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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 26  |  Issue : 1  |  Page : 87-92

Procalcitonin: Promising biomarker to detect sepsis in burns – A prospective study


Department of Plastic Surgery, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication11-Mar-2019

Correspondence Address:
Dr. H R. Naveen Kumar
Department of Plastic Surgery, Pondicherry Institute of Medical Sciences, Puducherry - 605 014
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijb.ijb_28_17

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  Abstract 


Background: Sepsis-3 guidelines published in the Journal of American Medical Association is thought to be a pathbreaking effort in the diagnosis of sepsis,[1],[2],[3],[4] but it has limitations with respect to burns population.[5] On the other hand, the American Burn Association (ABA) 2007 guideline[6] for sepsis in burn patients is noted for low specificity rate. However, an independent biomarker procalcitonin (PCT) could augment clinical findings and improve sepsis predictability rate in burn patients. This study is the first attempt to assess diagnostic validity of PCT in Indian population and to highlight its role in diagnosing sepsis in burns despite newer sepsis-3 guidelines.
Materials and Methods: This prospective study involved 33 consecutive thermal burn patients with 66 samples estimated for PCT. Samples were sent at each suspected episode of sepsis based on ABA guidelines. Baseline PCT estimation was done when the patient did not have sepsis. The positive blood or tissue culture was taken as a reference standard. The sample was divided into sepsis and nonsepsis group. All the parameters were documented on the graphical sheet which was interpreted by an independent analyzer. The sensitivity and specificity of each coordinate were plotted on receiver operating characteristic curve to identify the predictive ability of the test.
Results: The sensitivity and specificity of the test was 94.7% and 85.7%, respectively. The cutoff value to diagnose sepsis in burn patients was 3.5 ng/ml with an area under the curve of 0.974 at 95% confidence interval.
Conclusion: Good correlation between documented sepsis and elevated PCT levels makes PCT a promising biomarker in burns population.

Keywords: Biomarker, procalcitonin, sepsis


How to cite this article:
Kumar H R, Barreto E, Paul M K, Gupta AK. Procalcitonin: Promising biomarker to detect sepsis in burns – A prospective study. Indian J Burns 2018;26:87-92

How to cite this URL:
Kumar H R, Barreto E, Paul M K, Gupta AK. Procalcitonin: Promising biomarker to detect sepsis in burns – A prospective study. Indian J Burns [serial online] 2018 [cited 2019 Sep 18];26:87-92. Available from: http://www.ijburns.com/text.asp?2018/26/1/87/253852




  Introduction Top


The pathophysiology of sepsis in major burns is different from sepsis in general population because of the presence of hypermetabolic response to insult and absence of skin barrier. Hence, a trivial insult or inoculum of microbes may rapidly progress to sepsis and organ dysfunction in burn patients. The new sepsis-3 (2016) guidelines and Surviving Sepsis Campaign [1],[2],[3],[4] is thought to help in diagnosing sepsis at an earlier stage. However, sequential (sepsis-related) organ failure assessment score (SOFA), being the crux of sepsis-3 guidelines, begins at the onset of organ dysfunction which is reflected as late findings in burns sepsis. Furthermore, sepsis-3 study is based on general population cohort and has excluded major burns patients.[5] On the other hand, changes in clinical parameters are earliest to occur as sepsis sets in and the American Burn Association (ABA) 2007 guidelines [6] based on these clinical signs are still considered to be valid. However, in the absence of confirmatory blood or tissue culture, major drawback of ABA guidelines is its low specificity rate. This can be improved by considering an independent biomarker like procalcitonin (PCT) which can supplement the clinical findings and improve sepsis predictability at an earlier stage.[7] Many studies have been published confirming PCT as good sepsis marker, but different populations have difference in validity and predictability of the test. This is the first attempt to find the diagnostic validity of PCT in Indian burns population. Furthermore, we have attempted to clarify the timing of PCT estimation when the diagnosis of sepsis is equivocal in major burn patients.


  Materials and Methods Top


This was a prospective diagnostic study done over 9 months from March 1 to November 30, 2013 in the Department of Burns and Plastic Surgery at Christian medical college. This study was approved by the institutional review board (No: 7731/15). All consecutive patients with thermal burns more than 20% total body surface area (TBSA) were included in the study. Patients who had thermal burns <20% TBSA, pediatric age group (<16 years) and those who sustained electrical or chemical burns were excluded from this study. All patients received treatment as per the standard burns protocol in emergency department. Depending on the stability of patients, they were shifted to either burns ward or Intensive Care Unit (ICU) for further treatment. Baseline PCT estimation was done on the 1st day after burns or more precisely, when patient was not in sepsis. Afterward, the patient was continuously monitored for the development of signs of sepsis based on ABA 2007 guidelines.

As per 2007 ABA guidelines, sepsis is diagnosed if patients fulfill three or more of these criteria – (i) temperature >39°C or <36.5°C, (ii) progressive tachycardia (>110/min), (iii) progressive tachypnea (>25/min), (iv) thrombocytopenia, (v) hyperglycemia, and (vi) inability to continue enteral feeding for more than 24 h, plus documented infection (tissue or blood culture) or patients responding to empirical antimicrobials.

For our study purpose, the ABA criteria were divided into three parts. In the first part temperature, heart rate and respiratory rate were documented at every 2 h. The second part comprised monitoring blood sugar level and platelet counts (done twice a week) and documenting daily oral intake. Whenever patient fulfills any of three or more of above-mentioned criteria, sepsis was suspected and PCT estimation was done. Simultaneously, blood or tissue was sent for culture to confirm sepsis focus and started on empirical antibiotics, which formed the third part of ABA guidelines modified for our study.

The reference standard, blood culture, was sent at each suspected episode of sepsis. Positive culture confirmed sepsis and simultaneous PCT value was noted. The PCT estimations in some patients were done more than twice, as some patients developed multiple episodes of sepsis during their admission period. For our study purpose, only positive blood or tissue cultures were taken as confirmatory evidence of sepsis. However, some patients responded to empirical antibiotics, in spite of absent growth in blood or tissue culture, and those sample values were excluded from the study. The baseline PCT estimated on the 1st day of burn or when the patient was not in sepsis was considered under nonsepsis group.

All parameters were entered in a graphic sheet which was modified to accommodate all variables and PCT values at each sepsis episode [Figure 1] and [Figure 2]. At the end of the study, graphic sheets were assessed by an independent analyzer. Based on ABA guidelines, variables fulfilling parameters for sepsis episode and corresponding PCT values were noted. Finally, PCT values were divided into sepsis and nonsepsis group.
Figure 1: Sample case 1

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Figure 2: Sample case 2

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PCT estimation was done using the test kits obtained from BRAHMS (Kryptor method) Germany. The results were obtained within 19 min of the test. The analytical sensitivity of the test was 0.019 ng/ml and the functional assay sensitivity of 0.06 ng/ml with a probability of 95%.

The statistical analysis was carried out for the results. The variables were assessed in sepsis and nonsepsis group for mean, median, standard deviation, and standard error of mean. The coordinates were plotted on receiver operating characteristic (ROC) curve. The significance of association of PCT between sepsis and nonsepsis group was assessed by Mann–Whitney U-test with P < 0.001 taken as significant. The predictive value and likelihood ratios were also calculated. The analyses were done using SPSS 19.0 software (IBM).


  Results Top


There were 33 consecutive cases of thermal burns included in our study, among them 17 male and 16 female, with mean age of 30 years (17–59 years). The mean percentage of TBSA of burn was 48%, with an average of 38% TBSA in nonsepsis group and 55% TBSA in sepsis group. Data of 66 samples of PCT were analyzed. The median PCT value in nonsepsis and sepsis group was 1.0731 ng/ml and 15.3 ng/ml, respectively. Out of 33, 19 patients had sepsis and 14 cases did not have sepsis. Among 19 patients, 6 succumbed to multiorgan failure due to sepsis. The blood culture grew Pseudomonas in 10 (47%) patients, Klebsiella in 5 (29%), methicillin-resistant Staphylococcus aureus in 3 (18%), and Acinetobacter in 1 (6%). Thirteen patients responded to the treatment and survived. Among nonsepsis group, there were two mortalities; one had respiratory failure secondary to inhalation injury, and the other one succumbed to renal failure secondary to hypovolemic shock.

The predictive ability of PCT was determined using ROC curve [Figure 3] with an area under the curve of 0.974 at 95% confidence interval (upper bound 1.00, lower bound 0.925). Each value of PCT has been plotted as coordinates on ROC curve. The superior-most combination of sensitivity and specificity was taken to decide the cutoff value. Thus, at sensitivity of 94.7% and specificity of 85.7%, the cutoff value of PCT was 3.5 ng/ml. The distribution of PCT values in sepsis and non sepsis groups are shown in [Table 1]. The mean values across the group were statistically significant (P < 0.001 using Mann–Whitney U-test) suggesting that PCT value is not equally distributed among the groups. The various characteristics of diagnostic performance of PCT are highlighted in [Table 2].
Figure 3: Receiver operating characteristic curve to assess diagnostic performance of procalcitonin in sepsis

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Table 1: Median and distribution of procalcitonin in sepsis and nonsepsis group

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Table 2: Diagnostic performance of procalcitonin in sepsis

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  Discussion Top


Sepsis-3 versus American Burn Association guidelines

The validity of sepsis-3 published in the Journal of American Medical Association vis-à -vis ABA guidelines to diagnose sepsis in burns patients is debatable. In spite of major changes having made in sepsis-3, ABA has yet to make alterations in its guidelines to diagnose sepsis in burns. The guidelines of sepsis-3 criteria comprehensively address the molecular level of dysregulated host response toward the infection by considering SOFA score. The major disadvantage of sepsis-3 criteria is dependence on SOFA score exclusively, without any regards to clinical signs. It is evident that SOFA being an objective scoring is more specific than clinical signs, it requires continuous invasive monitoring for mean arterial pressure measurement and needs frequent sample collection to analyze arterial blood gas and other biochemical parameters (platelets, bilirubin, and creatinine). Only two criteria, Glasgow Coma Scale and urine output, do not require invasive monitoring. The SOFA scoring is possible when patient is admitted to intensive care unit (ICU) with invasive monitoring facility. In other words, invasive monitoring has increased the specificity of sepsis diagnosis. Hence, arguably, the criteria looks intensivist centric rather than clinician-oriented. In a resource-constrained set up where all hemodynamically stable burns patients are initially treated in burns ward, invasive monitoring of each suspected sepsis episode is not pragmatic. Care of patients in ICU is justified when sepsis is confirmed by culture and not responding to initial empiric treatment. Furthermore, though the sepsis-3 study had patient sample size of 150,000 cases, it did not include burns patients presumably due to the presence of persistence hypermetabolic response in them.

In view of this, ABA guidelines published in 2007 is still considered valid in diagnoses of sepsis in burns. According to ABA guidelines, the diagnosis of sepsis is based on clinical signs and confirmed by blood or tissue culture. In the presence of hypermetabolic response in major burns, clinical signs of sepsis are often either overlooked or underdiagnosed which might result in delayed treatment. Although blood culture is confirmatory, it takes 48 h to identify growth, and this may sometimes lead to the untoward outcome for the patient. To overcome this, there is need for an independent sepsis marker which bridges time gap between onset of clinical signs and identifying the causative organism to diagnose sepsis at the earliest. Our study shows that PCT has high sensitivity and specificity to diagnose sepsis in burns. The marker can be analyzed quickly and improves predictability of sepsis before the isolation and growth of causative organism in the laboratory. Thus, a positive PCT estimation would give more evidence to clinicians to treat sepsis episode before the availability of confirmatory culture report.

The pathophysiology of hypermetabolic response and sepsis in burns is well explained by two-hit hypothesis. The inflammatory mediator interferon alpha released at first hit caused by burns and tumor necrosis factor released at second hit caused by the onset of infection.[8] The other mediators released are cytokines (interleukin [IL] 6, IL 1), chemokines, platelet-activating factor, leukotrienes, thromboxane A2, C-reactive protein,[9] cytokines,[10] adrenomedullin,[11] atrial natriuretic peptide,[12] protein C,[13] endocan,[14] and neopterin.[15] It was postulated that estimation of concentration of these mediators in serum would reflect the sepsis severity and were studied extensively. However, nonspecificity to stimulus and very short half-life makes majority of the potential proposed markers not suitable as sepsis indicators.

From the above studies, it was noted that to consider a mediator as potential sepsis marker, particularly of bacterial origin, the concentration of the marker in circulation should increase several folds at the earliest stage, and half-life of the marker should be suitable so that it can be repeated at regular intervals. Its rising titers in blood should supplement clinical findings to increase predictive ability of sepsis. Furthermore, the marker level in circulation should reflect severity of sepsis and response to treatment. Fulfilling the above criteria, in 1990, Assicot et al. proposed PCT a potential sepsis marker.[16] Although PCT is more often used to diagnose sepsis of infective origin, it is likely to be more valuable in cases where diagnoses of sepsis are equivocal because of the presence of hypermetabolic response as seen in burns and polytrauma.

Many studies have been done to prove that PCT is more specific to sepsis due to bacterial origin.[17],[18],[19] Following this evidence, earlier studies highlighted the importance of estimation of PCT in burns patients [20],[21],[22] but were not widely accepted by burns practitioners across the world. There were also early studies stating no additional benefit while diagnosing burns sepsis by PCT estimation over routine inflammatory markers.[23],[24],[25] However, over the past decade, the importance of PCT estimation in burns sepsis regained momentum and was supported by both retrospective [26] and prospective studies,[27] as well as meta-analysis.[28],[29] The PCT cutoff value in other studies range from 0.5 ng/ml to 3.0 ng/ml that is comparable to our study, in which the value is 3.5 ng/ml. The higher value of PCT in our study could be attributed to persistence exaggerated hypermetabolic response in Indian population.

Emphasis on timing to consider procalcitonin estimation

Based on our clinical experience, there were many situations where PCT estimation was critical to rule out sepsis.

Avoiding development of multidrug-resistant organisms

One of the causes of mortality in burns sepsis is due to development of multidrug-resistant organisms. This could be result of generous use of empirical antibiotics.[30],[31] Evidently, treating each suspected episode of sepsis with empirical antibiotics, without confirming causative organism may lead to development of multidrug-resistant organisms. Hence, PCT estimation is helpful to rule out these suspected episodes and to wait for definitive culture report. On the other hand, positive titers help in starting empirical antibiotics immediately.

Repeated sepsis episodes

Repeated sepsis episodes within a short span of time may obscure the underlying clinical signs of sepsis at the early stage, making it difficult to take decision regarding commencement of antibiotic therapy. In this circumstance, PCT estimation can be very valuable. The availability of report within a few minutes makes it feasible to repeat this investigation whenever there is doubt of sepsis or till blood or tissue culture report is made available. The persistent rise in PCT concentration can be considered an indication to restart antibiotics.

Response to antibiotics

The effectiveness of antibiotics can be assessed by estimating the PCT concentration. If the antibiotic is effective against the causative organism(s), it is reflected by decrease in PCT levels in blood after instituting treatment. On the other hand, increasing PCT levels can be suggestive of unsusceptible organism(s) and a change in antibiotic treatment could be considered early enough.

Exaggerated clinical parameters in the absence of sepsis

The exaggerated clinical signs/parameters in the absence of sepsis may occur when there is inadequate analgesia for managing pain, the presence of thrombophlebitis or drug-induced adverse reactions. In these situations, assessment of PCT can aid in ruling out sepsis. On the other hand, the above-mentioned conditions can also mask the underlying or ongoing early sepsis, which can be detected by a simple, independent PCT estimation.

Superficial burns

Sepsis is unlikely during the initial postburn period with 20%–30% TBSA involvement, especially with superficial burn injury. However, an isolated temperature spike, persistent increase in heart rate or an episode of drop in blood pressure might be the earliest sign of imminent sepsis. Disregarding these signs might miss an opportunity to diagnose and treat sepsis at a very early stage. Thus, PCT estimation can be considered at this time when sepsis is least expected to diagnose sepsis to ensure positive outcomes.

Limitations of procalcitonin as a marker for sepsis

There are certain drawbacks of PCT as biomarker. PCT values add evidence to diagnostic criteria of sepsis, rather than confirming the sepsis condition. The confirmatory test will remain identifying the causative organism by blood or tissue culture. Moreover, temporal profile of PCT is more valuable than a single absolute value. In the absence of sepsis, higher PCT values are documented in the presence of electrical burns and polytrauma with multiorgan failure; these conditions should be excluded before making a diagnosis of sepsis.


  Conclusion Top


PCT as a biomarker may be useful to diagnose sepsis in the presence of hypermetabolic response in burns and has potential to bridge the existing gap between clinical signs and confirmatory culture report. Despite new recommendation of sepsis-3, there is need for burn specific guidelines aiming to identify sepsis at the earliest and use of PCT may hold a lot of promise in that direction.

Acknowledgment

The author would like to thank Dr. Pallab Chatterji and Dr. Mamatha for their valuable advice to complete this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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