Evidence-Based Complementary and Alternative Medicine
Volume 2018 (2018), Article ID 8620198, 6 pages
https://doi.org/10.1155/2018/8620198

Research Article

Japanese Herbal Kampo Hochu-Ekki-To or Juzen-Taiho-To after Surgery for Hip Fracture Does Not Reduce Infectious Complications

Yusuke Sasabuchi,1,2 Hiroki Matsui,² Alan Kawarai Lefor,³ Taisuke Jo,⁴ Nobuaki Michihata,⁴ Kiyohide Fushimi,⁵ and Hideo Yasunaga²

¹Data Science Center, Jichi Medical University, Tochigi, Japan
²Department of Clinical Epidemiology and Health Economics, The University of Tokyo, Tokyo, Japan
³Department of Surgery, Jichi Medical University, Tochigi, Japan
⁴Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
⁵Department of Health Policy and Informatics, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo, Japan

Correspondence should be addressed to Yusuke Sasabuchi; sasabuchi-tky@umin.ac.jp

Received 14 February 2018; Revised 8 April 2018; Accepted 12 April 2018; Published 29 April 2018

Academic Editor: Kenji Watanabe

Copyright © 2018 Yusuke Sasabuchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Infectious complications after hip fracture surgery are common in the elderly. Although experimental studies have suggested that kampo medicine, Hochu-ekki-to and Juzen-taiho-to, can prevent infectious complications, only a few small clinical studies have been published to date. Primary Study Objective. The aim of the present study is to investigate the impact of Hochu-ekki-to or Juzen-taiho-to on postoperative infectious complications in patients undergoing surgery for hip fracture. Methods and Design. In this retrospective cohort study using a nationwide inpatient database in Japan, we performed propensity score matching to compare patients who did or did not receive kampo medicine after surgery for hip fracture. Settings. A nationwide inpatient database. Participants. Patients who did or did not receive kampo medicine after surgery for hip fracture. Intervention. Kampo medicine after surgery for hip fracture. Primary Outcome Measures. Infectious complications. Results. The proportions of postoperative infectious complications were not significantly different between the 424 propensity-matched pairs with and without kampo medicine (11 versus 8, ). Conclusion. The present study suggests that Hochu-ekki-to or Juzen-taiho-to postoperatively is not associated with decreased occurrence of infectious complications in patients who underwent surgery for hip fracture.

1. Introduction

Hip fractures are common in the elderly. With an aging population, the incidence of hip fractures is increasing [1, 2]. The incidence of hip fractures worldwide is estimated to be 2.6 million by 2025 and to exceed 7 million by 2050 [3]. Pneumonia and surgical site infections are common complications after surgery for hip fracture [4, 5]. These complications have been reported to increase mortality after surgery for hip fracture [6, 7].

Japanese herbal kampo medicines have become popular in Japan [8]. Hochu-ekki-to and Juzen-taiho-to are two major kampo medicines, which are used to treat immunocompromised individuals [9, 10]. Experimental studies have suggested that Hochu-ekki-to and Juzen-taiho-to can prevent infectious diseases through enhancing the immune system [11–15]. Although Hochu-ekki-to and Juzen-taiho-to may be promising to prevent infectious diseases, only a few small clinical studies [16–21] have been published to date.

The aim of the present study is to investigate the impact of Hochu-ekki-to or Juzen-taiho-to on postoperative infectious complications in patients undergoing surgery for hip fracture, using a nationwide inpatient database in Japan.

2. Materials and Methods

The Institutional Review Board of the University of Tokyo approved this study. Informed consent was waived due to the anonymous nature of the data.

2.1. Data Source

Patient data were extracted from the Diagnosis Procedure Combination database, which is a nationwide administrative claims database with discharge abstracts representing approximately 50% of all admissions to acute care hospitals in Japan [22, 23]. The Diagnosis Procedure Combination database provides (i) patient demographic data, (ii) admission-precipitating diagnosis, preexisting comorbidities on admission, and complications during hospitalization coded with the International Classification of Diseases, Tenth Revision (ICD-10) codes, (iii) hospital identification number, (iv) dates of procedures performed and dates of medications administered, (v) discharge status, and (vi) dates of hospital or intensive care unit admission and discharge. Physicians in charge record data for diagnoses, comorbidities, and discharge status.

2.2. Patients

In the present study, patients were included if they (i) had a hip fracture (ICD-10 S720, S721, or S722) as the admission-precipitating diagnosis, (ii) underwent surgery (open reduction and internal fixation or hemiarthroplasty) for hip fracture, and (iii) were discharged between July 2010 and March 2014. Exclusion criteria included the following: (i) age < 40 years; (ii) body mass index data being unavailable, less than 10 kg/m² or more than 70 kg/m²; (iii) number of hospital beds being not available.

2.3. Exposure of Interest, Outcomes, and Other Variables

The exposure of interest was whether patients received Hochu-ekki-to or Juzen-taiho-to within seven days of surgery. These patients were defined as the kampo group. Other patients were defined as the control group.

Assessed outcomes include infectious complications and in-hospital deaths. Infectious complications include surgical site infection (SSI, ICD-10, T793, or T814), hospital acquired pneumonia (J10–18), and sepsis (A40 or A41).

Other variables evaluated include age, gender, body mass index, comorbidities extracted using algorithms developed by Quan et al. [24], fracture location, type of surgery, days between admission and the surgery, treatment year, the volume of red cell transfusion, and anesthesia time. As an index for severity, use of mechanical ventilation, administration of catecholamines, administration of red cell transfusion, renal replacement therapy, and admission to a high intensity care unit such as an intensive care unit or high care unit within seven days of surgery are also extracted.

2.4. Statistical Analysis

Continuous variables are presented as the average with the standard deviation. Categorical variables are presented as the number with a percentage. Differences in the baseline characteristics between the kampo group and control group are compared using standardized differences. A standardized difference < 10% indicates a negligible imbalance in baseline characteristics between groups [25].

To estimate the probability that a patient would receive Hochu-ekki-to or Juzen-taiho-to medicine, a propensity score was calculated for each patient using a multivariable logistic regression for receiving kampo medicine. As independent variables, the baseline characteristics shown in Table 1 are incorporated. Patients who received kampo medicine were 1-to-1 matched with patients in the control group on the basis of nearest neighbor matching without replacement. The caliper was set at 20% of the standard deviation of the propensity score. Outcomes between the two groups were compared using Fisher’s exact test. A value < 0.05 is considered statistically significant. Propensity score matching is performed using “Matching” package of R version 3.1.3 (The R Foundation, Vienna, Austria). All other analyses are performed using SPSS version 22 (SPSS Inc., Chicago, Illinois, US).

Table 1: Baseline characteristics before and after propensity score matching.

Prematching cohort
Propensity score matched cohort

Control
Kampo
SMD
Control
Kampo
SMD

Age, years, mean (SD)
82.1 (9.5)
83.0 (8.0)
0.110
83.2 (8.8)
83.0 (8.0)
0.022

Gender, (Female)
158327 (78.6)
332 (78.3)
0.007
334 (78.8)
332 (78.3)
0.011

BMI, kg/m², mean (SD)
20.6 (3.6)
19.7 (3.6)
0.247
19.6 (3.4)
19.7 (3.6)
0.029

Charlson comorbidity

    Myocardial infarction
2702 (1.3)
3 (0.7)
0.063
8 (1.9)
3 (0.7)
0.104

    Congestive heart disease
15246 (7.6)
30 (7.1)
0.019
30 (7.1)
30 (7.1)
<0.001

    Peripheral vascular disease
2766 (1.4)
10 (2.4)
0.073
9 (2.1)
10 (2.4)
0.016

    Cerebrovascular disease
20739 (10.3)
34 (8.0)
0.079
32 (7.5)
34 (8.0)
0.018

    Dementia
26861 (13.3)
62 (14.6)
0.037
68 (16.0)
62 (14.6)
0.039

    Chronic pulmonary disease
8368 (4.2)
35 (8.3)
0.171
44 (10.4)
35 (8.3)
0.073

    Rheumatic disease
4194 (2.1)
10 (2.4)
0.019
7 (1.7)
10 (2.4)
0.050

    Peptic ulcer
7915 (3.9)
31 (7.3)
0.147
31 (7.3)
31 (7.3)
<0.001

    Liver disease
9324 (4.6)
24 (5.7)
0.047
31 (7.3)
24 (5.7)
0.067

    DM without complications
30028 (14.9)
50 (11.8)
0.092
57 (13.4)
50 (11.8)
0.050

    DM with complications
5628 (2.8)
10 (2.4)
0.027
11 (2.6)
10 (2.4)
0.015

    Hemiparaplegia
967 (0.5)
0 (0.0)
0.098
2 (0.5)
0 (0.0)
0.097

    Renal disease
8508 (4.2)
18 (4.2)
0.001
21 (5.0)
18 (4.2)
0.034

    Malignancy
8426 (4.2)
37 (8.7)
0.186
35 (8.3)
37 (8.7)
0.017

    Metastatic cancer
953 (0.5)
10 (2.4)
0.160
8 (1.9)
10 (2.4)
0.033

Antibiotic use within 7 days of surgery
186699 (92.7)
424 (100)
0.398
386 (91.0)
424 (100)
0.444

Mechanical ventilation within 7 days of surgery
784 (0.4)
0 (0.0)
0.088
1 (0.2)
0 (0.0)
0.069

Catecholamine use within 7 days of surgery
11526 (5.7)
30 (7.1)
0.055
26 (6.1)
30 (7.1)
0.038

Transfusion within 7 days of surgery
54494 (27.0)
131 (30.9)
0.085
131 (30.9)
131 (30.9)
<0.001

Renal replacement therapy within 7 days of surgery
661 (0.3)
1 (0.2)
0.017
2 (0.5)
1 (0.2)
0.040

High intensity care unit admission within 7 days of surgery
8470 (4.2)
14 (3.3)
0.047
10 (2.4)
14 (3.3)
0.057

Fracture location

0.059

0.078

    Neck
104352 (51.8)
232 (54.7)

222 (52.4)
232 (54.7)

    Intertrochanteric
92156 (45.7)
182 (42.9)

187 (44.1)
182 (42.9)

    Subtrochanteric
4968 (2.5)
10 (2.4)

15 (3.5)
10 (2.4)

Type of surgery

0.032

0.049

    Open reduction and internal fixation
131393 (65.2)
270 (63.7)

280 (66.0)
270 (63.7)

    Hemiarthroplasty
70083 (34.8)
154 (36.3)

144 (34.0)
154 (36.3)

Anesthesia time category, min

0.113

0.078

    -120
140345 (69.7)
310 (73.1)

322 (75.9)
310 (73.1)

    121–180
46834 (23.2)
94 (22.2)

81 (19.1)
94 (22.2)

    181–240
9857 (4.9)
15 (3.5)

15 (3.5)
15 (3.5)

    241-
4440 (2.2)
5 (1.2)

6 (1.4)
5 (1.2)

Transfusion volume category, mL

0.124

0.090

    0
126060 (62.6)
243 (57.3)

240 (56.6)
243 (57.3)

    1–200
6090 (3.0)
12 (2.8)

12 (2.8)
12 (2.8)

    201–400
32747 (16.3)
77 (18.2)

88 (20.8)
77 (18.2)

    401–600
23752 (11.8)
55 (13.0)

55 (13.0)
55 (13.0)

    601-
12827 (6.4)
37 (8.7)

29 (6.8)
37 (8.7)

Interval between admission and surgery, days, mean (SD)
5.3 (7.3)
5.7 (5.3)
0.066
5.7 (4.7)
5.7 (5.3)
0.009

Hospital volume of surgery for hip fractures/year, mean (SD)
224 (135)
215 (156)
0.060
220.8 (124.1)
215.2 (156.1)
0.040

Fiscal year

0.147

0.022

    2010
29851 (14.8)
70 (16.5)

73 (17.2)
70 (16.5)

    2011
51846 (25.7)
121 (28.5)

120 (28.3)
121 (28.5)

    2012
61030 (30.3)
101 (23.8)

102 (24.1)
101 (23.8)

    2013
58749 (29.2)
132 (31.1)

129 (30.4)
132 (31.1)

Academic hospital
9766 (4.8)
12 (2.8)
0.105
10 (2.4)
12 (2.8)
0.030

Transferred by ambulance
104264 (51.8)
217 (51.2)
0.011
213 (50.2)
217 (51.2)
0.019

Number of beds categories

0.109

0.079

    -200
27331 (13.6)
61 (14.4)

61 (14.4)
61 (14.4)

    201–400
86723 (43.0)
164 (38.7)

167 (39.4)
164 (38.7)

    401–600
61855 (30.7)
149 (35.1)

153 (36.1)
149 (35.1)

    601–800
18835 (9.3)
37 (8.7)

35 (8.3)
37 (8.7)

    801-
6732 (3.3)
13 (3.1)

8 (1.9)
13 (3.1)

Numbers and percentages are presented unless otherwise stated. SD, standard deviation; SMD, standardized mean difference; BMI, body mass index; DM, diabetes mellitus.

3. Results

After inclusion and exclusion criteria were applied, a total of 201,900 patients were included in the analysis (Figure 1). Of these, 424 patients received Hochu-ekki-to (259 patients) or Juzen-taiho-to (165 patients) within seven days of surgery.

Figure 1: Study flow diagram.

Table 1 shows a comparison of baseline characteristics of patients in the kampo group and the control group before and after propensity score matching. Before propensity score matching, patients in the kampo group were more likely to have chronic pulmonary disease, peptic ulcer, and malignancy. Anesthesia time was shorter and the amount of transfusion was less in the kampo group. After propensity score matching, baseline characteristics between the two groups are well balanced.

Table 2 shows outcomes comparing the two groups. After propensity score matching, neither infectious complications nor in-hospital death was significantly different between the groups.

Table 2: Outcomes before and after propensity score matching.

Prematching cohort
Propensity score matched cohort

Control
Kampo

Control
Kampo

In-hospital death, (%)
3552 (1.8)
8 (1.9)
0.852
6 (1.4)
8 (1.9)
0.394

Infectious complications, (%)
4647 (2.3)
12 (2.8)
0.578
6 (1.4)
12 (2.8)
0.234

    Hospital-acquired pneumonia, (%)
2830 (1.4)
6 (1.4)

5 (1.2)
6 (1.4)

    Surgical site infection, (%)
1239 (0.6)
3 (0.7)

1 (0.2)
3 (0.7)

    Sepsis, (%)
710 (0.4)
4 (0.9)

2 (0.5)
4 (0.9)

4. Discussion

In this retrospective study using a nationwide administrative database in Japan, postoperative use of Hochu-ekki-to or Juzen-taiho-to was not associated with decreased occurrence of postoperative infectious complications or in-hospital death for patients undergoing surgery for hip fracture.

Previous animal studies have suggested immunostimulating properties of Hochu-ekki-to and Juzen-taiho-to. However, only a few small clinical studies have been conducted. Hochu-ekki-to prevented immunosuppression induced by surgery [17] or inhibited rhinovirus infection in airway epithelium [18]. Clinical studies of Juzen-taiho-to have shown improved host immunity in patients with brain tumors [21] and a significantly decreased frequency of otitis media was in children [19, 20].

There are several possible explanations why the results of the present study failed to show a favorable effect of the drugs. First, the timing of administration of the kampo medicine may not be appropriate. In the present study, the kampo group received Hochu-ekki-to or Juzen-taiho-to within seven days of surgery, whereas patients received kampo medicine before surgery in a previous study [17]. Postoperative administration of kampo medicine may not sufficiently reduce postoperative infectious complications in patients undergoing surgery for hip fracture. Second, previous studies mainly included infection-prone patients. Although the patients in the present study were older (mean age more than 80 years), most of these patients may have been immunocompetent. Hochu-ekki-to or Juzen-taiho-to may be effective in immunocompromised patients. Lastly, the lack of a significant reduction in infective complications may be due to type II error. Further study, including larger numbers of patients, is warranted.

We acknowledge that the present study has several limitations. First, despite the use of propensity score matching, residual confounding may bias the results because of the retrospective nature of the study. Second, the study does not show a preventive effect for infectious complications of kampo medicine; however, the sample size may not be sufficiently large to detect a difference between the groups. Third, the database does not contain information before admission or after discharge. Patients may have had Hochu-ekki-to or Juzen-taiho-to before surgery or may have suffered from infectious complications after discharge. Fourth, patients who received Hochu-ekki-to or Juzen-taiho-to were from 238 of 1147 hospitals. The fact that patients who received these kampo medicines were from a relatively small fraction of hospitals may bias the results. Fifth, antibiotic usage was not accounted for in estimating the propensity score because it was difficult to differentiate antibiotics use for prevention from use for treatment.

In conclusion, postoperative Hochu-ekki-to or Juzen-taiho-to is not associated with a decrease in the occurrence of infectious complications after surgery for hip fracture. It is possible that receiving Hochu-ekki-to or Juzen-taiho-to only after surgery is not sufficient to prevent postoperative complications.

Data Availability

Data cannot be made publicly available for ethical reasons as the data are patient data. The data are available to interested researchers upon request to the corresponding author, pending ethical approval.

Disclosure

The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. This study was performed at the University of Tokyo.

Conflicts of Interest

None of the authors has any potential financial conflicts of interest related to this manuscript.

Acknowledgments

This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan; and the Japan Agency for Medical Research and Development (AMED). The Department of Health Services Research, Graduate School of Medicine, the University of Tokyo, is funded in part by Tsumura Pharmaceuticals Co. Ltd. (Tokyo, Japan).

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