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Shock: Pharmacology

Shock: alteration in perfusion leading to diffuse cellular hypoxia & end-organ dysfunction
NOT synonymous with hypotension! Can have shock w/o hypotension or hypotension without shock (e.g. cyanide cant use O2)

Most organs regulate blood flow over a wide range of MAP This curve can be shifted to the right: may need a higher blood pressure to maintain blood flow (e.g. partially treated HTN)

Causes of shock: (generally all of these active in septic shock) Inadequate blood pressure Impaired cardiac function Hemodynamic parameters of distributive shock SVR CO (in other types of shock, CO SVR) filling pressure (PCWP), central venous pressure

Impaired vascular tone Impaired cellular function

Goals of therapy: Optimize end organ delivery Cardiac output Hemoglobin Oxygen delivery (cardiac index x arterial oxygen content; Hb / SaO2 drive arterial oxygen content) Blood pressure (but CO with many things we give to maintain BP!) ABCs too: Supplemental oxygen, establish airway; Vascular access, provide adequate volume; Support BP / CO

Treatment of septic shock: Overview

Strategy Establish likely diagnosis Notes Use Hx, clinical exam (urine output, peripheral exam, mentation) Consider pulmonary artery cath in rare circumstances Send Cx 1st, but dont wait for cultures to come back (start empiric therapy)
door-to-abx time is important! mortality with delay in antibiotic delivery - make sure the pt gets them! Your other measures are just stabilizing to buy time for abx to work

Give appropriate early abx

Volume resuscitation Vasopressors (& consider inotropes) Measure surrogates of organ perfusion / pressure Move patient to monitored area DO NOT HARM

Empiric coverage: most likely organisms (nursing home / community / etc) local resistance patterns Maintain organ perfusion Support organ perfusion Capillary refill, urine output, mentation MAP 65 mm Hg, CVP 8-12 mm Hg, urine output 0.5 cc/kg/hr Consider early measurement of lactate / venous O2 sat Get pt to where trained personnel can manage them Avoid nosocomial complications (cath infections, vent-assisted pneumonia, etc) 1

Vasoactive Medications for Shock

Volume resuscitation in shock
Prior to starting vasoactive medications, ENSURE ADEQUATE INTRAVASCULAR VOLUME You need lots of volume (these patients are leaky!) MAKE SURE YOU FILL THE TANK FIRST Give LOTS (e.g. 3L immediately, 6L in 6h, 8-9L over 24h) 0.9% NS Ringers Lactate CRYSTALLOID IS THE BEST, & GIVE A LOT OF IT! Easily accessible, cheap Potential rapid distribution into extravascular compartments Less volume needed Theory: oncotic pressure w/ distribution to extravascular compartments More expensive Meta-analysis does NOT support routine use of colloids



Albumin Gelatin Pentastarches

Blood products

Albumin isnt better than NS Pentastarch less fluid, but mortality (dont use!)

Theoretically best (can carry oxygen) But no routine value in non-hemorrhagic shock Doesnt increase O2 uptake

When to give vasopressors

When preload is adequate (adequate volume resuscitation), but patient still hypotensive Patient moribund (e.g. SBP 40) can give volume + vasopressors concomitantly Dont start prematurely: youre increasing afterload (PVR cardiac workload)

Vasopressor overview
Drugs that raise blood pressure (not synonymous with catecholamines, but many are) Norepinephrine Phenylephrine Epinephrine Vasopressin Dopamine

Most are catecholamines (dopamine, dobutamine, NE, E, isoproterenol, dopexamine) CV effects via adrenergic receptors (complex group of glycoproteins, use G-proteins to mediate action) Remember that they have multiple organ effects too need to recognize these effects! Types of adrenergic receptors involved in blood pressure -adrenergic -adrenergic Dopaminergic In peripheral vascular In cardiac muscle Vasoconstriction inotropy / chronotropy Endogenous catecholamine response SNS response; try to preserve homeostasis in face of shock / other stretches Norepi from sympathetic nerves (modulated by pH, adenosine concentration, PGE2) Epi primarily from adrenal gland; some contribution from other chromaffin tissue o Circulating hormone; small changes in [epi] big hemodynamic effects! Exogenous catecholamines Pts with shock have catecholamine levels (endogenous) But inadequate or inadequate end-organ response? Treatment give exogenous catecholamines (or other vasoactive meds) for shock pts 2

Specific vasopressors
Low doses: works on splanchnic circulation only (just dopaminergic receptors) High doses: works on alpha (vasoconstrict), beta receptors (ionotropic & chronotropic effects) more dopamine End result: increased HR & BP Limitation: increases HR (not great for patients with already highish HRs) Works on alpha > beta receptors, but both Has less chronotropy than dopamine but more alpha-adrenergic activity (better at maintaining BP) Maybe better than dopamine for patients with higher heart rates Really potent in high doses (both alpha & beta effects) Used for anaphylaxis mostly Beta effects: powerful inotrope & chronotrope No alpha effects - not a pressor, so you can't use it alone for shock Rarely used in general Beta effects: inotrope & chronotrope (a lttle less powerful than isoproterenol) No alpha effects (can't use alone for shock - not a pressor) Big alpha effects (good pressor) No beta effects (not a chronotrope / inotrope) - like the opposite of dobutamine phenylephrine Good for, say, a young patient with a good heart rate - want to increase BP w/o affecting HR But bad if the cardiac output is down (would just increase afterload & knock down CO even more!)





Catecholamines vs Pressors vs Inotropes

Pressors have effects Catecholamines that arent pressors: dobutamine & isoproterenol (CANT USE ALONE FOR SHOCK!) Inotropes have effects; may or may not have effects Inotropes that arent pressors: dobutamine, milronone/amrinone, isoproterenol (CANT USE ALONE FOR SHOCK!) Pressors that arent inotropes (or catecholamines) Phenylephrine, vasopressin, angiotensin,

Choosing a vasopressor
First line Excessive tachycardia Inadequate control of hypotension Anaphylaxis Generally dopamine or norepinephrine (pressors & inotropes) No good data to say one vs the other (see recent NEJM though) Phenylephrine, norepinephrine are 2nd choices Norepinephrine Epinephrine

Renal splanchnic blood flow theoretically low-dose dopamine should increase splanchnic / renal blood flow May increase urine output, but doesnt increase solute clearance Take-home: dont use dopamine for kidney failure (no evidence of benefit) 3

Adjunctive Therapies in Septic Shock

Goal-directed therapy
Oxygen delivery in sepsis May have a pathologic supply dependency Would mean that you need O2 delivery? But no benefit to increasing oxygen delivery with Rx CO or venous output but also consumption Doesnt help outcomes May be a benefit to early goal-directed therapy in the treatment of severe sepsis, septic shock Use complicated algorithm For instance, try to maintain venous O2 sat measured via central venous line; keep above 70%

Really complicated pathophysiology of sepsis No good way to target single immune mediators to change outcomes

Patients in septic shock have less arginine vasopressin Give vasopressin in septic shock can need for exogenous catecholamines o But multicenter trial: NE + vasopressin no better outcomes, but no worse either o Occasionally used if pt has complications from NE (can decrease dose of NE!)

NO synthase inhibitors
Blocking NO synthase NO blood pressure But risk of refractory shock, cardiac death patient mortality (DONT GIVE THIS

Lots of trials: maybe giving glucocortcoids can make end organs more responsive to catecholamines?
o o o High doses in early sepsis didnt really work; infectious compliations Lower doses in really sick patients ( lactate, SBP, even with vasopressors) maybe some benefit No effect in less sick patients with low doses

Take home: really sick patients with refractory hypotension may benefit; most patients dont

Lots of interest in blocking prothrombin thrombin conversion (e.g. antithrombin III, TFPi) AT III & TFPi didnt work, but activated protein C improves outcomes for some patients in some trials

Activated protein C Really expensive & intercranial bleeding is a big problem! Use rarely (only 1/20 pts you think about will meet the criteria) Cant use in ESRD / end-stage liver dz

Summary: Therapy of Sepsis

Therapy Give appropriate antibiotics early & empirically Use adequate fluids Crystalloids best for fluid resuscitation Use blood for sepsis infrequently Vasopressors to support MAP Steroids Goal-directed therapy with venous O2sat Activated protein C (APC) Vasopressin Notes Within 1h of hypotension Lots! Up to 9L in 1st 24h No benefit to giving albumin Primarily as part of early goal-directed therapy (hgb < 10) No benefit in established shock Choose based on physiologic effect, side effect profile Only if hypotensive for <1h and risk of steroids < benefit Reasonable in early septic shock (1st 6 h) Dont use after 48h For patients who meet PROWESS criteria Need APACHE II > 25, low risk of bleeding Not first line Consider to NE dose on pts already on NE