Shock Syndromes - ACCP€¦ · Zarychanski R, et al. JAMA 2013;309:678-88 Workbook Pages 1-154, 1-155. Agents to Treat Shock - Vasoactives Indicated when hypotension persists after

Updates in Therapeutics® 2015: Critical Care Pharmacy Preparatory Review Course

Shock SyndromesIshaq Lat, Pharm,D., FCCP, FCCM, BCPSRush University Medical CenterChicago, Illinois

Seth Bauer, Pharm.D., FCCM, BCPSCleveland ClinicCleveland, Ohio

Conflict of Interest Disclosures

Ishaq Lat I have no conflicts of interest to disclose

Seth Bauer Consultant for Johnson, Graffe, Keay, Moniz &

Wick Law (case regarding vasopressin)

Learning Objectives1. Distinguish between various shock syndromes

according to a patient’s clinical and hemodynamic parameters

2. Identify critical determinants affecting oxygen delivery

3. Construct a hemodynamic monitoring plan that incorporates data from monitoring devices and markers of perfusion

4. Devise a treatment strategy for the management of a patient with shock

Agenda What is “shock”? Pathophysiology of shock syndromes Monitoring techniques and markers of perfusion Differentiating between shock syndromes Resuscitation end points Treatment of shock

Hypovolemic Obstructive Distributive/Vasodilatory

Septic shock will be covered in a separate lecture Cardiogenic (will be covered in a separate lecture)

What is Shock?

Acute circulatory failure best characterized as “oxygen debt”

Hypotension may not always be the defining characteristic

Clinical exam: “windows” of perfusion Mentation Integumentary system Kidney function

Workbook Page 1-141

The Physiology of the Circulatory System MAP HR CO SVR CVP PCWP

Workbook Pages 1-141, 1-142

The Mechanisms of Oxygen Delivery VO2 = DO2

DO2 = 10 x CO x CaO2

CaO2 = (1.34 x Hgb x SaO2) + (0.003 x PaO2) VO2 = 10 x CO x (CaO2 – CvO2) DO2 is prioritized for the vital organs of the heart

and brain


Hemodynamic Monitoring Devices


Device Major Advantages LimitationsCentral venous catheter (CVC)

• Easier and safer to insert than a PAC

• Continuous ScvO2 available

• CVP not accurate predictorof fluid responsiveness

• ScvO2 ≠ SvO2

Pulmonary artery catheter (PAC)

• Directly measure CO and SvO2• Assess pulmonary artery pressures

• No superiority data• Arrhythmias• VO2 estimate typically used in Fick CO calculation

Arterial pulse pressure waveform analysis (FloTrac™/ Vigileo™, PiCCO™, LiDCO™)

• Continuous CO measurement• Assessment of stroke volume variation (SVV) and pulse pressure variation (PPV)

• Minimally invasive

• Accuracy issues• Arterial catheter waveform• Mitral or aortic valve dysfunction

• Arrhythmias (SVV and PPV more of a concern than CO or CI)

• SVV and PPV rely on positive pressure ventilation

ScvO2 = central venous oxygen saturation

Markers of Perfusion - Lactate Lactate usually produced under

anaerobic conditions Concentrations >2 mmol/L should be evaluated Elevated when production exceeds clearance

Causes of elevated lactate concentrations Tissue hypoxia (O2 demand > DO2) Impaired clearance (hepatic dysfunction) Aerobic glycolysis (epinephrine) Impaired oxidative phosphorylation (propofol)

Workbook Page 1-146 Kraut JA, Madias NE. N Engl J Med 2014;371:2309-19

Markers of Perfusion - SvO2, ScvO2

SvO2 and ScvO2 reflect tissue oxygen extractionHeart

TissuesArteriesVeinsCvO2

(SvO2 ~75%)DO2(SaO2 ~100%)

ERO2(~25%) SvO2 ≈ 1 - ERO2

ScvO2 ≠ SvO2, but correlate Femoral CVC cannot be used for ScvO2

Must be interpreted in context of other markers

Inadequate DO2 ↑ERO2 ↓SvO2

Workbook Page 1-146

Patient Case # 1

77-year-old male with light-headedness and fatigue

History: hypertension, asthma, and GERD Increasing melena over past 24 hours BP 88/54 mm Hg, HR 124 beats/min,

RR 18 breaths/min, temperature 39°C WBC: 10.2, Hgb: 6.6 g/dL, platelets 180,000 Which value most contributes to reduced DO2?

Workbook Page 1-148

Patient Case #1

A. History of hypertension

B. Hemoglobin

C. Tachycardia

D. Leukocytosis

Workbook Page 1-148

Differentiation of Shock StatesShock State CVP PCWP CO* SVR

Hypovolemic ↓ ↓ ↓ ↑Cardiogenic ↑ ↑ ↓ ↑Obstructive

Impaired diastolic filling ↑ ↑ ↓ ↑Impaired systolic contraction ↑ ↓ ↓ ↑

Vasodilatory/Distributive

Pre-resuscitation ↓ ↓ ↓ ↓Post-resuscitation ↑ ↑ ↑ ↓

*ScvO2 or LV function on echocardiography often used as a surrogate for CO

Workbook Page 1-149

Patient Case # 2 77 y/o man with cirrhosis p/w hematemesis Hgb 9.2 7.3 g/dL and BP 82/36 mm Hg Given 2L LR and 2 units blood Hgb 9.1 g/dL PAC placed: CVP 8 mm Hg, PCWP 14 mm Hg,

CO 7 L/min, MAP 58 mm Hg With which shock type are the patient’s

hemodynamic parameters most consistent?A. HypovolemicB. ObstructiveC. VasodilatoryD. Cardiogenic

Workbook Page 1-151

Blood pressure Generally MAP >65 mm Hg or SBP >90 mm Hg

Adequate end-organ perfusion Examples

Resolution of altered mental status Urine output >0.5 ml/kg/hr

May be challenging to assess Lack of fluid responsiveness Adequate DO2

Resuscitation End Points

Workbook Page 1-149

End Points - Fluid Responsiveness Fluid given to increase stroke volume and CO Giving unnecessary fluids may be detrimental Best predicted by dynamic markers CVP <8 or PCWP <12 mm Hg: ~50% prediction Stroke volume variation (SVV) or pulse pressure

variation (PPV): ~85-95% prediction SVV and PPV not accurate with arrhythmias

and require mechanical ventilation Passive leg raise (PLR) test another option

Osman D, et al. Crit Care Med 2007;35:64-8Marik PE, et al. Crit Care Med 2009;37:2642-47


End Points - Adequate DO2

CO, SvO2, and ScvO2

Shouldn’t target pre-defined “supra-normal” levels Best interpreted as “adequate” or “inadequate”

Adequacy determined with concomitant assessments If inadequate, target interventions to increase DO2

Fluids (if fluid responsive), blood (Hgb<7), or inotropes

Likely more important to optimize DO2 in early vs. later resuscitation

Gattinoni L, et al. N Engl J Med 1995;333:1025-32Teboul J-L, et al. Crit Care 2011;15:1005

Workbook Page 1-152

Adequate DO2, continued Lactate clearance and normalization Decline in lactate concentration suggests improved

global tissue perfusion Improving DO2 may decrease lactate Does not require invasive monitoring Most frequently utilized in patients with septic shock


Patient Case # 3 Previous patient developed hypoxemia requiring

intubation and mechanical ventilation FIO2 90% sedated and given atracurium Remained hypotensive with low urine output Which value best predicts fluid responsiveness?

A. CVP 7 mm Hg

B. PCWP 11 mm Hg

C. SVV 16%

D. MAP 62 mm Hg

Workbook Page 1-152

Agents to Treat Shock - Fluids Crystalloids usually initial resuscitation choice Similar outcomes with 0.9% NaCl and 4% albumin

Increasing interest in crystalloids with lower chloride content Chloride can cause afferent renal arteriole

vasoconstriction and lower the strong ion difference Chloride-poor fluids (e.g. LR) associated with less

AKI than chloride-rich fluids (e.g. 0.9% NaCl) Hydroxyethyl starches should be avoided

SAFE Study Investigators. N Engl J Med 2004;350:2247-56Yunos NM, et al. JAMA 2012;308:1566-72

Zarychanski R, et al. JAMA 2013;309:678-88Workbook Pages 1-154, 1-155

Agents to Treat Shock - Vasoactives Indicated when hypotension persists after fluid

resuscitation or severe hypoperfusion while fluids infusing

Workbook Page 1-156

53%

26% 24%

49%

20% 12%0%

25%

50%

75%

28-Day Mortality Open-label NE Arrhythmias

DopamineNorepinephrine (NE)

n=1679p=0.10

p<0.001 p<0.001

De Backer D, et al. N Engl J Med 2010;362:779-89

Selection of a specific agent based on shock state, pathophysiology, and therapeutic goal

Patient Case # 5 28 y/o male presented to SICU with shock after

appendectomy c/b perforation in the OR Given 2L LR, 1L 5% albumin, and 2L 6% HES MAP 64, lactate 5.2, NE 14 mcg/min, ScvO2 61% Echo: large ventricles with poor contractility Which action is best?

A. Start phenylephrine

B. Start vasopressin

C. Increase norepinephrine

D. Start epinephrineWorkbook Page 1-157

Hypovolemic Shock

Commonly attributed to trauma, hypovolemic shock can also occur due to: Gastrointestinal bleeding Surgical bleeding Obstetrical bleeding Pharmacologic toxicity

Estimated 2 million deaths per year due to hemorrhage following trauma

Workbook Page 1-157

Classification of Trauma Hemorrhage

Class I Class II Class III Class IV

Blood loss (mL)/% <750< 15%

750-100015-30%

1500-200030-40%

>2000>40%

HR (beats/minute) <100 >100 >120 >140

RR (breaths/minute) 14-20 20-30 30-40 >35

UOP (mL/hour) >30 20-30 5-15<5

CNS symptoms Normal Anxious Confused Lethargic

ATLS manual. American College of Surgeons, 1997:103-112Workbook Page 1-157

41-year-old male s/p motorcycle accident Rib, pelvis, and bilateral femur fractures BP: 82/4 mm Hg HR: 125 beats/minute RR 34 breaths/minute 35°C Which is the appropriate class of hypovolemic

shock according to the ATLS?

Workbook Page 1-139

SAQ #7

A. Class I

B. Class II

C. Class III

D. Class IV

Workbook Page 1-139, Answer: 1-176

SAQ #7

Physiologic Response to Hemorrhage Sympathetic response

Low-pressure and high-pressure receptors activated HR, myocardial contractility, arteriolar tone

Parasympathetic response vagal tone, HR

Intrinsic response Redistribution of interstitial fluid into vascular compartment

Humoral response RAAS activation

Workbook Page 1-158

Resuscitation of Hypovolemic Shock Due to Bleeding1. Identify and treat reversible bleeding cause2. Fluids

Indication: diminished mental status, SBP < 90 mm Hg LR and NS preferred (crystalloids)

3. Transfusion strategies Indication: > 30% total blood volume loss Maintain Hgb > 10 g/dL (trauma), > 7 g/dL (GIB)

4. Vasopressors Temporizing measure

Workbook Page 1-158

Burn Resuscitation

Third-spacing of intravascular fluid common following burn injury

Fluid resuscitation is needed to maintain intravascular volume

Therapeutic goals: UOP > 0.5 mL/kg/hr (adults), > 1 mL/kg/hr (children)

Parkland Formula: 4 mL/kg/% TBSA (LR)

2 mL/kg/% over first 8 hours 2 mL/kg/% over remaining 16 hours


Patient Case #6

29-year-old man (85 kg, 72 inches) 40% TBSA burn to lower extremity and buttocks Which is the best option for resuscitations?

Workbook Page 1-161

Patient Case #6

A. 15 L of LR over 24 hours: 1000 mL/hour x 12 hours, followed by 250 mL/hour, titrating to UOPof 1 mL/kg/hour

B. 13 L of LR over 24 hours: initiate 813 mL/hour x 8 hours, followed by 406 mL/hour, titrating to UOP of 0.5 mL/kg/hour

C. 12 L of LR over 12 hours: initiate 1 L/hour, titrating to UOP of 0.5 mL/kg/hour

D. 24 L of LR over 24 hours: initiate 1 L/hour, titrating to UOP of 0.5 mL/kg/hour

Workbook Page 1-161

Management of Coagulopathy

Correction of hypothermia (core > 34°C, acidemia (pH < 7.20), and hypocalcemia(ionized calcium > 4.4 mg/dL)

PRBCs: plasma: cryoprecipitate: platelets 1:1:1:1

Workbook Page 1-159

Treatment Options for Bleeding

rFVIIa PCCs Tranexamic acid Alpha-aminocaproic acid

Workbook Page 1-159

Recombinant factor VIIa

Activates TF, factor X, and factor IX RCT data lacking data to support survival

benefit Increased arterial and venous

thromboembolic events

Yank V, et al. Ann Intern Med 2011;154:529-40Workbook Page 1-159

Prothrombin Complex Concentrates (PCCs)

Factor II(units/vial)

Factor VII(units/vial)

Factor IX(units/vial)

Factor X(units/vial)

Bebulin VH 120 13 100 139

FEIBA* 650 1200 700 550

Kcentra† 380-800 200-500 400-620 500-1020

Profilnine SD 148 11 100 64

* Contains mainly non-activated factors II, IX, and X; factor VII is mainly in the activated form. Values expressed are for the FEIBA 500 units vial, which also contains Protein C 550 units.

† Values expressed are for the Kcentra 500 units vial, which also contains Protein C 420-820 units and Protein S 240-680 units.


Tranexamic Acid in Trauma Patients Competitive inhibition of plasminogen Prevents dissolution of fibrin clot

CRASH-2 study. 40 countries, n=20,211 adult trauma patients TXA (n=10,096) vs. placebo (n=10,115) 1 g over 10 minutes, 1 g infusion over 8 hours

All-cause mortality: 1463 (14.5%) vs. 1613 (16.0%) RR (0.91; 95% CI, 0.85-0.97, p=0.0035)

Death due to bleeding: 489 (4.9%) vs. 574 (5.7%) RR (0.85; 95% CI, 0.76-0.96, p=0.007)

Lancet 2010;376:23-32Workbook Pages 1-159, 1-160

Overview of Target-SpecificOral Anticoagulants

Warfarin Dabigatran Apixaban Rivaroxaban

Action Vitamin K antagonist

Factor II inhibitor

Factor X inhibitor

Factor X inhibitor

Peak action 4-5 days ~ 2 hours ~ 2 hours ~ 2 hours

Half-life ~ 2 days 24 hours 12 hours 12 hours

Renal elimination

-- +++(CI with CrCl< 30 mL/min)

+(CI with CrCl< 15 mL/min)

++(CI with CrCl< 30 mL/min)


Kcentra prescribing information. CSL Behring LLC, April 2013

Reversal of Warfarin Indications: Hgb decrease > 2 g/dL within 24 hours Bleeding in critical site

Warfarin: KcentraINR 2-4 INR 4-6 INR > 6

Kcentra dose(Factor IX units/kg)

25 35 50

Maximum dose(Factor IX units/kg)

2500 3500 5000


Treatment of Bleeding Due to Target-Specific Oral Anticoagulants Reversal of TSOACs is challenging Activated charcoal: ingestion < 2 hours Dabigatran: hemodialysis Proposed reversal with rFVIIa and PCCs is

variable in small studies Reversal agents in development

Rivaroxaban: r-Antidote (PRT064445), binds Xa site Dabigatran: aDabi-Fab, monoclonal antibody TSOACs: PER977, binds Xa and IIa

Workbook Page 1-160

Patient Case #7

67-year-old male shot in buttocks deer hunting 500-mL LR in transfer BP: 92/48 mm Hg HR: 118 beats/minute RR: 25 breaths/minute Temperature: 35°C Drowsy and incoherent following morphine 2 mg Which is the best resuscitative strategy?

Workbook Page 1-162

A. LR 1000 mL/hour to target UOP > 30 mL/hour and SBP > 100 mm Hg

B. Transfuse 2 units PRBCs, 1L LR bolus to target UOP > 1 mL/kg/hour

C. Transfuse 2 units PRBCs, 2 units FFP, and 1L bolus of LR to target normal mentation

D. LR 1L/hour to maintain UOP > 30 mL/hour, SBP > 90 mm Hg, and normal mentation

Patient Case #7

Workbook Page 1-162

Obstructive Shock Extra-cardiac obstruction to flow (↓CO) Impaired diastolic filling Examples include cardiac tamponade, tension

pneumothorax, and constrictive pericarditis Inhibition of venous return ↓RV preload Treatment

1. Mechanical (e.g., pericardiocentesis)2. Fluids (recommended, but may be ineffective)3. Vasopressors to maintain perfusion pressure Inotropes likely ineffective (not recommended)


Impaired Systolic Contraction Examples include

pulmonary embolism (PE) and acute on chronic pulmonary hypertension (PH)

Ventricular afterload acutely increased

Right ventricular (RV) pressure overload

Reduced cardiac output

Systemic hypotension

Reduced RV tissue perfusion

RV free wall ischemia

Reduced RV free wall contractility

Greyson CR. Crit Care Med 2008;36[Suppl.]:S57-S65Workbook Page 1-162

Fluids PH: Most require diuresis, not fluid administration PE: Recommended, but avoid RV volume overload

Vasopressors recommended (typically NE) Inotropes likely more effective in PH than PE Disease-specific therapies PH: Aerosolized pulmonary vasodilators (iNO, aEPO) PE: Thrombolytics or embolectomy

Impaired Systolic Contraction -Treatment


Thrombolytics for PE No mortality benefit in unselected patients Recommended for massive PE (hypotension) Controversial for submassive PE (RV

dysfunction or myocardial necrosis [or both])

Workbook Page 1-163, 1-164 Jaff MR, et al. Circulation 2011;123:1788-1830Meyer G, et al. N Engl J Med 2014;370:1402-11

2.6%

6.3%

2.4%

5.6%1.2% 0.2%0%

4%

8%

7-Day Death orDecompensation

Major ExtracranialBleeding

Stroke

TenecteplasePlacebo

n=1005p=0.02 p<0.001

p=0.003

Risk/benefit determined on case-by-case basis

Patient Case # 8

48 y/o female (weight 75 kg) with subsegmental PE Echo: No RV dilation or dysfunction HR 118, BP 98/62, TnT 0.06 ng/mL, BNP 60 pg/mL In addition to parenteral anticoagulation, which is

best for the patient?A. Tenecteplase 40mg bolus

B. Alteplase 100mg infusion over 2 hours

C. Alteplase 50mg bolus

D. No thrombolytic therapy

Workbook Page 1-166

Vasodilatory and Distributive Shock Hypoperfusion due to decreased SVR Most common shock type Septic shock most frequent cause Neurogenic shock and immune-mediated

(“anaphylactic”) shock are other causes Failure of vascular smooth muscle constriction Neurogenic shock: decrease in sympathetic outflow

from the CNS Immune-mediated shock: IgE-mediated mast cell or

basophil degranulation Vasodilation leads to decreased preload

Workbook Page 1-166 Landry DW, Oliver JA. N Engl J Med 2001;345:588-95

Address underlying cause Fluids Crystalloids initial fluid choice

Vasopressors Neurogenic: commonly norepinephrine first-line

Higher MAP target (85 mm Hg) in acute SCI Immune-mediated: epinephrine conventionally

Adjunctive agents (e.g., steroids) controversial

Vasodilatory and Distributive Shock, Treatment

Workbook Pages 1-167, 1-168 J Spinal Cord Med 2008;31:403-79Sampson HA, et al. J Allergy Clin Immunol 2005;115:584-91

Documents

Shock Syndromes - ACCP€¦ · Zarychanski R, et al. JAMA 2013;309:678-88 Workbook Pages 1-154, 1-155. Agents to Treat Shock - Vasoactives Indicated when hypotension persists after