Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM

Review Date: 9/17/2012

Definition

Sepsis is a serious medical condition due to infection where there is an inflammatory state affecting the whole body, known as systemic inflammatory response syndrome (SIRS).

SIRS requires 2 or more of the following (Adults):

• Temperature 36°C (96.8° F) or>38°C (100.4° F)
• Heart rate>90 bpm
• Respiratory rate>20/min or PaCO2 32 mm Hg (4.3 kPa)
• White blood cell count 4,000 cells/mm3 or >12,000 cells/mm3 (4×109 or >12×109 cells/L), or >10% band forms (immature white blood cells)

• Hypotension [SBP 90 mmHg (or>40 mmHg drop from patient's normal)]
• Hypoperfusion/lactic acidosis
• Evidence of organ dysfunction

• There is severe sepsis with hypotension despite adequate fluid resuscitation (generally defined as 40–60 mL/kg of crystalloid) AND/OR
• Lactate>4 mmol/L due to an infectious process

• SIRS/sepsis criteria to be met
• Evidence of 2 or more organs failing (most commonly pulmonary, cardiovascular, renal, and/or hepatic)

Description

• Sepsis is a complex systemic inflammatory condition associated with infection manifest as a response by the host to invading pathogens
• In cases of severe sepsis, the normal endothelial response to the invading pathogen (ie, release of inflammatory mediators and activation of the clotting cascade by endothelial cells) becomes dysfunctional leading to excessive, sustained, and generalized activation of the endothelium. The endothelium is no longer regulated by local negative feedback mechanisms which leads to severe disequilibrium of inflammatory response, generalized tissue injury, excessive vascular permeability, shock, and multi-organ failure

Epidemiology

Incidence/Prevalence

• Worldwide, 20 million cases of sepsis are reported annually, with a mortality rate of around 35%
• Sepsis is the 10th leading cause of death in the U.S. (2007) 750,000-900,000 cases/year and approximately 200,000 deaths/year occurring (US)
• Annual incidence of sepsis in the European Union is estimated at 90.4 cases/100,000 population

Age

• Two-thirds of patients are >65 years

Gender

• More common in men than women

Risk factors

• Age extremes (very young or very old)
• Alcoholism
• Complicated labor and delivery: Premature birth and/or premature rupture of the membranes; untreated maternal group B streptococcal colonization
• Critical illness (organ/system failure and dependence on devices for monitoring and therapy)
• Immunodeficiency (diabetes, HIV/AIDS, immunosuppressant use)
• Invasive devices: Indwelling catheters (intravascular, urinary, biliary), endotracheal, or tracheostomy tubes
• Infection (meningitis, cellulitis, pneumonia, urinary tract infection)
• Surgery (recent)
• Underlying malignancy

Etiology

• Gram-positive sepsis: Mainly caused by Staphylococcus aureus, coagulase-negative Staphylococci, Enterococci, and Streptococci
• Gram-negative sepsis: Mainly caused by Escherichia coli, Klebsiella spp, Proteus spp, Pseudomonas aeruginosa,and Neisseria meningitidis
• Less common infections: Fungal (Candida sp.), viral, rickettsia, parasitic
• Common sources: Lungs (pneumonia), urinary tract (pyelonephritis), abdomen (biliary tree, perforated viscous, peritonitis, diverticulitis, appendicitis), skin (cellulitis), brain (meningitis), bone (osteomyelitis), bloodstream, and invasive devices

History

• Presence of risk factors such as underlying malignancy, age >65 years, immunodeficiency, hemodialysis, and alcoholism
• Elderly patients and infants typically have fewer early symptoms of sepsis
• Typical organ/system failure in sepsis
• Pulmonary dysfunction (~30% patients have acute respiratory distress syndrome [ARDS])
• Cardiovascular failure (shock, lactic acidosis) is common
• Renal dysfunction
• Gastrointestinal dysfunction/catabolic nutritional deficits
• Coagulopathy (usually indicative of hepatic failure or DIC)
• Altered consciousness/delirium
• Anemia is common in critically ill patients (iatrogenic and pathophysiologic)

Physical findings on examination

• Fever >38°C or 100.4°F (patient may alternatively have a low temperature 36.0°C or 96.8°F)
• Tachycardia (heart rate >90 bpm)
• Tachypnea (respiratory rate >20 bpm)
• Acutely altered mental status
• Signs of circulatory insufficiency such as hypotension, poor capillary refill, or mottling of the skin
• Signs depending upon specific infection source:
• Respiratory tract: Cough, sputum production, dyspnea, hypoxia/cyanosis, chest pain
• Urinary tract: Dysuria, frequency, urgency, flank pain
• Intra-abdominal: Nausea, vomiting, diarrhea, constipation, abdominal pain or tenderness
• Central nervous system (CNS): Stiff neck, headache, photophobia, altered level of consciousness, focal neurological findings
• Skin: Cellulitis with hot erythematous skin with dermal edema
• Joints: Red swollen, painful, hot joint with decreased range of motion

• Hypotension [MAP 65 mmHg/SBP90 mmHg (or >40 mmHg drop from patient's normal)]
• Hypoperfusion/lactic acidosis
• Evidence of organ dysfunction

• There is severe sepsis with hypotension despite adequate fluid resuscitation (generally defined at 40–60 mL/kg of crystalloid or 20–30 mL/kg of colloid)
• Persisting elevated Lactate >4 mmol/L

• SIRS/sepsis criteria to be met
• Evidence of 2 or more organs failing (most commonly pulmonary, cardiovascular, renal, and/or hepatic)

Blood test findings

• Blood cultures: At least 2 cultures from separate sites (taken immediately and preferably before start of antibiotics). Only 50% of cases are positive, even in severe sepsis/septic shock
• CBC: WBC count >12×10⁹/L (12,000/microliter) or 4×10⁹/L (4000/microliter), or normal WBC count with >10% immature forms (bands); low platelets
• Coagulation studies (INR, aPTT): May be prolonged; severe sepsis: INR >1.5 or aPTT >60 seconds
• Serum creatinine: Increased creatinine (sign of severe sepsis) consistent with acute renal failure
• Blood urea and serum electrolytes: Serum electrolytes frequently deranged; blood urea may be elevated
• LFTs: Increased bilirubin, ALT, AST, alkaline phosphatase, and gamma-GT is common regardless of whether sepsis is originating from a hepatic or perihepatic infection or not. It is common to see hepatic transaminases elevate with any septic state
• Serum glucose: May be increased or decreased
• Arterial blood gas: May demonstrate increased A-a gradient, PaCO2 32 mmHg (4.3 kPa), metabolic acidosis and increased lactate level (levels >4 mmol/L are associated a significantly worse prognosis)

Other laboratory test findings

• Other cultures (eg, of sputum, stool, urine, wounds, catheters, prosthetic implants, epidural collections, pleural, joint, or peritoneal fluid) as clinically indicated; may demonstrate the causative organism

Radiographic findings

• Chest x-ray: May show evidence of infection, such as consolidation or pleural effusion, cardiac abnormalities, or pneumothorax. May also be consistent with ARDs

Other diagnostic test findings

• Relevant ultrasound, CT, and MRI scans performed to confirm infection source, as clinically required
• Diagnostic procedures/surgery
• Aspiration of potentially infected body fluids (pleural, joint, peritoneal, or CSF)
• Biopsy and drainage of potentially infected tissues (abscess, biliary tree, others)
• Electrocardiogram (ECG) and cardiac enzymes to evaluate for myocardial infarction. Note that troponin (troponin I and troponin T) and B-type natriuretic peptide (BNP) are frequently elevated in sepsis
• Pathological findings
• Abnormal hyperinflammatory response
• Immune dysfunction
• Inflammation at primary site of infection
• Noncardiogenic pulmonary edema

• Acute pancreatitis
• Adrenal failure (Addisonian crisis)
• Anaphylactic reactions: Drug-related reactions, insect bites, other bites
• Cardiogenic shock
• Cholesterol emboli syndrome
• Collagen vascular disease
• Dissociative shock (Carbon monoxide or cyanide poisoning, methemoglobinemia)
• Hepatic failure (fulminant)
• Hypothermia (due to environmental exposure)
• Idiopathic vasculitides
• ANCA-related vasculitides
• Cryoglobulinemia
• Giant cell arteritis
• Polyarteritis nodosa
• Systemic lupus erythematosus
• Serum sickness
• Microangiopathic hemolytic anemias: Hemolytic uremic syndrome (HUS), Thrombotic thrombocytopenic purpura (TTP), HELLP syndrome
• Noninfectious SIRS (trauma, burns, serum sickness, transfusion reaction, etc)
• Parasitic infections (eg, hydatid cyst, malaria)
• Preeclampsia
• Pulmonary embolism
• Snake bite (especially with envenomations resulting in coagulopathy and neurotoxic effects)
• Stevens-Johnsons syndrome (toxic epidermal necrolysis)
• Systemic vasculitis
• Toxic ingestion/poisoning
• Ulcerative colitis
• Viral illness: Viral hemorrhagic fevers and Hantavirus syndrome

General treatment items

• Care Bundle (6 hour) [Surviving Sepsis Campaign]
• The Surviving Sepsis Campaign has focused on best evidence practices and created a 6 hour bundle which should be completed in 100% of patients within 6 hours who present with severe sepsis, septic shock and/or a lactate >4 mmol/L (36 mg/dL). The items on the bundle should all be accomplished within the time guideline, as applicable to the patient.
• Item #1: Measure serum lactate
• Item #2: Obtain blood cultures prior to antibiotic administration
• Item #3: Administer broad-spectrum antibiotics within 3 hours of ED admission and within 1 hour of non-ED admission
• Item #4: Treat hypotension and/or elevated lactate with fluids, with delivery of an initial minimum of 20 mL/kg of crystalloid or an equivalent
• Item #5: In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate >4 mmol/L maintain adequate central venous pressure and central venous oxygen saturation:
• Achieve a central venous pressure (CVP) of >8 mm Hg
• Achieve a central venous oxygen saturation (ScvO2) > 70% or mixed venous oxygen saturation (SvO2) > 65%
• *Of note, the GENESIS project demonstrated this resuscitation bundle decreased mortality in severe sepsis and septic shock from 42.8% to 28.8% (P0.001) and decreased hospital length of stay from 20.7 to 15.6 days (P0.001).
• Supportive ICU care
• Cardiovascular monitoring (continuous ECG)
• DVT prophylaxis (heparin/heparinoid and compression stockings)
• Enteral or parenteral feeds
• Fluid resuscitation as needed with goal of urine output in adults to 0.5 mL/kg/hr
• Fluid resuscitation should be with crystalloids not colloids, as there is no evidence of benefit and best evidence indicates a significant increased risk of acute renal impairment with colloids as compared to crystalloids
• Glycemic control with insulin (glucose goal 140-180 mg/dL (7.8-10 mmol/L) if diabetic. Other's goal 70-150 mg/dL (3.9-8.3 mmol/L)
• Invasive monitoring if indicated (arterial line, CVP/PCWP)
• Renal replacement therapy
• Stress ulcer prophylaxis (PPI or H2 receptor antagonists)
• Vasopressors if required: Data from one large randomized clinical trial suggest that arginine vasopressin (AVP) plus norepinephrine (NE) infusion is safe and effective versus NE alone in patients with septic shock
• Ventilation if needed (lung protective)
• Removal of a focal source of infection
• Remove intravascular catheters and send for culture
• Replace drainage catheters
• CT or MRI to rule out occult disease
• Hemodynamic, respiratory and metabolic support
• IV fluids: Initial 20 mL/kg bolus of crystalloid (0.9% saline or Lactated Ringers) infused over minutes. After reassessment of patient status, continue with further boluses of crystalloid as needed to treat hypotension. It is not usual to require 20-60 mL/kg or more. This is followed by fluid infusion at a rate necessary to maintain parameters as listed below vasopressors may be necessary to achieve these pararmeters:
• Urine output at >0.5 mL/kg/hour
• Mean arterial blood pressure at >65 mmHg
• Central venous pressure at 8-12 cm H2O
• Pulmonary capillary wedge pressure at 12-16 mmHg
• Cardiac index at =4 (L/min)/m²
• Vasopressors (unresponsive to fluid resuscitation with MAP65 mmHg):
• Dopamine 5-20 µg/kg/min IV, titrate to effect
• Epinephrine 0.1-1 mcg/kg/min, IV, titrate to effect
• Norepinephrine 0.04-0.5 mcg/kg/min IV, titrate to effect. Note that norepinephrine may be preferred over dopamine in septic shock, including in patients with poor cardiac output, as it may induce fewer cardiac arrhythmias. In patients with cardiogenic shock, a survival benefit over dopamine was demonstrated in one study
• Inotropic drugs (in low cardiac output with adequate left ventricular filling pressure):
• Dobutamine 2.5 mcg/kg/min IV initially, titrated as needed, range 2.5-20 mcg/kg/min
• Glucocorticoids and mineralocorticoids in adrenal insufficiency; but not to be used routine. Harm is likely, based on best data, when low dose steroids are administered in sepsis (change in recommendation in Surviving Sepsis Campaign as of 2012)
• Antibiotics
• Antibiotic therapy should be started immediately and empirically for patients with sepsis. Empiric therapy is chosen based upon the suspected source of the infection and likely causative organisms. Other factors to consider include immunodeficiency, presence of indwelling IV lines or catheters, local resistance patterns, recent hospitalization, recent antibiotic use, history of infection with a multi-drug resistant pathogen (MDRP), and likelihood of methicillin-resistant S. aureus (MRSA)

If MRSA suspected, or the patient has an indwelling IV line, administer MRSA coverage in addition to other empiric antibiotics:

• Vancomycin
• Adult Dosing
• 1 g IV q12 hrs
• Pediatric Dosing
• 60 mg/kg/day IV,divided q8 hrs

orIf Vancomycin allergy:

• Linezolid
• Adult Dosing
• 600 mg IV q12 hrs
• Pediatric Dosing
• 10 mg/kg IV q8 hrs

If life threatening with unclear etiology (suspected intra-abdominal or skin source)

• Meropenem
• Adult Dosing
• 1 g IV q8 hrs
• Pediatric Dosing
• >3 months: 20 mg/kg IV q8 hrs
• >50 kg: 1 g IV q8 hrs

or If carbapenem allergy:

• Levofloxacin
• Adult Dosing
• 750 mg IV qd
• Pediatric Dosing (not FDA approved)
• 10 mg/kg IV q24 hrs

plus

• Metronidazole
• Adult Dosing
• 500 mg IV q8 hrs
• Pediatric Dosing
• 40 mg/kg/day IV, divided q8 hrs

or

• Vancomycin
• Adult Dosing
• 1 g IV q 12 hrs
• Pediatric Dosing
• 60 mg/kg/day IV, divided q8 hrs

or If Vancomycin allergy:

• Linezolid
• Adult Dosing
• 600 mg IV q 12 hrs
• Pediatric Dosing
• 10 mg/kg IV q 8 hrs

Biliary source:

• Ampicillin/sulbactam (Unasyn)
• Adult Dosing
• 3 g IV q6 hrs
• Pediatric Dosing
• 200-400 mg/kg/day IV, divided q6 hrs

or

• Piperacillin/tazobactam
• Adult Dosing
• 4.5 g (4 g piperacillin + 500 mg tazobactam) q6 hrs
• Pediatric Dosing
• 300-400 mg/kg/day IV, divided q6 hrs

or if PCN allergy:

• Levofloxacin
• Adult Dosing
• 750 mg IV qd
• Pediatric Dosing (not FDA approved)
• 10 mg/kg IV q24 hrs

plus

• Metronidazole
• Adult Dosing
• 500 mg IV q8 hrs
• Pediatric Dosing
• 40 mg/kg/day IV, divided q8 hrs

Intra-abdominal source:

• Meropenem
• Adult Dosing
• 1 g IV q8 hrs
• Pediatric
• >3 months: 20 mg/kg IV, divided q8hrs
• >50 kg: 1 g IV q8 hrs

or If carbanepem allergy:

• Levofloxacin
• Adult Dosing
• 750 mg IV qd
• Pediatric Dosing (not FDA approved)
• 10 mg/kg IV q24 hrs

plus

• Metronidazole
• Adult Dosing
• 500 mg IV q8hrs
• Pediatric Dosing
• 40 mg/kg/day q8 hrs

Urinary source:

• Piperacillin/tazobactam (Zosyn)
• Adult Dosing
• 4.5 g IV q8hrs
• Pediatric Dosing
• 6 months: 150-300 mg/kg/day IV q6-8 hrs
• >6 months: 300-400 mg/kg/day IV q6-8 hrs

Or If penicillin allergy:

• Levofloxacin
• Adult Dosung
• 750 mg IV q24 hrs
• Pediatric Dosing (not FDA approved)
• 10 mg/kg IV q24 hrs

Or

• Ciprofloxacin
• Adult Dosing
• 400 mg IV q12 hrs
• Pediatric Dosing
• 10-15 mg/kg IV q12 hrs

Or

• Gentamicin + ampicillin
• Adults Dosing
• 4-7 mg/kg gentamicin IV q24hrs Plus ampicillin 2 grams q6 hrs
• Pediatric Dosing
• 5-7 mg/kg gentamicin IV q24hrs plus ampicillin 50 mg/kg q6 hrs [Max 2 g/dose]

Pulmonary source:

• Piperacillin/tazobactam (Zosyn)
• Adults Dosing
• 4.5 g IV q6hrs
• Pediatric Dosing
• 6 months: 150-300 mg/kg/day IV q6-8 hrs
• >6 months: 300-400 mg/kg/day IV q6-8 hrs

plus

• Levofloxacin
• Adult Dosing
• 750 mg IV qd
• Pediatric Dosing
• Safety and effectiveness not established

or If penicillin allergy

• Levofloxacin
• Adult Dosing
• 750 mg IV qd
• Pediatric Dosing (not FDA approved)
• 10 mg/kg IV q24 hrs

plus

• Gentamicin
• Adult Dosing
• 4-7 mg/kg IV q24 hrs
• Pediatric Dosing
• Neonates 1 wk: 5 mg/kg/day IM/IV divided q12 hrs
• Infants: 7.5 mg/kg/day IM/IV divided q8 hrs
• Child: 6-7.5 mg/kg/day IM/IV divided q8 hrs

Petechial rash:

• Ceftriaxone
• Adult Dosing
• 2 g IV q12 hrs
• Pediatric Dosing
• 100 mg/kg/day IV divided q12-24 hrs [Max 2 g q12 hrs or 4 g q24 hrs]

• Antifungals
• Fluconazole
• Adult Dosing
• 400 mg IV q24 hrs
• Pediatric Dosing
• 6-12 mg/kg/day IV

or

• Micafungin
• Adult Dosing
• 100 mg IV infusion over 1 hrqd x 10-47 days (mean treatment duration of 15 days)
• Pediatric Dosing
• 40 kg: 2-3 mg/kg/dose IV qd; max dose: 150 mg/24 hrs
• 40 kg: 100-150 mg IV qd
• Antivirals
• Acyclovir
• Adult & Pediatric Dosing
• 10 mg/kg IV q8 hrs [Max 1000 mg/dose]
• Neonatal Dosing
• 20 mg/kg IV q8 hrs

Refer 'General treatment items' for complete dosing information

Dietary or Activity restrictions

• Advise NPO if intubation is being considered; otherwise, enteral feeds are preferred to help preserve mucosal integrity of the GI tract
• Use IV alimentation only if enteral feeding is contraindicated

Monitoring

• Unstable patients: Invasive hemodynamic monitoring including arterial line for ABGs and continuous BP, and central venous catheter placement for CVP monitoring
• Continuous ECG monitoring
• Electrolytes, BUN, creatinine, and CBC daily; lactate, mixed venous oxygen saturation every 2-4 hours in initial resuscitation, and daily INR/PTT, if DIC is a consideration
• Control blood glucose levels in both nondiabetic and diabetic patients
• Antibiotic drug levels when indicated

Complications

• ARDS
• Death
• Disseminated intravascular coagulation (DIC)
• Hepatic encephalopathy
• Hypotension
• Hyperglycemia
• Myocardial dysfunction and failure
• Multiple organ system failure
• Neurological sequelae
• Renal dysfunction

Prevention

• Keep vaccinations up to date
• Early treatment of infection
• Use of aseptic technique

Prognosis

• Mortality rate in severe sepsis is 28-50%
• ICU-specific mortality: 27% (sepsis), 32% (severe sepsis) and 50-70% (septic shock)
• Multi-organ dysfunction is common in advanced sepsis with variable residual morbidity
• Hyperglycemia in nondiabetics is associated with a higher mortality rate and worse outcomes

Associated conditions

• Alcoholism
• Burns
• Diabetes mellitus
• Hepatic disease (cirrhosis, other hepatic insufficiency)
• Immunosuppression
• Complement deficiency
• HIV/AIDS
• Hypo/agammaglobulinemia
• Medications such as corticosteroids, chemotherapy, TNF-alpha antagonists
• Neutropenia
• Splenectomy
• IV drug abuse
• Malignancy
• Malnutrition
• Trauma (especially severe)

Pregnancy/Pediatric effects on condition

• Complications of pregnancy and labor are a predisposing factor for sepsis. Neonates and infants are at high risk for developing sepsis

Synonyms/Abbreviations

Abbreviations

• Systemic inflammatory response syndrome = SIRS
• Multiple organ dysfunction syndrome = MODS

ICD-9-CM

• 995.91 Sepsis
• 995.91 Severe sepsis

ICD-10-CM

• A41.9 Sepsis, unspecified organism
• R65.20 Severe sepsis without septic shock

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