1. Shock

Septic shock and sepsis are significant causes of morbidity and mortality in the intensive care unit (ICU).

Sepsis is one of the most common reasons for admission into the ICU.

Definitions

Sepsis = known or suspected infection plus some of:

Temperature > 38.3°C or < 36.0°C

Heart rate > 90 or > 2× normal for age

Tachypnea

Inflammatory markers

WBC > 12,000 or < 4,000 or normal with >10% immature forms

C-reactive protein (CRP) > 2 SD normal value, procalcitonin > 2 SD above normal value

Keep in mind other indirect indicators of infection such as altered mental status and hyperglycemia

Severe sepsis = sepsis-induced hypoperfusion or organ dysfunction indicated by one or more of:

Septic shock: arterial hypotension = acute systolic blood pressure (SBP) < 90, mean arterial pressure (MAP) < 70, or SBP decrease > 40 from baseline

Arterial hypoxemia (PaO₂/FiO₂ < 300)

Acute lung injury (ALI) with PaO₂/FiO₂ < 250 in the absence of pneumonia

ALI with PaO₂/FiO₂ < 200 in the presence of pneumonia

Elevated lactate (>1.2 mmol/L)

Acute oliguria (UOP < 0.5 mL/kg for 2 hours despite fluid resuscitation)

Creatinine increase (>0.5 mg/dL or 2× baseline)

Hyperbilirubinemia (Tbili > 4 mg/dL acutely)

Thrombocytopenia (platelets < 100,000 acutely)

Acute coagulopathy (INR > 1.5 or aPTT > 60 s)

Mixed venous saturation > 80% (likely sepsis) or < 65% (rule out cardiogenic source)

Severe acute ileus

Decreased capillary refill or mottling

Common Causes to Remember

ANY infection can be complicated by sepsis!

Examples include:

Gram-positive bacteremia (i.e., Staphylococcus, Streptococcus, Clostridium) via exposed peptidoglycan in their cell walls, exotoxins

Gram-negative bacteremia (Escherichia coli, Pseudomonas, Acinetobacter) via endotoxins (lipopolysaccharides)

Pneumonia

Pancreatitis

Necrotizing fasciitis

Meningitis

Urinary tract infections, including pyelonephritis

Indwelling catheters

Epidemiology

28-day mortality rate of more than 30%

Associated with an increased risk of death in the ICU

Approximately 100,000 deaths per year in the United States

National incidence ~750,000 cases

Can occur at any age, but there is a correlation with advanced age and not only incidence of septic shock, but also increased mortality.

Key Pathophysiology

The pathogenesis of sepsis is a complicated process that occurs as a result of the interaction of several factors including the infectious organism, the patient’s concomitant medical problems, and his/her immune system.

The type of infectious source, the duration of exposure, and the patient’s underlying medical comorbidities are factors addressed with early goal-directed therapy and initiation of appropriate antibiotics.

Immune response

Pro-inflammatory response mediated by cytokines

Interleukin-1 (IL-1) and IL-6; tumor necrosis factor-α (TNF-α)

Activated by antigen–antibody complexes

The complement system is activated by bacterial wall sugars and endotoxin.

Activates neutrophils, lymphocytes, prostaglandins, and acute phase reactant proteins

Pro-inflammatory mediators are counteracted by anti-inflammatory mediators.

IL-4 andIL-10

Anti-inflammatory mediators can limit the effects of pro-inflammatory mediators, leading to a state of “relative” immunosuppression, which is referred to as immunoparalysis.

Leads to a reduction of HLA proteins on monocytes

Contributes to increased morbidity and mortality

Cellular dysfunction

Disturbance of mitochondrial oxygen utilization

Results in cytopathic hypoxia: low ATP production in the setting of adequate oxygen delivery

Pathogenic activation of apoptosis

Endothelial dysfunction and loss of hemostatic balance

Endothelial cells assist in regulation of vascular tone and coagulation (via expression of heparin sulfate)

Inflammation is a known procoagulant state.

Nitric oxide (NO) is a potent vasodilator produced by NO synthase.

In sepsis, inducible NO synthase is stimulated by IL-6 and TNF-α, leading to an increased production of NO and subsequent profound vasodilatation.

Endothelial surfaces normally have anticoagulant properties

In sepsis, this anticoagulant balance is disturbed by procoagulant inducers (CRP), leading to intravascular thrombosis.

Tissue edema develops secondary to capillary leakage.

Fluids are subsequently shifted into the third space.

Central nervous system dysfunction

Decreased oxygen delivery to the brain can lead to sepsis-induced encephalopathy (confusion, delirium, obtundation).

Cardiac and circulatory dysfunction

Tachycardia initially compensates for the arterial hypotension caused by severe systemic vasodilatation to maintain stroke volume.

Myocardial contractility will eventually decrease and further contribute to the marked hypotension.

Impaired oxygen delivery combined with increased oxygen consumption and cardiac work can lead to cardiac dysfunction.

Respiratory dysfunction

Sepsis is accompanied by an increased work of breathing.

Capillary leak within the lungs leads to oxygenation difficulties.

Over time some patients with severe sepsis can develop ALI or acute respiratory distress syndrome (ARDS).

Renal dysfunction

Hypotension can lead to impaired perfusion, causing oliguria.

Can also see acute tubular necrosis (ATN), which can further precipitate renal failure

In severe cases, patients may require renal replacement therapy:

Can be a transient requirement that resolves in weeks to months

Other times permanent dialysis is needed.

Hepatic dysfunction

Hypoperfusion can cause “shock liver,” characterized by transaminitis.

Cholestasis and hyperbilirubinemia may be present.

Endocrine dysfunction

Adrenal insufficiency

Sepsis can impair the normal stress response.

Results in inadequate increase in serum cortisol levels

Insulin deficiency

Impaired function of pancreatic β cells

Results in hyperglycemia that can be detrimental secondary to increased frequency of infections, delayed wound healing, and reduced granulocyte function.

Vasopressin deficiency

Usually secreted in response to hypotension and hypovolemia

Given that these are hallmarks in sepsis, one would predict that vasopressin secretion would increase.

However, vasopressin levels are actually decreased in patients with septic shock.

Possibly due to depletion of stored vasopressin in the pituitary and/or depression of the baroreflex

Differential Diagnosis

The diagnosis of sepsis can be as straightforward as fulfilling the definitions for the various subclassifications of sepsis.

However, there are patients who become hypotensive where the question of sepsis is less clear and etiologies of hypotension overlap.

Always try to rule out other causes of shock.

The mainstay of diagnosing sepsis and septic shock is the early identification of the etiology.

This begins by obtaining cultures: blood, urine, sputum, cerebrospinal fluid, and any other fluid sample (e.g., abdominal drains) appropriate to the clinical situation.

Diagnostic imaging may also be helpful with tools such as plain films, ultrasounds, and CT scans.

Management and Treatment

The combined work of multiple groups has resulted in the development of The Surviving Sepsis Campaign.

This effort brought evidence-based guidelines to the treatment of sepsis.

The most recent guidelines (2012) can be found at www.survivingsepsis.org

Campaign bundles

In the first 3 hours

Obtain lactate levels, blood cultures before administration of broad-spectrum antibiotics, and bolus crystalloid (30 cc/kg) for hypotension or lactate >4.

In the first 6 hours

Vasopressor therapy if MAP < 65 and not responding to initial fluid resuscitation, measure CVP and Scvo2, and recheck lactate if the initial lactate level was elevated.

Source control is KEY!

Identification of the causative agent and controlling the infection

Timely administration of antimicrobial therapy is a key component in treating sepsis.

The goal is to begin therapy within 1 hour of the presumptive diagnosis.

Ideally cultures are obtained prior to starting antimicrobial therapy.

Therapy is broad spectrum based on the presumed source and is narrowed once culture results are reported.

Fluid resuscitation plays a key role in ensuring adequate intravascular volume and maintaining perfusion.

Resuscitate within the first 6 hours of recognition of the shock state

Can consider colloids (albumin) when the patient continues to require a significant amount of crystalloid to maintain MAP.

Avoid hetastarches!

Typically, a central venous catheter is inserted to measure central venous pressure (CVP) and resuscitation is continued until a CVP of 8 to 12 is reached.

If MAP is < 65 mmHg or SBP is < 90 mmHg, vasopressors are initiated:

Norepinephrine is the first drug of choice.

Vasopressin (0.01–0.04 U/min) can also be administered as a second vasopressor.

Vasopressin levels are decreased in septic shock.

Dopamine should only be used in patients with very low risk for arrhythmias, low heart rate and/or cardiac output. Dobutamine can be considered for patients with cardiac dysfunction, i.e. those with high filling pressures and low cardiac output, or those with clinical signs of hypoperfusion despite restoration of systemic blood pressure.

Epinephrine is a second-line agent for patients that do not respond to norepinephrine.

When blood pressure goals are achieved, a mixed venous (>65%) or central venous saturation (>70%) may be obtained to assess oxygen delivery and extraction.

Hemoglobin (Hb) target of 7 to 9 is fine, as long as there are NO signs of coronary artery disease (CAD), tissue hypoperfusion, or hemorrhage.

If oxygen delivery goals are not met, then consideration is given to transfusion if Hb is not 10.0 or initiation of inotropic therapy.

Dobutamine or milrinone are agents that are typically used.

Dobutamine is helpful when there is evidence of myocardial dysfunction.

In this situation, one would observe high filling pressures with a low cardiac output.

Can also be used when there are ongoing signs of hypoperfusion despite adequate intravascular volume status and MAP.

Examples include:

Low cardiac output

Low CVP

Elevated filling pressures

Ultrasound evidence of a low ejection fraction

Ensure patients are well oxygenated and correct hypoxemia.

Hemodynamically unstable patients will often require endotracheal intubation.

Given that up to 40% of patients with septic shock will develop ALI, consider using ventilation with lung protective strategies (TV 6 cc/kg of ideal body weight and maintain plateau pressures <30 cm H₂O)

Avoid muscle relaxation in sepsis WITHOUT ARDS.

A short trial (˜48 hours) may be used for patients with early ARDS (PaO₂/FiO₂ < 150).

Corticosteroid administration

Remains controversial, but consider using in patients who remain hypotensive despite presumed adequate fluid resuscitation and/or those on escalating doses of vasopressor therapy.

Dosing = 50 mg hydrocortisone every 6 hours

Discontinue as soon as the patient is no longer on vasopressors

Do not use for >7 days

Glucose control

110 to 150

Hyperglycemia and hypoglycemia are associated with worse outcomes.

Ensure the patient receives a sugar source (D5W, D10) if he/she requires an insulin infusion.

Nutritional support

Adequate nutrition is key, as malnutrition can lengthen the course of sepsis and further increase complications.

Enteral nutrition is always preferred.

Do not initiate during the resuscitation phase.

Begin as soon as the patient has entered a phase of relative hemodynamic stability (vasopressor requirement is not increasing).

Stress ulcer prophylaxis

Outcomes

Early goal-directed therapy is key!

APACHE II scores aid in prediction of mortality.

SUGGESTED READINGS

Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310.

Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871.

Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and shock: 2012. Crit Care Med. 2013;41(2):580-637.

Desai KH, Tan CS, Leek JT, et al. Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study. PLoS Med. 2011;8(9):e1001093.

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348(2):138-150.

Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6): 1589-1596.

1.2

Hypovolemic Shock

Molly Moore

Definitions

Inadequate tissue oxygenation and end-organ hypoperfusion are seen as a result of the rapid decrease and/or subsequent lack of circulating intravascular volume.

MAP, CO, PAWP, and SVO₂ will also be decreased and SVR will be increased in an attempt to maintain blood pressure.

The approach to any patient in shock is to first rule out hypovolemia as a potential cause.

Common Causes to Remember

The most common types of shock identified in surgical, trauma, and burn patients.

Hemorrhage (Table 1.2.1)

Dehydration (due to gastrointestinal [GI] losses)

Third spacing (due to burns)

Epidemiology

Hypovolemia and hemorrhage are responsible for over half of deaths in trauma cases.

Approximately one third of these deaths occur out of the hospital.

Hemorrhage and resulting hypovolemic shock are major causes of mortality within 4 hours of injury.

The mechanism of injury and immediate availability of a trauma center play a role in the mortality of these afflicted patients.

Key Pathophysiology

Total body water in the average adult male is equal to 60% of lean body weight (versus 50% in females).

Two thirds of the total body water is intracellular fluid (ICF).

The remaining extracellular fluid (ECF) is further divided into interstitial fluid and plasma.

The average adult has approximately 5 to 6 L of blood, which is equivalent to about 8% of the total body water.

An example of this calculation is shown below for an 80-kg male:

0.6 × 80 kg = 48 L of total body water

2/3 × 48 L = 32 L ICF

TBW – ICF = ECF

48 L – 32 L = 16 L ECF

3/4 × 16 L= 12 L of interstitial fluid

1/4 × 16 = 4 L of plasma

When the body is hypovolemic, the earliest response is the movement of interstitial fluid into the capillaries.

This transcapillary fluid shift is able to replace up to 15% of the intravascular volume, thus providing the mechanism for compensation in stage I shock.