Dopamine Versus Norepinephrine for the Treatment of Vasopressor Dependent Septic Shock: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dopamine Versus Norepinephrine for the Treatment of Vasopressor Dependent Septic Shock (NCT00604019), a randomized phase 3 study. The primary outcome is Efficacy and Safety of Dopamine Versus Norepinephrine in Septic Shock.

2. Clinical Question

The registry describes a prospective, randomized, controlled trial in septic shock. Its primary outcome is mortality from any cause by 28 days, rather than a measure limited to a particular cause of death. The posted group counts record 67 participants with the event among 134 assigned to dopamine, and 51 among 118 assigned to norepinephrine.

The clinical question is therefore a comparison between two vasopressor strategies in the context of other care, not a comparison of either drug with no treatment. The summary mentions fluid resuscitation, early antibiotics, source control, and evaluation for drotrecogin alpha where considered appropriate as elements of standard care. The registry does not provide further details about how these co-interventions were applied or whether their use differed between groups. The reported comparison should be read as applying to the trial's randomized groups and care context, rather than as a claim about every patient with septic shock or every possible treatment setting.

3. Trial Design

The registry identifies this as a phase 3, randomized, parallel-group trial with no masking. The two intervention groups were dopamine and norepinephrine, each administered by infusion for hypotension. Enrollment is listed as 252. The posted outcome counts are 134 participants in the dopamine group and 118 in the norepinephrine group. The record gives the study start as 2003-03, primary completion as 2009-08, and status as completed.

The brief summary describes a prospective controlled trial. Participants were described as having suspected or documented infection and meeting 2 out of the three SIRS criteria, with septic shock requiring vasopressor support. The record also says participants received standard-of-care management, including fluid resuscitation, appropriate and early antibiotics, source control, and evaluation for drotrecogin alpha where deemed appropriate. These descriptions provide the broad clinical setting, but the registry record does not report a fuller eligibility list, recruitment procedures, or the detailed treatment protocol.

Randomization supports a comparison of assigned groups, while the parallel design means participants were assigned to one group rather than crossing between interventions. The record does not report the randomization method, allocation concealment procedures, or any stratification factors. Masking is listed as none; further information about who knew each assignment is not reported in the registry record. It also does not report treatment adherence, crossover, or the handling of participants who did not continue their assigned infusion.

The registry lists two outcome measures and one secondary outcome concerning whether arrhythmia occurred in each group. The primary outcome is 28-day all-cause mortality. Although the record is marked completed, details about the trial's original statistical design and analysis procedures are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Efficacy and Safety of Dopamine Versus Norepinephrine in Septic Shock, measured over 28 days.

The primary outcome is the number of randomized participants who died from any cause within 28 days. All-cause mortality counts deaths regardless of their attributed cause, so the outcome does not depend on assigning a specific cause of death. The registry describes the measure as 28-day mortality among randomized patients with septic shock managed under a vasopressor protocol containing either dopamine or norepinephrine.

Mortality is a binary outcome for each participant: the event is either recorded within the stated period or it is not. The posted results give event counts and group sizes: 67 of 134 in the dopamine group and 51 of 118 in the norepinephrine group. The outcome title mentions efficacy and safety, but the description specifically defines the primary measure as 28-day all-cause mortality. Arrhythmia is listed separately as a secondary outcome.

Using a fixed follow-up period makes the comparison about whether death occurred within 28 days, not about the timing of death within that period. A time-to-event outcome would retain information about when an event occurred; the registry's posted primary measure is instead expressed as a number of participants with the event. The record does not report how follow-up was conducted, whether vital status was available for every randomized participant, or the rules used for any missing outcome information. Those details matter when judging how completely the endpoint was ascertained.

7. Results Posted in the Registry

• Norepinephrine: 43.2% (51/118) versus 50.0% (67/134) on control; risk difference -6.8 percentage points (95% CI -19.1 to 5.5), risk ratio 0.86 (0.66–1.13); unadjusted two-proportion z-test p = 0.282.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: each participant either had a recorded death from any cause by 28 days or did not. For a binary outcome, an event proportion describes the share of participants in a group who experienced the event. The posted data report event counts and denominators for both randomized groups. The comparison is summarized using a risk difference, a risk ratio, and an odds ratio. These are different ways of expressing an association between group assignment and the event.

What does the risk difference describe?

A risk difference subtracts one group's event proportion from the other group's event proportion. The registry defines the comparison as norepinephrine relative to dopamine. A negative estimate therefore points toward a lower observed event proportion in the norepinephrine group in this comparison. The confidence interval for the reported risk difference includes zero, the value corresponding to no difference between the group proportions. Its inclusion of zero signals that the data do not pin down the direction of the difference with precision.

How do relative measures differ?

A risk ratio compares the two event proportions as a ratio. A value at its null point represents equal event proportions. An odds ratio compares event odds rather than event proportions; its null point also represents no group association. The posted confidence intervals for both relative measures include their null values. Risk differences, risk ratios, and odds ratios use different scales and can be useful for different interpretive purposes, but they all derive from the same event counts. They are not three independent replications of the result.

The registry lists an unadjusted p-value of 0.282. A p-value describes how incompatible the observed data are with a specified null model under the assumptions of the test; it is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of an effect. The test details and the trial's prespecified analysis plan are not reported in the registry record. The p-value should therefore be read alongside the estimate and its confidence interval, not by itself.

What does an unadjusted analysis leave out?

An unadjusted comparison uses the group outcomes without statistical adjustment for other measured characteristics. The record does not report a model adjusting for baseline variables or other factors. Random assignment is intended to create groups whose differences are not systematically determined by treatment assignment, but chance imbalances can occur. With no posted adjusted analysis or baseline comparison details, the registry results do not show whether adjustment would change the estimate.

Over-dispersion is a concern mainly for outcomes modeled as counts or rates, when observed variability exceeds what a chosen model assumes. General statistical principle: accounting for over-dispersion can prevent uncertainty from being understated in such models. The primary outcome is posted as participants with a binary event, not as a count rate. The record does not describe a model for over-dispersion, and no such procedure should be assumed.

Similarly, the record does not report time-to-event estimates, such as a hazard ratio. The primary endpoint is a count of participants who died within the stated 28-day period. A time-to-event analysis would use information about the timing of events and potentially account for differing follow-up, but the registry record does not say whether such an analysis was conducted. The posted comparison should not be recast as a time-to-event result.

When interpreting any randomized comparison, the population included in the analysis matters. An intention-to-treat analysis generally retains participants in their randomized groups, while other analysis populations may follow different rules. General statistical principle: excluding participants after randomization can affect comparability if exclusions are related to assignment or outcomes. The record does not state which analysis population was used, how participants who deviated from treatment were handled, or how missing endpoint data were treated. No particular analysis population can therefore be attributed to this result.

The registry lists zero analyses. That does not establish that no analysis was conducted; it means the record does not post analysis entries in the information summarized. No statistical test specification, covariate plan, interim analysis, or multiplicity procedure is reported in the registry record. Consequently, the reported unadjusted comparison can be described, but it cannot be fully matched to a prespecified statistical plan using the registry information alone.

10. Confidence Intervals and Precision

A confidence interval expresses uncertainty around an estimated effect. In general, it identifies a range of effect values compatible with the data and the method used to construct the interval; it is not a guarantee that the true effect lies within that particular interval. Its width conveys precision: wider intervals leave more possible values unresolved.

For the reported risk difference comparing norepinephrine with dopamine, the interval includes zero. Zero is the null value for a difference, so the interval does not rule out no difference. The interval also extends to both sides of zero, leaving room for effects in either direction. This is why the point estimate alone should not be read as a settled conclusion about which group had the lower underlying event proportion.

The relative-effect intervals also include their respective null values. For a ratio measure, the null is equality between groups. The shared message across the posted measures is that the estimates are not precise enough to exclude no association. The unadjusted p-value of 0.282 is consistent with that uncertainty, but it does not replace the intervals or describe the full range of plausible effects.

Precision depends on the amount of information available and on outcome variability. The posted event counts and group sizes are the information underlying the comparison, but the registry does not report a planned precision target, the original sample-size justification, or the confidence-interval method. The trial's own design assumptions are not reported in the registry record. Thus, the displayed uncertainty can be interpreted as the uncertainty associated with the posted comparison, while its relationship to the trial's original planning goals remains unknown.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations calculated from the observed effect, rather than the trial's original design calculation. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial's own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design that would have an 80% probability of detecting the specified effect under the stated assumptions, if that effect were the true effect and the assumptions held. The 90% power column uses a higher probability of detection under those same conditions. These are planning concepts, not guarantees about what a future study will find. The figures are not observed power: observed power is not an interpretation of the trial's result.

Rows using 100% of the observed effect use the full point estimate as the hypothetical effect to detect. Rows using 75% or 50% of the observed effect assume smaller effects. The posted illustrations require more participants per arm as the assumed effect becomes smaller. This reflects a general design principle: smaller differences are harder to distinguish from random variation and usually require more information for the same target power.

The 80% and 90% columns are not a description of the completed trial's probability of success. They are planning scenarios based on the observed estimate, which itself is uncertain. Because the confidence interval includes no difference, treating the point estimate as a known effect would be especially fragile. The illustrations should therefore be read as conditional planning aids, not as proof that the completed study was adequately or inadequately sized. The original protocol rationale and design assumptions are not reported in the registry record.

12. How the Sample Size Is Derived

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

Formula

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

Worked calculation for this trial

1. Control proportion p₀ = 0.500; treatment proportion p₁ = 0.432; average p̄ = 0.466.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7055 = 1.3827.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.7038 = 0.5924.
4. n = (1.3827 + 0.5924)² / (-0.0678)² = 848.7, rounded up to 849 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 <- 0.5                          # control proportion
p1 <- 0.432203389830508                          # 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(604019)
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 = 849 (80% power), 1,136 (90% power)
 75% of observed effect: n per arm = 1,513 (80% power), 2,025 (90% power)
 50% of observed effect: n per arm = 3,411 (80% power), 4,565 (90% power)
power.prop.test: 848.7 
Simulated power at n = 849 per arm: 0.797 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary mortality outcome and one secondary outcome concerning whether arrhythmia occurred in each group. The secondary outcome is named, but no results are posted for it. The record does not provide a complete outcome hierarchy, specify whether other outcomes were planned, or say how multiple comparisons were handled. A multiplicity adjustment or other error-control strategy is not reported in the registry record.

Multiplicity matters when several outcomes, time points, subgroups, or statistical tests are examined. General statistical principle: as the number of opportunities to find an apparently unusual result increases, interpretation can become more difficult unless the analyses and error-control approach are clearly specified. No adjustment should be assumed for this trial, and the posted unadjusted p-value should not be treated as if a multiplicity procedure had been applied.

Missing-data handling is also not described. The record does not state whether every randomized participant had mortality status ascertained at 28 days, how any unavailable outcome was handled, or whether follow-up differed by group. The posted denominators give the group sizes used for the reported counts, but do not by themselves explain completeness of follow-up or the analysis population.

The record does not identify an intention-to-treat, per-protocol, or other analysis population. Nor does it report how treatment discontinuation, crossover, or protocol deviations were addressed. These omissions limit assessment of whether the analysis preserved the randomized comparison and whether exclusions could have influenced the result. No interim analyses, stopping boundaries, or monitoring procedures are reported in the registry record. The available record supports description of the posted unadjusted outcome comparison, but not a full audit of multiplicity, missingness, or analysis-population decisions.

14. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

The posted adverse-event summary lists 134 participants at risk in the dopamine group and 118 in the norepinephrine group. For both groups, the serious adverse-event field records 0 affected participants, and the other adverse-event field also records 0 affected participants. No serious adverse-event terms are listed. These are the entries in the registry's adverse-event summary and should be read as such, rather than as proof that no adverse events of any kind occurred.

The registry does not provide further definitions of the serious and other adverse-event categories, event ascertainment procedures, or information about completeness of reporting. Death counts within this adverse-event summary are not reported in the record. Mortality is reported separately as the primary endpoint, with 67 events among 134 participants in the dopamine group and 51 among 118 in the norepinephrine group.

Arrhythmia is named as a secondary safety outcome, but its group results are not posted. The absence of affected participants in the adverse-event fields should not be substituted for those missing arrhythmia results. Nor do the safety entries establish comparative safety; the available information is limited to the recorded counts and lacks detail about definitions and reporting procedures.

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

The posted primary outcome counts are 67 of 134 participants in the dopamine group and 51 of 118 in the norepinephrine group. The unadjusted comparison estimates a lower event proportion in the norepinephrine group, but the confidence interval includes no difference and extends in both directions. The unadjusted p-value is 0.282. The result therefore leaves substantial uncertainty about the size and direction of any underlying difference.

These findings do not establish that one vasopressor is superior, and they do not establish that the groups are equivalent. A failure to rule out no difference is not evidence that all clinically relevant differences have been excluded. The confidence interval is essential to interpretation because it conveys uncertainty that a single point estimate cannot. No numerical clinical-importance threshold is reported in the registry record, so the posted data cannot be assessed against a stated threshold for an important difference.

The comparison concerns participants enrolled in this trial and the care context described in the registry. The summary includes standard-care measures such as fluid resuscitation, early antibiotics, and source control alongside vasopressor support. The results do not directly answer questions about other populations, treatment regimens, or settings that are not described in the record. The registry also does not report enough detail about adherence, missing outcomes, or analysis populations to determine how those factors may affect interpretation.

The secondary arrhythmia outcome has no posted group results. The adverse-event summary records zero affected participants in its serious and other event fields, but reporting detail is limited and mortality appears separately as the primary outcome. Taken together, the record supports a cautious account of an imprecise mortality comparison, not a broad conclusion about all aspects of efficacy or safety.

16. Why This Trial Matters Statistically

This trial illustrates why an event count, a point estimate, and an uncertainty interval answer different questions. The counts describe what was recorded in each randomized group. The risk difference summarizes the direction and size of the group contrast on an absolute scale, while relative measures express the comparison on ratio scales. The confidence intervals show that the apparent direction is not determined precisely by the posted data.

The result also demonstrates the distinction between lack of clear evidence for a difference and evidence of equivalence. The interval includes the null value, but it also permits effects on either side. Without a prespecified equivalence margin or a sufficiently precise interval that excludes differences considered important, equivalence cannot be concluded. The registry does not report an equivalence framework.

The planning illustrations underline how sample-size needs depend on the effect a future study aims to detect. Smaller assumed effects require more participants per arm under the listed assumptions. Because those illustrations are based on the observed effect and the observed estimate is uncertain, they should inform planning cautiously rather than be treated as a definitive target.

Finally, the record shows the limits of registry reporting for statistical appraisal. It identifies the randomized design, groups, endpoint, and unadjusted comparison, but does not report the detailed analysis plan, handling of missing data, analysis population, or multiplicity procedures. Those omissions matter because the interpretation of an estimate depends not only on its numerical value but also on how participants and outcomes were handled. A precise description of what is posted, alongside a clear account of what remains unreported, is central to responsible interpretation.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry entry provides only a limited account of the trial methods. Although it identifies a randomized design and no masking, it does not report how the random sequence was generated, how assignments were concealed, or who knew group assignments. The detailed inclusion and exclusion criteria are not reported in the registry record; the summary gives only the broad description of suspected or documented infection and 2 out of the three SIRS criteria.

The record does not describe the vasopressor dosing protocol, treatment targets, treatment duration, crossover, or adherence. It also does not report how standard-care co-interventions were delivered across groups. Because these details are unavailable, the registry record alone cannot establish how consistently the interventions or background care were applied.

For the primary outcome, the registry does not specify outcome ascertainment procedures, missing-outcome handling, or the analysis population. It does not post an adjusted analysis or a detailed statistical plan. The listed secondary arrhythmia outcome has no group results, and the adverse-event summary has limited definitions and reporting detail. No interim analyses or multiplicity procedures are reported in the registry record.

The record lists enrollment as 252 and gives group outcome denominators of 134 and 118. It does not explain any difference between the overall enrollment figure and the group counts. The study is marked completed, but the posted information does not provide a full account of participant flow or follow-up. These limitations do not change the posted comparison, but they constrain how confidently its conduct, completeness, and broader applicability can be assessed.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Dopamine Versus Norepinephrine for the Treatment of Vasopressor Dependent Septic Shock — NCT00604019.
• Registry record last updated 2023-01-11; status last verified 2022-12.
• Results first posted 2012-12-07.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

NCT00604019 is a completed phase 3, randomized, unmasked, parallel-group trial sponsored by Rush University Medical Center. It compares dopamine with norepinephrine, each given as an infusion for hypotension, in septic shock. The registry lists enrollment of 252, a study start of 2003-03, and primary completion of 2009-08.

The primary outcome is 28-day all-cause mortality. The posted counts are 67 events among 134 participants in the dopamine group and 51 among 118 in the norepinephrine group. The unadjusted p-value is 0.282, and the reported risk-difference confidence interval includes zero. The registry also lists arrhythmia as a secondary outcome but does not post its results. Detailed statistical planning, missing-data procedures, and analysis-population definitions are not reported in the registry record.