After any trial result, there is always a possibility that the true effect of an intervention is different to that shown in the sample who were studied. That is the whole rationale behind using statistics, a trial on a small sample will usually be compatible with a wide range of possible effects if the entire population had been treated. Exactly how to express the results of a negative trial is an ongoing debate.

Three simultaneously published trials in JAMA were all negative, that is they all showed no clear benefit of the intervention. The first was a multi-centre randomised trial in adults who are receiving assisted ventilation after a trauma (Albert RK, et al. Sigh Ventilation in Patients With Trauma: The SiVent Randomized Clinical Trial. JAMA. 2023). The intervention group had added sigh breaths, to reduce atelectasis, up to 35 cmH2O every 6 minutes. The primary outcome was ventilator-free days up to 28 days after admission, Which was scored as 0 if the patient died, and up to 28 if they were extubated immediately. The main results are presented thus

“The unadjusted mean difference in ventilator-free days between groups was 1.9 days (95% CI, 0.1 to 3.6) and the prespecified adjusted mean difference was 1.4 days (95% CI, −0.2 to 3.0). For the prespecified secondary outcome, patients randomized to sighs had 28-day mortality of 11.6% (30/259) vs 17.6% (46/261) in those receiving usual care (P = .05)”

The interpretation is that there might indeed be a benefit of sighs, based largely on the 28 day mortality outcome.

“…the addition of sigh breaths did not significantly increase ventilator-free days. Prespecified secondary outcome data suggest that sighs are well-tolerated and may improve clinical outcomes.”

The second trial was in adults with septic shock who were tachycardic (Whitehouse T, et al. Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial. JAMA. 2023); there are some observational data to suggest that such patients benefit from slowing down the catecholamine induced tachycardia with beta-blockade. So they performed this multi-centre RCT of landiolol with the primary outcome of “the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group.” There was no difference in the SOFA scores, but the trial was stopped as the mortality was somewhat increased with the beta-blocker

“The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08)”

Quite a large increase in mortality, in the “wrong” direction, but no “statistically significant” difference. Their interpretation:

landiolol “did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock”

The third report is from the addition of 2 similar RCTs, in patients hospitalised with COVID, of the administration of vitamin C (Lovit-Covid Investigators, et al. Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials. JAMA. 2023). Although previous investigations of Vitamin C use for critically ill patients have shown no benefit and its use has been largely abandoned, there was a SR and meta-analysis with a large number of tiny trials that showed the possibility of reduced mortality for COVID-19. Hence these two trials of intravenous vitamin C, one by the amazing Canadian Critical Care Trials group, the LO-VIT-COVID trial, and the other was the vitamin C arm of the REMAP-CAP trial “Both trials prospectively adopted the same intervention, outcomes, statistical analysis plan, and reporting, but the control groups were different. The LOVIT-COVID trial used a placebo for the control group and the REMAP-CAP trial used no vitamin C for the control group.”

The primary outcome was a composite of organ support–free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from –1 organ support–free days for patients experiencing in-hospital death to 22 organ support–free days for those who survived without needing organ support.

I will reproduce the majority of the results section of the abstract here, I think it is a model of clarity.

Enrollment was terminated after statistical triggers for harm and futility were met.

Among critically ill patients, the median number of organ support–free days was 7 (IQR, −1 to 17 days) for the vitamin C group vs 10 (IQR, −1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support–free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.

To clarify, the word “futility” has a definition in the statistical analysis section of the supplemental data, and has to do with the posterior probability of an advantage of vitamin C with an OR of >1.2 or more (I think), which these trials show is extremely unlikely. The first sentence of the discussion says it well:

In this large, harmonized, multinational randomized clinical trial, vitamin C administered to hospitalized patients with COVID-19 did not improve organ support–free days or hospital survival. On the contrary, there were high posterior probabilities (>90% for organ support–free days and >75% for hospital survival) that vitamin C worsened both outcomes in critically ill patients and those not critically ill.

As you can tell from the way the results are presented, these are Bayesian analyses, which give the probability of the real impact of an intervention, based on the prior probability (in this case, this was considered neutral) and the findings of the trial. Although there is overlap in the results from the 2 groups using traditional analysis, (“not statistically significant”), the Bayesian probabilities show it is unlikely that vitamin C is helpful, and most likely that it is, in fact, harmful.

The 3 trials are therefore reported as “no difference, but might be better than control”, “no difference, but might be worse than control”, and “probably worse, but almost certainly not better than control”. I must say I think that the Bayesian outcome presentation gives a better understanding of the likelihood that outcomes are worse with IV vitamin C. The other trials would have benefited from a posterior calculation of how likely it is that sighs improve survival (looks to be moderately likely, with a low likelihood of harm, I would guess), or how likely it is that beta-blockade is harmful (looks quite likely, and really unlikely to be beneficial). Also interesting is the primary outcomes used for the first trial. Duration of ventilator dependence and death are both part of the outcome, I am unsure how likely eventual survival is in adults who still need ventilation at 28 days after trauma, but you can see from these survival curves that there is almost no-one left intubated and alive by 24 days. This looks to me like a composite outcome that I could buy into, for this population.

Despite them being negative, or null trials, I think they will inform future practice, with sighs probably having a place in routine care of ventilated trauma patients, but not vitamin C for COVID, and especially not beta-blockade for tachycardia in septic shock.

The trial of late hypothermia among infants with HIE who didn’t arrive in time to start prior to 6 hours was also presented with a Bayesian analysis, which showed that, even though there was a null result by regular statistics, hypothermia was likely to be preferable for death or disability, with a posterior probablity of 76% of benefit. Laptook AR, et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017;318(16):1550-60. That sort of analysis can gives us some confidence (an exact degree of confidence) that cooling is beneficial even if started a little after 6 hours.