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

BMC Anesthesiol. 2022;22(232)

Conclusions

The HRG levels on POD 1 in patients who developed postoperative complications were significantly lower than those in patients who did not develop postoperative complications. Furthermore, the ability of HRG to predict postoperative complications was superior to that of WBC and CRP and similar to that of PCT and P-SEP. Thus, HRG levels may be useful biomarkers for predicting postoperative complications. Future studies are needed on the usefulness of HRG in predicting postoperative complications based on clinical departments and complications.

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Acknowledgements
We would like to thank Mariko Shimizu (Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan) for her help in obtaining informed consent and collecting samples and Hiroko Yasuda (Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan) for her help in obtaining informed consent and gathering samples and measurements. We would also like to thank Editage (www. edita ge. com) for English language editing.

Funding
This work was supported by KAKENHI provided by the Japan Society for the Promotion of Science [grant number, 19K18297] to KK.

Availability of data and materials
The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
This study was performed in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects. This study was approved by the institutional ethics review board of Okayama University Hospital (Okayama, Japan) on August 14, 2020 (approval number: 2007–006). According to the instruction of the ethics review board, after describing the study protocol, verbal informed consent for study participation was obtained from all patients. This information has been preserved as an electronic medical record. All patients received a detailed description of the study and were provided with contact information in case of further clarification, any additional questions, or concerns.

Consent for publication
Prior to inclusion in the study, verbal informed consent for publication was obtained from all patients. This information has been preserved as an electronic medical record.

Table 1. Patient characteristics
	No-complication group (n = 90)	Complication group (n = 60)	P-value
Preoperative factors
Age (years), and median (IQR)	63.0 (51.0–72.0)	71.0 (60.3–76.0)	0.009
Male sex, n (%)	42 (46.7)	36 (60.0)	0.134
Comorbidity, n (%)
Hypertension	40 (44.4)	30 (50.0)	0.510
Diabetes	22 (24.4)	10 (16.7)	0.311
Cardiovascular disease	11 (12.2)	16 (26.7)	0.030
Asthma	5 (5.6)	1 (1.7)	0.403
COPD	4 (4.4)	5 (8.3)	0.485
Liver cirrhosis	1 (1.1)	3 (5.0)	0.302
Chronic kidney disease (eGFR ≤ 50)	9 (10.0)	12 (20.0)	0.097
Acute infection	1 (1.1)	1 (1.7)	0.999
Autoimmune disease	7 (7.8)	4 (6.7)	0.999
Preoperative use of steroids	6 (6.7)	2 (3.3)	0.477
Preoperative use of heparin	1(1.1)	1(1.7)	0.999
ASA-PS ≥ III	17 (19.0)	23 (38.0)	0.014
Preoperative SOFA score, median (IQR)	0 (0–0)	0 (0–1)	0.085
Intraoperative factors
Operative time, min, median (IQR)	249.5 (159.5–379.5)	398.5 (291.3–565.0)	< 0.001
Volume of bleeding (mL), median (IQR)	97.5 (5.0–267.5)	300 (120.0–888.8)	< 0.001
Fluid balance (mL), median (IQR)	1432.5 (962.5–2109.5)	2710.5 (1665.0–3920.8)	< 0.001
SAS, median (IQR)	7.0 (6.0–8.0)	6.0 (4.3–7.0)	< 0.001
Postoperative factors
APACHE II score on admission to the ICU, median (IQR)	9 (7–11)	11 (9–14)	0.003
Postoperative SOFA score, median (IQR)	1.0 (0–3.0)	4.0 (2.3–5.8)	< 0.001
ICU stay (days), median (IQR)	2 (2–2)	4 (2–6)	< 0.001
Hospital stay (days), median (IQR)	16.0 (12.8–21.3)	29.0 (20.0–37.0)	< 0.001
Death within 28-days after surgery, n (%)	0	0	−

APACHE II Score Acute Physiology and Chronic Health Evaluation II Score, ASA-PS American Society Anesthesiologists Physical Status Classification, COPD chronic obstructive pulmonary disease, GFR estimated glomerular filtration rate, ICU intensive care unit, IQR interquartile range, n numbers, SAS surgical Apgar score, SOFA Score Sequential Organ Failure Assessment Score

Table 2. White blood cell, C-reactive protein, procalcitonin, and presepsin levels on postoperative day 1
	No-complication group (n = 90)	Complication group (n = 60)	P-value
WBC (/μL)	9265.0 (7275.0–11,927.5)	9585.0 (7557.5–11,267.5)	0.877
CRP (mg/dL)	3.32 (1.66–5.78)	4.68 (2.75–6.49)	0.036
PCT (ng/mL)	0.06 (0.03–0.18)	0.25 (0.12–0.75)	< 0.001
P-SEP (pg/mL)	447.5 (355.3–597.5)	778.5 (578.8–1047.5)	< 0.001

Expressed as median (IQR)
CRP C-reactive protein, IQR interquartile range, P-SEP presepsin, PCT procalcitonin, WBC white blood cell

Table 3. Associations between biomarkers and postoperative complications
Variables	Univariate analysis			Multivariate analysis
Variables	Unadjusted HR (95% CI)	P-value	Harrell C-index	Adjusted HR (95% CI)	P-value
HRG	0.92 (0.88–0.96)	< 0.001	0.65	0.94 (0.90–0.99)	0.014
WBC/1000	0.98 (0.90–1.06)	0.554	0.50	0.97 (0.89–1.06)	0.484
CRP	1.08 (1.003–1.16)	0.042	0.59	1.03 (0.96–1.11)	0.453
PCT	1.06 (1.01–1.11)	0.019	0.73	1.03 (0.98–1.09)	0.284
P-SEP/100	1.18 (1.12–1.24)	< 0.001	0.73	1.13 (1.06–1.20)	< 0.001

HR hazard ratio, Adjusted HR hazard ratio adjusted for age, presence of preoperative cardiovascular comorbidities, American Society Anesthesiologists Physical Status Classification, operative time, and volume of intraoperative bleeding, CRP C-reactive protein, HRG histidine-rich glycoprotein, P-SEP presepsin, PCT procalcitonin, WBC white blood cell