Continuous central venous oxygen saturation (ScvO2) monitoring became standard of care in adult septic shock following Rivers’ 2001 study on goal-directed therapy . Over the subsequent decade, care in adult sepsis improved significantly to the point where large multinational trials failed to replicate these results , likely because adults with sepsis are now recognized sooner and resuscitated early and more aggressively, such that ScvO2 is largely normalized by the time of trial enrollment . In comparison, pediatric studies using ScvO2 goal-directed therapy are sparse, but have shown improvement in mortality, indicating continued utility of ScvO2 [4, 5]. However, the pediatric studies are primarily in resource-limited settings, and are characterized by a high mortality in the control arms (Table 1) [4, 5]. The reasons for this are unclear, but may include late presentation, comorbidity (especially malnutrition), and a delay in recognition of signs of shock in children (who may be assessed initially by adult-trained frontline clinicians).
The preferred method of monitoring ScvO2, intermittent vs continuous, remains debatable [4, 5]. Adult studies have compared predominantly continuous vs no monitoring (Table 1), whilst the few pediatric studies have used both intermittent and continuous. Although seemingly attractive, adoption of continuous ScvO2 monitoring in young children has been hampered by lack of equipment, cost, and the need for a dedicated monitoring lumen in small central venous catheters (i.e., resulting in only double lumen catheters being available). In the January edition of Intensive Care Medicine, Sankar et al. present results from a randomized trial examining whether intermittent ScvO2 monitoring is non-inferior to continuous monitoring in pediatric septic shock . If proven non-inferior, this would justify preferential use of intermittent monitoring. The primary endpoint, reversal of shock at 6 h, was achieved in 19% (intermittent) and 36% (continuous), respectively. The authors failed to show non-inferiority, as the lower bound of the 95% confidence interval crossed the non-inferiority margin of − 20% (95% CI for absolute difference − 32% to − 4%). Thus, intermittent monitoring is not non-inferior to continuous. However, given that the upper margin of 95% CI did not cross zero (i.e., − 4%), can we postulate that continuous is actually superior to intermittent ScvO2 monitoring? Current guidance suggests that it may indeed be justifiable to also interpret a non-inferiority trial in terms of a superiority design in certain scenarios . Applying a standard, two-sided test of superiority (prtesti, StataCorp Texas) yields P = 0.015, consistent with evidence of superiority for continuous monitoring in Sankar’s study.
Thus, is this evidence from a single study strong enough to recommend continuous over intermittent ScvO2 monitoring in children? We would suggest “no, not yet”, based upon two key areas: methodological aspects of the current study and generalizability.
The authors have conducted a challenging study to a very high standard. The non-inferiority design is appropriate, in that they are asking whether a cheaper option (intermittent) is no worse than the more expensive and technologically challenging option (continuous). However, the a priori acceptable limit for non-inferiority of − 20% could be considered as too liberal, and likely represents a trade-off between adequate power and deliverability. In comparison, as alluded to by the authors, an alternative design utilizing a non-inferiority margin of − 10% (which perhaps is more clinically relevant), with 80% power would require approximately 594 patients! This is challenging: to provide context, the RESOLVE study in pediatric sepsis recruited 477 patients from 104 sites in 18 countries over 2.5 years .
A second methodological issue concerns potential for bias. This trial was unblinded, and the primary monitoring tool, ScvO2, also forms part of the primary endpoint (one of eight components that must be met to define shock resolution). Of note, the shock variables yielding the largest differences between the two trial arms at 6 h were: tachycardia resolution (13%), capillary refill time normalization (8%) and ScvO2 normalization (6%). Continuous ScvO2 monitoring creates a potential for “intervention bias”, in that the more a variable is measured, the higher probability of finding an abnormality and hence intervening in an attempt to normalize the variable. Of course, part of the point of continuous monitoring is to create more intervention, again creating a challenge in study design faced by the authors. The authors have helpfully re-analyzed the data on composite shock resolution at 6 h after excluding ScvO2; this now produces a reduced difference of 11% (35% versus 46%) in favor of continuous group, which is no longer significant (P = 0.17).
The primary endpoint (shock resolution), is sensible; however, the observed 6-h shock resolution difference of 17% (19 versus 36%) in the current study did not translate into perhaps more clinically meaningful “hard” endpoints, such as mortality, length of stay, need for mechanical ventilation, renal replacement therapy or inotrope duration.
A second point impacting generalizability of this, and of all three pediatric ScvO2 studies, is the high rate of mortality in the control groups: 39–54% [4,5,6]. These results are different from a large, multinational point prevalence study of pediatric sepsis (SPROUT) in 569 children from 128 PICU sites spanning 6 continents . The SPROUT mortality rate was 25%, and did not differ between developed and resource-limited countries. More recent data from Europe have suggested that the mortality from septic shock is even lower, at 10%, further limiting generalizability .
Sankar et al. are to be commended for completing a well-designed study in a challenging setting and adding to the knowledge base for sepsis monitoring and treatment . Unfortunately, as the results from this study are far from conclusive, this begs the obvious question: where to from here for future studies?
In settings where baseline mortality is high, a more detailed examination of factors contributing to mortality may be helpful. For example, the two groups in Sankar’s study received broadly similar therapies; however, there was a suggestion that the continuous group received more fluid and inotropes early on (albeit not reaching statistical significance). Is it thus possible that survivors, regardless of study group allocation, received more components of a recognized sepsis bundle earlier ? If so, sustained health education and bundle compliance monitoring could provide a cheaper alternative to ScvO2 monitoring. In lower-mortality settings, evaluation of the “added value” for ScvO2 monitoring, regardless of intermittent/continuous mode, is more problematic. The effect size for any hard endpoint is likely to be miniscule and any study would likely be hopelessly underpowered. Alternatives may include mechanistic endpoints (e.g., microvascular assessment), or avoidance of harm (e.g., does ScvO2-guided resuscitation increase fluid overload). We certainly do not claim to have the answers here, and will defer back to the reader….answers on a postcard, please.
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Taylor, M.D., Tibby, S.M. Sometimes more is not always better: ScvO2 monitoring in pediatric sepsis. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-05946-2