Goal-Directed Therapy in Septic Shock What Goals Matter, What Don’t, and Why We Should Care William Owens, MD Division of Pulmonary and Critical Care Medicine University of South Carolina

Disclosures I have no ties, financial or otherwise, with any companies or products discussed today. I do have biases, prejudices, and opinions completely unfounded in fact, which I am always happy to share!

Patients enrolled who had either: SBP < 90 after a 20 mL/kg fluid bolus, or SBP < 90 after a 20 mL/kg fluid bolus, or Lactate > 4 mmol/L Lactate > 4 mmol/L 46% vs 30%

INTERVENTION ARM

Early Antibiotics Fluid Resuscitation Good Genetics ScvO2 ≥ 70% Hemoglobin 10 g/dL CVP 8-12

GOAL: Fill The Tank! Pulmonary Artery Catheter Central Venous Pressure

AUC 0.56

MeasurementPPVNPV CVP< 851%65% CVP< 1247%67% CVP< 547%58% PAOP< 1154%74% PAOP< 11 + CVP< 854%63% CVP< 8 + SVI< 3061%39% PAOP< 12 + SVI< 3069%58%

(PP max – PP min ) (PP max + PP min /2) PPV≥13% correlates with preload responsiveness (AUC 0.91) * Tidal Volume should be 8 cc/kg * Breathing should be controlled and passive * Cardiac rhythm must be regular

12% change corresponds with fluid responsiveness PPV 93%NPV 92% Feissel M, Michard F, Faller J, Teboul J The respiratory variation in inferior vena cava diameter as a guide to fluid therapy Intensive Care Med (2004) 30:

LVEDA < 10 cm 2 or LVEDA/BSA < 5.5 cm 2 /m 2 corresponds with preload responsiveness

GOAL: Fill The Tank! CVP is not accurate at any level The PA catheter isn’t much better Ultrasound and PPV show promise Clinical Correlation Is Required!

GOAL: Hemoglobin ≥ 10 g/dL CaO 2 = 1.34 × Hgb × SaO 2 DO 2 = CO × CaO 2 × 10

838 patients randomized 838 patients randomized Transfusion triggers of g/dL versus g/dL Transfusion triggers of g/dL versus g/dL No difference in mortality overall No difference in mortality overall No difference in mortality in patients with coronary artery disease No difference in mortality in patients with coronary artery disease Shock Drop in Hgb > 3 g/dL Coronary Ischemia Not Applicable to Initial Resuscitation?

Inadequate Oxygen Delivery Transfusion Increases DO2 and VO2 Cells Can Use Delivered Oxygen Benefits Outweigh Risks

Inadequate Oxygen Delivery DO 2 crit in animals seems to be g/dL Microcirculatory hematocrit is relatively constant at 12-15% No necrosis at autopsy Healthy humans can tolerate hemodilution to 5 g/dL

Transfusion Increases DO 2 and VO 2 Mathematical Coupling Stored Blood Holds On To Oxygen Supply Dependency Doesn’t Exist In Septic Shock

Cells Can Use Delivered Oxygen RBCs are depleted of 2-3 DPG until 24 hours after transfusion Free Hemoglobin scavenges NO— inflammation, vasoconstriction, thrombosis, oxidative stress Increasing blood viscosity causes vasodilation via endothelium-released NO (much of the benefit of transfusion may be independent of CaO 2 )

80%95% Marik showed that patients transfused stored blood had consistently lower gastric mucosal pH (JAMA 1993;269(23):3024– 9)

GOAL: Hemoglobin ≥ 10 g/dL No evidence for arbitrary transfusion trigger Transfused RBCs may worsen microcirculatory perfusion Base decision to transfuse on signs of inadequate oxygen delivery Rising lactate Elevated troponin Elevated troponin Ischemic ECG findings Ischemic ECG findings Poor perfusion (i.e., the cold big toe) Poor perfusion (i.e., the cold big toe)

GOAL: Keep ScvO 2 ≥ 70% VO 2 = CO × 1.34 × Hgb × [SaO 2 –SvO 2 ]

Shoemaker (Chest, 1988) Get CI over 4.5 L/min/m 2Get CI over 4.5 L/min/m 2 DO 2 I >600 mL/min/m 2DO 2 I >600 mL/min/m 2 VO 2 I >170 mL/min/m 2VO 2 I >170 mL/min/m 2 Tuchschmidt (Chest, 1992) Supranormal DO 2 in Septic ShockSupranormal DO 2 in Septic Shock No Survival BenefitNo Survival Benefit Gattinoni (NEJM, 1995) CI >4.5 L/min/m 2CI >4.5 L/min/m 2 SvO 2 >70%SvO 2 >70% No Survival BenefitNo Survival Benefit Many patients couldn’t reach physiologic targetsMany patients couldn’t reach physiologic targets Nguyen et al: ED Resuscitation Improves Survival (Acad Emerg Med, 2000)

PRO Low ScvO 2 is useful for titrating inotropes in cardiogenic shock A low admission ScvO 2 may predict higher mortality A low admission ScvO 2 may predict higher mortality CON Global measurement of oxygen delivery Global measurement of oxygen delivery Transfusion of RBCs raises ScvO 2 but doesn’t improve sublingual microcirculatory flow Transfusion of RBCs raises ScvO 2 but doesn’t improve sublingual microcirculatory flow May be elevated due to pathologic shunting May be elevated due to pathologic shunting Septic shock is due to cellular dysoxia, not hypoxia Septic shock is due to cellular dysoxia, not hypoxia

Sources of Lactic Acid in Septic Shock Anaerobic Metabolism (bowel/hepatic ischemia) Acute Lung Injury/ARDS Dysfunctional Cellular Metabolism Inactivation of Pyruvate Dehydrogenase Inactivation of Pyruvate Dehydrogenase NO suppression of mitochondrial respiration NO suppression of mitochondrial respiration Excessive pyruvate production due to catecholamines Excessive pyruvate production due to catecholamines

Am J Surg 2001;182(5):481-5 Lactate Clearance: A Better Goal Than ScvO 2 ?

Fill the Tank, but Forget the Filling Pressures Bedside Ultrasound and Pulse Pressure Variation are superior to CVP and PAOP for guiding fluid resuscitation Preload Responsiveness Doesn’t Always Mean The Patient Needs Volume “Warm around the edges” is a good rule to follow

Transfuse Sparingly and Selectively A hemoglobin >7 g/dL is usually OK Raising the hematocrit may raise the SvO 2, but not necessarily tissue perfusion Your attendings were right—treat the patient, not the number

Markers of Dysoxia Are Better Than Markers of Hypoxia Septic shock is not a low-flow, low-oxygen disease Early aggressive resuscitation is key Babies may be big at Baptist, but lactate is also for the ICU

Division of Pulmonary, Critical Care, and Sleep Medicine