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Identification of predictors of early infection in acute burn patients
burns 39 (2013) 1355–1366
Available online at www.sciencedirect.com
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Identification of predictors of early infection in acute burn patients Laura Schultz a, Sandra A.N. Walker a,b,c,*, Marion Elligsen a, Scott E. Walker a,b, Andrew Simor c,d, Samira Mubareka c,d, Nick Daneman c,d a
Sunnybrook Health Sciences Centre, Department of Pharmacy, Canada University of Toronto, Leslie L. Dan Faculty of Pharmacy, Canada c Sunnybrook Health Sciences Centre, Department of Microbiology and Division of Infectious Diseases, Canada d University of Toronto, Faculty of Medicine, Canada b
article info
abstract
Article history:
Burn patients are at high risk for infections; however, common indicators of infection are
Accepted 10 April 2013
unreliable in this population and can lead to unnecessary use of antibiotics. The study objective was to determine if predictors of early infection in adult acute burn patients are
Keywords:
identified to provide clinicians with a practical tool to aid in the diagnosis of infection,
Acute burn injury
thereby minimizing unnecessary exposure to antimicrobials. A retrospective chart review of
Infection
all adult acute burn injury patients admitted over a 1 year period to the burn centre at
Predictors
Sunnybrook Health Sciences Centre was conducted. Early infection was defined as one that occurred within the first 10 days after injury and in accordance with American Burn Association guidelines. Those without infection were compared to patients with infection generally and also to patients with sepsis specifically. The period prevalence of early infection and sepsis in our patients was 50% (56/111) and 16% (18/111), respectively. It was determined that heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation were the best predictors of sepsis ( p < 0.05); and fraction of inhaled oxygen >25% and maximum temperature 39 8C were the best predictors of infection ( p < 0.05). This pilot project identified significant predictors of early infection and sepsis in acute burns and will be validated in a prospective study. # 2013 Elsevier Ltd and ISBI. All rights reserved.
1.
Introduction
Burn patients are at high risk for infection, including sepsis. After the development of effective therapy for fluid and electrolyte abnormalities caused by severe burns, infection and septicemia became the leading causes of mortality in burn patients [1]. Even though mortality related to infections has decreased significantly over the past 50 years, it is still an
important issue for burn patients. Currently, Multi Organ Dysfunction (MOD) is the major cause of mortality in acute burn injury patients. In about half of patients with MOD, infection is deemed responsible for the fatal clinical deterioration [2]. In patients with severe burns (>40% body surface area burns), 75% of all deaths are currently related to sepsis from the burn wound or other infectious complications and/or inhalation injury [3]. Sepsis prevalence in burn patients has been reported to range from 8 to 65% [4]. Common infections in
* Corresponding author at: Department of Pharmacy, E-302, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5. Tel.: +1 416 480 6756. E-mail address: [email protected] (Sandra A.N. Walker). 0305-4179/$36.00 # 2013 Elsevier Ltd and ISBI. All rights reserved. http://dx.doi.org/10.1016/j.burns.2013.04.009
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burn patients include pneumonia, catheter related infections, blood stream infections, burn wound infections and urinary tract infections [5]. Thermal injuries induce a state of immunosuppression and contribute to the risk of infection [3,6]. Besides the burn injury, there are other risk factors for infection that are commonly incurred during treatment. These risk factors include intubation, smoke inhalation injury and invasive indwelling devices such as urinary catheters or central lines [7]. The standard diagnostic criteria for infection and sepsis do not apply to acute burn injury patients as they have an elevated normal body temperature (reset to about 38.5 8C), tachycardia and tachypnea all of which can persist for months; along with significant changes in their white blood cell (WBC) count resulting from continuous exposure of healing skin to the environment [5]. Two recent studies in burned patients demonstrated that systemic inflammatory response syndrome (SIRS) criteria were not discriminatory in assisting to identify patients with true infection [8,9]. Mann-Salinas et al. [8] identified that >95% of critically ill burn injury patients met criteria for SIRS even when clinically stable; similarly Hogan et al. [9] found SIRS criteria not to be clinically discriminatory, since at least 2 criteria were satisfied in the majority of severe burn injury patients. Many patients receive empiric antibiotic therapy within their first week of burn because they are hemodynamically unstable and febrile with an elevated WBC. As many as 25% of patients without documented infection receive antibiotics during their admission [10]. Therefore, the identification of predictors of early infection in acute burn injury would allow for more effective clinical evaluation and use of antimicrobials in these patients. Some studies have been completed in an attempt to identify predictors of infection in burn patients. Mann-Salinas et al. found a multivariable model including heart rate >130 beats per minute, mean arterial pressure <60 mmHg, base deficit <6 mequiv./L, temperature <36 8C, use of vasoactive medications and glucose >150 mg/dl outperformed the ABA sepsis criteria [8]. Hogan et al. found that of the clinical criteria defined by the ABA sepsis criteria, only temperature and heart rate were found to correlate with bacteremia [9]. Gottschlich et al. determined that percent burn, percent third-degree burn, a1-acid glycoprotein, prealbumin, C reactive protein (CRP) and the Prognostic Inflammatory and Nutritional Index (PINI) score were variables that were associated with infection in burn patients [11]. Morath et al. showed deficits in serum albumin, serum transferrin, total lymphocyte count and skin test reactivity on post burn day 10 were predictive of an imminent septic episode [12]. Rodgers et al. concluded that type of burn, percent total body surface area (TBSA) involved and depth of injury were the highest risks for developing infections in pediatric patients [13]. Csontos et al. found that an overwhelming anti-inflammatory response after burn injury, reflected in marked elevation of IL-10 levels, was associated with a more frequent occurrence of sepsis and higher mortality rate [14]. Procalcitonin (PCT) levels have been proposed to be an inflammatory marker of sepsis in both adults and children with acute burn injury [15–18]. However the utility of PCT is limited by absence of validation in acute
burn injury, and lack of availability of rapid and inexpensive tests for clinical use. The laboratory at Sunnybrook Health Sciences Centre did not offer a PCT assay during the study period, and therefore, we were unable to assess this parameter. Elevated CRP has also been observed to be a potential biological marker of sepsis in burn patients [19]. Housinger et al. evaluated a pediatric burn population and found that death was caused by Multisystem Organ Failure and sepsis in all patients, and all developed a decline in platelet count to less than 0.1 1012/L, which preceded all other signs of sepsis [20]. Although these studies [8,9,11–20] have identified isolated markers of infection in acute burn injury, many of the parameters mentioned in these studies are not routinely measured in burn centres across Canada and no study has developed a practical predictive tool for clinicians to use that would assist in the diagnosis of infection or sepsis in acute burn injury patients. Therefore, the objective of this study was to determine if predictors of early infection in adult acute burn injury patients could be identified to provide clinicians with a practical tool to aid in the diagnosis of infection in acute burn injury and thereby, minimize unnecessary exposure to antimicrobials.
2.
Methods
2.1.
Location
This study was conducted at the Ross Tilley Burn Centre at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Sunnybrook Health Sciences Centre is a 1275 bed tertiary care teaching hospital in Toronto, with a total of 14 adult burn centre beds, the largest burn centre in Canada. This study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre on January 11 2011.
2.2.
Study design
A retrospective chart review of all acute burn patients admitted to the burn centre at Sunnybrook Health Sciences Centre between March 12th, 2010 and March 11th, 2011 was conducted. Patients were identified for eligibility for this study using the SPIRIT database of the Antimicrobial Stewardship Program Hospital [21], charts for the patients identified were obtained from Health Data Resources and reviewed. Patients were excluded if they were admitted more than 10 days following their burn injury, if the admission was for inhalation injury only, if a burn injury was not the reason for admission or if the injury was due to frostbite. Of 163 patients admitted to the burn centre during the study period, 111 patients were included in the final analysis (Fig. 1).
2.3.
Data collection
During the data collection periods, relevant data were extracted from the SPIRIT database and the patient’s chart and entered into a Microsoft Excel file. Patients were assessed for a true infection within the first 10 days of admission (early infection) if the patient was started on antibiotics (yes/no); and if yes, if they met the criteria for an infection diagnosis (based
burns 39 (2013) 1355–1366
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Fig. 1 – Inclusion and exclusion criteria.
on accepted criteria for different infectious diseases outlined by the American Burn Association [5]) (Appendix 1). Patients with confirmed, probable and possible pneumonia were considered to have pneumonia [5]. Patients who received no antibiotics and those who were only given antibiotics for surgical prophylaxis or for gastric motility were considered to have ‘‘no infection’’. Parameters that were obtained included: gender, age, weight, number of days in the burn centre prior to initiation of antibiotic therapy, number of days from burn to initiation of antibiotic therapy, type of burn, percent total body surface area burned (% partial thickness/% full thickness), inhalational injury (yes/no, grade of inhalational injury), burn excision (yes/no and number of days from burn injury to excision), allograft (yes/no), autograft (yes/no), use of topical antimicrobials (yes/no, agent), chest X-ray results (normal/abnormal). At Sunnybrook Health Sciences Centre, grade of inhalational injury is determined from findings at initial bronchoscopy and is based on the Abbreviated Injury Score criteria [22]. The following parameters were determined from admission to day 10 of burn centre stay for patients not treated with antibiotics; and from 72 h before the day of initiation of antibiotic therapy
consecutively to day 7 of antibiotic therapy for those patients who were treated with antibiotics: lowest blood pressure, highest heart rate, highest respiratory rate, fraction of inspired oxygen (FiO2), minute ventilation, highest ventilation mode, ventilator days, vasopressor use (yes/no), highest temperature (TMax), lowest temperature (TMin), total white blood cell count, neutrophil count, platelets, C-reactive protein, lactate, blood urea nitrogen, serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, international normalized ratio (INR), serum glucose, prothrombin time, activated partial thromboplastin time, cultures (source and organism) and burn centre survival (yes/no and cause of death).
2.4.
Sample size calculation
This study included all patients admitted to the burn unit at Sunnybrook hospital during a one year time period. Agreement in the literature is lacking regarding how many patients are needed per variable analyzed when doing factor analysis. Anywhere from 2:1 to 10:1 patients per variable has been proposed [23–27]. One hundred and eleven patients
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Table 1A – All patients: patient characteristics (N = 111).
were included in the study, with an infection rate of 50%, which is likely to be able to identify 5 variables (at a ratio of 10:1), but possibly as many as 25 variables (at a ratio of 2:1).
Parameter
Mean (SD) (Range) (% of patients)
2.5.
Sex (male) Age (years)
80 (72%) 46 (20) (15–92) 5 (4.50%) 80 (18) (45–140)
Statistics
The mean time to initiation of antibiotics after acute burn in patients with early infection was determined to be 4 days (standard deviation – 2.5 days; median – 3 days) and this was used to derive a baseline time comparator in non-infected patients. Parameters obtained in non-infected patients from day 4 of their burn were compared to parameters obtained in infected patients and the septic sub-group of patients on the day of antibiotic start using a two-tailed unpaired t-test for interval data and Fisher’s exact along with an odds ratio for nominal data. Parameters with a p-value of <0.05 following univariate analysis were analyzed by multiple binary logistic regression (SPSS1) and the model having the lowest significant p-value ( p < 0.05) with the greatest number of variables was selected as the best model for predicting infection and sepsis. CART analysis was used to determine breakpoints for variables found significant via multiple regression (CART1 Professional Extended Edition, Salford Systems Salford Predictive Modeling Suite1). Sensitivity and specificity analysis was conducted on the best model for infection and sepsis.
Mortality Weight (kg) Type of burn Thermal Electrical Partial thickness burn (%) Full thickness burn (%) Total body surface area burned Inhalation injury Grade of inhalation injurya Grade 1 Grade 2 Grade 3 Intubation Length of intubation (days) Patients with confirmed infection Septic patients
103 (93%) 8 (7%) 8% (9%) (0–52%) 6% (14%) (0–99%) 13% (15%) (0–99%) 24 (22%) 16 (70%) 5 (22%) 2 (9%) 48 (43%) 9 (15) (0–89) 56 (50%b) 18 (16%b overall and 32% of infected patients)
a
3.
Results
One hundred and sixty-three patients were admitted to the burn centre during the study period. Fifty-two patients were excluded (Fig. 1) and 111 patients were included in the study. Fifty-six patients (50%) were identified as having an infection and 18 patients (16% of patients overall and 31% of infected patients) had sepsis within the first 10 days of admission over the 1 year study period (period prevalence of early infection = 50%; period prevalence of early sepsis = 16%). Sixty-two of 111 patients (56%) had 10% TBSA burned and 98/111 (88%) had 30% TBSA burned (Fig. 2). Patient demographics and clinical characteristics are summarized in Tables 1A–1C. Types of infection and causes of sepsis are summarized in Table 2.
1 patient had inhalation injury but no grade of inhalation injury was assigned. b Period prevalence (period prevalence = # acute burn injury patients with infection during 1 year study period/# acute burn injury patients [30]).
When comparing patients with infection to those without infection the parameters that were significant ( p < 0.05) following univariate analysis were sex, % partial thickness burn, intubation, TMax and FiO2. The parameters that continued to be significant after multiple binary logistic regression were FiO2 and TMax ( p < 0.05). The CART determined break points for these parameters were FiO2 > 25% and TMax 39 8C. When both parameters were satisfied the tool has a positive predictive value (PPV), positive post-test probability and specificity of 100% (Table 3). However the negative predictive
Fig. 2 – Histogram of total body surface area (TBSA) burned in all patients.
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Table 1B – Infectiona versus no infection day 4 post burn (N = 101). Parameter
Infectionb
No infectionb
Number of patients Sex (male) Age (years)
56 (55%) 37 (66%) 46 (20) (18–92) 2 (4%) 82 (20) (45–140)
45 (45%) 38 (84.4%) 45 (20) (16–84) 3 (7%) 76 (13) (52–100)
53 (95%) 3 (5%) 10 (11) (0–52) 7 (12) (0–75) 16 (15) (0.25–75) 14 (25%) N = 13 7 (54%) 4 (31%) 2 (15%) 25 (45%) 13 (19) (0–89) 109 (18) (69–150) 57 (13) (35–90) 107 (22) (70–160) 19 (3) (16–29) 11 (3) (6–22) 38.1 (0.9) (36.7–40.5) 36.8 (1.1) (31.5–38.3) 0.40 (0.20) (0.20–1.00) 5 (9%) 1.2 (0.2) (0.9–1.7) 34.7 (8.4) (24.0–65.5) 56 (19) (35–107) 27 (32) (7–148) 44 (50) (12–202) 17 (20) (4–85) 5.1 (3.0) (1.3–15.1) 88 (117) (27–608) 189 (77) (36–317) 7.1 (3.1) (1.1–13.0) 7.9 (2.4) (4.6–14.6) 1.7 (1.2) (0.7–5.9)
Mortality Weight (kg) Type of burn Thermal Electrical % Partial thickness burn % Full thickness burn Total body surface area burned (%) Inhalation injury Grade of inhalation injury Grade 1 Grade 2 Grade 3 Intubation on day of ABX start or day 4 post burn Length of intubation (days) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per minute) Respiratory rate (breaths per minute) Minute ventilation (L/min) TMax (8C) TMin (8C) FiO2 Pressors Prothrombin time (INR) aPTT (s) ALP (IU/L) ALT (IU/L) AST (IU/L) Bilirubin (mmol/L) BUN (mmol/L) Creatinine (mmol/L) CRP (mg/L) Neutrophils (109) Blood glucose (mmol/L) Lactate (mmol/L)
p-value
OR
95% CI for OR
0.042 0.840
0.4
0.2–0.6
0.653 0.235
0.5
0.1–2.9
40 (89%) 5 (11%) 6 (5) (0–27) 5 (17) (0–99) 10 (16) (0–99) 7 (16%) N=7 6 (86%) 1 (14%) 0 (0%) 1 (2%) 2 (3) (0–11) 116(15) (88–150) 60 (10) (34–80) 91 (17) (64–129) 19 (3) (14–26) N/A*
0.461
2.2 0.4
0.7–6.8 0.1–1.4
1.8
1.1–3.0
37.4 (0.6) (36.4–38.7) 36.8 (0.5) (36.0–37.8) 0.23 (0.05) (0.21–0.45) 1 (3%) 1.1 (0.1) (0.9–1.4) 31.9 (6.5) (26.4–47.2) N/A
<0.001
0.034 0.638 0.083 0.327 0.328 0.613 0.521 <0.001 0.037
0.01–3.5 0.1–53.3 – 4.1–303.5
4.3
0.4–49.2
0.075 0.306 <0.001 0.285 N/A
0.831 0.002 0.660 0.136 0.339 N/A
N/A
N/A
N/A
N/A
N/A
N/A
4.9 (3.4) (1.4–12.9) 72 (22) (42–122) N/A
0.797
5.7 (2.5) (2.5–10.2) 8.1 (2.6) (5.5–13.6) 1.4 (0.1) (1.3–1.4)
0.2 2.7 – 35
0.658 N/A 0.150 0.814 0.659
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Table 1B (Continued ) Parameter 9
Platelets (10 ) Albumin (g/L) WBC (109) a b
Infectionb
No infectionb
p-value
185 (93) (12–567) N/A 10.8 (4.0) (4.2–20.3)
181(101) (53–378) N/A 8.3(3.2) (4.0–14.7)
0.891
95% CI for OR
N/A 0.053
Includes patients with sepsis. N/A = Not enough data available. Mean (SD) (Range).
value (NPV), accuracy and sensitivity are all less than 50% and the negative post-test probability is 61% (complement of NPV). When comparing patients with sepsis to those without infection the parameters that were significant ( p < 0.05) following univariate analysis were % partial thickness burn, % total body surface area burned, inhalation injury, intubation, systolic blood pressure (SBP), heart rate (HR), TMax, FiO2, vasopressor use and INR. The parameters that continued to be significant after multiple binary logistic regression were HR, SBP and intubation ( p < 0.05). The CART determined break these parameters were: HR 110 bpm, points for SBP 100 mmHg and intubation. When all three parameters were met, similar to the infection tool, there was a specificity, positive post-test probability and PPV of 100% (Table 4). The NPV, sensitivity, accuracy and negative post-test probability (complement of NPV) were 81%, 61%, 85% and 19%, respectively. To remove the influence of prevalence of infection, we determined likelihood ratios (LR) for a patient having infection or sepsis when the tool parameters were positive (LR+) and negative (LR). The LR+ for both infection and sepsis were infinite. Thus, using Baye’s nomogram [28,29] the post-test probability of having an infection or sepsis when the tool results are positive (PPTP) is 100%. The LR for infection and sepsis from the tools was 0.82 and 0.39, respectively, which corresponds to a negative post-test probability (NPTP) of having an infection or sepsis, respectively, of 46% and 19%, using Baye’s nomogram [28,29]. Therefore, our tool is no better than a coin toss at ruling out infection. However, our tool is more useful at ruling out sepsis, with a NPTP of sepsis of 19% when the results of the tool for sepsis are negative.
4.
OR
Discussion
Burn patients are at high risk for infection but common indicators of infection are unreliable in this population. Many patients receive empiric antibiotics within the first week after burn injury but there may be no documented infection. The objective of this study was to determine if predictors of early infection in adult acute burn injury patients could be identified in order to provide clinicians with a practical predictive tool to aid in the diagnosis of infection in acute burn injury and thereby, minimize unnecessary exposure to antimicrobials. The parameters for the tool to assess infection include fraction of inhaled oxygen >25% and maximum temperature 39 8C. This tool has a specificity, positive post-test probability and PPV of 100% and thus, effectively identifies true positive,
true negative and false positive patients. Therefore, if all parameters in this tool are satisfied, antibiotic treatment is indicated. However, the tool for infection had a low sensitivity, negative predictive value and accuracy; all less than 50%, a LR of 0.82 and a negative post-test probability of 61% (determined as the complement of NPV) or 46% (determined from Baye’s nomogram using LR of 0.82). Therefore, the infection tool cannot be used to rule out infection (risk of false negative). Although our study included a broad distribution of infection sources, including pneumonia, bacteremia and urinary tract infection, fifty-six percent of patients with infection had a burn wound infection (Table 2). Since the diagnosis of a burn wound infection does not rely on systemic signs of infection, inclusion of these patients in our study may have affected our ability to discover systemic predictors of infection and may have affected the sensitivity, accuracy, negative predictive value, and negative post-test probability of the infection tool. Prospective evaluation of the infection tool with a larger sample size of infected patients, where burn wound infection patients are excluded, is necessary to evaluate and validate the tool for infection. Our tool is meant to complement diagnostic criteria used for infection in acute burn injury, such as the American Burn Association criteria [5]. However the American Burn Association Guidelines are based on consensus and not founded on prospective clinical studies [18]. The American Burn Association guidelines use a temperature of >39 8C as a parameter for diagnosis of pneumonia, blood stream infection and cellulitis [5]. The CART identified breakpoint determined in our study provides data to support the recommendations given by the American Burn Association. Conversely, while our study identified intubation as a parameter; this was not a parameter listed to assist in the diagnosis of any infection using the American Burn Association criteria [5]. The tool for sepsis includes a heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation. Similar to the tool for infection, this tool has a specificity, positive post-test probability and PPV of 100% and thus, effectively identifies true positive, true negative and false positive patients, indicating antibiotic treatment is warranted if all parameters are met. The tool for sepsis may be useful as an initial screening tool in patients with a presumed diagnosis of sepsis, since it identifies 81% of patients who truly do not have sepsis, corresponding to a negative post-test probability of 19% (determined as the complement of NPV or determined from Baye’s nomogram using LR of 0.39). Therefore, although the sepsis tool cannot be used to rule out sepsis, it can be used as an initial screening tool for sepsis.
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Table 1C – Septic versus no infection day 4 post burn (N = 63). Parameter Number of patients Sex (male) Age (years) Mortality Weight (kg) Type of burn Thermal Electrical % Partial thickness burn % Full thickness burn Total body surface area burned (%) Inhalation injury Grade of inhalation injury Grade 1 Grade 2 Grade 3 Intubation on day of ABX start or day 4 post burn Length of intubation (days) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per minute) Respiratory rate (breaths per minute) Minute ventilation (L/min) TMax (8C) TMin (8C) FiO2 Pressors Prothrombin time (INR) aPTT (s) ALP (IU/L) ALT (IU/L) AST (IU/L) Bilirubin (mmol/L) BUN (mmol/L) Creatinine (mmol/L) CRP (mg/L) Neutrophils (109) Blood glucose (mmol/L) Lactate (mmol/L)
Sepsisa
No infectiona
p-value
18 (29%) 11 (61%) 54 (23) (18–92) 2 (11%) 81 (11) (60–101)
45 (71%) 38 (84%) 45 (20) (16–84) 3 (7%) 76 (13) (52–100)
18 (100%) 0 (0%) 13 (16) (0–52) 13 (19) (0–75) 26 (20) (5–75) 9 (50%) N=8 3 (37%) 3 (37%) 2 (25%) 16 (89%) 19 (23) (0–89) 99 (18) (69–140) 50 (9) (35–68) 122 (18) (80–160) 21 (5) (17–24) 13 (3) (8–22) 38.7 (0.9) (37.4–40.1) 36.6 (1.7) (31.5–38.3) 0.56 (0.30) (0.21–1.00) 5 (28%) 1.3 (0.2) (1.0–1.7) 38.2 (10.9) (26.1–65.5) 44 (6) (38–52) 21 (18) (7–50) 43 (50) (18–132) 19 (20) (4–54) 5.9 (3.8) (2.5–15.1) 118 (177) (27–608) 190 (84) (36–317) 5.5 (3.4) (1.1–11.5) 8.7 (2.1) (5.3–14.6) 1.8 (0.6) (1.2–2.8)
40 (89%) 5 (11%) 6 (5) (0–27) 5 (17) (0–99) 10 (16) (0–99) 7 (16%) N=7 6 (86%) 1 (14%) 0 (0%) 1 (2%) 2 (3) (0–11) 116 (15) (88–150) 60 (10) (34–80) 91 (17) (64–129) 19 (3) (14–26) N/A
0.310
37.4 (0.6) (36.4–38.7) 36.8 (0.5) (36.0–37.8) 0.23 (0.05) (0.21–0.45) 1 (3%) 1.1 (0.1) (0.9–1.4) 31.9 (6.5) (26.4–47.2) N/A
<0.001
95% CI for OR
0.089 0.152
0.3
0.1–0.6
0.618 0.291
1.7
0.3–10.6
1 0
1 Undefined
0.008 0.118 0.002 0.001 0.119 0.569 0.467 <0.001 0.010
5.4 0.1 3.6 – 352
2.5–11.7 0.0–2.8 0.1–101.0 – 15.7–7869.0
0.001 <0.001 <0.001 0.434 N/A
0.556 <0.001 0.020 0.028 0.119 N/A
N/A
N/A
N/A
N/A
N/A
N/A
4.9 (3.4) (1.4–12.9) 72 (22) (42–122) N/A
0.467
5.7 (2.5) (2.5–10.2) 8.1 (2.6) (5.5–13.6) 1.3 (0.1) (1.3–1.4)
OR
0.406 N/A 0.925 0.488 0.286
17
1.3–216.1
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Table 1C (Continued ) Sepsisa
Parameter 9
Platelets (10 )
155 (77) (58–335) N/A 10.3 (5.6) (4.2–20.3)
Albumin (g/L) WBC (109)
No infectiona
p-value
181 (101) (53–378) N/A 8.3 (3.2) (4.0–14.7)
0.444
OR
95% CI for OR
N/A 0.267
N/A = not enough data available. Mean (SD) (range).
a
Table 2 – Types of infection. Infection
Parameter Number of patients Number of infectionsb Burn wound infection Pneumonia Cellulitis Blood stream infection Cholecystitis Mixed infectionc Pneumonia Cellulitis UTI Burn wound infection Gastrointestinal
56 61 34 11 4 4 1 7 6 4 2 1 1
(56%) (18%) (7%) (7%) (2%) (11%)
Sepsisa 18 22 2 8 4 3 0 5 5 4 1 0 0
(9%) (36%) (18%) (14%) (0%) (23%)
a
All septic patients are included in information for patients with infection. b Some patients had more than 1 distinct infection during the first 10 days of admission. c Infections were classified as being mixed if there were two potential sources of infection concurrently.
Our findings provide evidence to support the consensus derived recommendations [18] of the American Burn Association guidelines for use of a heart rate greater than 110 bpm in the diagnosis of sepsis [5]. While blood pressure is not included in the diagnosis of sepsis in acute burn injury, it is included in the diagnosis of septic shock according to the American Burn
Association [5]. However, the consensus derived American Burn Association criteria for septic shock is a systolic blood pressure of less than 90 mmHg, while the breakpoint identified in our study was <100 mmHg. Intubation is not included in the American Burn Association guidelines [5] for the diagnosis of sepsis in acute burn injury patients and was identified as a significant parameter in the predictive tool for sepsis in our study. Prospective evaluation with a larger sample size is necessary to evaluate and validate the tool for sepsis. Mann-Salinas et al. found a multivariable model including heart rate >130 beats per minute, mean arterial pressure <60 mmHg, base deficit <6 mequiv./L, temperature <36 8C, use of vasoactive medications and glucose >150 mg/dl outperformed the ABA sepsis criteria [8]. Like Mann-Salinas et al., we also identified low blood pressure and high heart rate as predictors of sepsis. Intubation was identified as an additional risk factor in our study. However, our study was completed for early infection in acute burn injury patients, whereas the study by Mann-Salinas et al. was completed over the entire length of hospital admission and included sicker patients (mean hospital day = 102, mean ICU day = 81, mean TBSA = 49%) [8]. This may account for some of the differences in predictors identified. Hogan et al. showed that out of the ABA criteria for sepsis only temperature and heart rate correlated with bacteremia [9]. This is similar to our findings as heart rate and temperature were the only criteria for sepsis that were identified as significant for inclusion in our tools for either infection or sepsis.
Table 3 – Infection vs. no infection (using CART analysis determined break points).
Gold Standard (ABA criteria for Infection) N= 85 FiO2 >25% and TMax ≥39˚C
Infection
No Infection
patients Infection
TP = 10
FP = 0
No Infection
FN = 46
TN = 29
£
Sensitivity = 18% PP = 66%
Specificity = 100% LR+ = ∞* LR- =0.82
PPV = 100% PPTP= 100% NPV= 39%
NPTP =46%¥
Accuracy = 46%
Acronyms: positive post test probability = PPTP, negative post-test probability = NPTP, pretest probability (prevalence) = PP, likelihood ratio positive test = LR+, likelihood ratio negative test = LRS. £ 26 patients not included because data not available or patient did not completely meet American Burn Association Guidelines for infection. ¥ Baye’s nomogram determined negative post test probability. * Since specificity is 100%.
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Table 4 – Sepsis vs. no infection (using CART analysis determined break points).
Gold Standard (ABA criteria for Sepsis)
HR ≥ 110, Systolic BP <100 and Intubated
N=48 patients£ Infection
Sepsis
No Infection
TP =11
FP =0
PPV = 100%
PPTP = 100%
No Infection
FN =7
TN =30
NPV= 81%
NPTP = 19%¥
Sensitivity = 61% PP = 37%
Specificity = 100%
Accuracy = 85%
LR+ = ∞* LR- =0.39
Acronyms: positive post test probability = PPTP, negative post-test probability = NPTP, pretest probability (prevalence) = PP, Likelihood ratio positive test = LR+, Likelihood ratio negative test = LRS. £ 18 patients not included because data not available or patient did not completely meet American Burn Association Guidelines for sepsis. ¥ Baye’s Nomogram determined negative post test probability. * Since specificity is 100%.
This study has several limitations because of the retrospective study design. For many of the lab parameters that were included in the analysis, lab samples were not taken often enough to ensure a robust number of data points to assess some specific parameters (risk of type II error). It was difficult to obtain a complete complement of data in all patients to definitively diagnose infection for each patient, since charted information was relied upon as the sole source of information. In particular, it was difficult to assess infections such as cellulitis and burn wound infection, as these diagnoses rely heavily on the physical examination of the patient. Patients were characterized as having cellulitis if the physician described it as ‘‘red’’, ‘‘cellulitic’’, ‘‘painful’’ or ‘‘erythemic’’. One of the diagnostic criteria for sepsis according to the ABA guidelines is inability to continue enteral feedings >24 h [5]. Although we looked for chart documentation to identify this parameter, it was not identified in any patient charts. Our inability to identify and therefore, include, this parameter in the evaluation of sepsis is an unfortunate consequence of the retrospective study design. Our study assessed predictors of early infection in acute burn injury patients, defined as patients admitted to our burn centre within 10 days of burn injury and diagnosed with infection within 10 days of burn centre admission. This patient population was selected because of the difficulty that exists in diagnosing infection in acute burn injury. However, as a result, the applicability of our tool to assess infection and sepsis in more chronic burn injury patients is unknown, and requires investigation. Finally, over 50% of our patients had 10% TBSA burns and 88% had 30% TBSA burns, necessitating caution in using the tool for patients with more extensive burn injury and requiring further evaluation in patients with a higher TBSA burned. The one year period prevalence of early infection in our acute burn injury patients was 50% and sepsis was 16%. Robust published data on the overall incidence and prevalence of infection and sepsis in acute burn injury patients is lacking, which makes it difficult to determine whether our acute burn injury patients are reflective of those seen in other centres. However, a recent systematic review reported a prevalence of
sepsis in burn patients ranging between 8 and 65% [4], which broadly includes our observed period prevalence of 16%. If the prevalence of infection or sepsis in other burn centres is lower, then the PPV observed in our study would be predicted to decrease and the NPV would be predicted to increase, since both parameters are dependent on the prevalence of the condition in question. Therefore, clinicians would need to know the prevalence of infection in their burn centres to determine the utility of the predictive tools identified in this study to their patient population if just PPV and NPV were reported. To overcome this limitation, we determined the likelihood ratios for infection and sepsis with both positive and negative results from the tools, since likelihood ratios are not affected by prevalence of a condition, and then determined the post-test probability using the likelihood ratios and Baye’s nomogram [28,29]. From this analysis, both tools had a post-test probability of infection of 100% when the parameters of the tools were positive, and thus, antimicrobials would be indicated if all parameters were satisfied in either the infection or sepsis tools. However, our tool is not as useful in ruling out infection (LR of 0.82 and 0.39 with a NPTP of infection or sepsis, respectively, of 46% and 19%) and clinical acumen is essential to evaluate any potential parameters of infection as a constellation before discontinuing antimicrobials. Since this is a retrospective study we have little control over potential confounders. This patient population is very complex and there is a wide range of variability among patients. Although this study has many limitations by virtue of its retrospective design, it developed a clinically practical predictive tool for the diagnosis of early infection or sepsis in acute burn injury patients, which may assist in limiting inappropriate antibiotic use. Our study proposes data based breakpoints for early infection in acute burn injury patients for blood pressure, heart rate, FiO2 and fever for infection and sepsis and provides one year period prevalence data for early infection and sepsis in an adult burn centre. This was a pilot project that identified two tools by retrospective analysis that will need evaluation and validation with a prospective study design which includes patients with extensive burn injury (>30% TBSA burns).
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Conclusion
We identified two simple tools that may assist clinicians in diagnosing true infection and sepsis in acute burn injury patients and thereby, limit inappropriate antibiotic use. The parameters for the tool to assess infection include fraction of inhaled oxygen >25% and maximum temperature 39 8C. The tool for sepsis includes a heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation. These tools will be validated in a prospective study.
contaminant, i.e., diphtheroids, Bacillus species, Propionibacterium species, coagulase-negative Staphylococci, or micrococci) cultured from two or more blood cultures, or one positive blood culture, in the presence of sepsis (as defined above). 2. Patient has a common skin contaminant cultured from two or more blood cultures drawn on separate occasions (including one drawn by venipuncture) and the patient has clinical signs of sepsis.
A.3. Catheter-Related Infection
Appendix 1. Definition for common infections in burn patients A.1. Pneumonia Diagnosis of Pneumonia [5]: I. The clinical diagnosis of pneumonia includes two of the following: A. Chest X-ray revealing a new and persistent infiltrate, consolidation, or cavitation. B. Sepsis (see A.6.). C. A recent change in sputum or purulence in the sputum. II. It also must be remembered that there are diagnoses that may mimic pneumonia (Acute Respiratory Distress Syndrome, tracheobronchitis, chest contusion). III. Microbiologic Data: the clinical diagnosis can be modified post hoc with the microbiologic data into one of three categories A. Confirmed: clinical + pathogen isolated. B. Probable: clinically present without microbiological confirmation. C. Possible: abnormal chest X-ray with uncertain cause with low or moderate clinical suspicion, but with microbiologic definite criteria met or pathogen identified. IV. Positive Microbiology A. Tracheal aspirate: 105 organisms. B. Bronchoalveolar lavage (BAL): 105 organisms (Blind is OK). C. Protected bronchial brush (PBB): 103 organisms (Blind brush is OK). D. We recognize that there are other criteria for special organisms that we may not include in the diagnosis. E. (The burn wound can be a source of the pathogens spread hematogenously).
A.2. Blood Stream Infection Diagnosis of Blood Stream Infection [5]: One of two criteria must be met for a blood stream infection (BSI) 1. Patient has a recognized pathogen (defined as a microorganism not usually regarded as a common skin
Diagnosis of Catheter Related Infection [5]: Any bacteremia or fungemia in a patient with an intravascular catheter with the microbial growth from at least one blood culture obtained from a vein or artery separate from the catheter site, clinical signs of infection (as noted elsewhere), and no other documented source of the infection or one of the following: 1. Any bacteremia or fungemia in a patient with an intravascular catheter with greater than 15 colony forming units (>15 cfu) per catheter segment on semiquantitative culture analysis or greater than 103 colony-forming units (>103 cfu) per catheter segment on quantitative culture analysis, with the same organism (species and antimicrobial sensitivity) isolated from a blood culture from a separate vein or arterial sample is a central venous catheter infection (CVCI). 2. Simultaneous quantitative blood cultures drawn from both the central venous catheter and a separate venous or arterial site with a greater than 5:1 catheter vs. other site ratio is a CVCI. 3. If a differential period of culture growth occurs with catheter blood growing pathogenic organisms more than 2 h before a separate site, then a CVCI is present.
A.4. Burn Wound Infection Diagnosis of Wound Infection [5]: I. Objective A. Quantitative biopsy (can be used to confirm but is not reliable. It may help with identifying the organism), B. Quantitative swab (poor test but may help with identifying organism), C. Tissue histology, D. Superficial culture. II. Subjective A. Pain, erythema, color changes, B. Unexpected change in the appearance or depth of the wound, C. Systemic changes, D. Premature separation of burn eschar. In order to be the most inclusive, the patient will be diagnosed with burn wound infection in they have one objective or one subjective criteria.
burns 39 (2013) 1355–1366
Diagnosis of Cellulitis: Bacteria present in the wound and/or wound eschar at high concentrations. Examination of surrounding tissue reveals advancing erythema, induration, warmth, tenderness. Sepsis must be present.
A.5. Urosepsis Diagnosis of urosepsis [5] (Modified CDC criteria): 1. One of the following: fever (>39.5 8C and no other source of the fever), urgency, frequency, dysuria or suprapubic tenderness, and a urine culture 105 cfu/ml (cfu = colony forming units) with no more than two species of organisms or 2. Two of the following: fever (>39.5 8C), urgency, frequency, dysuria or suprapubic tenderness, and any of the following: a. positive dipstick for leukocyte esterase and/or nitrate b. pyuria (10 WBC/ml or 3 WBC/high-power field of unspun urine) c. organisms seen on Gram stain of unspun urine d. two urine cultures with repeated isolation of the same uropathogen with 102 cfu/ml in a nonvoided specimen e. two urine cultures with 105 cfu/ml of single uropathogens in a patient being treated with appropriate antimicrobial therapy.
A.6. Sepsis Sepsis is a change in the burn patient that triggers the concern for infection. It is a presumptive diagnosis where antibiotics are usually started and a search for a cause of infection should be initiated. While there is need for clinical interpretation, the diagnosis needs to be tied to the discovery of an infection (defined below). The trigger includes at least three of the following: 1.) Temperature >398 or <36.5 8C, 2.) Progressive tachycardia >110 bpm, 3.) Progressive tachypnea >25 bpm not ventilated (minute ventilation >12 L/min ventilated), 4.) Thrombocytopenia (will not apply until 3 days after initial resuscitation) <100,000/mcl, 5.) Hyperglycemia (in the absence of pre-existing diabetes mellitus) Untreated plasma glucose >200 mg/dl or equivalent mM/L or Insulin resistance—examples include >7 units of insulin/hr intravenous drip (adults) or significant resistance to insulin >25% increase in insulin requirements over 24 h), 6.) Inability to continue enteral feedings >24 h. A. Abdominal distension, B. Enteral feeding intolerance, C. Uncontrollable diarrhea (>2500 ml/d). In addition, it is required that a documented infection (defined below) is identified
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A. Culture positive infection, or B. Pathologic tissue source identified, or C. Clinical response to antimicrobials.
references
[1] Lindberg R, Moncrief J, Switzer W, Order S, Mills W. The successful control of burn wound sepsis. J Trauma 1965;5(5):601–16. [2] Bloemsma G, Dokter J, Boxma H, Oen I. Mortality and causes of death in a burn centre. Burns 2008;34:1103–7. [3] Church D, Elsayed S, Reid O, Winston B, Lindsay R. Burn wound infections. Clin Microbiol Rev 2006;19(April (2)): 403–34. [4] Mann E, Baun M, Meininger J, Wade C. Comparison of mortality associated with sepsis in the burn, trauma and general intensive care unit patient: a systematic review of the literature. Shock 2012;37(1):4–16. [5] Greenhalgh DG, Saffle JR, Holmes 4th JH, Gamelli RL, Palmieri TL, Horton JW, et al. American Burn Association consensus conference to define sepsis and infection in burns. J Burn Care Res 2007;28:776–90. [6] Mayhall G. The epidemiology of burn wound infections: then and now. Clin Infect Dis 2003;15(August (37)):543–50. [7] Weber J, McManus A. Infection control in burn patients. Burns 2004;30:A16–24. [8] Mann-Salinas EA, Baun MM, Meininger JC, Murray CK, Aden JK, Wolf SE, et al. Novel predictors of sepsis outperform the American Burn Association sepsis criteria in the burn intensive care unit patient. J Burn Care Res 2013;34:31–43. [9] Hogan BK, Wolf SE, Hospenthal DR, D’Avignon LC, Chung KK, Yun HC, et al. Correlation of American Burn Association sepsis criteria with the presence of bacteremia in burned patients admitted to the intensive care unit. J Burn Care Res 2012;33:371–8. [10] Appelgren P, Bjornhagen V, Bragderyd K, Jonsson C, Ransjo U. A prospective study of infections in burn patients. Burns 2002;28:39–46. [11] Gottschlich M, Baumer T, Jenkins M, Khoury J, Warden G. The prognostic value of nutritional and inflammatory indices in patients with burns. J Burn Care Rehabil 1992;13(January/February (1)):105–13. [12] Morath M, Miller S, Finley R. Nutritional indicators of postburn sepsis. J Parenter Enteral Nutr 1981;5(November/ December (6)):488–91. [13] Rodgers G, Mortensen J, Fisher M, Lo A, Cresswell A, Long S. Predictors of infectious complications after burn injuries in children. Pediatr Infect Dis J 2000;19(October (10)):990–5. [14] Csontos C, Foldi V, Palinkas L, Bogar L, Roth E, Weber G. Time course of pro and anti-inflammatory cytokine levels in patients with burns – prognostic value of interleukin-10. Burns 2010;36:483–94. [15] Neely A, Fowler L, Kagan R, Warden G. Procalcitonin in pediatric burn patients: an early indicator of sepsis? J Burn Care Rehabil 2004;25(1):76–80. [16] Lavrentieva A, Kontakiotis T, Lazaridis L, Tsotsolis N, Koumis J, Kyriazis G. Inflammatory markers in patients with severe burn injury – what is the best indicator of sepsis? Burns 2007;39:553–6. [17] Sachse C, Machens HG, Felmerer G, Berger A, Henkel E. Procalcitonin as a marker for the early diagnosis of severe infection after thermal injury. J Burn Care Rehabil 1999;20:354–60. [18] Mann E, Wood G, Wade C. Use of Procalcitonin for the detection of sepsis in the critically ill burn patient: a systematic review of the literature. Burns 2011;37:549–58.
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[19] Neely A, Smith W, Glenn D. Efficacy of a rise in C-reactive protein serum levels as an early indicator of sepsis. J Burn Care Rehabil 1998;19(2):102–5. [20] Housinger T, Brinkerhoff C, Warden G. The relationship between platelet count, sepsis and survival in pediatric burn patients. Arch Surg 1993;128(1):65–7. [21] Elligsen M, Walker S, Simor A, Daneman N. Prospective audit and feedback of antimicrobial stewardship in critical care: program implementation, experience, and challenges. Can J Hosp Pharm 2012;65(1):31–6. [22] Endorf F, Gamelli R. Inhalation injury, pulmonary perturbations, and fluid resuscitation. J Burn Care Res 2007;28:80–3. [23] Everitt S. Multivariate analysis: the need for data and other problems. Br J Psychiatry 1975;126:237–40.
[24] Nunnally J. Psychometric theory, 2nd ed., New York: McGraw-Hill; 1978. [25] Gorsuch R. Factor analysis, 2nd ed., Hillsdale, NJ: Erlbaum; 1983. [26] Velicer W, Fava J. Effects of variable and subject sampling on factor pattern recovery. Psychol Methods 1998;3:231–51. [27] Anderson T, Rubin H. Statistical inference in factor analysis. Berkeley: University of California Press; 1956. [28] Fagan T. Nomogram for Bayes theorem [letter]. N Engl J Med 1975;293(5):257. [29] Attia J. Moving beyond sensitivity and specificity: using likelihood ratios to help interpret diagnostic test. Aust Prescr 2003;26:111–3. [30] Streiner D, Norman G. Measurement (chapter 4) PDQ epidemiology, 2nd ed., Hamilton: BC Decker Inc.; 1998: 79–120.
Available online at www.sciencedirect.com
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Identification of predictors of early infection in acute burn patients Laura Schultz a, Sandra A.N. Walker a,b,c,*, Marion Elligsen a, Scott E. Walker a,b, Andrew Simor c,d, Samira Mubareka c,d, Nick Daneman c,d a
Sunnybrook Health Sciences Centre, Department of Pharmacy, Canada University of Toronto, Leslie L. Dan Faculty of Pharmacy, Canada c Sunnybrook Health Sciences Centre, Department of Microbiology and Division of Infectious Diseases, Canada d University of Toronto, Faculty of Medicine, Canada b
article info
abstract
Article history:
Burn patients are at high risk for infections; however, common indicators of infection are
Accepted 10 April 2013
unreliable in this population and can lead to unnecessary use of antibiotics. The study objective was to determine if predictors of early infection in adult acute burn patients are
Keywords:
identified to provide clinicians with a practical tool to aid in the diagnosis of infection,
Acute burn injury
thereby minimizing unnecessary exposure to antimicrobials. A retrospective chart review of
Infection
all adult acute burn injury patients admitted over a 1 year period to the burn centre at
Predictors
Sunnybrook Health Sciences Centre was conducted. Early infection was defined as one that occurred within the first 10 days after injury and in accordance with American Burn Association guidelines. Those without infection were compared to patients with infection generally and also to patients with sepsis specifically. The period prevalence of early infection and sepsis in our patients was 50% (56/111) and 16% (18/111), respectively. It was determined that heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation were the best predictors of sepsis ( p < 0.05); and fraction of inhaled oxygen >25% and maximum temperature 39 8C were the best predictors of infection ( p < 0.05). This pilot project identified significant predictors of early infection and sepsis in acute burns and will be validated in a prospective study. # 2013 Elsevier Ltd and ISBI. All rights reserved.
1.
Introduction
Burn patients are at high risk for infection, including sepsis. After the development of effective therapy for fluid and electrolyte abnormalities caused by severe burns, infection and septicemia became the leading causes of mortality in burn patients [1]. Even though mortality related to infections has decreased significantly over the past 50 years, it is still an
important issue for burn patients. Currently, Multi Organ Dysfunction (MOD) is the major cause of mortality in acute burn injury patients. In about half of patients with MOD, infection is deemed responsible for the fatal clinical deterioration [2]. In patients with severe burns (>40% body surface area burns), 75% of all deaths are currently related to sepsis from the burn wound or other infectious complications and/or inhalation injury [3]. Sepsis prevalence in burn patients has been reported to range from 8 to 65% [4]. Common infections in
* Corresponding author at: Department of Pharmacy, E-302, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5. Tel.: +1 416 480 6756. E-mail address: [email protected] (Sandra A.N. Walker). 0305-4179/$36.00 # 2013 Elsevier Ltd and ISBI. All rights reserved. http://dx.doi.org/10.1016/j.burns.2013.04.009
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burn patients include pneumonia, catheter related infections, blood stream infections, burn wound infections and urinary tract infections [5]. Thermal injuries induce a state of immunosuppression and contribute to the risk of infection [3,6]. Besides the burn injury, there are other risk factors for infection that are commonly incurred during treatment. These risk factors include intubation, smoke inhalation injury and invasive indwelling devices such as urinary catheters or central lines [7]. The standard diagnostic criteria for infection and sepsis do not apply to acute burn injury patients as they have an elevated normal body temperature (reset to about 38.5 8C), tachycardia and tachypnea all of which can persist for months; along with significant changes in their white blood cell (WBC) count resulting from continuous exposure of healing skin to the environment [5]. Two recent studies in burned patients demonstrated that systemic inflammatory response syndrome (SIRS) criteria were not discriminatory in assisting to identify patients with true infection [8,9]. Mann-Salinas et al. [8] identified that >95% of critically ill burn injury patients met criteria for SIRS even when clinically stable; similarly Hogan et al. [9] found SIRS criteria not to be clinically discriminatory, since at least 2 criteria were satisfied in the majority of severe burn injury patients. Many patients receive empiric antibiotic therapy within their first week of burn because they are hemodynamically unstable and febrile with an elevated WBC. As many as 25% of patients without documented infection receive antibiotics during their admission [10]. Therefore, the identification of predictors of early infection in acute burn injury would allow for more effective clinical evaluation and use of antimicrobials in these patients. Some studies have been completed in an attempt to identify predictors of infection in burn patients. Mann-Salinas et al. found a multivariable model including heart rate >130 beats per minute, mean arterial pressure <60 mmHg, base deficit <6 mequiv./L, temperature <36 8C, use of vasoactive medications and glucose >150 mg/dl outperformed the ABA sepsis criteria [8]. Hogan et al. found that of the clinical criteria defined by the ABA sepsis criteria, only temperature and heart rate were found to correlate with bacteremia [9]. Gottschlich et al. determined that percent burn, percent third-degree burn, a1-acid glycoprotein, prealbumin, C reactive protein (CRP) and the Prognostic Inflammatory and Nutritional Index (PINI) score were variables that were associated with infection in burn patients [11]. Morath et al. showed deficits in serum albumin, serum transferrin, total lymphocyte count and skin test reactivity on post burn day 10 were predictive of an imminent septic episode [12]. Rodgers et al. concluded that type of burn, percent total body surface area (TBSA) involved and depth of injury were the highest risks for developing infections in pediatric patients [13]. Csontos et al. found that an overwhelming anti-inflammatory response after burn injury, reflected in marked elevation of IL-10 levels, was associated with a more frequent occurrence of sepsis and higher mortality rate [14]. Procalcitonin (PCT) levels have been proposed to be an inflammatory marker of sepsis in both adults and children with acute burn injury [15–18]. However the utility of PCT is limited by absence of validation in acute
burn injury, and lack of availability of rapid and inexpensive tests for clinical use. The laboratory at Sunnybrook Health Sciences Centre did not offer a PCT assay during the study period, and therefore, we were unable to assess this parameter. Elevated CRP has also been observed to be a potential biological marker of sepsis in burn patients [19]. Housinger et al. evaluated a pediatric burn population and found that death was caused by Multisystem Organ Failure and sepsis in all patients, and all developed a decline in platelet count to less than 0.1 1012/L, which preceded all other signs of sepsis [20]. Although these studies [8,9,11–20] have identified isolated markers of infection in acute burn injury, many of the parameters mentioned in these studies are not routinely measured in burn centres across Canada and no study has developed a practical predictive tool for clinicians to use that would assist in the diagnosis of infection or sepsis in acute burn injury patients. Therefore, the objective of this study was to determine if predictors of early infection in adult acute burn injury patients could be identified to provide clinicians with a practical tool to aid in the diagnosis of infection in acute burn injury and thereby, minimize unnecessary exposure to antimicrobials.
2.
Methods
2.1.
Location
This study was conducted at the Ross Tilley Burn Centre at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Sunnybrook Health Sciences Centre is a 1275 bed tertiary care teaching hospital in Toronto, with a total of 14 adult burn centre beds, the largest burn centre in Canada. This study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre on January 11 2011.
2.2.
Study design
A retrospective chart review of all acute burn patients admitted to the burn centre at Sunnybrook Health Sciences Centre between March 12th, 2010 and March 11th, 2011 was conducted. Patients were identified for eligibility for this study using the SPIRIT database of the Antimicrobial Stewardship Program Hospital [21], charts for the patients identified were obtained from Health Data Resources and reviewed. Patients were excluded if they were admitted more than 10 days following their burn injury, if the admission was for inhalation injury only, if a burn injury was not the reason for admission or if the injury was due to frostbite. Of 163 patients admitted to the burn centre during the study period, 111 patients were included in the final analysis (Fig. 1).
2.3.
Data collection
During the data collection periods, relevant data were extracted from the SPIRIT database and the patient’s chart and entered into a Microsoft Excel file. Patients were assessed for a true infection within the first 10 days of admission (early infection) if the patient was started on antibiotics (yes/no); and if yes, if they met the criteria for an infection diagnosis (based
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Fig. 1 – Inclusion and exclusion criteria.
on accepted criteria for different infectious diseases outlined by the American Burn Association [5]) (Appendix 1). Patients with confirmed, probable and possible pneumonia were considered to have pneumonia [5]. Patients who received no antibiotics and those who were only given antibiotics for surgical prophylaxis or for gastric motility were considered to have ‘‘no infection’’. Parameters that were obtained included: gender, age, weight, number of days in the burn centre prior to initiation of antibiotic therapy, number of days from burn to initiation of antibiotic therapy, type of burn, percent total body surface area burned (% partial thickness/% full thickness), inhalational injury (yes/no, grade of inhalational injury), burn excision (yes/no and number of days from burn injury to excision), allograft (yes/no), autograft (yes/no), use of topical antimicrobials (yes/no, agent), chest X-ray results (normal/abnormal). At Sunnybrook Health Sciences Centre, grade of inhalational injury is determined from findings at initial bronchoscopy and is based on the Abbreviated Injury Score criteria [22]. The following parameters were determined from admission to day 10 of burn centre stay for patients not treated with antibiotics; and from 72 h before the day of initiation of antibiotic therapy
consecutively to day 7 of antibiotic therapy for those patients who were treated with antibiotics: lowest blood pressure, highest heart rate, highest respiratory rate, fraction of inspired oxygen (FiO2), minute ventilation, highest ventilation mode, ventilator days, vasopressor use (yes/no), highest temperature (TMax), lowest temperature (TMin), total white blood cell count, neutrophil count, platelets, C-reactive protein, lactate, blood urea nitrogen, serum creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, international normalized ratio (INR), serum glucose, prothrombin time, activated partial thromboplastin time, cultures (source and organism) and burn centre survival (yes/no and cause of death).
2.4.
Sample size calculation
This study included all patients admitted to the burn unit at Sunnybrook hospital during a one year time period. Agreement in the literature is lacking regarding how many patients are needed per variable analyzed when doing factor analysis. Anywhere from 2:1 to 10:1 patients per variable has been proposed [23–27]. One hundred and eleven patients
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Table 1A – All patients: patient characteristics (N = 111).
were included in the study, with an infection rate of 50%, which is likely to be able to identify 5 variables (at a ratio of 10:1), but possibly as many as 25 variables (at a ratio of 2:1).
Parameter
Mean (SD) (Range) (% of patients)
2.5.
Sex (male) Age (years)
80 (72%) 46 (20) (15–92) 5 (4.50%) 80 (18) (45–140)
Statistics
The mean time to initiation of antibiotics after acute burn in patients with early infection was determined to be 4 days (standard deviation – 2.5 days; median – 3 days) and this was used to derive a baseline time comparator in non-infected patients. Parameters obtained in non-infected patients from day 4 of their burn were compared to parameters obtained in infected patients and the septic sub-group of patients on the day of antibiotic start using a two-tailed unpaired t-test for interval data and Fisher’s exact along with an odds ratio for nominal data. Parameters with a p-value of <0.05 following univariate analysis were analyzed by multiple binary logistic regression (SPSS1) and the model having the lowest significant p-value ( p < 0.05) with the greatest number of variables was selected as the best model for predicting infection and sepsis. CART analysis was used to determine breakpoints for variables found significant via multiple regression (CART1 Professional Extended Edition, Salford Systems Salford Predictive Modeling Suite1). Sensitivity and specificity analysis was conducted on the best model for infection and sepsis.
Mortality Weight (kg) Type of burn Thermal Electrical Partial thickness burn (%) Full thickness burn (%) Total body surface area burned Inhalation injury Grade of inhalation injurya Grade 1 Grade 2 Grade 3 Intubation Length of intubation (days) Patients with confirmed infection Septic patients
103 (93%) 8 (7%) 8% (9%) (0–52%) 6% (14%) (0–99%) 13% (15%) (0–99%) 24 (22%) 16 (70%) 5 (22%) 2 (9%) 48 (43%) 9 (15) (0–89) 56 (50%b) 18 (16%b overall and 32% of infected patients)
a
3.
Results
One hundred and sixty-three patients were admitted to the burn centre during the study period. Fifty-two patients were excluded (Fig. 1) and 111 patients were included in the study. Fifty-six patients (50%) were identified as having an infection and 18 patients (16% of patients overall and 31% of infected patients) had sepsis within the first 10 days of admission over the 1 year study period (period prevalence of early infection = 50%; period prevalence of early sepsis = 16%). Sixty-two of 111 patients (56%) had 10% TBSA burned and 98/111 (88%) had 30% TBSA burned (Fig. 2). Patient demographics and clinical characteristics are summarized in Tables 1A–1C. Types of infection and causes of sepsis are summarized in Table 2.
1 patient had inhalation injury but no grade of inhalation injury was assigned. b Period prevalence (period prevalence = # acute burn injury patients with infection during 1 year study period/# acute burn injury patients [30]).
When comparing patients with infection to those without infection the parameters that were significant ( p < 0.05) following univariate analysis were sex, % partial thickness burn, intubation, TMax and FiO2. The parameters that continued to be significant after multiple binary logistic regression were FiO2 and TMax ( p < 0.05). The CART determined break points for these parameters were FiO2 > 25% and TMax 39 8C. When both parameters were satisfied the tool has a positive predictive value (PPV), positive post-test probability and specificity of 100% (Table 3). However the negative predictive
Fig. 2 – Histogram of total body surface area (TBSA) burned in all patients.
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Table 1B – Infectiona versus no infection day 4 post burn (N = 101). Parameter
Infectionb
No infectionb
Number of patients Sex (male) Age (years)
56 (55%) 37 (66%) 46 (20) (18–92) 2 (4%) 82 (20) (45–140)
45 (45%) 38 (84.4%) 45 (20) (16–84) 3 (7%) 76 (13) (52–100)
53 (95%) 3 (5%) 10 (11) (0–52) 7 (12) (0–75) 16 (15) (0.25–75) 14 (25%) N = 13 7 (54%) 4 (31%) 2 (15%) 25 (45%) 13 (19) (0–89) 109 (18) (69–150) 57 (13) (35–90) 107 (22) (70–160) 19 (3) (16–29) 11 (3) (6–22) 38.1 (0.9) (36.7–40.5) 36.8 (1.1) (31.5–38.3) 0.40 (0.20) (0.20–1.00) 5 (9%) 1.2 (0.2) (0.9–1.7) 34.7 (8.4) (24.0–65.5) 56 (19) (35–107) 27 (32) (7–148) 44 (50) (12–202) 17 (20) (4–85) 5.1 (3.0) (1.3–15.1) 88 (117) (27–608) 189 (77) (36–317) 7.1 (3.1) (1.1–13.0) 7.9 (2.4) (4.6–14.6) 1.7 (1.2) (0.7–5.9)
Mortality Weight (kg) Type of burn Thermal Electrical % Partial thickness burn % Full thickness burn Total body surface area burned (%) Inhalation injury Grade of inhalation injury Grade 1 Grade 2 Grade 3 Intubation on day of ABX start or day 4 post burn Length of intubation (days) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per minute) Respiratory rate (breaths per minute) Minute ventilation (L/min) TMax (8C) TMin (8C) FiO2 Pressors Prothrombin time (INR) aPTT (s) ALP (IU/L) ALT (IU/L) AST (IU/L) Bilirubin (mmol/L) BUN (mmol/L) Creatinine (mmol/L) CRP (mg/L) Neutrophils (109) Blood glucose (mmol/L) Lactate (mmol/L)
p-value
OR
95% CI for OR
0.042 0.840
0.4
0.2–0.6
0.653 0.235
0.5
0.1–2.9
40 (89%) 5 (11%) 6 (5) (0–27) 5 (17) (0–99) 10 (16) (0–99) 7 (16%) N=7 6 (86%) 1 (14%) 0 (0%) 1 (2%) 2 (3) (0–11) 116(15) (88–150) 60 (10) (34–80) 91 (17) (64–129) 19 (3) (14–26) N/A*
0.461
2.2 0.4
0.7–6.8 0.1–1.4
1.8
1.1–3.0
37.4 (0.6) (36.4–38.7) 36.8 (0.5) (36.0–37.8) 0.23 (0.05) (0.21–0.45) 1 (3%) 1.1 (0.1) (0.9–1.4) 31.9 (6.5) (26.4–47.2) N/A
<0.001
0.034 0.638 0.083 0.327 0.328 0.613 0.521 <0.001 0.037
0.01–3.5 0.1–53.3 – 4.1–303.5
4.3
0.4–49.2
0.075 0.306 <0.001 0.285 N/A
0.831 0.002 0.660 0.136 0.339 N/A
N/A
N/A
N/A
N/A
N/A
N/A
4.9 (3.4) (1.4–12.9) 72 (22) (42–122) N/A
0.797
5.7 (2.5) (2.5–10.2) 8.1 (2.6) (5.5–13.6) 1.4 (0.1) (1.3–1.4)
0.2 2.7 – 35
0.658 N/A 0.150 0.814 0.659
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Table 1B (Continued ) Parameter 9
Platelets (10 ) Albumin (g/L) WBC (109) a b
Infectionb
No infectionb
p-value
185 (93) (12–567) N/A 10.8 (4.0) (4.2–20.3)
181(101) (53–378) N/A 8.3(3.2) (4.0–14.7)
0.891
95% CI for OR
N/A 0.053
Includes patients with sepsis. N/A = Not enough data available. Mean (SD) (Range).
value (NPV), accuracy and sensitivity are all less than 50% and the negative post-test probability is 61% (complement of NPV). When comparing patients with sepsis to those without infection the parameters that were significant ( p < 0.05) following univariate analysis were % partial thickness burn, % total body surface area burned, inhalation injury, intubation, systolic blood pressure (SBP), heart rate (HR), TMax, FiO2, vasopressor use and INR. The parameters that continued to be significant after multiple binary logistic regression were HR, SBP and intubation ( p < 0.05). The CART determined break these parameters were: HR 110 bpm, points for SBP 100 mmHg and intubation. When all three parameters were met, similar to the infection tool, there was a specificity, positive post-test probability and PPV of 100% (Table 4). The NPV, sensitivity, accuracy and negative post-test probability (complement of NPV) were 81%, 61%, 85% and 19%, respectively. To remove the influence of prevalence of infection, we determined likelihood ratios (LR) for a patient having infection or sepsis when the tool parameters were positive (LR+) and negative (LR). The LR+ for both infection and sepsis were infinite. Thus, using Baye’s nomogram [28,29] the post-test probability of having an infection or sepsis when the tool results are positive (PPTP) is 100%. The LR for infection and sepsis from the tools was 0.82 and 0.39, respectively, which corresponds to a negative post-test probability (NPTP) of having an infection or sepsis, respectively, of 46% and 19%, using Baye’s nomogram [28,29]. Therefore, our tool is no better than a coin toss at ruling out infection. However, our tool is more useful at ruling out sepsis, with a NPTP of sepsis of 19% when the results of the tool for sepsis are negative.
4.
OR
Discussion
Burn patients are at high risk for infection but common indicators of infection are unreliable in this population. Many patients receive empiric antibiotics within the first week after burn injury but there may be no documented infection. The objective of this study was to determine if predictors of early infection in adult acute burn injury patients could be identified in order to provide clinicians with a practical predictive tool to aid in the diagnosis of infection in acute burn injury and thereby, minimize unnecessary exposure to antimicrobials. The parameters for the tool to assess infection include fraction of inhaled oxygen >25% and maximum temperature 39 8C. This tool has a specificity, positive post-test probability and PPV of 100% and thus, effectively identifies true positive,
true negative and false positive patients. Therefore, if all parameters in this tool are satisfied, antibiotic treatment is indicated. However, the tool for infection had a low sensitivity, negative predictive value and accuracy; all less than 50%, a LR of 0.82 and a negative post-test probability of 61% (determined as the complement of NPV) or 46% (determined from Baye’s nomogram using LR of 0.82). Therefore, the infection tool cannot be used to rule out infection (risk of false negative). Although our study included a broad distribution of infection sources, including pneumonia, bacteremia and urinary tract infection, fifty-six percent of patients with infection had a burn wound infection (Table 2). Since the diagnosis of a burn wound infection does not rely on systemic signs of infection, inclusion of these patients in our study may have affected our ability to discover systemic predictors of infection and may have affected the sensitivity, accuracy, negative predictive value, and negative post-test probability of the infection tool. Prospective evaluation of the infection tool with a larger sample size of infected patients, where burn wound infection patients are excluded, is necessary to evaluate and validate the tool for infection. Our tool is meant to complement diagnostic criteria used for infection in acute burn injury, such as the American Burn Association criteria [5]. However the American Burn Association Guidelines are based on consensus and not founded on prospective clinical studies [18]. The American Burn Association guidelines use a temperature of >39 8C as a parameter for diagnosis of pneumonia, blood stream infection and cellulitis [5]. The CART identified breakpoint determined in our study provides data to support the recommendations given by the American Burn Association. Conversely, while our study identified intubation as a parameter; this was not a parameter listed to assist in the diagnosis of any infection using the American Burn Association criteria [5]. The tool for sepsis includes a heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation. Similar to the tool for infection, this tool has a specificity, positive post-test probability and PPV of 100% and thus, effectively identifies true positive, true negative and false positive patients, indicating antibiotic treatment is warranted if all parameters are met. The tool for sepsis may be useful as an initial screening tool in patients with a presumed diagnosis of sepsis, since it identifies 81% of patients who truly do not have sepsis, corresponding to a negative post-test probability of 19% (determined as the complement of NPV or determined from Baye’s nomogram using LR of 0.39). Therefore, although the sepsis tool cannot be used to rule out sepsis, it can be used as an initial screening tool for sepsis.
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Table 1C – Septic versus no infection day 4 post burn (N = 63). Parameter Number of patients Sex (male) Age (years) Mortality Weight (kg) Type of burn Thermal Electrical % Partial thickness burn % Full thickness burn Total body surface area burned (%) Inhalation injury Grade of inhalation injury Grade 1 Grade 2 Grade 3 Intubation on day of ABX start or day 4 post burn Length of intubation (days) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per minute) Respiratory rate (breaths per minute) Minute ventilation (L/min) TMax (8C) TMin (8C) FiO2 Pressors Prothrombin time (INR) aPTT (s) ALP (IU/L) ALT (IU/L) AST (IU/L) Bilirubin (mmol/L) BUN (mmol/L) Creatinine (mmol/L) CRP (mg/L) Neutrophils (109) Blood glucose (mmol/L) Lactate (mmol/L)
Sepsisa
No infectiona
p-value
18 (29%) 11 (61%) 54 (23) (18–92) 2 (11%) 81 (11) (60–101)
45 (71%) 38 (84%) 45 (20) (16–84) 3 (7%) 76 (13) (52–100)
18 (100%) 0 (0%) 13 (16) (0–52) 13 (19) (0–75) 26 (20) (5–75) 9 (50%) N=8 3 (37%) 3 (37%) 2 (25%) 16 (89%) 19 (23) (0–89) 99 (18) (69–140) 50 (9) (35–68) 122 (18) (80–160) 21 (5) (17–24) 13 (3) (8–22) 38.7 (0.9) (37.4–40.1) 36.6 (1.7) (31.5–38.3) 0.56 (0.30) (0.21–1.00) 5 (28%) 1.3 (0.2) (1.0–1.7) 38.2 (10.9) (26.1–65.5) 44 (6) (38–52) 21 (18) (7–50) 43 (50) (18–132) 19 (20) (4–54) 5.9 (3.8) (2.5–15.1) 118 (177) (27–608) 190 (84) (36–317) 5.5 (3.4) (1.1–11.5) 8.7 (2.1) (5.3–14.6) 1.8 (0.6) (1.2–2.8)
40 (89%) 5 (11%) 6 (5) (0–27) 5 (17) (0–99) 10 (16) (0–99) 7 (16%) N=7 6 (86%) 1 (14%) 0 (0%) 1 (2%) 2 (3) (0–11) 116 (15) (88–150) 60 (10) (34–80) 91 (17) (64–129) 19 (3) (14–26) N/A
0.310
37.4 (0.6) (36.4–38.7) 36.8 (0.5) (36.0–37.8) 0.23 (0.05) (0.21–0.45) 1 (3%) 1.1 (0.1) (0.9–1.4) 31.9 (6.5) (26.4–47.2) N/A
<0.001
95% CI for OR
0.089 0.152
0.3
0.1–0.6
0.618 0.291
1.7
0.3–10.6
1 0
1 Undefined
0.008 0.118 0.002 0.001 0.119 0.569 0.467 <0.001 0.010
5.4 0.1 3.6 – 352
2.5–11.7 0.0–2.8 0.1–101.0 – 15.7–7869.0
0.001 <0.001 <0.001 0.434 N/A
0.556 <0.001 0.020 0.028 0.119 N/A
N/A
N/A
N/A
N/A
N/A
N/A
4.9 (3.4) (1.4–12.9) 72 (22) (42–122) N/A
0.467
5.7 (2.5) (2.5–10.2) 8.1 (2.6) (5.5–13.6) 1.3 (0.1) (1.3–1.4)
OR
0.406 N/A 0.925 0.488 0.286
17
1.3–216.1
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Table 1C (Continued ) Sepsisa
Parameter 9
Platelets (10 )
155 (77) (58–335) N/A 10.3 (5.6) (4.2–20.3)
Albumin (g/L) WBC (109)
No infectiona
p-value
181 (101) (53–378) N/A 8.3 (3.2) (4.0–14.7)
0.444
OR
95% CI for OR
N/A 0.267
N/A = not enough data available. Mean (SD) (range).
a
Table 2 – Types of infection. Infection
Parameter Number of patients Number of infectionsb Burn wound infection Pneumonia Cellulitis Blood stream infection Cholecystitis Mixed infectionc Pneumonia Cellulitis UTI Burn wound infection Gastrointestinal
56 61 34 11 4 4 1 7 6 4 2 1 1
(56%) (18%) (7%) (7%) (2%) (11%)
Sepsisa 18 22 2 8 4 3 0 5 5 4 1 0 0
(9%) (36%) (18%) (14%) (0%) (23%)
a
All septic patients are included in information for patients with infection. b Some patients had more than 1 distinct infection during the first 10 days of admission. c Infections were classified as being mixed if there were two potential sources of infection concurrently.
Our findings provide evidence to support the consensus derived recommendations [18] of the American Burn Association guidelines for use of a heart rate greater than 110 bpm in the diagnosis of sepsis [5]. While blood pressure is not included in the diagnosis of sepsis in acute burn injury, it is included in the diagnosis of septic shock according to the American Burn
Association [5]. However, the consensus derived American Burn Association criteria for septic shock is a systolic blood pressure of less than 90 mmHg, while the breakpoint identified in our study was <100 mmHg. Intubation is not included in the American Burn Association guidelines [5] for the diagnosis of sepsis in acute burn injury patients and was identified as a significant parameter in the predictive tool for sepsis in our study. Prospective evaluation with a larger sample size is necessary to evaluate and validate the tool for sepsis. Mann-Salinas et al. found a multivariable model including heart rate >130 beats per minute, mean arterial pressure <60 mmHg, base deficit <6 mequiv./L, temperature <36 8C, use of vasoactive medications and glucose >150 mg/dl outperformed the ABA sepsis criteria [8]. Like Mann-Salinas et al., we also identified low blood pressure and high heart rate as predictors of sepsis. Intubation was identified as an additional risk factor in our study. However, our study was completed for early infection in acute burn injury patients, whereas the study by Mann-Salinas et al. was completed over the entire length of hospital admission and included sicker patients (mean hospital day = 102, mean ICU day = 81, mean TBSA = 49%) [8]. This may account for some of the differences in predictors identified. Hogan et al. showed that out of the ABA criteria for sepsis only temperature and heart rate correlated with bacteremia [9]. This is similar to our findings as heart rate and temperature were the only criteria for sepsis that were identified as significant for inclusion in our tools for either infection or sepsis.
Table 3 – Infection vs. no infection (using CART analysis determined break points).
Gold Standard (ABA criteria for Infection) N= 85 FiO2 >25% and TMax ≥39˚C
Infection
No Infection
patients Infection
TP = 10
FP = 0
No Infection
FN = 46
TN = 29
£
Sensitivity = 18% PP = 66%
Specificity = 100% LR+ = ∞* LR- =0.82
PPV = 100% PPTP= 100% NPV= 39%
NPTP =46%¥
Accuracy = 46%
Acronyms: positive post test probability = PPTP, negative post-test probability = NPTP, pretest probability (prevalence) = PP, likelihood ratio positive test = LR+, likelihood ratio negative test = LRS. £ 26 patients not included because data not available or patient did not completely meet American Burn Association Guidelines for infection. ¥ Baye’s nomogram determined negative post test probability. * Since specificity is 100%.
burns 39 (2013) 1355–1366
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Table 4 – Sepsis vs. no infection (using CART analysis determined break points).
Gold Standard (ABA criteria for Sepsis)
HR ≥ 110, Systolic BP <100 and Intubated
N=48 patients£ Infection
Sepsis
No Infection
TP =11
FP =0
PPV = 100%
PPTP = 100%
No Infection
FN =7
TN =30
NPV= 81%
NPTP = 19%¥
Sensitivity = 61% PP = 37%
Specificity = 100%
Accuracy = 85%
LR+ = ∞* LR- =0.39
Acronyms: positive post test probability = PPTP, negative post-test probability = NPTP, pretest probability (prevalence) = PP, Likelihood ratio positive test = LR+, Likelihood ratio negative test = LRS. £ 18 patients not included because data not available or patient did not completely meet American Burn Association Guidelines for sepsis. ¥ Baye’s Nomogram determined negative post test probability. * Since specificity is 100%.
This study has several limitations because of the retrospective study design. For many of the lab parameters that were included in the analysis, lab samples were not taken often enough to ensure a robust number of data points to assess some specific parameters (risk of type II error). It was difficult to obtain a complete complement of data in all patients to definitively diagnose infection for each patient, since charted information was relied upon as the sole source of information. In particular, it was difficult to assess infections such as cellulitis and burn wound infection, as these diagnoses rely heavily on the physical examination of the patient. Patients were characterized as having cellulitis if the physician described it as ‘‘red’’, ‘‘cellulitic’’, ‘‘painful’’ or ‘‘erythemic’’. One of the diagnostic criteria for sepsis according to the ABA guidelines is inability to continue enteral feedings >24 h [5]. Although we looked for chart documentation to identify this parameter, it was not identified in any patient charts. Our inability to identify and therefore, include, this parameter in the evaluation of sepsis is an unfortunate consequence of the retrospective study design. Our study assessed predictors of early infection in acute burn injury patients, defined as patients admitted to our burn centre within 10 days of burn injury and diagnosed with infection within 10 days of burn centre admission. This patient population was selected because of the difficulty that exists in diagnosing infection in acute burn injury. However, as a result, the applicability of our tool to assess infection and sepsis in more chronic burn injury patients is unknown, and requires investigation. Finally, over 50% of our patients had 10% TBSA burns and 88% had 30% TBSA burns, necessitating caution in using the tool for patients with more extensive burn injury and requiring further evaluation in patients with a higher TBSA burned. The one year period prevalence of early infection in our acute burn injury patients was 50% and sepsis was 16%. Robust published data on the overall incidence and prevalence of infection and sepsis in acute burn injury patients is lacking, which makes it difficult to determine whether our acute burn injury patients are reflective of those seen in other centres. However, a recent systematic review reported a prevalence of
sepsis in burn patients ranging between 8 and 65% [4], which broadly includes our observed period prevalence of 16%. If the prevalence of infection or sepsis in other burn centres is lower, then the PPV observed in our study would be predicted to decrease and the NPV would be predicted to increase, since both parameters are dependent on the prevalence of the condition in question. Therefore, clinicians would need to know the prevalence of infection in their burn centres to determine the utility of the predictive tools identified in this study to their patient population if just PPV and NPV were reported. To overcome this limitation, we determined the likelihood ratios for infection and sepsis with both positive and negative results from the tools, since likelihood ratios are not affected by prevalence of a condition, and then determined the post-test probability using the likelihood ratios and Baye’s nomogram [28,29]. From this analysis, both tools had a post-test probability of infection of 100% when the parameters of the tools were positive, and thus, antimicrobials would be indicated if all parameters were satisfied in either the infection or sepsis tools. However, our tool is not as useful in ruling out infection (LR of 0.82 and 0.39 with a NPTP of infection or sepsis, respectively, of 46% and 19%) and clinical acumen is essential to evaluate any potential parameters of infection as a constellation before discontinuing antimicrobials. Since this is a retrospective study we have little control over potential confounders. This patient population is very complex and there is a wide range of variability among patients. Although this study has many limitations by virtue of its retrospective design, it developed a clinically practical predictive tool for the diagnosis of early infection or sepsis in acute burn injury patients, which may assist in limiting inappropriate antibiotic use. Our study proposes data based breakpoints for early infection in acute burn injury patients for blood pressure, heart rate, FiO2 and fever for infection and sepsis and provides one year period prevalence data for early infection and sepsis in an adult burn centre. This was a pilot project that identified two tools by retrospective analysis that will need evaluation and validation with a prospective study design which includes patients with extensive burn injury (>30% TBSA burns).
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5.
burns 39 (2013) 1355–1366
Conclusion
We identified two simple tools that may assist clinicians in diagnosing true infection and sepsis in acute burn injury patients and thereby, limit inappropriate antibiotic use. The parameters for the tool to assess infection include fraction of inhaled oxygen >25% and maximum temperature 39 8C. The tool for sepsis includes a heart rate 110 bpm, systolic blood pressure 100 mmHg and intubation. These tools will be validated in a prospective study.
contaminant, i.e., diphtheroids, Bacillus species, Propionibacterium species, coagulase-negative Staphylococci, or micrococci) cultured from two or more blood cultures, or one positive blood culture, in the presence of sepsis (as defined above). 2. Patient has a common skin contaminant cultured from two or more blood cultures drawn on separate occasions (including one drawn by venipuncture) and the patient has clinical signs of sepsis.
A.3. Catheter-Related Infection
Appendix 1. Definition for common infections in burn patients A.1. Pneumonia Diagnosis of Pneumonia [5]: I. The clinical diagnosis of pneumonia includes two of the following: A. Chest X-ray revealing a new and persistent infiltrate, consolidation, or cavitation. B. Sepsis (see A.6.). C. A recent change in sputum or purulence in the sputum. II. It also must be remembered that there are diagnoses that may mimic pneumonia (Acute Respiratory Distress Syndrome, tracheobronchitis, chest contusion). III. Microbiologic Data: the clinical diagnosis can be modified post hoc with the microbiologic data into one of three categories A. Confirmed: clinical + pathogen isolated. B. Probable: clinically present without microbiological confirmation. C. Possible: abnormal chest X-ray with uncertain cause with low or moderate clinical suspicion, but with microbiologic definite criteria met or pathogen identified. IV. Positive Microbiology A. Tracheal aspirate: 105 organisms. B. Bronchoalveolar lavage (BAL): 105 organisms (Blind is OK). C. Protected bronchial brush (PBB): 103 organisms (Blind brush is OK). D. We recognize that there are other criteria for special organisms that we may not include in the diagnosis. E. (The burn wound can be a source of the pathogens spread hematogenously).
A.2. Blood Stream Infection Diagnosis of Blood Stream Infection [5]: One of two criteria must be met for a blood stream infection (BSI) 1. Patient has a recognized pathogen (defined as a microorganism not usually regarded as a common skin
Diagnosis of Catheter Related Infection [5]: Any bacteremia or fungemia in a patient with an intravascular catheter with the microbial growth from at least one blood culture obtained from a vein or artery separate from the catheter site, clinical signs of infection (as noted elsewhere), and no other documented source of the infection or one of the following: 1. Any bacteremia or fungemia in a patient with an intravascular catheter with greater than 15 colony forming units (>15 cfu) per catheter segment on semiquantitative culture analysis or greater than 103 colony-forming units (>103 cfu) per catheter segment on quantitative culture analysis, with the same organism (species and antimicrobial sensitivity) isolated from a blood culture from a separate vein or arterial sample is a central venous catheter infection (CVCI). 2. Simultaneous quantitative blood cultures drawn from both the central venous catheter and a separate venous or arterial site with a greater than 5:1 catheter vs. other site ratio is a CVCI. 3. If a differential period of culture growth occurs with catheter blood growing pathogenic organisms more than 2 h before a separate site, then a CVCI is present.
A.4. Burn Wound Infection Diagnosis of Wound Infection [5]: I. Objective A. Quantitative biopsy (can be used to confirm but is not reliable. It may help with identifying the organism), B. Quantitative swab (poor test but may help with identifying organism), C. Tissue histology, D. Superficial culture. II. Subjective A. Pain, erythema, color changes, B. Unexpected change in the appearance or depth of the wound, C. Systemic changes, D. Premature separation of burn eschar. In order to be the most inclusive, the patient will be diagnosed with burn wound infection in they have one objective or one subjective criteria.
burns 39 (2013) 1355–1366
Diagnosis of Cellulitis: Bacteria present in the wound and/or wound eschar at high concentrations. Examination of surrounding tissue reveals advancing erythema, induration, warmth, tenderness. Sepsis must be present.
A.5. Urosepsis Diagnosis of urosepsis [5] (Modified CDC criteria): 1. One of the following: fever (>39.5 8C and no other source of the fever), urgency, frequency, dysuria or suprapubic tenderness, and a urine culture 105 cfu/ml (cfu = colony forming units) with no more than two species of organisms or 2. Two of the following: fever (>39.5 8C), urgency, frequency, dysuria or suprapubic tenderness, and any of the following: a. positive dipstick for leukocyte esterase and/or nitrate b. pyuria (10 WBC/ml or 3 WBC/high-power field of unspun urine) c. organisms seen on Gram stain of unspun urine d. two urine cultures with repeated isolation of the same uropathogen with 102 cfu/ml in a nonvoided specimen e. two urine cultures with 105 cfu/ml of single uropathogens in a patient being treated with appropriate antimicrobial therapy.
A.6. Sepsis Sepsis is a change in the burn patient that triggers the concern for infection. It is a presumptive diagnosis where antibiotics are usually started and a search for a cause of infection should be initiated. While there is need for clinical interpretation, the diagnosis needs to be tied to the discovery of an infection (defined below). The trigger includes at least three of the following: 1.) Temperature >398 or <36.5 8C, 2.) Progressive tachycardia >110 bpm, 3.) Progressive tachypnea >25 bpm not ventilated (minute ventilation >12 L/min ventilated), 4.) Thrombocytopenia (will not apply until 3 days after initial resuscitation) <100,000/mcl, 5.) Hyperglycemia (in the absence of pre-existing diabetes mellitus) Untreated plasma glucose >200 mg/dl or equivalent mM/L or Insulin resistance—examples include >7 units of insulin/hr intravenous drip (adults) or significant resistance to insulin >25% increase in insulin requirements over 24 h), 6.) Inability to continue enteral feedings >24 h. A. Abdominal distension, B. Enteral feeding intolerance, C. Uncontrollable diarrhea (>2500 ml/d). In addition, it is required that a documented infection (defined below) is identified
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A. Culture positive infection, or B. Pathologic tissue source identified, or C. Clinical response to antimicrobials.
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