When options matter. Vasopressor Reloaded. Balance in Haemodynamics - Only Survival Matters

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1 When options matter Vasopressor Reloaded Balance in Haemodynamics - Only Survival Matters

2 Vasopressin Synthesis and Release Physiologic Importance in Septic Shock Hypothalamus Brain Vasopressin deficiency contributes to vasodilation of septic shock 5 v1-receptor Vasopressin into circulation Pituitary Renal V 2 receptors: AH 2 O permeability in collecting duct retain H 2 O Secretion triggers: A Osmolality G Plasma Volume A Angiotensin II Vascular V1 receptors: A Aterial BP Hypothalamus Plasma Vasopressin Level (pg/ml) 2 1 Normal Early Late Septic Shock Vasopressin- Defizit Vasoconstriction v2-receptor Water retention in the kidney v3 (v1b)-receptor Vasopressin (synonyma: argipressin, arginin vasopressin, antidiuretic hormone) is a small neurohypophysial hormone, synthesized in the hypothalamus and stored in the posterior pituitary gland. It is made as part of a larger precursor molecule. Cleavage leads to release of vasopressin, neurophysin II and copeptin. 1 The main stimuli for vasopressin release from its storage granules are increased plasma osmolality and decreased plasma volume, as for example in hemodynamic changes. 2 After release into the bloodstream, vasopressin can exert its anti-diuretic and vasoconstrictive actions via V2 (renal) and V1 (vascular) receptors. 1 In septic shock, relative vasopressin deficiency has been reported. 3 After an initial rise of circulating vasopressin, levels fall significantly within hours without returning to basal values. This phenomenon might be due to depletion of stored vasopressin as well as inhibition of new vasopressin synthesis and release within the hypothalamus and pituitary. 4 Vasopressin plasma levels therefore are sub-optimally low during septic shock, which contributes to hypotension. 5 This explains the rationale for adding low dose vasopressin to substantially improve patient management in this life-threatening condition. 5 ACTH AVP Endocrine cells release ACTH into the circulation which stimulates cortisol release from the adrenal gland 2 3

3 Vasopressin: Increasing Mean Arterial Pressure And Decreasing Norepinephrine in Septic Shock Vasopressin added to norepinephrine increases MAP significantly 6 Vasopressin is associated with a norepinephrine sparing effect 8 MAP mmhg Surviving Sepsis Campaign Guidelines 7 International Guidelines for Management of Sepsis and Septic Shock: 2016 Vasopressin (up to 0.03 IU/min) can be added to norepinephrine with the intent of raising MAP or decreasing norepinephrine dosage NE 0h 1h 12h 24h 48h p<0.001 VA/NE Rate of all norepinephrine infusions (mg/min, median + IQR) Rate of NE in the norepinephrine-treated group Rate of NE in the vasopressin-treated group VASST Trial Time from study drug infusion (days) Vasopressor therapy targets a MAP of 65 mmhg. 7 With vasopressin the target MAP is achieved while saving Norepinephrine. 8 p<

4 Norepinephrine Not Too Much, Not Too Long Norepinephrine Causes Tachyarrhythmia 10 Mortality in septic shock increases with the dose of norepinephrine 9 Mortality is higher in septic shock patients with increasing norepinephrine requirements and tachycardia % Patients dying during NE-infusion % Patients dying after cessation of NE-infusion 28 day mortality (%) in patients with different dosage of norepinephrine Heart Rate 95 bpm < 95 bpm Death Rate (percentage) ( ) ( ) ( ) (0.64-1) [1 10] 2 Range of norepinephrine dosage (mcg/kg/min) < >0.3 p<0.01 mcg/kg/min NE Heart rate measured 24h after initiation of norepinephrine therapy 11 A threshold of 0.5 mcg/kg/min NE is associated with > 2x increase of mortality. A dosage greater than 1 mcg/kg/min is associated with a death rate greater than 90%. 9 Catecholamine vasopressor therapy is associated with incidence of tachyarrhythmia, elevated heart rate and myocardial cell damage

5 Better Outcome with Vasopressin in Less Severe Septic Shock VASST-Study: significantly higher probability of survival with vasopressin in less severe septic shock patients 8,17 Better Survival in Patients at Renal Risk VASST-Study: patients at risk for renal failure according to RIFLE criteria* with vasopressin added 12 Probability of survival (%) Catecholamine vasopressors + Vasopressin (28 day mortality 26.5%) + Norepinephrine (28 day mortality 35.7%) Days since initiation of study drug p=0.05 day 28 p=0.03 day 90 Probability of survival (%) No. Patients (%) Catecholamine vasopressors + Vasopressin Catecholamine vasopressors + Vasopressin + Norepinephrine p= Days from study inclusion No. Patients (%) Catecholamine vasopressors + Norepinephrine Need for RRT during 28-day 9/ % 20/ % 0.02 P-value * Rifle Criteria Risk patients : Increased serum creatinine x 1.5 In the VASST study 378 less severe septic shock patients defined as treatment < 15μg / min Norepinephrine at randomization had better survival rate at 28 and 90 days when Vasopressin was added. 8 VASST-Study: patients at risk of renal failure* had significantly better survival rate and less need for renal replacement therapy (RRT) when vasopressin was added

6 Early Vasopressin Reduces Incidence of New Onset Arrhythmias Low Lactate Predictive of Beneficial Response to Vasopressin Less new onset of rapid atrial fibrillation or ventricular tachycardia 13 VASST-Study: patients with low lactate (< 1.4 mmol/l) show beneficial response to vasopressin versus norepinephrine Late Vasopressin added after 6h up to 48h Early Vasopressin added within 6h n=23/36 n=13/ % 62.9% Probability of mortality (%) lactate 1.4 mmol/l Catecholamine vasopressors + Vasopressin (n=90) + Norepinephrine (n=77) p<0.001 Onset of rapid atrial fibrillation / ventricular tachycardia Days p<0.05 In septic shock, when vasopressin was added early within 6h of catecholamine initiation, it was associated with a significantly decreased incidence of new onset arrhythmias*. 13 Survival curves comparing vasopressin added to norepinephrine (NE) versus sole norepinephrine in patients with lactate level 1.4 mmol/l show significant beneficial response to vasopressin. 14 *New onset arrhythmia was defined as rapid atrial fibrillation (>160 beats per minute) or ventricular tachycardia in a patient without a documented history of that arrhythmia 10 11

7 Vasopressin in Patients with Pulmonary Hypertension Recommendations Empressin Therapy in Septic Shock Vasopressin does not effect 15, 18, 19 pulmonary vascular tone Empressin is indicated for the treatment of catecholamine refractory hypotension following septic shock in patients older than 18 years Human pulmonary arteries A catecholamine refractory hypotension is present if the mean arterial blood pressure cannot be stabilized to target despite adequate volume substitution and application of catecholamines. 16 %KPSS maximum Drug concentration log M Vasopressin Norepinephrine Phenylephrine Empressin (up to 0.03 IU/min) can be added to norepinephrine with the intent of raising MAP or decreasing NE dosage 7 Mortality rate in septic shock increases with an increase in norepinephrine dose. 9 Therefore Empressin added to NE should be used in less severe septic shock patients* with the intent of decreasing NE. 8,17 *Defined as patients with treatment NE<15 μg/min (~0.214mcg/kg/min in case of body weight 70kg) In contrast to catecholamine-based vasopressor agents such as norepinephrine or phenylephrine, vasopressin does not constrict pulmonary arteries. This supports the use of vasopressin 15, 18, 19 in patients with pulmonary hypertension. Empressin added to norepinephrine should be used - early in patients at risk for renal failure* 12 - within first 6h after start of catecholamine vasopressors 13 - prior to increase of serum lactate >2mmol/L 14 * RIFLE criteria risk : increased serum creatinine x

8 Empressin Dosage Recommendation 16 References Empressin dose up to 0.03 IU/min can be added to norepinephrine with the intent of increasing MAP to target, or decrease norepinephrine dosage 7 Increase dose every minutes Dose Empressin /min Dosage Empressin 40 I.U./ 2 ml solution for injection (= one ampoule) Prepare a solution for infusion by diluting 2 ml of the concentrate with 48 ml of Sodium chloride 9 mg/ml (0.9%) solution (equivalent to 0.8 I.U. argipressin per ml). The total volume after dilution should be 50 ml. Titration dose 0.01 I.U. Empressin per minute (syringe pump) Dose Empressin /hour The usual mean arterial pressure (MAP) target in intensive care patients is > 65 mmhg up to 0.03 I.U. per minute (Doses above 0.03 I.U. per minute should only be applied as an emergency treatment.) Infusion rate 0.01 I.U. 0.6 I.U ml / hour 0.02 I.U. 1.2 I.U ml / hour 0.03 I.U. 1.8 I.U ml / hour 1 Holt NF et al.: Vasopressin: a review of therapeutic applications. J Cardiothorac Vasc Anesth 2010; 24(2): Morgenthaler NG et al.: Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. Shock 2007; 28(2): Sharshar T et al.: Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31(6): Sharshar T et al.: Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med 2002; 30(3): Landry DW et al.: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95: Dünser M.W.: Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study; Circulation May 13;107(18): Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R.,... & Rochwerg, B. (2017). Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: Intensive care medicine, 43(3), Russell JA : Bench-to-bedside review: Vasopressin in the management of septic shock. Crit Care. 2011; 15(226): Martin C et al.: Norepinephrine: Not Too Much, too long; Shock 2015 Oct;44(4): Schmittinger CA et al.: Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med.2012;38(6): Domizi R. & al. «Relationship between catecholamine dose, tachycardia and outcome in septic shock: A multicentre evaluation» ESICM, 2014,abstract 12 Gordon A.C. et al.: The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med 2010; 36: Reardon DP et al.: Early vasopressin reduces incidence of new onset arrhythmias. J Crit Care 2014 ;29(4): Wacharasint P et al.: Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock 2012;38(1): Currigan DA et al.: Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries. Anesthesiology 2014; 121: Summary of Product Characteristics, current version 17 Russel JA: Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008; 358: Chan C et al.: Sepsis and Pulmonary Arterial Hypertension in the ICU. Advances in Pulmonary Hypertension.2015;13:4: Holmes CL et al.: Science Review: Vasopressin and the cardiovascular system part 2 - clinical physiology. Crit Care Feb;8(1):15-23 NAME OF THE MEDICINAL PRODUCT: Empressin 40 I.U./2 ml concentrate for solution for infusion QUALITATIVE AND QUANTITATIVE COMPOSITION: One ampoule with 2 ml concentrate for solution for infusion contains argipressin acetate corresponding to 40 I.U. argipressin (equating 133 microgram). 1 ml concentrate for solution for infusion contains argipressin acetate corresponding to 20 I.U. argipressin (equating 66.5 microgram). Excipients with known effect: Each ml contains less than 23 mg of sodium. List of excipients: Sodium chloride, glacial acetic acid or ph adjustment, water for injections. Therapeutic indications: Empressin is indicated for the treatment of catecholamine refractory hypotension following septic shock in patients older than 18 years. A catecholamine refractory hypotension is present if the mean arterial blood pressure cannot be stabilised to target despite adequate volume substitution and application of catecholamines (see section 5.1 of the published SmPC). Pharmacotherapeutic group: Vasopressin and analogues, ATC code: H01BA01 Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the published SmPC. Nature and contents of container: Clear glass ampoules (Type I, with a broken ring on the narrow part of the ampoule) with 2 ml concentrate for solution for infusion. Pack sizes: 5 and 10 ampoules. Not all pack-sizes may be marketed. MARKETING AUTHORISATION HOLDER: Orpha-Devel Handels und Vertriebs GmbH, Wintergasse 85/1B, 3002 Purkersdorf, Austria DATE OF REVISION OF THE TEXT: 02 / 2018 Prescription status/ Delivery by pharmacies: Prescription only medicine/ Pharmacy-only For information on undesirable effects, special warnings and precautions for use, interaction with other medicinal products and other forms of interaction, use in pregnancy and lactation and impact on fertility please refer to the published SmPC

9 VAS049_0518INT When options matter Increase chances of survival by using in early septic shock 8 Ensure haemodynamic stabilization by reversing vasopressin deficiency 5 Balance norepinephrine toxicity by enabling decatecholaminization 8 Medicine when it matters most