Trials in adult critical care that show increased mortality of the new intervention: Inevitable or preventable mishaps?

Abstract

Several promising therapies assessed in the adult critically ill in large, multicenter randomized controlled trials (RCTs) were associated with significantly increased mortality in the intervention arms. Our hypothesis was that there would be wide ranges in sponsorship (industry or not), type(s) of intervention(s), use of DSMBs, presence of interim analyses and early stopping rules, absolute risk increase (ARI), and whether or not adequate prior proof-of-principle Phase II studies were done of RCTs that found increased mortality rates of the intervention compared to control groups. We reviewed RCTs that showed a statistically significant increased mortality rate in the intervention compared to control group(s). We recorded source of sponsorship, sample sizes, types of interventions, mortality rates, ARI (as well as odds ratios, relative risks and number needed to harm), whether there were pre-specified interim analyses and early stopping rules, and whether or not there were prior proof-of-principle (also known as Phase II) RCTs. Ten RCTs (four industry sponsored) of many interventions (high oxygen delivery, diaspirin cross-linked hemoglobin, growth hormone, methylprednisolone, hetastarch, high-frequency oscillation ventilation, intensive insulin, NOS inhibition, and beta-2 adrenergic agonist, TNF-α receptor) included 19,126 patients and were associated with wide ranges of intervention versus control group mortality rates (25.7–59 %, mean 29.9 vs 17–49 %, mean 25 %, respectively) yielding ARIs of 2.6–29 % (mean 5 %). All but two RCTs had pre-specified interim analyses, and seven RCTs were stopped early. All RCTs were preceded by published proof-of-principle RCT(s), two by the same group. Seven interventions (except diaspirin cross-linked hemoglobin and the NOS inhibitor) were available for use clinically at the time of the pivotal RCT. Common, clinically available interventions used in the critically ill were associated with increased mortality in large, pivotal RCTs even though safety was often addressed by interim analyses and early stopping rules.

Research progress of viral sepsis: etiology, pathophysiology, diagnosis, and treatment

“…Corticosteroids are recommended only when septic shock cannot be corrected with adequate fluid resuscitation and vasopressors. [98] Antibodies against IL-6 have become effective drugs for the treatment of COVID-19. Tocilizumab, an IL-6 receptor antagonist, reduces the risk of progression to severe ARDS.…”

The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy

“…The researches of immunomodulatory therapy in sepsis have been going on for decades, and countless anti-inflammatory and immune-enhanced drugs have been tried, but the vast majority have become passers-by, so far no one obtained solid support by enough evidences and to be unanimously accepted by clinicians. 32 , 33 In the surviving sepsis campaign guidelines, immunotherapy is really in a blank state, 34 including its latest version of the anti-COVID-19 guideline. 35 In China, there is also no specific item of immunomodulatory therapy in the COVID-19 diagnosis and treatment protocol (trial version 7) released by the National Health Commission (NHC).…”

“…Once the hypotension was corrected, corticosteroid was required to discontinue. 33 A meta-analysis published in 2018 also concluded that though the duration of shock, mechanical ventilation and intensive care unit (ICU) stay are reduced, the short- and longer-term mortality are unaffected and adverse events increased regarding septic shock treated with low dose corticosteroids. 40 More impressive, a survey of more than 1.5 million out-of-hospital users of prednisone showed that even in short-term (5–7 days) and with low-dose (17.5–20 mg/d) of oral prednisone, the incidence rate of fractures, venous thrombosis and sepsis were still very high.…”

Outcomes following surgery: are we measuring what really matters?

“…Randomised controlled trials often use objective measures which, although they may correlate with patient benefit and are easier to analyse statistically, ultimately do not matter to patients. Indeed, there are several examples in critical care where targeting objective measures has led to increased harm . From the orthopaedic literature, where the vast majority of work related to PROMs has been carried out, there is evidence that, although subjective measures do not always correlate with objective measures, patient satisfaction does .…”