Histidine-rich Glycoprotein as a Novel Predictive Biomarker of Postoperative Complications in Intensive Care Unit Patients

A Prospective Observational Study

Masahiko Oiwa; Kosuke Kuroda; Naoya Kawanoue; Hiroshi Morimatsu

Disclosures

BMC Anesthesiol. 2022;22(232) 

In This Article

Results

Patient Characteristics

Patient characteristics are shown in Table 1. Eligible patients were prospectively included from September 17, 2020 to November 11, 2020. Figure 1 shows the patient flow. The data of 150 patients were included in the final sample and analyzed. None of the patients dropped out during the follow-up period. The patients were hospitalized in the departments of respiratory surgery (31 patients), neurosurgery (30 patients), hepato–biliary–pancreatic surgery (25 patients), gastrointestinal surgery (19 patients: esophageal surgery, 17 patients and colorectal surgery, two patients), cardiovascular surgery (12 patients), urology (nine patients), oral surgery (eight patients), otolaryngology (seven patients), orthopedic surgery (five patients), and breast–thyroid surgery (four patients).

Figure 1.

Patient flow chart. ICU intensive care unit

Ninety patients with Clavien–Dindo grades 0–I were included in the 'no-complication group', and 60 patients with Clavien–Dindo grades II–IV were included in the 'complication group'. The overall incidence of postoperative complications was 40%. In the complication group, 33 patients had Clavien–Dindo grade II, nine had grade III (eight patients, grade IIIa and one patient, grade IIIb), and 18 patients had grade IV (14 patients had grade IVa and four patients had grade IVb). Postoperative complications included hypotension in 11 patients, hemorrhage in seven patients, atelectasis/sputum excretion difficulty in six patients, thrombosis/embolism in six patients, intraabdominal abscess in six patients, and others in 24 patients. Twenty-seven patients underwent drainage or change in antibiotics due to infection. Details of postoperative complications are provided in Supplementary Table 1 in Additional file 1. The distribution of the participants in the no-complication and complication groups per clinical department is shown in Supplementary Table 2 in Additional file 2. Postoperative complications developed on median POD 3 (IQR, 1–5 days).

Regarding preoperative factors, patients in the complication group had significantly higher age, higher incidence of cardiovascular diseases, and more instances of ASA-PS ≥ III than those in the no-complication group. Regarding the intraoperative factors, patients in the complication group had a significantly longer operative time and greater amount of bleeding and intraoperative fluid balance than those in the no-complication group. The SAS in the complication group was significantly lower than that in the no-complication group. Regarding postoperative factors, ICU and hospital stays in the complication group were significantly longer than those in the no-complication group. Among all patients, no deaths occurred within the first 28 days after surgery.

HRG and Other Biomarker Levels

Figure 2 shows that the HRG levels on POD 1 in the complication group (21.50 μg/mL [IQR, 18.12–25.74 μg/mL]) were significantly lower than those in the no-complication group (25.46 μg/mL [IQR, 21.05–31.63 μg/mL]) (P < 0.001). Table 2 shows the WBC, CRP, PCT, and P-SEP levels on POD 1. The CRP, PCT, and P-SEP levels on POD 1 in the complication group were higher than those in the no-complication group. The WBC levels on POD 1 were not significantly different between the two groups.

Figure 2.

Plasma HRG levels on postoperative day 1 in the groups with and without postoperative complications. The box shows the median, 25th, and 75th percentiles. Bars represent the 5th and 95th percentiles. The Mann–Whitney U test was used. P < 0.05 was considered significant. HRG histidine-rich glycoprotein, POD 1 postoperative day 1

Biomarkers' Ability to Predict Postoperative Complications

Table 3 shows the association between biomarkers and postoperative complications. In the univariate analyses, we found that the HRG, CRP, PCT, and P-SEP levels were significantly associated with postoperative complications, but the WBC levels were not. Furthermore, the Harrell C-index scores for postoperative complications were HRG, 0.65; WBC, 0.50; CRP, 0.59; PCT, 0.73; and P-SEP, 0.73. In multivariate analyses, after adjustment for confounding factors, such as age, presence of preoperative cardiovascular comorbidities, ASA-PS, operative time, and volume of intraoperative bleeding, only HRG and P-SEP were found to be independent predictors of complications.

Furthermore, we performed ROC curve analysis to compare the predictive ability of each biomarker. The area under curve (AUC) was HRG, 0.69; P-SEP, 0.76; PCT, 0.77; CRP, 0.60; and WBC, 0.51. The AUC for HRG was significantly higher than that of WBC (P = 0.005). There was no significant difference among the AUCs of HRG, P-SEP, PCT, and CRP. The sensitivity and specificity of the HRG levels to predict postoperative complications at the cut-off level of 24.21 μg/mL were 0.73 and 0.57, respectively (Figure 3). Furthermore, when the analyzed patients were divided into a high-HRG group and a low-HRG group using this cut-off level, the postoperative complication rate of the low HRG group (n = 83) was significantly higher than that of the high HRG group (n = 67) (Figure 4).

Figure 3.

Receiver operating characteristic curves for predicting postoperative complications. Receiver operating characteristic curves of HRG, P-SEP, PCT, CRP, and WBC. CRP C-reactive protein, HRG histidine-rich glycoprotein, P-SEP presepsin, PCT procalcitonin, WBC white blood cell

Figure 4.

Kaplan–Meier curves. Patients were classified into two groups of high (n = 67) and low (n = 83) HRG levels, using a cut-off level of 24.21 μg/mL. The Kaplan–Meier method and log-rank test were used. P < 0.05 was considered significant. HRG histidine-rich glycoprotein

HRG Levels Between the Subgroups With and Without Postoperative Complications by Clinical Department

We examined the differences in the means of the HRG levels on POD 1 between the no-complication and complication groups in patients of the respiratory surgery (n = 31) and hepato–biliary–pancreatic surgery (n = 25) departments. The difference was set as [means of HRG levels on POD 1 in the no-complication group] minus [means of HRG levels on POD 1 in the complication group] and was found to be nonsignificant. For details, see Supplementary Figure 1 in Additional file 3. The number of patients in the other clinical departments did not suffice for examining between-group differences.

HRG and Other Biomarker Levels in the Groups With and Without Postoperative Infectious Complications

We classified the complication group into two subgroups: those who developed infectious complications (infectious-complication group, n = 27) and those who developed non-infectious complications (non-infectious-complication group, n = 33). HRG and other biomarker levels on POD 1 were compared between the no-complication, non-infectious-complication, and infectious-complication groups. The HRG, PCT, and P-SEP levels on POD 1 were significantly different among the three groups (HRG, P < 0.001; PCT, P < 0.001; P-SEP, P < 0.001, respectively). However, there was no significant difference in HRG, PCT, and P-SEP levels on POD 1 between the infectious- and non-infectious-complication groups. The CRP and WBC levels on POD 1 were not significantly different among the three groups. For details, see Supplementary Figure 2 in Additional file 4.

HRG and Other Biomarker Levels and Severity of Postoperative Complications

We divided the complication group into two subgroups: those classified as Clavien–Dindo grade II (mild-complication group; n = 33) and those classified as Clavien–Dindo grades III and IV (severe-complication group; n = 27). The HRG and other biomarker levels on POD 1 were compared between the no-complication, mild-complication, and severe-complication groups. The HRG, PCT, and P-SEP levels on POD 1 were significantly different among the three groups (HRG, P < 0.001; PCT, P < 0.001; P-SEP, P < 0.001, respectively). Furthermore, the P-SEP levels on POD 1 in the severe-complication group were higher than those in the mild-complication group. However, there was no significant difference in the HRG and PCT levels on POD 1 between the mild- and severe-complication groups. The CRP and WBC levels on POD 1 were not significantly different among the three groups. For details, see Supplementary Figure 3 in Additional file 5.

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