Tools
Laboratory Evaluation of Sepsis
Introduction
Sepsis, defined by the Society of Critical Care Medicine (SCCM) Sepsis-3 criteria, is life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis and septic shock are high causes of mortality worldwide, resulting in the death of 1 in 3 to 1 in 6 patients in whom sepsis is identified.[1] Sepsis and septic shock are considered medical emergencies requiring time-sensitive evaluation and management; early identification and treatment initiation improve outcomes in sepsis patients. Specifically, early treatment with antimicrobial therapy is one of the most effective interventions that decreases in-hospital mortality in patients with sepsis.[2][3]
Identifying sepsis and septic shock can prove problematic on initial presentation. The clinical presentation of sepsis is highly variable, the differential diagnosis of sepsis is exceedingly broad, and the underlying etiology of the presenting symptoms may not be immediately evident. This is particularly true for patients presenting with suggestive signs and symptoms in the emergency department.[4] Various screening tools for sepsis are used depending on the location of the evaluation. Most of these tools utilize criteria incorporating clinical evaluation, vital signs, and laboratory data to screen for sepsis and predict mortality. Some tools commonly used to screen for sepsis include the Systemic Inflammatory Response Syndrome (SIRS) criteria, quick Sequential Organ Failure Score (qSOFA), Sequential Organ Failure Assessment (SOFA) criteria, National Early Warning Score (NEWS), and Modified Early Warning Score (MEWS).[1]
Sepsis is evaluated with various laboratory studies, including different biomarkers essential for diagnosis, early recognition of severity, risk stratification, and prognosis. These studies also have a role in dictating management and antibiotic stewardship. The initial management of a patient with suspected sepsis includes evaluation for the source of infection, severity assessment, treatment and prevention of hypotension, intravenous fluids, vasopressors, antibiotics, and infection source control. The severity of sepsis is determined through physical examination and laboratory evaluation.[4]
The laboratory workup for patients with suspected sepsis includes blood lactate, complete blood count with differential (CBC), chemistry panel, and liver function tests (LFTs). Using this laboratory data, along with clinical findings, is essential in stratifying the severity of the disease. The SOFA score is used to define sepsis and has prognostic and therapeutic value. This scoring system allows clinicians to assess organ dysfunction, the characterizing feature of sepsis and septic shock, and evaluates the respiratory, cardiovascular, hepatic, renal, hematologic, and central nervous systems. The scores range from 0 to 4, with high scores signifying higher predicted mortality and the likelihood of requiring intensive care.[4][5]
Etiology and Epidemiology
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Etiology and Epidemiology
The incidence of sepsis is estimated to be 189 hospital-treated cases per 100,000 person-years. The mortality of hospital-treated sepsis is estimated to be 26.7%. The incidence of ICU-treated sepsis is estimated at 58 per 100,000 person-years, of which the mortality has been estimated to be 41.9% before hospital discharge. Sepsis is an important cause of mortality, a significant cause of morbidity in those who survive the condition, and associated with significant healthcare costs.[6] This data is likely an underestimate due to evolving definitions of sepsis and variations in institutional practices for identifying and managing suspected cases. Most sepsis-related studies originate from high-income countries; the true incidence of sepsis is likely much higher and will most likely increase as new data emerges.[7][8]
Organ dysfunction per the Sepsis-3 guidelines is identified as an acute change in total SOFA score ≥2 points consequent to the infection.[9] The most common sources of infection in sepsis are bacterial pneumonia and urinary tract infections.[10][4] In the absence of a clinically obvious source of infection, chest radiography and urinalysis are frequently recommended. Viral infections may also lead to sepsis; frequent viral pathogens include influenza and SARS-CoV-2. Fungal infections may also lead to sepsis. Greater than 90% of cases of fungemia-induced sepsis are due to Candida spp; patients with a history of invasive Candida infections, those receiving total parenteral nutrition or corticosteroids, and those with chronic vascular catheters or neutropenia are at significant risk.[11][4]
Pathophysiology
In healthy hosts, infection causes an inflammatory response that is ideally localized and controlled. This host response is protective against microbial proliferation and dissemination. Certain microorganisms contain molecular constituents, such as gram-negative bacterial lipopolysaccharide and fungal beta-D-glucan, termed pathogen-associated molecular patterns (PAMPs). These PAMPs are recognized by pattern recognition receptors (PRRs), including but not limited to Toll-like receptors (TLRs), which initiate an inflammatory response. Additionally, the release of intracellular contents into the circulation by damaged host cells, termed damage-associated molecular patterns (DAMPs), potentiates the host inflammatory response. These molecules activate the TLRs of antigen-presenting cells (APCs) and monocytes, increasing the expression of various transcription factors, including nuclear factor-κB and AP-1. This subsequently results in the release of proinflammatory interleukins (IL), tumor necrosis factor-alpha (TNF-α), cytokines, interferons (IFNs), and chemokines.[12][13][14]
Severe infection stimulates the release of both mature and immature neutrophils via emergency granulocyte maturation. Immature neutrophils have decreased phagocytic abilities and a reduced capacity for oxidative burst. Elevated levels of immature neutrophils and increased production of neutrophil extracellular traps (NETs) are directly linked to clinical deterioration. NETs are designed to trap various microbial pathogens, including bacteria, viruses, fungi, protozoa, and parasites. Chemokines, cytokines, and platelet agonists trigger the production and release of NETs. Increased NETs are associated with hypercoagulability and endothelial dysfunction.[14]
The immune response to infection includes cellular and chemical mediators that lead to the activation of other components, and inactivation occurs via counterregulatory processes to restore homeostasis after the resolution of the acute phase of infection. Derangement of this process results in organ dysfunction and sepsis. Multifactorial systemic derangements, including increased vascular permeability, decreased organ perfusion, and hypercoagulability secondary to increased leukocyte adhesion and endothelial and platelet dysfunction cause organ dysfunction in sepsis. Decreased tissue perfusion leads to tissue hypoxia and cellular and mitochondrial dysfunction, which can persist even after restoring adequate tissue perfusion.[15]
Specimen Requirements and Procedure
Appropriate preanalytical specimen management, which includes specimen collection, transport, storage, and rejection criteria, is critical for optimizing diagnostic accuracy.[16] Specimen quality impacts test result interpretation. Clinicians must select and collect specimens from appropriate body sites, follow specified guidelines, and promptly transport them to the laboratory. A thorough understanding of laboratory requirements through training and education, good communication between laboratory and clinical staff, and easy access to laboratory references via a website or portal assist in optimizing preanalytical processes.[17] Poorly or improperly collected specimens may lead to erroneous or misleading results that directly impact patient care and outcomes by influencing therapeutic decisions, length of stay, hospital and laboratory costs, and laboratory efficiency.[18]
The initial management of patients with suspected sepsis includes clinical and laboratory evaluation to identify any new or worsening organ dysfunction in patients with confirmed or suspected infection. An evaluation of the source of infection should include bacterial and viral specimens and a urinalysis.[4]
Blood Specimens
Blood samples should be obtained for laboratory tests, such as a complete blood count (CBC) and clinical chemistry. Samples should be drawn in the correct tube, as each tube differs in the additives they contain based on the test that needs to be performed. Samples for a CBC should be drawn in lavender-capped blood collection tubes; hematology testing requires irreversible anticoagulation with EDTA. Coagulation studies should be conducted on samples drawn in light blue-capped blood tubes that contain sodium citrate, a reversible anticoagulant. Clinical chemistry and immunochemistry testing are performed on samples that contain only serum or samples anticoagulated with lithium-heparin, collected in red- or light-green–capped blood sample tubes, respectively. Poor technique or errors in sample collection can result in delays in diagnosis and treatment. Common causes of specimen nonconformity include hemolysis, insufficient specimen volume, wrong container, and undue clotting.[19]
Blood Cultures
Blood cultures should ideally be obtained before administering antibiotics, though treatment should not be delayed. Blood cultures obtained after initiating antibiotic treatment may result in a lower yield and have been linked to increased healthcare costs and longer hospital stays.[20] Blood cultures should be obtained as soon as possible unless obtaining cultures would delay antibiotic administration. Two sets of cultures in 4 bottles, 2 aerobic and 2 anaerobic bottles, are recommended; the total draw should approximate 30 to 40 mL. Each bottle should contain 8 to 10 mL of blood to avoid false negative results. However, overfilling the bottles can cause false positive results due to high CO2 production by white blood cells.
For specimen collection, hand hygiene should be performed, and disposable gloves should be used. Sterile gloves may be considered on an institutional basis, depending on local contamination rates. Before collection, antisepsis of the puncture site must be performed to avoid contamination; 2% chlorhexidine in 70% isopropyl alcohol is preferred. An area of skin 6 cm in diameter should be scrubbed for 30 seconds; the area should be allowed to dry for 30 seconds to allow the antiseptic solution to dry. Peripheral venous blood is the site of choice for blood culture specimen collection, although arterial blood is a reasonable alternative. Sampling existing intravenous access sites carries an increased risk of contamination and should be performed in addition to standard peripheral venous blood draws to identify catheter-associated bloodstream infections.[21]
The media and additive types used for modern blood culture samples consist of soybean casein digest (trypticase soy broth) and sodium polyanethol sulfonate for anticoagulation. The bottles contain CO2 and N2, along with reducing agents for anaerobic bottles and ambient air supplemented with CO2 for aerobic bottles. The incubation time of blood cultures is typically 4 to 7 days, with approximately 99% of pathogens detected within 5 days of incubation.[22]
Viral Specimens
Viral specimen yields are highest early in the infectious process; these samples should be obtained and tested for the most likely agent based on the patient's age, exposure, vaccination history, and immune status. Presenting symptoms and the probable site of infection should dictate the type of specimen to collect. The period of viremia varies depending on the infecting virus. Blood or urine samples can be used in cases of systemic infection, as with arbovirus or measles. Stool samples may be taken in cases of enteric viral illness, as with rotavirus or poliovirus. Respiratory tract sampling with nasopharyngeal or oropharyngeal swabs with Dacron or Rayon tips can be used in patients with signs and symptoms of respiratory illness. Cerebrospinal fluid samples may be required in suspected central nervous system infections. Reverse transcription polymerase chain reaction (RT-PCR) is commonly used to identify viral pathogens during the acute phase of viral illness. Antibody testing, specifically IgM, is used after several days of symptom onset.[23]
The required blood sample volume for viral molecular testing varies between 2 to 10 mL. EDTA tubes are preferred; anticoagulants have been shown to inhibit PCR. Clotted blood may be sampled for serology testing in serum separation tubes (SST), which permit the separation of red blood cells and serum via centrifugation. Depending on the virus, viral isolation is possible from EDTA or clotted blood samples.[24][25]
Fungal Specimens
Testing for fungal infection typically includes serological testing for the fungal cell wall components such as galactomannan, galactomannan antigen antibodies, and (1-3)-β-d-glucan. Other testing methods for fungal infection include reverse-transcriptase polymerase chain reaction (RT-PCR) and culture of surveillance sites for Candida spp to differentiate between colonization and invasive Candida infection. Candida spp are cultured on Sabouraud dextrose agar with 0.05% chloramphenicol and chromogenic medium plates to identify polymicrobial cultures.[25] Cultures should be examined daily for up to 6 days before being considered negative. The diagnosis of invasive Aspergillus spp requires a positive culture of an otherwise sterile site or positive histopathology, as Aspergillus spp in respiratory tract secretions typically represent colonization and not necessarily an infectious process. Diagnostic methods for Mucorales are limited; the diagnosis is typically established with histopathology using hematoxylin-eosin, Grocott-methenamine-silver, and periodic acid-Schiff stains.[26][27]
The recovery of fungi depends on collecting a good-quality specimen at an adequate volume that will allow for specimen concentration and pretreatment to maximize sensitivity. Collection from the active site of infection is best, preferably before initiating antifungal therapy.[28]
Urine samples
Urine samples may be obtained via spontaneous voiding or catheterization in patients who cannot provide a spontaneous sample. The most convenient specimen is clean-catch or mid-stream urine. Mid-stream urine can be self-collected by washing out the initial urine stream to void contaminating urethral flora and collecting the mid-stream urine. A volume of 15 to 30 mL is sufficient for accurate analysis.[29] Urethral catheterization is performed by introducing a catheter through the urethral meatus after cleansing the area to avoid contamination.[30]
Urine collection bags may be employed for infants and young children. However, specimens from urine bags are considered low-quality; most laboratories will not accept bag specimens for urine culture due to the high likelihood of false positive results. Although not acceptable for culture, these specimens can be useful for performing urinalysis screens.[31]
Specimens should not be obtained from the collection bag in patients with indwelling urinary catheters, as this area is considered contaminated. Urine should not be kept at room temperature for longer than 30 minutes and should be stored at refrigerator temperature if not sent for culture within 30 minutes of sample collection.[32] Reflex urine culture is typically ordered after a positive pyuria screen on urinalysis; however, this practice is institution-dependent.[24]
Surgical Samples
Patients undergoing surgical procedures for source control of sepsis of intraabdominal origin, soft tissue infection, and osteomyelitis should be cultured intraoperatively for pathogen identification and antibiotic stewardship.[33] Samples that may be obtained for culture from suspected sources include swab cultures from the suspected site of infection, tissue biopsy, collection aspirate, and samples of foreign material such as surgical mesh. In cases of soft tissue infection where debridement is performed, tissue biopsy and culture should be obtained from multiple sites.[34] Patients with suspected osteomyelitis should undergo open or percutaneous bone biopsy for pathology testing and culture.[35]
In patients with intraabdominal infections that are considered high-risk, such as those who are critically ill or have acquired the infection in the hospital, it is advisable to obtain intraperitoneal specimens for microbiological analysis. These intraperitoneal specimens should be collected whenever the patient undergoes a surgical intervention.[36] The most appropriate specimens are peritoneal fluid and tissue samples from the suspected site of infection. The specimens should be of sufficient volume, at least 1 to 2 mL, and handled carefully to prevent contamination or deterioration. An airless sterile syringe with a combi-stopper can be used, or the sample can be transferred to a sterile test tube when collected. The specimens can be inoculated in anaerobic and aerobic bottles for culture and identification. The laboratory should perform Gram stain, culture, and susceptibility testing on the specimens to guide the antimicrobial therapy.[37]
Respiratory Samples
Respiratory samples can be obtained via various methods as dictated by the clinical situation and type of pathogen. Respiratory sampling techniques can be classified as invasive and noninvasive. Noninvasive techniques include sputum or endotracheal aspiration. Sputum can be collected by spontaneous expectoration or induction with hypertonic saline or other agents. Endotracheal aspiration involves suctioning secretions from a tracheostomy or endotracheal tube. Invasive techniques include fiberoptic bronchoscopy aspirate and bronchoalveolar lavage.[38]
The quality of respiratory samples is determined by <10 squamous cells and >25 leukocytes per optical microscopy field; this is considered suitable for respiratory culture. The threshold for microbiological diagnosis is the presence of a pathogenic microorganism >105 colony-forming units/mL in samples obtained from sputum, endotracheal aspirate, and bronchoscopy. Growth >104 colony-forming units/mL is considered positive for samples obtained via bronchoalveolar lavage. Invasive methods of respiratory cultures appear to have a higher diagnostic yield than noninvasive sampling methods.[39]
Diagnostic Tests
In addition to cultures and testing to identify causative pathogens, diagnostic tests used in evaluating sepsis include those that have proven utility in identifying systemic inflammatory response syndrome (SIRS) and organ dysfunction. These tests usually include the CBC, clinical chemistry, and arterial blood gas.
Host-response and pathogen-specific biomarkers have been described in the literature as having utility in staging disease severity, prognosis, and response to treatment. Some common host-response biomarkers used in regular practice include C-reactive protein (CRP), lactate, and procalcitonin (PCT).[40] However, many biomarkers have been discovered to play a role in sepsis, including complement, cytokines, chemokines, DAMPs, calprotectin, and E-selectin. Their use in daily practice is limited, and more research is needed to identify combinations of biomarkers that can impact diagnosis and treatment and improve patient outcomes.[41]
Testing Procedures
A CBC is usually performed by an automated hematology analyzer, which counts cells and collects information on their size and structure.[42] Hematology analyzers may use one of several methods, including electrical impedance, flow cytometry, and fluorescence flow cytometry. The Coulter method is also used for CBC analysis. The Coulter method accurately counts and sizes cells by detecting and measuring changes in electrical resistance when a particle in a conductive liquid passes through a small aperture. Fully automated hematology analyzers employ two principal methods of counting blood cells: volumetric impedance and light-scatter technique.[43]
Various methods may be used to determine CRP levels. Commonly used methods include turbidimetric assays, lateral flow assays, sandwich immunoassays, fluorescence assays, chemiluminescence assays, enzyme-linked immunosorbent assays (ELISA), immunoturbidimetry, and nephelometric assays. The method employed depends on sensitivity, specificity, cost, and availability of equipment and reagents.[44] High-sensitivity CRP (hs-CRP) assays can detect lower levels of CRP, while standard assays have a higher detection limit.[45]
Several methods are available to determine serum creatinine. These include the colorimetric method, spectrophotometric method, enzymatic method, chromatographic method, and the Jaffe reaction method.[46] The Jaffe method is widely used for its simplicity and low cost, but it is less specific and more prone to interference than the enzymatic method.[47] Isotope dilution mass spectroscopy (IDMS) is highly accurate and precise but impractical for routine use.[48]
Some commonly employed methods to determine lactate are the spectrophotometric, enzymatic, and lactate oxidase-based methods. The spectrophotometric method is simple and inexpensive. The enzymatic method is more specific and less prone to interference than other methods.[49]
PCT is most often measured with a quantitative immunoassay using monoclonal antibodies. Automated blood culture systems are widely used in clinical laboratories to detect the presence of microorganisms in blood samples.[50]
Interfering Factors
Most instruments count red blood cells (RBCs) and white blood cells (WBCs) within the same channel. Therefore, a high WBC count may result in a spuriously increased RBC count, particularly in anemic patients. High WBC counts also falsely increase the hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Multiple abnormal RBC indices should alert the user to potentially erroneous results.[51]
Interferences at the lower size and volume thresholds of WBC counting can be an important clue to the presence of artifacts. These artifacts include sample clotting, platelet clumping, or giant platelets that can lead to falsely low platelet counts, high WBC counts, and an erroneously high lymphocyte percentage. Most instruments flag significant particle interference in this region.[52] A falsely low WBC count can be seen secondary to neutrophil agglutination in the presence of EDTA. This can be seen in acute and chronic inflammatory conditions, liver diseases, or the presence of cold agglutinins. A spuriously high WBC count may result from platelet aggregation, large platelets, cryoglobulins, lipids, insufficiently lysed RBCs, nucleated RBCs, and microorganisms.[53]
EDTA-induced thrombocytopenia is a well-documented in vitro phenomenon induced by circulating autoantibodies against platelet membrane glycoprotein IIb/IIIa. Falsely low platelet counts can be secondary to platelets resetting around neutrophils, a rare condition known as platelet satellitism. Preanalytic factors such as clot formation within the sample also should be considered if the platelet count is abnormally low.[54] Large platelets may be counted as WBCs by specific analyzers. For example, platelets can be larger than RBCs in some patients with May-Hegglin anomalies.[55]
Platelet counts may be erroneously high when using impedance methodology in the presence of increased schistocytes, cryoglobulins, bacteria, fungi, lipids, and fragments of nucleated cells frequent in leukemias and lymphomas. Error flags by automated instruments are important because they may indicate an erroneous platelet count.[51] Verifying the platelet count by slide estimate is usually the first investigative step when error flags occur. If a slide examination reveals platelet clumping, the platelet count is likely spuriously low, and the WBC count is spuriously high. If the sample is clotted, it should be redrawn. A correct platelet count can often be obtained with an EDTA-dependent platelet agglutinin by collecting the blood in citrate anticoagulant and multiplying the results by the dilution effect from the liquid anticoagulant or by using a heparinized blood sample in which case there is no need to correct for dilution.[56]
Specimens with high titers of rheumatoid factor can potentially interfere with CRP immunoassays, but most reagent manufacturers incorporate dithiothreitol to destroy rheumatoid factor by reducing disulfide bonds.[57] CRP can increase dramatically in inflammatory states, resulting in falsely low results due to antigen excess.[58] This prozone effect may be seen for single-antibody nephelometric and turbidimetric methods. Several sites have reported evidence of prozone effects at varying CRP concentrations ranging from <50 mg/L to 510 mg/L.[59][60]
The Jaffe reaction is not specific to creatinine. Many compounds have been reported to produce a Jaffe-like chromogen, including protein, glucose, ascorbic acid, levulose, ketone bodies, pyruvate, guanidine, amino hippurate, uric acid, blood-substitute products, and cephalosporins. Ascorbic acid, levulose, glucose, and uric acid can reduce picrate to picramate, and this product, with its absorbance maximum of 485 nm, causes an overestimation of creatinine.[61] The degree of interference from these compounds depends on the precise reaction conditions chosen and the concentration of the interferent present in the sample.[62]
Hemolysis or high bilirubin concentrations has been reported to interfere with some lactate methods.[63] High concentrations of pyruvate and malic acid can interfere with some enzymatic methods used to determine lactate.[64]
Results, Reporting, and Critical Findings
White Blood Count
The CBC has long been considered integral in evaluating sepsis and septic shock. The initial definition of SIRS and the SCCM Sepsis-2 criteria included an abnormal white blood cell count, leukocytosis, or leukopenia as diagnostic criteria for sepsis.[65][66] In contrast, the SCCM Sepsis-3 criteria consider leukocytosis in the context of SIRS as a clinical tool for sepsis screening, not as a parameter to diagnose sepsis.[1] In clinical practice, leukocytosis usually triggers an investigation for possible infection; the data supporting this practice is limited. While sepsis and septic shock can lead to leukocytosis or leukopenia, most patients fall between the cutoff parameters, and many patients with bacteremia have a normal WBC count.[67] When measured at presentation in the Emergency Department, the sensitivity and specificity of leukocytosis or leukopenia for predicting severe sepsis or septic shock versus no sepsis are estimated to be 57.1% and 78.7%, respectively.[68]
The left shift is represented by increased production and release of immature granulocytes, including myelocytes, metamyelocytes, and band neutrophils. This process occurs secondary to the production of cytokines and has a relatively low sensitivity but high specificity for infection. Therefore, if bandemia is present, it should be considered potential evidence of sepsis until proven otherwise. This release of immature cells from the bone marrow usually occurs at least 12 to 24 hours after infection and could lead to a missed diagnosis if relied upon as criteria to diagnose sepsis on initial presentation.[67][69]
The neutrophil-to-lymphocyte ratio could be useful in differentiating acutely ill patients as a marker of physiological stress. An increase in this ratio could be used to indicate sepsis and risk for septic shock, as it is seen early on, within 6 hours of the acute phase of infection.[69][70]
Within the SIRS Criteria, three variables are considered when evaluating the WBC: leukocytosis >12,000/mm3, leukopenia <4,000/mm3, or bandemia >10%.[71]
Platelet Count
Platelets are an acute phase reactant, and thrombocytosis or thrombocytopenia can be seen in patients with infection. Due to platelet consumption, thrombocytopenia is frequently seen in patients with sepsis and septic shock. Thrombocytopenia is a predictor of increased mortality in patients with sepsis and is an integral component of the SOFA Score.[67][72] The inflammatory response and endothelial damage in sepsis lead to platelet activation and consumption. Activated platelets recruit neutrophils to the site of injury and promote the formation of NETs. The interaction of platelets with PAMPs, neutrophils, and endothelial damage in sepsis results in platelet consumption plus simultaneous microvascular thrombosis, leading to microvascular occlusion, directly contributing to organ failure. Thrombocytopenia is considered severe if the platelet count is less than 50,000/mm3.[73] The SOFA score calculation defines coagulation dysfunction as a platelet count <150,000/mm3.[72]
Serum Creatinine
When used as a component of the SOFA score to characterize patients with sepsis, the cutoff for creatinine is <1.2 mg/dL.[72] The presence of underlying chronic kidney disease (CKD), particularly if undiagnosed, can skew the SOFA score towards increased mortality, especially when baseline SOFA is assumed to be 0.[74] Creatinine is an important marker for detecting renal dysfunction in sepsis. Inflammatory mediators released in septic patients decrease the metabolic rate, leading to decreased muscle production of creatinine and conversion of creatinine from creatine in the liver. This process has been described as a basis for why minimal increases in creatinine are associated with significantly increased mortality in patients with sepsis.[75]
Bilirubin
The cutoff for normal bilirubin level in the SOFA score is <1.2 mg/dL. Hyperbilirubinemia is considered a late event in critically ill patients with sepsis. Hyperbilirubinemia in sepsis is thought to be secondary to sepsis-induced cholestasis, hemolysis, and direct hepatocellular injury resulting in hepatic dysfunction. Excess bilirubin levels are often seen in septic patients without primary liver or biliary disease.[76] Hyperbilirubinemia at the time of admission is associated with increased mortality secondary to the development of sepsis-related acute respiratory distress syndrome. Excess bilirubin has been shown to increase the oxidative stress that promotes hemolysis, in addition to promoting apoptosis and further perpetuating the systemic inflammatory response.[77]
Serum Lactate
Within the SCCM Sepsis-3 criteria, the serum lactate value is used as a marker to detect septic shock. Septic shock can be diagnosed using two criteria: persistent hypotension despite fluid resuscitation requiring vasopressors to maintain a mean arterial pressure (MAP) >65 mmHg or serum lactate >2 mmol/L. Lactate is considered a sensitive marker for septic shock. Patients with sepsis and a serum lactate >2 mmol/L are deemed to be in a similar condition as those who are hypotensive and require vasopressors with serum lactate levels <2 mmol/L. Patients with elevated lactate and comorbid hypotension are at risk of increased mortality when compared to patients identified with either isolated condition.[78]
Traditionally, lactic acidosis has been associated with tissue hypoxia. However, it has been demonstrated that lactic acidosis is more likely an adaptive response to the metabolic derangement caused by systemic inflammation and severe infection. Lactate elevation in septic shock appears to be closely related to the stimulation of beta-2 adrenergic receptors by increased levels of endogenous epinephrine and norepinephrine, making lactate a marker of endogenous catecholamine release and possibly useful for diagnosing occult or compensated shock in septic patients at risk for later developing hypotension requiring vasopressors. Other factors contributing to hyperlactatemia include impaired tissue oxygen extraction and impaired clearance in patients with new-onset hepatic dysfunction or preexisting hepatic disease.[79][80]
Procalcitonin
Procalcitonin (PCT) is a precursor of the hormone calcitonin secreted by nonendocrine, parenchymal cells in numerous tissues at high concentrations in response to inflammatory cytokines such as TNF-α and IL-1β and bacterial toxins such as lipopolysaccharide, and thus can function as a marker of inflammatory states. PCT has been studied as a gauge for initiating and de-escalating antimicrobial therapy. Serial PCT levels, with a cutoff of <0.5 ug/L or >80% decrease from peak levels, assist in earlier antibiotic discontinuation in hemodynamically stable patients.[81] Studies have shown that using PCT to guide the duration of antibiotic treatment improved mortality and decreased antibiotic exposure. PCT should not be used to guide the initiation of antimicrobial therapy in sepsis, as available data suggests inadequate sensitivity and specificity for diagnosing sepsis.[82] PCT levels have also been investigated as a marker for bacterial coinfection in patients with viral pneumonia but have not proven reliably diagnostic; microbiological investigation remains the gold standard.[83]
C-reactive Protein
C-reactive protein (CRP) is an acute-phase reactant.[84] CRP is synthesized in the liver and is under the direct transcriptional control of interleukin-6 and indirect control of IL-1β, TNF-α, and other cytokines. CRP rises proportionally to the degree of inflammation. The serum levels are determined only by the rate of production, begin to rise within 6 to 12 hours of the initial insult, and peak in 2 to 3 days; levels may be affected by underlying liver dysfunction given the single-organ origin.[84]
CRP levels correlate with the severity of inflammation and improve in response to appropriate antibiotic therapy if elevated due to infection; poor patient outcomes are associated with persistently elevated CRP levels.[85][86] In a systematic review and meta-analysis, CRP had an estimated pooled sensitivity of 75% and a specificity of 67% for differentiating bacterial infection from noninfectious causes of inflammation.[87] However, extremely elevated CRP levels may have greater diagnostic and prognostic utility, as one study showed that infection was present in 88% of cases with a CRP >500 mg/L.[88]
A study of pediatric patients with a systemic inflammatory response found that a panel of 8 biomarkers, including CRP and PCT, had a 90% negative predictive value in identifying patients without a bacterial infection.[89] CRP is often used in the diagnosis of bone and joint infections in children and adults, and decreasing serial CRP values correlate with the resolution of these infections.[90][91] Decreases in serial CRP measurements have also been used to time the transition to oral antibiotic therapy in managing pediatric bone and joint infections.[92][93]Decreasing serial CRP measurements also correlate with the resolution of other infections, such as cellulitis, ventilator-associated pneumonia, bloodstream infections, and sepsis.[94][95]
CRP is useful as an index of systemic inflammation but is considered less reliable than PCT for bacterial infection. The onset and offset of CRP in response to inflammatory insults are slow when compared to PCT.[96] CRP appears to be useful for predicting mortality in sepsis, with some studies using serial CRP measurements to estimate the severity of the inflammatory response.[97] A CRP cutoff of >100 mg/dL on the third measurement day appears predictive of increased mortality.[98][99]
Urinalysis
The urinalysis (UA) is the most frequently ordered test to evaluate possible urinary tract infections (UTIs). A UA is considered negative for infection when nitrites, leukocyte esterase, and microscopic detection of WBCs are absent. A negative UA is fairly specific (92%) for the absence of UTI. UA results that yield high sensitivity as indicators of UTI include leukocyte esterase and WBC >10/hpf. UA results that are highly specific for the diagnosis of UTI include any amount of bacteria present and positive nitrites. An elevated pH is poorly specific for UTI; the pH can be elevated if urea-splitting organisms such as Proteus mirabilis are present. The classic indicator of bacterial infection is the presence of bacteria >5/hpf, which tends to correspond to 100,000 colony-forming units/mL on urine culture. In many cases, urine cultures would be ordered if bacteria, leukocyte esterase, WBC >10/hpf, or nitrites were detected independently.[100][101]
Blood Culture
Blood cultures with true pathogens tend to result within 5 days of incubation. The initial step in evaluating a positive culture is Gram stain, and the results should be reported to the primary treatment team immediately; Gram stain results directly impact antibiotic stewardship and are available much sooner than final susceptibility testing. Molecular testing can be performed on positive blood cultures at institutions with this capability. Molecular testing could identify organisms within a few hours when reflexed from a positive culture via large panel testing. Rapid molecular tests can provide important information on antimicrobial susceptibility via genetic markers that indicate likely resistance patterns. Antimicrobial stewardship based on susceptibility testing improves patient outcomes, reduces unnecessary antimicrobial exposure, and improves resource allocation.[22]
Repeat blood cultures have utility in patients with Staphylococcus aureus bacteremia; persistent bacteremia despite antibiotic therapy can guide decision-making on management and source control. Blood cultures should be repeated within 48 hours of achieving source control in patients with S aureus bacteremia or with an endovascular source of infection. This practice is considered low-yield in patients with gram-negative and streptococcal bacteremia. Another indication for repeat blood cultures is clinical deterioration. However, fever alone should not reflex new blood culture sampling, as the persistence of fever is not associated with increased mortality, and patients can remain febrile for several days after antibiotic treatment is initiated.[102]
Fungal Cultures
The most common causes of fungal infection in critically ill patients include Candida, Aspergillus, and mucormycosis. The primary etiologic agent of fungal infection in the critically ill population is Candida albicans. Serological testing for the components of fungal cell walls is specific for fungal infections but has low sensitivity. RT-PCR has low sensitivity for Candida fungemia but has utility in diagnosing deep-seated candidiasis with negative blood cultures. One screening method for fungal infection in at-risk patients is the Candida colonization index (CI).[103]
Candida colonization is defined as repeated yeast growth from two separate sites. The CI is a ratio calculated using the number of culture-positive nonbloody body surveillance sites for Candida spp to the number of sites cultured. Samples are typically collected from multiple sites for mycological surveillance; sample sites can include the pharynx, rectum, axillae, urine, blood, and tracheal secretions or gastric contents. Once the CI is calculated, a corrected colonization index (CCI) can be obtained using the ratio of distinct body sites demonstrating heavy growth to those with growth of Candida spp The CCI has been shown to better differentiate between colonized and infected patients. Patients with a CCI >0.4 or CI >0.5 should receive empirical antifungal treatment for Candida.[27][103]
Clinical Significance
Healthcare teams should assess patients based on clinical findings and laboratory data to screen for, diagnose, and treat sepsis effectively. Once sepsis is suspected clinically, different clinical decision-making algorithms and tools may be used to assess for severity and guide treatment; these algorithms and tools may be institution dependent. Current guidelines endorsed by the American College of Emergency Physicians and the Society of Critical Care Medicine recommend collecting the data required to calculate the Sequential Organ Failure Assessment (SOFA) score for stratifying disease severity and estimating patient mortality.
The SOFA score assesses organ dysfunction, and most of the data required to calculate an accurate SOFA score is readily available through clinical assessment and commonly performed laboratory testing. An important limitation of the SOFA criteria is the scoring of respiratory dysfunction, which requires a PaO2 value to obtain the PaO2/FiO2 ratio.[104] Routinely performing an arterial blood gas to calculate a respiratory SOFA score in patients where the results would not otherwise dictate a change in management is not currently recommended. A proposed alternative to the PaO2/FiO2 ratio is using pulse oximetry (SpO2) values to approximate the likely PaO2/FiO2 ratio described in the original SOFA scoring criteria.[105][106]
Increases in the SOFA score within 24 hours of admission to the intensive care unit (ICU) may indicate clinical deterioration. Additionally, increases of 2 points or more imply an increased risk of in-hospital mortality and prolongation of ICU length of stay by 3 days or more. Some studies have shown that the mean and maximum or worst SOFA score in critically ill patients was a significant predictor of 28-day mortality. SOFA demonstrated the best capacity to estimate these outcomes compared to other scoring systems in the Third International Consensus Definition for Sepsis and Septic Shock.[107]
Quality Control and Lab Safety
The clinical laboratory is involved in many aspects of the analytical phase to ensure high-quality testing. The clinical laboratory oversees quality management procedures that include quality control (QC), or the initial step of controlling a procedure, and quality assurance (QA), which is a broader component that includes proficiency testing, personnel competency testing, monitoring of inventory, and calibration and maintenance of equipment. Importantly, the clinical laboratory actively monitors key QA metrics, including test result positivity rates, critical test results turnaround time, and test accuracy.[108] Regular review of these metrics allows the identification of irregularities that may require further investigation to address the root cause of the issue or communication with other stakeholders, including higher levels of management.[109]
For non-waived tests, laboratory regulations require, at the minimum, analysis of at least 2 levels of quality control materials once every 24 hours. If necessary, laboratories can assay QC samples more frequently to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance.[110]
The acceptable range and rules for interpreting QC results are based on the probability of detecting a significant analytical error condition with an acceptably low false-alert rate. The desired process control performance characteristics must be established for each measurement before selecting the appropriate QC rules.[111] Westgard multi-rules are usually used to evaluate the quality control runs. If a run is declared out of control, investigate the system to determine the cause of the problem. Do not perform any analysis until the issue has been resolved.[112]
Laboratories that use automated blood culture machines typically have QA protocols in place. These protocols include regular calibration and maintenance of the machines and proficiency testing to ensure accurate and reliable results. It is important to note that specific QC measures may vary depending on the manufacturer and model of the automated blood culture machine. Laboratories should follow the manufacturer's instructions and guidelines for QC procedures.[113]
The laboratory must participate in the external quality control or proficiency testing program. This is a regulatory requirement published by the Centers for Medicare and Medicaid Services (CMS) in the Clinical Laboratory Improvement Amendments (CLIA) regulations. It is helpful to ensure the accuracy and reliability of the laboratory compared to other laboratories performing the same or comparable assays.[114] Required participation and scored CMS and voluntary accreditation organizations monitor results. The PT plan should be included as an aspect of the QA plan and the overall quality program of the laboratory.[115]
Consider all specimens, control materials, and calibrator materials as potentially infectious. Exercise the usual precautions required for handling all laboratory reagents. Disposal of all waste material should be in accordance with local guidelines. Wear gloves, a lab coat, and safety glasses when handling human blood specimens. Place all plastic tips, sample cups, and gloves that come into contact with blood in a biohazard waste container. Discard all disposable glassware into sharps waste containers. Protect all work surfaces with disposable absorbent bench top paper, discarded into biohazard waste containers weekly or whenever blood contamination occurs. Wipe all work surfaces weekly.[116]
Enhancing Healthcare Team Outcomes
Managing sepsis and septic shock requires the collaborative effort of healthcare professionals such as physicians, nurses, patient care technicians, and pharmacists, among others, to enhance patient-centered care and improve outcomes. Early identification of sepsis and treatment with antimicrobial therapy is the most effective intervention that decreases in-hospital mortality in patients with sepsis.
The diagnosis of sepsis can be complex due to the broad differential diagnosis, which requires a combination of clinical evaluation, vital signs, and laboratory data using various screening tools such as SIRS, qSOFA, SOFA, NEWS, and MEWS. A laboratory workup, including CBC, chemistry panel, LFTs, and biomarkers such as blood lactate, is essential for diagnosis, risk stratification, and prognosis of sepsis. The SOFA score is used to define sepsis and has diagnostic and prognostic value. Evaluation for the source of infection, severity assessment, treatment and prevention of hypotension, intravenous fluids, vasopressors, antibiotics, and infection source control are essential in managing patients with suspected sepsis.
Healthcare professionals should be aware of the complexity and potential outcomes involved in caring for septic patients. They should engage in interprofessional communication and care coordination to enhance team performance and patient safety. Thorough understanding of laboratory evaluations of sepsis can better aid the healthcare team in delivering patient care promptly and improving patient outcomes.
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