Vasopressin in Vasodilatory Shock Vasopressin Antidiuretic hormone Vasodilatory shock Vasoplegia Sepsis

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  • Vasopressin in Vasodilatory Shock

    Ida-Fong Ukor, MBBS, FANZCA, FCICM, Keith R. Walley, MD*

    KEYWORDS

    � Vasopressin � Antidiuretic hormone � Vasodilatory shock � Vasoplegia � Sepsis

    KEY POINTS

    � Vasodilatory shock is the final common pathway for all forms of severe shock. � Vasopressin deficiency seems to play a significant role in vasodilatory shock. � In contrast to catecholamines, vasopressin acts through alternate signaling pathways and uniquely modulates the pathophysiology of vasodilatory shock.

    INTRODUCTION

    Vasodilatory shock is characterized by a failure of peripheral vascular vasoconstriction in the face of low systemic arterial pressure, resulting in inadequate tissue perfusion.1

    Several causes have been identified that result in vasodilatory shock, the most com- mon of these being sepsis, which is also the leading cause of mortality in hospitalized critically ill patients.2 Vasoplegia, a subset of vasodilatory shock, is a phenomenon that encompasses not only a failure of vasoconstriction but also a diminished respon- siveness to vasopressor therapy. Furthermore, it is well accepted that vasodilatory shock and vasoplegia are the common consequence of all prolonged states of severe shock of any etiology.1

    Treatment of vasodilatory shock includes infusion of vasopressors. The most commonly used vasopressors are catecholamines, including norepinephrine (NE), epinephrine, and phenylephrine. It is increasingly clear, however, that the addition of noncatecholamine vasopressors, such as vasopressin (VP) and angiotensin II, may be helpful. These agents engage alternate signaling pathways resulting in a different spectrum of actions that may be usefully used in certain clinical situations. This article reviews the role of VP in the management of vasodilatory shock.

    Disclosure Statement: The authors have no conflicts of interest with respect to this article. Sup- port: Canadian Institutes of Health Research FDN 154311. Division of Critical Care Medicine, Centre for Heart Lung Innovation, University of British Columbia, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada * Corresponding author. E-mail address: Keith.Walley@hli.ubc.ca

    Crit Care Clin - (2018) -–- https://doi.org/10.1016/j.ccc.2018.11.004 criticalcare.theclinics.com 0749-0704/18/ª 2018 Elsevier Inc. All rights reserved.

    mailto:Keith.Walley@hli.ubc.ca https://doi.org/10.1016/j.ccc.2018.11.004 http://criticalcare.theclinics.com

  • Ukor & Walley2

    MECHANISMS OF VASODILATORY SHOCK AND VASOPLEGIA

    The pathophysiology underlying vasodilatory shock and vasoplegia is incompletely elucidated. Several mechanisms have been shown to be contributory, involving an interplay between nitric oxide (NO)-mediated pathways; endothelium-derived hyper- polarizing factor (EDHF) activity; ATP-sensitive potassium (KATP) channel activation; down-regulation of vasopressor receptors, leading to vasopressor hyposensitivity; and deficiency of the neuropeptide hormone VP.1,3

    Nitric Oxide–mediated Vasodilatation

    Over-production of NO is a key component of the vasodilation and vasopressor refractoriness of vasodilatory shock.4 The increase in NO synthesis results from up- regulation of the inducible form of NO synthase (iNOS), a calcium (Ca21)-independent and calmodulin-independent isoform of NO synthase (NOS). Inflammatory cytokines, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), interferon-g, and bacterial lipopolysaccharide, are inducers of iNOS in vascular smooth muscle,5,6

    importantly via the inflammatory transcription factor nuclear factor (NF)-kB.5,7 Endo- thelial NOS (eNOS) seems to play a facilitatory role in iNOS induction.5

    NO produced as a result of increased iNOS activity leads to activation of soluble guanylyl cyclase (sGC), increased intracellular cyclic guanosine monophosphate (cGMP), and vascular smooth muscle relaxation.8,9 Increased cGMP and the subse- quent fall in intracellular calcium (Ca21i) cause vasodilation through a combination of KATP channel and large-conductance Ca

    21-dependent potassium (K1) channel activation. There is concurrent increased activity of small-conductance Ca21-depen- dent K1 channels, also causing hyperpolarization of smooth muscle cells and vasodi- lation.10 Typically, these channels open in response to raised Ca21i and mitigate the effects of vasoconstrictors that raise Ca21i, such as a-adrenergic stimulation of vascular smooth muscle.1,11 Persistent activation of iNOS and sGC in this way contrib- utes to profound vasodilation and the resultant state of shock.12

    Endothelium-derived Hyperpolarizing Factors

    Several EDHFs have thus far been demonstrated, including epoxyeicosatrienoic acids, K1 ions, gap junctions, and hydrogen peroxide (H2O2).

    13 Activation of these fac- tors results in increased K1 conductance through small-conductance K1 channels, hyperpolarization, and vasodilation as with the NO-mediated pathway, described pre- viously. EDHFs are believed to provide an alternative vasodilatory pathway in the setting of impaired NO-mediated responses.14 Several studies support the finding that EDHFs have an important role in management of microvascular perfusion and have demonstrated a greater effect of EDHFs in smaller resistance vessels than in large arteries.5,15 eNOS-derived reactive oxygen species, such as H2O2, are a source of EDHFs; however, there are several contributory enzymatic pathways for the pro- duction of superoxide anions and H2O2 in human and animal models.

    10,16

    Adenosine Triphosphate-Sensitive Potassium Channel Activation and Vascular Smooth Muscle Hyperpolarization

    Activation of KATP channels causes an efflux of intracellular K 1 ions, leading to hyper-

    polarization of the cell membrane, inactivation of voltage-gated Ca21 channels, vaso- dilation, and improved regional blood flow.17,18 KATP channels are activated by increases in intracellular lactate and hydrogen ions and decreases in cellular ATP, thereby coupling their function to cellular respiration. Excessive activation of KATP channels in vasodilatory shock is believed in part responsible for vascular smooth

  • Vasopressin in Vasodilatory Shock 3

    muscle vasopressor hyporeactivity. Additional activators of KATP channels include atrial natriuretic peptide, calcitonin gene-related peptide, and adenosine, which have all been identified in significantly elevated plasma levels in septic shock.19–21

    Despite promising animal studies,22–24 the therapeutic use of KATP antagonists, such as the sulfonylurea glibenclamide, in humans with septic vasodilatory shock thus far has proved unsuccessful, improving neither arterial blood pressure nor vaso- pressor sensitivity.2,25–27

    Vasoconstrictor Receptor Down-regulation and Hyposensitivity

    With prolongation of the vasodilatory shocked state, vascular smooth muscle exhibits progressively impaired responses to circulating vasoconstrictors.28 This is believed due to decreased vasoconstrictor receptor activity either through receptor down- regulation, uncoupling from intracellular second messengers, or both, in response to circulating inflammatory mediators.28,29 As highlighted in a recent review by Burg- dorff and colleagues,3 down-regulation or decreased activity of several vasocon- strictor receptors has been demonstrated in vivo and in vitro in several human and animal models of vasodilatory shock due to sepsis. Decreased expression and/or function of angiotensin receptor type 1 and angiotensin receptor type 2, a1-adrenergic receptors, and the V1 VP receptor subtype (V1R) have all been demonstrated in response to the activity of several cytokines, including IL-1b, TNF-a and INF- g.3,30–36 Despite good evidence supporting V1R down-regulation due to cytokine ac- tivity, there seems to be an exaggerated pressor effect of exogenously administered VP.1,37,38 Furthermore, this occurs in the setting of relative deficiency of circulating endogenous VP in the established stages of vasodilatory shock, a major contributor to the pathologic vasodilation of this state.39,40 The exact mechanism underlying this phenomenon is not clear; however, these findings have led to a focus on VP as a key element not only in the pathophysiology of vasodilatory shock but also poten- tially in its management.40,41

    VASOPRESSIN

    VP is a cyclic nonapeptide hormone also known as antidiuretic hormone. It plays an important role in the homeostatic mechanisms of the cardiovascular system, exhibit- ing multiple hormonal and osmoregulatory effects beyond its pressor activity.40 Its sig- nificance in vasodilatory shock has been extensively investigated, and it has been identified as a primary protagonist in the acute vasoconstrictor response to both hem- orrhagic and vasodilatory shock.37–39,42–44 Equally important is the fall in VP levels identified in late-stage shock, which has raised the possibility of VP deficiency as a key factor in persistent vasodilatory shock as well as a possible target for therapeutic intervention.37–39,44

    VP is synthesized in the magnocellular neurons of the paraventricular and supraop- tic nuclei of the hypothalamus. It subsequently migrates as a prohormone bound to the axonal carrier protein, neurohypophysin, to the pars nervosa of the posterior pituitary via the supraoptic-hypophyseal tract. VP-containing storage granules in the posterior pituitary release VP from hypothalamic magnocellular neuron axonal terminals in response to depolarization.40,45 Only 10% to 20% of the stored hormone can be rapidly released from the posterior pituitary, with the rate of release falling significantly thereafter, despite appropriate stimulation. This offers an explanation