Professional Documents
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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
Definitions
The ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992.
SIRS
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
Definitions
The 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:
Multiple Organ System Failure: Abnormal function of two or more organs such that homeostasis cannot be achieved without intervention.
Brief Pathophysiology
Mediators
TNF
Immunosuppressive
(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 Vasodilation (nitric oxide) Vascular permeability
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.
Interventions
Volume infusion
Vasopressors Inotropes
Intravenous Fluids
Practice 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
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)
ASAP after blood cultures collected Modify as culture results dictate 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.
Goal: Maintain oxygen delivery (DO2) at levels that match tissue O2 needs (VO2)
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
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
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 1.292.84, 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
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