VASOPRESSORS AND INOTROPES USED IN ICU

Emergency drugs in icu

1. VASOPRESSOR AND INOTROPES IN ICU MODERATOR –DR ARINDAM PHUKAN ASSISTANT PROFESSOR DEPARTMENT OF ANAESTHESIOLOGY & CRITICAL CARE AMCH SPEAKER:DR DEBOLINA SARKAR PGT 2 nd YEAR

2. Inotropes An inotrope is an agent that alters force of contraction of cardiac muscle without affecting the preload & afterload. positive inotropes increase contractility negative inotropes weakens force of contraction Term “inotrope” generally used to describe positive effect CLASS 1: intracellular calcium include Ca ions, drug increases Camp, drug affecting Na-K ATPase digoxin CLASS 2: sensitivity actomyosin to Calcium ions CLASS 3: Metabolic / endocrinological –T3 classification

3. Positive inotropic agents include: Calcium Ca sensitizers:Levosimendan Cardiac myosin activators: Omecamtiv Catecholamines : - Dopamine,Dobutamine,Epinephrine,Isoprenaline Norepinephrine,Dopexamine Cardiac Glycosides : Digoxin PDE III inhibitors : - Enoximine , Piroximine - Milrinone - Amrinone PGE2 Glucagon

4. Receptor Physiology ALPHA -1 adrenergic -1 Location Vascular wall Heart Effect Vasoconstriction Iris dilatation Piloerection duration of contraction without increased chronotropy ß - Adrenergic ß1-heart inotropy & chronotropy Lipolysis Vasodilation,bronchodilation , glycolysis,uterine relaxation ß2-Blood Vessels Dopamine D1: Renal splanchnic(mesenteric) Coronary Cerebral D2: SUBTYPE Vasodilation antiemetic action of Droperidol VASOCONSCTRICTION

5. Catecholamines are drugs that promote blood flow and BP by stimulating adrenergic receptors

6. LEVOSIMENDAN Pyridazone-dinitrile derivative Ca channel senstizer MOA: ↑ sensitivity of the heart to Ca → ↑cardiac contractility without a rise in intracellular Ca→positive inotropic effect by binding to cardiac troponin C in a Ca dependent manner Vasodilatory effect by opening ATP-sensitive K channels in vascular smooth muscle to cause smooth muscle relaxation Combined inotropic & vasodilatory action result in ↑FOC,↓ preload & afterload

7. LD : 6-12 Ug /Kg Iv Over 10 Min F/B Continous Infusion 0.05-0.2 Ug /Kg/Min For 24 Hrs Peak Effects : 10-30 Min Duration Of Action :75-78 Hrs To 1 Week Indication : Inotropic Support In Acutely Decompensated Severe CHF, Refractory Pulmonary HTN , & Dilated Cardiomyopathy C/I : Moderate To Severe Renal Impairment , Severe Hepatic Impairment , Severe Ventricular Filling & Outflow Obstruction ,Severe Hypotension & Tachycardia & H/O Torsades De Pointes Adverse Effects : Headache, Hypotension, Arrhythmias, MI, Hypokalaemia

8. EPINEPHRINE Prototype sympathomimetic Circulating hormone synthesized,stored & released from adrenal medulla Regulation of myocardial contractility,HR,vascular & bronchial smooth muscle tone,glandular secretion ,metabolic process such as glycogenolysis & lipolysis Potent activator of  adrenergic receptors & activation β 1 & β 2 receptors It is available in Ampule containing 1mg/ml Onset – immediate if given iv Duration:3-5 min when given iv Metabolism & Elimination:COMT & MAO enzymes Adverse effects: tachycardia,HTN,MI,arrythmias

9. DOSING REGIMEN: Epinephrine infusion –initial dose rate 0.01-0.2ug/kg/min The usual maintenance dose range 0.01-0.5ug/kg/min Range of maximum dose used in refractory shock : 0.5-2ug/kg/min

10. CLINICAL USES : Life threatening allergic reaction/anaphylactic 1:1000 (means 1 g of adrenaline in 1000 ml of that solution. 1000 mg in 1000 ml. each ml contains 1 mg of adrenaline) 0.5-1 mg im .(0.5ml 1:1000 sol) 50-100ug boluses iv ( 1 : 1 ) 100-500ug sc It is a histamine antagonist Treatment of severe asthma,bronchospasm , To treat bone cement ,adrenaline used in iv bolus 25-50ug administrating during CPR(1mg iv every 3-5 min)→exerting  effect→vasocontriction→CPP . as a vital therapeutic drug,administration during periods of hemodynamic instabilty to promote myocardial contractilty & vascular resistance & continous support.By lusitropic property →improves ventricular relaxation → therby improving Coronary Blood Flow

11. Promote inotropy during weaning from CPB Used to O2 delivery & cardiac output in sepsis It is added with Local anaesthetic solution to decrease systemic reabsorption used in concentration of 1:200000 prolonging duration of action of anaesthetic for regional & local anaesthesia,component of epidural test dose Used in local & field blocks to promote a bloodless surgical field Racemic Adrenaline(2.25%) is a mixture of Laevo & dextro isomers of adrenaline-causes less tachycardia & used to treat laryngeal edema HR must be monitored clearly after nebulization C/I ventricular outlet obstruction

12. Cvs St imulates α & β adrenergic receptors,as a inotrope 0.01-0.2 microgram/kg/ min.In lower doses β effects prominent ( inotropy,chronotropy ) but in larger doses  effect (vasoconstriction) more prominent Stimulation of 1 receptors-arteriolar vasoconstriction & pulmonary artery vasoconstriction,dose dependent increase in HR,SV,BP Net effect of these changes on peripheral vascular tone is preferential distribution of CO to skeletal muscles & systemic vascular resistance

13. Renal blood flow is substantially ,even on absence of changes in systemic BP It stimulates β 1 receptors -↑ in HR,myocardial contractility & CO.There may be mild ↓ in DBP reflecting vasodilation in skeletal muscle vasculature due to β 2 receptors It ↑ conduction velocity & ↓ refractory period in AV node,bundle of his,purkingefibres & ventricular muscle,↑automaticity of latent pacemaker CBF is enhanced by epinephrine even at doses that alter systemic BP

14. AIRWAY SMOOTH MUSCLE : -are released by Epinephrine induced stimulation of β 2 receptors -↑ cAMP → β 2stimulation →↓release vasoactive mediators associated with symptoms of Bronchial Asthma METABOLIC EFFECTS : - β 1 stimulation – epinephrine ↑ liver glycogenolysis & adipose tissue lipolysis -1 stimulation →(-) release of insulin -infusion of epinephrine- ↑ plasma concentration of glucose,cholesterol,phospholipids,LDL , ↑ lactate production ELECTROLYTE - Β 2-adrenergic Agonist- Stimulation Of Na-k Pump In Skeletal Muscle,leading To A Transfusion Of K+ Into Cell →Epinephrine Induced Hypokalemia Contribute To Cardiac Dysrhythmias Which Ocassionally Accompany Stimulation Sympathetic Nervous System

15. OCULAR EFFECTS: -Contraction of radial muscles of iris producing mydriasis ↓ Contraction of orbital muscles produces an apperance of exophthalmos GIT & GENITOURINARY SYSTEM: - Produces relaxation of GI smooth muscles -stimulation of β -adrenergic receptors releases detrusor muscle of bladder -stimulation of  - adrenergic receptors –contracts trigone & sphincter muscles ↓ hepato splanchnic oxygen exchanges It may be dependent on severity of shock state & epinephrine COAGULATION -accelerated by epinephrine -↑ TLC -potent induction of platelet aggregation & factor V

16. Cutaneous infiltration of dilute solution of EPINEPHRINE for hemostatsis during HALOTHANE anaesthesia can result in ventricular dysarrhythmias Children can tolerate high dose of subcutaneous epinephrine than adults during halothane anaesthesia The arrhythmogenic dose of epinephrine in children receiving halothane atleast 10ug/kg may be used safely in normostatic & hypocarbic pediatric patients without CHD. The presence of Premature Atrial Contraction & tachycardia emphasize the need of continous ECG monitoring & caution receiving halothane

17. NOR EPINEPHRINE Endogenous Neurotransmitter Synthesized & Stored In Postganglionic Sympathetic Nerve Ending Immediate Precursor Of Epinephrine NE→stimulation Of Β 1 & 1 Adrenergic Receptor Potent 1 Agonist –Intense Arterial & Venous Vasoconstrictionexcept For Coronary Artery It Stimulates ↑ SVR& DBP,MAP,SBP Than Epinephrine Minimal Metabolic Effects Peripheral Vasoconstriction May ↓ Tissue Blood To The Extent That Metabolic Acidosis Occurs Refractory Hypotension:rx-continous Infusion Of NORAD 1-3.3ug/Kg/Min

18. Dosing regimen : - It is available in 2ml Ampules containing 2mg/ml of Noradrenaline bitartarate . -NE infusion usually started @0.05-0.15 ug /kg/min & dose rate is then titrated ↑ or downward to maintain MAP of atleast 65mmHg -Effective dose rate in septic shock is usually . 2 5 - . 5 ug/kg/min ONSET: Immediate Duration: 3-5 min METABOLISM & ELIMINATION: COMT & MAO enzymes CLINICAL USES : -Primary use as a potent vasocontrictor to ↑ PVR & MAP - Severly hypotensive septic patient-NE induced vasoconstriction & redistribution of flow thereby ↑ splanchnic blood flow & CO -NE also used for patient with ↓ SVR after CPB

19. SIDE EFFECTS : -used cautiously in Rt ventricular failure patients ↓ ↑VR to heart & ↑Pulmonary artery pressure via stimulating pulmonary vascular 1 adrenergic receptors -↑ Perpheral resistance & afterload by ↓ CO & ↑work of left ventricle -Excessive vasoconstriction & ↓ perfusion of renal,splanchnic & peripheral vascular beds may lead to end organ hypoperfusion & ischaemia -Renal arteriolar vasoconstricton-Oliguiria & Renal Failure CAUTION: Infusion of catecholamine should preferably given through central venous catheter

20. DOPAMINE - Endogenous catecholamine that is the immediate precursor of NE This differentially stimulates a variety of D1 & D2 receptors & the  & β adrenergic receptors D1 receptor- postsynaptically - stimulates vasodilator in renal,mesenteric,coronary & cerebral vascular beds & (-) Na-K adenosine triphosphatase →stimulation of adenyalte cyclase D2 receptors (pituitary gland,emetic center of medulla & kidney) ↓ Presynaptic principally ↓ (-) Adenylate cyclase activity & release of NE in ANS & adrenergic nerve leading to vasodilation

21. At low dose,0.5-3ug/kg/min ↓ D1 & D2 receptors ↓ Vasodilation,↓ arterial BP,↑splanchnic vascular blood flow induces natriuresis & diuresis ↓ ↓DBP-↑Reflex in HR 3-10ug/kg/min ↓ + β 1 adrenergic receptors+  receptors in perpheral vasculature -stimulates NE release from vascular sympathetic neurons -↑CO( chronotropy & contractility along with vasodilator & after load reduction) >10ug/kg/min-Infusion rate –stimulates 1 receptors →arterial & venous constriction,↑SVR , ↑BP, ↑CO, ↑Perfusion pressure Reflex bradycardia

22. ↑Myocardial oxygen consumption It undergoes metabolism in liver & conjugation to sulfates & glucoronides,pulmonary endothelium by COMT & excretion by kidneys CVS: Dose related sinus tachycardia & potential to cause ventricular arrythmias→may predispose to MI by precipitating HR↑, ↑contractility, ↑ afterload & precipitating coronary & vasospasm GIT: ↑ flow to muscle layer of gut with ↓ flow to mucosal layer with detrimental effects & possibly gut ischemia -Dopamine infusion in septic shock ↓ ↑ hepatosplanchnic perfusion ENDOCRINE & IMMUNOLOGIC EFFECTS: - It disrupts metabolic & immunologic functions through its effect on hormones & lymphocyte function

23. D opamine ↓ Immune Status ↓ S erum Prolactin Levels Affecting T & B Lymphocyte -It Inhibits Lymphocyte Proliferation,Ig Synthesis ,Cytokine Production & Promotes Lymphocyte Apoptosis -It Inhibits Growth Hormone Secretion & Impaired Anabolism & (-) Nitrogen Balance -It Inhibits Thyrotropin Releasing Hormone → Euthyroid Sick Syndrome → Affecting Leutenizing Hormone -Overall Effect Is To Supresss Secretion & Function Of Anterior Pituitary → Aggrevates Catabolism & Cellular Immune Function

24. Respiratory Effect: - Low dose in healthy subjects & heart failure with ventilatory response to arterial hypoxemia & hypercapnia reflecting the role of dopamine as an inhibition of neurotransmitor at carotid bodies →resulting in depression of ventilation in patients who are being treated with dopamine to ↑ myocardial contractility -It ↓arterial oxygen saturation by impairing regional V/P matching in lungs -It ↓ PVR in COPD patients -Improves Respiratory muscles contraction -↑lung edema clearance -(-) of bronchoconstriction

25. IOP : - continous infusion in critically ill patients ↑IOP, ↑ prexisting glucoma specially if they are sedated & mechanically ventilated

26. CARDIAC GLYCOSIDES D igitalis is term used for cardiac glycosides that occur naturally in many plants,including the foxglove plant I.v use→onset time is 10-30 min with peak effect 2-4 hrs after administration MOA: The inotropic effect evoked by cardiac glycosides includes directly effects on heart that modify its electrical & mechanical activity & indirect effects evolved by reflex alteration ANS It selectively & reversibly (-) Na+-K+ ATPase in sarcolemma of cardiac cells→resulting ↑ in Na intracellular,Ca2+ ↑ is the primary mechanism of inotropic action of digitalis It has + ve inotropic effect(↑ SV,↓Heart size & ↓LVEDP),without change in HR& are associated with ↓ in left ventricular preload,afterload,wall tension & oxygen consumption in failing heart

27. Management of Supraventricular tachydysrthymias (Paroxysmal Atrial Tachycardia,Atrial Fibrilliation,Atrial Flutter associated with a rapid ventricular response based on the ability of these drugs to slow conduction of cardiac muscles through AV node It causes cardiac dysrhythmias It continues to have important therapeutic role in Rx of Ch CHF c/ i:Wolf-Parkinson –White Syndrome,digitalis shortens refractoriness in accessory conduction pathway to the point that rapid atrial impulses can cause ventricular fibrillation Digoxin may be harmful in patients with hypertrophic subaortic stenosis because of ↑ myocardial contractility intensifies the resistance to ventricular ejection T1/2 is inversely proportional to GFR & increases with age or renal disease

28. SYNTHETIC CATECHOLAMINE : 1)  

29. 2)DOBUTAMINE : Synthetic catecholamine derived from isoproterenol consisting of 50:50 racemic mixture of 2 isomers The (-) enantiomers is potent 1 adrenergic agonist as well as weak β 1- β 2 adrenergic agonist The (+)enantiomers is a competitive antagonist at 1 receptors as well aspotent β 1& β 2 agonist It primary acts as a + ve inotropic agent ↓ ↑intracellular cAMP ↓ ↑ Ca release from SR→ ↑ contractilty ↑CO → ↑SV It has wide effects on vascular tone causing peripheral vasodilation

30. It acts on SA Node automaticity as well asAV nodal & ventricular conduction Higher dose >10ug/kg/min iv predispose the patient to tachycardia & cardiac dysarrythmias Patients with Pulmonary artery pressure after mitral replacement,an infusion of dobutamine ( upto 10ug/kg/min)-↑CO&↓systemic & pulmonary vascular resistance It inhibits Hypoxic Pulmonary Vasoconstriction It is used for weaning from CPB Used in patients with Pulmonary HTN Myocardial Oxygen consumption is ↑ sed –tachycardia & contractility Whereas CBF ↓ by vasodilation:These properties makes dobutamine useful for pharmacologic stress test to detect potential areas of MI

31. DOPEXAMINE Structural Analogue Of Dobutamine Potential Advantage Over Dobutamine Because It Has Less Β 1-adrenergic( arrhythmogenic ) & -Adrenergic Effects It Has Specific Effect On Renal Perfusion Dose : Infusion Should Be Started @0.5ug/Kg/Min -↑1ug/Kg/Min At Interval Of 10-15 Min To Maxium Rate 6ug/Kg/Min

32. DOBUTAMINE + NORADRENALINE OR EPINEPHRINE

33. SELECTIVE PHOSPHODIESTERASE INHIBITORS: MILRINONE : It is phosphodiesterase inhibitor III→↑ intracellular concentration c AMP & Ca2+→ inotropy It is available in 10 ml Ampules containing 1mg/ml of Milrinone lactate Cardiac Output improves both as a result of inotropy as well as vascular smooth muscles relaxation of peripheral & pulmonary vessels ↓ in LVEDP,MAP,CVP,pulmonary artery occlusion pressure,pulmonary vascular resistance & SVR occur as well as improvement in diastolic function Iv bolus 50ug/kg over 10 min followed by a continous infusion of 0.375-0.75 ug /kg/min to maintain plasma concentraion at or above therapeutic level

34. Onset:immediate Duration:3-6 hrs when given iv Useful in Mx of Acute Left ventricular dysfunction such as after cardiac surgery Successful weaning of high risk patient from CPB may be enhanced by administration of milrinone S/ E:Rapid administtration of large iv Loading Dose may be associated with arrthymias Elimination: Liver

35. CHOICE OF INOTROPE: Guided: The expected need of inotrope Clinical evidence of depressed myocardial function Emperical drug choice & titration , with careful hemodynamic monitoring Ideal positive inotrope enhance contractility without significant ↑ in HR preload,afterload & myocardial oxygen consumption Enhance the diastolic function Maintain the diastolic CPP & thus an adequate myocardial blood flow It finally should have rapid titration times & onset of action & a short T1/2

36. VASOPRESSORS: Vaso -vessels Pressors -pressure Vasopressors Are Class Of Drugs That ↑ Map By Inducing Vasoconstriction Many Drugs Have Both Vasopressors & Inotropic Effects Vasopressors Are Indicated For A ↓ Of 30mmhg From Baseline Systolic Bp Or Map <60 Mmhg When Either Condition Results In End Organ Dysfunction Secondary To Hypoperfusion

37. EPHEDRINE: Indirect acting synthetic sympathomimetic that stimulates  & ß adrenergic receptors The pharmacologic effects of ephedrine are partly due to direct stimulation of adrenergic receptors(Direct acting) & partly due to stimulation of endogenous Noradrenaline (indirectly acting) Upto 40% single dose Ephedrine is excreted unchanged in urine & some is deaminated by MAO & hepatic conjugation CLINICAL USE: 5-10mg iv Adult, ↑SBP in presence of Sympathetic Nervous System inhibition produced by regional anaesthesia or hypotension due to inhaled or injected anaesthesia Recent review of trial Ephedrine&Phenylephrine,the later is associated with a higher umbilical artery pH at delivery than ephedrine →preferable for Rx of Maternal Hypotension Chronic oral medication to treat Bronchial Asthma → Bronchodilating effects of stimulation β 2 Adrenergic effects 0.5mg/kg im antiemetic effect

38. CVS: ↑ SBP→is less intense ↑systemic & DBP ,tachycardia & ↑CO Renal & splanchnic blood flow ↓ Coronary & skeletal muscle flow ↑ ↑ myocardial contractility due to stimulation of β 1 receptors

39. PHENYLEPHRINE 3 dihydroxy phenyl ethyl amine,synthetic non catecholamine Phenylphrenine lacking a 4-hydroxy group on the benzene ring Stimulation 1-adrenergic receptors by direct effect & indirect acting →release NE Phenyl primarily causes vasoconstriction CNS stimulation is minimal 50-200 ug iv bolus , is administered to adults to treat systemic BP decrease ,that accompany systemic nervous system blockade produced by a regional anaesthesia & peripheral vasodilation following administration of injected & inhaled anaesthesia Useful in CAD & AS because it ↑ CPP without chronotropic side effect Continous infusion 20-100ug/min in adult to maintain normal BP during surgery ↑ systemic BP in combination with inhaled Nitrous Oxide →greater improvement in arterial O2

40. Topically applied→Nasal decongestant Nasal spray→1% solution →the same concentration as undiluted phenylephrine ampule in operating room CVS: Dose dependent peripheral vasoconstriction & ↑ in SBP ,accompanied ↓ in CO Rapid administration 1 ug /kg to anaesthesized with CAD →transient impairement of Left ventricular global function Pulmonary artery pressure is ↑ Renal,Splanchnic,cutaneous blood flow ↓ Coronary Blood Flow ↑

41. METABOLIC EFFECTS: Stimulation of  receptors by continous infusion of phenylephrine during acute potassium loading intereferes with movement of potassium ion across cell membrane into cells

42. VASOPRESSIN Available in 2ML Ampoules containing 20IU/ml of synthetic vasopressin Onset:immediate given iv Duration 20min Management of refractory hypotension during anaesthesia (1mg) in patients who have taken ACEI & ARB.& uncontrolled hemorrhage from esophageal varices Hemodynamic stabilization in the presence of hemorrhage & septic shock Management of refractory cardiac arrest Lypressin is synthetic analogue of AVP that produces antidiuresis for about 4 hours after intranasal administration

43. MEPHENTERMINE Mephentermine sulphate Availability: It is available in 10 ml vials containing 30 mg/ml of mephentermine . It is also available as 1 ml ampoule containing 15 mg/ml of mephentermine . Uses, dose and route : As a vasopressor: Mephentermine is an indirectly-acting vasopressor, acting on both alpha and beta receptors. It is usually diluted to a concentration of 6 mg/ml. It is given as 6 mg bolus and repeated as required. It is one of the commonest vasopressors used to treat hypotension under anaesthesia . Adverse effects : Mephentermine may cause uterine artery constriction and is not the preferred drug to treat hypotension consequent to spinal anaesthesia in pregnant patients for Caesarean section. Onset : Almost immediately if given IV, within 5-15 min if given IM Duration : 15-30 minutes when given IV, 1-4 hours if given IM Elimination : It is metabolized by liver by demethylation and excreted in the urine.

44. SEPTIC SHOCK The typical hemodynamic pattern in septic shock includes low cardiac filling pressures(CVP or wedge pressure ),a high cardiac output & a low systemic vascular resistance i.e , Typical Pattern: Low CVP / High CO /Low SVR Because of the high cardiac output & peripheral vasodilation, septic shock is known as hyperdynamic shock or warm shock In the advanced stages,cardiac dysfunction is more prominent & CO is reduced ,resulting in hemodynamic pattern that resembles cardiogenic shock( i.e ↑CVP,↓ CO,↑ SVR)

45. Sepsis is life threatening organ dysfunction caused by dysregulated host response to infection Sepsis screening,education,measurement of sepsis bundle performance,patient outcomes & actions for identified opportunity Sepsis standard operating procedure-Early Goal Directed Therapy,Components of Sepsis Bundle,Early identification

46. SURVIVING SEPSIS CAMPGAIN: International Guidelines for Management of Sepsis and Septic Shock 2021 SCREENING AND EARLY TREATMENT For hospitals and health systems, using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment recomended . Strong recommendation, moderate quality of evidence for screening. Strong recommendation, very low-quality evidence for standard operating procedures >A variety of clinical variables & tools – Systemic Inflammatory Response Syndrome criteria,vital signs,signs of infection,quick Sequential Organ Failure or Sequential Organ Failure Assesment criteria,National Early Warning score,Modified Early warning score

47. 2 . INITIAL RESUSCITATION > Sepsis and septic shock are medical emergencies, treatment and resuscitation should begin immediately. Best practice statement >For patients with sepsis induced hypoperfusion or septic shock at least 30mL/ kg of IV crystalloid fluid should be given within the first 3hr of resuscitation suggested 3. MEAN ARTERIAL PRESSURE . > For adults with septic shock on vasopressors, an initial target mean arterial pressure (MAP) of 65mm Hg over higher MAP targets recommended. Strong , moderate-quality evidence 4. INFECTION For adults with suspected sepsis or septic shock but unconfirmed infection, continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected . Best practice statement

48. > .Administration of intravenous antimicrobials should be initiated as soon as possible after recognition and within one hour for both a) septic shock and b) sepsis without shock ” Strong, very low quality of evidence (Sepsis without shock) strong recommendation > For adults with possible sepsis without shock , rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness . > Empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage) recommended 5. HEMODYNAMIC MANAGEMENT For adults with sepsis or septic shock, crystalloids as first-line fluid for resuscitation used using starches for resuscitation not recommended. Strong , high-quality evidence

49. For adults with septic shock, using norepinephrine as the first-line agent over other vasopressors recommended Started with a dose of 0.05-0.15ug/kg/mi n For adults with septic shock on norepinephrine(range of . 2 5 - . 5 μg /kg/ min ) with inadequate mean arterial pressure levels, we suggest adding vasopressin(0.01-0.04U/min) instead of escalating the dose of norepinephrine Weak, moderate quality evidence

50. For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, adding epinephrine( initial dose rate 0.01-0.2ug/kg/min to a max dose of 0.5-2ug/kg/min) Suggested Weak , low quality of evidence For adults with septic shock, suggestion is against using terlipressin . Weak, low quality of evidence For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, either adding dobutamine (usual 2-5ug/kg/min ) to norepinephrine(0.05ug/kg/min) or using epinephrine alone suggested. Weak, low quality of evidence

51. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, suggestion against using levosimendan . Weak , low quality of evidence (NEW) For adults with septic shock, invasive monitoring of arterial blood pressure over noninvasive monitoring, as soon as practical and if resources are available. Weak, very low quality of evidence For adults with septic shock, starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Weak, very low quality of evidence (NEW) Using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock ” Weak recommendation, low quality of evidence U sing crystalloids over gelatins when resuscitating patients with sepsis or septic shock.” Weak recommendation, low quality of evidence

52. 5.VENTILATION For adults with sepsis-induced ARDS, using a low tidal volume ventilation strategy (6mL/kg), over a high tidal volume strategy (> 10mL/kg) & using an upper limit goal for plateau pressures of 30cm H2O, over higher plateau pressures recommended prone ventilation for greater than 12hr daily 6. ADDITIONAL THERAPIES IV hydrocortisone to treat septic shock patients is not suggested if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability . If this is not achievable, IV hydrocortisone at a dose of 200mg/day recommended.”

53. For adults with sepsis or septic shock a restrictive (over liberal) transfusion strategy used For adults with sepsis or septic shock, using pharmacologic venous thromboembolism (VTE) prophylaxis unless a contraindication to such therapy exists. using low molecular weight heparin over unfractionated heparin for VTE prophylaxis For adults with sepsis or septic shock, initiating insulin therapy at a glucose level of ≥ 180mg/ dL (10 mmol /L ). 7. LONG-TERM OUTCOMES AND GOALS OF CARE For adults with sepsis or septic shock, discussing goals of care and prognosis with patients and families over no such discussion.

54. ANAPHYLACTIC SHOCK It Is An Immediate Threat To Life,with Profound Hypotension From Systemic Vasodilatation & Massive Fluid Loss Through Leaky Capillaries Because Of The Potential For Rapid Deterioration,anaphylactic Shock Requires Prompt & Aggressive Management

55. EPINEPHRINE: Life threatening allergic reaction/anaphylactic 0.5-1 mg im .(0.5ml 1:1000 sol) 50-100ug boluses iv 100-500ug sc VOLUME RESUSCITATION: It can begin by infusing 1-2 L of crystalloid(or20ml/kg) or 500 ml of isotonic colloid fluid ( eg 5% albumin) over the first 5 min REFRACTORY HYPOTENSION: Persistant hypotension despite epinephrine infusion & volume resuscitation can be managed by adding glucagon or another vasopressor such Norepinephrine or dopamine

56. SUMMARY Understand appropriate clinical application of vasopressors & inotropic agents In hyperdynamic septic shock , norepinephrine is the 1 st agent.Vasopressin as second line agent to reduce need for other pressors For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, either adding dobutamine to norepinephrine or using epinephrine alone suggested . In anaphylactic shock,1 st line shock is Epinephrine followed by vasopressin as 2 nd line agent Epinephrine is the 1 st line agent in hypotension after CABG