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What's new in sepsis?

Foran, Catherine K. MSN, RN, CCRN

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doi: 10.1097/01.CCN.0000433802.04295.d1
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In Brief

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Figure

Mr. L, 82, is admitted to your surgical care unit after a bowel resection for a large bowel obstruction. During bedside handoff, the night shift nurse states that Mr. L rested comfortably, experienced good pain control, and maintained normal vital signs: temperature, 98.8° F (37.1° C); heart rate, 74; respiratory rate, 18; and BP, 101/72. However, during your initial assessment, you note temperature, 101.3° F (38.5° C); heart rate, 100; respiratory rate, 28; and BP, 101/72. In addition, Mr. L seems restless and slightly confused. His recent abdominal surgery, along with the changes in his vital signs and mental status, cause you to suspect Mr. L may be showing signs of sepsis. The rapid response team is dispatched, a diagnosis of sepsis is confirmed, and treatment is quickly initiated to prevent Mr. L's condition from progressing to severe sepsis and septic shock.1 (See Sepsis 101.)

Although this patient's condition was diagnosed and treated using established protocols that exist at many hospitals, you may not be aware of new sepsis guidelines available for the management of severe sepsis and septic shock. This article reviews updates to the Surviving Sepsis Campaign guidelines and how you and your facility can implement best practices and improve outcomes in adults.

Surviving Sepsis Campaign

The Surviving Sepsis Campaign is an international initiative that helps to increase worldwide awareness and reduce mortality from severe sepsis and septic shock. In 2003, medical experts from 11 international organizations met and developed evidence-based guidelines for the management of severe sepsis and septic shock. These guidelines were updated in 2008, and as a result of targeted education, sepsis protocols were established in many hospitals. Fulfilling its commitment to periodically update the guidelines with the most current evidence, the campaign issued revised guidelines in 2012.2,3 (See Revised Surviving Sepsis Campaign bundles.)

Management of severe sepsis and septic shock guideline update

The new Surviving Sepsis Campaign 2012 guidelines provide an update on several aspects of managing severe sepsis in critically ill patients, some of which include initial resuscitation, diagnosis, and antimicrobial therapy; fluid therapy and the use of vasopressors and corticosteroids; and supportive therapies such as mechanical ventilation of sepsis-induced acute respiratory distress syndrome (ARDS), glucose control, and new pharmacologic restrictions.2,3Here are some of the highlights of the latest changes to the guidelines:

Initial resuscitation

Recommendation: Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion persisting after initial fluid challenge or blood lactate concentration greater than or equal to 4 mmol/L. Goals: During the initial 6 hours of resuscitation, goals include central venous pressure (CVP) 8 to 12 mm Hg, mean arterial pressure (MAP) greater than or equal to 65 mm Hg, urine output greater than or equal to 0.5 mL/kg/hour, central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2) 70% or 65%, respectively.3

Mr. L is transferred to the ICU and a central venous catheter (CVC) is inserted for measurement of CVP and ScvO2. Central venous access will allow for more rapid fluid infusion and administration of vasopressors if he doesn't respond to fluid therapy. Mr. L's abdomen becomes increasingly distended and he complains of increased abdominal pain that's exacerbated with movement. In addition, he complains of nausea and suddenly vomits. It's likely that Mr. L has developed peritonitis as a complication of his colon surgery.

Infection issues

Recommendation: Cultures should be obtained before antimicrobial therapy is started if cultures don't cause significant delay (>45 minutes) in start of therapy; imaging studies should be performed to confirm source of infection. Goals: I.V. administration of antimicrobials within the first hour of recognition of septic shock and severe sepsis without septic shock.3

Blood cultures and antibiotics are ordered to identify and treat Mr. L's infection. The 2012 guidelines strongly recommend administration of broad-spectrum antibiotics within the first hour of suspected sepsis, if possible.3,4 Current evidence shows a measurable increase in mortality for every hour antibiotics are delayed.3 Blood cultures should be drawn before antibiotics are administered, as they may influence the growth of pathogens and alter the culture results. If obtaining blood cultures delays antibiotic therapy for more than 45 minutes, the committee suggests reevaluating if the delay puts the patient at risk.3 In addition to blood cultures, cultures should be obtained from every suspected infection source (such as wounds, urine, pulmonary secretions), and imaging studies (X-rays, computed tomography) should be performed to identify the infection source.3 Mr. L is scheduled for a CT scan of the abdomen to confirm the clinical diagnosis of peritonitis.

Fluid therapy in severe sepsis

Recommendation: Crystalloids should be used as initial fluid of choice in resuscitation of severe sepsis and septic shock; hydroxyethyl starches aren't recommended; albumin should be initiated in patients who require substantial amounts of crystalloids.3

Despite adequate fluid resuscitation and timely administration of antibiotics, Mr. L's clinical status worsens. His BP decreases to 88/40, MAP to 56, ScvO2 to 54%, and he's oliguric. Bloodwork reveals a leukocytosis of 30,000/mm3, an elevated BUN, creatinine, and liver enzymes. His nurse receives critical lab results of lactate, 5.6 mmol/L, and a procalcitonin level of 13 ng/mL. Procalcitonin is a relatively new blood test that can be used with other lab findings and clinical assessments to help diagnose severe sepsis. (See What isprocalcitonin?) The nurse recognizes that Mr. L's severe tissue hypoperfusion and signs of organ dysfunction indicate he may be in septic shock given that he's received fluid resuscitation and has failed to respond to treatment.1

Crystalloids, such as normal saline, remain the fluid of choice for resuscitation; however, the new guidelines recommend aggressive resuscitation with a minimum of 30 mL/kg instead of 20 mL/kg, followed by boluses of up to 1,000 mL as long as there's hemodynamic improvement. In addition, according to the new 2012 guidelines, Mr. L's attending physician should consider adding albumin to the initial fluid therapy, as there's evidence to suggest albumin can help achieve resuscitation goals.3,4 Another new update from the 2012 committee is a strong recommendation against using synthetic colloids or starches (hetastarch) for resuscitation, as review of the current evidence doesn't support the benefit of these products.3,4

Vasopressor therapy

Recommendation: Vasopressor therapy should initially target a MAP of 65 mm Hg; norepinephrine is the first choice, with vasopressin added with the intent to raise MAP to target or decrease norepinephrine; dopamine is an alternate agent to norepinephrine only in patients with low risk of tachydysrhythmias and absolute or relative bradycardia; phenylephrine isn't recommended in the treatment of septic shock except in circumstances where norepinephrine is associated with serious dysrhythmias, cardiac output is known to be high and BP persistently low or, as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve MAP target.3

Because Mr. L fails to respond to fluid resuscitation, his nurse follows the sepsis pathway and considers vasopressor therapy. Norepinephrine is still the first-line choice to correct hypotension, but dopamine is no longer recommended as a reasonable alternative. Norepinephrine is preferred over other vasopressors because it's a potent vasoconstrictor without the adverse side effects of tachycardia and other dysrhythmias. Current evidence suggests dopamine should only be used in select patients with a low risk of dysrhythmias or with bradycardia.3,4

If Mr. L's BP doesn't improve on norepinephrine, or if he requires additional BP support, the guidelines recommend vasopressin as an alternative, or added therapy.3,4 If Mr. L shows signs of low cardiac output despite adequate fluid resuscitation and MAP, the guidelines recommend the addition of dobutamine as first-choice inotrope to improve cardiac output and tissue perfusion.3,4

Mr. L is started on norepinephrine administered through his CVC. His nurse carefully titrates the infusion with the goal to maintain his MAP at 65 mm Hg or more. The attending physician inserts a radial artery catheter to continuously monitor the patient's BP.

Corticosteroids

Recommendation: I.V hydrocortisone isn't recommended if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability; I.V hydrocortisone is suggested only if fluid resuscitation and vasopressor therapy are insufficient.3

Because Mr. L is in septic shock, he likely has developed relative adrenal insufficiency (an inadequate stress response).6 Instead of recommending steroids for all patients in septic shock, the guidelines recommend not administering corticosteroids unless the patient requires high doses of vasopressors to maintain adequate BP despite appropriate fluid resuscitation. In addition, the guidelines suggest administering hydrocortisone in a continuous infusion instead of intermittent bolus doses.3,4

Following the new guidelines, Mr. L's attending physician orders a continuous infusion of hydrocortisone over a 24-hour period.

Mechanical ventilation in sepsis-induced ARDS

Recommendation: Clinicians should target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS; positive end-expiratory pressure (PEEP) should be applied to avoid alveolar collapse at end expiration; patients should maintain 30 and 45 degree head of bed to limit aspiration risk and prevent development of ventilator-associated pneumonia (VAP).3

Mr. L begins to have difficulty breathing and his nurse determines that he's agitated and confused. His respiratory rate is 32 and his continuous pulse oximeter displays an oxygen saturation of 86% and an end-tidal CO2 of 28 mm Hg despite oxygen therapy. The nurse auscultates bibasilar crackles. Arterial blood gases are drawn and reveal he's acidotic and hypoxic. His nurse suspects he's developing ARDS. In ARDS, diffuse, inflammatory lung injury leads to increased pulmonary vascular permeability. As a result, fluid leaks from the capillaries into the alveoli, which interferes with gas exchange.7

To reduce the work of breathing and improve oxygenation, Mr. L is endotracheally intubated and placed on mechanical ventilation. PEEP is used to help prevent end-expiratory alveolar collapse and optimize gas exchange. To keep him comfortable, Mr. L is maintained on continuous I.V. sedation and analgesia for pain. Daily sedation interruptions and awakenings help decrease the amount of time Mr. L is mechanically ventilated.3

The new guidelines offer additional support for mechanically ventilated patients with sepsis. Implementation of the ventilator bundle to prevent the development of VAP includes the following components: maintaining the head of bed at 30 to 45 degrees unless contraindicated, deep vein thrombosis prophylaxis, and stress ulcer prophylaxis. In addition, routine oral care with chlorhexidine is recommended to reduce the risk of VAP.3

Glucose control

Recommendation: Initiate insulin dosing for management of patients with severe sepsis when two consecutive blood glucose levels are more than 180 mg/dL; blood glucose values should be monitored every 1 to 2 hours until values and insulin infusion rates are stable, then monitor blood glucose levels every 4 hours. Goal: Upper target blood glucose less than or equal to180 mg/dL rather than an upper target blood glucose less than or equal to 110 mg/dL.3

Mr. L's blood glucose is 340 mg/dL. Maintaining tight glycemic control is important and has been shown to decrease mortality in surgical patients.3 The new guidelines recommend an upper target blood glucose of 180 mg/dL or less.2,3 The higher upper target has been shown to reduce the risk of complications from unintentional hypoglycemia. Because of his hyperglycemia, Mr. L is started on a continuous insulin infusion and his glucose levels are closely monitored.

Contraindication

Use of recombinant human-activated protein C (rhAPC). The guidelines no longer support the use of rhAPC due to recent studies that have found it ineffective in less severely ill patients with severe sepsis.3

One of the most significant changes in the guidelines is the removal of drotrecogin alfa (activated) (Xigris), an rhAPC indicated for adult patients with severe sepsis and acute organ dysfunction. A review of the current evidence failed to support a benefit from administration of this medication. Substantial controversy regarding its benefit, safety, and cost led to the removal of this drug from the market.3,4

Other supportive therapies for severe sepsis not recommended by the guidelines include the use of I.V. immunoglobulins, I.V. selenium, sodium bicarbonate, and neuromuscular blocking agents, except in patients with ARDS due to the risk of prolonged neuromuscular blockade following discontinuation.3,4

Road to recovery

After several days of intensive medical and nursing care, Mr. L's clinical status begins to improve. His lactate is 1.4 mmol/L and the rest of his lab values continue to improve. His urine output is adequate and his BP remains stable as his nurse weans him off the norepinephrine. He's extubated and on his way to recovery. Mr. L's story has a positive outcome due to an early diagnosis and treatment by the rapid response team. The ICU nurses supported and managed Mr. L's condition using evidence-based sepsis guidelines that have been shown to reduce mortality in patients with severe sepsis and septic shock.2,3 Because Mr. L's physicians and nurses were aware of the most current Surviving Sepsis Campaign guidelines, he received the best possible care for his life-threatening condition.

Sepsis 1011,3

Sepsis is a complex condition that progresses rapidly as the infectious organism releases endotoxins into the bloodstream. In reaction to these endotoxins, the body initiates an exaggerated immune response that causes significant vasodilatation, resulting in hypotension and decreased tissue perfusion. If left untreated, sepsis will progress to severe sepsis or septic shock, leading to multiple organ failure.

Diagnostic criteria for sepsis

Sepsis is defined as the presence of documented or suspected infection in addition to some of the following systemic manifestations of infection.3

General variables:

  • Temperature >38.3 or <36° C
  • Heart rate >90 beats/minute, or >2 standard deviations (SDs) above normal value for age
  • Tachypnea, respiratory rate more than 20 breaths/minute
  • Altered mental status
  • Significant edema or positive fluid balance (>20 mL/kg over 24 hours)
  • Hyperglycemia (plasma glucose >140 mg/dL) in the absence of diabetes.3

Inflammatory variables:

  • Leukocytosis, white blood cell (WBC) count >12,000/mm3 or <4,000/mm3
  • Normal WBC count with >10% immature forms
  • Plasma C-reactive protein >2 SDs above normal value
  • Plasma procalcitonin >2 SDs above normal value.

Hemodynamic variables:

Arterial hypotension (systolic blood pressure [SBP] <90 mm Hg, MAP <70 mm Hg, or an SBP decrease >40 mm Hg in adults or <2 SD below normal value for age)

Organ dysfunction variables:

  • central venous oxygen saturation (ScvO2)
  • Arterial hypoxemia (PaO2/FiO2 <300)
  • Acute oliguria (urine output <0.5 mL/kg/hour for at least 2 hours despite adequate fluid resuscitation)
  • Creatinine increase >0.5 mg/dL
  • Coagulation abnormalities (international normalized ratio [INR] >1.5 or activated partial thromboplastin time >60 seconds)
  • Ileus (absent bowel sounds)
  • Thrombocytopenia (platelet count <100,000/mm3)
  • Hyperbilirubinemia (plasma total bilirubin >4 mg/dL).

Tissue perfusion variables:

  • Hyperlactatemia (>1 mmol/L)
  • Decreased capillary refill or mottling

Severe sepsis is sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following believed to be a result of the infection)3:

  • Sepsis-induced hypotension
  • Lactate above upper limits of laboratory normal
  • Urine output <0.5 mL/kg/hour for more than 2 hours despite adequate fluid resuscitation
  • Acute lung injury with PaO2/FiO2 <250 in the absence of pneumonia as infection source
  • Acute lung injury with PaO2/FiO2 <200 in the presence of pneumonia as infection source
  • Creatinine >2.0 mg/dL
  • Bilirubin >2 mg/dL
  • Platelet count <100,000/mm3
  • Coagulopathy (INR >1.5).

Septic shock is sepsis-induced hypotension despite adequate fluid resuscitation, which may be defined as infusion of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent).

Adapted and updated from: UpToDate. Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis. http://www.uptodate.com/contents/sepsis-and-the-systemic-inflammatory-response-syndrome-definitions-epidemiology-and-prognosis.

Revised Surviving Sepsis Campaign bundles3

In the updated 2012 guidelines, the previous management bundle was dropped and the resuscitation bundle was broken into two parts.

To be completed within 3 hours:

  1. Measure lactate level
  2. Obtain blood cultures prior to administration of antibiotics
  3. Administer broad-spectrum antibiotics
  4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L.

To be completed within 6 hours:

  1. 5. Apply vasopressors (for hypotension that doesn't respond to initial fluid resuscitation) to maintain a MAP ≥65 mm Hg
  2. 6. In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L:
    • Measure CVP*
    • Measure central venous oxygen saturation (ScvO2).*
  3. Remeasure lactate if initial lactate was elevated with normalization as the target.

*Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg, ScvO2 of ≥70%.

Adapted and updated from: Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

What is procalcitonin?5

Procalcitonin (PCT) is a precursor of the hormone calcitonin, which along with parathyroid hormone helps regulate the body's calcium and phosphate balance. In healthy individuals, PCT is produced by specialized cells in the thyroid, lung, and intestine. PCT isn't normally detected in the blood; however, in response to systemic inflammation, serum levels will rise significantly if the source of the infection is bacterial. Levels won't rise significantly with viral or noninfectious causes of inflammation (surgery, trauma, burns).

How is it used?

Serum PCT is used as a biomarker to detect sepsis and severe sepsis caused by a bacterial organism. It should be drawn as soon as there's a suspected infection. Used in conjunction with other lab findings and clinical assessment, it can help confirm the diagnosis of sepsis, severe sepsis, or septic shock. PCT levels can also guide antibiotic therapy. Decreasing PCT levels in a patient treated for a severe bacterial infection indicate a response to therapy. PCT levels should be repeated every 24 to 48 hours to help determine effectiveness of treatment and patient prognosis.

How should PCT levels be interpreted?

In response to a bacterial infection, PCT levels rise within 3 to 6 hours, peaking at 12 hours, with a half-life of 24 hours. PCT levels <0.05 ng/mL is considered normal. PCT levels can be interpreted in the following ways:

  1. PCT ≥0.5 and <2.0 ng/mL indicates systemic inflammatory response is present, which may be due to infection, severe trauma, or surgery
  2. PCT ≥2 and <10 ng/mL indicates sepsis is likely
  3. PCT ≥10 ng/mL indicates severe sepsis or septic shock, organ dysfunction, increased mortality.

REFERENCES

1. UpToDate. Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis. http://www.uptodate.com/contents/sepsis-and-the-systemic-inflammatory-response-syndrome-definitions-epidemiology-and-prognosis.
2. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296–327.
3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.
4. Jancin B. A look at the upcoming surviving sepsis 2012 guidelines. http://www.internalmedicinenews.com/news/infectious-diseases/single-article/a-look-at-upcoming-surviving-sepsis-2012-guidelines/d4f3afed90f336b12e171e7461b350cd.html.
5. McGee KA, Baumann NA. Procalcitonin: clinical utility in diagnosing sepsis. Clin Laboratory News. 2009;35(7):10–12. http://www.aacc.org/publications/cln/2009/july/Pages/series0709.aspx#.
6. UpToDate. Corticosteroid therapy in septic shock. http://www.uptodate.com/contents/corticosteroid-therapy-in-septic-shock.
7. UpToDate. Acute respiratory distress syndrome: clinical features and diagnosis. http://www.uptodate.com/contents/acute-respiratory-distress-syndrome-clinical-features-and-diagnosis.
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