Effect of Nitric Oxide Pathway Inhibition on the Evolution of Anaphylactic Shock in Animal Models: A Systematic Review

SIMPLE SUMMARY: Anaphylactic shock (AS) is the most serious consequence of anaphylaxis, with life-threatening sequelae including hypovolemia, shock, and arrhythmias. The literature lacks evidence for the effectiveness of interventions other than epinephrine in the acute phase of anaphylaxis. Our objective was to assess, through a systematic review, how inhibition of nitric oxide (NO) pathways affects blood pressure, and whether such blockade improves survival in AS animal models. AS was induced in all included studies after or before drug administration that targeted blockade of the NO pathway. In all animal species studied, the induction of AS caused a reduction in arterial blood pressure. However, the results show different responses to the inhibition of nitric oxide pathways. Overall, seven of fourteen studies using inhibition of nitric oxide pathways as pre-treatment before induction of AS showed improvement of survival and/or blood pressure. Four post-treatment studies from eight also showed positive outcomes. This review did not find strong evidence to propose modulation of blockade of the NO/cGMP pathway as a definitive treatment for AS in humans. Well-designed in vivo AS animal pharmacological models are needed to explore the other pathways involved, supporting the concept of pharmacological modulation. ABSTRACT: Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial for the prevention and/or treatment of AS. A predesigned protocol for this systematic review was published in PROSPERO (CRD42019132273). A systematic literature search was conducted till March 2022 in the electronic databases PubMed, EMBASE, Scopus, Cochrane and Web of Science. Heterogeneity of the studies did not allow meta-analysis. Nine hundred ninety unique studies were identified. Of 135 studies screened in full text, 17 were included in the review. Among six inhibitors of NO pathways identified, four blocked NO synthase activity and two blocked guanylate cyclase downstream activity. Pre-treatment was used in nine studies and post-treatment in three studies. Five studies included both pre-treatment and post-treatment models. Overall, seven pre-treatment studies from fourteen showed improvement of survival and/or arterial blood pressure. Four post-treatment studies from eight showed positive outcomes. Overall, there was no strong evidence to conclude that isolated blockade of the NO/cGMP pathway is sufficient to prevent or restore anaphylactic hypotension. Further studies are needed to analyze the effect of drug combinations in the treatment of AS.