Shock and Sepsis


Pathophysiology of Shock

  1. Definition of Shock
    • circulation fails to deliver to cellular mitochondria sufficient oxygen to sustain aerobic metabolism
    • many different etiologies exist, but the ultimate result is a dysfunction of cellular biochemistry leading to acidosis and decreased energy (ATP) production

  2. Aerobic and Anaerobic Metabolism
    1. Aerobic Metabolism
      • for energy, cells depend on the hydrolysis of high energy phosphate bonds from ATP
      • the hydrolysis of ATP also results in the production of a proton
      • in normal circumstances, oxidative phosphorylation (aerobic metabolism) reclaims the proton in resynthesis of ATP from ADP
      • oxidative phosphorylation is dependent on oxygen, since oxygen is the final electron acceptor in the electron transport chain
      • glycolysis converts glucose to 2 pyruvates, producing a net gain of 2 ATP
      • when cellular oxygen delivery is sufficient, pyruvate crosses the mitochondrial membrane and enters the energy efficient Krebs cycle
      • net result is production of 38 ATP from 1 glucose molecule

    2. Anaerobic Metabolism
      • if there is insufficient cellular oxygen to support aerobic metabolism, pyruvate cannot enter the Krebs cycle
      • anaerobic glycolysis is inefficient, only producing 2 ATP from each glucose molecule

      1. Acidosis
        • ATP hydrolysis is the source of acidosis in cellular hypoxia
        • inefficient regeneration of ATP allows the accumulation of H+ in the cell
        • pyruvate is converted to lactate, which buffers the excess protons and is converted to lactic acid
        • production of lactate is not the cause of cellular acidosis, but rather is a marker of the magnitude of shock
        • acidosis will affect calcium signaling and normal hormone and enzyme functioning

      2. Consequences of Decreased ATP Production
        • all ATP-dependent cell processes are affected, including maintenance of the cell membrane potential, cell signaling, synthesis of proteins and enzymes, and DNA repair mechanisms
        • gene transcription will also be affected

Sepsis and Septic Shock

  1. Definitions
    1. Systemic Inflammatory Response Syndrome (SIRS)
      • clinical syndrome that is a form of dysregulated inflammation
      • no longer considered the earliest form of sepsis since it may be present in noninfectious conditions as well (pancreatitis, surgery, trauma, burns)
      • defined as two or more abnormalities in temperature, heart rate, respiratory rate, and WBC count:

      SIRS Criteria
    2. Sepsis
      • defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection
      • continuum of severity ranging from infection, bacteremia, sepsis, and septic shock
      • these new definitions are controversial, and have not yet been endorsed by many important societies

      Sepsis Definitions
  2. Pathophysiology
    • the inflammatory response to infection or tissue injury is mediated by cells of the innate immune system: macrophages, monocytes, and neutrophils
    • these cells elaborate numerous inflammatory and anti-inflammatory cytokines
    • when the local proinflammatory response exceeds the ability of the local anti-inflammatory response to contain the inflammatory process, the inflammatory response becomes systemic
    • the systemic release of proinflammatory cytokines leads to the alterations seen in sepsis and septic shock: fever, leukocytosis, increased cardiac output, decreased peripheral vascular resistance, tachycardia, hyperglycemia, and organ dysfunction

  3. Risk Factors
    • ICU admission
    • bacteremia
    • age ≥ 65
    • immunosuppression
    • diabetes
    • obesity
    • malignancy
    • previous hospitalization within 90 days

  4. Diagnosis
    • often made empirically at bedside using a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data
    • the identification of a culprit organism occurs in less than 50% of cases

    1. Clinical Presentation
      • typical presentation includes tachycardia, fever, and hypotension
      • in the early stages of sepsis, the skin may be warm
      • signs of organ dysfunction may also be present: oliguria, respiratory insufficiency, altered mentation

    2. Laboratory Evaluation
      • there is no single laboratory test that is diagnostic of sepsis
      • CBC with differential, electrolytes, liver function tests, and coagulation studies may support the diagnosis and indicate the severity of organ dysfunction present
      • ABGs will indicate the degree of acidosis, hypoxemia and hypocarbia present
      • lactate may also indicate the degree of sepsis and is useful for following the therapeutic response
      • blood cultures should be obtained from peripheral sites as well as from any central lines
      • urine, sputum, and wound cultures should be obtained as clinically indicated

    3. Imaging
      • CXR to evaluate for pneumonia
      • CT scan to look for drainable fluid collections in the abdomen or chest

    4. Sequential Organ Failure Assessment (SOFA) Score
      • used more in critical care research than at the bedside
      • sepsis-3 definition of sepsis requires an acute increase of 2 or more SOFA points, which is a marker for organ dysfunction

      Sequential Organ Failure Assessment Score (SOFA)
    5. Quick SOFA (qSOFA) Score
      • developed as a simple screening tool to identify patients with possible sepsis
      • qSOFA score ≥ 2 identifies patients at high risk for a poor outcome
      • importantly, the qSOFA score has failed validation in several large studies

      Quick Sequential Organ Failure Assessment Score (qSOFA)
  5. Management
    1. Surviving Sepsis Campaign Bundles
      • outlines tasks to be completed within 3 and 6 hours
      • early identification of patients with sepsis, early IV fluid administration, early IV antibiotic administration, and early source control are the goals of sepsis management

      Surviving Sepsis Bundle - 3 Hours
      Surviving Sepsis Bundle - 6 Hours
    2. ABCs
      • secure the airway, if necessary
      • administer supplemental oxygen and monitor with continuous pulse oximetry
      • patients who require mechanical ventilation should be managed like ARDS patients (low tidal volumes (6 mL/kg) and low peak plateau pressures (< 30 cm H2O))
      • most patients will require a central line for fluids, pressors, and blood products
      • the central line can also be used for CVP and central venous oxyhemoglobin saturation (ScvO2) monitoring

    3. Fluid Resuscitation
      • after securing the airway, restoration of circulatory volume is the next priority
      • 30 mL/kg of crystalloid should be infused over 3 hours for hypotension or a lactate ≥ 4 mmol/L
      • additional fluid boluses should be given as necessary
      • blood transfusions should be limited to patients with a Hg < 7
      • initial resuscitation endpoints are a MAP ≥ 65 mm Hg or a urine output of 0.5 mL/kg/hr
      • a normal serum lactate also indicates adequate resuscitation
      • if a central line is in place, a CVP of 8 – 12 and a ScvO2 of 70% also indicate adequate resuscitation

    4. Antibiotics
      • empiric antibiotics are given based on the most likely pathogens
      • antibiotics should be given within 1 - 3 hours of presentation
      • empiric antifungal therapy is indicated in immunocompromised patients
      • coverage should be narrowed once culture data is available

    5. Vasopressors
      • will be necessary if hypotension does not respond to fluids
      • norepinephrine is usually the first choice
      • septic patients may be resistant to catecholamines
      • vasopressin is added in norepinephrine-resistant patients
      • occasionally the addition of an inotrope like dobutamine or milrinone can increase tissue perfusion

    6. Source Control
      • IV antibiotics are not usually sufficient treatment in surgical patients
      • abscesses must be drained, infected catheters removed, and dead tissue debrided as soon as possible

    7. Glucose Control
      • insulin resistance and hyperglycemia are typical in critically ill and septic patients
      • goal of treatment is a glucose between 140 – 180 mg/dL, which prevents most episodes of hypoglycemia

    8. Corticosteroids
      • sepsis is often associated with adrenal insufficiency
      • multiple studies have shown conflicting results about the efficacy of steroids in patients with sepsis
      • hydrocortisone 200 mg in divided doses can be considered in patients with hypotension refractory to fluids and pressors

    9. Immune Modulation
      • antiendotoxin antibodies, anticytokine antibodies, cytokine receptor antagonists, nitric oxide synthase inhibitor, O2 radical scavengers have all been developed to treat sepsis
      • to date, these agents have not shown efficacy in human trials

Multiple Organ Dysfunction Syndrome (MODS)

  1. Pathophysiology
    • most common cause of death in SICUs
    • appears to be the final pathway to death after sepsis, SIRS, and trauma
    • studies have identified microvascular thrombosis and end organ ischemia as the histopathological features of MODS
    • the actual mechanism of MODS remains unclear
    • one current theory proposes that cellular hypoxia leads to mitochondrial injury, which in turn results in dysfunction in oxidative metabolism

  2. Clinical Features
    • there is a spectrum of organ dysfunction, from mild and reversible to complete failure
    • the organ systems most commonly involved are the lungs, liver, kidneys, cardiovascular system, CNS, and bone marrow
    • organ dysfunction typically begins 24 – 48 hours after the origin of the insult
    • most commonly, the lungs are the first organ affected, followed by the liver and kidneys

  3. Organ System Dysfunction
    1. Acute Lung Injury
      1. Definition
        • characterized by hypoxemia
        • stratified by the ratio of partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2)
        • ARDS = PaO2/FiO2 < 100

      2. Management
        • goal is to maintain the oxygen saturation > 92%
        • a second goal is to minimize barotrauma and oxygen toxicity
        • ventilator management includes the use of PEEP, low tidal volumes, and airway pressures < 30 cm H2O

    2. Acute Kidney Injury
      1. Definition
        • stratified by the serum creatinine level and urine output
        • creatinine ≥ 5 or a urine output < 200 ml/d represents the highest degree of renal injury, and carries a high mortality rate

      2. Management
        • maintain renal perfusion to avoid worsening the injury
        • avoid nephrotoxic drugs
        • continuous renal replacement therapy is often used in unstable patients, but it has not been shown to be superior to intermittent hemodialysis

    3. Liver Dysfunction
      1. Definition
        • stratified by the serum bilirubin concentration
        • total bilirubin > 12 corresponds to the highest degree of liver injury
        • etiology is likely related to splanchnic vasoconstriction and hypoperfusion
        • ‘shock’ liver initially presents with elevated transaminases, followed by increasing bilirubin
        • synthetic dysfunction (↑ INR) is a later finding

      2. Management
        • supportive care involves maintaing perfusion, avoiding hepatotoxins, providing nutrition, and managing encephalopathy

    4. Cardiovascular Dysfunction
      1. Definition
        • characterized by the MAP and the need for pressors

      2. Management
        • initial management is with the use of fluids to support blood pressure
        • norepinephrine is the preferred pressor agent
        • vasopressin is added when norepinephrine alone cannot keep the MAP > 65
        • invasive monitoring with pulmonary artery catheters has not improved outcomes
        • bedside echocardiography shows some promise for monitoring and titrating therapy

    5. CNS Dysfunction
      1. Definition and Management
        • defined by the Glasgow coma scale
        • clinical presentation may range from delirium to coma
        • besides the brain injury resulting from MODS, the neurologic system is also affected by premorbid dementia, substance abuse, pain, altered sleep-wake cycles in the ICU, and medications
        • Haldol is the most efficacious drug for delirium, and benzodiazepines must be avoided
        • sitters, minimizing restraints, and transferring out of the ICU if possible are additional management strategies to consider

  4. Nutrition in MODS
    • early enteral nutrition improves outcomes in patients with MODS
    • calories and protein requirements are titrated to the underlying disease process, with trauma and burn patients requiring the highest calories and protein
    • glutamine supports the gut mucosa and improves outcomes in MODS
    • omega-3 fatty acids support immune function and reduce infectious complications
    • vitamins and minerals (zinc, selenium, vitamin C and folate) must be supplemented to support wound healing and immune function







References

  1. Schwartz, 10th ed., pgs 109 – 131
  2. Cameron, 13th ed., pgs 1426 - 1432, 1432 - 1439
  3. UpToDate. Evaluation and Management of Suspected Sepsis and Septic Shock in Adults. Schmidt, Gregory. Aug 18, 2021, Pgs 1 - 55.
  4. UpToDate. Sepsis Syndromes in Adults: Epidemiology, Definitions, Clinical Presentation, Diagnosis, and Prognosis. Neviere, Remi. Aug 25, 2021, Pgs 1 – 42.
  5. Sepsis 2018: Definitions and Guideline Changes. Napolitano, Lisa. Surgical Infections, Volume 19, Number 2, 2018. Pgs 117 - 125