Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass (NCT02151877), a randomized na study. The primary outcome is Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op).

2. Clinical Question

The study also describes goals concerning platelet activation, postoperative bleeding and transfusion requirements, organ dysfunction, mortality, and morbidity. These are stated as research aims, not as demonstrated effects. Secondary outcomes listed in the registry record include total fluid balance at 48 hours, time until diuretic therapy starts, inotropic score on day 1, and length of intubation and PSHU stay. The record does not provide numerical results for these outcomes in the registry record for this analysis.

3. Trial Design

This was a randomized, parallel-group pilot study of nitric oxide administration during neonatal cardiopulmonary bypass. The registry record identifies the masking as triple, but does not specify which groups of people were masked or describe how masking was maintained. It records 24 participants enrolled. The intervention and control groups each have 12 participants at risk in the adverse-event record; additional detail about allocation procedures is not reported in the registry record.

The intervention was inhaled nitric oxide delivered through the CPB circuit during cardiac surgery. The control group is described as not receiving inhaled nitric oxide into the circuit. Although placebo appears in the intervention list, how it was used is not reported in the registry record. The trial status is completed. The record gives a study start of 2014-07 and a primary completion date of 2018-08-15. The phase is listed as NA.

The primary endpoint concerns change in biochemical markers of ischemia/reperfusion injury and oxidative damage, with pre-operative baseline and follow-up measurements up to 12 hours after surgery. The endpoint description lists several biomarkers rather than defining one primary marker or one combined outcome. Secondary outcomes cover fluid balance, diuretic timing, inotropic score, and time receiving intubation and PSHU care.

The record labels the primary endpoint population as intent to treat. It does not report the randomization sequence, allocation concealment, the identities of those masked, or detailed eligibility criteria. Further protocol details, including the planned statistical tests and handling of missing measurements, are not reported in the registry record. The study is described as a pilot; a formal sample-size justification is 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

Analysis population for the primary outcome, as defined in the registry: Intent to treat (ITT)

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 Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op), measured over Pre-op baseline and up to 12 hours after surgery.

The primary endpoint is described as change in biochemical markers of ischemia/reperfusion injury and oxidative damage. The planned marker set includes cardiac troponin I, interleukins, tumor necrosis factor, N-terminal prohormone for brain natriuretic peptide (NT-proBNP), lactate dehydrogenase (LDH), plasma antioxidant levels, and plasma malondialdehyde (MDA) levels. The stated unit is ng/ml, the summary measure is the mean, and dispersion is described using the standard deviation. The record characterizes a positive change as an increase from pre-operative measurement.

These biomarkers are used as measurable indicators of biological processes that may accompany injury and inflammation. In general, repeated measurements can describe how marker levels change over time, while a comparison between randomized groups can assess whether their observed patterns differ. A marker is an indirect measure: it does not, on its own, establish a change in a patient's clinical condition.

The stated timeframe runs from pre-operative baseline to up to 12 hours after surgery. Because the endpoint includes several markers, the registry description does not identify one result as the definitive primary comparison. Numerical changes, between-group estimates, and uncertainty intervals for the markers are not reported in the registry record. The direction label also matters: an increase is defined as positive, but the record's description alone does not indicate whether any observed increase or decrease favored either group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a randomized, parallel-group design with triple masking. In a parallel-group trial, participants are assigned to one study group and remain in that group for the comparisons. Random assignment is intended, in general, to reduce systematic differences between groups at the start of a study. The record does not describe the sequence-generation method, concealment of allocation, or the people covered by triple masking, so these implementation details cannot be assessed.

What does a mean and standard deviation convey?

The primary endpoint is described using means and standard deviations. In general, a mean summarizes the average observed measurement in a group, while a standard deviation describes the spread of individual measurements around that average. The mean can be useful for continuous biomarker data, but a group average does not show the full distribution or indicate whether all participants changed in the same direction. The registry record does not state how each marker's change score was calculated or whether the analysis compared follow-up values, changes from baseline, or both.

How should a confidence interval be read?

In general, a confidence interval expresses the precision of an estimated effect and shows a range of values compatible with the data under the statistical procedure used. A narrow interval indicates greater precision than a wide interval. The interval must be interpreted with its estimate, outcome scale, and analysis in view; it is not a guarantee that the true value lies within its limits. No confidence intervals for the primary biomarker results are reported in the registry record, so the precision of those comparisons cannot be evaluated.

What can a p-value tell a reader?

In general, a p-value measures how unusual the observed data, or data more extreme, would be under a specified null model and its assumptions. It does not measure the size or clinical importance of an effect, and it does not give the probability that the null hypothesis is true. A p-value is most informative when reported alongside an effect estimate and a measure of uncertainty. The statistical tests and p-values for the primary endpoints are not reported in the registry record.

Why does the biomarker set matter for analysis?

The primary endpoint description names multiple biomarkers, each potentially measured at multiple times. These outcomes may have different distributions, scales, and biological interpretations. Examining several results creates a multiplicity issue: in general, the more comparisons considered, the greater the chance that some may appear unusual by chance if each is judged separately. A prespecified hierarchy, adjustment procedure, or clear distinction between confirmatory and exploratory outcomes can help readers interpret such analyses. Those details are not reported in the registry record, and no single marker is identified as the sole primary comparison in the available description.

Biomarker measurements may also be correlated. In general, correlation means results for different markers or time points are not independent. An analysis that accounts for repeated measurements can differ from one that treats each measurement separately. The registry record does not state whether a repeated-measures model, baseline adjustment, or another approach was used. It also does not provide sufficient numerical results to reproduce or check the analysis.

What is over-dispersion, and why can it matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model understates the variability, standard errors and uncertainty intervals may be too small, making results appear more precise than they are. This issue can arise in some outcome models, but the registry record does not identify the primary analysis model or provide enough data to assess whether over-dispersion is relevant to these endpoints.

The registry identifies the primary endpoint population as intent to treat (ITT). In general, ITT analysis compares participants according to their randomized assignment, regardless of later adherence, and can preserve the benefits of randomization. However, the record does not report how many participants were included in each primary biomarker analysis, whether all randomized participants were retained in the analysis, or how missing measurements were handled. The ITT label alone does not answer those questions.

The sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. These are planning illustrations, not the trial's design justification and not observed power. The registry record does not report the trial's own sample-size justification. Any planning estimate based on an observed effect is conditional on that effect estimate and its uncertainty; it should not be interpreted as a guarantee that a future study will detect an effect.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint description encompasses multiple biochemical markers, and the record also lists secondary outcomes. When several outcomes or time points are examined, multiplicity is relevant because separate statistical tests can increase the chance of at least one apparently notable result arising by chance. In general, investigators can address this with a prespecified primary outcome, an adjustment for multiple comparisons, or a transparent exploratory interpretation. Whether any such strategy was planned or applied is not reported in the registry record. The description does not identify one marker as the sole primary comparison.

The registry labels the primary endpoint population as intent to treat. That label generally means participants are analyzed according to randomized assignment, which can preserve the randomized comparison. It does not establish that every randomized participant had an observed biomarker measurement or was included in every analysis. The number analyzed for each marker and time point is not reported in the registry record.

Missing-data methods are not reported in the registry record. It does not state whether missing measurements occurred, whether any were excluded, or whether imputation or sensitivity analyses were used. These details matter because missingness can affect both the amount of information available and the interpretation of group comparisons, especially when measurements are planned at multiple times.

Interim analyses, stopping rules, a prespecified statistical analysis plan, and the handling of protocol deviations are not reported in the registry record. Without these details, readers cannot assess whether the reported analysis plan was fixed before outcomes were examined. The available information also does not include marker-specific results or uncertainty estimates with which to evaluate the primary analysis.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event record lists 12 participants at risk in each group. It reports 0 serious adverse events in the nitric oxide group and 0 in the control group. For other adverse events, it reports 2 affected participants in the nitric oxide group and 1 in the control group. Deaths are listed as 0 in each group.

These figures are counts, not estimates of a treatment effect. They do not indicate whether an event was judged related to nitric oxide, how severe the other events were, when they occurred, or whether any participant experienced more than one event. Such details are not reported in the registry record. The absence of reported serious events in these groups should be interpreted as a description of this study's recorded experience, not as proof that serious events cannot occur or that the groups have equivalent safety.

The record does not provide a detailed adverse-event definition, ascertainment schedule, or statistical comparison. In general, safety interpretation depends on how events were defined and collected, the number of participants observed, and the completeness of reporting. The listed counts alone cannot establish a comparative safety profile.

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

The registry record describes a randomized pilot study that evaluated nitric oxide delivered through the cardiopulmonary bypass circuit during surgery for complex congenital heart defects in neonates. Its primary aim was to examine biochemical markers of ischemia/reperfusion injury and oxidative damage, with measurements beginning at pre-operative baseline and extending up to 12 hours after surgery. The record also lists secondary outcomes and broader goals concerning bleeding, transfusion, organ dysfunction, mortality, and morbidity.

The registry entries do not include numerical primary outcome results. There are no reported marker-specific group summaries, treatment contrasts, confidence intervals, or p-values to establish the direction, size, or precision of any biomarker difference. The study aims should therefore not be presented as evidence that nitric oxide reduced injury or improved clinical outcomes. Likewise, the lack of numerical findings does not establish that there was no effect.

The listed adverse-event counts provide limited descriptive information: no serious adverse events or deaths are listed in either group, while other adverse events are recorded for participants in both groups. The record does not provide event descriptions or causal assessments, and the counts alone cannot show whether treatment caused or prevented events.

In general, biochemical markers can help characterize biological responses, but they are not interchangeable with clinical outcomes. A change in a marker does not by itself demonstrate a change in postoperative morbidity, organ function, or survival. The registry's goals concerning these outcomes are questions the study sought to address, not conclusions established by the information.

The appropriate reading is therefore limited: the record identifies a randomized pilot design, a multi-marker primary endpoint, secondary outcomes, and a small set of adverse-event counts. It does not provide enough primary outcome information to quantify or interpret a treatment effect. Further analysis would require marker-specific results, participant counts for each analysis, uncertainty estimates, and the statistical methods used.

13. Why This Trial Matters Statistically

This study raises statistical issues common in clinical research that uses multiple biomarkers and repeated measurements. The primary endpoint description includes several markers, while the measurement window extends from pre-operative baseline to up to 12 hours after surgery. That structure makes it important to know which marker and comparison were designated as primary, how repeated measurements were modeled, and whether multiplicity was addressed. Those analysis details are not reported in the registry record.

The trial is described as a pilot study and records 24 participants enrolled. Pilot studies can be useful for evaluating study procedures and generating information for later research. In general, estimates from a small study may be uncertain, and a lack of a clearly reported effect estimate prevents readers from judging precision. The registry record does not report a formal sample-size justification, so its enrollment should not be interpreted as evidence that the study was designed to give a definitive test of every listed outcome.

The endpoint also illustrates the distinction between a biological measure and a clinical outcome. Biomarkers may offer information about physiological processes, while bleeding, organ dysfunction, and postoperative course concern clinical events or care. A complete statistical interpretation would need to keep those outcome types distinct and avoid treating a marker change as proof of clinical benefit.

Finally, transparent reporting of analysis populations, missing measurements, and uncertainty is essential to assessing randomized comparisons. The record specifies an ITT population for the primary endpoint but does not describe the number analyzed, missing-data handling, or detailed analysis methods. These omissions leave important questions about the evidence's precision and robustness unresolved.

14. 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 main limitation for interpreting the trial is that numerical primary biomarker results are not reported in the registry record. The primary endpoint covers several markers, but the available description does not identify a single marker-level comparison as the primary result. Without estimates and uncertainty intervals, readers cannot assess effect direction, magnitude, or precision.

The registry record does not report detailed methods for randomization or allocation concealment, or identify who was masked under the triple-masking description. It also does not describe how the control procedure related to the listed placebo intervention. These omissions prevent a detailed assessment of implementation and masking.

Although the primary endpoint population is labeled ITT, the number of participants contributing to each marker and measurement time is not reported. Missing-data handling, exclusions, protocol deviations, and the statistical model are also not reported in the registry record. The record does not describe whether repeated measures or baseline values were accounted for in the analysis.

The endpoint includes multiple biomarkers, and the record also lists secondary outcomes. A multiplicity strategy and the distinction between confirmatory and exploratory analyses are not reported. The registry gives no primary outcome estimates for the secondary outcomes, either. Therefore, the study aims involving bleeding, transfusion, organ dysfunction, mortality, and morbidity cannot be evaluated from these registry entries.

Safety reporting is limited to counts. Event descriptions, severity and timing details, causal attribution, and the method of adverse-event collection are not reported in the registry record. The sample-size justification and interim-analysis plans are also not reported. Together, these gaps limit assessment of the statistical strength, completeness, and clinical interpretation of the trial record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass — NCT02151877.
• Registry record last updated 2024-10-08; status last verified 2024-10.
• Results first posted 2020-04-03.
• 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.

18. Record Summary

The registry record describes a completed randomized, triple-masked, parallel-group pilot study of nitric oxide administered through the cardiopulmonary bypass circuit during neonatal cardiac surgery. It records 24 participants enrolled. The primary endpoint concerns changes in several biochemical markers from pre-operative baseline to up to 12 hours after surgery, and the stated primary analysis population is ITT.

The record lists secondary outcomes concerning fluid balance, diuretic therapy, inotropic score, and time receiving intubation and PSHU care. The numerical primary outcome findings and detailed statistical methods are not reported in the registry record. The adverse-event record lists no serious adverse events or deaths in either group, and other adverse events affecting 2 participants in the nitric oxide group and 1 participant in the control group.