Selepressin in Septic Shock: Sharpening the 1/ASST Effects of Vasopressin?* Joshua A. Marks, MD Jose L. Pascual, MD, PhD, FACS, FRCS(C) Department of Surgery Division of Traumatology, Surgical Critical Care, and Emergency Surgery Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA
n this issue of Critical Care Medicine, Maybauer et al (1) compare the selective vasopressin type la receptor ago nist selepressin (formally FE202158) with the nonselective mixed VI a/V2 receptor agonist vasopressor hormone arginine vasopressin (AVP) as first-line vasoactive therapy concurrent with crystalloid resuscitation in a sophisticated septic shock ovine model of Pseudomonas aeruginosa pneumonia. They evaluate the hemodynamic and fluid balance variables in both groups and also in a third group that received both selepressin and the selective V2 receptor agonist desmopressin to deter mine if differences found could be isolated to the additional effect of AVP on the V2 receptor. They conclude that the V2 receptor agonist effects of AVP render it inferior to selepressin for the treatment of septic shock due to its worsening of vas cular leak and resultant increased net fluid balance. This work contributes to our developing knowledge of the hemodynamic and, more importantly, the volume balance in patients with septic shock who receive vasopressin or its analogues. Since Landry et al (2) first described the vasopressin-defi cient state intricately related to septic shock, AVP has been the source of much inquiry in the treatment of critically ill patients. AVP in diverse trials evaluating patients with sepsis has been shown to increase blood pressure and urine output while decreasing norepinephrine dose exposure (3). Even as first-line therapy, a retrospective study found AVP to be non inferior to norepinephrine in achieving mean arterial pressure (MAP) goals (4). Another cohort study comparing fixed-dose (0.04 units/min) AVP to titrated dopamine or norepinephrine also found that AVP increased MAP at 1 hour in patients with septic shock and was an appropriate alternate first-line agent for hemodynamic support (5). However, in a randomized controlled trial, first-line AVP failed to increase MAP in the
I
*See also p. e525. Key Words: capillary leak syndrome; selepressin; sepsis; vasoconstrictor agents; vasopressin The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000420
Critical Care Medicine
first hour but maintained it above 70 mm Hg in two thirds of patients at 48 hours (6). A British multicenter clinical trial is currently underway investigating AVP as first-line therapy in the treatment of septic shock (VAsopressin vs Noradrenaline as Initial therapy in Septic sHock trial [ISRCTN20769191]) (7). The vasopressor effect of AVP is mediated through the Via receptor. V2 receptor stimulation, on the other hand, is thought to augment sepsis-induced vasodilation, contribute to fluid accumulation through antidiuresis, and lead to microvascular thrombosis through procoagulant effects related to von Willebrand factor release. Although the Vasopressin and Septic Shock Trial (VASST) (8) did not demonstrate a survival advan tage of AVP as compared with norepinephrine, the updated Surviving Sepsis Campaign guidelines (9) continue to recom mend that AVP be added as adjunctive therapy to norepineph rine in volume and catecholamine refractory septic shock. The selective Via agonism of selepressin as a targeted AVP ana logue but without the catecholamine side effects or the del eterious effects of V2 receptor activation makes it a potentially ideal agent to employ clinically (7). In the study by Maybauer et al (1), selepressin maintained MAP effectively but unlike AVP required uptitration through out the experiments. This is different to most clinical uses of AVP that habitually employ a fixed dose with minimal titra tion. Nonetheless, the most important study finding was that selepressin but not AVP appeared to block sepsis-induced microvascular leakiness. Furthermore, when desmopressin was added to selepressin, this benefit was negated confirming that AVP effects on V2 receptors were responsible for the posi tive fluid balance. As the authors acknowledge, hemoconcentration, which was used to guide fluid infusion, is not used in clinical practice to titrate fluid resuscitation, but this approach permitted the indirect quantification of vascular leak by mea suring the fluid intake requirements and the associated fluid balance (fluid intake minus urine output). The study further strengthened these results by demonstrating near-sham levels of total plasma protein concentration and oncotic pressure in selepressin animals. Although decreasing plasma protein concentration may relate to capillary leaking, the association is unfortunately weak. Microvascular leakiness arises in sepsis in a progressive fashion, over time where the “porosity” or disrupted endothe lial junctions in vessel walls increase gradually, allowing greater and greater molecular sizes to “leak out.” Thus, plasma will leak out first and in greater volumes before macromolecules or proteins also ultimately leak out. The observed fall in plasma protein and oncotic pressure in the AVP, but not selepressin group, may consequently have occurred as a result of greater crystalloid administration. It thus is problematic to equate greater plasma oncotic pressure or plasma protein levels to lack w w w .c c m jo u r n a l.o r g
1747
Editorials
of leakiness. Indeed, it remains unclear why plasma protein/ oncotic pressure fell in septic animals if their fluid administra tion was being titrated to another protein, hemoglobin. These results remain intriguing and are supported by the postmor tem histology and gross pathology confirming greater edema in the septic animal lungs. Analysis of such tissue samples quantifying water content and microscopic tissue appearance in the AVP and selepressin groups would have been of addi tional interest. Nonetheless, the selepressin group received less fluid overall and had a near net even fluid balance. As the authors note, the results of both VASST and Sepsis Occurrence in Acutely 111 Patients trials indicate a direct relation between positive fluid balance and greater ICU mortality in patients with sepsis (10). Similar findings for the role of selective Via receptor agonism to those reported in the study by Maybauer et al (1) were noted in ovine models of fecal peritonitis and methicillinresistant Staphylococcus aureus pneumonia causing severe sep sis (11-13). In those studies, selective V ia agonism reduced fluid accumulation and norepinephrine requirements while increasing MAP, pulmonary gas exchange, and global oxygen transport (11). Furthermore, two of these studies found this group to have less postmortem histological alveolar edema and lower pulmonary wet-to-dry-weight ratios (12,13). The findings in the various animal models suggesting the benefits of selepressin over AVP in septic shock are promis ing. A clinical trial, Investigating FE202158 (Selepressin) as a Potential Primary Treatment in Patients with Early Septic Shock (NCT010612676), is currently underway to assess these potential benefits in humans (7). The results of this and other similar human trials will determine if the numerous animal and human studies supporting the use of vasopressins in sepsis may be translated clinically by more selective receptor targeting.
1748
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REFERENCES 1. Maybauer MO, Maybauer DM, Enkhbaatar P, et al: The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis. Crit Care Med 2014; 42:e525-e533 2. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125 3. Russell JA: Vasopressin in vasodilatory and septic shock. Curr Opin Crit Care 2007; 13:383-391 4. Daley MJ, Lat I, Mieure KD, et al: A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock. Ann Pharmacother 2013; 47:301 -3 1 0 5. Hall LG, Oyen LJ, Taner CB, et al: Fixed-dose vasopressin compared with titrated dopamine and norepinephrine as initial vasopressor ther apy for septic shock. Pharmacotherapy 2004; 24:1002-1012 6. Lauzier F, Levy B, Lamarre P, et al: Vasopressin or norepinephrine in early hyperdynamic septic shock: A randomized clinical trial. Intensive Care Med 2006; 32:1782-1789 7. Radermacher P, Thiemermann C: Receptor-selective vasopressin analogs: A new push for “decatecholaminization”? Shock 2013; 39:539-540 8. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877-887 9. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580-637 10. Vincent JL, Sakr Y, Sprung CL, et al; Sepsis Occurrence in Acutely III Patients Investigators: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34:344-353 11. Rehberg S, Ertmer C, Vincent JL, et al: Role of selective V ia receptor agonism in ovine septic shock. Crit Care Med 2011; 39:119-125 12. Su F, He X, Taccone FS, et al. 123: Early administration of the selec tive V1 a receptor agonist selepressin is superior to arginine vasopres sin or norepinephrine in a sheep model of septic shock. Crit Care Med 2012; 40:1-328 13. Rehberg S, Yamamoto Y, Sousse L, et al: Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. Am J Physiol Heart Circ Physiol 2012; 303:123
July 2014 • Volume 42 • Number 7
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
n this issue of Critical Care Medicine, Maybauer et al (1) compare the selective vasopressin type la receptor ago nist selepressin (formally FE202158) with the nonselective mixed VI a/V2 receptor agonist vasopressor hormone arginine vasopressin (AVP) as first-line vasoactive therapy concurrent with crystalloid resuscitation in a sophisticated septic shock ovine model of Pseudomonas aeruginosa pneumonia. They evaluate the hemodynamic and fluid balance variables in both groups and also in a third group that received both selepressin and the selective V2 receptor agonist desmopressin to deter mine if differences found could be isolated to the additional effect of AVP on the V2 receptor. They conclude that the V2 receptor agonist effects of AVP render it inferior to selepressin for the treatment of septic shock due to its worsening of vas cular leak and resultant increased net fluid balance. This work contributes to our developing knowledge of the hemodynamic and, more importantly, the volume balance in patients with septic shock who receive vasopressin or its analogues. Since Landry et al (2) first described the vasopressin-defi cient state intricately related to septic shock, AVP has been the source of much inquiry in the treatment of critically ill patients. AVP in diverse trials evaluating patients with sepsis has been shown to increase blood pressure and urine output while decreasing norepinephrine dose exposure (3). Even as first-line therapy, a retrospective study found AVP to be non inferior to norepinephrine in achieving mean arterial pressure (MAP) goals (4). Another cohort study comparing fixed-dose (0.04 units/min) AVP to titrated dopamine or norepinephrine also found that AVP increased MAP at 1 hour in patients with septic shock and was an appropriate alternate first-line agent for hemodynamic support (5). However, in a randomized controlled trial, first-line AVP failed to increase MAP in the
I
*See also p. e525. Key Words: capillary leak syndrome; selepressin; sepsis; vasoconstrictor agents; vasopressin The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000420
Critical Care Medicine
first hour but maintained it above 70 mm Hg in two thirds of patients at 48 hours (6). A British multicenter clinical trial is currently underway investigating AVP as first-line therapy in the treatment of septic shock (VAsopressin vs Noradrenaline as Initial therapy in Septic sHock trial [ISRCTN20769191]) (7). The vasopressor effect of AVP is mediated through the Via receptor. V2 receptor stimulation, on the other hand, is thought to augment sepsis-induced vasodilation, contribute to fluid accumulation through antidiuresis, and lead to microvascular thrombosis through procoagulant effects related to von Willebrand factor release. Although the Vasopressin and Septic Shock Trial (VASST) (8) did not demonstrate a survival advan tage of AVP as compared with norepinephrine, the updated Surviving Sepsis Campaign guidelines (9) continue to recom mend that AVP be added as adjunctive therapy to norepineph rine in volume and catecholamine refractory septic shock. The selective Via agonism of selepressin as a targeted AVP ana logue but without the catecholamine side effects or the del eterious effects of V2 receptor activation makes it a potentially ideal agent to employ clinically (7). In the study by Maybauer et al (1), selepressin maintained MAP effectively but unlike AVP required uptitration through out the experiments. This is different to most clinical uses of AVP that habitually employ a fixed dose with minimal titra tion. Nonetheless, the most important study finding was that selepressin but not AVP appeared to block sepsis-induced microvascular leakiness. Furthermore, when desmopressin was added to selepressin, this benefit was negated confirming that AVP effects on V2 receptors were responsible for the posi tive fluid balance. As the authors acknowledge, hemoconcentration, which was used to guide fluid infusion, is not used in clinical practice to titrate fluid resuscitation, but this approach permitted the indirect quantification of vascular leak by mea suring the fluid intake requirements and the associated fluid balance (fluid intake minus urine output). The study further strengthened these results by demonstrating near-sham levels of total plasma protein concentration and oncotic pressure in selepressin animals. Although decreasing plasma protein concentration may relate to capillary leaking, the association is unfortunately weak. Microvascular leakiness arises in sepsis in a progressive fashion, over time where the “porosity” or disrupted endothe lial junctions in vessel walls increase gradually, allowing greater and greater molecular sizes to “leak out.” Thus, plasma will leak out first and in greater volumes before macromolecules or proteins also ultimately leak out. The observed fall in plasma protein and oncotic pressure in the AVP, but not selepressin group, may consequently have occurred as a result of greater crystalloid administration. It thus is problematic to equate greater plasma oncotic pressure or plasma protein levels to lack w w w .c c m jo u r n a l.o r g
1747
Editorials
of leakiness. Indeed, it remains unclear why plasma protein/ oncotic pressure fell in septic animals if their fluid administra tion was being titrated to another protein, hemoglobin. These results remain intriguing and are supported by the postmor tem histology and gross pathology confirming greater edema in the septic animal lungs. Analysis of such tissue samples quantifying water content and microscopic tissue appearance in the AVP and selepressin groups would have been of addi tional interest. Nonetheless, the selepressin group received less fluid overall and had a near net even fluid balance. As the authors note, the results of both VASST and Sepsis Occurrence in Acutely 111 Patients trials indicate a direct relation between positive fluid balance and greater ICU mortality in patients with sepsis (10). Similar findings for the role of selective Via receptor agonism to those reported in the study by Maybauer et al (1) were noted in ovine models of fecal peritonitis and methicillinresistant Staphylococcus aureus pneumonia causing severe sep sis (11-13). In those studies, selective V ia agonism reduced fluid accumulation and norepinephrine requirements while increasing MAP, pulmonary gas exchange, and global oxygen transport (11). Furthermore, two of these studies found this group to have less postmortem histological alveolar edema and lower pulmonary wet-to-dry-weight ratios (12,13). The findings in the various animal models suggesting the benefits of selepressin over AVP in septic shock are promis ing. A clinical trial, Investigating FE202158 (Selepressin) as a Potential Primary Treatment in Patients with Early Septic Shock (NCT010612676), is currently underway to assess these potential benefits in humans (7). The results of this and other similar human trials will determine if the numerous animal and human studies supporting the use of vasopressins in sepsis may be translated clinically by more selective receptor targeting.
1748
w w w .ccm journal.org
REFERENCES 1. Maybauer MO, Maybauer DM, Enkhbaatar P, et al: The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis. Crit Care Med 2014; 42:e525-e533 2. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125 3. Russell JA: Vasopressin in vasodilatory and septic shock. Curr Opin Crit Care 2007; 13:383-391 4. Daley MJ, Lat I, Mieure KD, et al: A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock. Ann Pharmacother 2013; 47:301 -3 1 0 5. Hall LG, Oyen LJ, Taner CB, et al: Fixed-dose vasopressin compared with titrated dopamine and norepinephrine as initial vasopressor ther apy for septic shock. Pharmacotherapy 2004; 24:1002-1012 6. Lauzier F, Levy B, Lamarre P, et al: Vasopressin or norepinephrine in early hyperdynamic septic shock: A randomized clinical trial. Intensive Care Med 2006; 32:1782-1789 7. Radermacher P, Thiemermann C: Receptor-selective vasopressin analogs: A new push for “decatecholaminization”? Shock 2013; 39:539-540 8. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877-887 9. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580-637 10. Vincent JL, Sakr Y, Sprung CL, et al; Sepsis Occurrence in Acutely III Patients Investigators: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34:344-353 11. Rehberg S, Ertmer C, Vincent JL, et al: Role of selective V ia receptor agonism in ovine septic shock. Crit Care Med 2011; 39:119-125 12. Su F, He X, Taccone FS, et al. 123: Early administration of the selec tive V1 a receptor agonist selepressin is superior to arginine vasopres sin or norepinephrine in a sheep model of septic shock. Crit Care Med 2012; 40:1-328 13. Rehberg S, Yamamoto Y, Sousse L, et al: Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. Am J Physiol Heart Circ Physiol 2012; 303:123
July 2014 • Volume 42 • Number 7
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
