Sildenafil in endotoxin-induced pulmonary hypertension: an experimental study
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
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
References
1 M. Singer, C.S. Deutschman, C.W. Seymour, et al. The Thrid International Consensus Definitions for Sepsis and Septic Shock (Sepsis -3) JAMA. (2016), pp. 315801-315810
2 W.J. Sibbald, N.A. Paterson, R.L. Holliday, et al. Pulmonary hypertension in sepsis: measurement by the pulmonary arterial diastolic-pulmonary wedge pressure gradient and the influence of passive and active factors Chest., 73 (1978), pp. 583-591
3 CM Chan, JR Klinger The right ventricle in sepsis Clin Chest Med., 29 (2008), pp. 661-676
4 L.C. Clavijo, M.B. Carter, P.J. Matheson, et al. Platelet-activating factor and bacteremia-induced pulmonary hypertension J Surg Res., 88 (2000), pp. 173-180
5 A. Kleinsasser, A. Loeckinger, C. Hoermann, et al. Sildenafil modulates hemodynamics and pulmonary gas exchange Am J Respir Crit Care Med., 163 (2001), pp. 339-343
6 S.G. Raja, M.D. Danton, K.J. MacArthur, et al. Treatment of pulmonary arterial hypertension with sildenafil: from pathophysiology to clinical evidence J Cardiothorac Vasc Anesth., 20 (2006), pp. 722-735
7 D. Santi, E. Giannetta, A.M. Isidori, et al. Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis Eur J Endocrinol., 172 (2015), pp. R103-14
8 M.A. Venneri, E. Giannetta, G. Panio, et al. Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice PLoS One., 10 (2015), Article e0126580
9 RA Kloner Novel phosphodiesterase type 5 inhibitors: assessing hemodynamic effects and safety parameters Clin Cardiol., 27 (2004), pp. I20-5
10 S. Bhatia, R.P. Frantz, C.J. Severson, et al. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy Mayo Clin Proc., 78 (2003), pp. 1207-1213
11 J. Krebs, A. Kolz, C. Tsagogiorgas, et al. Effects of lipopolysaccharide-induced inflammation on initial lung fibrosis during open-lung mechanical ventilation in rats Respir Physiol Neurobiol., 212–214 (2015), pp. 25-32
12 E. Cadirci, Z. Halici, F. Odabasoglu, et al. Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study Clin Exp Immunol., 166 (2011), pp. 374-384
13 R. Schmidhammer, E. Wassermann, P. Germann, et al. Infusion of increasing doses of endotoxin induces progressive acute lung injury but prevents early pulmonary hypertension in pigs Shock., 25 (2006), pp. 389-394
14 M. Lipcsey, A. Larsson, M.B. Eriksson, et al. Effect of the administration rate on the biological responses to a fixed dose of endotoxin in the anesthetized pig Shock., 29 (2008), pp. 173-180
15 C.F. Schaefer, B. Biber, D.J. Brackett, et al. Choice of anesthetic alters the circulatory shock pattern as gauged by conscious rat endotoxemia Acta Anaesthesiol Scand., 31 (1987), pp. 550-556
16 M.S. Chew, W.J. Hawthorne, J. Bendall, et al. No beneficial effects of levosimendan in acute porcine endotoxaemia Acta Anaesthesiol Scand., 55 (2011), pp. 851-861
17 AP Wheeler, GR. Bernard Acute lung injury and the acute respiratory distress syndrome: a clinical review Lancet., 369 (2007), pp. 1553-1564
18 H.M. Wang, M. Bodenstein, K. Markstaller Overview of the pathology of three widely used animal models of acute lung injury Eur Surg Res., 40 (2008), pp. 305-316
19 M.J. Griffee, M.J. Merkel, K.S. Wei The role of echocardiography in hemodynamic assessment of septic shock Crit Care Clin., 26 (2010), pp. 365-382
20 T. Furian, C. Aguiar, K. Prado, et al. Ventricular dysfunction and dilation in severe sepsis and septic shock: relation to endothelial function and mortality J Crit Care., 27 (2012) 319.e9–15
21 S.R. Orde, J.N. Pulido, M. Masaki, et al. Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function Crit Care., 18 (2014), p. R149
22 A. Harmankaya, H. Akilli, M. Gul, et al. Assessment of right ventricular functions in patients with sepsis, severe sepsis and septic shock and its prognostic importance: a tissue Doppler study J Crit Care., 28 (2013) 1111.e7–e11
23 E. Haase, D.L. Bigam, O. Cravetchi, et al. Dose response of intravenous sildenafil on systemic and regional hemodynamics in hypoxic neonatal piglets Shock., 26 (2006), pp. 99-106
24 P.K. Ryhammer, L.S. Shekerdemian, D.J. Penny, et al. Effect of intravenous sildenafil on pulmonary hemodynamics and gas exchange in the presence and absence of acute lung injury in piglets Pediatr Res., 59 (2006), pp. 762-766
25 H.A. Ghofrani, R. Wiedemann, F. Rose, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial Lancet., 360 (2002), pp. 895-900
26 A.K. Roy, B.N. McCullagh, R. Segurado, et al. Detection of high-sensitivity troponin in outpatients with stable pulmonary hypertension identifies a subgroup at higher risk of adverse outcomes J Card Fail., 20 (2014), pp. 31-37
27 E.K. Bajwa, P.D. Boyce, J.L. Januzzi, et al. Biomarker evidence of myocardial cell injury is associated with mortality in acute respiratory distress syndrome Crit Care Med., 35 (2007), pp. 2484-2490
28 MA Hassan, AF Ketat Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T BMC Pharmacol., 5 (2005), p. 10
29 T. Kiss, K. Kovacs, A. Komocsi, et al. Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt PLoS One., 9 (2014), Article e104890
30 V. Lagente, E. Naline, I. Guenon, et al. A nitric oxide-releasing salbutamol elicits potent relaxant and anti-inflammatory activities J Pharmacol Exp Ther., 310 (2004), pp. 367-375