Paediatric cardiopulmonary bypass surgery: the challenges of heterogeneity and identifying a meaningful endpoint for clinical trials
Survival following paediatric surgery for congenital heart disease (CHD) has improved dramatically over the past two decades; 30-day mortality estimates are now 2.5–4% . However short- and long-term morbidity remain significant issues and hospital length of stay remains unchanged . Both are costly and are linked to poorer long-term neurodevelopmental outcomes . We are now operating on a greater proportion of younger, smaller patients; many with associated extra-cardiac anomalies and chromosomal disorders . Ideally trials should report both immediate perioperative and post-discharge outcomes .
Morbidity and mortality are influenced by perioperative myocardial dysfunction. A postoperative low cardiac output syndrome (LCOS) is common, can compromise end organ function, and require inotropic and mechanical cardiovascular support including extracorporeal membrane oxygenation (ECMO). The incidence of LCOS is related to the duration of cardiopulmonary bypass (CPB), CPB-mediated inflammation, ischaemia–reperfusion injury (IRI) and the “controlled trauma” of surgery. Therefore, interventions that reduce inflammation and attenuate IRI are of potential interest. Addition of nitric oxide (NO) into the oxygenator during bypass is one such candidate. NO acts as both an antioxidant and anti-inflammatory agent and has beneficial effects on cell signalling (inhibition of nuclear transcription factors-NF-κ B/AP-1) . NO therapy is normally delivered via inhalation and its effects have been considered to be limited to the pulmonary circulation owing to an extremely rapid inactivation following contact with haemoglobin . However, NO is now thought to remain active in the bloodstream for longer; plasma nitrosylated NO species act to conserve and transport NO, providing systemic effects .
In vitro models have shown that addition of NO to the sweep gas during CPB prevents the usual drop in cyclic guanosine monophosphate for up to 3 h, as well as attenuating the typical fall in platelets . Two small clinical studies of NO during CPB have suggested benefit with a reduction of the duration of postoperative mechanical ventilation alongside reduced serum markers of inflammation and myocardial injury [9, 10].
In a recent article in Intensive Care Medicine, James et al. extended these findings in a well-conducted single-centre randomised controlled trial in 198 children undergoing surgery with CPB . The primary outcome measure was the incidence of LCOS, which the authors defined as one or more of the following: lactate greater than 4 mmol/l and ScvO2 less than 60% (or SaO2 − ScvO2 difference greater than 35% in a single ventricle), a vasoactive inotrope score (VIS) greater than 10 or the need for ECMO. This study demonstrated a very large effect size, with NO being associated with a 50% relative reduction in the incidence of LCOS compared to children receiving standard treatment (15% compared to 31%, p = 0.007). The fact that this effect size was greatest in patients less than 2 years of age has biological plausibility; the neonatal/infant myocardium is more vulnerable to reactive oxygen species .
Unfortunately there is no accepted standard definition of LCOS. The detail of the definition used may have an impact on the generalisability of the findings of this important study. Is this result ‘fragile’ to the definition used?
Nine patients required ECMO and in five (55%) of these, ECMO was initiated in the operating theatre where it is often initiated because of the presence of residual anatomical lesions . None of these patients met any of the authors’ other predefined definitions of LCOS and therefore are unlikely to have benefited from NO therapy.
In addition the cut-off value of at least 10 for VIS was modest, and may, as the authors acknowledge, have resulted in an overdiagnosis of LCOS. For example a patient receiving 0.5 μg/kg/min of milrinone and 5 μg/kg/min of dopamine would have a VIS of at least 10, which could be classed as standard postoperative support in many units. This is supported by the data provided in James et al.’s supplementary Tables 2 and 4 , demonstrating that only 18% (7/40) of patients with a VIS score of at least 10 had a raised lactate and low SvO2, suggesting inadequate systemic oxygen delivery.
If the authors had selected a more stringent definition of LCOS, for example by setting the VIS threshold at 15 and excluding the patients receiving ECMO, who had no other features of LCOS, the effect size for the primary outcome (LCOS) in this study would still be clinically important: 12% (NO) versus 17.5% (control), with a relative risk reduction of 31%. However using conventional indices of inadequate systemic delivery (high lactate and a low SvO2), would have led to only 4% of the patients in the NO group and 3% of controls being defined as having LCOS. This, and the lack of any significant effect on any of the more standard clinical outcomes, emphasises the inadequacy of our present definition of LCOS.
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Conflicts of interest
The authors declare that they have no competing interests..
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