182 Review Article Vasopressin in Pediatric Critical Care Karen Choong1 1 Department of Pediatrics, Critical Care, Epidemiology and Address for correspondence Karen Choong, MB, BCh, MSc, Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Pediatrics, Critical Care, Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Room 3E20, J Pediatr Intensive Care 2016;5:182–188. Hamilton, Ontario, Canada L8S4K1 (e-mail: [email protected]). Abstract Vasopressin is a unique hormone with complex receptor physiology and numerous physiologic functions beyond its well-known vascular actions and osmoregulation. While vasopressin has in the past been primarily used in the management of diabetes insipidus and acute gastrointestinal bleeding, an increased understanding of the physiology of refractory shock, and the role of vasopressin in maintaining cardiovascular homeostasis prompted a renewed interest in the therapeutic roles for this hormone in the critical care setting. Identifying vasopressin-deficient individuals for the purposes of assessing responsiveness to exogenous hormone and prognosticating outcome has expanded research into the evaluation of vasopressin and its precursor, copeptin as Keywords useful biomarkers. This review summarizes the current evidence for vasopressin in ► vasopressin critically ill children, with a specific focus on its use in the management of shock. We ► pediatrics outline important considerations and current guidelines, when considering the use of ► shock vasopressin or its analogues in the pediatric critical care setting. Introduction complex, and are summarized in ►Table 1. The diversity of its actions is related to the location and density of tissue-specific Since its isolation in the 1950s, vasopressin has been recog- G-protein–coupled vasopressin receptor subtypes, which are nized as an essential posterior pituitary hormone with both currently classified into V1 vascular (V1R), V2 renal (V2R), V3 antidiuretic and vasoconstrictor actions, and hence has pri- pituitary (V3R), oxytocin-type receptors (OTR), and P2 puri- marily been used in the management of diabetes insipidus nergic receptors.3 V1R are located on vascular smooth muscle and acute gastrointestinal (GI) bleeding.1 However, an in- and mediate vasoconstriction. However, in the pulmonary crease in the understanding of its key functions in maintain- circulation, activation of V1R stimulates the release of nitric ing cardiovascular homeostasis prompted a renewed interest oxide (NO) and pulmonary vasodilation. V2R are located in in the therapeutic roles for this hormone in the critical care the renal collecting duct where it is responsible for the setting in the late 1990s. The objective of this review is to hormone’s antidiuretic action. It is also expressed in the summarize the current evidence for vasopressin in critically vascular endothelium, where specific activation mediates ill children, with a specific focus on its use in the management vasodilation and the release of von Willebrand factor and of shock. factor VIIIc. OTR has equal affinity for vasopressin and oxytocin, and is hence known as the “nonselective” vasopres- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1 The Physiology of Vasopressin sin receptor. The many actions of vasopressin may be summarized as follows: (1) systemic vasoconstriction (via Vasopressin Receptor Physiology V1R); (2) vasodilation of the renal, cerebral, and potentially Vasopressin is a unique hormone with complex receptor coronary circulations (via V2R- or OTR-mediated NO release); physiology and numerous physiologic functions beyond its (3) decreased pulmonary vascular resistance via V1R-medi- well-known vascular actions and osmoregulation.2 The ef- ated pulmonary vasodilation and ANP release; (4) antidiu- fects of vasopressin on various vascular beds and tissues are retic effect in the setting of increased serum osmolarity (V2R received Issue Theme Endocrinology in Pediatric Copyright © 2016 by Georg Thieme DOI http://dx.doi.org/ August 31, 2015 Critical Care; Guest Editors: Kusum Verlag KG, Stuttgart · New York 10.1055/s-0036-1583282. accepted after revision Menon, MSc, MD, and Dayre McNally, ISSN 2146-4618. October 15, 2015 MSc, PhD published online May 9, 2016 Vasopressin in Pediatric Critical Care Choong 183 Table 1 Vasopressin receptor physiology, mechanism of action, and principle effects Receptors Signal pathway Location Principle effects V1R • Increases intracellular calcium via • Vascular smooth muscle • Systemic vasoconstriction, the phosphatidylinositol-biphosph- • Renal medulla pulmonary vasodilation onate pathway • Platelets • Selective renal efferent ar- • Brain, testis, superior cervical teriolar constriction ganglion, liver, cardiac • Platelet aggregation myocytes V2R • Increased cAMP via the Gs and • Renal distal tubule and col- • Antidiuretic adenylate cyclase pathway lecting ducts • VWF and FVIII:c release • Mobilization of aquaporin channels • Vascular endothelium • NO-mediated vasodilation • Renal afferent arteriolar vasodilation V3R • Phosphokinase C pathway activa- • Pituitary • ACTH release tion, increased cAMP OTRs • Increases intracellular calcium via • Myometrium, endometrium, • Uterine contractions the phospholipase C and phophoi- ovary • NO-mediated vasodilation nositide pathway • Vascular endothelium • ANP release • Heart Purinergic (P2R) • Increase in intracellular calcium via • Myocardium • Myocardial contractility phospholipase C activation • Cardiac endothelium • Selective coronary vasodilation Abbreviations: ACTH, adrenocorticotropic hormone; ANP, atrionatriuretic peptide; cAMP, cyclic adenosine monophosphate; FVIII:c, factor VIII: coagulant; NO, nitric oxide; OTR, oxytocin-type receptor; VWF, von Willebrand factor. response); (5) increased glomerular filtration and mainte- shock prior to starting vasopressin8,9; however others report nance of urine output through selective vasoconstriction of elevated levels and no difference between children with and the efferent arterioles (V1R) and vasodilation of renal afferent without septic shock.10 Depleted vasopressin stores have arterioles (V2R) in the setting of shock; (6) endocrine effects been identified in children following cardiopulmonary by- through ACTH and increased plasma cortisol, as well as the pass; however, low levels were not accompanied by hemody- stimulation of atrionatriuretic peptide (ANP), angiotensin-II, namic instability in all patients, nor did they reliably predict prolactin, and endothelin-I release; and finally (7) procoagu- patients at higher risk of developing a low cardiac output lant effects, through the activation of platelet aggregation and state.11 Possible reasons for inconsistencies in measured the stimulation of von Willebrand factor and factor VIIIc. vasopressin levels between the adult and pediatric studies may be attributed to the difference in hemodynamic physiol- Vasopressin Response during Shock ogy seen in children.12 While vasodilatory shock may be the A biphasic vasopressin response has been described particu- predominant physiology in adult septic shock, pediatric larly in vasodilatory shock states where high levels are sepsis more commonly presents with low cardiac index, observed in the initial phase of hypotension, followed by high systemic vascular resistance, and a hemodynamic state inappropriately low levels as shock progresses.4 Several that often changes over time, making it challenging to dis- mechanisms responsible for vasopressin deficiency during criminate clinically.13 Furthermore, there are several limita- refractory shock have been proposed: depletion of neurohy- tions to the measurement of plasma vasopressin. pophyseal stores, impaired baroreflex-mediated release of This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. vasopressin, and downregulation of vasopressin production.5 Assessing Vasopressin Levels during Shock This latter mechanism is mediated by central NO production, While identifying vasopressin-deficient individuals and re- and may also have important implications in the pathogene- sponsiveness to exogenous hormone is an attractive approach sis of critical illness-related adrenal insufficiency, as vaso- to management and prognosis in critically ill patients, the pressin also modulates adrenocorticotropic hormone (ACTH) measurement of circulating plasma vasopressin levels is production.6 Inflammatory cytokines, such as interleukin-1β, challenging because the mature hormone is unstable, has a tumor necrosis factor-α, and interferon-γ, may also contrib- short half-life, and circulates largely attached to platelets. ute to vasopressin receptor downregulation and reduced Hence, the interpretation of static measurements of vaso- efficacy of exogenous hormone.7 pressin may be misleading. Vasopressin is derived from a While absolute or relative vasopressin deficiency has been larger, more stable precursor peptide known as copeptin, used to justify a role for exogenous vasopressin in catechol- which is secreted in an equimolar ratio to vasopressin. amine-refractory shock, supporting evidence for its existence Copeptin reliably mirrors vasopressin release, and has there- in children is inconsistent. Several studies have demonstrated fore been proposed as a more sensitive and potential prog- low endogenous hormone levels in children with vasodilatory nostic biomarker in sepsis. Copeptin is not specific to sepsis, Journal of Pediatric