sepsis

Introduction

Life-threatening organ dysfunction caused by a dysregulated host response to infection.

The presence of various pus-forming & other pathogenic organisms or their toxins, in the blood or tissues. The same organism is often isolated in both the blood & the primary site of infection. Sepsis has features of systemic inflammatory response syndrome (SIRS).

Etiology

• gram negative organisms account for 2/3 of positive blood cultures
• gram positive cocci account for 10-20% of positive blood cultures
• fungi account for 5% of positive blood cultures
• in nursing home population, 50% gram positive orgamisms, 45% gram negative organisms & 5% fungal infection; 47% due to multidrug-resistant organisms
• Rickettsia (Rocky Mountain spotted fever)
• malaria
• in infants
  • Escherichia coli most common cause, especially when associated with urinary tract infection
  • Listeria monocytogenes 2nd most common cause
• PCV13 vaccines have reduced incidence of bacteremia in young children & shifted the most-commonly isolated pathogens from pneumococcus to E coli, S aureus, & Salmonella
• lower respiratory tract infections (pneumonia), abdominal infections, urinary tract infections & soft tissue infections most common
• risk factors
  • extremes of age < 10 years, > 70 years
  • comorbidities (cirrhosis, alcoholism, diabetes, cardiopulmonary diseases, malignancy)
  • immunosuppression
  • major surgery, trauma, or burns
  • invasive procedures (catherization & other intravascular devices, prosthetic devices, endotracheal tubes)
  • previous antibiotic treatment
  • prolonged hospitalization
  • genetic susceptibility
  • obstetric factors (childbirth, abortion)
  • malnutrition

Epidemiology

• most sepsis is community-acquired; however, healthcare exposure within 1 month of hospitalization with sepsis is common
• incidence of sepsis & sepsis-related mortality has not changed in recent years

Pathology

• microbial invasion of the blood stream is not essential for the development of sepsis
• microbial endotoxins can lead to systemic symptoms
• myocardial depression due to tumor necrosis factor (TNF)
  • ventricular dilation
  • reduced ventricular ejection fraction
  • maintenance of stroke volume
• in early stages of sepsis, cardiac output is maintained or even increased

Genetics

• CASP12 implicated in susceptibility to severe sepsis

Clinical manifestations

• fever
• tachycardia
• tachypnea
• hypotension
• delirium
• early recognition of sepsis is based of signs of developing end organ failure
  • severe symptoms in septic shock
    • ileus
    • oliguria
    • metabolic acidosis
• cough, dyspnea & sputum production suggest pulmonary source
  • ARDS (see complications)
• dysuria, frequency & flank pain suggest urosepsis
• nausea, vomiting & diarrhea suggest gastroenteritis
• petechiae or purpura associated with Neisseria meningitidis
• petechial lesions associated with Rocky Mountain spotted fever
• generalized erythroderma associated with Staphylococcus aureus or Streptococcus pyogenes
• ecthyma gangrenosum is a cutaneous ulceration associated with Pseudomonas aeruginosa

Diagnostic criteria

(Clinical criteria)

• temp > 38 C or < 36 C
• heart rate > 90/min
• respiratory rate > 20/min or paCO2 < 32 torr
• WBC > 12,000 cells/mm3 or < 4000 cells/mm3 or > 10% bands
• documented infection

Laboratory

• serum lactate
  • persistently elevated despite fluid resuscitation in severe sepsis/septic shock
  • predicts mortality about as well as MEDS score
  • measure within 1 hour (part of 1 hour bundle)
    • > 2 mmol/L despite adequate hydration
    • remeasure with 2-4 hours if > 2 mmol/L
    • normal serum lactate is one endpoint of resuscitation
• blood cultures prior to administration of antibiotics:
  • 2 cultures at different sites (aerobic & anaerobic)
  • 3 cultures 60 minutes apart
  • 6 cultures over 2 days if endocarditis suspected
• sputum cultures
• urinalysis & urine cultures (all patients)
• complete blood count (CBC)
  • leukocytosis with predominance of neutrophils & band forms with bacteremia
  • leukopenia may be present especially in elderly & immunocompromised
  • thrombocytopenia with severe sepsis
  • a normal WBC count does not rule out bacteremia
• serum chemistries
  • basic metabolic panel
    • serum Na+ (hyponatremia), serum K+ (hyperkalemia)
    • serum Cl- (calculation of anion gap)
    • serum HCO3- may be low consistent with metabolic acidosis
    • BUN, serum creatinine to assess oliguria
    • serum glucose
  • procalcitonin in serum
    • only if probability of infection is low
    • may shorten antibiotic duration by about 1 day (10 vs 11 days)
    • use serum procalcitonin as an antibiotic de-escalation strategy in sepsis
      • if serum procalcitonin < 0.5 ng/mL, consider antibiotic discontinuation (MKSAP20)
• remove & culture all indwelling catheters
• aspiration of joint if joint infection suspected
• gram stain & culture of wounds
• paracentesis of ascites fluid
• as indicated
  • lumbar puncture if intracranial infection is suspected
  • serum bilirubin > 4 mg/dL with severe sepsis
  • serum ALT, serum AST
  • serum amylase
  • DIC panel (PT/PTT, plasma fibrinogen, D-dimer)
  • arterial blood gas (ABG): PaO2/FiO2 < 300
    • target central venous oxygen saturation > 70% in patients with central venous catheters
  • serum cortisol (adrenal insufficiency)
  • cosyntropin stimulation test (see Management)
• repeat blood cultures for gram-negative sepsis most likely positive if patient is febrile
• see ARUP consult

Diagnostic procedures

• electrocardiogram:
  • 12 lead EKG
  • cardiac monitor
• echocardiogram for all septic patients
  • obtain transthoracic echocardiogram (TTE)
  • if TTE is negative, obtain transesophageal echocardiogram (TEE)

Radiology

• chest X-ray (all patients)
• ultrasound or CT of kidneys if complicated urosepsis suspected
• imaging of abdominal contents if indicated

Complications

• septic shock
  • adrenocortical insufficiency
• acute respiratory distress syndrome (ARDS) (18-38%)
  • usually within 12-48 hours of inciting event
• stroke (HR=6.0)
• new-onset atrial fibrillation
  • associated with increased mortality (HR-1.5)
• persistent cognitive impairment & functional disability in the elderly
• increased risk of post-operative venous thrombosis & arterial thrombosis
• delays in treatment of early sepsis are associated with higher mortality
• increased mortality in elderly persists for at least 2 years
• 74% of in-hospital mortality with sepsis on admission
  • sepsis is the immediate cause of death in 35% of patients & contributes to the deaths of another 8%
  • nearly all deaths attributed to sepsis considered to be unpreventable
• 30-day hospital readmission for sepsis more common than readmission for any of the 4 CMS index conditions*, associated with longer length of stay after readmission, & is associated with higher cost
• increased risk for seizures up to 8 years after hospital discharge (RR=5.0)
• 47% of hospitalizations with sepsis from nursing homes are due to multidrug-resistant organisms

* readmission used by CMS as quality markers for index conditions (heart failure, MI, pneumonia, COPD)

Differential diagnosis

• anaphylaxis
• drug overdose
• pancreatitis
• burns
• adrenal insufficiency
• pulmonary embolism
• ruptured aortic aneurysm
• myocardial infarction
• hemorrhage
• cardiac tamponade
• drug withdrawal
• neuroleptic malignant syndrome
• systemic vasculitides
• exensive crush injury
• heatstroke
• dehydration
• systemic inflammatory response syndrome (SIRS)

Management

• monitor:
  • temperature
  • blood pressure:
    • mean arterial BP > 65
    • target systolic BP 120-140 mm Hg
  • heart rate
  • respiratory rate
  • pulse oximetry
  • urine output
  • mental status
  • sepsis alerts, based on qSOFA score, lower 90-day inpatient mortality
• NPO (nothing by mouth) until respiratory & mental status are stable
• oxygen to maintain SaO2 > 90%
• mechanical ventilation as indicated
  • low tidal volume 6 mL/kg
  • plateau pressures < 30 cm H2O
• one hour sepsis bundle
• hydration/volume
  • lactated Ringer's preferred vs normal saline
    • lactated Ringer's associated with lower 30-day mortality than saline
    • do not use synthetic colloid (hydroxyethyl starch)
    • initial bolus of 30 mL/kg within 3 hours
  • fluid resuscitation with normal saline vs lactated Ringer's result in similar outcomes
  • keep central venous pressure 8-12 mm Hg
    • central venous pressure monitoring & targeting do not improve outcomes
  • central venous oxygen saturation > 70%
  • urine output >= 0.5 mL/kg/hour
  • 30 mg/kg crystalloid for hypotension or serum lactate >= 4 mmol/L
  • time to completion of fluid bolus not associated within-hospital mortality
  • assessment of volume responsiveness after initial fluid bolus before initiating vasopressors
  • caution in patients with heart failure or renal failure
  • aggressive fluid management associated with excess mortality in HIV-positive patients in Zambia
  • no benefit to fluid restriction in patients with septic shock
• antimicrobial therapy
  • intravenous empiric antimicrobial therapy within 1 hour after specimens for blood culture & other appropriate cultures have been obtained (severe sepsis or septic shock)
    • begin within 1 hour even if obtaining cultures is incomplete
    • continuous infusion of beta-lactam (especially Zosyn) improves outcomes
    • early antibiotics for severe sepsis associated with lesser progression to septic shock & lower mortality
    • rapid administration of antibiotics associated with lower in-hospital mortality
    • prehospital antibiotics in the ambulance does not improve outcomes (unclear whether blood cultures were obtained in ambulance prior to antibiotics)
    • a 1 hour mandate lacks evidence of benefit & is achieved in only 29% of patients in the emergency department
    • no mortality benefit to antibiotics within 1 hour vs 1-3 hours after emergency department arrival in patients with sepsis or septic shock
  • adjust antibiotics according to culture & sensitivities
    • discontinue antibiotics if cultures negative
  • duration of therapy: 7-10 days (3-6 weeks for S. aureus)
    • intravenous vancomycin or daptomycin for 4-6 weeks if MRSA sepsis with prosthetic joint
    • 7 days of therapy adequate for gram-negative sepsis & neutropenia due to hematologic malignancy or hematopoietic stem cell transplantation
    • 7 days of therapy adequate for uncomplicated bacteremia
    • use serum procalcitonin as an antibiotic de-escalation strategy in sepsis
      • if serum procalcitonin < 0.5 ng/mL, consider antibiotic discontinuation (MKSAP20)
  • monotherapy with third generation cephalosporin or carbapenam for community-acquired septic shock
    • cefepime associated with lower mortality than Zosyn when used as initial monotherapy
  • coverage for MRSA & an anti-pseudomonas beta-lactam & either a fluoroquinolone or an aminoglycoside for nosocomial infections, immunosuppression or recent antibiotic use
    • cefepime, levofloxacin & vancomycin
      • Zosyn & cefepime similarly likely to cause acute kidney injury
    • aztreonam, levofloxacin & vancomycin if penicillin allergy
  • addition of clindamycin to decrease toxin production for suspected toxic shock syndrome
  • no benefit from the addition of moxifloxacin to meropenem for the management of the severe sepsis
  • 3 days of IV antibiotics prior to step-down oral therapy with fluoroquinolone or beta-lactam antibiotic for Streptococcal sepsis
  • for patients with gram-negative sepsis responding to IV antibiotics, switch to oral therapy after 3-5 days
• catheter management
  • central venous access as needed
    • pulmonary artery catheterization not routinely indicated
  • removal of indwelling catheter when not needed
    • see catheter-related infection
• prevention of septic shock (see septic & distributive shock)
  • assessment of volume responsiveness after initial fluid bolus before initiating vasopressors
  • vasopressor added if hypotension persists despite volume resuscitation
    • norepinephrine vasopressor of choice
      • epinephrine added if adequate blood pressure cannot be maintained
      • circumstances may exist where epinephrine may be substituted for norepinephrine
  • initiate vaspressor via peripheral access, vs waiting for placement of central venous access
  • target mean arterial pressure > 65 mm Hg
  • phenylephrine not recommended except if
    • norepinephrine is associated with serious arrhythmias
    • cardiac output is high & blood pressure persistently low
  • add dobutamine up to 20 ug/kg/minute if cardiac output low despite norepinephrine
  • intravenous glucocorticoid if ongoing vasopressor therapy
• corticosteroid replacement
  • of no benefit
    • hydrocortisone 50 mg bolus followed by 200 mg IV infusion daily does not prevent septic shock
    • no role in sepsis without septic shock
    • adrenocortical insufficiency
  • AVOID in the absence of refractory shock
  • other, older
    • if serum cortisol is < 9 ug/dL after 250 ug cosyntropin stimulaton test
    • hydrocortisone 15-240 mg IV every 12 hours
    • low dose corticosteroid (< 300 mg cortisol QD equivalent) for 5-11 days may improve outcomes
    • grade 2C recommendation
    • thiamine, vitamin C (6 g IV QD), hydrocortisone (50 mg Q6h)
      • may reduce mortality (9% vs 41% in a single-center study)
      • does not increase ventilator- & vasopressor-free days
      • vitamin C not recommended - intravenous vitamin C associated with increased 28 day mortality
    • IV hydrocortisone (200 mg/day) suggested for patients who are hemodynamically unstable despite fluids & vasopressors
    • mortality is lower with 200 mg hydrocortisone QD at 28 days, but not at 90 days
• blood transfusion
  • after tissue hypoperfusion is corrected, RBC transfusion only when blood hemoglobin < 7.0 g/dL
    • target blood hemoglobin of 7.0-9.0 g/dL in adults
• platelet transfusion indicated for patients with severe sepsis (possible DIC) when platelet count is < 10,000/mm3
• sodium bicarbonate should not be used if arterial pH >= 7.15
• stress ulcer prophylaxis - ranitidine 50 mg IV every 8 hours
• DVT prophylaxis - TEDs/SCD or subcutaneous heparin
• IV insulin for hyperglycemia after initial stabilization
  • maintain plasma glucose < 180 mg/dL
  • see glycemic control
• recombinant human activated protein C (drotrecogin alfa) for severe sepsis & high risk of death if risk of bleeding is low
• early broad-spectrum antibiotics & drotrecogin alfa independently associated with lower hospital mortality in ICU patients
• continued statin use associated may improve outcomes in ICU patients with sepsis
  • benefit of statins only apparent in prior statin users
• - no mortality benefit to early renal replacement therapy
• early enteral nutrition if possible

Notes

• New York has a mandate that all hospitals use evidence-based protocols for identification & management of sepsis & that they report data on protocol adherence & clinical outcomes to the state
• more rapid completion of a 3-hour bundle of sepsis care associated with lower in hospital mortality
  • Severe Sepsis/Septic Shock Early Management Bundle (SEP-1) adherence 54%
• sepsis-related mortality decreases with mandated bundled care & reporting
• CMS Sepsis Performance Measure (SEP-1) has not improved outcomes

More general terms

• bacterial infection
• bacteremia
• systemic inflammatory response syndrome (SIRS)

More specific terms

• gram-negative sepsis; gram-negative bacteremia
• Lemierre syndrome (septic thrombosis of the jugular vein)
• neonatal sepsis
• pyemia
• septic shock
• urosepsis

Additional terms

• distributive shock; vasodilatory shock (multiple organ dysfunction syndrome)
• mortality in emergency department sepsis (MEDS) score
• Severe Sepsis/Septic Shock Early Management Bundle (SEP-1)