• Hemorrhagic (GI bleed, trauma, surgery, internal bleeding)
• Non-Hemorrhagic (dehydration, fluid shifting, cutaneous loss)

• Decreased PCWP and Decreased CVP due to decreased venous return (preload)
• Decreased CO due to decreased venous return (decreased SV)
• Compensatory increase in SVR to maintain BP, however often inadequate compensation --> hypotension and hypoperfusion prevail

• Fluid resuscitation
• Correct inadequate tissue perfusion and oxygenation
• CVP > 12 mmHg, CI > 2.2 L/min
• Rapid infusion of IV fluids (crystalloids or colloids) is necessary to restore intravascular volume

• Non-Mechanical (acute MI, acute CHf exacerbation, cardiomyopathy)
• Mechanical (Mitral or aortic valve insufficiency, severe aortic stenosis, septum or free wall rupture)

• Decrease CO due to pump failure
• Compensatory increase SVR to maintain BP
• Increase PCWP or CVP (esp. in CHF) b/c heart cannot pump blood through circulation --> volume overload
• Overall, decrease in arterial BP and hypoperfusion -- can lead to ischemia in various organs

• Selection of agent(s) depends on patient presentation and etiology: Inotropes, diuretics, vasodilators, vasopressors, IV fluids, intra-aortic balloon pump, ventricular assist device
• CI > 2.5, PCWP < 18, MAP > 65

• Septic shock
• Anaphylaxis
• Neurogenic causes -- spinal injury, cerebral damage, etc.
• Drug-induced -- anesthesia, overdose of opiods, etc.
• Acute adrenal insufficiency

Must meet 2 out of the 4 following criteria:

1. Temp < 36°C or > 38°C
2. HR > 90 beats/min
3. RR > 20 RPM or PaCO2 < 32 mmHg
4. WBC < 4000 or > 12000 or > 12% bands

• All critically ill patients
• Severe Community-Acquired Pneumoniae (CAP)
• Intra-Abdominal Surgery
• Meningitis
• Chronic diseases (DM, HF, Chronic HF, COPD)
• Compromised Immune Status (HIV/AIDS, use of cytotoxic and immunosuppressive agents, malignant neoplasms, alcoholism)
• Cellulitis
• UTIs
• Severe Injuries (bullet wounds, severe burns, etc.)

• Age > 65
• Underlying comorbidities
• Pre-existing organ dysfunction
• Higher body weight
• Medical Treatment with a medical device

1.  Inflammation

• In response to an infection, ischemia, or injury -- inflammatory cytokines are produced by the body
• Release of cytokines and other mediators lead to:

↑ capillary permeability (↓ intravascular volume) --> vasodilation of blood vessels (hypoperfusion) and ultimately cellular death and multiple organ failure

• TNF-α is one of the primary mediators of sepsis

2.  Coagulation

• Activation of coagulation cascade --> pro-coagulation --> microvascular thrombosis
• Increased Pro-Coagulants:

Thrombin

Plasminogen activator inhibitor

Thrombin activatable fibrinolysis inhibitor

• Decreased Anticoagulants

Protein C

Plasminogen

Antithrombin III

• Fever/Chills/Myalgias
• Increased/Decreased WBCs: left shift
• Hypoxia (PaO2 < 70%)
• HR > 90
• Hyperventilation (RR > 20, PaCO2 > 30)
• Changes in mental status

• Oliguria/Anuria (UO < 0.5 ml/kg/hr)
• Increased SCr
• Lactic Acidosis (lactic acid > 1.5 ULN)
• Hypotension/Myocardial Depression
• Elevated LFTs
• Disseminated Intravascular Coagulopathy (decreased platelets/decrease fibrinogen)
• ARDS (lung injury)

1.  Presumed or known site of infection

• Purulent sputum or respiratory sample
• Chest radiograph with new infiltrates not explained by a noninfectious process
• Spillage of bowel contents noted during operation
• Radiographic or physical examination evidence of an infected collection
• WBCs in normally sterile fluid
• Positive blood culture
• Evidence of infected mechanical hardware by physical or radiographic examination

2.  Evidence of SIRS (2 out of 4 criteria)

3.  Sepsis-Induced Organ failure

• Cardiovascular dysfunction (MAP < 60 mmHg) - need vasopressors to maintain BP in the face of adequate intravascular volume (CVP > 8-10) or after an adequate fluid challenge has been given
• Respiratory organ failure - respiratory distress requiring mechanical ventilation
• Renal dysfunction - UO < 0.5 ml/kg/hr for 1 hr in the face of adequate intravascular volume or after an  adequate fluid challenge
• Hematologic dysfunction - thrombocytopenia or a 50% drop in platelets in the previous 3 days, INR > 1.2 that cannot be explained by liver dz or warfarin usage
• Anion-Gap Metabolic Acidosis - pH < 7.30, plasma lactate > 1.5 x the upper limit of normal

Should be started in the ER, within the initial 6 hrs, and not delayed until patient reaches ICU

• CVP 8-12 mmHg (12-15 if pt on ventilator)
• MAP > 65
• UO > 0.5 ml/kg/hr
• Central Venous O2 saturation (SVO2) > 70% or Mixed Venous O2 Saturation (MVO2) > 65%

1.  Crystalloids

• Rate of 500-1000 ml q 15-30 min
• Isotonic sol'n -- 0.9% NaCl or LR
• Recommended initially to expand intravascular volume -- cheaper than colloids and more readily available

2.  Colloids

• Expand intravascular space for longer duration than crystalloids
• More expensive and more side effects -- higher incidence of renal failure when pts put on hetastarch compared to LR
• May be beneficial in pts w/ low albumin or pts not responding to crystalloids

• First Line Agents: Dopamine or Norepinephrine
• Vasopressors increase MAP
• Initiate if hemodynamic instability (MAP < 65 mmHg) persists despite adequate fluid resuscitation (CVP 8-10 mmHg)
• Refractory hypotension despite high doses of NE -- consider adding vasopressin 0.04 units/min

• Indicated if SVO2 < 70% and Hct < 30%
• Transfuse to achieve a Hct of 30%

• First Line Agent: Dobutamine
• Increases CO
• Indicated if SVO2 < 70% and Hct > 30%

• Obtain cultures prior to antibiotc therapy
• Antibiotics should be administered within 1 hr of recognizing the clinical syndrome of sepsis
• Choice of antibiotics should cover MRSA and P. aeruginosa and other G-, G+, and Anaerobic organisms
• Empiric double coverage of Pseudomonas from 2 different classes as well as MRSA coverage
• Choice of antibiotics similar to Late Onset/MDR Pathogen Nosocomial Pneumonia treatment

Antipseudomonal Cephalosporin

OR

Antipseudomonal Carbapenem

OR

β-Lactam/β-Lactamase Inhibitor

OR

Aztreonam (if β-Lactam allergy)

PLUS:

Antipseudomonal Fluoroquinolone

OR

Aminoglycoside

PLUS:

Vancomycin

OR

Linezolid

OR

Tigecycline

OR

Daptomycin

• All pts presenting with signs and symptoms of sepsis should be evaluated for source/site of infection
• Unable to identify via physical assessment --> X-Ray/Ultrasound/CT Scan/MRS, etc.
• Once focal source identified:

Abcess - drainage/debridement

Wound - debridement of necrotic/infected tissue

Medical Device - removal of device if possible

• Evaluate risk vs benefit of intervention for source removal
• Inability/failure to remove source of infection prolongs sepsis and leads to poor outcomes

• 7-10 days recommended
• Should be dictated by patient response and site of infection
• Should treat for recommended duration for specific infection that caused sepsis (ie, endocarditis 4-6 weeks, osteomyelitis 4-6 weeks, etc.)

• Relative Adrenal Insufficiency commonly occurs in sepsis:

-inflammatory cytokines released in response to infection suppress the cortisol response to Adrenocorticotropic Hormone (ACTH)

-this leads to relative adrenal insufficiency

-ultimately leads to deregulation of inflammatory process and loss of vascular tone --> hypotension

• Guidelines recommend use in septic shock when hypotension remains poorly responsive to adequate fluid resuscitation AND vasopressors
• Steroids may be DC'd or weaned once vasopressors are no longer required

Hydrocortisone 200-300 mg IV divided 3-4 x daily

+/-

Fludrocortisone 50 mcg PO daily

Benefits:

• improvement in shock reversal in pts unresponsive to fluid resuscitation and vasopressors

Risks:

• immunosuppressive properties -- increasing risk of infection
• increased risk of critical care myopathy (especially when used while pt. on neuromuscular blockers)
• increased risk of GI bleed
• hyperglycemia

• Recombinant activated protein C (rhAPC)
• Activated protein C decreased in sepsis leading to inflammation and coagulopathy
• rhAPC inhibits clotting factors Va and VIIIa --> ↓ thrombin production
• Also promotes anti-inflammatory (suppresses TNF-α, IL-1, and IL-6) and pro-fibrinolytic response

• Adults with Sepsis-Induced Organ Dysfunction or Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
• Clinical assessment of high-risk of death
• No contraindications
• Optimal results if started within 24 hrs of sepsis onset

Adverse Effect:

Bleeding

CI:

• Platelets < 30,000
• Hemorrhagic stroke within 3 months
• Severe head trauma
• Intracranial or intraspinal surgery within 2 months
• Need for epidural catheter
• Any factor that would increase likelihood of life-threatening bleeding

• Hyperglycemia associated w/ insulin resistance common in sepsis
• Prolonged hyperglycemia can lead to:

infectious complications

critical-illness polyneuropathy

multiple organ failure

• Target blood glucose 140-180 mg/dL
• ICU insulin protocols should be implemented
• Sliding-scale insulin protocols and/or continuous IV insulin

• All patients with sepsis should receive stress ulcer prophylaxis
• H2 blocker (famotidine, ranitidine, etc.)
• Proton Pump Inhibitor (Omeprazole, Esomeprazole, etc.)

Risk Factors for Stress Ulcers:

1. Mechanical ventilation
2. Coagulopathy
3. Acute renal failure
4. Acute hepatic failure
5. Major surgery
6. Severe head trauma
7. Major burns

• Incidence of DVT ranges from 10-80% in ICU patients
• All patients without CI should receive DVT prophylaxis with either:

Heparin 5000 units SubQ TID

Enoxaparin 40 mg  SubQ daily

Fondaparinux 2.5 mg SubQ daily

• Patients with CI UFH/LMWH should receive mechanical prophylaxis (graduated compression stockings or intermittent compression devices)
• Very high risk pts should receive a combination of pharmacological therapy and mechanical therapy