Rising C-Reactive Protein and Procalcitonin Levels Precede Early Complications After Esophagectomy

Upon ICU admission (day 0), baseline patient characteristics were recorded. Disease severity was estimated using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and organ failure was calculated by the Sequential Organ Failure Assessment (SOFA) score. The preoperative risk assessment was done by using the American Society of Anesthesiologists (ASA) classification and Portsmouth predictor modification of the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM). Clinical parameters and blood samples for routine laboratory parameters, leukocyte counts, and CRP and PCT levels were collected directly post-operatively on ICU admission (day 0) and in the morning of post-operative days 1, 2, and 3. Leukocyte counts were measured using the Sysmex SE-9000 analyzer (Toa Medical Instruments, Kobe, Japan), and normal values are 3.5–10 × 10⁹/L. CRP was measured by an immunoturbidimetric assay (Modular analytics <P> Roche diagnostics, Mannheim, Germany), and normal values are < 9 mg/L. PCT was measured using the PCT sensitive for the Kryptor compact system (Brahms Diagnostica, Hennigsdorf, Germany). Assays were performed according to the manufacturer’s guidelines, the lower detection limit being 0.02 ng/mL, with an upper limit in healthy volunteers of 0.05 ng/mL. The functional assay sensitivity (FAS) of this test is 0.06 ng/mL, with an intra-assay coefficient of variation (CV) and inter-assay CV of < 6 % in samples containing > 0.3 ng/mL.

All complications up to 10 days post-esophagectomy as decided by attending physicians were recorded, only if additional medical or surgical treatment was required, notably grade 2 or higher on the Accordion Severity Grading System.4,5 The definitions of complications used in this study are depicted in Table 1. The 10-day cutoff was chosen based on a previous study from this group.12 Infections were defined according to the International Sepsis Forum Consensus Conference criteria,23 as agreed upon by the attending intensivists. Diagnostic imaging and collection of specimens and blood for microbial culture were left at the attending intensivist’s discretion. Specimens were processed according to standardized culture protocols, and Gram stains were prepared. Cultures reflecting colonization rather than infection were excluded from final analysis. For example, blood cultures containing coagulase-negative staphylococci were considered contaminated if only one bottle showed growth. Because reporting of definite culture results can take several days, the day of specimen collection was considered the day of infection diagnosis. Patients were considered to have sepsis when presenting at least two SIRS criteria: body temperature < 36 °C or > 38.3 °C, heart rate > 90 bpm, respiratory rate > 20 breaths/min or mechanical ventilation, and a leukocyte count of either < 4.0 × 10⁹/L or > 12.0 × 10⁹/L, in the presence of a probable or proven infection, according to the American College of Chest Physicians/Society of Critical Care Medicine guidelines.24 Shock was defined by a systolic pressure < 90 mmHg or a mean arterial pressure < 60 mmHg for at least 1 h, despite adequate fluid resuscitation, or requirement of vasopressor support to maintain mean arterial pressure. Shock in the presence of sepsis was considered septic shock. We report 30-day mortality.

Patients were categorized into two groups, i.e., patients developing complications and without complications. In addition, to translate the results to clinical recommendations and to reflect complication severity, patients with post-operative complications were categorized into three mutually exclusive complication groups. Patients could either have purely surgical complications, purely infectious complications, or combined surgical and infectious complications. We studied biomarker levels at days 0–3 and their fractional change (∆) at day 3, i.e., day 3 divided by day 0 biomarker levels. Since most symptoms of complications appear after post-operative day 3, the levels measured between days 0 and 3 were considered early diagnostic for complications presenting between days 4 and 10. We used IBM SPSS statistics for Windows version 20 (IBM SPSS, Chicago, IL, USA) to analyze the data, except for analyzing the area under the receiver operating characteristics curve (AUROC). We present data as median (inter-quartile range) since many continuous data were non-normally distributed (Kolmogorov-Smirnov test, P < 0.05). We used a Kruskal-Wallis test and Mann-Whitney U test to study group differences in continuous variables and the X ² or Fisher exact test for categorical variables. To evaluate the early diagnostic value of biomarker levels for groups, we calculated the AUROCs, for which non-Gaussian data were logarithmically transformed. Only the AUROC analyses were performed using MedCalc for Windows, version 13 (MedCalc Software, Ostend, Belgium). We considered an AUROC ≥ 0.70 as clinically relevant. The optimal diagnostic cutoff value was calculated as suggested by Zweig and Campbell.25 To calculate the optimal criterion, this method takes the disease prevalence and cost of true- and false-positive and true- and false-negative decisions into account.25 The Holm-Bonferroni method was used to correct for multiple testing.26 We used multiple logistic regression with backward selection of logarithmically transformed biomarker levels to study their interdependency for the diagnosis of post-operative complications in general, complication subtypes, and anastomotic leakage. We performed the Hosmer-Lemeshow test to evaluate the goodness of fit. All tests were two-sided, and P values < 0.05 were considered statistically significant; exact P values are given unless < 0.001.