Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1016/j.bjane.2021.05.016
Brazilian Journal of Anesthesiology
Experimental Trials

Sildenafil in endotoxin-induced pulmonary hypertension: an experimental study  

Sildenafil na hipertensão pulmonar induzida por endotoxina: um estudo experimental

Daniella Aparecida Godoi Kemper, Denise Aya Otsuki, Débora Rothstein Ramos Maia, Cristina de Oliveira Mossoco, Rogério Anderson Marcasso, Ligia Cristina Câmara Cunha, José Otávio Costa Auler Jr., Denise Tabacchi Fantoni

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Abstract

Background
Sepsis and septic shock still represent great challenges in critical care medicine. Sildenafil has been largely used in the treatment of pulmonary arterial hypertension, but its effects in sepsis are unknown. The aim of this study was to investigate the hypothesis that sildenafil can attenuate endotoxin-induced pulmonary hypertension in a porcine model of endotoxemia.

Method
Twenty pigs were randomly assigned to Control group (n = 10), which received saline solution; or to Sildenafil group (n = 10), which received sildenafil orally (100 mg). After 30 minutes, both groups were submitted to endotoxemia with intravenous bacterial lipopolysaccharide endotoxin (LPS) infusion (4 µg.kg-1.h-1) for 180 minutes. We evaluated hemodynamic and oxygenation functions, and also lung histology and plasma cytokine (TNFα, IL-1β, IL6 and IL10) and troponin I response.

Results
Significant hemodynamic alterations were observed after 30 minutes of LPS continuous infusion, mainly in pulmonary arterial pressure (from Baseline 19 ± 2 mmHg to LPS30 52 ± 4 mmHg, p < 0.05). There was also a significant decrease in PaO2/FiO2 (from Baseline 411 ± 29 to LPS180 334 ± 49, p < 0.05). Pulmonary arterial pressure was significantly lower in the Sildenafil group (35 ± 4 mmHg at LPS30, p < 0.05). The Sildenafil group also presented lower values of systemic arterial pressure. Sildenafil maintained oxygenation with higher PaO2/FiO2 and lower oxygen extraction rate than Control group but had no effect on intrapulmonary shunt. All cytokines and troponin increased after LPS infusion in both groups similarly.

Conclusion
Sildenafil attenuated endotoxin-induced pulmonary hypertension preserving the correct heart function without improving lung lesions or inflammation.

Keywords

Phosphodiesterase V inhibitorsAcute lung injuryLPSSeptic shockExperimental modelSwine

Resumo

Introdução

A sepse e o choque séptico ainda representam grandes desafios na medicina intensiva. O sildenafil tem sido amplamente utilizado no tratamento da hipertensão arterial pulmonar, mas seus efeitos na sepse são desconhecidos. O objetivo deste estudo foi investigar a hipótese de que o sildenafil pode atenuar a hipertensão pulmonar induzida por endotoxina em um modelo suíno de endotoxemia.

Métodos

Vinte porcos foram aleatoriamente designados para o grupo Controle (n = 10), que receberam solução salina; ou ao grupo Sildenafil (n = 10), que recebeu sildenafil via oral (100 mg). Após 30 minutos, ambos os grupos foram submetidos à endotoxemia com infusão intravenosa de endotoxina lipopolissacarídica bacteriana (LPS) (4 µg.kg-1.h-1) por 180 minutos. Avaliamos funções hemodinâmicas e de oxigenação, além de histologia pulmonar e resposta plasmática de citocinas (TNFα, IL-1β, IL6 e IL10) e troponina I.

Resultados

Alterações hemodinâmicas significativas foram observadas após 30 minutos de infusão contínua de LPS, principalmente na pressão arterial pulmonar (da linha de base 19 ± 2 mmHg para LPS30 52 ± 4 mmHg, p < 0,05). Houve também uma diminuição significativa na PaO2/FiO2 (da linha de base 411 ± 29 para LPS180 334 ± 49, p < 0,05). A pressão arterial pulmonar foi significativamente menor no grupo Sildenafil (35 ± 4 mmHg no LPS30, p < 0,05). O grupo Sildenafil também apresentou valores mais baixos de pressão arterial sistêmica. Sildenafil manteve a oxigenação com maior PaO2/FiO2 e menor taxa de extração de oxigênio do que o grupo controle, mas não teve efeito sobre o shunt intrapulmonar. Todas as citocinas e troponina aumentaram após a infusão de LPS em ambos os grupos de forma semelhante.

Conclusão

Sildenafil atenuou a hipertensão pulmonar induzida por endotoxina preservando a função cardíaca correta sem melhorar as lesões pulmonares ou a inflamação.

Palavras-chave

Inibidores da Fosfodiesterase V; Lesão pulmonar aguda; LPS; Choque séptico; Modelo experimental; suíno

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