Methylene Blue vs Cyanokit for Intraoperative Vasoplegic Syndrome in Liver Transplant Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Methylene Blue vs Cyanokit for Intraoperative Vasoplegic Syndrome in Liver Transplant Patients (NCT04054999), a randomized phase 4 study. The primary outcome is Systemic Vascular Resistance (SVR).

2. Clinical Question

3. Trial Design

This was a Phase 4 randomized, parallel-group trial sponsored by Mayo Clinic. The registry record gives the study status as completed and enrollment as 19. It lists a start date of 2019-11-30 and a primary completion date of 2023-02-27. These record details describe the trial’s registration and conduct, but do not establish how many participants contributed to each outcome analysis.

The two arms received different single-dose treatments during liver transplantation. The Cyanokit arm received hydroxocobalamin as a 5g intravenous infusion over 15 minutes. The Methylene Blue arm received methylene blue at 2 mg/kg by intravenous bolus over 15 minutes. The registry describes the study as randomized and non-masked, with a parallel model. It does not report the allocation ratio or further details about sequence generation or concealment.

The primary outcome was SVR measured at 15, 30, 60, 90 and 120 minutes after treatment initiation. The registry specifies the median and full range as the intended summary. The number of participants with measurements differs across time points: some participants had completed surgery and were no longer in the surgical room by later measurement times. It also states that data were not collected or analyzed for one participant in the Methylene Blue arm.

Secondary outcomes listed in the record include post-operative ICU length of stay, hospital length of stay and post-operative complications. The record lists seven outcome measures but no statistical analyses. It does not report how the secondary outcomes were analyzed or provide their results in the registry record for this analysis.

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: Data was not collected nor analyzed at all for one participant in the Methylene Blue arm. The number of participants analyzed at each time point differs due to some participants completing their surgery earlier than others. Those participants were out of the surgical room by those time points and data was not collected nor analyzed.

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 Systemic Vascular Resistance (SVR), measured over 15, 30, 60, 90 and 120 minutes after initiation of treatment.

The primary endpoint is systemic vascular resistance (SVR), reported in dyne*sec/cm^5. The registry defines SVR as resistance to blood flow offered by the systemic vasculature, excluding the pulmonary vasculature. It was scheduled for measurement during surgery at 15, 30, 60, 90 and 120 minutes after treatment began.

SVR is a hemodynamic measure: in general, it characterizes resistance in the systemic circulation. Tracking it at multiple times can describe how that measure changes during the period after treatment begins. The registry’s use of the median and full range would describe the middle observed value and the span of observed values at each time point, rather than only an average.

SVR is a physiological endpoint, not by itself a summary of all clinical outcomes. The registry also lists post-operative ICU length of stay, hospital length of stay and post-operative complications as secondary outcomes, but their results are not reported in the available record. The primary SVR results, including the medians and ranges by arm and time point, are not reported in the registry record. Consequently, the endpoint’s intended measurement is clear, but its observed values and comparative pattern cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, non-masked, parallel-group design. Randomization is intended, in general, to reduce systematic differences between treatment groups at allocation. A parallel design means participants are assigned to one treatment arm rather than receiving both treatments in sequence. The record does not state the allocation ratio, describe the randomization procedure, or report whether allocation was concealed before assignment. Non-masked means the trial is recorded as having no masking; additional details about who knew treatment assignment are not reported.

What does the median and full range describe?

The primary outcome is specified as a median with full range at each measurement time. In general, the median is the middle value in an ordered set of observations. It can be less influenced by unusually high or low values than the mean. The full range gives the lowest and highest observed values, so it conveys the span of the data but does not show how observations are distributed between those extremes. A range can be sensitive to a single unusually low or high observation, especially when the number of observations is limited.

Those summaries are descriptive. On their own, they do not quantify the uncertainty around a treatment contrast or establish whether a difference is compatible with chance variation. The registry does not report the SVR summaries themselves, a confidence interval, or a test result. It also does not state a model for comparing the arms. Any inferential method beyond the listed descriptive summary is therefore not reported in the registry record.

Why do the measurement times matter?

SVR was scheduled at 15, 30, 60, 90 and 120 minutes after treatment initiation. Measurements from the same participant over time are generally related; they should not automatically be treated as independent observations. In general, an analysis of repeated measurements may account for this within-participant relationship and may assess both differences between arms and changes over time. The registry does not report whether such an analysis was planned or performed, nor does it specify a primary time point among the listed measurements.

The record says the number analyzed differs by time point because some participants completed surgery earlier and were out of the surgical room by later times. This is a reason that measurements may be unavailable at later time points, but it does not establish how the missing measurements were handled statistically. The registry does not state whether the analysis used available measurements, imputation, a model that accommodates incomplete follow-up, or another approach.

What is not established by the planning illustration?

The registry’s planning assumptions describe an illustration based on an observed effect: two-sided significance level 0.05, equal allocation between arms, a normal approximation, and an effect specified as a fraction of the observed effect. For time-to-event tables, the stated quantity is the total number of events; for other planning illustrations, it is participants per arm. These are planning assumptions, not evidence that the trial was designed with those assumptions, and they do not establish the trial’s actual power. The registry does not report the protocol’s sample-size justification or say that these assumptions were used to plan the trial.

In general, a sample-size illustration can show how a hypothetical future study might be sized under stated assumptions. It is not an observed result and is not observed power. The record gives no values for a particular planning scenario in the registry record for this analysis, so no planning count can be described. The observed enrollment is not a sample-size calculation, and no new count can be inferred from it.

How should uncertainty be understood?

In general, a confidence interval describes a range of values compatible with the data and the method used to calculate it. A narrow interval indicates greater precision than a wide interval, though the interval does not by itself determine clinical importance. No confidence intervals are reported for the primary endpoint. The registry also does not report a variance estimate or another uncertainty measure that would support reconstructing an interval from summary data.

Over-dispersion is a general concern when observed variability exceeds what an analysis model assumes. If present, it can make standard errors too small and confidence intervals too narrow unless the analysis accounts for it. The registry does not provide outcome distributions or a fitted model from which over-dispersion could be assessed. It would be speculative to claim that it occurred or to state how it was handled.

Finally, the registry lists seven outcome measures and no analysis entries. It does not specify a statistical analysis plan, explain how multiple outcomes or multiple measurement times were handled, or identify a prespecified analysis population. Those omissions limit assessment of the inferential methods; they do not demonstrate that a particular method was or was not used outside the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is measured at several post-treatment times, and the registry lists seven outcome measures, including secondary outcomes. Examining multiple outcomes or time points can raise a multiplicity issue: in general, the more comparisons made, the greater the chance that at least one result appears notable by chance if each is assessed separately. A prespecified approach can clarify which comparisons are primary and whether any adjustment or hierarchy is used. The registry does not report a multiplicity strategy, a designated primary time point, or a hierarchy among the outcomes.

The registry lists no statistical analyses. It does not report a statistical analysis plan, the tests or models used, how within-participant repeated measurements were handled, or whether analyses were adjusted for any baseline variables. These details are not reported in the registry record; their absence from the record does not establish what may have been done outside it.

Missing measurements are also relevant. The registry states that data were not collected or analyzed for one participant in the Methylene Blue arm. It further explains that the number analyzed at each time point differs because some participants had completed surgery and left the surgical room before later measurements. The record does not give time-specific analysis counts or state whether the primary summaries used all available observations. It does not describe imputation or another method for handling missing outcome data.

The analysis population is not specified. The record does not say whether the primary analysis followed randomized assignment regardless of treatment received, included only participants who received treatment, or used another definition. Without those details and the underlying outcome results, the effect of missing data or analysis-population choices cannot be evaluated.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for both arms. In the Cyanokit arm, 0 of 9 participants at risk had a serious adverse event; in the Methylene Blue arm, 0 of 10 participants at risk had a serious adverse event. These are observed counts in the registry, not proof that serious adverse events cannot occur. With no serious events recorded in these groups, the counts alone do not precisely establish the underlying risk.

For other adverse events, the record reports 1 of 9 participants at risk in the Cyanokit arm and 2 of 10 in the Methylene Blue arm. The record also lists 1 death in each arm. It does not report the cause, timing, relatedness to treatment, or further context for these deaths. The available information therefore does not support attributing them to either study treatment.

These counts are descriptive and should be read separately from the primary SVR endpoint. The registry does not provide a comparative safety analysis, confidence intervals, or detailed event terms for the serious adverse events. The listed counts do not establish that one treatment is safer than the other.

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

The registry record establishes that a randomized, non-masked, parallel-group study compared intraoperative hydroxocobalamin with methylene blue in liver transplant patients with vasoplegic syndrome. It identifies SVR at 15, 30, 60, 90 and 120 minutes after treatment initiation as the primary outcome, and gives the treatment regimens and descriptive summary intended for that endpoint.

It does not report the observed SVR values, arm differences, confidence intervals or p-values. Accordingly, the record does not show whether SVR differed between the arms, how large any difference was, or how precisely it was estimated. The same limitation applies to the listed secondary outcomes: their results are not reported in the registry record for this analysis. The completed status of a trial is not itself a result.

The information also does not establish whether a possible observed difference would be clinically important. Statistical evidence and clinical importance are distinct questions. In general, an estimate’s magnitude and uncertainty must be considered together with the clinical context and the outcome’s relevance. The registry record does not supply an estimate or the context needed to make that assessment.

Nor do the adverse-event counts settle comparative safety. They describe events recorded among participants at risk, but the registry does not provide event attribution or a comparative statistical analysis. In particular, the death counts cannot be interpreted as treatment-caused deaths from the information reported.

The appropriate conclusion is limited: the record documents the study design, treatment procedures, outcome schedule and some safety counts, but does not contain the primary outcome results or a reported statistical analysis. No conclusion about comparative efficacy or safety can be drawn from these registry entries alone.

13. Why This Trial Matters Statistically

This trial raises a useful statistical question because its primary outcome is measured repeatedly during an operation. Multiple measurements can describe how a physiological measure changes over time, but they also create analysis choices: which time point is most important, how repeated observations from the same participant are handled, and how comparisons across times are interpreted. The registry names the times but does not report a model or analysis strategy.

Outcome availability is another important issue. The registry notes that some participants completed surgery and left the surgical room before later measurements, so the number analyzed changes across time. It also reports that data were not collected or analyzed for one participant in the Methylene Blue arm. These details illustrate why enrollment and time-specific analysis counts are not interchangeable. Without the number contributing at each time and the method for handling missing observations, the precision and comparability of time-specific estimates cannot be assessed.

The record’s primary endpoint is a physiological measure, while the listed secondary outcomes concern length of stay and post-operative complications. These outcomes answer different kinds of questions. A change in a physiological measure does not, by itself, establish a change in later clinical outcomes. The registry lists those secondary outcomes but does not report their results.

Finally, the planning assumptions are described as an illustration based on an observed effect, not as the trial’s own design justification. This distinction matters: planning calculations are prospective tools under assumptions, whereas trial results are estimates from observed data. The registry gives no inferential results with which to connect the planning illustration to the treatment comparison. The case therefore demonstrates why a completed-trial record can describe design and measurements while still leaving the central comparative statistical question unanswered.

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 primary limitation for interpreting this trial is that the registry record does not report the primary SVR results. There are no arm-specific medians or full ranges at the specified times, and no treatment contrast, confidence interval or test result. The primary endpoint can therefore be described, but not compared from the information available.

The record gives limited detail about outcome availability. It says one participant in the Methylene Blue arm had no data collected or analyzed, and that analysis counts vary across measurement times because some participants completed surgery earlier. It does not report the number analyzed at each time point, explain the handling of missing values, or identify the analysis population. The reasons stated for time-varying availability do not establish whether the resulting missingness could bias a comparison.

Although the design is described as randomized, non-masked and parallel, further methodological information is not reported in the registry record. This includes the allocation ratio, randomization procedure, concealment details, protocol-based sample-size justification, statistical analysis plan and any analysis of repeated measurements. The registry lists no analysis entries, so the methods used to estimate or test treatment differences cannot be assessed.

The registry identifies secondary outcomes and reports some safety counts, but does not provide secondary outcome results or detailed context for deaths and adverse events. It does not report the relationship of those events to treatment. The sample-size assumptions are described as a planning illustration rather than the trial’s own design, and no scenario-specific planning results are available in the registry record for this analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Methylene Blue vs Cyanokit for Intraoperative Vasoplegic Syndrome in Liver Transplant Patients — NCT04054999.
• Registry record last updated 2024-06-24; status last verified 2024-06.
• Results first posted 2024-06-24.
• 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

NCT04054999 is a completed Phase 4 randomized, non-masked, parallel-group study sponsored by Mayo Clinic. The registry lists 19 enrolled participants and compares a single intraoperative dose of hydroxocobalamin, identified as Cyanokit, with a single intraoperative dose of methylene blue.

The primary outcome is SVR, summarized as median and full range at 15, 30, 60, 90 and 120 minutes after treatment begins. The record notes that one Methylene Blue participant had no data collected or analyzed and that the number analyzed varies by time point because some participants left the surgical room after completing surgery. Secondary outcomes include post-operative ICU length of stay, hospital length of stay and post-operative complications.

The registry does not report the primary outcome results, secondary outcome results, or statistical analyses. It lists 0 serious adverse events among 9 at risk in the Cyanokit arm and among 10 at risk in the Methylene Blue arm, other adverse events in 1 and 2 participants respectively, and 1 death in each arm. The record does not report event attribution.