Management of Septic Shock

Epidemiology of Sepsis

751K cases annually in the United States and rising Most common cause of death in non-coronary ICU 30% Mortality when shock present Severe sepsis $22K/pt, $16 billion/year

DefinitionsThe ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992.

SIRS– Widespread inflammatory response– Two or more of the following

Temp>38 C<36 C Heart Rate >90 bpm Tachypnea RR>20 or hyperventilation PaCO2 <32 mmHg WBC >12,000<4000 or presence of >10% immature neutrophils.

Sepsis: SIRS + definitive source of infection Severe Sepsis: Sepsis + organ dysfunction, hypoperfusion,

or hypotension

DefinitionsThe ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992.

Septic Shock:– Sepsis + hypotension despite fluids– Perfusion abnormalities

Lactic acidosis Oliguria Acute AMS

Multiple Organ System Failure: Abnormal function of two or more organs such that homeostasis cannot be achieved without intervention.

Brief Pathophysiology

Proinflammatory response to infection– Mediators

TNF Alpha, IL-1, IL-6 Complement system (C5 alpha) Bacterial factors

– Endotoxin, bacterial cell wall products, bacterial toxins

Immunosuppressive

Time-course of inflammatory response during sepsis(modified from Management of Severe Sepsis and Septic Shock. Curr Opin Crit Care 2004;10:354-363)

(Modified from The Pathophysiology and Treatment of Sepsis. N Engl J Med 2003;348:138-150)

Cellular dysfunction

Cellular hypoxia– Reduced surface area for diffusion– Reduction in RBC deformability– Impaired utilization of oxygen by mitochondria

Circulatory system dysregulation– Vasodilation (nitric oxide)– Vascular permeability

Acute Organ Dysfunction

Neuro: altered mental status Respiratory: Mechanical ventilation? (PF ratio <250, PEEP

>7.5) CV: Pressors? SBP<90 or MAP<70 despite fluids Renal: UO <0.5ml/cc/kg/hr, 50% increase in Cr, acute

dialysis Heme: Platelets <100,000 or PT/PTT elevated Metabolic: pH <7.3, high lactate Hepatic: LFTs >2x normal GI: Bacterial overgrowth and translocation

Management of Sepsis

Resuscitate: ABCs Restore tissue perfusion Identify and eradicate source of infection Assure adequate tissue oxygenation Activated Protein C Steroids Glucose Control Nutrition

Resuscitation

Airway: AMS, unable to protect airway Breathing: Respiratory failure Circulation: Restoration of blood pressure

to levels which perfuse core organs.– Sphygmomanometer unreliable– Arterial catheter– CVP – Mixed Venous O2 sat

Restoration of tissue perfusion

Causes of poor tissue perfusion– Leaky vessels– Decreased vascular

tone– Myocardial depression

Interventions– Volume infusion

Intravenous fluids PRBCs

– Vasopressors– Inotropes

Intravenous FluidsPractice parameters for hemodynamic support of sepsis in adult patient in sepsis . Task Force of the ACCCM/SCCM. Critical Care Medicine 1999

Administered in well-defined, rapidly infused boluses

Continued until blood pressure, tissue perfusion, and oxygen delivery acceptable or presence of pulmonary edema

Colloid vs. Crystalloid: No evidence to recommend one over the other.

Vasopressors Second-line agents Hypotensive despite fluid resuscitation,

Cardiogenic pulmonary edema, or elevated wedge pressure (>18)

Vascoconstrictors– Phenylephrine, Norepinephrine, Dopamine,

Epinephrine, Vasopressin

Vasopressors

Catecholamines may modulate immune system Epinephrine may decrease splanchnic perfusion and pH Dopa and norepi have similar effects on renal function Dopamine may result in greater splanchnic acidosis vs

norepinephrine Observational studies suggest Norepinephrine as first line

agent for fluid refractory hypotension

Martin et al Chest 1993;103(6):1826-31

Vasopressors

Vasopressin– Limited data, studies suggest may be useful in vasodilatory shock– Vasopressin deficiency contributes to the vasodilation of septic

shock. Circulation 1997. VP levels low in septic shock 10 patients in septic shock and already receiving catecholamines with

improvement of hypotension and decreased need for catecholamines – Hemodynamic and metabolic effects of low-dose VP infusions in

vasodilatory septic shock. Critical Care Medicine 2001 VP given to 16 septic patients with refractory hypotension. VP infusion improved MAP and SVR

– Current recs are to consider with refractory hypotension despite adequate fluid resuscitation and high-dose conventional vasopressors.(infusion rates of 0.01-0.04 units per min)

Eradicate infectious source

Empiric broad spectrum antibiotics– ASAP after blood cultures collected– Modify as culture results dictate

Remove infectious source– Remove catheter, Drain abscess/fluid

collections, Divert gut, etc

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. NEJM. Nov 8, 2001

Study design: Prospective, randomized study in urban emergency department enrolling 263 patients

Inclusion Criteria: Adults severe sepsis, septic shock, or sepsis syndrome. SIRS. SBP<90 (after fluid bolus) or lactate>4.

Exclusion Criteria: Age<18, pregnancy, acute CVA, ACS, pulmonary edema, status asthmaticus, arrhythmia, GIB, seizure, drug OD, burns, trauma, immediate surgery, uncured cancer, immunosupressed, DNR.

Treatment: In ER 500 ml crystalloid given q 30 min to achieve CVP 8-12 mmHg. Pressors given to achieve MAP >65. If MAP >90 vasodilators given until <90. If ScvO2<70, transfused to Hct of 30. +/-Dobutamine.

Results: Improved in-hospital mortality (30.5% vs. 46.5%). Higher mean ScvO2, lower lactate, lower base deficit and a higher pH. Lower APACHE scores.

Assuring adequate tissue oxygenation

Goal: Maintain oxygen delivery (DO2) at levels that match tissue O2 needs (VO2)

– Supratherapeutic oxygenation not consistently shown to be effective

Detection of tissue hypoxia--Lactate– May be difficult to interpret

Treatment of tissue hypoxia– Maximize arterial oxygen content– Keep SaO2 >97%– Augment cardiac output– Support hematocrit

Activated protein C

Known inflammatory and procoagulant host responses to infection.– TNF-alpha, IL-1, IL-6, thrombin

Diffuse endovascular injury, multiorgan dysfunction and death.

Activated Protein C– anticoagulant, modulates the inflammatory response– reduced levels of protein C found in majority of patients with

sepsis and are associated with increased risk of death.

Efficacy and Safety of Recombinant Human

Activated Protein C for Severe Sepsis. NEJM 2001. Randomized, double-blind,

placebo-controlled, multicenter trial enrolling 1,690 patients with severe sepsis.

96 hour infusion of recombinant APC or placebo beginning within 24 hours of presentation.

28 day mortality significantly lower in the APC group

– 24.7 vs. 30.8% Trend towards increased bleeding

(3.5 vs/ 2.0% p=0.06)

Activated Protein C Guidelines

Glucocorticoids

Ten prospective, randomized, controlled trials of pharmacologic doses of glucocorticoids in sepsis/septic shock

Steroid controversy in sepsis and septic shock: A meta-analysis. Critical Care Medicine 1995– Glucocorticoids offer no benefit– Positive findings reported in 1/10 trials

Revisiting Steroids…

Adrenal Insufficiency– 25-40% of ICU patients with septic shock– Mortality is more than double that of patients

with normal adrenal responsiveness– Hypotension refractory to vasopressors– hyponatremia, hyperkalemia, weakness, and

hyperpigmentation not specific enough in ICU setting

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002 Placebo-controlled, randomized, double-blind, parallel-group trial

performed in 19 French ICUs. 300 adults with severe sepsis who underwent corticotropin test were

randomly assigned to receive hydrocortisone and fludrocortisone or placebo for 7 days.

Main outcome measure: 28 day survival in patients with abnormal corticotropin test.

Results: Corticosteroids vs. Placebo– Deaths: 53% vs 63%(Hazards ratio 0.67, 95% CI 0.47-0.95, p=0.02)– Withdraw of pressors: 57% vs 40% (Hazards ratio 1.91, 95% CI 1.29-

2.84, p=0.001)– No difference in adverse outcomes.

Conclusion: 7 day treatment with steroids beneficial in patients with sepsis and adrenal insufficiency.

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002

Glucose Control

Recs are to keep serum glucose levels < 150

Nutrition

Start early Route: preferably enteral Nutritional support improves wound healing

and decreases susceptibility to infection. Nutritional support results in higher

lymphocyte counts and higher serum albumin (surrogate markers of immune competency)

Summary

Ensure tissue perfusion: resuscitate early with liberal IVF, pressors and inotropes.

Ensure tissue oxygenation: oxygen content, oxygen saturation, cardiac output

Identify and eradicate infection APC in patients with severe sepsis Consider corticosteroids Glucose Control

Septic Shock Algorithm Example(modified from Septic Shock. Lancet 2005;365:63-78.)