Procalcitonin: Usefulness in Acute Care Surgery and Trauma

Abstract

Background:

Procalcitonin (PCT) is a serum biomarker currently suggested by the Surviving Sepsis Campaign to aid in determination of the appropriate duration of therapy in sepsis patients. We review the use of procalcitonin in patients after trauma or acute care surgery.

Method:

A MEDLINE search via PubMed was performed using the combination of “procalcitonin” and “humans” and “injuries, trauma,” “wounds and injuries,” or “wounds.” Studies of burn patients, children, other biomarkers, and non-acute care surgery were excluded.

Results:

Procalcitonin may be useful in identifying infection in trauma and post-operative acute care surgery. However, heterogenity exists among patients, and surgery and trauma alone elevate PCT even in the absence of infection.

Conclusions:

Although trends in PCT concentrations may offer insight, no standard approach can be recommended currently.

Sepsis remains a devastating complication in post-operative and trauma patients, resulting in greater morbidity and more deaths. Current Surviving Sepsis Campaign recommendations highlight the need for early resuscitation, source control, and use of broad-spectrum empiric antibiotics directed at the most likely pathogens [1]. Initiation of appropriate antibiotic selection quickly, coupled with appropriate source control, is the key but must be balanced with optimal duration of therapy, given the possible complications of antibiotic use [2 –4]. Emerging studies are demonstrating the effectiveness of short durations of therapy for a variety of infections, including intra-abdominal infection [5]. However, the heterogeneity of patients cared for by the acute care surgery team makes it difficult to determine the appropriate duration for all types of infections.

Procalcitonin (PCT), a precursor to the hormone calcitonin, coupled with the usual clinical assessment, may be useful in two primary areas. One, the identification of bacterial infection, may be possible, and two, the duration of therapy in various infectious states may be decreased. This paper reviews the available literature regarding PCT in commonly seen infections in acute care surgery and trauma patients.

Procalcitonin Measurement

Procalcitonin is produced in a variety of cells in response to inflammation or bacterial infection, being triggered by inflammatory mediators, such as tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1, or bacterial endotoxins and lipopolysaccharides [6]. Serum PCT typically is measured by immunoassay with a turn-around time of about one hour. The initial PCT assay was developed by Brahms Inc. (Thermo Fisher Scientific). This assay utilized two monoclonal antibodies to PCT that were subsequently licensed to several other in-vitro diagnostic companies, making most contemporary PCT assays somewhat standardized with good concordance at the recommended clinical decision limits. These assays measure PCT in serum or plasma precisely and sensitively [7].

Procalcitonin is potentially best measured two to four hours after bacterial infection begins to allow for an increase in production from normally undetectable concentrations (<0.0005 ng/mL). It has a half-life of ≥22 hours and declines rapidly with control of infection [6,8].

Clinical Applications

Studies utilizing PCT for commonly encountered infections in acute care surgery and trauma were identified by a MEDLINE search via PubMed for English-language articles. Infections included in this review are necrotizing soft-tissue infection (NSTI), Clostridium difficile infection (CDI), mesenteric ischemia/ischemic colitis, peritonitis, surgical site infection (SSI), and anastomotic leak. These infections were included because of the volume of patients seen as well as the difficulty in identifying their onset or progression or the need for intervention. Studies of burn patients were excluded because the number of publications would necessitate a separate review. Studies including children and those evaluating the use of PCT in non-acute care surgery (e.g. elective cardiac surgery) also were excluded.

PCT and necrotizing soft-tissue infection

Necrotizing soft-tissue infections necessitate immediate surgical intervention along with antibiotic use targeted at the most commonly encountered organisms. The need for subsequent debridement is a difficult challenge that the acute care surgeon faces and often requires a return to the operating room.

Friederichs et al. evaluated PCT as a means to predict the need for and type of re-operation, debridement, and major amputation [9]. Serum PCT and C-reactive protein (CRP) concentrations were measured in 38 septic patients with NSTI on post-operative day POD 1 and 2 after radical surgical treatment. A PCT ratio was calculated in a total of 58 operations. Those that achieved eradication of infection had significantly higher PCT ratios (1.67 ± 0.65) than those with persistent infection (0.9 ± 0.36; p < 0.001). The authors determined an optimal cut-off value of 1.14, with ratios below this value suggesting persistent infection and possible need for further surgical intervention.

Al-Thani et al. retrospectively reviewed 331 patients with NSTI seen over a 13-year period of whom 62 had PCT concentrations determined within 24 hours of admission, all during the last 2 years of the study [10]. All 62 patients had elevated PCT concentrations. Of these, 21 patients had septic shock, and their PCT concentrations were all >5.6 ng/mL. The authors concluded that initial PCT concentrations have prognostic value and correlate well with Sequential Organ Failure Assessment (SOFA) scores in predicting the development of septic shock. Unfortunately, 30% of the patients with a PCT value of 0.5–2 ng/mL also developed septic shock.

These studies show that PCT can be used as another clinical datapoint to guide the surgeon on the best care of the patient, be it repeated debridements or a shorter duration of antibiotic therapy. Although promising, larger trials should be performed to determine the best fit for PCT use in patients with NSTI.

PCT and Clostridium difficile infection

Clostridium difficile infection is a devastating complication of antibiotic use that can carry significant morbidity and death. Although its use is associated with the disease, the mainstay of medical treatment remains antibiotic therapy, with surgical options for fulminant progression, including diverting loop ileostomy with colonic lavage or total colectomy [11 –13]. The early identification of CDI is the key to its successful treatment.

In 2013, Rao et al. published the results of a trial in 69 inpatients at least 18 years of age who had their PCT serum concentration measured within 24 to 72 hours after a positive test for C. difficile toxin [14]. There was no correlation between PCT concentrations and CDI severity. However, PCT concentrations <0.2 ng/mL had an NPV of 90% for severe CDI. With further study, this may prove to have clinical implications in guiding the aggressiveness of therapy (i.e., medical versus surgical treatment).

In 2015, Dazley et al. performed a retrospective review of 53 patients with a PCT measured within 24 hours of diagnosis of CDI [15]. The authors defined severe CDI as the presence of CDI plus either a white blood cell count (WBC) >15,000/mL, fever of >38.2°C, 50% increase in serum creatinine concentration from baseline, or hypotension (systolic blood pressure <90 mm Hg or mean arterial pressure <60 mm Hg). They determined that a PCT cut-off value of >0.5 mcg/mL was a good indicator of severe CDI with a positive predictive value (PPV) of >90%.

In the same year, Popiel et al. reported a prospective observational study of 44 and 20 patients with polymerase chain reaction (PCR)-positive and -negative CDI, respectively, who had serum PCT measured within 48 hours prior to collection of a stool sample [16]. The authors reported no correlation between the serum PCT concentration and PCR positivity. However, the authors noted the limitations of their small sample and the lack of differentiation between colonization and true CDI.

Despite these promising results, there does not seem to be a clear cut-off value that would suggest initiation of surgical intervention for severe CDI. Larger trials are needed to determine if PCT aids in identifying the progression of CDI to fulminant pseudomembranous colitis, as well as the duration of antimicrobial drug therapy in patients with initial or recurrent disease.

PCT and ischemic colitis/mesenteric ischemia

Ischemic colitis and mesenteric ischemia are acute vascular deficiencies that often require emergency surgical intervention. Using the statistical gray zone approach, predictive values of serum PCT concentrations may be able to identify those patients with intestinal necrosis, its extent, and their prognosis.

In 2004, Merle et al. performed a prospective observational study of 131 patients with mesenteric infarction with the aim of identifying prognostic factors for early death [17]. They found that the 60% of patients who died within the first 72 hours had PCT concentrations that were significantly greater than those in survivors during that time (0.059 ± 0.024 ng/mL versus 0.021 ± 0.0046 ng/mL). The authors developed a prognostic score including PCT ≥0.04 ng/mL, serum lactate ≥5 mmol/L, aspartate aminotransferase ≥200 units/L, and pre-operative heart failure. A patient presenting with three or four factors had a probability of death of 84% or 97%, respectively.

Over a 7.5-year period, Cosse et al. retrospectively reviewed 128 patients with ischemic colitis and mesenteric infarction requiring exploratory laparotomy with bowel resection and who had procalcitonin concentrations available in the medical record [18]. The authors sought to determine the predictive value of PCT for diagnosing intestinal necrosis, extension of necrosis, and prognosis [18]. They found that PCT concentrations <2.47 ng/mL correlated with salvageability and reversible damage. The PCT concentrations >3.88 ng/mL indicated extension of the ischemia, and although this threshold may not dictate whether a patient needs an operation, it may assist in pre-operative planning, such as discussing palliation if the concentration is well above the threshold. The authors found pre-operative PCT concentrations >7.87 ng/mL to be associated with a high probability of death, with a PPV of 78.3%. Although the PCT concentration may not be the sole determinant of operative decisions, the laboratory values can aid in the discussion a surgeon has with the patient or family.

In 2017, the same group sought to find the PCT threshold that could determine the need for surgical intervention. Cosse et al. reported their retrospective review of patients with post-operative ischemic colitis to determine the correlation of colonoscopic findings and serum PCT with disease severity based on Favier classification (stage 1: ischemia limited to the mucosa with petechiae and small ulcerations with separate areas of healthy mucosa; stage 2: ischemia extending to the muscularis mucosa with large areas of ulceration; stage 3: transmural ischemia with necrosis of the muscularis and possible perforation) [19]. They found that the serum PCT concentration increased linearly between stages 1 and 2 and exponentially between stages 2 and 3, showing a strong correlation with the Favier stage (Spearman's ρ 0.701; p < 0.0001). They determined that the optimal threshold for post-operative stage 2/3 ischemic colitis requiring surgery was ≥5 ng/mL, which had a PPV of 82.3%. The majority of these cases were following cardiac surgery, where non-occlusive mesenteric ischemia (NOMI) is common [19].

Klingele et al. published an observational cohort study of 865 patients who underwent elective cardiac surgery, of whom 78 experienced NOMI. Those investigators performed logistic regression analysis of pre-operative and post-operative PCT concentrations. Patients with NOMI had higher post-operative concentrations than controls (20.8 ± 3.2 ng/mL versus 2.3 ± 1.1 ng/mL; p < 0.001). Procalcitonin was an independent predictor of NOMI even after adjusting for confounders. A serum PCT concentration >6.6 ng/mL foretold a 22-fold higher risk of NOMI [20].

Systemic bacterial infection is a late complication of acute mesenteric ischemia. Procalcitonin concentrations have not been studied in this setting, and the pathophysiology of PCT in the ischemic state is unclear.

PCT and tertiary peritonitis and anastomotic leak

Tertiary peritonitis often is ill defined and offers a wide range of severity on presentation, from a simple abscess after appendectomy to anastomotic dehiscence after major open abdominal surgery [21]. Given the heterogeneity of patients at risk and the difficulty in diagnosis, Novotny et al. sought to determine predictive indicators of post-operative sepsis in patients who underwent major intestinal surgery or an operation for perforation. These patients had either peritonitis or post-operative complications. The authors found that serum PCT measured on the day of onset of sepsis and the Acute Physiology and Chronic Health Evaluation (APACHE II) score were the only two significant independent predictors of death. However, no thresholds for PCT values were identified. Rather, the authors utilized both measures to develop a prognosis score using binary logistic regression analysis. Although this may be helpful in differentiating lethal sepsis early in the disease process, it does not lend itself to identification of post-operative sepsis earlier [22].

Anastomotic leak traditionally is diagnosed with the clinical constellation of fever, abdominal pain, tachycardia, and tachypnea and often requires surgical intervention. Several studies have been conducted utilizing PCT to assess the risk of development of anastomotic leak. Many excluded patients were those requiring emergency surgery or having disorders related to cancer. Garcia-Granero et al. showed that low serum PCT concentrations on POD 3 and 5 (cut-off values of 0.64 and 0.31 ng/mL, respectively) excluded anastomotic leak; however, their data are limited by the small sample. Unfortunately, high PCT concentrations were not indicative of an anastomotic leak. This may in part be attributable to infections or other inflammatory processes that otherwise would increase the PCT concentration independently [23].

In 2014, Giaccaglia et al. reported the results of their pilot study of patients who underwent elective colorectal surgery requiring an anastomosis and had WBC, CRP, and PCT measured on PODs 1, 3, and 5. They found a PCT concentration of <5 ng/mL on POD 3 to have an NPV of 96.7%. A PCT concentration <2 ng/mL on POD 5 had the same NPV. The authors concluded that PCT concentrations below these cut-off values along with low CRP concentrations on POD 3 could aid in assessing qualification for early discharge in patients undergoing these elective procedures [24].

In 2016, the same team published the results of their multicenter, prospective observational study on the use of serum PCT to predict early anastomotic leak after elective colorectal surgery. The authors similarly found a high NPV when serum PCT concentrations were monitored on POD 3 and 5. They reported better diagnosis of anastomotic leak when serum PCT was assessed in combination with CRP to assist in early discharge; however, no length-of-stay data were compared in this study [25].

In a prospective, observational study of 472 patients, De Magistris et al. evaluated a possible association of pre-operative inflammation and its potential impact on post-operative incision healing in elective colorectal surgery. The serum PCT concentration (unlike CRP and albuminemia, which both reached statistical significance) was not associated with a greater risk of post-operative infectious complications. Therefore, PCT cannot be used to assess the likelihood of anastomotic failure [26].

Most biomarker data using PCT after colorectal surgery utilize serum concentrations. Some have sought to determine whether samples from intra-abdominal fluid could predict anastomotic leak; however, controversy exists over whether these operations necessitate drain placement for any indication other than this sampling [27,28].

PCT and surgical site infection and in colorectal surgery

Despite the greater knowledge of modifiable intrinsic and extrinsic risk factors, SSI remains a common, morbid, and costly complication, with 20% of all hospital-acquired infections being SSI [29]. More than half of SSIs are estimated to be preventable, and new pay-for-performance standards have highlighted the importance of decreasing these infections.

In 2013, Takakura et al. studied the predictive value of PCT for SSI after colorectal cancer surgery. They measured PCT, WBC, and CRP on PODs 1 and 3 in 114 patients and found that those with SSI had a significantly higher PCT concentration than those without (p < 0.01). A receiver operating characteristic (ROC) analysis identified a PCT cut-off value of 0.77 ng/mL on POD 1 as the most reliable predictor of SSI. On POD 3, this value increased to 1.50 ng/ml, which had better specificity but diminished sensitivity. Procalcitonin was the only significant predictor of SSI identified [30].

Oberhofer et al. also compared PCT with CRP in patients serially on PODs 1, 2, 3, and 5 after elective colorectal surgery. The PCT concentrations were significantly higher in patients regardless of complications. A PCT cut-off value of 1.34 ng/mL on POD 2 was similar in sensitivity and specificity to the CRP threshold on the same day. The authors concluded that serial PCT concentrations measured after elective colorectal surgery offered no benefit compared with the use of the CRP concentration in predicting infectious complications [31].

Although surgeons do not rely on laboratory values for detection of post-operative complications, CRP remains one of the most reliable measures. The use of PCT can add a diagnostic tool to identify SSI and initiate appropriate workup and therapy.

PCT and trauma

Trauma patients experience various degrees of stress that elicit an inflammatory response, which causes an elevation in PCT concentration related to the severity of the injury even in the absence of infection [32]. Billeter et al. studied the use of PCT with IL-6 and 24-hour serum lactate clearance in trauma patients with an Injury Severity Score (ISS) >16. The PCT concentrations were statistically significantly higher on days 1 through 5 after trauma in patients who later developed septic infections, being highest on day 1 [33].

Sakran et al. prospectively studied 18 trauma patients admitted to the intensive care unit (ICU), and the PCT concentration was measured at admission, at six hours and 12 hours, and then daily. The data were reviewed retrospectively to determine if the patients had systemic inflammatory response syndrome (SIRS), sepsis, or neither. There was a transient increase in the PCT concentration after injury, with the value returning to baseline within two days. In addition, the research team found a statistically significant difference between PCT concentrations in sepsis and SIRS, with mean concentrations of 6.6 ng/mL and 0.9 ng/mL, respectively. The authors concluded that a cut-off PCT concentration of >0.82 ng/mL had a sensitivity of 87% and a specificity of 82% for sepsis in this particular cohort. On univariable analysis, PCT concentrations of ≥5 ng/mL on day 2 were associated with more deaths. On multivariable logistic analysis, the PCT concentration was the sole independent predictor of sepsis. The authors concluded that an elevated PCT concentration warrants further workup for sepsis in critically ill victims of trauma [34].

PCT and antibiotic stewardship

A joint policy statement from the Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society defines antimicrobial stewardship as the “coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents by promoting the selection of the optimal antimicrobial drug regimen including dosing, duration of therapy, and route of administration” [35]. Maseda et al. studied the duration of antibiotic therapy retrospectively in surgical ICU patients who underwent an operation for secondary peritonitis. Patients had serum PCT concentration measured daily and per physician discretion were continued on antibiotic(s) until clinical resolution or a PCT value <0.5 ng/mL or a decrease of at least 80% of the peak. The PCT-guided group showed a 50% reduction in the duration of antibiotic therapy (mean 5.0 ± 2.1 days versus 10.2 ± 3.7 days; p < 0.001) with no difference in ICU or hospital length of stay, mortality rate, or clinical complications. This outcome is consistent with that of the STOP-IT trial [5,36].

A study conducted by Schroeder et al. showed similar results; however, the criteria for the PCT-guided group recommended discontinuation when the PCT concentration was <1 ng/mL or reached a value of less than 35% of the initial concentration within three days. The mean duration of antibiotic therapy was decreased significantly (6.6 ± 1.1 days versus 8.3 ± 0.7 days; p < 0.001) in the PCT-guided group [37].

The same authors, using the same criteria for antibiotic discontinuation, found not only a statistically significant decrease in the duration of antibiotic therapy (14.3 ± 1.2 to 9.0 ± 1.7 days; p = 0.02) but also a decrease in ventilator hours, ICU length of stay, and ICU re-infection [38]. Hohn et al. later reviewed their population after implementation of a PCT-guided protocol and found a decrease in total antibiotic use density guided by defined daily doses, which also led to a change in the spectrum of antibiotics given [39].

Future Directions

There is thus a growing body of literature on the use of PCT in primary care, mostly in the setting of community-acquired pneumonia, acute respiratory tract infection, and exacerbations of chronic obstructive pulmonary disease [40,41], culture-negative sepsis [42], and distinguishing between SIRS and sepsis [8,42] there has been a focus on non-surgical patient populations so far.

Discussion

Given the numerous infectious complications faced by patients suffering from trauma or having undergone acute care surgery, it is not surprising that PCT concentrations differ among them. It is difficult to select a cut-off value for the PCT concentration in surgical patients, as these values are time specific, and the optimal time point is as yet unknown. Many other questions also exist. Is the change in PCT concentration more important than a single static concentration? Or is it the trend in the PCT concentration that really matters? Table 1 displays various cut-off values of PCT studied for these infectious complications; however, one must be cautious about about interpretation, as disease prevalence was not included in the individual reports.

Table 1.

Cut-Off Values and Performance for Serum Procalcitonin

Infection	Series	PCT cut-off (ng/mL)	Sensitivity (%)	Specificity (%)	NPV (%)	PPV (%)
NSTI	Friedrichs et al. (2013) [9]	>1.14 (PCT ratio)	83.3	71.4	80	75.8
NSTI	Al-Thani H et al. (2015) [10]	5.6	81	67	–	50^a
CDI	Rao et al. (2013) [14]	<0.2 (unlikely to be severe)	81	73	90	–
	Dazley et al. (2015) [15]	>0.5	88.2	86.1	75	93.9
AMI	Cosse C et al. (2015) [18]	≥7.87 (for death)	72	79.6	73.6	78.3
		≥2.47 (for necrosis)	94.6	68	80.9	89.8
		≥3.88 (for necrotic extension)	76.3	84.2	45.7	95.3
	Cosse C et al. (2017) [19]	≥5	81.6	78	79.1	82.3
	Klingele et al. (2015) [20]	>6.6	71	94	–	–
Secondary peritonitis	Maseda et al. (2015) [36]	Mentions whether it reduced length of ICU stay or duration of antibiotic therapy
Antibiotic stewardship	Maseda et al. (2015) [36]
SSI (colorectal surgery)	Takakura et al. (2013) [30]	0.77 (POD 1)	83.3	63.5	95.3	30
	Takakura et al. (2013) [30]	1.50 (POD 3)	50	94.8	91	64.3
	Oberhofer et al. (2012) [31]	1.34 (POD 2)	69	78.7	–	–
Trauma	Sakran et al. (2012) [34]	0.82	87	82	–	–
Trauma	Castelli et al. (2009) [43]	0.85 vs 3.32 (1 d before and after sepsis)	–	–	–	–
AL	Lagoutte et al. (2012) [44]	680	70	70	–	–
	Garcia-Granero et al. (2013) [23]	0.31 (POD 5)	100	72	100	17
	Giaccaglia et al. (2014) [24]	<5 (POD 3)	–	95.7	–	96.7
	Giaccaglia et al. (2014) [24]	<2 (POD 5)	–	94.6	–	96.7
	Giaccaglia et al. (2016) [25]	<2.7 (POD 3)	59.3	91.7	96.9	34
<2.3 (POD 5)	Giaccaglia et al. (2016) [25]	69.6	93	98.3	32

Calculated using data from article.

AL = anastomotic leak; AMI = acute mesenteric ischemia; CDI = Clostridium difficile infection; ICU = intensive care unit; NPV = negative predictive value; NSTI = necrotizing soft tissue infection; PCT = procalcitonin; POD = postoperative day; PPV = positive predictive value; SSI = surgical site infection

Conclusion

Procalcitonin may be useful in identifying infection in trauma and post-operative acute care surgery patients. However, heterogeneity exists among patients, and surgery and trauma alone are known to elevate PCT in the absence of infection. No standard approach can be recommended at present.

Footnotes

Author Disclosure Statement

All authors report no conflicts of interest, including pharmaceutical or industry support, regarding any of the information contained in this report. No relevant funding from any organization was provided to any of the authors regarding this manuscript or the ideas contained herein.

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