Review of Sepsis in Burn Patients in 2020

Abstract

Background:

Severe burn injury results in substantial damage to the skin, inhibiting its ability to perform as the primary barrier to infection. Additionally, severe burn injury can lead to critical illness and extensive time in the intensive care unit (ICU). These two factors work to increase the risk of sepsis in the burn patient compared with other hospitalized patients. The increased risk of sepsis is compounded by the difficulty of diagnosing sepsis in severely burned patients because the pathophysiology of large burns mimics sepsis, leading to possible delay in diagnosis and initiation of treatment.

Methods:

A literature review was performed to discuss and review the diagnostic difficulties and criteria used to identify patients with sepsis. Additionally, the most current management of sepsis was reviewed and described in caring for burn patients with sepsis.

Results:

The incidence of sepsis in patients with more than 20% total body surface area (TBSA) burns is between 3% and 30% and is the most common cause of death in the burn patient, with pneumonia being the most common etiology. Several different diagnostic criteria for diagnosing sepsis in burn patients exist, however, none of these criteria have proven to be superior to clinical diagnosis by an experienced burn surgeon. As with sepsis in other patient populations, prompt diagnosis, initiation of antibiotic agents, and source control remain the standard management of sepsis in the burn patient.

Conclusions:

Because of the loss of the primary infection barrier function of the skin after a substantial burn injury, this patient population is at increased risk for sepsis. Because of the pathophysiology of burn injuries, diagnosing sepsis in the burn population remains challenging. Understanding the most common etiologies of sepsis in burn patients may help with more expedient diagnosis and initiation of treatment.

Thermal, chemical, and electrical injuries often result in substantial damage to the skin, which is the largest organ system, with resulting loss of the primary barrier to infection. This breach in the barrier, coupled with immunosuppression and a massive systemic inflammatory response, i.e., hypermetabolic response, places burn patients at a severe risk for infectious complications and sepsis [1,2]. For patients who survive the initial 72 hours after a burn injury, infection is the most common cause of death [3]. In patients with more than 20% total body surface area (TBSA) burns, the incidence of sepsis is noted to be between 3% and 30% [4,5]. Prevalence increases dramatically to 65% in all patients who have succumbed to their burn injury [6]. Compared with the trauma population and general surgical critical care population, despite a relatively lower age, burn patients have a higher prevalence of sepsis [7].

Definitions and Pathophysiology

Recognizing the need to update the definition of sepsis because of greater understanding of the underlying pathobiology, a 2016 joint task force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) defined sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection [8]. The current definition displaces the previous definition of the presence of two of four systemic inflammatory response syndrome (SIRS) criteria plus the presence of an infection [9]. Additionally, the task force did away with the term severe sepsis, and defines septic shock as, “a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone” [8]. To assist with diagnosis of sepsis, a quick sequential organ failure assessment (qSOFA) score was created that is based on three parameters: altered mental status (Glasgow Coma Scale [GCS] <15), tachypnea (respiratory rate >22 breaths per minute, and hypotension (systolic blood pressure <100 mm Hg) [8].

The pathophysiology of sepsis is complex and remains incompletely understood. However, we do know that it involves a widespread systemic response to bacteria or their toxins that includes inflammatory and anti-inflammatory cytokines. The early response to sepsis involves immune cells such as macrophages and neutrophils releasing a series of cytokines that activate other cells, essentially initiating the proinflammatory cascade. The released cytokines include tumor necrosis factor (TNF)-α and interleukin (IL)-1 that leads to the release of vasodilators from endothelial cells, such as nitric oxide (NO) and prostaglandins. These vasodilatory substances act on vascular smooth muscle and are responsible for the early hemodynamic changes seen in sepsis [10]. Additionally, NO can block mitochondrial respiration by inhibiting cytochrome a,a3, thus impairing oxygen utilization in the mitochondria [11].

Endotoxins from bacterial cell walls have also been implicated in impairing oxygen utilization in mitochondria by inhibition pyruvate dehydrogenase in mitochondria, further reducing mitochondrial respiration [12]. The inflammatory reaction also leads to alterations in intercellular endothelial junctions and the shedding of the endothelial glycocalyx, resulting in increased capillary permeability and tissue edema, as well as relative hypovolemia [10,12,13]. The release of proinflammatory mediators also creates a procoagulant state by activating tissue factor, leading to the initiation of the coagulation cascade. Additionally, a reduction in the synthesis of the anticoagulant protein C, protein S, and antithrombin shifts the balance toward the procoagulant process. Anti-inflammatory mediators such as IL-4 and IL-10 are also released during sepsis, which not only works to limit the proinflammatory cascade, but can also lead to a state of relative immunosuppression in patients with sepsis [14].

Diagnosing Sepsis in the Burn Patient

Patients with large burns experience severe physiologic derangement, including a sustained systemic inflammatory response, hypermetabolism and immunosuppression [15,16], rendering the diagnosis of sepsis difficult in this patient population. Prior to the 2016 SCCM and ESICM taskforce, the definition of sepsis relied on the presence of two of four SIRS criteria [9], which consisted of alterations in temperature, heart rate, respiratory rate, and leukocyte count (Table 1).

Table 1.

Syndrome Systemic Inflammatory Response Syndrome Criteria

Temperature: >38.0°C or <36.0°C
Tachycardia: >90 bpm
Tachypnea: >20 breaths/min
WBC: >12,000/mm³ or <4,000mm

bpm = beats per minute; WBC = white blood cell count.

Recognizing the limitations of utilizing SIRS to define sepsis in a patient population undergoing a systemic inflammatory response at baseline, the American Burn Association Consensus Conference on Burn Sepsis and Infection Group developed sepsis criteria for burn patients in 2007 [17] that is outlined in Table 2.

Table 2.

American Burn Association Consensus Conference on Burn Sepsis and Infection Group Developed Sepsis Criteria for Burn Patients

Temperature >39°C or <36.6°C
Progressive tachycardia
Adults >110 bpm
Children >2 SD above age-specific norms (85% age-adjusted maximum heart rate)
Progressive tachypnea
Adults >25 bpm not ventilated
Children >2 SD above age-specific norms (85% age-adjusted maximum respiratory rate)
Thrombocytopenia (will not apply until 3 d after initial resuscitation)
Adults <100,000 mcL
Children <2 SD below age-specific norms
Hyperglycemia (in the absence of pre-existing diabetes mellitus)
Untreated plasma glucose >200 mg/dL or equivalent mM/L
Insulin resistance
>7 units of insulin per hour intravenous drip (adults)
Significant resistance to insulin (>25% increase in insulin requirements over 24 h)
Inability to continue enteral feeding >24 h
Abdominal distension
Enteral feeding intolerance (residual >150 mL/h in children or two times feeding rate in adults)
Uncontrollable diarrhea (>2,500 mL/d for adults or >400 mL/d in children)

bpm = beats per minute; SD = standard deviation.

A burn patient meets sepsis criteria if three of the criteria in Table 2 are present, as well as a documented infection (culture-positive infection or pathologic tissue source or clinical response to antimicrobial agents) is present. Other recommendations regarding organ dysfunction were made and are outlined in Table 3.

Table 3.

American Burn Association Recommendation About Regarding Dysfunction

1. ACCP/SCCM consensus criteria for sepsis should not used
2. Organ dysfunction/failure should not be assessed until approximately post-burn day 3 (when the acute resuscitation is completed)
3. Organ dysfunction scores that grade the degree of organ failure as opposed to those that merely designate organ failure as being present or absent
4. One of four MODS scoring systems be used and that the system should be simple, utilize common criteria, and that characteristics of the burn population be unlikely to confound
5. The Modified-Marshall Score be used initially

ACCP = American College of Clinical Pharmacy; SCCM = Society of Critical Care Medicine; MODS = multiple organ dysfunction syndrome.

Although the American Burn Association (ABA) sepsis criteria recognized the limited utility of the SIRS criteria for diagnosing sepsis in the burn patient, as well as the need for criteria more specific to this patient population, subsequent studies have called into question its accuracy. A 2012 study by Hogan et al. [15] evaluating the correlation between the presence of ABA sepsis criteria in the 24 hours prior to the drawing of blood cultures found a poor correlation with bacteremia in burn patients and the ABA sepsis criteria. In 2013, Mann-Salinas et al. [16] developed a set of novel predictors of sepsis for burn patients that outperformed the ABA sepsis criteria in the ability to predict positive blood cultures. These novel predictors of burn sepsis are outlined in Table 4.

Table 4.

Predictors of Burn Sepsis from Study by Mann-Salinas et al. [16]

1. Tachycardia >130 bpm
2. Mean arterial pressure <60 mm Hg
3. Base deficit ≤6 mEq/L
4. Hypothermia <36°C
5. Use of vasoactive medications
6. Hyperglycemia >150 mg/dL

bpm = beats per minute.

Despite the development of a new definition of sepsis, as well as burn-specific sepsis criteria [8,16,17], diagnosing sepsis in burn patients remains difficult. A 2018 study by Yan et al. [18] compared the ability of Sepsis-3 SOFA score, ABA sepsis criteria, and Mann-Salinas novel predictors to diagnose sepsis based on positive blood or tissue cultures. That study found that although the Sepsis-3 criteria was the most predictive of the three, none of the criteria had the accuracy to be a diagnostic standard in burn patients. When individual predictors from all three criteria were examined, respiratory rate less than 22, altered mental status, progressive tachypnea, temperature variations, tachycardia, and systolic blood pressure <100 mm Hg most strongly correlated with a clinical diagnosis of sepsis [18].

Diagnosing sepsis in the burn patient remains challenging despite attempts to create various diagnostic criteria. Clinical diagnosis by an experienced burn surgeon is still likely the best predictor of the presence of sepsis in the burn patient.

Biomarkers

Early diagnosis and initiation of treatment is of paramount importance. As an adjunct to clinical criteria, many clinicians and researchers are utilizing biomarkers. The most common biomarkers in clinical use include procalcitonin, TNF-α, IL-6, IL-8, IL-10, and presepsin. Of these, procalcitonin, IL-6, and TNF-α have been studied the most [19,20].

Procalcitonin is a 116-amino acid polypeptide that is the prohormone of calcitonin, the production of which is increased when bacterial infection is present. Since first studied in burn patients by Assicot et al. [21], several studies have revealed mixed data, questioning the sensitivity and specificity in adult and pediatric patients [22 –25]. A recent meta-analysis by Cabral et al. [26] demonstrated positive results leading the authors to conclude that serum levels greater than 1.5 ng/mL indicated the presence of sepsis, potentially heralding the start of antibiotic therapy.

Tumor necrosis factor-α is a proinflammatory cytokine that is produced in response to endotoxins, bacterial products, other cytokines and complement system activators. Burn patients with sepsis have elevated serum levels and improved mortality has correlated with decreasing levels. Despite its prognostic value, the utility of TNF-α in the clinical settings has been limited [19,27,28]. Interleukin-6 is a pleiotropic cytokine with several studies demonstrating elevated levels in burn patients with sepsis and usage as a prognostic marker as it correlates with mortality and burn size [25,29].

Recent research has demonstrated newer biomarkers that have yet to be studied extensively in burns thereby limiting current clinical application. These include CD14, vasopressin, thrombomodulin, heat shock proteins, granzyme A and B, intracellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), metalloproteinases, as well as various molecular markers that are based on the cellular response to sepsis as well as genomic variations [20].

Risk Factors

Several studies have noted similar risk factors for sepsis and multiple organ dysfunction syndrome (MODS), namely age over 50, %TBSA burn, inhalation injury, and male gender [30,31]. Patients with a compromised immune status including diabetes, renal failure, liver failure, and malignancy are at higher risk as well [1]. Interestingly, burn shock caused by inadequate or difficulty in resuscitation is not a risk factor for sepsis [31]. The onset of sepsis is as early as one-week post-burn with a peak in the second week and subsequent decrease beyond the third week. Early onset of sepsis within the first two weeks has been shown to be associated with a greater survival rate [32].

Management

The cornerstone of the management of sepsis is early antibiotic administration, fluid resuscitation, and source control. The Surviving Sepsis Campaign recommends 30 mL/kg fluid resuscitation within the first three hours of the recognition of sepsis, as well as broad-spectrum antibiotic administration within the first hour of diagnosis, and early source control [33]. Of these three measures, early antibiotic administration has been proven to have the biggest impact on sepsis mortality [34]. Although the Surviving Sepsis Campaign recommends a large fluid resuscitation early after sepsis diagnosis, subsequent studies have revealed that although early administration of fluids improved outcomes, noncompliance with the 30 mL/kg of IV fluid resuscitation recommendation does not lead to worse outcomes [35,36]. Recognizing this, as well as the dangers of fluid overload [37 –40], has led to calls for an individualized approach to fluid resuscitation in patients with sepsis [41,42]. Given that burn patients are already at risk for fluid overload as a result of receiving large volumes during initial fluid resuscitation and ensuing fluid creep [43,44], judicious and patient-specific fluid resuscitation in the septic burn patient is imperative.

The most common sources of sepsis in the burn patient are pneumonias, urinary tract infections (UTI), wound infections, and blood stream infections (BSI), the diagnosis and management of which are addressed briefly below [45].

Pneumonia

Pneumonia is the leading cause of morbidity and mortality among burn patients, with incidence currently estimated at two to 16 infections per 1,000 ventilator days in all hospitalized patients [46]. Patients suffering from large burns often require prolonged intubation and mechanical ventilation because of high metabolic demands, need for frequent operative interventions, and to prevent airway compromise. Unfortunately, this places them at a high risk for ventilator-associated pneumonia, and presence of inhalation injury further increases this risk [47].

Pathologic organisms enter the lung either through direct contamination of the airway or via hematogenous spread from other sites, especially the burn wound. There is evidence of cross-colonization between the burn wound and tracheobronchial tree [46]. In patients with inhalation injury, direct injury to the respiratory epithelium, increased mucous secretions, impaired ciliary clearance, and bronchoconstriction lead to areas of atelectasis and post-obstruction sequestration of materials that provide an optimum medium for growth of bacteria. Furthermore, decreased clearance by alveolar macrophages slows the removal of these materials and accelerates the development of pneumonia [48].

According to the American Burn Association Consensus Definition, the clinical diagnosis of pneumonia includes two of the following: (1) chest radiograph showing a new and persistent infiltrate, consolidation, or cavitation; (2) sepsis, as defined for burn patients; and (3) a change in sputum or purulence in the sputum. This clinical diagnosis is then modified post hoc with the microbiologic data into one of three categories: (1) confirmed—positive clinical criteria and positive microbiology, (2) probable—positive clinical criteria without positive microbiology, or (3) possible—abnormal chest radiograph with low or moderate clinical suspicion and positive microbiology. The microbiologic specimen can be obtained either via tracheal aspirate (TA), bronchoalveolar lavage (BAL), or protected bronchial brush (PBB). A positive microbiology is then defined as TA with 10⁵ or more organisms, BAL with 10⁴ or more organisms, or PBB with 10³ or more organisms [17]. In burn patients, BAL and PBB are recommended over TA for definitive diagnosis and to guide treatment [46].

After clinical diagnosis is made and microbial sample obtained, empiric treatment with broad-spectrum antibiotic agents is begun to cover all likely pathogens. Because of cross-colonization from burn wounds, this empiric therapy must also cover organisms identified in the burn wound. Once microbial cultures result, the antibiotic regimen must be narrowed to limit the development of multi-drug–resistant organisms. A seven- to eight-day course of antibiotic agents is sufficient to treat ventilator-associated pneumonia, compared with longer courses [49]. There is no role for prophylactic antibiotic therapy to prevent pneumonia in ventilated burn patients.

Utilization of a ventilator-associated pneumonia prevention bundle has been associated with a reduction in pneumonia. These bundles include items such as head-of-bed elevation, oral decontamination with chlorhexidine gel, sedation vacation, and ventilator weaning protocols [50]. Also, patients must be extubated as soon as clinically possible.

Urinary Tract Infection

Patients in the burn intensive care unit (ICU) have the highest incidence of urinary tract infections (UTI) compared with all other units [51,52]. According to the U.S. National Burn Repository, UTIs are the third leading cause of morbidity among burn patients [45]. Critically ill burn patients are especially susceptible because urine output is the standard used to guide resuscitation. As a result, majority of them receive urinary catheters at the time of admission, and these catheters remain in place for a prolonged period of time because of the critical nature of the illness and need for multiple interventions, or presence of genital burns. The longer a urinary catheter remains in place, the greater the risk of developing a urinary tract infection.

The Infectious Disease Society of America (IDSA) has categorized catheter-associated bacteriuria into two categories: catheter-associated urinary tract infections (CAUTI) and catheter-associated symptomatic bacteriuria (CA-ASB). A CAUTI is defined as the presence of signs/symptoms of a UTI with no other identified source combined with ≥10³ colony forming units per milliliter (CFU/mL) of ≥1 bacterial species in a single catheter urine sample or a midstream voiding sample in a patient whose catheter has been removed in the previous 48 hours. Signs and symptoms include new onset or worsening of fever, rigors, altered mental status, malaise or lethargy with no other cause; flank pain; costovertebral angle tenderness; acute hematuria and pelvic discomfort; and if the catheter has been removed, dysuria, urgency or increased frequency, suprapubic pain or tenderness. It is vital to distinguish this from CA-ASB, which is the presence of ≥10⁵ CFU/mL of ≥1 bacterial species without signs or symptoms consistent with a UTI [53]. In a somewhat similar fashion, the US Centers for Disease Control and Prevention (CDC) guidelines categorizes CAUTIs as either CA-ASB or symptomatic urinary tract infections (SUTI [54].

In their consensus statement, Greenhalgh et al. [17] stated the diagnosis of UTI in burn patients can be made by the presence of fever (>39.5°C and no other source of fever), urgency, frequency, dysuria, or suprapubic tenderness, and a urine culture ≥10⁵ CFU/mL with no more than two species of organisms. It can also be made by the presence of two of the following: fever (>39.5°C), urgency, frequency, dysuria, or suprapubic tenderness, and any one of the following: positive dipstick for leukocyte esterase and/or nitrate; pyuria (≥10 white blood cell (WBC) count per microliter or ≥3 WBC/high-power field (hpf) of unspun urine); organisms seen on gram stain of unspun urine; two urine cultures with repeated isolation of the same uropathogen with ≥10² CFU/mL in a non-voided specimen; or two urine cultures with ≤10⁵ CFU/mL of single uropathogen in a patient being treated with appropriate antimicrobial therapy [17]. However, the ISDA strongly recommends against using pyuria as diagnostic criteria for CA-ASB or CAUTI. In addition, the ISDA guidelines recommend against using the presence, absence, or degree of pyuria to differentiate CA-ASB and CAUTI and that pyuria along with CA-ASB should not be an indication to start antibiotic agents. Finally, the ISDA recommends that the absence of pyuria in a symptomatic patients suggest an alternative diagnosis than CAUTI [53].

Ideally the treatment of a UTI involves removing the catheter and administration of broad-spectrum antibiotic agents. It is unclear if there is a role of changing the catheter and we recommend a least some catheter-free time. This antibiotic regimen must be narrowed based on the results of urine culture [55]. The best way to prevent these infections is to remove urinary catheters as soon as clinically possible. When this is not practical, providers must ensure aseptic technique when placing these catheters, and adhere to standard urinary catheter maintenance and daily chlorhexidine sterilization.

Catheter-Related Blood Stream Infection

Catheter-related blood stream infection (CRBSI) is a clinical definition used by the IDSA and is often used interchangeably with the CDC surveillance term central line-associated bloodstream infection (CLABSI), which refers to a primary blood stream infection meeting at least one of the criteria for a laboratory-confirmed blood stream infection (LCBI) in a patient with a central catheter [56]. Criteria for the diagnosis of an LCBI include: patient has a recognized bacterial or fungal pathogen cultured from one or more blood cultures and the pathogen is not related to an infection at another site; patient has a common commensal organism in two or more blood cultures on different or from different sites that is not related to an infection at another site and that occurs in the setting of one of the following signs or symptoms: fever (38.0°C), chills or hypotension; and patients younger than one year of age has one of the following signs/symptoms: fever, hypothermia (<36.0°C), apnea or bradycardia. Alternate sources of infection must first be identified before making the diagnosis of a CRBSI [57].

A CRBSI should be suspected in patients with fever, chills, or hypotension when a catheter has been placed at least 48 hours prior to developing symptoms. In addition, erythema, pain, swelling, or purulence at the site of a catheter should raise caution. Two sets of peripheral blood cultures should be obtained, however, if this not feasible then one set may be drawn from the catheter. Culturing the tip or a segment of the intravascular catheter is no longer recommended [57].

Wound Infection

Burn wound infections occur in approximately 1%–6% of patients, with rates having decreased considerably since early excision was adopted. However, patients with more than 15%–20% TBSA burns remain at high risk [58,59]. Burn wounds can be colonized with gram-positive organisms in as early as 48 hours, and with gram-negative organisms in five to seven days [2]. Considerable differences still remain with the classification of burn wound infections, although most clinicians have categorized burn wound infections into the following: burn wound cellulitis, non-invasive infections, invasive infections, and burn surgical site infection (related to excised or grafted areas and donor sites) [58 –60]. Based on the presentation and clinical findings, the treatment for burn infections may include topical antimicrobial agents or systemic antimicrobial agents and in cases of invasive infection, may involve excision or surgical debridement.

Outcomes

Mortality rates for septic burn patients vary and range from 6%–63%, with higher rates reported in low-middle income countries (LMIC). Factors associated with higher mortality rates include MODS, higher TBSA burn, and the presence of inhalation injury [5,6,30,61]. Consistent with the prevalence of sepsis in comparison groups of trauma and general critically ill patients, burn patients with sepsis have the highest mortality rate.

Funding Information

The authors have no funding sources to disclose.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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