Sepsis: Managing the Systemic Response

Sepsis is one of the most common reasons for critically ill patients to be admitted to an intensive care unit (ICU).^[1] Patients with severe sepsis requiring ICU care have very high rates of overall hospital mortality, with estimates ranging from 18% to 50%, but mortality has tended to fall over the past 12 years, presumably as a consequence of improved overall recognition and care.^[2] Associated morbidity is also very high. Risk factors for death from sepsis include underlying illness, increased age, and multisystem organ failure.

The Surviving Sepsis Campaign was launched in 2002 as a collaboration between the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). The aim was to reduce mortality from sepsis and septic shock around the world by standardizing care on the basis of data from clinical trials. The Campaign's current guidelines underscore the need for early recognition of sepsis, appropriate cultures to identify the infecting organisms, early use of broad-spectrum antibiotics, and appropriate and often aggressive resuscitation efforts, followed by a programmatic longer-term management approach aimed at avoiding complications of critical illness and its treatment.^[3]

Image courtesy of Medscape.

A 52-year-old woman presents to the emergency department (ED) with urinary frequency over the preceding 3 days. On the morning of the visit, she awoke with right-side back pain, and she now feels generally "unwell." She has a history of type II diabetes mellitus, for which she takes metformin, and hypertension, which is controlled with lisinopril. She has no known drug allergies. She is awake and alert, and her skin is warm and slightly diaphoretic.

Upon physical examination, the patient has a temperature of 101.2°F (38.4°C), a heart rate (HR) of 118 beats/min, a respiratory rate (RR) of 22 breaths/min, and a blood pressure (BP) of 105/54 mm Hg. Her arterial oxygen saturation (SaO₂) is 97% on room air. Her fingerstick blood glucose level is 145 mg/dL. Her mental status is normal, with no meningeal signs. She has no respiratory symptoms, and the lungs are clear. No abdominal or suprapubic tenderness is present, but reproducible bilateral costovertebral angle tenderness is noted.

Does this patient have the clinical picture of acute infection, often referred to as the systemic inflammatory response syndrome (SIRS)? How is SIRS defined?

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Answer: Yes, the patient has SIRS. SIRS is a clinical response to a nonspecific insult of either infectious or noninfectious origin. It is defined as the presence of two or more of the following variables:

• Temperature higher than 38°C (100.4°F) or lower than 36°C (96.8°F)
• HR higher than 90 beats/min
• RR higher than 20 breaths/min or arterial carbon dioxide tension (PaCO₂) lower than 32 mm Hg
• Abnormal white blood cell (WBC) count (>12,000/µL or <4000/µL or >10% immature [band] forms)^[4]

How does SIRS differ from sepsis?

Image courtesy of Medscape.

Answer: Sepsis is the systemic response to infection and is defined as the presence of SIRS in addition to a documented or presumed infection.

Sepsis that becomes associated with organ dysfunction, hypoperfusion, or hypotension is classified as severe sepsis. Sepsis-induced hypotension is defined as the presence of a systolic BP that is lower than 90 mm Hg or is reduced by more than 40 mm Hg from baseline in the absence of other causes of hypotension. Patients who have persistent hypotension and perfusion abnormalities despite adequate fluid resuscitation meet the criteria for septic shock. Multiple organ dysfunction syndrome (MODS) is a state of physiologic derangements in which organ function is incapable of maintaining homeostasis.^[5]

At this point, what diagnostic tests should be considered for this patient? Is the patient in a septic state?

Image adapted from Bone et al. Chest 1992:101:1644; Wheeler et al. N Engl J Med 1999;340:207.

Answer: At a minimum, a complete evaluation for SIRS requires a complete blood count (CBC) with differential to evaluate for leukocytosis or leukopenia. A WBC count above 12,000/µL or below 4000/µL or with more than 10% immature (band) forms on the differential is a criterion for SIRS. An increased percentage of bands is associated with an increased incidence of infectious causes of SIRS.

In this patient, the CBC reveals a WBC count of 18,500/µL, a hemoglobin (Hb) concentration of 12 g/dL, and a hematocrit (Hct) of 36%. The serum lactic acid concentration is 4.6 mg/dL. Electrolytes and renal function are normal, with an anion gap of 16, and urinalysis confirms an acute cystitis. A chest x-ray is unremarkable, and electrocardiography (ECG) reveals a sinus tachycardia with a ventricular rate of 122 beats/min and no evidence of ischemia. With SIRS criteria met and an obvious acute cystitis present, the patient has urosepsis.

What is the diagnostic importance of the serum lactic acid concentration? What are some causes of lactic acidosis?

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Elevated lactic acid levels can be a marker for suboptimal supply of oxygen to the tissues; they are associated with increased mortality in sepsis. Hyperlactatemia is common in critical illness. It can occur during sepsis from several causes, including (1) inadequate oxygen delivery to the tissues, (2) increased glycolysis, (3) nonhypoxic lactic acid release by activated inflammatory cells, and (4) delayed hepatic clearance. Although high lactate levels suggest a poor prognosis and decreasing lactate levels suggest improved survival, there is no relation between resuscitation efforts in sepsis and increased lactate clearance. Indeed, two large trials showed that targeting blood pressure and individualized care was as good as early goal-directed therapy (EGDT) that required measures of lactate and central venous oxygen saturation (ScvO₂) in ED treatment of septic shock patients.^[6,7] Clearly, some patients with severe sepsis and elevated lactate are at increased risk for mortality, despite a normal ScvO₂. In these patients, measuring venoarterial carbon dioxide tension (PCO₂) differences can help identify cellular hypoperfusion; differences greater than 6 mm Hg indicate tissue hypoperfusion.^[8]

What additional goals of management should be considered in this septic patient?

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Surviving Sepsis guidelines and clinical trials support early resuscitation of all patients with septic shock (ie, in the first 6 hours). Mean arterial pressure (MAP) should be at least 65 mm Hg, or 75-80 mm Hg if the patient had a history of hypertension before sepsis.^[9] Restoration of organ perfusion should be ensured, as evidenced by improved organ function (sensorium, urine output, and skin temperature). However, targeting a specific central venous pressure (CVP) is not indicated. Although measuring ScvO₂ can be useful for identifying hypoperfusion if the value is low (<70%), ScvO₂ is not useful if it is not low.^[6,7]

The image shows an indwelling arterial catheter, which can be used for continuous BP monitoring, frequent blood sampling, and arterial blood gas (ABG) measurement.

Image courtesy of Medscape.

Both the ProCESS (Protocolized Care for Early Septic Shock) study and the ARISE (Australasian Resuscitation in Sepsis Evaluation) study showed that after an MAP of 65 mm Hg had been targeted, protocolized care guided by ScvO₂ or Hb yielded no added benefit, and inotropic therapy was rarely needed once fluid resuscitation was provided and adequate MAP achieved.^[6,7] In these studies, the protocolized-care and standard-treatment arms received nearly identical amount of crystalloid solutions over the first 8 hours. Although the use of a central venous catheter was not mandated in the usual-practice arms, approximately 30-40% of patients treated in those arms received central venous catheterization by 8 hours into resuscitation. Thus, individualized aggressive care represents best practice.

Image courtesy of Wikimedia Commons.

The first Surviving Sepsis Campaign Guidelines were published in Critical Care Medicine in 2004 and included 52 recommendations of varying strength and level of evidentiary support.^[10] Because the guideline development process was sponsored by Eli Lilly and Edwards Life Sciences, concerns were raised about the integrity of the guidelines.^[11] Furthermore, it appeared that the guideline implementation process was part of the marketing strategy for the Eli Lilly Company.

In 2008, the Surviving Sepsis Campaign Guidelines were updated. Although in this iteration they were free of corporate sponsorship and somewhat broader in scope (containing 85 recommendations),^[12] the core recommendations remained largely unchanged.

The latest guidelines, developed in 2012, removed most of the initial industry-sponsored endorsements because of the proven lack of efficacy in prospective clinical trials.^[3] The core recommendations were principally based on the results of a small single-center study by Rivers et al,^[13] which must now be supplanted by the results of the ProCESS and ARISE trials.^[6,7] However, because the results of these larger clinical trials were only published in 2014, newer guidelines that take them into account have not yet been developed. Still, the fundamental principle of early aggressive resuscitation to sustain an MAP higher than 65 mm Hg and then targeting blood flow to sustain organ perfusion remains valid and appropriate.^[14]

What expensive drug initially recommended in the 2008 Surviving Sepsis Campaign guidelines was removed from the market?

Answer: Drotrecogin alfa (recombinant activated protein C), initially recommended in the 2008 Surviving Sepsis Campaign guidelines, was voluntarily removed from the commercial market and is no longer available for use.

The drug was withdrawn after the completion of the PROWESS (Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock) trial, which failed to demonstrate any survival benefit in the subgroup of patients previously thought to benefit from activated protein C treatment. In light of this withdrawal, the Surviving Sepsis Campaign guidelines provide a brief history about the evolution in the recommendations for use by the Surviving Sepsis Campaign.^[14]

At the 2012 SCCM meeting, the Surviving Sepsis committee revealed some updated guidelines, including the following.^[14] (1) Potentially infected seriously ill patients should be routinely screened for severe sepsis to allow earlier therapy. (2) Initial fluid challenge should be ≥1 L of crystalloid and ≥30 mL/kg in the first 4-6 hours, with incremental boluses continued as long as patient improve hemodynamically (grade 1A). (3) Norepinephrine should be the first-choice vasopressor (grade 1B). (4) Dobutamine is strongly recommended for patients with cardiac dysfunction as evidenced by high filling pressures and low cardiac output (grade 1C). (5) Dopamine is recommended only in highly selected patients whose risk for arrhythmias is felt to be very low and who have a low HR and/or cardiac output (grade 2C). (6) Continuous infusion of hydrocortisone totaling 200 mg/24 hr is recommended only for those with vasopressor-refractory septic shock (grade 2C). (7) Monitoring normalization of lactate levels is recommended if central venous oxygenation monitoring is not available (grade 2C).

The 2012 Surviving Sepsis recommendations also included the following suggestions based on consensus opinion or weak evidence with respect to the treatment of patients with acute respiratory distress syndrome (ARDS; shown) due to severe sepsis^[14]:

• Using higher levels of positive end-expiratory pressure (PEEP) (grade 2C);
• Recruitment maneuvers for patients with severe hypoxemia while receiving high PEEP and fraction of inspired oxygen (FiO₂) (grade 2C),
• Prone positioning for patients whose PaO₂/FiO₂ ratio is less than 100 despite such maneuvers (grade 2C)

Image courtesy of Radiopaedia.org.

After the original study by Rivers et al,^[13] EGDT rapidly became standard care for patients with severe sepsis. These treatment protocols were implemented at hospitals around the world, though it was never clear which interventions in the treatment bundles were responsible for the benefits observed in the original study. Many investigators began to question whether certain recommendations included in the standard EGDT protocol were necessary or even helpful.

On March 18, 2014, the results of the ProCESS trial were published in the New England Journal of Medicine.^[6] In this multicenter randomized trial, which included 1341 patients with severe sepsis or septic shock (SIRS plus hypotension) at EDs in 31 US hospitals, investigators randomly assigned subjects to one of the following treatment regimens:

• Protocol-based EGDT emulating the Rivers protocol (n = 439), with mandatory placement of a central line to continuously monitor ScvO₂ and CVP, administration of intravenous (IV) fluids, vasopressors, dobutamine, and packed red blood cells (PRBCs)
• Protocol-based standard therapy (n = 446), defined as 6-hour protocol prompted resuscitation with administration of IV fluids to "clinical" euvolemia and PRBC transfusion to a goal hemoglobin level of ≥7.5 g/dL; central venous catheter placement and ScvO₂ measurements were not mandatory
• Usual care (n = 456), with the bedside provider directing all care without any prompted protocol

What did the trial reveal?

Answer: The investigators found no significant differences in 60-day, 90-day, or 1-year mortality among groups.^[6] In addition, they found no significant differences with respect to secondary endpoints, including cardiovascular failure, respiratory failure, hospital length of stay, and discharge disposition; the incidence of acute renal failure was higher in protocol-based standard therapy.

The ProCESS investigators concluded that protocol-based resuscitation of patients in whom septic shock was diagnosed in the ED did not improve outcomes. Almost identical results were reported by the ARISE investigators from the ANZICS (Australian and New Zealand Intensive Care Society) study,^[7] though this study had only two arms (ie, usual care and EGDT).

The ProCESS and ARISE trials confirm the most important elements in management of sepsis—namely, early recognition, early administration of antibiotics, and early adequate volume resuscitation using clinical parameters and avoiding overtransfusion.^[6,7] If these essential aspects of care are in place, protocolized measurements of central hemodynamics and oxygen saturation apparently do not improve patient outcomes measurably.