AKI is one of the most common diagnoses encountered in acute care in the United States. It affects more than 20% of hospitalized patients,7 and more than 30% of critically ill patients.8 The development of AKI is independently associated with increased mortality. In noncritically ill hospitalized patients, the presence of AKI was associated with an overall mortality rate of 10% compared to 1.5% in patients without AKI. The mortality rate increases with the severity of AKI. In critically ill patients, mortality rates are based on the severity of AKI: stage I AKI is associated with a mortality rate of 13.9%; stage II AKI of 16.4%; and stage III AKI of 33.8%.9
The current diagnostic criteria used to define AKI are based primarily on increases in serum creatinine (SCr) levels relative to baseline, with high associated morbidity and mortality. The search for novel serum biomarkers identifying AKI earlier after the initial renal insult, has led to the recognition of neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a protein that is transcribed early in the process of renal injury, and can be reliably measured in the plasma by point-of-care immunoassay.10 In a prospective, observational study of 301 patients, investigators evaluated the utility of NGAL as an early serum biomarker of AKI compared to the commonly used RIFLE criteria.10 The RIFLE criterion, which utilizes SCr and GFR, was defined by the Acute Dialysis Quality Initiative (ADQI) group in 2004.11 Results demonstrated that NGAL levels were elevated up to 48 hours prior to the diagnosis of AKI based on the RIFLE criteria (Figure 7–2). Plasma NGAL levels greater than 150 ng/mL were associated with an increased incidence of AKI of 11.8 (95% confidence interval [CI], 3.5-39.2). In addition, NGAL levels greater than 150 ng/mL were also a good predictor of renal replacement therapy. Further evaluation is required to determine if plasma NGAL will ultimately translate into the renal “troponin” in clinical practice.
Mean plasma NGAL concentrations at various timepoints in patients with acute kidney injury. (Reproduced with permission from Cruz DN, de Cal M, Garzotto F, et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population, ntensive Care Med. 2010 Mar;36(3):444-451.)
While NGAL has been demonstrated as a renal biomarker, there are others under investigation including kidney injury molecule 1 (KIM-1), cystatin-C, interleukin (IL)-6, IL-18, urinary N-acetyl-beta-(D) glucosaminidase activity (NAG), and matrix metalloproteinase 9 (MMP-9).10
In the United States, sepsis-related health care costs remain the number one economic burden accounting for more than $20 billion as of 2011.12 Even more alarming are the number of reported cases (> 1,000,000), and the incidence of hospital admissions due to sepsis continues to rise each year from 266,895 in 2005 to 353,516 in 2011.13 However, mortality rates related to sepsis remain high (25%-50%), and account for greater than 200,000 deaths each year.14
Studies have evaluated numerous biomarkers involved in the sepsis cascade as potential targets for therapy. Unfortunately, immunotherapy trials (ie, recombinant activated protein C, eritoran tetrasodium—E5564, a toll-like receptor 4 antagonist, and talactoferrin alpha) have failed to demonstrate mortality benefit.15 Focus may need to be on when to target each biomarker with immunotherapy, instead of just inhibiting or augmenting an ongoing process in the sepsis cascade. In a study of patients with severe sepsis and septic shock, levels of serum biomarkers (ie, IL-1 beta, 1ra, 6, 8, and 10; intercellular adhesion molecule, tumor necrosis factor alpha, caspase 3, d-dimer, high-mobility group protein 1, vascular endothelial growth factor, matrix metalloproteinase, and myeloperoxidase) known to be involved in the pathogenesis of sepsis were measured at various times (0, 3, 6, 12, 24, 48, 60, and 72 hours).15 The results demonstrated various times to peak levels of each biomarker ranging from 3 to 48 hours, and different patterns (ie, bimodal) of peak and nadir levels. These results indicate a 3-hour window for appropriate intervention from peak levels of some of the above biomarkers and development of sepsis. In contrast, for other biomarkers, successful immunotherapy may require multiple time-sensitive interventions based on changing levels. Further understanding of biomarkers and sepsis will lead to a new paradigm of early and “time-sensitive” goal-directed therapies.
During shock, anaerobic glycolysis produces lactate, which is converted to glucose via the Cori cycle in the liver as a source of energy. Approximately 1300 to 1500 mmol of lactate is produced each day under normal physiologic conditions by various organs including the brain, skeletal muscle, intestine, skin, and red blood cells.16 Normal serum lactate levels are less than 2 mmol/L.
Hyperlactatemia (> 2 mmol/L) is caused by excess production (ie, anaerobic glycolysis), reduced clearance, or a combination of both states. Hyperlactatemia occurs in patients with tissue dysoxia, or in other conditions where hypoxia is not the primary etiology such as SIRS and sepsis. Lactate clearance (ie, decrease of 10% from baseline levels within 2 hours and up to 12 hours), or normalization of lactate levels within 24 hours is associated with decreased mortality, organ failure, and ICU days.16,17,18
A randomized, multicenter trial evaluated the mortality outcomes of a protocol-driven treatment plan, comparing the use of the ScvO2 greater than 70% versus lactate clearance of 10% within 2 hours of initiating resuscitation.19 Patients with severe sepsis or septic shock were treated with a protocol consistent with the SSC guidelines. The two treatment groups utilized resuscitation to sequentially achieve a central venous pressure (CVP) greater than or equal to 8 mm Hg, then a mean arterial pressure greater than or equal to 65 mm Hg, followed by either an ScvO2 greater than 70% or lactate clearance greater than 10% (within 2 hours of initiating the protocol). The mortality rate in the ScvO2 group was 23%, versus 17% in the lactate clearance group, demonstrating a mortality benefit of 6% when using lactate clearance as a primary goal of initial resuscitation.
Other studies have also supported the concept of lactate normalization, as it is known that hyperlactatemia is independently associated with increased morbidity and mortality regardless of the etiology.16,20
Procalcitonin: Diagnosis of Bacterial Infections/Sepsis & Guidance of Antibiotic Therapy
Discrimination of sepsis (defined as probable or documented infection) from noninfectious causes of SIRS remains a challenge. The difficulty in diagnosing bacterial infection is a reflection of the nonspecific symptoms and signs of SIRS. Studies have revealed promise with the use of procalcitonin in the diagnosis of bacterial infection, sepsis, and response to antibiotic therapy.21 However, there is no single biomarker of sepsis that has 100% sensitivity or specificity.
PCT is a prohormone of calcitonin, which is synthesized in the parafollicular C cells of the thyroid gland.22 In response to inflammatory and noninflammatory mediators released by bacterial infection, procalcitonin is upregulated and produced by C cells of the thyroid and other organs (ie, liver, lung, small intestine, kidney) throughout the body. Upregulation and plasma levels increase within 6 to 12 hours of bacterial infection. PCT is specific for bacterial infection since interferon gamma is released in response to viral infection and inhibits the upregulation of PCT. Once appropriate antibiotic therapy has been administered, the levels of endotoxin and cytokines fall resulting in the decline of serum PCT levels by 50% each day. PCT has a plasma half-life of 25 to 30 hours. Plasma PCT levels correlate with the severity of infection, prognosis, allow for monitoring response to antibiotic therapy, and guide duration of treatment. The implementation of algorithms using PCT in clinical practice have been studied and validated. Different patient populations and care settings have led to the development of practical algorithms (see Figure 7–1) with specific cutoff values of PCT.21,23 In low-acuity (ie, outpatient) and moderate acuity (ie, emergency department and inpatient) settings, antibiotic therapy is encouraged if the PCT level is greater than or equal to 0.25 μg/L, and strongly encouraged if the level is greater than or equal to 0.5 μg/L. In high-acuity settings (ie, ICU) or with septic patients, PCT levels should not be used to determine when to initiate antibiotic therapy but rather to guide early discontinuation of treatment.