Sildenafil in endotoxin-induced pulmonary hypertension: an experimental study

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

doi:10.1016/j.bjane.2021.05.016

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Brazilian Journal of Anesthesiology

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Sumário

EXPERIMENTAL TRIALS • para Braz. J. Anesthesiol. 73 (4) • Jul-Aug 2023 • https://doi.org/10.1016/j.bjane.2021.05.016 copy

Sildenafil in endotoxin-induced pulmonary hypertension: an experimental study

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Methods

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 inhibitors; Acute lung injury; LPS; Septic shock; Experimental model; Swine

	Baseline	LPS0	LPS30	LPS60	LPS90	LPS120	LPS150	LPS180	RM ANOVA
DO₂ (mL.min^-1.m^-2)									P1 = 0.952
CTL	484 ± 85	531 ± 103	469 ± 124	667 ± 77^a a p< 0.05 vs. baseline.	711 ± 57^a a p< 0.05 vs. baseline.	702 ± 85^a a p< 0.05 vs. baseline.	679 ± 133^a a p< 0.05 vs. baseline.	643 ± 127^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	511 ± 102	516 ± 70	528 ± 106	629 ± 104^a a p< 0.05 vs. baseline.	699 ± 120^a a p< 0.05 vs. baseline.	683 ± 109^a a p< 0.05 vs. baseline.	649 ± 107^a a p< 0.05 vs. baseline.	656 ± 127^a a p< 0.05 vs. baseline.	P3 = 0.648
VO₂I (mL.min^-1.m^-2)									P1 = 0.027
CTL	125 ± 22	122 ± 12	129 ± 33	129 ± 19	132 ± 21	128 ± 16	126 ± 41	135 ± 23	P2 = 0.336
SIL	125 ± 26	113 ± 24	99 ± 19	114 ± 19	108 ± 17	113 ± 13	119 ± 10	127 ± 19	P3 = 0.317
ERO₂ (%)									P1 = 0.084
CTL	26 ± 4	24 ± 3	29 ± 8	20 ± 3^a a p< 0.05 vs. baseline.	19 ± 3^a a p< 0.05 vs. baseline.	18 ± 2^a a p< 0.05 vs. baseline.	18 ± 5^a a p< 0.05 vs. baseline.	22 ± 7	P2 < 0.001
SIL	25 ± 3	22 ± 6	19 ± 4^b b p< 0.05 CTL vs. SIL.	19 ± 5^a a p< 0.05 vs. baseline.	16 ± 3^a a p< 0.05 vs. baseline.	17 ± 4^a a p< 0.05 vs. baseline.	19 ± 5^a a p< 0.05 vs. baseline.	20 ± 5	P3 < 0.009
Qs/Qt									P1 = 0.521
CTL	5,3 ± 1,1	6,0 ± 1,4	6,0 ± 1,8	7,4 ± 1,2^a a p< 0.05 vs. baseline.	8,2 ± 1,8^a a p< 0.05 vs. baseline.	9,3 ± 2,6^a a p< 0.05 vs. baseline.	9,9 ± 2,5^a a p< 0.05 vs. baseline.	9,9 ± 3,3^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	5,6 ± 0,9	6,7 ± 1,7^a a p< 0.05 vs. baseline.	6,8 ± 1,0	7,7 ± 2,0^a a p< 0.05 vs. baseline.	9,1 ± 1,8^a a p< 0.05 vs. baseline.	8,6 ± 1,9^a a p< 0.05 vs. baseline.	7,9 ± 1,5^a a p< 0.05 vs. baseline.	8,0 ± 1,7^a a p< 0.05 vs. baseline.	P3 = 0.066
PaO₂/FiO₂									P1 = 0.364
CTL	411 ± 29	401 ± 32	369 ± 71^a a p< 0.05 vs. baseline.	389 ± 30	383 ± 32	365 ± 42^a a p< 0.05 vs. baseline.	348 ± 48^a a p< 0.05 vs. baseline.	334 ± 49^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	405 ± 26	392 ± 33	410 ± 34^b b p< 0.05 CTL vs. SIL.	387 ± 39	380 ± 29	380 ± 28	379 ± 25	370 ± 33^a a p< 0.05 vs. baseline. ,^b b p< 0.05 CTL vs. SIL.	P3 < 0.001
Lactate (mmol.L^-1)									P1 = 0.427
CTL	1.8 ± 0.6	1.7 ± 0.5	1.6 ± 0.4	1.9 ± 0.4	2.1 ± 0.5	2.4 ± 0.7^a a p< 0.05 vs. baseline.	2.7 ± 0.8^a a p< 0.05 vs. baseline.	2.8 ± 0.8^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	2 ± 1.0	1.9 ± 0.9	1.8 ± 0.7	2.1 ± 0.7	2.2 ± 0.7	2.5 ± 0.7^a a p< 0.05 vs. baseline.	2.9 ± 1.1^a a p< 0.05 vs. baseline.	3.2 ± 1.3^a a p< 0.05 vs. baseline.	P3 = 0.942
SvO₂ (%)									P1 = 0.070
CTL	73.1 ± 3.9	75.7 ± 3.3	70.4 ± 8.2	79.5 ± 2.9^a a p< 0.05 vs. baseline.	80.4 ± 3.2^a a p< 0.05 vs. baseline.	80.4 ± 2.5^a a p< 0.05 vs. baseline.	80.4 ± 5.7^a a p< 0.05 vs. baseline.	76.6 ± 7.2^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	74.8 ± 3.1	77.0 ± 6.2	80.1 ± 4.5^b b p< 0.05 CTL vs. SIL.	80.5 ± 4.8^a a p< 0.05 vs. baseline.	83.5 ± 2.6^a a p< 0.05 vs. baseline.	82.1 ± 3.8^a a p< 0.05 vs. baseline.	80.1 ± 4.6	79.0 ± 5.3	P3 < 0.008

	Baseline	LPS0	LPS30	LPS60	LPS120	LPS180	RM ANOVA
LV EF (%)							P1 = 0.719
CTL	62.6 ± 4.9	64.5 ± 6.5	61.6 ± 11.9	66.6 ± 7.5	62.9 ± 6.6	67.0 ± 6.4	P2 = 0.279
SIL	61.2 ± 3.2	63.8 ± 8.4	63.9 ± 8.5	66.1 ± 4.2	66.3 ± 4.8	63.0 ± 7.3	P3 = 0.391
LV EDV (mL)							P1 = 0.541
CTL	25.5 ± 6.1	26.6 ± 4.5	23.2 ± 4.5	27.6 ± 4.8	24.3 ± 5.8	21.4 ± 5.9^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	21.9 ± 4.8	22.0 ± 4.3	23.7 ± 6.5	21.4 ± 6.1	20.0 ± 2.7	17.4 ± 3.2^a a p< 0.05 vs. baseline.	P3 = 0.059
LV ESV (mL)							P1 = 0.512
CTL	9.8 ± 3.3	8.8 ± 2.5	9.0 ± 4.1	9.8 ± 3.7	9.2 ± 3.2	7.2 ± 2.8^a a p< 0.05 vs. baseline.	P2 = 0.002
SIL	8.4 ± 1.9	7.9 ± 2.1	8.0 ± 1.9	7.0 ± 1.4	6.8 ± 1.0	6.3 ± 1.6^a a p< 0.05 vs. baseline.	P3 = 0.691
RV EDV (mL)							P1 < 0.001
CTL	9.9 ± 2.1	10.7 ± 2.2	20.1 ± 3.3^a a p< 0.05 vs. baseline.	13.9 ± 3.6^a a p< 0.05 vs. baseline.	13.4 ± 3.0	13.6 ± 1.9^a a p< 0.05 vs. baseline.	P2 < 0.001
SIL	10.5 ± 1.7	10.7 ± 3.6	11.8 ± 4.4^b b p< 0.05 CTL vs. SIL.	10.5 ± 3.6^b b p< 0.05 CTL vs. SIL.	10.8 ± 2.3^b b p< 0.05 CTL vs. SIL.	8.0 ± 1.7^b b p< 0.05 CTL vs. SIL.	P3 < 0.001

	Control	Sildenafil	p-value
Atelectasis	1 (3-0)	2 (3-0)	> 0.05
Overinsuflation	12 (10-12)	12 (12-12)	> 0.05
Inflammation	10 (7-12)	9.5 (7-12)	> 0.05
Edema	0 (0-0)	0 (0-0)	> 0.05
Hemorrhage	3 (0-6)	3.5 (0-6)	> 0.05

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E-mail: editor.bjan@sbahq.org

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[1] * Corresponding author. E-mail:auler.junior@hc.fm.usp.br (J.O. Auler Jr.).