Refractory Shock pharmacologic aspects of the 2016 Surviving Sepsis - PDF document

10/4/18 Objectives Pharmacist Objectives 1. Review the Surviving Sepsis Bundle 2018 update and pertinent Refractory Shock pharmacologic aspects of the 2016 Surviving Sepsis Campaign 2. Describe mechanisms of novel pharmacologic hemodynamic support in refractory shock 3. Identify evidence based clinical rolls of novel pharmacologic hemodynamic Spencer Laehn, PharmD, BCCCP support Eileen T. Shannon, PharmD, MS, BCCCP Technician Objectives 1. Demonstrate importance of timely application of hemodynamic supporting medications 2. Understand the use of various agents for refractory shock Overview Updated Sepsis Definitions § Sepsis: life threatening organ dysfunction caused by dysregulated host § Review of Septic Shock o response to infection (qSOFA score >/=2) Updated definitions o Treatment summary § Septic shock: subset of sepsis with circulatory and cellular/metabolic o 2018 bundle update dysfunction associated with a higher risk of mortality (persistent hypotension § Refractory Shock requiring vasopressors and lactate > 2 mmol/L) o Definition o Pathophysiology Old Sepsis Definitions o Treatment: angiotensin II, acidemia reversal, nitric oxide inhibitors, metabolic resuscitation § Sepsis: 2 or more SIRs criteria + likely source of infection o SIRs: WBC >12,000 or <3,000, HR>90, RR>20, temp >38 or <36 § Severe sepsis: sepsis with signs of end organ damage o Elevated lactate, hypotension § Septic shock: severe sepsis refractory to fluid resuscitation Crit Care Med . 2017;45(3):486-552. Surviving Sepsis Guidelines 2016 Surviving Sepsis Campaign Bundle 2018 Update Initial management: § Major change: three and six hour Bundle Elements bundles combined into single § Fluid resuscitation with crystalloid 30 ml/kg and additional PRN based on Measure lactate level. Re-measure if initial lactate is > 2 “Hour 1 Bundle” hemodynamic status mmol/L Begin resuscitation and o § Broad spectrum antibiotics within 1 hour management immediately Obtain blood cultures prior to administration of antibiotics Reflects clinical reality of clinician at § Target mean arterial pressure (MAP) of 65 o the bedside § Trend lactate, provide fluid resuscitation until normalized Administer broad spectrum abx § Initiate vasopressors to achieve MAP goal if unresponsive to fluid Rapidly administer 30 ml/kg crystalloid for hypotension or Norepinephrine as first choice pressor o lactate >/= 4 mmol/L o Add vasopressin or epinephrine if cannot achieve MAP goal or to reduce norepinephrine requirement Apply vasopressors if patient is hypotensive during or after § IV hydrocortisone (200 mg/day) if fluids + vasopressors are inadequate *Resuscitation may take more than 1 hour **No data specific to burn or immunocompromised populations Crit Care Med . 2017;45(3):486-552. Crit Care Med. 2018;46(6):997-1000. 1

10/4/18 What is Refractory Shock? Pathophysiology of Refractory Shock § No universal consensus definition: Hypoxia, acidosis, hyperlactemia Drug Dose Norepinephrine o Failure to achieve a BP goal despite Equivalent Reactive oxygen Dysregulated nitric vasopressor therapy species overproduction ATP-sensitive K+ Epinephrine 0.1 ug/kg/min 0.1 ug/kg/min oxide metabolism Need for rescue vasopressor o channel activation o Need for high vasopressor doses Dopamine 15 ug/kg/min 0.1 ug/kg/min Endothelial dysfunction Altered microcirculatory flow Membrane hyperpolarization Mitochondrial dysfunction Norepinephrine 0.1 ug/kg/min 0.1 ug/kg/min Decreased bactericidal activity Cellular relaxation Coagulation modulation Vasorelaxation Phenylephrine 1 ug/kg/min 0.1 ug/kg/min Dysregulated mitochondrial respiration Vasopressin 0.04 units/min 0.1 ug/kg/min Vascular smooth Impaired responsiveness muscle relaxation to catecholamine Refractory shock: an inadequate response to high-dose vasopressor therapy Hyperglycemia Hypocalcemia Uncontrolled production (defined as >/= 0.5 ug/kg/min norepinephrine-equivalent dose REFRACTORY Corticosteroid deficiency of NO and PGI2 VASODILATORY SHOCK Chest. 2018;154(2):416-426. Image adapted from Chest. 2018;154(2):416-426. Potential Treatments for Refractory Shock Vasopressor/Inotrope pharmacology review Therapy Dose Mechanism of Action Adverse Effects A1 B1 B2 DA V1 V2 PDE3-I Angiotensin II Starting: 2-10 ng/kg/min Angiotensin II receptor Hypertension, metabolic acidosis, Norepinephrine ++++ ++ Max: 20-40 ng/kg/min activation risk of clots Epinephrine ++ +++ ++ Sodium bicarbonate 1-2 mEq/kg Reversal of metabolic acidosis Hypernatremia, ionized hypocalcemia, respiratory acidosis Phenylephrine ++++ Hydroxocobalamin 5 g IV over 10 min Scavenetging of NO Interference with hemodialysis Vasopressin ++++ ++ sensors Dopamine (low) + + +++ Methylene Blue Bolus: 1-2 mg/kg every 4-6 h Inhibition of NOS Serotonin Syndrome, hypoxia, (High dose) ++++ ++ + Infusion: 0.25-1 mg/kg/h pulmonary hypertension Dobutamine + ++++ ++ Thiamine 200 mg every 12 h Improved lactate clearance Minimal Milrinone ++++ Ascorbic Acid 25 mg/kg every 6 h or 1.5 g Increased catecholamine and Minimal every 6 h vasopressin synthesis Isoproterenol ++++ ++++ Table adapted from Chest. 2018;154(2):416-426. Circulation. 2008;18(10):1047-1056. Angiotensin II: Physiology review Angiotensin II: Physiology review § Naturally occurring hormone 1. Renal blood flow reduced from renin-angiotensin pathway 2. Kidney converts pro-renin to renin § Potent vasoconstrictor 3. Renin converts angiotensinogen to § Involved in water and sodium angiotensin I homeostasis 4. Angiotensin I is converted to angiotensin II via angiotensin converting enzyme (ACE) 5. Angiotensin II (potent vasoconstrictor) increases blood pressure via activation of AT1 and AT2 Compr Physiol. 2014;4(3):1201-1228. Compr Physiol. 2014;4(3):1201-1228. 2

10/4/18 Angiotensin II: Physiology review History of Angiotensin II use § Protein first isolated in 1930s § Case reports describe the successful use of various bovine and human angiotensin II formulations as rescue therapy for patients with refractory shock § Small pilot study published in 2014 supported its use as a vasopressor o 20 patients o Primary endpoint was effect of angiotensin II on standing norepinephrine dose required to maintain MAP of 65 Mean norepinephrine dose reduced from 27.6 +/- 29.3 u cg/min (in placebo) vs 7.4 +/1 12.4 o u cg/min, P=0.06 o Determined initial dose range: 2-10 ng/kg/min Compr Physiol. 2014;4(3):1201-1228. Crit Care . 2014;18(5):534. Clinical Trials: ATHOS-3 ATHOS-3 Criteria § International, multi-center, randomized, double-blind, placebo-controlled trial Inclusion Criteria Exclusion Criteria § Sponsored by La Jolla (manufacturer of Giapreza) § Primary Endpoint: the response with respect to mean arterial pressure § 18 years or older § Burns > 20% BSA (MAP) at hour 3 § Vasodilatory shock despite IV § ACS o Response defined as MAP of 75 mm Hg or higher or an increase in MAP from baseline of at volume resuscitation (minimum 25 Bronchospasm § least 10 mm Hg without an increase in the dose of background vasopressor ml/kg over past 24 hours) and high Liver failure § § Secondary Endpoints: changes in SOFA and cardiovascular SOFA score dose vasopressors § Mesenteric ischemia from baseline to 48 hours, adverse events, mortality at 7 and 28 days § Shock defined as MAP between § Active bleeding 55- 70 mm Hg § AAA § High dose vasopressor = § Neutropenic patients norepinephrine dose of 0.2 § VA-ECMO u cg/kg/min or equivalent dose § Receiving high dose steroids N Engl J Med. 2017;377(5):419-430. N Engl J Med. 2017;377(5):419-430. ATHOS-3 Methods ATHOS-3 Results § Baseline MAP measured as mean of three readings § Study regimen initiated in 321 patients § Initial 3 hours: angiotensin II initiated at 20 ng/kg/min and titrated to maintain o 163 received angiotensin II o 158 received placebo MAP of 75 mm Hg (max dose 200 ng/kg/min) § No differences noted between groups in any baseline characteristics o During this period, doses of other vasopressors were held constant § Patients in both groups were extremely ill (high APACHE II scores, elevated § After 3 hours, study drug or placebo or background vasopressors were baseline vasopressor doses) adjusted to maintain MAP 65-75 § After 48 hours, study drug was titrated off per protocol N Engl J Med. 2017;377(5):419-430. N Engl J Med. 2017;377(5):419-430. 3