Phosphodiesterase inhibitors in the treatment of sepsis and septic shock
Keywords:Drug Therapy; Phosphodiesterase Inhibitors; Inflammation; Animal experimentation.
Sepsis is a prevalent syndrome defined as a life-threatening organ dysfunction caused by a host's unregulated response to an infection, which can manifest itself in several ways. The pathophysiology of the syndrome involves the inflammatory and immunological pathways, and the response of the circulatory system plays a fundamental role in ischemia and organic injury. Phosphodiesterase inhibitors (iPDE) act by increasing the levels of cyclic nucleotides (cAMP and / or cGMP). These agents promote several effects according to their selectivity, among them: vasodilation, increased cardiac output, decreased endothelial permeability, inhibition of pro-inflammatory cytokines, and inhibition of coagulation. In view of this, the hypothesis was raised that iPDE could be beneficial in the treatment of sepsis. Clinical studies that used iPDE agents to treat sepsis show promising results. Animal models have been used to investigate the mechanisms involved in the pathology of sepsis, as well as new therapeutic options. The phosphodiesterase enzyme is classified in 11 families, and the research is focused on non-selective PDE inhibitor drugs, iPDE-3, iPDE-4 and iPDE-5. Two main septic models are used: application of Escherichia coli lipopolysaccharide and ligation and cecal puncture surgery. The drugs are administered intraperitoneally or intravenously before sepsis induction, in different doses. Despite the large number of positive results, the differences found between the septic models show the need for standardization of methods to obtain reliable data that can be used in clinical research.
Andersson, K. E. (2018). PDE5 inhibitors–pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol, 175(13), 2554-2565.
Barton, P., Garcia, J., Kouatli, A., Kitchen, L., Zorka, A., Lindsay, C., et al. (1996) Hemodynamic effects of iv milrinone lactate in pediatric patients with septic shock: A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest, 109(5), 1302-1312.
Benli, E., Ayyildiz, S. N., Cirrik, S., Koktürk, S., Cirakoglu, A., Noyan, T., et al. (2017). The effect of tadalafil therapy on kidney damage caused by sepsis in a polymicrobial septic model induced in rats: a biochemical and histopathological study. Int Braz J Urol, 43(2), 345-355.
Bone, R. C., Balk, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest, 101(6), 1644-1655.
Cadirci, E., Halici, Z., Odabasoglu, F., Albayrak, A., Karakus, E., Unal, D., et al. (2011). 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(3), 374-384.
Cecconi, M., Evans, L., Lvy, M. & Rhodes, A. (2018) Sepsis and septic shock. Lancet, 392(10141), 75-87.
Chang, C. K. (2015). Cilostazol inhibits HMGB1 release in LPS-activated RAW 264.7 cells and increases the survival of septic mice. Thromb Res, 136(1), 456-464.
Coopersmith, C. M., Baker, D., Deutschman, C. S., Ferrer, R., Lat, I., Machado, F. R., et al. (2018). Surviving sepsis campaign: research priorities for sepsis and septic shock. Intensive Care Med, 44(9), 1400-1426.
Cryer, H. M., Garrison, R. N. & Harris, P. D. (1988). Role of muscle microvasculature during hyperdynamic and hypodynamic phases of endotoxin shock in decerebrate rats. J Trauma, 28(3), 312-318.
Derici, M. K., Sadi, G., Cenik, B., Güray, T. & Demirel-Yilmaz, E. (2019). Differential expressions and functions of phosphodiesterase enzymes in different regions of the rat heart. Eur J Pharmacol, 844(5),118-129.
Ercole, F. F., Melo, L. S. D., & Alcoforado, C. L. G. C. (2014). Revisão integrativa versus revisão sistemática. REME, 18(1), 9-12.
Fakioglu, H., Gelvez, J., Torbati, D., Glover, M. L., Olarte, J. L., Camacho, M. T., et al. (2004). Aminophylline therapy during endotoxemia in anesthetized spontaneously breathing rats. Pharmacol Res, 49(1), 45-50.
Fang, M. & Dong, S. (2014). Effects of levosimendan on hemodynamics and cardiac function in patients with septic shock. Ann Transl Med, 26(10), 692-696.
Feng, H., Chen, J., Wang, H., Cheng, Y., Zou, Z., Zhong, Q., et al. (2017). Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice. Lab Invest, 97(9), 1008-1019.
Flemming, S., Schlegel, N., Wunder, C., Meir, M., Baar, W., Wollborn, J., et al. (2014). Phosphodiesterase 4 inhibition dose dependently stabilizes microvascular barrier functions and microcirculation in a rodent model of polymicrobial sepsis. Shock, 41(6), 537-545.
Gotts, J. E. & Matthay, M. A. Sepsis: pathophysiology and clinical management. Bmj, 353,1585.
Harada, H., Ishizaka, A., Yonemaru, M., Mallick, A. A., Hatherill, J. R., Zheng, H., et al. (1989). The effects of aminophylline and pentoxifylline on multiple organ damage after Escherichia coli sepsis. Am J Respir Crit Care Med, 140(4), 974-980.
Haskó, G., Szabó, C., Németh, Z. H., Salzman, A. L. & Vizi, E. S. (1988). Suppression of IL‐12 production by phosphodiesterase inhibition in murine endotoxemia is IL‐10 independent. Eur J Immunol, 28(2), 468-472.
Hollenberg, S. M. (2005). Mouse models of resuscitated shock. Shock, 24, 58-63.
Holthoff, J. H., Wang, Z., Patil, N. K., Gokden, N. & Mayeux, P. R. (2013). Rolipram improves renal perfusion and function during sepsis in the mouse. J Pharmacol Exp Ther, 347(2), 357-364.
Iversen, S., Mayer, E., Hake, U., Schmiedt, W., Jakob, H. & Oelert, H. (1992). Efficacy of phosphodiesterase inhibitor enoximone in management of postcardiotomy cardiogenic shock. Scand J Thorac Cardiovasc Surg, 26(2), 143-149.
Kaukonen, K. M., Bailey, M., Pilcher, D., Cooper, D. J. & Bellomo, R. (2015). Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med, 372(17), 1629-1638.
Kern, H., Schröder, T., Kaulfuss, M., Martin, M., Kox, W. J. & Spies, C. D. (2001). Enoximone in contrast to dobutamine improves hepatosplanchnic function in fluid-optimized septic shock patients. Critical Care Med, 29(8), 1519-1525.
Korneev, K. V. (2019). Mouse Models of Sepsis and Septic Shock. Mol Biol, 53(5), 704-717.
Kovalski, V., Prestes, A. P., Oliveira, J. G., Alves, G. F., Colarites, D. F., Mattos, J. E, et al. (2017). Protective role of cGMP in early sepsis. Eur J Pharmacol, 807, 174-181.
Kumar, V. (2020). Sepsis roadmap: What we know, what we learned, and where we are going. Clin Immunol, 210, 108264
Levy, M. M., Fink, M. P., Marshall, J. C., Abraham, E., Angus, D., Cook, D., et al. (2003). 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference. Intensive Care Med, 29(4), 530-538.
Lu, X., Wang, J., Chen, X., Jiang, Y. & Pan, Z. K. (2020). Rolipram Protects Mice from Gram-negative Bacterium Escherichia coli-induced Inflammation and Septic Shock. Sci Rep, 10(1), 1-8.
Marshall, J. C. (2014). Why have clinical trials in sepsis failed? Trends Mol Med0, 20(4), 195-203.
Martich, G. D., Parker, M. M., Cunnion, R. E. & Suffredini, A. F. (1992). Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. J Appl Physiol, 73(3), 925-931.
Mcveigh, S. E. (2020). Sepsis Management in the Emergency Department. Nurs Clin North Am, 55(1), 71-79.
Miyakawa, H., Oishi, K., Hagiwara, S., Kira, S., Kitano, T., Iwasaka, H., et al. (2004). Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model. Acta Anaesthesiol Scand, 48(5), 637-641.
Montana, J. G. & Dyke, H. J. (2002). Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs, 11(1), 1-13.
Murphy, T. J., Paterson, H. M., Kriynovich, S., Zang, Y., Kurt-Jones, E. A., Mannick, J. A. & Lederes, J. A. (2005). Linking the “two‐hit” response following injury to enhanced TLR4 reactivity. J Leukoc Biol, 77(1), 16-23.
Németh, Z. H., Hasko, G., Szabó, C., Vizi & E. S. (1997). Amrinone and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice. Shock, 7(5), 371-375.
Özer, Ö., Topal, U. & Sem, M. (2020). The effects of specific and non-specific phosphodiesterase inhibitors and N-acetylcysteine on oxidative stress and remote organ injury in two-hit trauma model. Ulus Travma Acil Cerrahi Derg, 36(4), 517-525.
Pammi, M. & Haque, N. (2004). Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev, 1(3), 1-44.
Pan, J., Yang, Y. M., Zhu, J. Y. & Lu, Y. Q. (2019). Multiorgan Drug Action of Levosimendan in Critical Illnesses. BioMed Res Int, 2019(1), 1-8.
Paterson, H. M., Murphy, T. J., Purcell, E. J., Shelley, O., Kriynovich, S. J., Lien, E., et al. (2003). Injury primes the innate immune system for enhanced Toll-like receptor reactivity. J Immunol, 171(3), 1473-1483.
Pereira, A. S., Shitsuka, D. M., Parreira, F. J., & Shitsuka, R. (2018). Metodologia da pesquisa científica. Ed (pp. 3-9). UAB/NTE/UFSM. https://repositorio. ufsm. br/bitstream/handle/1/15824/Lic_Computacao_Metodologia-Pesquisa-Cientifica. pdf.
Piper, R. D., Cook, D. J., Bone, R. C. & Sibbald, W. J. (1996). Introducing critical appraisal to studies of animal models investigating novel therapies in sepsis. Crit Care Med, 24(12), 2059-2070.
Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R., et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med, 43(3), 304-377.
Ringe, H. I. G., Varnholt, V. & Gaedicke, G. Cardiac rescue with enoximone in volume and catecholamine refractory septic shock. Pediatr Crit Care Med, 4(4), 471-475.
Rittisch, D., Huber-Lang, M. S., Flierl, M. A. & Ward, P. A. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc, 4(1), 31-36.
Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. R., et al. (2020). Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet, 395(10219), 200-211.
Russell, J. A., Rush, B. & Boyd, J. (2018). Pathophysiology of septic shock. Crit Care Clin, 34(1), 43-61.
Sakai, M., Suzuki, T., Tomita, K., Yamashita, S., Palikhe, S., Hattori, K., et al. Diminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation. Am J Physiol Heart Circ Physiol, 312(6),1224-1237.
aSchimidt, W., Tinelli, M., Walther, A., Gebhard, M. M., Martin, E. & Schimidt, H. (2000). Influence of amrinone on tissue oxygenation of jejunal mucosa during endotoxemia. J Surg Res, 93(1), 9-15.
bSchimidt, W., Tinelli, M., Secchi, A., Gebhard, M. M., Martin, E. & Schimidt, H. (2000) Milrinone improves intestinal villus blood flow during endotoxemia. Can J Anaesth, 47(7), 673.
Schmittinger, C. A., Dünser, M. W., Haller, M., Ulmer, H., Luckner, G., Torgersen, C., et al. (2009). Combined milrinone and enteral metoprolol therapy in patients with septic myocardial depression. Crit Care, 12(4), 99.
Shih, Y. N., Chen, Y. T., Chu, H., Shih, C. J., Ou, S. M., Hsu, Y. T., et al. (2017). Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. Respir Med, 125, 33-38.
Sims, C. R., Singh, S. P., Mu, S., Gokden, N., Zakaria, D., Nguyen, T. C., et al. (2017). Rolipram improves outcome in a rat model of infant sepsis-induced cardiorenal syndrome. Front Pharmacol, 8, 237.
Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., et al. (2016). The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 315(8), 801-810.
Staubach, K. H., Schröder, J., Stüber, F., Gehrke, K., Traumann, E. & Zabel, P. (1988). Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study. Arch Surg, 133(1), 94-100.
Takeuchi, K., Pedro, J., Ibrahim, A. E., Cao-Danh, H., Friehs, I., Glynn, P., et al. (1998). Vesnarinone and amrinone reduce the systemic inflammatory response syndrome. J Thorac Cardiovasc Surg, 117(2), 375-382.
Tian, J., Shen, P., Pan, K. & Zhou, Q. (2019). Efficacy of pentoxifylline treatment for neonatal sepsis: a meta-analysis of randomized controlled studies. Riv Ital Pediatr, 45(1), 108.
Vafaei, A., Heydari, K., Hashemi-Nazari, S. S., Izadi, N., & Zadeh, H. H. (2019). PIRO, SOFA and MEDS scores in predicting one-month mortality of sepsis patients; a diagnostic accuracy study. Arch Acad Emerg Med, 7(1), e59.
Vincent, J. L., Domb, M., Van der Linden, P., Motte, S., Boelpaepe, C., Contempré, B., et al. (1988). Amrinone administration in endotoxin shock. Circ Shock, 25(2), 75-83.
Vincent, J. L., Rello, J., Marshall, J., Silva, E., Anzueto, A., Martin, C. D., et al. (2009). International study of the prevalence and outcomes of infection in intensive care units. Jama, 302(21), 2323-2329.
Xu, X., Liao, L., Hu, B., Jiang, H. & Tan, M. (2020). Roflumilast, a Phosphodiesterases-4 (PDE4) Inhibitor, Alleviates Sepsis-induced Acute Kidney Injury. Med Sci Monit, 26, e921319-1.
Yamashita, S., Suzuki, T., Iguchi, K., Sakamoto, T., Tomita, K., Yokoo, H., et al. (2018). Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis. Naunyn Schmiedebergs Arch Pharmacol, 391(9), 1021-1032.
Zangrillo, A., Putzu, A., Monaco, F., Oriani, A., Frau, G., De Luca, M., et al. (2015). Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Critic Care, 30(5), 908-913.
How to Cite
Copyright (c) 2021 Gabrielle Delfrate; Daniel Fernandes; Gilson Cesar Nobre Franco
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.