Presented by: Kiung Hsia Ling Date: 4/02/09

Introduction Pathogenesis Clinical & hemodynamic features Therapeutic approach Initial resuscitation Hemodynamic support & adjunctive therapy Other supportive therapy of severe sepsis Fluid therapy Vasopressors Inotropic agents References

Septic shock is associated with a high

mortality rate Approximately 500,000 cases of sepsis syndrome annually, with mortality rates ranging from about 30% at 1 month to 50% at 5 months Approximately 25% of patients with sepsis syndrome progress to septic shock

ACCP/SCCM Consensus Conference Definitions
Bacteremia Systemic inflammatory response syndrome (SIRS) Presence of viable bacteria in the blood Systemic inflammatory response to a variety of severe clinical insults. The response is mainfested by two or more of the following conditions: • temperature >38°C or <36°C • heart rate >90 beats/min • Respiratory rate >20 breaths/min •WBC > 12,000 cells/mm2 , < 4,000 cell/mm3 The systemic response to infection. The systemic response is manifested by two or more of the following conditions as a result of infection: • temperature >38°C or <36°C • heart rate >90 beats/min • Respiratory rate >20 breaths/min •WBC > 12,000 cells/mm2 , < 4,000 cell/mm3 a/w organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status Sepsis with hypotension, despite adequate fluid resuscitation, along with perfusion abnormalities that may include, but are not limited to , lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.


Severe sepsis

Septic shock

Systemic Inflammation or Inflammatory Response Diffuse Endothelial Disruption and Microcirculation Defects

Seve Global Tissue Hypoxia re and Sepsi Organ Dysfunction s The initial response to an infecting organism is a systemic response, with release of inflammatory mediators and activation of the coagulation cascade. Septic Shock Microvascular injury, thrombosis, and diffuse endothelial disruption follow, resulting in imbalance between oxygen delivery and oxygen consumption. Global tissue hypoxia and cytophathic hypoxia develop, leading to multiple organ dysfunction and

Clinical and Hemodynamic Features
 Hemodynamic signs:

- hypotension - tachycardia - elevated CO - low SVR - low PCWP  Even though CO is high, it is inadequate to maintain BP that will perfuse the essential organs in the face of a decreased SVR, evidenced by low oxygen delivery and consumption  Metabolic acidosis (anaerobic metabolism, due to decreased perfusion causing lactic acidosis, and CO is inadequate to meet oxygen requirements of the tissues)  Decreased urine output (decreased renal perfusion)  Altered sensorium (decreased cerebral perfusion)  Increased WBC count  Spiking fever

Therapeutic approach
Management of septic shock is directed toward three primary areas: 1. Eradication of the source of infection 2. Hemodynamic support and control of tissue hypoxia 3. Inhibition or attenuation of the initiators and mediators of sepsos

Eradication the source of infection
Leading cause: aerobic or anaerobic bacteria Fungal, mycobacterial, rickettsial, protozoal, viral

infections may also be encountered Use of an appropriate antibiotic regimen is a/w significant increase in survival Selection of antibiotics should take into account the presumed site of infection; whether the infection is community- or hospital-acquired; recent invasive procedures, manipulations, or surgery; any predisposing conditions; and the likelihood of drug resistance If the source of infection is unclear, early institution of broad-spectrum antibiotics is generally recommended while awaiting culture results A combination of two antibiotics is suggested to provide for possible synergy and to reduce the emergence of resistant organisms

Empirical antimicrobial recommendations
Sepsis Source Unknown source Recommended Antimicrobial Regimen (Standard Adult Dosing ) Comments Vancomycin 1g BD & levofloxacin Consider abdominal/pelvic 750mg OD & gentamicin 7mg/kg imaging if physical examination, OD chest radiograph, and urinalysis do not reveal an infection source

Community Vancomycin 1g BD & levofloxacin Consider Pneumocystis carinii -acquired 750mg OD (& gentamicin 7mg/kg pneumonia treatment in AIDS pneumonia OD if recent patietns and obtain an hospitalization/nursing home echocardiogram to evaluate residence, recent antibiotic use, endocarditis with septic emboli in or bronchiectasis) intravenous drug users Meningitis Vancomycin 1g BD & ceftriaxone If altered mental status or focal 2g BD neuroloigc abnormalities, consider adding acyclovir (10mg/kg TDS) to treat herpes encephalitis

Empirical antimicrobial recommendations
Sepsis Source UTI Recommended Antimicrobial Regimen (Standard Adult Dosing ) Piperacillin/tazobactam 3.375g QID & gentamicin 7mg/kg OD Comments If nitrite production or Gram’s stain suggests Enterobacteriaceae, levofloxacin or ceftriaxone can be substituted for gentamicin Obtain imaging to identify infection focus and potential for percutaneous or open drainage, and/or surgical cosultation For suspected necrotizing infections, obtainsurgical consultation for tissue debridement as soon as possible

Intraabdo Piperacillin/tazobactam 3.375g minal/pelvi QID & gentamicin 7mg/kg OD c infection

Skin and Vancomycin 1g BD & soft tissue piperacillin/tazobactam 3.375g infection/n QID & clindamycin 900mg TDS ecrotizing infection

Initial Resuscitation
Immediate goal:

- maximize oxygen delivery to the tissues Fluid resuscitation: mainstay of therapy & improves oxygen delivery by increasing CO Inotropic & vasopressor: required for additional cardiovascular support A favourable response to immediate resuscitative efforts: reversal or halt in the progression of the metabolic acidosis, improved sensorium, and increased UO

Initial Resuscitation & Infection Issues
Initial resuscitation (first 6 hours)

- Begins resuscitation immediately in patients with hypotension or elevated serum lactate > 4mmol/L - Resuscitation goals:
 CVP 8-12 mmHg  MAP ≥ 65 mmHg  UO ≥ 0.5 ml/kg/hr  central venous oxygen saturation ≥ 70%

- If venous oxygen saturation target is not achieved
consider further fluid  transfuse packed red blood cells if required to Hct ≥ 30%  start dobutamine infusion, max: 20µg/kg/min

Initial Resuscitation & Infection Issues
Antibiotic therapy

- Begin IV antibiotics as early as possible & always within the first hour of recognizing severe sepsis & septic shock - Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens & with good penetration into presumed source - Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs - Duration of therapy typically limited to 7-10 days; longer if response is slow or there are undrainable foci of infection or immunologic deficiencies

Hemodynamic Support & Adjunctive Therapy
Fluid therapy

- Fluid-resuscitate using crystalloids or colloids - Target a CVP ≥ 8 mmHg (≥ 12 mmHg if mechanically ventilated) - Use a fluid challenges of 1000mL of crystalloids or 300500mL of colloids over 30 mins. - Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement

Hemodynamic Support & Adjunctive Therapy

- Maintain MAP ≥ 65mmHg - Norepinephrine and dopamine centrally administered are the initial vasopressors of choice - Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor. Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone - Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly responsive to norepinephrine or dopamine - Do not use low-dose dopamine for renal protection

Hemodynamic Support & Adjunctive Therapy
Inotropic therapy

- Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low CO - Do not increase CI to predetermined supranormal levels Steroids - Consider IV hydrocortisone when hypotension responds poorly to adequate fluid resuscitation & vasopressors - Hydrocortisone is preffered to dexamethasone - Steroid therapy may be weaned one vasopressors are no longer required - Hydrocortisone dose should be ≤ 300mg/day

Other Supportive Therapy of Severe Sepsis
Blood product administration

- Give RBCs when Hgb decreases to <7.0 g/dL to target of 7-9 g/dL . A higher Hgb level may be required in special circumstances (e.g. myocardial ischaemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, lactic acidosis) - Do not use erythropoietin to treat sepsis-related anemia - Do not use antithrombin therapy - Administer platelets when:
 counts are <5000/mm3 regardless of bleeding  counts are 5000-30,000/mm3 & there is significant bleeding


Other Supportive Therapy of Severe Sepsis
Mechanical ventilation of sepsis-induced ALI/ARDS

- Target a tidal volume of 6mL/kg body weight - Set PEEP to avoid extensive lung collapse at end-expiration - Maintain mechanically ventilated patients in a semirecumbent position (head of the bed raised to 45°) - Do not use a pulmonary artery catheter for the routine monitoring  Glucose control - Use IV insulin to control hyperglycemia - Aim to keep blood glucose < 150mg/dL - Provide a glucose calorie source and monitor BG values every 1-2 hours (4 hrs when stable)

Other Supportive Therapy of Severe Sepsis
Bicarbonate therapy

- Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-induced lactic acidemia with pH ≥ 7.15 Deep vein thrombosis prophylaxis - Use either low-dose UFH or LMWH, unless contraindicated - Use a mechanical prophylactic device, such as compression stockings, when heparin is contraindicated - Use a combination of pharmacologic & mechanical therapy for patients who are at very high risk for DVT - In patietns at very high risk, LMWH should be used rather than UFH

Other Supportive Therapy of Severe Sepsis
Stress ulcer prophylaxis

- Using H2 blocker or PPI - Benefits of prevention of upper GI bleeding must be weighed against the potential for development of ventilator-acquired pneumonia

Fluid Therapy
First parameter to target in hemodynamic optimization is

intravascular volume with the use of fluid therapy Choice: crystalloids & colloids No outcome benefit has been demonstrated in using colloids compared to crystalloids with respect to mortality or hospital length of stay The volume of crystalloids required may be 2 to 3 times than colloids to restore optimal volume E.g. 1 L of NS adds 275mL to the plasma volume, whereas 1 L of 5% albumin will increase plasma volume by 500mL For patients with low CVP & concurrent pulmonary edema, a colloid may be combined with crystalloid to avoid large volume of crystalloid & to rapid achieve the CVP goal


- Potent α-adrenergic agent with less pronouced βadrenergic activity - Useful when potent vasoconstriction of peripheral vascular beds is desired - 0.01-3µg/kg/min: increase BP with little change in HR or CI - More potent than dopamine in refractory septic shock - Despite earlier concern of decreased renal blood flow a/w norepinephrine, data in humans & animals demonstrate a norepinephrine-induced renal blood flow as well as urine & cardiac output


- Nonspecific α- and β-adrenergic agonist - Capable of increasing CI & producing significant peripheral vasoconstriction in dose of 0.10.5µg/kg/min - Undesirable effects: propensity to increase lactate level & to impair blood flow to the splanchnic system - Reserved for patients who failed to respond to traditional therapies for increasing or maintaining BP


- Selective α1-agonist, rapid onset, short duration, primary vascular effect - Appears useful when tachycardi limits the use of other vasopressors Vasopressin - α-agonist, deficiency in many septic shock patients, is an endogenously produced hormone - Not considered a first-line agent - May a/w a decrease in CO - Commonly used in combination with other vasoactive agents

Inotropic Agents

- α- and β-adrenergic agent with dopaminergic activity, appears to increase MAP effectively in patients who remain hypotension with reduced cardiac function after aggressive fluid resuscitation - Initial choice in sepsis because of combined vasopressor & inotropic effects - Low-dose dopamine: 1-5 µg/kg/min, effective in maintaining renal perfusion - Higher dose: >5 µg/kg/min, exhibit α and β activity & are used frequently to support BP & to improve cardiac function such as increase in CI

Inotropic Agents

- β-adrenergic inotropic agent - Preferred drug for improvement of CO & oxygen delivery, particularly in early sepsis before significant peripheral vasodilation has occurred - 2-20 µg/kg/min: increase CI (ranging from 20-66%). However, HR often increase significantly - Should be considered in severely septic patients with adequate filling pressure & BP but low CI

Severe sepsis and septic shock: review of the literature and emergency

department mangement guidelines. N. Bryant, R. Emanuel, A. Fredrick, M. Gregory, A. Edward, T. Stephen, Annals of Emergency Medicine 2006;48(1):28-54 Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. D. Phillip, L. Mitchell, C. Jean, B. Julian, P. Margaret, J. Roman, Critical Care Medicine 2008;34:1-33 Adams VR, Yee GC. Lymphoma. In: Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 6th edition. New York: McGraw-Hill; 2006. Chapter 117 pg 2131-42 Koda-Kimble MA. Applied therapeutics: the clinical use of drugs. 8thedition. USA: Lippincott Williams &Wilkins; 2005. Chapter 22: pg 1-37

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