Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis (NCT00464204), a randomized phase 3 study. The primary outcome is Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization.

2. Clinical Question

The trial’s broader rationale connected fluid resuscitation with hemodynamics and the tolerability of enteral nutrition. The registry description notes that the timing and quantity of enteral calories may relate to morbidity and mortality, but the primary endpoint itself is the amount of study fluid required to meet the stabilization definition. It therefore addresses a specific resuscitation measure rather than every aspect of the study’s broader clinical question.

The stabilization criterion combined normalization of mean arterial pressure with at least two of three other measures: central venous pressure, urine output, and central venous oxygen saturation. The specified normalization had to be maintained for four hours under conditions that also limited changes in vasopressor or ionotropic therapy and additional study drug administration. This operational definition makes the endpoint more specific than a single measurement, while also meaning that conclusions apply to this particular definition and population.

3. Trial Design

The registry identifies this as a phase 3, randomized, parallel-group study with quadruple masking. It compared Voluven® with 0.9 % NaCl in patients with severe sepsis. Recorded enrollment was 196. The study status is completed; its recorded start was 2007-07 and primary completion was 2010-05. The sponsor was Fresenius Kabi.

The primary endpoint was analyzed as a continuous measure: mean volume of study drug, in milliliters, required to achieve initial hemodynamic stabilization. The posted group summaries include 88 participants in the Voluven® arm and 86 in the NaCl arm. The endpoint’s stated analysis population was the full analysis set, defined as all randomized patients treated with study drug who reached hemodynamic stabilization. This definition does not include every randomized patient by definition; reaching stabilization is part of the stated inclusion criterion.

Random allocation supports a planned comparison between treatment groups, while masking is intended generally to limit knowledge of assignment from influencing trial conduct or assessment. The registry record does not report the method used to generate or conceal the allocation sequence, which roles were masked, or how masking was maintained. It also does not report the original statistical analysis plan, the trial’s original sample-size assumptions, or whether any interim efficacy analyses were conducted. Those details should not be inferred from the design labels.

The registry summary says a Data Monitoring Committee would review safety data regularly. That statement describes planned safety monitoring; it does not establish that an interim efficacy analysis was performed or specify decision rules. The registry record lists secondary outcomes concerning time to stabilization, fluid use over four days, timing and quantity of enteral nutrition, and lengths of stay. The posted primary result should be interpreted as an endpoint-specific comparison, not as a summary of all those outcomes.

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: Participants were screened in intensive care units of the participating study sites in France and Germany.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.

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 Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization, measured over until hemodynamic stabilization (up to 48 hours).

The primary endpoint is the amount of study drug, measured in milliliters, used until initial hemodynamic stabilization, with the assessment period extending up to 48 hours. The posted summary expresses this as a mean and standard deviation for each arm. The endpoint is useful for describing the volume of fluid associated with reaching a prespecified stabilization state under the trial’s definition.

That definition requires normalization of mean arterial pressure and normalization of at least two among central venous pressure, urine output, and central venous oxygen saturation. The normalization must persist for four hours, with no increase in vasopressor or ionotropic therapy and no more than 1 L of additional study drug during that interval. In general, combining several criteria can make a clinical endpoint more structured than relying on a single observation. It also makes the result specific to the selected criteria and their implementation.

The endpoint is not itself a measure of survival, organ failure, nutrition tolerance, or length of stay. A difference in mean fluid volume cannot establish a difference in those other outcomes. The population definition also matters: the reported primary analysis includes randomized patients treated with study drug who reached stabilization. The registry record does not report how patients who did not reach stabilization were handled in other analyses or whether any additional sensitivity analyses were performed.

7. Results Posted in the Registry

• NaCl 0.9 % Arm: mean 1,709 versus 1,379 on control; difference 330.00 (95% CI 22.12 to 637.88), standardized effect d = 0.32; z-test p = 0.036.

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.

Time From Start of Fluid Resuscitation With Study Drug to the Initial Hemodynamic Stabilization

• 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:
  • NaCl 0.9 % Arm: mean 14.30 versus 11.80 on control; difference 2.50 (95% CI -0.66 to 5.66), standardized effect d = 0.24; z-test p = 0.120.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between NaCl 0.9 % Arm and the control. The interval gives the range of effects that remain compatible with the data.

Quantity of Study Drug in 4 Days

• 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:
  • NaCl 0.9 % Arm: mean 2,788 versus 2,615 on control; difference 173.00 (95% CI -319.60 to 665.60), standardized effect d = 0.10; z-test p = 0.491.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between NaCl 0.9 % Arm and the control. The interval gives the range of effects that remain compatible with the data.

Time From Start of Study Drug to Start of Enteral Nutrition in the Subgroup of Patients Who Received Enteral Nutrition

• 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:
  • NaCl 0.9 % Arm: mean 26.90 versus 24.60 on control; difference 2.30 (95% CI -9.18 to 13.78), standardized effect d = 0.07; z-test p = 0.695.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between NaCl 0.9 % Arm and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover related but distinct parts of the study: the time to initial hemodynamic stabilization, study-drug quantity over four days, timing of enteral nutrition among patients who received it, and measures of enteral calories and length of stay. These outcomes extend the clinical description beyond the primary fluid-volume measure, but they do not all measure the same construct or use the same analysis population.

Across the secondary comparisons with posted group summaries, the point estimates generally favor lower values in the Voluven® group for time to stabilization, total study-drug quantity over four days, and time to enteral nutrition. The corresponding unadjusted intervals include zero and the unadjusted p-values are not small by conventional thresholds. Those results are compatible with a range of differences, including little or no difference; they do not establish equivalence or prove that groups are the same.

These secondary estimates are related to the primary result because they describe resuscitation timing, fluid exposure, and nutrition timing. They are not direct replications of the primary endpoint: each has its own measurement, timeframe, and sometimes a selected subgroup. In particular, the enteral-nutrition timing outcome is reported for the subgroup who received enteral nutrition. Conditioning on a post-randomization event can change the makeup of the groups being compared, so the interpretation is not automatically the same as for an analysis of all randomized participants.

Unadjusted secondary comparisons carry less weight when many outcomes are examined because repeated testing increases the chance that some apparent differences arise by chance. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes. The overall pattern is therefore best treated as exploratory context around the primary result, rather than as a set of independent confirmations. The registry record lists additional secondary outcomes for which results are not included in the posted summaries described in the record; missing results should not be inferred from the outcomes that do have summaries.

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

• Time From Start of Fluid Resuscitation With Study Drug to the Initial Hemodynamic Stabilization
• Quantity of Study Drug in 4 Days
• Time From Start of Study Drug to Start of Enteral Nutrition in the Subgroup of Patients Who Received Enteral Nutrition
• Time From Start of Fluid Resuscitation With Study Drug to Start of Enteral Nutrition After Hemodynamic Stabilization
• Total Amount of Enteral Calories During the First Seven Days of Enteral Nutrition
• Length of Stay in the Intensive Care Unit (ICU)
• Length of Stay in the ICU
• Length of Stay in the Hospital

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant’s endpoint is a volume, and the group summaries report a mean and standard deviation. A mean describes the arithmetic average within a group; a standard deviation describes the spread of individual observations around that average. The standard deviation is not the uncertainty in the group mean. Uncertainty in a mean depends both on the observed variability and on the number of observations contributing to that summary.

What does the mean difference represent?

The recalculated comparison expresses the NaCl group mean minus the Voluven® group mean. A positive estimate therefore means that the posted mean volume was higher in the NaCl group. The estimate of 330.0 milliliters describes the difference between the two observed group means under this unadjusted calculation. It is not a difference for every participant, and it does not imply that each person in one group required more fluid than each person in the other.

An unadjusted comparison uses the posted group summaries without adjustment for other participant characteristics. That makes the calculation transparent, but it does not reproduce any covariate-adjusted analysis that may have been conducted separately. The registry record does not report covariates used in an adjusted primary analysis. It also does not report a detailed statistical analysis plan, so the recalculation should be understood as a simple summary-based comparison rather than as a reconstruction of every trial analysis decision.

How should the confidence interval be read?

A confidence interval gives a range of values compatible with the observed data under the method used to calculate it. For the recalculated primary difference, the 95% interval is 22.12 to 637.9 milliliters. In general, a narrower interval indicates greater precision, while a wider interval indicates more uncertainty about the magnitude. The interval does not assign a probability to the true effect after the data have been observed. Its interpretation depends on the assumptions of the procedure used to construct it.

The primary interval lies on the positive side of zero for the stated direction, NaCl minus Voluven®. This is consistent with the unadjusted p-value of 0.036 for a test of no mean difference under the recalculation. A p-value measures how incompatible the observed data are with a specified null model, assuming the model and test conditions apply. It is not the probability that there is no difference and does not assess whether the estimated volume difference is important in clinical practice.

Why do the sponsor’s statistics look different?

The sponsor’s reported result gives a mean difference of -331, a 95% confidence interval from -640 to -21, and a one-sided p-value of 0.018. The sign is reversed because the group order is reversed relative to the recalculated NaCl-minus-Voluven® contrast. The estimates are similar in direction and approximate size, but one analysis is explicitly one-sided and the recalculation is an unadjusted comparison. The registry record does not report enough methodological detail to attribute every difference in the inferential results to a particular choice.

A one-sided test evaluates evidence in a specified direction, whereas a two-sided test allows departures in either direction. In general, the direction and sidedness should be prespecified to avoid choosing a favorable test after observing the data. The registry record’s reported analysis identifies a one-sided t-test, but does not report the original protocol rationale or the complete analysis plan. The recalculated p-value should not be substituted for the sponsor’s result as though the analyses were identical.

What do the assumptions mean?

A t-test compares group means using an estimate of variability and the information available in each group. In general, the usual interpretation depends on how well the model represents the data and on the design and analysis population. The registry provides means, standard deviations, and group sizes for this endpoint, but not the participant-level distribution. It is therefore not possible to inspect skewness, outliers, or the influence of individual observations from the summary statistics alone.

Fluid volume can, in general, have a distribution with a long upper tail, and unusual observations may affect a mean and standard deviation. That is a general consideration, not a claim about the distribution in this trial. The registry record does not report a distributional assessment, robust analysis, transformation, or nonparametric sensitivity analysis for the primary endpoint. Nor does it report how missing endpoint values were handled beyond defining the full analysis set as treated randomized patients who reached stabilization.

Randomization is intended to balance prognostic factors across groups on average, but it does not guarantee that every characteristic is identical. Masking can limit some sources of bias, but the registry record’s quadruple-masking label does not specify which people were masked. The endpoint’s use of a defined stabilization rule supports consistent interpretation, although the judgment and measurement processes used to assess its components are not described in the reported record.

The observed data and the recalculated test answer a narrow question: whether the posted group means differ under a simple unadjusted comparison. They do not by themselves verify all assumptions, resolve concerns about unreported data handling, or establish effects on the trial’s secondary or broader clinical outcomes. Statistical significance, interval width, endpoint definition, analysis population, and study context all contribute to a measured interpretation.

11. Confidence Intervals and Precision

The recalculated primary mean difference is 330.0 milliliters, with a 95% confidence interval from 22.12 to 637.9 milliliters. The interval is entirely above zero for the stated contrast, NaCl minus Voluven®, but it is wide enough to leave considerable uncertainty about the magnitude. The lower end is close to zero relative to the range of values covered, while the upper end allows a substantially larger difference. The point estimate should therefore not be read as a precise prediction of the difference that would necessarily occur in another study.

Precision is distinct from statistical significance. A confidence interval that excludes zero can coexist with uncertainty about whether the effect is small or large in practical terms. The interval describes sampling uncertainty under its calculation method; it does not account for every possible source of bias, such as unreported missing-data handling or limitations in outcome measurement. The registry record does not report the original sample-size justification or a detailed plan for interval estimation.

Group variability is substantial in relation to the mean values: the reported standard deviations were 886.0 milliliters for Voluven® and 1164.0 milliliters for NaCl. Standard deviations describe variation among observations, not the confidence interval for the mean difference. The posted analysis includes 88 participants in one arm and 86 in the other for the primary outcome, but the stated analysis population conditions on treatment and reaching stabilization.

The sponsor’s reported interval, -640 to -21, is expressed using the opposite contrast direction and accompanies a one-sided test. Reversing the contrast direction aligns its direction with the recalculation, but the two inferential summaries should still be distinguished because their analysis details are not fully reported in the registry record.

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 figures are illustrations based on the observed effect, not the trial’s original design calculation. For these continuous outcomes, the listed figures are participants per arm, not total participants. The stated 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 the stated fraction of the observed effect. The registry record does not report the trial’s original design assumptions.

The 80% power column gives the illustrative number of participants per arm under those assumptions for an analysis to have an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column uses a higher target chance of detection and therefore requires more participants for the same assumed effect. Power is conditional on the assumed effect and statistical model; it is not a guarantee that a future trial will detect an effect.

Rows that plan for 75% or 50% of the observed effect assume a smaller difference than the observed estimate. Smaller effects are harder to distinguish from random variation, so the planning figures increase as the target effect gets smaller. These numbers are not observed power: they are planning illustrations computed from the observed effect, not a measure of the probability that this completed trial detected a real effect.

The figures should not be interpreted as evidence that the original study was designed around the observed difference. They also do not establish that an effect of a particular size is clinically important. The illustration depends on the assumptions and does not incorporate unreported design features, adjustment choices, attrition, or the trial’s original justification.

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 = 330.000; pooled standard deviation σ = 1032.779.
2. n = 2 × (1.96 + 0.842)² × 1032.779² / 330.000² = 153.8, rounded up to 154 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 <- 330                      # observed difference in means
sigma <- 1032.7790799135                     # 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(464204)
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 = 154 (80% power), 206 (90% power)
 75% of observed effect: n per arm = 274 (80% power), 366 (90% power)
 50% of observed effect: n per arm = 616 (80% power), 824 (90% power)
power.t.test: 154.7 
Simulated power at n = 154 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. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis is a one-sided t-test. It gives a mean difference of -331, a 95% confidence interval from -640 to -21, and a p-value of 0.018. The group order in that analysis is Voluven® followed by NaCl, so its negative estimate corresponds in direction to the recalculated contrast written as NaCl minus Voluven®, which is positive.

The recalculated unadjusted result is a mean difference of 330.0 milliliters, a 95% confidence interval from 22.12 to 637.9 milliliters, and an unadjusted p-value of 0.036. The estimates are close in magnitude, but the p-values and intervals are not identical. The sponsor’s analysis is identified as one-sided, while the planning illustration assumes a two-sided significance level of 0.05. The registry record does not give enough detail to establish the full reasons for the differences or to reproduce the sponsor’s analysis exactly.

The discrepancy flag is false. The sponsor’s result remains the trial’s reported analysis, and the recalculation is a simple unadjusted comparison from posted summary statistics, not a replacement for the sponsor’s analysis. The registry record does not report additional details about adjustment, missing-data methods, or the prespecified rationale for test direction.

15. Multiplicity, Missing Data and Analysis Populations

The registry record lists multiple secondary outcomes spanning hemodynamic stabilization, fluid volume, enteral nutrition, and length of stay. Examining several outcomes creates a multiplicity issue: even if no underlying differences exist, repeated statistical tests can produce some small p-values by chance. In general, a prespecified hierarchy, adjustment procedure, or clear designation of exploratory outcomes helps readers understand how to interpret results across multiple tests. The registry record does not report whether such a procedure was used.

The primary comparison has a reported sponsor analysis and a separate unadjusted recalculation. The record identifies the sponsor’s test as one-sided, but does not report the original protocol rationale for that direction or the complete analysis plan. It also does not report whether the primary endpoint was adjusted for other variables, whether interim efficacy analyses were conducted, or whether any stopping boundaries were used. The statement that a Data Monitoring Committee would regularly review safety data does not establish that efficacy testing occurred at interim reviews.

Missing-data methods are not reported in the registry record. The primary population is defined as randomized patients treated with study drug who reached hemodynamic stabilization. That definition clarifies who contributes to the endpoint analysis, but it does not explain the disposition of randomized patients who were untreated, did not reach stabilization, or otherwise lacked an endpoint value. The registry record does not describe imputation, exclusions beyond the stated population definition, or sensitivity analyses for missing outcomes.

Analysis populations matter because randomization applies at assignment, whereas the stated primary population also requires treatment and reaching stabilization. In general, exclusions or conditioning after randomization can affect the comparability created by random assignment. The available information does not establish whether the sponsor conducted other population-based analyses or what they showed.

These omissions limit the ability to assess the robustness of the posted estimates, not merely their statistical significance. The full protocol, analysis plan, participant disposition, and outcome-level missingness are not reported in the registry record. Conclusions should therefore stay anchored to the defined endpoint population and the analysis details that are actually stated.

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: haemodilution (9.4%), septic shock (9.0%), multi-organ failure (7.0%), cardiac arrest (6.2%), condition aggravated (4.0%).

The registry reports serious adverse events among 100 participants at risk in the Voluven® arm, with 53 affected, and among 96 participants at risk in the NaCl arm, with 44 affected. For other adverse events, it reports 100 at risk and 99 affected in the Voluven® arm, and 96 at risk and 95 affected in the NaCl arm. These are the registry’s recorded counts; they should be read with their stated at-risk groups rather than treated as a direct comparison of severity or causation.

The listed serious-event terms include Haemodilution at 9.4%, Septic shock at 9.0%, Multi-organ failure at 7.0%, Cardiac arrest at 6.2%, Condition aggravated at 4.0%, and Pneumonia at 4.0%. The registry record does not provide enough detail to determine whether a listed event was judged related to study drug, how events were defined for this summary, or whether participants could contribute to more than one event term. Deaths are not reported in the registry record.

Adverse-event counts describe events recorded during the study and do not, by themselves, establish that treatment caused an event. Differences in counts should not be interpreted as a safety advantage or disadvantage without fuller context, including follow-up, event definitions, severity, and attribution.

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

The posted primary data show a higher mean volume of study drug required to reach initial hemodynamic stabilization in the NaCl group than in the Voluven® group. The recalculated mean difference is 330.0 milliliters for NaCl minus Voluven®, with a 95% confidence interval from 22.12 to 637.9 milliliters. The sponsor’s reported analysis points in the same direction when its opposite group ordering is taken into account.

This finding concerns a defined continuous endpoint in the stated analysis population. It does not establish that one fluid is better for patients overall, that one treatment changes survival or organ failure, or that the measured difference improves enteral nutrition tolerance. Those are separate clinical questions. Nor does a difference in average fluid volume imply a uniform difference for individual participants.

The confidence interval indicates uncertainty about the size of the average difference, and the registry record does not provide the original protocol, complete statistical analysis plan, or missing-data methods needed to assess every analytic decision. The endpoint population is restricted to randomized patients treated with study drug who reached stabilization. As a result, the estimate should not automatically be generalized to all randomized patients or to every patient with severe sepsis.

The secondary outcomes add context, but the registry record does not report a multiplicity procedure, and the secondary comparisons are not independent confirmations of the primary finding. Safety counts also require cautious interpretation: the listed events are not proof of treatment causation, and deaths are not reported in the registry record. Overall, the posted results support a limited statistical statement about mean fluid volume under a specified definition; they do not settle broader questions of clinical benefit, harm, or treatment choice.

18. Why This Trial Matters Statistically

This trial illustrates why an endpoint’s operational definition is central to interpretation. “Hemodynamic stabilization” is not a single measurement in the registry record; it combines mean arterial pressure with additional physiologic criteria and requires sustained normalization under specified treatment conditions. A difference in fluid volume therefore refers to a defined clinical process, not to an abstract quantity independent of how stabilization was assessed.

It also illustrates the distinction between an estimated effect and its precision. The primary comparison has a positive recalculated mean difference and an interval that excludes zero, but the interval still spans a broad range of plausible magnitudes. A p-value alone would conceal that uncertainty. Reading the estimate, interval, endpoint definition, and analysis population together gives a more complete statistical interpretation.

The sponsor analysis and the unadjusted recalculation use different contrast directions and report different inferential details. Recognizing the sign convention prevents a reversed sign from being mistaken for a disagreement in direction. At the same time, similar point estimates do not make different analysis methods interchangeable. The registry record’s limited methodological detail is important when assessing how fully the sponsor result can be reproduced.

Finally, the secondary outcomes show why multiplicity and population definition matter in clinical research. Several outcomes explore connected but nonidentical questions, and at least one is restricted to participants who received enteral nutrition. Without a reported multiplicity strategy and full missing-data information, secondary findings should be treated as supporting context rather than decisive evidence. These are general statistical lessons illustrated by the information recorded for this trial.

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.

The registry record does not report the full protocol or the original sample-size justification, so it is not possible to determine the design assumptions that guided enrollment. The planning illustrations based on the observed effect do not fill that gap. The complete statistical analysis plan, rationale for the sponsor’s one-sided test, and any covariate-adjusted primary analysis are also not reported.

The primary analysis population is defined by treatment and reaching hemodynamic stabilization. The registry record does not describe the outcomes or disposition of randomized patients who did not meet that definition, nor does it report missing-data methods or sensitivity analyses. This limits assessment of how the endpoint population relates to the randomized population as a whole.

Only summary statistics are available for the primary comparison. Without participant-level data or reported distribution checks, the shape of the volume distribution, influence of extreme observations, and robustness of the mean-based analysis cannot be assessed. The registry record does not report whether alternative analyses were performed.

The sponsor’s analysis is reported as a one-sided t-test, but details needed to reproduce it are not reported in the registry record. The unadjusted recalculation is based on group summaries and should not be mistaken for a reproduction of an undocumented analysis plan. The registry record also does not report a multiplicity procedure for the secondary outcomes, complete results for all listed outcomes, or sufficient detail to interpret adverse-event attribution and overlap. These limitations qualify the scope and certainty of interpretation; they do not establish that any unreported analysis would change the findings.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis — NCT00464204.
• Registry record last updated 2012-01-11; status last verified 2011-08.
• Results first posted 2011-08-02.
• 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

This completed phase 3 trial randomized patients with severe sepsis to Voluven® or 0.9 % NaCl in a parallel-group, quadruple-masked design. Recorded enrollment was 196. The primary outcome was the mean amount of study drug required to achieve initial hemodynamic stabilization, measured in milliliters until stabilization, up to 48 hours.

The posted means were 1379.0 milliliters for Voluven® and 1709.0 milliliters for NaCl. The recalculated unadjusted difference, NaCl minus Voluven®, was 330.0 milliliters (95% confidence interval 22.12 to 637.9; p = 0.036). The sponsor reported a mean difference of -331 in the opposite group order, with a 95% confidence interval from -640 to -21 and a one-sided p-value of 0.018.

Interpretation is limited to the stated endpoint and analysis population. The registry record does not report the original design assumptions, complete analysis plan, or missing-data methods. Secondary comparisons and safety counts add context but do not independently establish broader clinical effects or causation.