Endpoints of Resuscitation for Circulatory Shock: When Enough is Enough?

Endpoints of Resuscitation for Circulatory Shock: When Enough is Enough? Emanuel P. Rivers, MD, MPH, IOM Vice Chairman and Research Director Departments of Emergency Medicine and Surgery Henry Ford Hospital Detroit, Michigan erivers1@hfhs.org Supplemental oxygen ± endotracheal intubation and mechanical ventilation Central venous and arterial catheterization Sedation and/or paralysis (if intubated) 8-12 mm Hg CVP <8 mm Hg Crystalloid Colloid Intubation and Mechanical Ventilation =65 and =9 mm Hg MAP ScvO 2 <65 mm Hg >9 mm Hg <7% Vasopressor or Nitroglycerin Transfusion of red cells to hematocrit =3% =7% <7% =7% Dobutamine & Digoxin Goals achieved Yes No Hospital admission 1

Communication Avoids Misunderstanding and Prevents Problems Inflammatory Mediators Produce Cardiovascular Insufficiency Increased Metabolic Demands: Fever, Tachypnea Hypovolemia,Vasodilation & Myocardial Depression Microvascular Alterations: Impaired Tissue Oxygen Utilization Cytopathic Tissue Hypoxia Fink, Crit Care Clin, 22 2

The Purpose of Resuscitation Perhaps Forgotten VO2 Delivery Dependent Endpoints and Tools Global tissue hypoxia Critical DO 2 Delivery Independent Optimum region DO 2 The Problem Uniformity of terminology Uniformity of goals Under-resuscitation Over-resuscitation Multiple outcome measures in clinical trials How do we solve the problem? Substrates Goal Directed Optimization of Cardiac Function O 2 ATP Glucose Endpoints of Resuscitation SvO 2 Lactate - Stress - Pain - Hyperthermia - Shivering - Work of breathing Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure DO 2 - PaO 2 - Hemoglobin - Cardiac Output (a-v)co 2 Microcirculation Happy Cell Base Deficit phi Mediators DO 2 3

Macro Endpoints Delivery Dependent Delivery Independent VO2 Physical Exam Heart Rate Blood Pressure Shock Index Urine Output CVP/PCWP Global tissue hypoxia Optimum region Critical DO 2 DO 2 Substrates Goal Directed O 2 ATP Glucose Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure 4

Effects of perfusion pressure on tissue perfusion in septic shock OBJECTIVE: To measure the effects of increasing MAP on systemic O2 metabolism and regional tissue perfusion in septic shock. DESIGN: Prospective study. SETTING: MICU and SICU patients in a tertiary care teaching hospital. PATIENTS: 1 patients with septic shock requiring pressor agents to maintain a MAP > 6 mm Hg after fluid resuscitation to a PAOP > 12 mm Hg. LeDoux, Crit Care Med, 2 Effects of perfusion pressure on tissue perfusion in septic shock INTERVENTIONS: Norepinephrine was titrated to MAPs of 65, 75, and 85 mm Hg in 1 patients with septic shock. Cardiac Index Lactate A-Gastric pco2 Urine Output 65 mmhg 4.7+/-.5 L/min/m2 3.1+/-.9 meq/l 13+/-3 mm Hg (1.7+/-.4 kpa) 49+/-18 ml/hr 85 mmhg 5.5+/-.6 L/min/m2 (p <.3) 3.+/-.9 meq/l (NS) 16+/-3 at 85 mm Hg (2.1+/-.4 kpa) (NS) 43+/-13 ml/h (NS) LeDoux, Crit Care Med, 2 5

Effects of perfusion pressure on tissue perfusion in septic shock CONCLUSIONS: Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism skin microcirculatory blood flow urine output splanchnic perfusion. LeDoux, Crit Care Med, 2 Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients Critical Care Medicine 1998;26:1646-1649 Todd Dorman, MD, FCCM; Michael J. Breslow, MD, FCCM; Pamela A. Lipsett, MD; Jeffrey M. Rosenberg, MD, PhD; Jeffrey R. Balser, MD, PhD; Yaniv Almog, MD; Brian A. Rosenfeld, MD, FCCM Radial artery pressure underestimates central pressure in hypotensive septic patients receiving high-dose vasopressor therapy. The higher mean femoral arterial pressures: immediate reduction in norepinephrine infusions in 11 of the 14 patients. Clinical management, based on radial pressures, may lead to excessive vasopressor administration. 6

6 58% 54% Mortality (%) 4 2 2% 37% No Vasopressor No Vasopressor to Low Dose Vasopressor No Vasopressor to High Dose Vasopressor Low Dose to High Dose Vasopressor 15% % Receiving Vasopressors 6 5 4 3 2 1-6 hours 6-72 hours -72 hours No Corticosteroids 8

Substrates Goal Directed O 2 ATP Glucose DO 2 - PaO 2 - Hemoglobin - Cardiac Output Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure An ICU Therapy Forever Changed A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy 9

Stop An International Crisis Transfusions do make a difference in shock or global tissue hypoxia states. Abuse to the clinician after giving blood Conservative management during the convalescent phase. Hemodilution After Volume 14 4 12 1 8 6 Control Treatment 35 3 25 * * * Control Treatment 4 2-6 hours 6-72 hours -72 hours 2 15 Baseline 3 hours 6 hours 7-72 hours 3.6 Liters More Fluid 6 ml No difference in blood transfused over 72 hours between groups 5 45 4 35 3 25 2 15 1 5 447.13 339.49 18 ml -72 hours 1

Hemodynamic Phases of Sepsis Transfusion Decisions Depend on the Clinical Sate Delivery Dependent Delivery Independent S OER Lactate S OER Lactate S OER Lactate DO 2crit DO 2 Even SvO 2 is a combination of various tissue beds. The coronary circulation is at the highest risks. 11

Hemodynamic Phases of Sepsis Transfusion Decisions Depend on the Clinical Sate Delivery Dependent Delivery Independent S OER Lactate S OER Lactate S OER Lactate DO 2crit DO 2 Transfusion Decisions Depend on the Clinical Sate Delivery Dependent Delivery Independent Dietrich, Critical Care, Med, 2 S OER Lactate Marik, S JAMA, 2 Herbert, NEJM, 21 OER Vincent, JAMA, 22 Lactate DO 2crit DO 2 12

Transfusion Studies EGDT, NEJM, 22 Hebert, NEJM, 1999 Vincent, JAMA, 22 Marik, JAMA, 1993 Setting ED ICU ICU ICU Time (hours) <1 24 hours Over 2 weeks Up to 48 hours Age 62-67 57-58 53-59 49.6 Hemoglobin 11.3 11.4 8.2-8.2 1.1-12.2* 9.9 Lactate (mm/l) 6.9-7.7 1.8±1.8-1.8±2.1 ---- 2.6 SvO 2 (%) 48.6-49.2 ---- ---- 69.5 CVP (mmhg) 5.3-6.1 ---- ---- Resuscitated Cardiac Index 1.7 1.9 ---- ---- 3.4 Transfusion Studies EGDT, NEJM, 22 Hebert, NEJM, 1999 Vincent, JAMA, 22 Marik, JAMA, 1993 APACHE 2.4±7.4-21.4±6.9 2.9±7.3-21.3±8.1 16.5-13.5 ---- Mortality And Endpoints 56-3.5% 22.2 vs. 28.1% (.5) 18.5-1% ICU 22-17% 28 day Decreased phi In shock or global tissue hypoxia? 1% 16-13% 2-23% Excluding dialysis patients, patients likely to die in 24 hours and patients in established septic shock (systolic blood pressure <9 mmhg). 13

Substrates Goal Directed O 2 ATP Glucose - Stress - Pain - Hyperthermia - Shivering - Work of breathing Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure DO 2 - PaO 2 - Hemoglobin - Cardiac Output 14

ScvO 2 SvO2 7-75% - + Stress Pain Hyperthermia Shivering Work of breathing DO 2 PaO2 Hgb Cardiac Output Using Metabolic Endpoints SvO 2 15

Lactate and Outcome (Mizock, Dis Mon, 1989) (Weil, Circulation, 197) Survivors Non-survivors Lactate (mm/l) 6 5 4 3 2 1 Clearance <24 hrs 24-48 hrs >48 hrs N = 76 8 16 24 36 48 Time (hrs) Survivors Nonsurvivors %Survival 27 1 21 6 77.8 3 19 13.6 (Abramson and Scalea, J Trauma, 1993) 16

Crit Care Med 24 Vol. 32, No. 8 Lactate (ED Admission - ED Discharge) ED Length of Stay (hrs) No clearance < mm/l/hr Intermediate clearance -1 mm/l/hr High clearance >1 mm/l/hr Lactate (mm/l) 14 12 1 8 6 4 2 14 N = 114 No Clearance 84 16 High Clearance ED Admission ED Discharge Crit Care Med 24 Vol. 32, No. 8 Lactate (ED Admission - ED Discharge) ED Length of Stay (hrs) Lactate Clearance % 8 7 6 5 4 3 2 1-1 -2-3 1 2 3 4 Quartiles of Lactate Clearance N = 243 17

Early Lactate Clearance 11 No Clearance 1 Intermediate Clearance High Clearance 9 MODS 8 7 6 5 4 3 6 12 24 36 48 6 72 Time (hr) p<.5 Mortality (%) 5 45 4 35 3 25 2 15 1 5 5 23 No Clearance Intermediate Clearance 12 High Clearance % Lactate Clearance Quartiles and mean Biomarker Levels over 72 Hours 1 9 8 Caspase-3 (ng/ml) 7 6 5 4 3 2 1 1 2 3 4 Lactate Clearance Quartiles 18

% Lactate Clearance Quartiles and mean Biomarker Levels over 72 Hours 1 9 8 7 IL-8 (pg/ml) 6 5 4 3 2 1 1 2 3 4 12 Lactate Clearance Gropus 1 Tumor necrosis factor a (pg/ml) 11 1 9 8 7 6 5 4 3 2 1 Caspase-3 (ng/ml) 9 8 7 6 5 4 3 2 1 1 2 3 4 1 2 3 4 Substrates Goal Directed O 2 ATP Glucose - Stress - Pain - Hyperthermia - Shivering - Work of breathing Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure DO 2 - PaO 2 - Hemoglobin - Cardiac Output Microcirculation Crit Care Med 24 Vol. 32, No. 9 19

The oxygen consumption-delivery relationship Microcirculatory Dysfunction 2

Lancet 22 Orthogonal polarization spectral (OPS) imaging allows visualisationof the microcirculation. Assessing microcirculatory flow in septic-shock patients who had a MAP > 6 mm Hg and CVP > 12 mm Hg. The infusion of.5 mg of nitroglycerin resulted in a marked increase in microvascular flow on OPS imaging. Improved recruitment of the microcirculation could be a new resuscitation endpoint in septic shock. Micro-Circulatory Defects Vascular occlusion and vasopressor use Ischemia and Cellular Hypoxia 21

Increasing O2 Consumption Bihari, NEJM, 1987 3-minute infusion of a vasodilator, prostacyclin (5 ng/kg/min in 27 critically ill patients with acute respiratory failure and measured: O2 delivery and uptake to tissues Extraction ratio (uptake/delivery) In the survivors: O2 extraction ratio fell increased. In the patients who died: O2 extraction ratio rose did not change. Increasing O2 Consumption Bihari, NEJM, 1987 Conclusion: (an underappreciated endpoint) Substantial O2 debt or cryptic shock in patients who subsequently die. Inadequate tissue oxygenation may be difficult to recognize Important mechanism in the development of irreversible multiple organ failure. 22

Oxygen Debt: To Pay or Not to Pay Direct Association of Decreased Increased Mortality Cardiac arrest (Rivers, Chest, 1994) Trauma (Moore, J of Trauma, 1992) Sepsis (Tuchschmidt, Chest, 1991) Acute myocardial infarction (Rady, Chest, 1993) Heart transplantation (Mancini, J Clin Monit, 1991) Liver transplantation (Chest, 1992) ARDS (Appel, Chest, 1992) 23

Substrates Goal Directed O 2 ATP Glucose Endpoints of Resuscitation SvO 2 Lactate - Stress - Pain - Hyperthermia - Shivering - Work of breathing Hemodynamic - Preload (CVP, PCWP) - Afterload (MAP, SVR) - Contractility (SV) - Heart Rate (BPM) - Shock Index (HR/SBP) - Coronary Perfusion Pressure DO 2 - PaO 2 - Hemoglobin - Cardiac Output (a-v)co 2 Microcirculation Happy Cell Base Deficit phi Mediators DO 2 Metabolic Endpoints of Resuscitation Delivery Dependent Delivery Independent VO2 ScvO 2 (a-v)pco 2 Gastric Tonometry Sublingual Cap. Base Deficit Lactate Global tissue hypoxia O 2 extraction Optimum region Pulmonary Artery Catheter in the ICU Critical DO 2 DO 2 24

(a-v) pco 2 Gradient < 5 mmhg PaCO 2 but PvCO 2 in circulatory failure and low flow states (Mecher, Crit Care Med, 199) PcvCO 2 PmvCO2 Inverse relationship between CI and (a-v) pco 2 (Ducey, Crit Care Med, 1992), (Durkin, J Crit Care, 1993) (Rackow, Crit Care Med, 1994), (Teboul, Crit Care Med, 1998) PaCO 2 (a-v) pco 2 increases mortality (Bakker, Chest, 1992) (a-v) pco 2 and Cardiac Index CI pac (L/min/m 2 ) 1 8 6 4 2 Mixed venous N = 83 CI pac (L/min/m 2 ) 1 8 6 4 2 Central venous 2 4 6 8 1 (a-mv)pco 2 (mmhg) 2 4 6 8 1 (a-cv)pco 2 (mmhg) ln(ci) = 1.942 -.18(a-mv)pCO 2 r 2 =.87 ln(ci) = 1.884 -.173(a-cv)pCO 2 r 2 =.9 (Cuschieri, Rivers and Donnino, Int Care Med, 25) 25

Sublingual Capnometry Weil, Crit Care Med 1999; 27:1225-1229. healthy volunteers without clinical signs of shock physical signs of circulatory shock PSL CO 2 mm Hg 45.2 +/-.7 53 +/- 8 81 +/- 24 Lactate (mm/l) < 2.5 >2.5 N 5 2 26 Died from shock Survivors Initial PSL CO 2 mm Hg 93 + 27 58 + 11 Correlation with lactate (r 2 =.84; p <.1) N 12 34 When P SL CO ( 2 ) > 7 mm Hg, its positive predictive value for the presence of physical signs of circulatory shock was 1.. When it was <7 mm Hg, it predicted survival with a predictive value of.93. 26

Base Deficit Amount of base required to titrate 1L blood to normal ph. Indicator of volume deficit. Guide to resuscitation in trauma patient.(davis, J Trauma, 1988) Affected by administration of bicarbonate, temp, ETOH, heparin. Can I use Base Deficit or Anion Gap? Lactate Range mmol/l 4. to 6.9 7. to 9.9 >1 Serum HCO3>22 and A.G. <15 11.1% 8.3% % Wira and Rivers, Crit Care Med, 25 27

Crit Care Med, 27 Moderate Global Tissue Hypoxia: Lactate < 4 and >2 mmole/liter and ScvO2 < 7% Resuscitated: Lactate < 2 mmole /liter and ScvO2 > 7% Severe Global Tissue Hypoxia: Lactate > 4 mmole/liter and ScvO2 < 7%) 28

IL-8 murine (pg/ml) 5 4 3 2 1 EGDT Standard Therapy 3 6 12 24 36 48 6 72 Hours after the start of treatment 14 12 1 Il-8 (pg/dl) 8 6 4 2 3 6 12 24 36 48 6 72 Hours after the start of treatment Lactate > 4 mm/l and ScvO2 <7% Lactate > 2 and < 4 mm/l and ScvO2 <7% Lactate < 2 mm/l and ScvO2 > 7% Chest, 25 1 Tumor Necrosis Factor 2 175 75 15 TNF- α (pg/ml) 5 TNF-α (pg/ml) 125 1 75 25 5 25 3 6 12 24 36 48 6 72 Hours after the start of treatment 3 6 12 24 36 48 6 72 Hours after the start of treatment 5 4 Caspase-3 1 9 8 Caspase-3 (ng/ml) 3 2 1 3 6 12 24 36 48 6 72 Hours after the start of treatment Caspase-3 (ng/ml) 7 6 5 4 3 2 1 3 6 12 24 36 48 6 72 Hours after the start of treatment 29

IL-1 receptor Antagonist 15 EGDT Control 125 2 175 15 Lactate>4 and ScvO2<7% Lactate>2 and ScvO 2<7% Lactate<2 and ScvO 2 >7% IL-1ra (pg/ml) 1 75 5 25 IL-1ra (ng/ml) 125 1 75 5 25 3 6 12 24 36 48 6 72 Hours after the start of treatment 3 6 12 24 36 48 6 72 Hours after the start of treatment 5 Intracellular Adhesion Molecule 6 4 5 ICAM-1 (ng/ml) 3 2 ICAM-1 (ng/ml) 4 3 2 1 1 3 6 12 24 36 48 6 72 Hours after the start of treatment 3 6 12 24 36 48 6 72 Hours after the start of treatment 3

Optimization Trials A Closer Look Late Early Mortality (Boyd, New Horiz, 1996) (Kern, Crit Care Med, 22) 32