Presented by: Kiung Hsia LingDate: 4/02/09

Contents IntroductionPathogenesisClinical & hemodynamic featuresTherapeutic approachInitial resuscitationHemodynamic support & adjunctive therapyOther supportive therapy of severe sepsisFluid therapyVasopressorsInotropic agentsReferences

IntroductionSeptic shock is associated with a high

mortality rateApproximately 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 DefinitionsBacteremia Presence of viable bacteria in the blood

Systemic inflammatory response syndrome (SIRS)

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

Sepsis 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

Severe sepsis 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

Septic shock 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.

Pathogenesis Systemic Inflammation

orInflammatory

Response Diffuse Endothelial Disruption

and Microcirculation Defects

Global Tissue Hypoxia and

Organ Dysfunction

SevereSepsis

Septic Shock

The initial response to an infecting organism is a systemic response, with release of inflammatory mediators and activation of the coagulation cascade. 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 irreversible shock

Clinical and Hemodynamic Features Hemodynamic signs: - hypotension - tachycardia - elevated CO - low SVR - low PCWPEven 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 countSpiking fever

Therapeutic approachManagement of septic shock is directed toward

three primary areas:1. Eradication of the source of infection2. Hemodynamic support and control of tissue

hypoxia3. Inhibition or attenuation of the initiators and

mediators of sepsos

Eradication the source of infectionLeading cause: aerobic or anaerobic bacteriaFungal, mycobacterial, rickettsial, protozoal, viral

infections may also be encounteredUse of an appropriate antibiotic regimen is a/w

significant increase in survivalSelection 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

Recommended Antimicrobial Regimen

(Standard Adult Dosing )

Comments

Unknown source

Vancomycin 1g BD & levofloxacin 750mg OD & gentamicin 7mg/kg OD

Consider abdominal/pelvic imaging if physical examination, chest radiograph, and urinalysis do not reveal an infection source

Community-acquired pneumonia

Vancomycin 1g BD & levofloxacin 750mg OD (& gentamicin 7mg/kg OD if recent hospitalization/nursing home residence, recent antibiotic use, or bronchiectasis)

Consider Pneumocystis carinii pneumonia treatment in AIDS patietns and obtain an echocardiogram to evaluate endocarditis with septic emboli in intravenous drug users

Meningitis

Vancomycin 1g BD & ceftriaxone 2g BD

If altered mental status or focal neuroloigc abnormalities, consider adding acyclovir (10mg/kg TDS) to treat herpes encephalitis

Empirical antimicrobial recommendations Sepsis Source

Recommended Antimicrobial Regimen (Standard Adult

Dosing )

Comments

UTI Piperacillin/tazobactam 3.375g QID & gentamicin 7mg/kg OD

If nitrite production or Gram’s stain suggests Enterobacteriaceae, levofloxacin or ceftriaxone can be substituted for gentamicin

Intraabdominal/pelvic infection

Piperacillin/tazobactam 3.375g QID & gentamicin 7mg/kg OD

Obtain imaging to identify infection focus and potential for percutaneous or open drainage, and/or surgical cosultation

Skin and soft tissue infection/necrotizing infection

Vancomycin 1g BD & piperacillin/tazobactam 3.375g QID & clindamycin 900mg TDS

For suspected necrotizing infections, obtainsurgical consultation for tissue debridement as soon as possible

Initial ResuscitationImmediate goal: - maximize oxygen delivery to the tissuesFluid resuscitation: mainstay of therapy &

improves oxygen delivery by increasing COInotropic & vasopressor: required for

additional cardiovascular supportA favourable response to immediate

resuscitative efforts: reversal or halt in the progression of the metabolic acidosis, improved sensorium, and increased UO

Initial Resuscitation & Infection IssuesInitial 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

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

Initial Resuscitation & Infection Issues

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

300- 500mL of colloids over 30 mins. - Rate of fluid administration should be reduced if

cardiac filling pressures increase without concurrent

hemodynamic improvement

Vasopressors - 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 levelsSteroids - 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

Hemodynamic Support & Adjunctive Therapy

Other Supportive Therapy of Severe SepsisBlood 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 risk

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 ≥ 7.15Deep 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

Other Supportive Therapy of Severe Sepsis

Fluid TherapyFirst parameter to target in hemodynamic optimization is

intravascular volume with the use of fluid therapyChoice: crystalloids & colloidsNo 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

Vasopressors Norepinephrine - Potent α-adrenergic agent with less pronouced β-

adrenergic 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

Epinephrine - Nonspecific α- and β-adrenergic agonist - Capable of increasing CI & producing significant

peripheral vasoconstriction in dose of 0.1-

0.5µg/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

Vasopressors

Phenylephrine - Selective α1-agonist, rapid onset, short duration, primary

vascular effect - Appears useful when tachycardi limits the use of other vasopressorsVasopressin - 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

Vasopressors

Inotropic AgentsDopamine - 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

Dobutamine

- 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

Inotropic Agents

References 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, et.al. 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, et.al. 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