1. How is sepsis-associated acute kidney injury (SA-AKI) defined?

SA-AKI is characterized by the simultaneous presence of AKI (based on a consensus definition such as the Acute Kidney Injury Network [AKIN] or Kidney Disease Improving Global Outcomes [KDIGO] criteria; see Chapter 10 ) and the 2016 consensus criteria for sepsis (defined as life-threatening organ dysfunction caused by a dysregulated response to infection). Causes of AKI not related to sepsis (e.g., nephrotoxic drugs or rhabdomyolysis) should be ruled out. However, there is no standardized method for distinguishing SA-AKI from other causes of AKI, and in many cases the cause of AKI may be multifactorial and thus difficult to attribute to sepsis.

2. What are the key epidemiologic aspects of AKI in the setting of sepsis?

Sepsis is common among intensive care unit (ICU) patients with a prevalence ranging from 8.2% to 35.3% of all ICU patients. Sepsis is becoming more common. A recent large study in the United States showed an increase of 8.7% of sepsis as the primary diagnosis from the previous year. However, the overall sepsis-associated mortality rate appears to be decreasing (between 18% and 25%). Sepsis is associated with significant deleterious effects on outcomes:

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  Extended mechanical ventilation

  
  
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  Prolonged hospitalization

  
  
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  Secondary infections

  
  
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  Increased long-term mortality

Although the etiology of AKI in patients who are critically ill is often multifactorial, sepsis has consistently been found to be an important, if not the most important, contributing factor. Several studies have shown that approximately 40% to 50% of patients with AKI on presentation to an ICU have concomitant sepsis and that up to 64% of patients who are critically ill with a diagnosis of severe sepsis or septic shock have concomitant AKI.

3. Does the degree of sepsis determine the incidence and severity of AKI?

In contrast to AKI, sepsis syndrome has benefited from the development of a consensus-driven standardized definition for more than 20 years. This definition was modified to reflect advances in the pathobiology, management, and epidemiology of sepsis. In this new schema, sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” Organ dysfunction is best identified as an acute change in the total Sequential Organ Failure Assessment score ≥2 points, which reflects an overall mortality risk of approximately 10%. Septic shock is the most severe form of sepsis with profound cellular, metabolic, and hemodynamic abnormalities that include hypotension (requiring vasopressors), as well as elevated serum lactate levels. Septic shock is associated with mortality rates over 40%.

While there are no studies assessing the incidence of AKI utilizing the new definition of sepsis, prior studies have shown that there is a stepwise increase in the severity of AKI in patients who are stratified by the severity of sepsis. For instance, in one study, the incidence and severity of AKI, defined by the AKIN criteria, increased markedly when stratified by sepsis severity. Furthermore, as patients progress from sepsis to severe sepsis to septic shock, the incidence of AKI that requires dialysis also increased. See Table 11.1 .

Definitions:

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  Sepsis : criteria for systemic inflammatory response syndrome (SIRS) with suspected or present source of infection. SIRS criteria:

  
  
  
  
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    Temperature >38°C or <36°C

    
    
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    Heart rate >90/min

    
    
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    Respiratory rate >20/min or PaCO ₂ < 32 mm Hg

    
    
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    White blood cell count >12,000/mm ³ , <4000/mm ³ or >10% bands

  
  
  
  
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  Severe Sepsis : sepsis plus organ dysfunction, hypotension, or hypoperfusion as defined by:

  
  
  
  
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    Lactic acidosis

    
    
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    Systolic blood pressure <90

    
    
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    Systolic blood pressure drop ≥40 mm Hg of normal

  
  
  
  
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  Septic Shock : severe sepsis with hypotension despite adequate fluid resuscitation

4. What is the timing of AKI resulting from sepsis?

AKI in sepsis is usually evident at the time of ICU admission or develops early in the illness course. In a multicenter study of patients who were critically ill presenting with septic shock, investigators found 64% had AKI within 24 hours of developing shock.

5. When should physiologic derangements in sepsis be corrected?

In 2001, a seminal paper from Rivers et al. demonstrated that timely intervention, called “early goal-directed therapy” (EGDT), for the treatment of severe sepsis and septic shock improved outcomes. In particular, treatment goals for improving tissue oxygenation, such as central venous pressure (CVP), mean arterial blood pressure (MAP), central venous oxygen saturation (ScvO ₂ ), and blood lactate concentration, were achieved as a protocolized bundle within 6 hours after presentation. These measures were codified as the surviving sepsis care bundles:

• a.
  

  To be completed within 3 hours:

  
  
  
  
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    Measure lactate level

    
    
  • ii.
    

    Obtain blood cultures prior to administration of antibiotics

    
    
  • iii.
    

    Administer broad-spectrum antibiotics

    
    
  • iv.
    

    Administer 30 mL/kg crystalloid solutions for hypotension or serum lactate ≥4 mmol/L

  
  
  
  
• b.
  

  To be completed within 6 hours:

  
  
  
  
  • i.
    

    Add vasopressors (for hypotension refractory to initial fluid resuscitation) to maintain MAP ≥ 65 mm Hg

    
    
  • ii.
    

    In the event of persistent arterial hypotension despite volume resuscitation (shock) or initial serum lactate ≥4 mmol/L:

    
    
    
    
    • 1.
      

      Measure CVP with goal of ≥8 mm Hg

      
      
    • 2.
      

      Measure ScvO ₂ with a goal of ≥70%

    
    
    
    
  • iii.
    

    Re-measure serum lactate if initial serum lactate was elevated (goal is normalization of lactate)

  
  

Since the institution of this bundle, the prognosis for patients with sepsis has improved, and one study demonstrated a fall in in-hospital mortality of 59%. However, in 2014, two studies (the PROCESS and ARISE studies) raised uncertainties regarding the efficacy of protocol-based EGDT in contributing to improvements in mortality. In the ARISE study, in critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. In the PROCESS study, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes as well. A third study in 2015 reached a similar conclusion that EGDT did not lead to improvements in outcome but was also associated with increased costs. Importantly, in all three of these studies, the majority of patients met the goals of the 3-hour bundle, highlighting the importance of rapid antibiotic administration and fluid resuscitation, and downgrading the benefits of hemodynamic targets, such as CVP and ScvO ₂ .

6. What is the role of resuscitation strategies on the incidence of AKI in patients with septic shock?

In the ProCESS trial, the development of AKI was common (approximately 38%) and was not influenced by protocolized resuscitation compared with usual care. Furthermore, the duration of AKI and the need for dialysis did not differ between the protocolized care and usual care groups. Of note, 60-day hospital mortality was 6.2% for patients without AKI, 16.8% for those with stage 1, and 27.7% for stages 2 to 3. Thus, while AKI is common in patients with septic shock and is associated with significant mortality, its rates and outcomes do not appear to be influenced by resuscitation protocols.

7. Is there an optimal fluid management approach for patients with AKI and sepsis?

Several studies have addressed whether various intravenous fluids are superior to one another in the treatment of patients with sepsis. These trials have compared albumin, normal (0.9%) saline, various starches, and a balanced pH solution (such as lactated ringers or in various combinations). The bottom line from trials is that volume expansion with normal (0.9%) saline is either associated with similar if not better outcomes than other intravenous solutions. Of note, the various starch solutions have been associated with an increased incidence of AKI and poor outcomes, and should be avoided. Thus, a reasonable initial approach for volume resuscitation in the patient with sepsis is to initiate therapy with intravenous normal (0.9%) saline, and if the patient develops a metabolic acidosis associated with a high chloride load, then switch to a more balanced pH solution, such as Lactated Ringer’s.