Levosimendan, Vasopressin, Terlipressin Theory vs Reality
Lynn Choo BPharm (Hons), MScPharmPrac, MSHP, MRPharmS Specialist Pharmacist (Intensive Care) John Hunter Hospital, Australia Allied Health Symposium: Critical Care Pharmacy 1 Shock Shock Failure to deliver and / or utilise oxygen adequately
Give oxygen Clinical signs, lactate +/- Hypotension
Vincent JL and De Backer D. NEJM 2013; 369:1726-34 Antonelli M et al. ICM 2007; 33: 575-90 Types of shock
Distributive Cardiogenic Hypovolaemic Obstructive
Septic Myocardial infarction Haemorrhage Massive PE Anaphylactic Arrhythmia Severe dehydration Cardiac tamponade Neurogenic Heart failure Fluid redistribution Tension pneumothorax Cardiomyopathy Valvular disease Myocarditis
Vasodilation Poor cardiac output Plasma or blood loss Blockage in blood flow
‘Periphery’ issue Pump issue Volume issue 2 Vasoactive agents Terminology
“Inotrope”
Vasopressor
Inodilator Drug class
Endogenous: dopamine, noradrenaline, adrenaline Catecholamines Synthetic: dobutamine, isoprenaline, phenylephrine
Sympathomimetic Metaraminol
Other hormones Endogenous: vasopressin Synthetic: terlipressin
PDE Inhibitor Milrinone
Calcium sensitiser Levosimendan
The French Study (Annane 2007)
Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock Lancet 2007; 370: 676-84
• RCT (19 ICUs in France) • n = 330 • no difference in 28 and 90 day mortality, LOS, time to haemodynamic stabilisation • adrenaline – transient metabolic side effects CAT Study (Myburgh 2008)
A comparison of epinephrine and norepinephrine in critically ill patients Intensive Care Med 2008; 34: 2226-34
• RCT (4 ICUs in Australia) • n = 280 • no difference in time to reach MAP goal, 28 and 90 day mortality • adrenaline – transient metabolic side effects SOAP II Trial (De Backer 2010)
Comparison of dopamine and norepinephrine in the treatment of shock NEJM 2010; 362: 779-89
• RCT (8 ICUs in Belgium, Austria, Spain) • n = 1679 • no difference in overall mortality (ICU, hospital, 6 and 12 month) • dopamine higher 28-day mortality in cardiogenic shock subgroup • dopamine more arrhythmias ANZICS Dopamine Trial (Bellomo 2000)
Low-dose dopamine in patients with early renal dysfunction Lancet 2000; 356: 2139-43
• RCT (23 ICUs in Australia, NZ and Hong Kong) • n = 328 • dopamine 2 microg/kg/min vs placebo • “renal dose” dopamine DID NOT reduce peak creatinine, need for renal replacement therapy, LOS, mortality Noradrenaline, Adrenaline or Dobutamine?
• Receptor affinity and effects
• No evidence of superiority
• Use based on interpretation of physiology, familiarity, personal or unit preference, cost, availability Dopamine??
More arrhythmias compared to noradrenaline
More deaths compared to noradrenaline
No ‘renal dose’ dopamine
Review: Circulatory shock Vincent J and De Backer D. NEJM 2013; 369: 1726-34
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction? SMACC 2013 Video https://vimeo.com/66601916
Inotropes, vasopressors and other vasoactive agents Life in the fast lane: Critical Care Compendium http://lifeinthefastlane.com/ccc/inotropes-vasopressors-and- other-vasoactive-agents/
Vasopressors in shock: too early to move away from catecholamines? De Backer D and Scolletta S. BJP 2012; 165: 2012-14
Review: Use of inotropes and vasopressor agents in critically ill patients Bangash M et al. BJP 2012; 165: 2015-33
Inotrope and vasopressor therapy of septic shock Hollenberg S. Crit Care Clin 2009; 25: 781-802 3 Levosimendan The theory
Interesting Novel mode of action pharmacokinetics Inodilator Calcium sensitiser
Opens ATP-dependent K channels
Increase CO and diastolic relaxation without increase in myocardial
O2 demand
Reduces after load
Ok with beta-blockers ACTIVE levosimendan 98% protein bound (albumin) half-life 1 hour
Extensively metabolised via 2 pathways
95% conjugated into 5% reduction by intestinal flora and acetylation inactive metabolites to ACTIVE metabolite OR-1896 excreted via urine & faeces Effect lasts up to 9 days after stopping 24 hr • Half-life 80 hours infusion • 50% renally excreted • 40% protein bound The reality… 203 Levosimendan LIDO Dobutamine Haemodynamics Low output 24 mcg/kg + 2002 5 – 10 mcg/kg/min [24 h] Mortality LVEF < 35% 0.1 - 0.2 mcg/kg/min [24 h]
199 Levosimendan Placebo or CASINO Mortality NYHA IV 16 mcg/kg + Dobutamine 2004 *unpublished LVEF ≤ 35% 0.2 mcg/kg/min [24 h] 10 mcg/kg/min [24 h]
600 Levosimendan Mortality trend REVIVE II ADHF 12 mcg/kg + Placebo Hypotension, AF 2006 LVEF ≤ 35% 0.2 mcg/kg/min [24 h] *unpublished
1327 Levosimendan SURVIVE Dobutamine No difference ADHF 12 mcg/kg + 2007 ≥ 5 mcg/kg/min [≥ 24 h] Hypotension LVEF < 30% 0.1 – 0.2 mcg/kg/min [24 h]
Levosimendan RUSSLAN 504 6 – 24 mcg/kg + Placebo No difference 2002 LVF post MI 0.1 – 0.4 mcg/kg/min [6 h]
1 Availability 2 $$$
3 Patient selection
4 Dosing regime
5 Hypotension and arrhythmias
6 Consensus and guideline 4 Vasopressin The theory
a.k.a. arginine vasopressin or antidiuretic hormone
Stimulates V1 receptors vasoconstriction
Relative deficiency in septic shock
Infusion as adjunct and physiological replacement
Risk of cardiac, splanchnic, digital ischaemia at high doses The reality…
VASST VACS VANISH VASST Russell J et al. NEJM 2008; 358: 877-87 Vasopressin in Septic Shock Trial
• 780 patients (27 centres in Canada, Australia, US) • Noradrenaline (5 – 15 microg/min) +/- Vasopressin (0.01 – 0.03 unit/min) • No difference in mortality or serious adverse events • Vasopressin reduced catecholamine requirements • Positive interaction with hydrocortisone VACS Gordon A et al. Crit Care Med 2014; 43: 1325-33 Vasopressin and Hydrocortisone in Septic Shock
• Pilot RCT, 61 patients (4 ICUs in London) • Vasopressin (up to 0.06 unit/min) as initial vasopressor +/- hydrocortisone • Open label catecholamine vasopressor if required • Hydrocortisone reduced vasopressin requirements and duration, did not alter vasopressin levels Gordon A et al. BMJ Open 2014; 4: e005866 Vasopressin vs Noradrenaline as Initial Therapy in Septic Shock
• UK multi-center RCT, 412 patients recruited • Vasopressin (0 - 0.06 unit/min) vs Noradrenaline (0 - 12 microg/min) • +/- Hydrocortisone when max vasopressor dose reached • + additional open-label catecholamine if required • Primary outcome: difference in renal failure-free days • Secondary outcome: need for RRT, survival rates, other organ failures, resource utilisation 1 Availability
2 When to start?
3 Dose?
4 Concurrent hydrocortisone?
Gordon A. Vasopressin in septic shock. JICS 2011; 12: 11 - 14 5 Terlipressin The theory
Synthetic, long-acting vasopressin analogue
Half-life 4 to 6 hours
Relative specificity for splanchnic circulation
Acute variceal bleed and hepato-renal syndrome
Septic shock? Continuous terlipressin vs vasopressin in septic shock
• randomised pilot, 45 patients, single centre TERLIVAP • T 1.3 microg/kg/h, V 0.03 unit/min or N 15 microg/min Morelli A et al. Critical Care 2009; 13: R130 • + open label noradrenaline
• dobutamine to achieve SvO2 65% • hydrocortisone 200mg/d for all groups
Terlipressin reduced noradrenaline requirements Limitations • Single centre, small number • Non-equivalent dosing? TERLIVAP • Only 48 hour intervention period Morelli A et al. Critical Care 2009; 13: R130 • Different to Australian and NZ practice
• Dobutamine to achieve SvO2 >65% • Activated protein C • Mortality rates 50 – 66%
Large RCTs required Continuous terlipressin infusion in septic shock
• Estimated 1000 patients China Trial • Multicenter RCT ClinicalTrials.gov NCR01697410 • T 0.66 – 2.66 microg/min v N 7.5 – 30 microg/min • Primary outcome: 28 day mortality • Secondary outcomes • SAFA scores • Days alive and free of vasopressor • 90 day mortality The reality…
Potential option where vasopressin unavailable
Optimum dosing regimen still unclear Need large trials ? 6
Adrenaline AUD 50 per day NZD 50 per day 0.5 microg/kg/min for 70 kg Noradrenaline AUD 250 per day NZD 190 per day 0.5 microg/kg/min for 70 kg Dobutamine AUD 20 per day NZD 100 per day 10 microg/kg/min for 70 kg Milrinone AUD 225 per day NZD 270 per day 0.5 microg/kg/min for 70 kg Vasopressin AUD 180 per day NZD 150 per day 0.03 unit/min Levosimendan AUD 1250 per dose NZD 1450 per dose 12.5mg dose (1 vial) 7 Take home messages Catecholamines remain first line
Levosimendan: 2nd or 3rd line for decompensated heart failure?
Vasopressin: adjunct to noradrenaline in septic shock
Terlipressin: potential option where vasopressin unavailable QUESTIONS ?