Procalcitonin as a Biomarker for Postoperative Pneumonia: A Study on Dynamics Following Cardiopulmonary Bypass in Adults

doi:10.21203/rs.3.rs-4983060/v1

Objective

Postoperative pneumonia (POP) frequently complicates cardiac surgery that involves cardiopulmonary bypass (CPB). This study was aimed to assess the diagnostic utility of procalcitonin (PCT) for identifying pneumonia subsequent to CPB-assisted cardiac surgery.

Methods

Patients diagnosed with postoperative pneumonia were enrolled into the retrospective matched case-control study, who were admitted to a Grade III general hospital in Nanjing in 2023. POP diagnosis was determined based on a combination of clinical and microbiological criteria.PCT and white blood cell count (WBC) data were systematically collected from day 1 (T1) to day 5 (T5). Receiver operating characteristic (ROC) curve analysis and subject operating characteristics were utilized to evaluate the diagnostic performance of biomarkers,while a binary logistic regression model was developed to identify factors that influence the diagnosis of POP.

Results

The study included 220 age- and sex-matched patients, comprising 56 individuals with POP and 164 uninfected patients constituting the non-POP group. ROC curve analysis revealed that serum PCT concentration exhibited an AUC > 0.7 from day 2 to day 5, whereas other indices demonstrated AUCs < 0.7 at these time points.Univariate and multivariate analyses highlighted serum PCT concentration on day 2, WBC count on day 5, the PCTT4-T1 variation rate, and days of mechanical ventilation as significant predictive factors for POP diagnosis, each demonstrating statistical significance (P < 0.05). The calculated AUC was 0.837 (95%CI: 0.773–0.902). The absolute PCT value exhibited superior diagnostic performance relative to its variance rate and WBC count, with a cutoff value of 3.45 ng/ml yielding optimal diagnostic accuracy.

Conclusion

Serum PCT absolute value demonstrates higher sensitivity and specificity when compared to other indices, thereby offering superior diagnostic potential for predicting postoperative pneumonia.

Cardiopulmonary bypass

Cardiac surgery

Postoperative pneumonia

Procalcitonin

In contemporary cardiac surgery, cardiopulmonary bypass (CPB) was recognized as a foundational technique, offering significant advancements in patient prognosis and broadening surgical possibilities^[1]. However, the application of CPB was associated with inherent risks, triggering a cascade of physiological and pathological responses that include systemic inflammation, immune system disruption, and changes in multi-organ function^[2]. These responses can lead to a spectrum of postoperative complications, notably pulmonary infections, which significantly impact the patient's recovery and long-term prognosis. Given the severity and prevalence of early pneumonia, an accurate diagnosis is crucial for prompt therapeutic interventions and improving patient prognosis.Regrettably, diagnosing postoperative pneumonia (POP) remains challenging in current clinical practice, especially due to the lack of specific and sensitive biomarkers^[3]. Consequently, identifying novel biomarkers for the accurate diagnosis of early postoperative pneumonia has become an urgent research priority within the medical community. In this context, procalcitonin (PCT) has emerged as a highly promising biomarker, attracting increasing interest among researchers. Serum procalcitonin concentrations are exceedingly low in healthy individuals. However, they show a significant increase during bacterial infections, making PCT a robust candidate for the diagnosis of such conditions^[4].Previous studies have shown the superior specificity of procalcitonin (PCT) over traditional inflammatory markers in indicating postoperative infections; however, the patterns of PCT changes following adult extracorporeal cardiac surgery and its potential for early pneumonia diagnosis have not been thoroughly studied.The existing literature offers divergent interpretations regarding changes in PCT levels, and a comprehensive validation of its sensitivity and specificity in diagnosing early pneumonia is still lacking^[5–6].Therefore, this study aims to assess the natural progression of PCT changes after extracorporeal cardiac surgery in adults and to explore its potential in diagnosing early pneumonia.We anticipate that this investigation will yield a more precise diagnostic tool for clinical use, while laying a solid scientific groundwork for infection management and therapeutic decision-making after cardiac surgery, thus informing early intervention strategies and ultimately improving patient prognosis.

Study Design and Sample

This study utilized a matched case-control design. Following approval from the Medical Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2024-SR-535), this study included patients admitted to the Department of Cardiac and Major Vascular Surgery in 2023. These patients developed postoperative pneumonia (POP) within seven days following cardiopulmonary bypass (CPB) cardiac surgery and were matched with a control group in a 1:3 ratio based on age and gender. Inclusion criteria were: (1) adult patients aged 18 to 80 years undergoing CPB cardiac surgery, and (2) availability of comprehensive laboratory test data. Exclusion criteria included: (1) preoperative temperature ≥ 38°C; (2) cardiac surgery performed due to trauma, infective endocarditis, tumor, malignancy, or emergency; and (3) diagnosis of any other infectious disease (e.g., surgical site infection, sepsis), 220 patients met the inclusion criteria: 56 in the POP group and 164 in the non-POP group, matched by age and sex, without hospital-acquired infections.

Data collection

1.2.1 Baseline data for patients, including demographic characteristics, preoperative diagnoses, surgical methods, duration of mechanical ventilation, ICU stays, length of hospital stay, and microbiological examination results, were collected via the hospital's electronic case system. Times for CPB and aortic cross-clamp were obtained from the intraoperative CPB manual registry. Serum PCT concentrations and WBC counts were meticulously recorded from postoperative day 1 to day 5 (T1 to T5) for each patient. The PCT variability rate was calculated using the formula^[7]:(PCT_delayed−PCT_T1)/PCT_T1×100%. PCT_delayed represents the serum PCT concentration measured from T2 to T5, with negative values signifying a decrease in PCT concentration. All data were collected by the Xinglin Real-Time Nosocomial Infection System and Intelligent Integrated Health(iih) platform.
1.2.2 Preoperative nutritional evaluation: BMI and CONUT indicators were assessed based on the data. (1) BMI^[8]: BMI (kg/m²) = weight (kg) / height² (m); (2) CONUT Score^[9–10]: Calculated based on serum albumin (ALB), total cholesterol (TC), and lymphocyte count (TLC). Scores are assigned as follows: For ALB, ≥ 35g/L scores 0, 30-34.9g/L scores 2, 25-29.9g/L scores 4, < 25g/L scores 6. For TC, ≥ 4.68mmol/L scores 0, 3.64-4.67mmol/L scores 1, 2.60-3.63mmol/L scores 2, < 2.60mmol/L scores 3. For TLC, ≥ 1.60×10⁹/L scores 0, 1.20–1.59×10⁹/L scores 1, 0.80–1.19×10⁹/L scores 2, < 0.80×10⁹/L scores 3. The total score determines nutritional status: 0–1 indicates normal nutrition, 2–4 indicates mild malnutrition, 5–8 indicates moderate malnutrition, and 9–12 indicates severe malnutrition.

Diagnostic criteria for pneumonia

The primary outcome of this study concerned the incidence of pneumonia within 7 days post-surgery.Diagnosis of postoperative pneumonia was based on the 2018 CDC diagnostic criteria for pneumonia^[11–12], outlined as follows:(1) Presence of at least one of the following on a minimum of two chest radiographs (only one chest radiograph is necessary for patients lacking underlying cardiopulmonary disease): a. New or progressive persistent infiltrative shadows; b. Solid lesions; c. Cavitation;(2) Fulfillment of at least one of the following criteria: a. Unexplained fever > 38°C; b. WBC count decreased (< 4 x 10^9/L) or increased (> 12 x 10^9/L); c. Unexplained change in mental status in adults aged 70 years or older;(3) At least two of the following criteria are met: a. New onset of purulent sputum, change in sputum character, increase in respiratory secretions, or increased need for suctioning; b. New or worsening cough, dyspnoea, or shortness of breath; c. Lung rales or bronchial breath sounds; d. Deterioration in gas exchange function (hypoxaemia, increased oxygen demand, or increased ventilator requirements).In addition, the results of pathogenic cultures serve as a foundational basis for the diagnosis of postoperative pneumonia.

Perioperative management

All surgeries were conducted via median sternotomy. CPB was utilized in all patients. The ascending aorta was cannulated with an appropriately sized cannula. Venous cannulation with separate cannulas in the superior and inferior vena cava was selected. Cardiac arrest fluids primarily consisted of Histidine-mono-tryptophan-mono-ketoglutarate arrest fluid (HTK) and Del Nido cardiac arrest fluid (DN), which have been demonstrated in multiple studies to offer the most cardioprotective and ease of perfusion, thereby optimizing the outcome and simplifying the surgical procedure^[13]. Perioperative prophylactic antibiotic therapy is routinely administered to prevent infection, with the first dose of antibiotics being administered intravenously within 60 minutes of incision and subsequently every 3 to 4 hours during surgery. Additionally, we continue to administer adequate antibiotics according to the guidelines for 48 hours postoperatively. Cefuroxime is typically selected as a prophylactic IV antibiotic.

Statistical analyses

Using IBM SPSS 29 statistical software, continuous variables were assessed for normal distribution via the Shapiro-Wilk test; variables adhering to a normal distribution were presented as mean ± standard deviation (SD), while comparisons between groups of continuous variables utilized the t-test. Measures indicative of skewed distributions were depicted as median (interquartile range [IQR]), and comparisons were conducted using the Mann-Whitney U test. Count data were represented as n (%), with inter-group comparisons conducted via the χ2 test. ROC curves and AUC were employed to evaluate the diagnostic utility of WBC, PCT, and PCT variants in POP. Logistic multivariate regression models were utilized to evaluate postoperative factors that were independently predictive of POP. All reported P-values were two-sided, with P < 0.05 considered indicative of statistical significance.

Incidence of pneumonia after cardiac surgery

Over the past three years, the prevalence of cardiac macrovascular postoperative pneumonia (POP) has been 5.87%, 5.90%, and 3.99%, respectively. The proportions of POP within hospital-acquired infections have been 78.39%, 81.82%, and 75%, respectively. Notably, a significant decrease in the incidence of POP was observed in 2023 (P < 0.05), whereas no statistically significant difference was noted in the component ratios (P > 0.05)(Table 1).

Table 1

Incidence of pneumonia after cardiac surgery
times	Rate of infection		Component ratio
times	Number of discharges	Infection rate n (%)	General infection	Component ratio (%)
2021	2162	127 (5.87)	162	127(78.39)
2022	2287	135 (5.90)	165	135(81.82)
2023	2632	105 (3.99)	140	105(75.00)
χ²	12.145		2.098
P-value	0.002		0.350

Baseline patient characteristics

No significant differences were observed between the two groups of patients regarding age, gender, BMI, underlying diseases, types of cardiac surgery, smoking status, alcohol consumption, and preoperative nutritional scores (CONUT). A longer duration of CPB and a longer duration of aortic cross-clamp were significantly associated with the development of POP in the POP group (P < 0.05). Patients in the POP group underwent mechanical ventilation, required intensive care, and experienced hospitalization for significantly longer periods (P < 0.001) (Table 2).

Table 2

Comparison of clinical baseline data between the two groups of patients
variant		POP Group (n = 56)	Uninfection group (n = 164)	χ² /Z value	P-value
Sex: Male		39 (69.64)	102 (62.19)	1.006	0.316
Age (years)
	< 30	0(0)	1 (0.61)	3.393	0.335
	30 ~ 49	6 (10.71)	16 (9.76)
	50 ~ 69	31 (55.36)	110 (67.07)
	>=70	19 (33.93)	37 (22.56)
BMI
	too light	2 (3.57)	7 (4.27)	1.288	0.732
	normalcy	29 (51.78)	71 (43.29)
	overweight	17 (30.36)	61 (37.19)
	obese	8 (14.29)	25 (15.24)
Smoking history: Yes		22 (39.28)	50 (30.49)	1.468	0.226
Drinking history: Yes		12 (21.43)	49 (29.88)	1.487	0.223
Complication (medicine)
	History of hypertension: Yes	23 (41.07)	56 (34.15)	0.870	0.351
	History of diabetes: Yes	8 (14.28)	13 (7.93)	1.955	0.162
	Cerebrovascular diseases: Yes	8 (14.28)	18 (10.97)	0.439	0.508
CONUT score
	Normal nutrition	18 (32.14)	68 (41.46)	6.214	0.102
	mild malnutrition	32 (57.14)	90 (54.88)
	Moderate malnutrition	5 (8.93)	6 (3.66)
	severe malnutrition	1 (1.79)	0(0)
Types of cardiovascular surgery
	coronary artery	9 (16.07)	17 (10.36)	2.094	0.718
	valve surgery	35 (62.50)	114 (69.51)
	Aortic surgery	5 (8.93)	13 (7.93)
	congenital heart disease	2 (3.57)	9 (5.49)
	the rest	5 (8.93)	11 (6.71)
CPB time (min)		142 (117, 179)	128 (106, 160)	-2.406	0.016
Aortic cross-clamp time(min)		100 (82, 128)	86 (67, 112)	-2.919	0.004
Mechanical ventilation (days)		5(2,12.75)	2(1,3)	-5.652	< 0.001
ICU (days)		10(6,19)	6(5,8)	-4.192	< 0.001
Postoperative antimicrobial use (days)		18(13,23)	12(9,15)	-5.565	< 0.001
Length of stay (days)		27(20,36)	20(16,25)	-4.370	< 0.001

Postoperative kinetics of WBC, PCT and PCT variability in the two groups of patients

Changes in the indexes were observed postoperatively from T1 to T5. Serum PCT concentrations demonstrated a trend of increasing and then decreasing in the infection group at each postoperative time point, reaching the peak on the 2nd postoperative day. In contrast, the control group exhibited a gradual decrease. Furthermore, the concentration of PCT in the infection group was consistently and significantly higher than that in the control group at all time points, with statistically significant differences (P < 0.05). The WBC count peaked on the 2nd postoperative day. Notably, a significant difference was only observed in patients who were infected on the 5th postoperative day (P < 0.05). The PCT variability rate was notably higher in the infected groups compared to the control group (P < 0.05) (Table 3, Fig. 1). ROC curves indicated that serum PCT concentrations had an AUC > 0.7 from T2 to T5, and an AUC < 0.7 for the remaining points (Table 4). Results indicated that the diagnostic utility of serum PCT concentrations was superior to both the PCT variability rate and WBC count(Fig. 2).

Table 3

Comparative analysis of postoperative PCT, leukocyte and PCT clearance changes and indicators in the two groups of patients
variant	POP Group n = 56	Uninfection group n = 164	Z-value	P-value
PCT (ng/mL)
T₁	4.80 (1.39, 4.80)	1.96 (0.85,5.14)	-3.188	0.001
T₂	5.94 (2.06,13.15)	1.72 (0.76,4.42)	-4.987	< 0.001
T₃	4.55 (1.35,10.78)	1.14 (0.52,2.90)	-5.174	< 0.001
T₄	2.96 (1.05,8.25)	0.71 (0.33,1.95)	-5.370	< 0.001
T₅	2.13 (0.73,6.43)	0.49 (0.21,1.18)	-6.005	< 0.001
WBC (10^9/L)
T₁	11.13 (8.89, 13.21)	10.88 (8.94, 13.58)	-0.091	0.927
T₂	12.11 (8.76,14.53)	12.44 (10.12, 16.67)	-1.677	0.094
T₃	10.84 (7.74,13.32)	10.97 (8.17, 13.30)	-0.354	0.723
T₄	10.35 (7.74,13.06)	9.07 (7.39, 12.10)	-1.698	0.089
T₅	10.11 (7.97, 12.55)	8.72 (6.64, 11.27)	-2.571	0.010
PCT variation rate
T₂ -T₁	0.00(-0.31,0.58)	-0.19 (-0.35,0.14)	-2.384	0.017
T₃ -T₁	-0.32(-0.53,0.69)	-0.45(-0.62,0.18)	-2.699	0.007
T₄ -T₁	-0.48 (-0.70,0.71)	-0.66 (-0.77,0.39)	-3.012	0.003
T₅ -T₁	-0.63(-0.78,0.06)	-0.76(-0.86,0.60)	-3.656	< 0.001

Table 4

Comparison of AUC and efficiency of PCT, WBC, and PCT clearance in diagnosing postoperative infections
variant	AUC (95% CI)	Cut-off	Sensitivity	Specificity	Jordon index
PCT(ng/mL)
T₁	0.643 (0.555,0.730)	3.845	0.589	0.707	0.297
T₂	0.723 (0.643,0.804)	3.450	0.696	0.695	0.392
T₃	0.732 (0.650,0.813)	2.650	0.661	0.744	0.405
T₄	0.740 (0.661,0.820)	1.325	0.732	0.665	0.397
T₅	0.769 (0.693,0.844)	0.700	0.786	0.640	0.426
WBC(10^9/L)
T₁	0.496 (0.408,0.584)	9.880	0.679	0.396	0.075
T₂	0.425 (0.337,0.513)	25.820	0.018	0.982	0.000
T₃	0.484(0.394,0.574)	12.445	0.375	0.677	0.052
T₄	0.576 (0.490,0.662)	10.130	0.554	0.628	0.182
T₅	0.615(0.532,0.698)	9.435	0.607	0.604	0.211
PCT variation rate
T₂ -T₁	0.607 (0.516,0.698)	20.970	0.018	0.994	0.012
T₃ -T₁	0.621(0.532,0.710)	-0.155	0.429	0.774	0.203
T₄ -T₁	0.635(0.544,0.725)	-0.265	0.429	0.829	0.258
T₅ -T₁	0.664 (0.579,0.748)	-0.695	0.607	0.646	0.253

Analysis of risk factors for pneumonia after CPB cardiac surgery

Multivariate logistic regression analysis indicated that the absolute PCT value on postoperative day 2, WBC value on postoperative day 5, PCT variability from T4 to T1, and the number of days of mechanical ventilation significantly predicted POP, as demonstrated in Table 5. The Hosmer-Lemeshow goodness-of-fit test indicated a better fit (χ² =10.428, P > 0.05), suggesting that the model possesses a good predictive performance. The area under the ROC curve (AUC) was 0.837, with a 95% CI of 0.773–0.902, indicating that the model exhibits good discriminative ability (Fig. 3).

Table 5

Regression model identifying factors associated with lung infection within 7 days after CPB cardiac surgery
variant	β	SE	Wald χ²	P-value	OR (95 per cent CI)
PCT T₂	0.086	0.026	11.274	0.001	1.089 (1.036,1.145)
WBC T₅	0.119	0.056	4.574	0.032	1.126 (1.010, 1.256)
PCT T_4 ~ 1	0.427	0.164	6.764	0.009	1.533 (1.111, 2.114)
mechanical ventilation	0.235	0.051	21.212	< 0.001	1.265 (1.144,1.398)
constant	-3.697	0.673

Impact of postoperative pneumonia on clinical outcomes

Comparison of clinical outcomes between the two patient groups using box plots revealed that the total number of hospital days, length of postoperative ICU stay, and length of postoperative antimicrobial drug use were all significantly greater in the POP group compared to the uninfected group (P < 0.001)(Fig. 4).

The incidence of postoperative pneumonia is influenced by various factors, including the type of surgery, the patient's baseline health status, and nosocomial infection control measures^[14–15].Given the absence of a uniform diagnostic standard, reported incidences of POP significantly vary across hospitals, with overall incidences ranging from 0.9–1.6%. However, certain studies indicate incidences as high as 15.8%, with postoperative bacterial pneumonia incidence at 21.6%, trailing only behind postoperative incision and urinary tract infections. In China, the incidence of postoperative bacterial pneumonia was 21.6%, second only to postoperative incisional infections and urinary tract infections.The incidence of surgical POP significantly varies by site; however, major thoracic and upper abdominal surgeries tend to impair respiratory muscles, leading to a notably higher incidence of POP compared to other sites^[16].Regarding cardiac surgery, the incidence of postoperative pneumonia also demonstrates variability, with previous literature reporting a range from as low as 2.1% to as high as 24.2%^[17–18]. The incidence of postoperative pneumonia after cardiac surgery at our institution remained around 5% for three consecutive years, exhibiting a significant downward trend in 2023 and presenting as comparatively low against other relevant reports.This outcome can be attributed to the medical team's efficient collaboration, stringent medical procedures, and ongoing quality improvement initiatives.

Although the incidence of pneumonia post-cardiac surgery remains relatively low, it's crucial to recognize that, despite its infrequency, the severe complications that can ensue from pneumonia significantly impact patient recovery and long-term prognosis. Figure 3 illustrates that patients with POP experienced significantly longer hospital stays, intensive care unit (ICU) stays, and antimicrobial usage compared to the non-infected group.To identify lung infections early and implement timely interventions, this study evaluated the postoperative dynamics of infectious markers like PCT and their clinical diagnostic utility for POP. As shown in Table 2, key factors potentially affecting the study outcomes, including smoking history, surgery type, and comorbidities, were excluded.Notably, preoperative nutritional status represents a significant influential factor^[19]. This study incorporated the CONUT score, a less frequently addressed indicator in previous research on risk factors for postoperative cardiac infections. Previous studies primarily utilized nutritional indices like BMI, ALB, TLC, etc.Compared to a single laboratory marker, a composite marker offers a more comprehensive assessment of patients' nutritional status^[20]. However, this study found no significant difference in preoperative nutritional status between the two groups.

Calcitoninogen, a peptide precursor synthesized by thyroid C-cells, is increasingly utilized to assess the risk of systemic infection or sepsis.Recently, its application in medicine has expanded, particularly in predicting post-surgical infections, gaining considerable attention.PCT's utility in predicting postoperative infections across various surgical disciplines—including organ transplantation^[21], orthopaedic^[22], abdominal^[23], neuro^[24], and gynaecological surgery^[25]—has been well-documented.Interpreting calcitonin levels alongside other clinical indicators and assessing the patient's overall condition aids in identifying high-risk patients.This study systematically assessed the patterns of calcitoninogen changes following extracorporeal cardiac surgery in adults to evaluate its diagnostic value in early pneumonia detection.Results indicated significantly higher calcitoninogen levels in patients with early postoperative pneumonia, underscoring its potential as a diagnostic biomarker for early pneumonia.ROC curve analysis revealed that PCT exhibited the highest diagnostic accuracy among the studied parameters, making it an optimal indicator for the early diagnosis of lung infection post-cardiac surgery.Our study offers more detailed insights into calcitoninogen dynamics compared to existing research. In-depth analysis revealed that PCT levels peaked on the second postoperative day, with concentrations in the infected group significantly surpassing those in the control group at all measured time points. Additionally, WBC counts peaked on the second day, yet notable differences were observed on the fifth day among infected patients.Crucially, the rate of PCT variation was markedly higher in the infected group, further illustrating the significant impact of infection on PCT fluctuations.These observations offer vital insights for refining postoperative management and infection control protocols. Furthermore, our study incorporated leukocyte and PCT variability rates to prevent the over-interpretation of fluctuations in individual biomarkers. A study encompassing 423 patients who underwent cardiac surgery with CPB assessed the predictive value of combining CRP, WBC, and PCT levels for postoperative infections. It confirmed that the combined assessment of PCT and leukocyte levels during the initial three postoperative days accurately predicted infections up to 30 days following cardiac surgery, providing a robust tool for early detection and management of potential post-surgical infections^[26] .

In the multivariate analysis, the procalcitonin (PCT) level on day 2 post-surgery, WBC count on day 5 post-surgery, PCT variability on day 4, and the duration of mechanical ventilation were included.Notably, the duration of mechanical ventilation has been identified as an independent risk factor for postoperative pneumonia in a range of surgical procedures, extending beyond cardiac surgery. This underscores the significance of monitoring mechanical ventilation duration alongside PCT levels and WBC counts as part of a comprehensive approach to assessing the risk of postoperative pneumonia^{[7, 27]}, This study further confirms that the PCT level on the second postoperative day serves as a more effective predictor of postoperative pneumonia, diverging from the kinetic changes observed in pediatric cardiac surgery^[28] but aligning closely with those seen after adult cardiac surgery^[29]. Considering the kinetics of PCT response to bacterial infections, possible explanations include: (1) a delayed response to infection, where PCT levels typically rise in response to systemic bacterial infections, making postoperative day 2 a more predictive marker for postoperative pneumonia. This implies that a postoperative infection might require time to trigger a systemic response significant enough to manifest in PCT levels.This delay can be attributed to the time needed for the infection to establish itself and for the body to mount a systemic inflammatory response.(2) Specificity of PCT for bacterial infections: PCT shows heightened sensitivity to bacterial infections over other infection types, such as viral infections.Given that postoperative pneumonia is predominantly bacterial, an elevated PCT level on postoperative day 2 serves as a specific marker for bacterial pneumonia.This specificity renders PCT an invaluable biomarker for the early detection of bacterial infections.(3) Surgical stress response: Surgery initiates an inflammatory response influencing the levels of various biomarkers, PCT included.However, the initial increase in inflammatory markers post-surgery may more likely reflect surgical stress as opposed to infection.By day 2, distinguishing between surgical and infection-induced inflammation may become more apparent, thereby rendering PCT a more reliable infection marker at this juncture.The ROC curve analysis results, indicating an optimal cut-off value of 3.45 ng/ml for PCT on postoperative day 2, suggest clinicians might need to perform early diagnostic assessments. This approach could optimize antibiotic use and minimize unnecessary antibiotic exposure, along with its associated risks, such as drug resistance.In conclusion, the significant predictive value of PCT levels on postoperative day 2 for POP underscores the critical importance of understanding the body's temporal response dynamics to surgery and infection, enabling timely and appropriate clinical interventions.Furthermore, the leukocyte count on postoperative day 5 emerged as an independent risk factor for postoperative pneumonia, a discovery potentially linked to our study's inclusion criteria.Specifically, our study's case group comprised only patients who developed pneumonia within the first 7 days following surgery.Within this group, leukocyte counts peaked by postoperative day 5, leading to generally higher leukocyte counts in the infected versus noninfected groups. This contrasts with prior studies where leukocytes were seldom considered as an independent predictor of postoperative infection^[30] .

Another key finding of this study is that the diagnostic value of the absolute PCT level surpasses that of PCT variability and WBC count, diverging from conclusions of prior research.PCT variability reflects the dynamic infection process and condition changes, with studies indicating that patients with postoperative infections typically exhibit higher PCT variability, marking a significant distinction from non-infected patients.Thus, PCT variability emerges as a crucial diagnostic marker for postoperative infection, potentially surpassing the absolute PCT level in diagnostic efficacy^[7] .However, there remains no definitive conclusion regarding the superior diagnostic value of either metric.Additionally, this study reveals that calculating the PCT variation rate is complex, necessitating continuous PCT level monitoring and change rate calculation, thereby somewhat limiting its clinical utility. Conversely, the absolute PCT level offers the benefits of rapidity, simplicity, and ease of operation, facilitating widespread clinical application.Consequently, in clinical practice, physicians may select the most appropriate diagnostic metric based on the patient's specific circumstances and clinical requirements.

However, this study has several limitations. Firstly, as a single-center retrospective study, the results might be influenced by specific surgical techniques and management strategies, thereby somewhat limiting their generalizability and necessitating further validation in broader clinical settings. Secondly, the analysis excluded some risk factors potentially associated with the development of POP, such as disease severity. Thirdly, the study's observed outcome was the incidence of pneumonia within 7 days postoperatively, whereas the typical diagnostic window for postoperative pneumonia extends to 30 days post-surgery. This lack of follow-up to 30 days could introduce bias into the classification of some cases as non-infected. Finally, PCT's specificity to bacterial infections and the lack of comprehensive infection marker data, due to non-routine CRP and interleukin-6 kinetic monitoring in clinical settings, suggest future studies should explore integrating calcitonin with other infection markers to enhance the detection of postoperative infections' sensitivity and specificity. Additionally, the diverse kinetics of these biomarkers could monitor treatment efficacy, offering a more nuanced approach to managing postoperative infections.

PCT: Procalcitonin; CPB: Cardiopulmonary bypass; POP: Postoperative pneumonia;White blood cell:WBC;ROC: Receiver operating characteristic; CRP: C-reactive protein;Odds Ratio:OR.

Ethic approval

The study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (ethics number: 2024-SR-535). All patients participating in the study signed the informed consent form.

Consent for publication

All authors agree and support the submission and publication of the article.

Availability of data and materials

The datasets during this current study are not publicly according to the regulation of The First Affiliated Hospital of Nanjing Medical University. Datasets are available from the corresponding author upon request.

Conflict of Interest. All authors declare no competing interests.

Fundings. This study was supported by Jiangsu Provincial Hospital Association Hospital Management Innovation Research Project (JSYGY-3-2020-756), and youth Foundation Cultivation Programme of the First Affiliated Hospital of Nanjing Medical University (PY2022017), and the third Outstanding Young and Middle-aged Talent Training Programme of Jiangsu Provincial People's Hospital (YNRCQN0314), and the National Key Research and Development Programme Fund (2020YFC0848100), and research Project on Hospital Management Innovation of Jiangsu Hospital Association (JSYGY-3-2020-692, JSYGY-3-2019-48).

Author contributions: Wensen Chen conceived and designed the study. Feng zang wrote the manuscript. Other authors were involved in the investigation and validation of data. Guangxu Mao was involved in study methodology and managed the statistical analysis. All authors have read and agreed to the published version of the manuscript.

Gerstein NS, Panikkath PV, Mirrakhimov AE, Lewis AE, Ram H. Cardiopulmonary Bypass Emergencies and Intraoperative Issues. J Cardiothorac Vasc Anesth. 2022 Dec;36(12):4505-4522.
Kallel S, Abid M, Jarraya A, Abdenadher M, Mnif E, Frikha I, Ayadi F, Karoui A. Cinétique et intérêt diagnostique et pronostique de la procalcitonine après chirurgie cardiaque [Kinetics, diagnostic and prognostic value of procalcitonin after cardiac surgery]. Ann Biol Clin (Paris). 2012 Oct 1;70(5):567-80.
Chen W, Zhong K, Guan Y, Zhang HT, Zhang H, Pan T, Pan J, Wang DJ. Evaluation of the significance of interleukin-6 in the diagnosis of postoperative pneumonia: a prospective study. BMC Cardiovasc Disord. 2022 Jul 7;22(1):306.
Aïssou L, Sorbets E, Lallmahomed E, Goudot FX, Pop N, Es-Sebbani S, Benouda L, Nuel G, Meune C. Prognostic and diagnostic value of elevated serum concentration of procalcitonin in patients with suspected heart failure. A review and meta-analysis. Biomarkers. 2018 Jul;23(5):407-413.
Sager R, Kutz A, Mueller B, Schuetz P. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med. 2017 Jan 24;15(1):15.
Abu Elyazed MM, El Sayed Zaki M. Value of procalcitonin as a biomarker for postoperative hospital-acquired pneumonia after abdominal surgery. Korean J Anesthesiol. 2017 Apr;70(2):177-183.
Jin H, Gu SP, Wang Y, Pan K, Chen Z, Cao HL, Wang D. Diagnosis Value of Procalcitonin Variation on Early Pneumonia after Adult Cardiac Surgery. Heart Surg Forum. 2021 Aug 25;24(4):E734-E740.
Bramante CT, Palzer EF, Rudser KD, Ryder JR, Fox CK, Bomberg EM, Bensignor MO, Gross AC, Sherwood NE, Kelly AS. BMI metrics and their association with adiposity, cardiometabolic risk factors, and biomarkers in children and adolescents. Int J Obes (Lond). 2022 Feb;46(2):359-365.
Mureșan AV, Hălmaciu I, Arbănași EM, Kaller R, Arbănași EM, Budișcă OA, Melinte RM, Vunvulea V, Filep RC, Mărginean L, Suciu BA, Brinzaniuc K, Niculescu R, Russu E. Prognostic Nutritional Index, Controlling Nutritional Status (CONUT) Score, and Inflammatory Biomarkers as Predictors of Deep Vein Thrombosis, Acute Pulmonary Embolism, and Mortality in COVID-19 Patients. Diagnostics (Basel). 2022 Nov 11;12(11):2757.
Hara M, Fujii T, Masuhara H, Kawasaki M, Tokuhiro K, Watanabe Y. The prognostic impact of the controlling nutritional status (CONUT) score in patients undergoing cardiovascular surgery. Gen Thorac Cardiovasc Surg. 2020 Oct;68(10):1142-1147.
Iosifidis E, Pitsava G, Roilides E. Ventilator-associated pneumonia in neonates and children: a systematic analysis of diagnostic methods and prevention. Future Microbiol. 2018 Sep;13:1431-1446.
Abbott TEF, Fowler AJ, Pelosi P, Gama de Abreu M, Møller AM, Canet J, Creagh-Brown B, Mythen M, Gin T, Lalu MM, Futier E, Grocott MP, Schultz MJ, Pearse RM; StEP-COMPAC Group. A systematic review and consensus definitions for standardised end-points in perioperative medicine: pulmonary complications. Br J Anaesth. 2018 May;120(5):1066-1079.
Gambardella I, Gaudino MFL, Antoniou GA, Rahouma M, Worku B, Tranbaugh RF, Nappi F, Girardi LN. Single- versus multidose cardioplegia in adult cardiac surgery patients: A meta-analysis. J Thorac Cardiovasc Surg. 2020 Nov;160(5):1195-1202.e12.
Bardia A, Blitz D, Dai F, Hersey D, Jinadasa S, Tickoo M, Schonberger RB. Preoperative chlorhexidine mouthwash to reduce pneumonia after cardiac surgery: A systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2019 Oct;158(4):1094-1100.
Nam K, Park JB, Park WB, Kim NJ, Cho Y, Jang HS, Hwang HY, Kim SH, Lee Y, Lee S, Bae J, Cho YJ, Kim EJ, Kim M, Jeon Y. Effect of Perioperative Subglottic Secretion Drainage on Ventilator-Associated Pneumonia After Cardiac Surgery: A Retrospective, Before-and-After Study. J Cardiothorac Vasc Anesth. 2021 Aug;35(8):2377-2384.
Chen B, Chen Y, Li C, Huang X, Zhou P, Wu A. Incidence and Risk Factors of Postoperative Pneumonia in Abdominal Operations Patients at a Teaching Hospital in China. Infect Control Hosp Epidemiol. 2018 Apr;39(4):504-506.
Vera Urquiza R, Bucio Reta ER, Berríos Bárcenas EA, Choreño Machain T. Risk factors for the development of postoperative pneumonia after cardiac surgery. Arch Cardiol Mex. 2016 Jul-Sep;86(3):203-207.
Allou N, Bronchard R, Guglielminotti J, Dilly MP, Provenchere S, Lucet JC, Laouénan C, Montravers P. Risk factors for postoperative pneumonia after cardiac surgery and development of a preoperative risk score*. Crit Care Med. 2014 May;42(5):1150-1156.
Tian Y, Zhu Y, Zhang K, Tian M, Qin S, Li X. Relationship Between Preoperative Hypoalbuminemia and Postoperative Pneumonia Following Geriatric Hip Fracture Surgery: A Propensity-Score Matched and Conditional Logistic Regression Analysis. Clin Interv Aging. 2022 Apr 13;17:495-503.
Mureșan AV, Hălmaciu I, Arbănași EM, Kaller R, Arbănași EM, Budișcă OA, Melinte RM, Vunvulea V, Filep RC, Mărginean L, Suciu BA, Brinzaniuc K, Niculescu R, Russu E. Prognostic Nutritional Index, Controlling Nutritional Status (CONUT) Score, and Inflammatory Biomarkers as Predictors of Deep Vein Thrombosis, Acute Pulmonary Embolism, and Mortality in COVID-19 Patients. Diagnostics (Basel). 2022 Nov 11;12(11):2757.
Nadziakiewicz P, Grochla M, Krauchuk A, Pióro A, Szyguła-Jurkiewicz B, Baca A, Zembala MO, Przybyłowski P. Procalcitonin Kinetics After Heart Transplantation and as a Marker of Infection in Early Postoperative Course. Transplant Proc. 2020 Sep;52(7):2087-2090.
Zhu X, Li K, Zheng J, Xia G, Jiang F, Liu H, Shi J. Usage of procalcitonin and sCD14-ST as diagnostic markers for postoperative spinal infection. J Orthop Traumatol. 2022 Jun 1;23(1):25.
Jerome E, McPhail MJ, Menon K. Diagnostic accuracy of procalcitonin and interleukin-6 for postoperative infection in major gastrointestinal surgery: a systematic review and meta-analysis. Ann R Coll Surg Engl. 2022 Sep;104(8):561-570.
Yu Y, Li HJ. Diagnostic and prognostic value of procalcitonin for early intracranial infection after craniotomy. Braz J Med Biol Res. 2017 Apr 20;50(5):e6021.
Kong X, Liu K. The Predictive Value of PCT and Other Infection Indicators in Postoperative Infection of Epithelial Ovarian Cancer. Infect Drug Resist. 2023 Mar 17;16:1521-1536.
Heredia-Rodríguez M, Bustamante-Munguira J, Lorenzo M, Gómez-Sánchez E, Álvarez FJ, Fierro I, Conejo E, Tamayo E. Procalcitonin and white blood cells, combined predictors of infection in cardiac surgery patients. J Surg Res. 2017 May 15;212:187-194.
Fernández-Ugidos P, Barge-Caballero E, Gómez-López R, Paniagua-Martin MJ, Barge-Caballero G, Couto-Mallón D, Solla-Buceta M, Iglesias-Gil C, Aller-Fernández V, González-Barbeito M, Vázquez-Rodríguez JM, Crespo-Leiro MG. In-hospital postoperative infection after heart transplantation: Risk factors and development of a novel predictive score. Transpl Infect Dis. 2019 Aug;21(4):e13104.
Li X, Wang X, Li S, Yan J, Li D. Diagnostic Value of Procalcitonin on Early Postoperative Infection After Pediatric Cardiac Surgery. Pediatr Crit Care Med. 2017 May;18(5):420-428.
Jin H, Gu SP, Wang Y, Pan K, Chen Z, Cao HL, Wang D. Diagnosis Value of Procalcitonin Variation on Early Pneumonia after Adult Cardiac Surgery. Heart Surg Forum. 2021 Aug 25;24(4):E734-E740.
Sharma P, Patel K, Baria K, Lakhia K, Malhotra A, Shah K, Patel S. Procalcitonin level for prediction of postoperative infection in cardiac surgery. Asian Cardiovasc Thorac Ann. 2016 May;24(4):344-349.

No competing interests reported.

Procalcitonin as a Biomarker for Postoperative Pneumonia: A Study on Dynamics Following Cardiopulmonary Bypass in Adults

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Materials and Methods

Study Design and Sample

Data collection

Diagnostic criteria for pneumonia

Perioperative management

Statistical analyses

Results

Incidence of pneumonia after cardiac surgery

Baseline patient characteristics

Postoperative kinetics of WBC, PCT and PCT variability in the two groups of patients

Analysis of risk factors for pneumonia after CPB cardiac surgery

Impact of postoperative pneumonia on clinical outcomes

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1