Editorial
October 9, 2024
Ventilator Weaning Strategies—Managing Interaction Between Randomized Treatments
Steven A. Webb, Lindsay R. Berry, Ary Serpa Neto
JAMA. Published online October 9, 2024. doi:10.1001/jama.2024.19853
Weaning of mechanical ventilation is a critical aspect of care for patients in intensive care units (ICUs). The process of weaning involves the gradual reduction in intensity of ventilatory support sufficient to allow the patient to resume spontaneous breathing. This transition is crucial because prolonged mechanical ventilation can lead to complications that affect survival and the quality of survival.1 Spontaneous breathing trials (SBTs) and screening for readiness to wean are central to this process, but the optimal strategies for these interventions remain uncertain, with significant variations in practice globally.2
Despite the importance of weaning in the management of patients receiving mechanical ventilation, substantial gaps in the evidence base limit guidance for clinical decision-making. The optimal frequency of screening for weaning readiness and the most effective SBT technique are uncertain. It is also uncertain, but plausible, that baseline patient characteristics (such as duration of ventilation, primary cause of respiratory failure, or comorbidities and severity of illness) influence the optimal strategy.
In this issue of JAMA, Burns et al3 present the results of a multicenter, 2 × 2 factorial, randomized clinical trial that aimed to address some of these clinically important gaps. The trial randomized patients to a screening frequency (once-daily vs more frequent screening) and an SBT technique (pressure-supported vs T-piece SBT). The primary outcome was time to successful extubation, which is an outcome that is important to patients, families, clinicians, and hospitals. Conducted across 23 North American ICUs, the study included 797 critically ill adults who were receiving invasive mechanical ventilation for at least 24 hours.
The prespecified primary statistical analysis compared once-daily screening vs more frequent screening and T-piece SBT vs pressure-supported SBT, assuming no interaction between the crossed interventions. The primary analysis did not show a statistically significant difference between the use of either screening frequency or the use of either SBT technique. However, a secondary analysis resulted in a nominally significant interaction effect between screening frequency and SBT technique, and called into question the results of the primary analysis. A subsequent analysis was performed, which is appropriate once an interaction is observed, and suggested that time to extubation was shortest when using the combination of once-daily screening and pressure-supported SBT. There are implications from this trial3 for both the way clinical evidence is generated and clinical practice.
Most trials in clinical medicine undertake an isolated comparison of 2 alternative treatment approaches (ie, nonfactorial comparison). However, most diseases are managed with multiple treatments that are administered in combination. Two treatments that are administered concomitantly may interact, meaning that the effect of one treatment depends on whether the first treatment is given with the second treatment.4,5 An interaction occurs if the effect of a combination of 2 treatments is not equal to the sum of the individual effects of those treatments. Interactions can be negative or positive. A negative (or antagonistic) interaction occurs when the effect of the combination of 2 treatments is less than the sum of the individual effects. A positive (or synergistic) interaction occurs when the effect of the combination of 2 treatments is more than the sum of the individual effects. If there is no interaction, the combination is said to be additive. When an interaction occurs, the optimal treatment regimen depends on the main effects of each treatment as well as the direction and magnitude of the interaction effect.
When a nonfactorial trial is conducted, there is a design assumption (often unacknowledged) that there is no interaction between the randomized interventions and the background concomitant treatment. Such trials provide an accurate estimate of an average treatment effect that applies to patients who receive the spectrum of concomitant treatments during the trial. However, the presence of an interaction could have implications for external validity and how the trial results are translated into practice because changes in background care may occur over time and an interaction may result in heterogeneity of the treatment effect.
An important decision in trial design is how background care is handled. For example, a trial comparing screening frequency could leave the SBT technique up to the clinician (resulting in a clinician preference–based mixture of T-piece and pressure-supported SBTs) or the trial could strictly dictate the SBT technique used via the trial protocol (eg, all patients must have T-piece SBTs). Such a trial cannot answer the question about interactions because the SBT technique is not randomized. For a nonfactorial trial, if there is an interaction with background care, the design does not lead to the identification of the optimal combination of treatments. It is a substantial strength of the trial by Burns et al3 that a factorial design was used because it permitted identification of an unsuspected but clinically important interaction.
One of the important known unknowns in trial science is how frequently unsuspected interactions between treatments exist, in part because relatively few trials are multifactorial or have examined interactions systematically and with sufficient power. Multifactorial trials (both 2 × 2 designs and multidomain platform trials) are being used more commonly.6 The use of these trial designs will assist in understanding the frequency with which unsuspected interactions occur. The increasing use of these designs leads to the question: How should interactions be evaluated and factorial trials be analyzed?
One approach would be that, unless an interaction has already been excluded by previous trials, the statistical analysis plan should specify that any interaction will be evaluated in the primary or secondary analysis, with prespecification of the plan for subsequent analyses if a statistically and clinically significant interaction is identified. Whether interactions are evaluated in primary or secondary analyses should be determined by pretrial judgment of the biological likelihood of interactions. In the context of multidomain platform trials, evaluation of an interaction may only be possible after the conclusion of pairs of domains, but within such platform trials the estimate of the treatment effect in one domain should be adjusted for the treatment effect of randomization within other domains.7,8
What are the clinical implications from this trial? At least until there is further trial evidence, it is reasonable for clinicians to undertake daily screening (with important resource use implications) and use the pressure-supported SBT technique. Although the reported analysis was not prespecified, the subsequent analysis methods used were appropriate after identifying an unsuspected interaction along with the reporting of the pairwise treatment effect of the 4 combinations of screening frequency and SBT technique. It should also be noted that the trial excluded patients who had a tracheostomy. The results of this trial apply to patients receiving mechanical ventilation via an endotracheal tube and should not be extrapolated to patients who have a tracheostomy.
This study adds valuable insights about the best practices for weaning patients from mechanical ventilation. The findings suggest that a strategy incorporating once-daily screening with pressure-supported SBTs is more effective than other strategies. Further studies of the component treatments that contribute to ventilatory weaning should incorporate the possibility of an interaction and explore the effects of different weaning strategies on patient-centered outcomes.
