outcome data were handled.

Randomization can help balance prognostic factors between groups at assignment, while masking can reduce some forms of bias in care and assessment. The registry identifies the study as randomized and quadruple masked, but does not describe the masking procedures or the people covered by that term. General statistical interpretation should therefore distinguish the design labels from details that are not reported in the registry record.

11. Confidence Intervals and Precision

Precision concerns how tightly the data locate an estimated comparison. For the primary outcome, the HS-versus-HSD risk difference is -0.015, with a 95% confidence interval from -0.094 to 0.064. For normal saline versus HSD, the risk difference is -0.003, with a 95% confidence interval from -0.076 to 0.069. Both intervals include zero, so neither pairwise recalculation provides a clear direction of difference at the stated confidence level.

The intervals also show why a point estimate near zero should not be read as proof of equivalence. The range of values compatible with the data extends on both sides of zero. In general, a confidence interval is a measure of statistical uncertainty under the calculation method; it is not a guarantee that the true value lies within the particular interval. The registry does not report an equivalence or noninferiority margin, so these comparisons cannot be interpreted as formal evidence that the fluids are equivalent or noninferior.

The primary comparison is based on 220 participants in HSD, 256 in HS, and 376 in normal saline. The unequal group sizes and the outcome counts contribute to the precision of the estimates. The registry does not provide a confidence interval for the sponsor’s overall three-group test. The pairwise intervals are recalculations from the posted summaries, while the sponsor reports the overall test for proportions.

Precision is different from statistical significance and from clinical importance. A p-value summarizes compatibility with a null model, while a confidence interval communicates a range of plausible effect sizes under the method. Neither alone establishes whether a difference matters clinically. The registry does not report a threshold for a clinically important survival difference. Accordingly, the estimates should be read as uncertain comparisons, not as proof of no effect or proof of a meaningful benefit or harm.

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 sample-size illustrations are planning calculations based on the observed effects, not the trial’s original design assumptions. For these binary outcomes, the figures are participants per arm. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The calculation considers detecting the stated fraction of the observed effect. The original trial’s sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions, if that effect were the true effect. The 90% power column gives the corresponding number for a 90% chance. Power is a design property calculated under a specified effect and model; it is not a measure of how likely the observed result is to be true.

Rows describing planning for 100% of the observed effect use the full observed effect as the target. Rows describing planning for 75% or 50% of the observed effect use smaller target effects. Smaller effects are harder to distinguish from random variation, so they require more participants per arm under the same assumptions. The figures can therefore rise substantially as the target effect gets smaller, especially when the observed effect is close to zero.

These calculations are hypothetical planning illustrations based on the posted effect estimates. They are not observed power, and they do not establish that the trial was adequately or inadequately designed. Because the observed effect is itself uncertain, planning directly from it can produce unstable estimates, particularly when it is small. The illustrations should be read as conditional: if the stated effect and assumptions held, the calculated enrollment would be associated with the specified power.

13. How the Sample Size Is Derived

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

Formula

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

Worked calculation for this trial

1. Control proportion p₀ = 0.745; treatment proportion p₁ = 0.730; average p̄ = 0.738.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6219 = 1.2189.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6218 = 0.5233.
4. n = (1.2189 + 0.5233)² / (-0.0150)² = 13,515.7, rounded up to 13,516 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 <- 0.745454545454545                          # control proportion
p1 <- 0.73046875                          # 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(316017)
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 = 13,516 (80% power), 18,094 (90% power)
 75% of observed effect: n per arm = 23,918 (80% power), 32,019 (90% power)
 50% of observed effect: n per arm = 53,564 (80% power), 71,707 (90% power)
power.prop.test: 13515.7 
Simulated power at n = 13,516 per arm: 0.803 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The sponsor’s posted primary analysis is a test for proportions across HSD, HS, and normal saline, with p = 0.91. The pairwise estimates and intervals are recalculations from the posted counts and denominators; they compare HS with HSD and normal saline with HSD separately. The overall analysis and pairwise recalculations are not identical tests, so their p-values need not match.

The recalculated primary risk differences are -0.015 for HS versus HSD and -0.003 for normal saline versus HSD. Their respective 95% confidence intervals are -0.094 to 0.064 and -0.076 to 0.069. Both include zero. The recalculation is unadjusted and does not replace the sponsor’s own analysis. Because there is no discrepancy flagged between the posted values and recalculations, both can be described, while the sponsor’s reported overall result remains the trial’s own analysis.

The sponsor’s analysis method is reported, but the registry does not provide further details about model specification, covariate adjustment, handling of missing data, or any multiplicity procedure. Those details should not be inferred from the overall p-value or from the recalculated pairwise comparisons.

15. Multiplicity, Missing Data and Analysis Populations

The registry reports one primary outcome and many secondary outcomes. It lists 22 outcome measures and 21 posted secondary outcomes. The sponsor’s primary analysis is an overall test across three groups; secondary analyses include tests for proportions and ANOVA. However, the statistical plan describing how the primary and secondary tests were ordered or interpreted is not reported in the registry record.

Multiplicity arises when several hypotheses are tested. In general, repeated testing increases the chance that one or more results may appear statistically notable even when there is no underlying effect. A prespecified approach can control or otherwise address this issue, but the registry does not report whether a family-wise error adjustment, false-discovery approach, hierarchical testing plan, or another strategy was used. The recalculated pairwise comparisons are explicitly unadjusted and should not be treated as multiplicity-controlled confirmatory results.

The registry states that the primary analysis used a per-protocol population: participants had to receive the randomized study fluid, defined as the fluid being connected to the patient’s IV. How many randomized participants were excluded from this outcome population, and the reasons for any exclusions, are not reported in the registry record. Whether an intention-to-treat analysis was conducted is also not reported.

Handling of missing outcome data, including any imputation, censoring, or sensitivity analyses, is not reported in the registry record. The registry also does not describe interim analyses, stopping boundaries, or the detailed statistical analysis plan. The study status is terminated, but the reason for termination is not reported. These absences limit assessment of whether the analyses were fully prespecified and how robust the results are to alternative population or missing-data choices. They do not by themselves show that a particular method was or was not used.

16. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: increased intracranial hemorrrhage (5.5%), hypernatremia that did not required therapeutic intervention (3.2%), hypernatremia that required therapeutic intervention (2.0%).

The registry’s adverse-event figures list serious adverse events affecting 21 of 220 participants in the HSD group, 25 of 256 in the HS group, and 21 of 376 in the normal-saline group. The non-serious adverse-event figures list one affected participant in each group, with the same group denominators. These are descriptive counts; the registry record does not provide comparative statistical analyses for these figures.

The listed leading serious adverse-event terms are increased intracranial hemorrrhage at 5.5%, hypernatremia that did not required therapeutic intervention at 3.2%, and hypernatremia that required therapeutic intervention at 2.0%. The registry does not identify the group-specific denominators for these term percentages in the adverse-event listing. Death counts in that listing are null, so deaths by adverse-event group are not reported in the registry record.

These summaries should be read as reported safety counts and terms, not as evidence that a fluid caused or prevented an event. The record does not provide enough information in this listing to compare event severity, timing, attribution, or risk statistically across groups.

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

The posted primary data describe survival through 28 days among participants in the per-protocol analysis population. The sponsor’s overall test for proportions across the three randomized groups is p = 0.91. Pairwise recalculations against HSD yield risk differences near zero, and both 95% confidence intervals include zero and extend in both directions. The results therefore do not identify a clear difference in survival among the compared groups, while also leaving uncertainty about the size and direction of possible differences.

This is not the same as demonstrating that the fluids have identical effects. A failure to distinguish groups statistically does not prove equivalence. Formal equivalence or noninferiority conclusions require an appropriate prespecified margin and analysis; such a margin is not reported in the registry record. The confidence intervals also do not reduce the uncertainty to a narrow range around zero.

The interpretation applies to the defined per-protocol population and to the registered survival follow-up. The registry does not report whether an intention-to-treat result was also obtained, how missing outcomes were handled, or the reasons the study was terminated. These omissions restrict what can be concluded about other analysis populations and about the conduct of the trial’s full statistical plan.

The secondary outcomes provide additional context, but their results should not be treated as a substitute for the primary endpoint or as a set of definitive independent tests. Several outcomes were considered, and the registry does not report a multiplicity strategy. Nor do the adverse-event counts establish causal effects or fully characterize safety differences. In general, statistical results describe patterns and uncertainty in the analyzed data; they do not alone determine clinical importance or guide individual care.

18. Why This Trial Matters Statistically

This trial is statistically informative because it compares three resuscitation fluids in a randomized, masked, parallel-group design and reports a survival outcome with explicit group counts and analysis denominators. The trial also makes clear that the primary result was based on a per-protocol population defined by connection of the assigned study fluid to the patient’s IV. That detail is essential for understanding which participants contribute to the reported comparison.

The contrast between an overall three-group test and pairwise estimates illustrates why statistical summaries should be read together. The sponsor’s p = 0.91 addresses an overall comparison, while the recalculated risk differences and confidence intervals describe specific contrasts with HSD. The intervals show the range of uncertainty that a p-value alone cannot convey. They support a cautious reading: the posted data do not resolve a clear difference, but they do not demonstrate equivalence.

The record also highlights the limits of registered summaries. It reports the study status as terminated but not the reason, and it does not report the original sample-size justification, missing-data procedures, or multiplicity plan. These are not minor technicalities: they shape how confidently readers can evaluate prespecification, precision, and the robustness of conclusions.

Finally, planning calculations based on observed effects can help illustrate the enrollment needed to target effects of different sizes, but they do not reconstruct the trial’s actual design rationale. Keeping those planning illustrations separate from observed results and original design assumptions is important for sound statistical interpretation.

19. 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.

Several limitations specific to this record affect interpretation. First, the primary analysis was per protocol and required the randomized fluid to be connected to the patient’s IV. The registry does not report the number or characteristics of participants who did not meet this definition, whether an intention-to-treat analysis was performed, or how exclusions affected the group comparisons.

Second, the registry reports enrollment of 895, but the primary outcome denominators are 220, 256, and 376. The reason the outcome denominators do not account for all enrolled participants is not reported in the registry record. Missing primary-outcome data and their handling are also not described. The results should therefore be understood using the posted analysis population rather than assumed to cover every enrolled participant.

Third, the study is listed as terminated, but the reason for termination and any relationship to enrollment, safety, or efficacy are not reported. Interim analyses and stopping rules are not reported either. It would be inappropriate to infer why termination occurred or what role any interim findings may have played.

Fourth, the registry does not report the original sample-size justification, detailed analysis plan, covariate adjustment, or multiplicity strategy. The planning illustrations based on observed effects are not substitutes for those missing protocol details. Finally, the registry gives summary adverse-event counts and selected serious event terms, but does not report enough detail to establish event attribution or compare event risks using a stated statistical method.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Hypertonic Resuscitation Following Traumatic Injury — NCT00316017.
• Registry record last updated 2011-03-01; status last verified 2011-02.
• Results first posted 2010-11-11.
• 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.

23. Record Summary

NCT00316017 is a phase 3 randomized, quadruple-masked, parallel-group study of HSD, HS, and 0.9% normal saline for traumatic injury with hypovolemic shock. The registry reports enrollment of 895, a start date of 2006-05, primary completion in 2009-08, and terminated status. The reason for termination is not reported in the registry record.

The primary outcome was survival through 28 days from Emergency Department arrival, analyzed per protocol among participants whose randomized study fluid was connected to the patient’s IV. The sponsor reported an overall test for proportions with p = 0.91. Pairwise recalculations against HSD have confidence intervals that include zero. The registry lists 21 posted secondary outcomes, but does not report the original sample-size justification, missing-data procedures, or multiplicity plan.