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- Alexandra Lee 1
- Warwick Butt 2, 3, 4
Alexandra Lee was funded by the Stuart Green Memorial Trust and Sands Cox Society, but there was no funding for this article. The authors and researchers who assisted in developing this article had full access to all the data used (including statistical reports and tables), and can take responsibility for the integrity of the data and the accuracy of the data analysis.
Inhaled nitric oxide has been used for 30 years to improve oxygenation and decrease pulmonary vascular resistance. In the past 15 years, there has been increased understanding of the role of endogenous nitric oxide on cell surface receptors, mitochondria, and intracellular processes involving calcium and superoxide radicals. This has led to several animal and human experiments revealing a potential role for administered nitric oxide or nitric oxide donors in patients with systemic inflammatory response syndrome or ischaemia–reperfusion injury, and in patients for whom exposure of blood to artificial surfaces has occurred.
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Eligibility criteriaThis review includes human data from adult and paediatric patients who underwent CPB and suffered IRi as a direct consequence of CPB, plus data from animal studies including IRi. Studies must have included exposure to exogenous NO during CPB or the peri-ischaemic period, and must have included a comparison with controls where NO was not administered. Outcomes examined encompass end-organ effects or biological markers. Pulmonary outcomes (eg, improved gas exchange or pulmonary hypertension) were excluded from this review as the effects of NO on pulmonary outcomes are already well known. Study designs that were considered eligible included randomised control trials, cohort studies and case–control studies; conference abstracts describing small case series were excluded.
Search strategyElectronic searches of MEDLINE, Scopus and EMBASE were conducted in May 2018, and updated in August 2019. A predefined search strategy was developed for MEDLINE using Medical Subject Headings (MeSH) terms and keywords and operating theatre/room to capture relevant citations. In addition, references were reviewed to identify potentially relevant papers missed by the searches. Results were limited to articles written in English but no date restrictions were applied. Separate databases of human and animal studies were constructed in Endnote (Clarivate Analytics, Philadelphia, PA, US) with duplicates removed. The results were reviewed, and full text articles were selected based on predefined criteria. If eligibility was unclear, the full text article was retrieved. Articles were reviewed and results were synthesised qualitatively.
ResultsA total of 1267 studies relating to NO use in animal models were initially identified, and these were narrowed down to seven by screening titles and abstracts and reviewing full text articles. A total of 499 studies of trials in humans were retrieved from the electronic search, of which four were included in the final review that followed screening of the results. One study on the safety of NO in patients receiving ECMO was also included. The human studies were categorised based on the patient population: adult (n = 3) or paediatric (n = 2). All five studies were prospective randomised trials, and blinding was used in three.
Review of animal studies
Results of further studies, using the same murine model, concur with these results. Nagasaka and colleagues showed a reduction in markers of myocardial injury in mice that inhaled NO before reperfusion, and a 32% decrease in size of MI when NO was inhaled for an hour before reperfusion (P < 0.05). 19
Results of several studies indicate that NO may also confer protection against ischaemic injury in neuronal tissue. Although cerebral blood flow is not altered by NO in normal physiological conditions, there is evidence that NO has a vasodilatory effect in experimental models of cerebral ischemia. Terpolilli and colleagues subjected mice to 45 minutes of ischaemia, through occlusion of the middle cerebral artery, and then stained coronal brain slices with cresyl violet to highlight infarcted tissue. 20
Review of human studies
Studies that have translated this animal research to human patients are summarised in Table 2. A small non-blinded study was conducted by Kamenshchikov and colleagues, 21
Similarly, Kamenshchikov and colleagues measured CK-MB and cTnI levels as proxy markers for myocardial necrosis after ischaemia induced by CPB. 22
It has also been reported that the incidence of acute kidney injury (AKI) following CPB is lowered by concurrent NO administration. 23
Only two studies to date have been conducted in paediatric populations. A cardioprotective effect was observed by Checchia and colleagues in a population of 16 children undergoing tetralogy of Fallot repair who were recruited to the randomised, blinded, placebo-controlled study. 24
James and colleagues examined low cardiac output syndrome (LCOS) as a specific primary endpoint, defined as lactate greater than 4 mmol/L and central venous oxygen saturation below 60%, or vasoactive inotrope score 10 or over or ECMO requirement. 25
Results from the study by Checchia et al indicated that although there was no difference in duration of hospital stay, there were significant reductions in time spent on mechanical ventilation (8.4 ± 7.6 v 16.3 ± 6.5 hours; P < 0.05) and time spent in the cardiac intensive care unit (53.8 ± 19.7 v 79.4 ± 37.7 hours; P < 0.05). 24
Chiletti and colleagues describe their experience of 30 consecutive children supported with ECMO and receiving 20 ppm NO in the oxygenator of the ECMO circuit (which is similar to a CPB circuit). 26
DiscussionThis review highlights possible new uses of NO either inhaled through the lungs or delivered in the fresh gas flow of the oxygenator of a CPB or ECMO circuit. In children, NO delivery during CPB is associated with reduced levels of serum inflammatory markers and decreased incidence of LCOS. In adults, a reduced inflammatory response is also seen, and the likelihood of developing AKI after CPB is reduced. These clinical findings are consistent with results from both human trials using surrogate biochemical markers, to quantify organ injury, and evidence from animal models of ischaemia–reperfusion injury. For example, NO appears to convey neuroprotective and cardioprotective effects in mice. These results make the potential benefits in humans plausible. Previous studies have proposed roles for NO in preventing platelet aggregation, impact on white cell migration and function and also providing anti-inflammatory effects 3
The strength of this review is the rigor of the methods used — the search strategy was as inclusive as possible, and references were reviewed to ensure capture of all relevant articles. A limitation is the small number of relevant human clinical trials conducted to date. Nonetheless, these initial results show improved clinical outcomes with the use of NO, particularly in paediatric patients after CPB.
Most of the outcomes discussed in this review were based on surrogate markers that assess end-organ function, as opposed to clinical outcomes. While these results are promising, the full extent of the effect of NO remains unclear, so further clinical trials are needed.
Currently, it appears that NO is safe and could mitigate IRi and SIRS in patients after CPB and children receiving mechanical support. Its antiplatelet effect could lead to increased circuit survival time and its potential benefits in brain injury and hypoxia ischaemia may lead to improved neurological outcomes.
Two large scale randomised trials looking at NO after CPB in children will compare NO to placebo, providing data on the effect of NO on LCOS, morbidity and mortality in children undergoing surgery for congenital heart defects. 31