ARTICLE IN PRESS

Phytomedicine 16 (2009) 683689

www.elsevier.de/phymed

Clinical observation of Danhong Injection (herbal TCM product from

Radix Salviae miltiorrhizae and Flos Carthami tinctorii) in the treatment
of traumatic intracranial hematoma
M. Suna, J.-J. Zhangb, J.-Z. Shana,, H. Zhangc, C.-Y. Jina, S. Xua, Y.-L. Wanga
a
Department of Traditional Chinese Medicine, Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou,
Zhejiang 310009, PR China
b
Chinese Journal of Integrative Medicine Press, Beijing 100091, PR China
c
Department of Neurosurgery, Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou,
Zhejiang 310009, PR China

Abstract
Danhong Injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae
Miltiorrhizae and Flos Carthami tinctorii, has the actions of promoting blood circulation and resolving stasis to
promote regeneration. The clinical therapeutic effects of DHI on traumatic intracranial hematoma (TICH) were
observed. Eighty patients with TICH were randomly assigned to trial group and a control group (40 patients per
group), and all were administered with routine medication. Additionally, DIH was administered intravenously to
patients in the trial group. Pre and post-treatment GCS was observed in the two groups, along with GOS after therapy.
The intracranial hematoma absorption, hemorheological changes, and changes in coagulation indexes pre- and post-
treatment were evaluated. The results indicated that GCS and GOS after therapy for the trial group were superior to
those for the control group (po0.05). There was a signicant post-treatment difference in the intracranial hematoma
absorption between the two groups (po0.01). Each hemorheological index in the trial group improved signicantly as
compared with that of the control group (po0.05 or po0.01). The plasma levels of brinogen and D-dimer in the trial
group were signicantly decreased after therapy (po0.01). These results suggest that DHI is conducive to the recovery
of patients with TICH.
r 2009 Elsevier GmbH. All rights reserved.

Keywords: Danhong injection (Salvia miltiorrhiza; Carthamus tinctorius); Traumatic intracranial hematoma; Clinical observation;
Hemorheology; Coagulation function

Introduction
Traumatic intracranial hematoma (TICH) is a com-
mon severe encephalopathy secondary to brain injury.
Corresponding author. Tel./fax: +86 571 51216168.
E-mail addresses: shan6666@yahoo.cn,
shan6666@sina.com (J.-Z. Shan).
Its incidence has increased along with the increased use
of motor vehicles, along with higher fatality and
deformity rates (Holm et al. 2005). Brain tissue injury
and intracranial hematoma after brain injury may
induce brain edema and increased intracranial pressure.
Cerebral blood ow may decrease, resulting in the
contraction of vessels all over the body, contraction of
local cerebral vessels and disorders of cerebral blood

0944-7113/$ - see front matter r 2009 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2009.03.020
 ARTICLE IN PRESS
684 M. Sun et al. / Phytomedicine 16 (2009) 683689
circulation, including cerebral capillary spasm, increased
vasopermeability, hemorheological changes (Daniel et al.
1997). These factors may further accelerate cerebral
ischemia and hypoxia, thus further aggravating the
edema of injured brain tissue. Cerebral edema is the
most signicant secondary pathological lesion after
brain injury. Therefore, reducing cerebral edema and
improving cerebral microcirculation disturbance are
of great signicance for the treatment of brain injury
(Cao et al. 2002).
The diagnosis rate of TICH has improved greatly with
the use of computed tomography (CT) and Magnetic
resonance imaging (MRI). These also provide reliable
scientic evidence for clinical tracing, observation, and
absorption judgment of small and moderate-sized hema-
tomas in nonsurgical treatment. Symptomatic treatments
such as dehydration therapy to reduce cranial pressure,
pain relief, and so on are often adopted in neurosurgery
for those having small and moderate-sized, non-life-
threatening hematomas. The therapeutic course is rather
longer, but the clinical results obtained are not satisfac-
tory (Li et al. 2003). However, TICH treated with
additional Chinese materia medica in the early phase
may result in satisfactory therapeutic effects with im-
proved safety (Liu et al. 2007; Chen and Shao 2005).
Danhong Injection (DHI), a Chinese materia medica
standardized product extracted from the herbal Radix
Salviae Miltiorrhizae and Flos Carthami, promotes
blood circulation and resolves stasis, and removes stasis
to promote regeneration. Its main components include
tanshinone, tanshinol acid, safor yellow, etc. Pharma-
cological studies show that Radix Salviae miltiorrhizae
extract dilates cerebral arteries, lowers vascular resis-
tance and blood viscosity, and enhances erythrocyte
deformability; it also can clear oxygen free radicals,
antagonize the inow of calcium ions, and improve the
activities of adenosine triphosphatase. Meanwhile, it
may also improve the anti-hypoxia capacities of brain
tissue and exhibit protection of brain tissue (Tai et al.
2005). The avanoid Safor yellow is one of the main
compounds in Flos Carthami, with pharmacological
activities including vasodilation, antioxidation, protect-
ing cardiac muscle and brain from injury, decreasing
blood pressure, and suppressing immune function.
Flos Carthami extract in vivo and in vitro clearly
inhibits platelet aggregation, shows certain inhibition
of the activation of the intrinsic coagulation system,
and plays a role in increasing the blood ow of cerebral
arteries and nourishing brain cells (Xin et al. 2004).
DHI has shown signicant therapeutic effect when
applied extensively to the treatment of TICH in the
authors hospital. Therefore, the aim of this clinical
study was to observe the short- and long-term ther-
apeutic effects of DHI in the treatment of acute TICH,
and to explore its possible mechanisms using hemor-
heological indexes.
Materials and methods
Subjects
Eighty patients with TICH at the Second Hospital
afliated to Zhejiang University from Dec 2005 to
Mar 2008 participated in the study. The causes for
TICH ranged from trafc accident injury to falling from
higher places, to being hit. The patients were randomly
assigned to the two groups upon admission to the
hospital. The patients met the diagnostic criteria of mild
and moderate TICH (Wang 2005), as follows: those who
were admitted within 24 hours after a cerebral injury
conrmed by CT; with an intracranial hemorrhage
volume between 10 and 40 ml; with no continuously
enlarged hematoma after consecutive head CT exam-
inations within 3 days, but not scheduled for surgery;
aged between 16 and 65 years; and all with Glasgow
coma score (GCS) greater than 8 (Teasdale and Jennett
1974). Exclusion criteria were: severe cardio-/cerebral
vascular diseases; liver or renal diseases; diabetes
mellitus; other severe organ injuries; coagulation dis-
orders; obviously enlarged hematoma conrmed by
head CT and/or aggravated symptoms indicating a need
for surgery. Written informed consent was obtained
from each subject after the nature, purpose and
potential risks of the study had been explained.
Preparation of Danhong Injection
DHI is manufactured by Shandong Buchang Phar-
macy Co. Ltd. The raw materials of danshen root and
safower were from a standard medicinal herbs resource
base established by Buchang Pharmacy. The two core
technologies adopted were ultra-high speed centrifugal
separation and membrane separation in the manufac-
turing technology. Quantities of 750 g danshen root and
250 g safower were boiled twice with 1000 ml water
added, for 1 h each time. The decoction was combined,
ltered, claried after cold storage, and then ltered. A
suitable amount of gelatin was added to the ltrate, and
the ltrate was cold stored and ltered. The ltrate was
concentrated to the relative density of 1.10-1.20, and
alcohol was added to the raise alcohol content to more
than 80%. The ltrate was then cold stored and ltered,
with the pH value readjusted. Following cold storage,
the alcohol was recovered from the ltrate till it had no
alcohol taste, water was added to achieve a volume of
1000 ml, then the ltrate was cold stored. The ltrate
was ltered once more, with water added to the ruled
volume, subpackaged and sterilized. Thus the DHI was
obtained. HPLC ngerprint analysis (Fig. 1) shows that
the total amount of danshensu sodium and Protocate-
chuic Aldehyde was 1.5 mg/ml, containing 11 mg/ml
safor yellow.
 ARTICLE IN PRESS
M. Sun et al. / Phytomedicine 16 (2009) 683689
VWD1 A, Wavelength = 288 nm (DANHONG\04041205.D)
70
60
50
40
mAU
30
20 3
2 5
10 1 4
0
0 10 20
Fig. 1. HPLC-ngerprint analysis of Danhong injection provided by Shangdong Buchang Pharmacy Co. Ltd. (1) Protocatechuic
aldehyde, (2) protocatechuic acid, (S) danshensu sodium (Hydroxy-dihydro-caffeic acid), (4) safor yellow A, (6) salvianolic acid B,
(13) Quercetin.
Performance of HPLC-ngerprint analysis of
Danhong Injection (Fig. 1)
HPLC-analysis was performed using an LC-system
consisting of an HP Agilent 1100 series quaternary
pump with a degasser and photodiode array detector.
The samples were injected to an HP Agilent 1100
Autosampler with thermostated column compartment
(Temp. 30 1C) with Diamonsil ODS C18 column (5 mm,
200 mm, 4.6 mm). Detection wavelength was 288 nm
and ow rate 1.2 ml/min. Mobile phase: acetonitrile-
o-phosphoric acid (0.026%).
Gradient elution ratio was:
0 min: acetonitrile 2, o-phosphoric acid 98
30 min: acetonitrile 22, o-phosphoric acid 78
60 min: acetonitrile 26, o-phosphoric acid 74
Study design
This study was a random clinical study, which
was approved by the Medical Ethics Committee. The
patients were randomly assigned to two groups of
40 each. In the trial group, there were 31 males and
9 females, aged 1664 years, 38.23714.25 years on
average; among them were 13 cases of epidural
hematoma, 10 of subdural hematoma, 10 of TICH,
and 7 of multiple hematoma. The average intracranial
hemorrhage had a volume of (28.2377.89) ml. There
were 32 males and 8 females in the control group,
aged 1765 years, 38.58712.79 years on average;
among them were 12 cases of epidural hematoma, 12
of subdural hematoma, 11 of TICH, and 5 of multiple
hematoma. The average intracranial hemorrhage had
a volume of (27.2878.84) ml. Differences in age and
685
12
8 14
10
67 9 11 13
30 40 50
min
intracranial hemorrhage volume between the two groups
were not statistically signicant. Routine Western
medical therapies, including dehydration, cranial pres-
sure lowering, infection prevention and treatment with
antibiotics, brain cell nourishment, stress ulcer preven-
tion and treatment were applied to both groups. Other
hemostasis and symptomatic therapies were also used if
necessary. DHI, a standard extract injection of Shan-
dong Buchang Pharmaceutical Co. Ltd. (10 ml each,
containing Radix Salviae Miltiorrhizae 7.5 mg and Flos
Carthami 2.5, mg respectively), 30 ml in 250 ml normal
saline was additionally administered intravenously to
patients in the trial group, once daily for 7 days as one
therapeutic course, for 2 successive courses.
Glasgow coma score (GCS) and Glasgow outcome
score (GOS)
Each patient was scored by a specically appointed
person according to GCS (Jennett et al. 1981) and GOS
pre-treatment and on the 14th day of the therapy. The
short-term efcacies of treatment in the two groups were
judged according to GCS (Philipp et al. 2008) and the
intracranial hemorrhage volume. The long-term efca-
cies of treatment in the two groups were evaluated
according to GOS: (1: death; 2: persistent vegetative
state; 3: severe disability; 4: moderate disability; 5: good
recovery). 3 months post-treatment was set as the
evaluation time.
Detection of hemorheological indexes
Blood samples were collected according to routine
clinical protocol. Venous blood was withdrawn pre-
treatment and on the 14th day of the therapy to detect
 ARTICLE IN PRESS
686 M. Sun et al. / Phytomedicine 16 (2009) 683689
the hemorheological indexes of the two groups, using an
automatic analyzer (Zhongchiweiye, ZL9000 plus),
including whole blood viscosity (1 S 1, 5 S 1, 30 S 1,
and 200 S 1), plasma viscosity, and erythrocyte aggre-
gation index. The equipment was operated according
to the protocols by the technicians at the Department
of clinical laboratory in Second Hospital afliated to
Zhejiang University.
Coagulation detection
5 ml venous blood was withdrawn pre-treatment and
on the 14th day of the therapy to detect prothrombin
time (PT), PT international normalized ratio (INR),
activated partial thromboplatin time (APTT), thrombin
time (TT), brinogen (Fbg), D-dimer (DD). The
equipment was operated according to the protocols
by the technicians at the Department of Tests (Sysmex
CA-7000) in Second Hospital afliated to Zhejiang
University.
Assess of intracranial hematoma volume
The hematoma volume was calculated using Tadas
formula (Tada et al. 1981) according to head CT
(16-row spiral CT, Siemens). Head CT examinations
were conducted pre-treatment, on the 7th and 14th days
post-treatment to ascertain the absorption of intracra-
nial hematoma. The patient data of the two groups pre-
treatment showed no signicant difference (p40.05).
Monitoring of adverse reaction
During the study, various side-effects (i.e. dizziness,
cardiopalmus, fever, rash, et al.) were monitored. 5 ml
venous blood was withdrawn pre-treatment and on the
14th day of the therapy to test the blood routine
(Beckman coulter LH9000), liver and renal functions
(OLYMPUS AU4000) in the two groups pre- and post-
treatment. The equipment was operated according to the
protocols by the technicians at the Department of Tests
in Second Hospital afliated to Zhejiang University.
Statistical analysis
All experimental data are presented as mean7
standard deviation. A paired t-test was used for pre-
and post- treatment comparisons. An independent-
samples t-test was used to compare the post-treatment
data between the trial group and the control group,
and a Chi-square test was taken for nonparametric data.
All analyses were performed using the SPSS statistical
software package (version 16.0), and po0.05 was
considered statistically signicant.
Results
Effect on GCS
Table 1 showed signicant difference in GCS of the
trial group between pre- and post-treatment (po0.01);
and an obvious difference in GCS of the control group
between pre- and post-treatment (po0.05). The post-
treatment score of the trial group was clearly higher
than that of the control group, with signicant
difference (po0.01).
Comparison of hemorheological indexes in the two
groups pre- and post-treatment
Table 2 showed that each hemorheological index in
the two groups pre-treatment increased with no
signicant difference. There was signicant difference
in the hemorheological indexes of the trial group pre-
and post-treatment (po0.01). There was obvious
difference in the hemorheological indexes of the control
group pre- and post-treatment (po0.05). The improve-
ment of each index in the trial group was obviously
superior to that in the control group with signicant
difference (po0.05 or po0.01).
Comparison of coagulation indexes in the two groups
pre- and post-treatment
Table 3 showed signicant difference in the brinogen
and D-dimer in the trial group between pre- and post-
treatment tests (po0.05). There was also a signicant
difference in the two indexes between the two groups
post-treatment (po0.01). There was no signicant
difference in the rest of the indexes between the two
groups pre- and post-treatment (p40.01).
Comparison of intracranial hematoma absorption in
the two groups pre- and post-treatment
Fig. 2 shows that the post-treatment hematoma
volume of the trial group was signicantly reduced
as compared with pre-treatment volume (po0.01).
Table 1. Comparison of GCS score in the control and trial
groups (Score).
Group Pre-treatment Post-treatment
Trial 9.9871.31 11.8870.97a,b
Control 10.0371.23 11.1071.15c
a
po0.01, pre-treatment vs. post-treatment.
b
po0.01, trial group vs. control group of post-treatment.
c
po0.05, pre-treatment vs. post-treatment.
 ARTICLE IN PRESS
M. Sun et al. / Phytomedicine 16 (2009) 683689 687

Table 2. Comparison of hemorheological indexes in the two groups pre- and post-treatment.

Group Whole blood viscosity (mpa s) Plasma Viscosity Erythrocyte

(mpa s) aggregation
1 1 1 1
1S 5S 30 S 200 S

Trial
Pre-treatment 20.8671.14 9.1870.19 5.4870.19 4.2170.21 1.6270.67 7.4670.67
Post-treatment 17.6170.85a,b 7.1670.15a 4.8070.23a,b 3.5470.25a,c 1.3770.06a,b 5.3470.25a,b

Control
Pre-treatment 20.6571.21 9.1070.22 5.3670.24 4.2070.19 1.6070.11 6.8770.78
Post-treatment 19.8371.22d 8.5770.30d 4.9970.29d 3.9870.24d 1.4870.82d 5.9170.42d
a
po0.01, pre-treatment vs. post-treatment.
b
po0.05.
c
po0.01, compared with the control group post-treatment.
d
po0.05, pre-treatment vs. post-treatment, control group.

Table 3. Comparison of coagulation functions in the two groups pre- and post-treatment.

Group PT (s) INR APTT (s) TT (s) Fbg (g) DD (ug/l)

Trial
Pre-treatment 12.0370.42 1.0270.55 27.7877.01 15.7073.05 4.4870.59 240.327181.03
Post-treatment 12.0970.63 1.0870.44 28.1275.12 16.2175.51 3.8970.48a,b 189.207101.74a,b

Control
Pre-treatment 12.1070.81 1.0570.30 27.5377.15 15.3976.62 4.5670.67 230.087155.42
Post-treatment 12.0870.51 1.0470.52 27.4478.11 15.6275.37 4.2370.61 214.147144.62
a
po0.05, pre-treatment versus post-treatment.
b
po0.01, compared with the control group post-treatment. PT: prothrombin time; INR: international normalized ratio; APTT: activated partial
thromboplatin time; TT: thrombin time; Fbg: brinogen; DD: D-dimer.

Fig. 2. *po0.05, comparison of intracranial hematoma volume after 1 week and 2 weeks of treatment, vs. pre- and post-treatment.

The post-treatment hematoma volume of the control
group was signicantly reduced as compared with pre-
treatment volume (po0.05). There was a signicant
difference in the hematoma volume between the two
groups post-treatment (po0.05).
Comparison of GOS in the two groups pre- and post-
treatment
The post-treatment GOS in the trial group was
(4.4871.11), with total effective rate of 100%, while
 ARTICLE IN PRESS
688 M. Sun et al. / Phytomedicine 16 (2009) 683689
that in the control group was (4.0270.91), with total
effective rate of 87.5%. There was signicant difference
in GOS between the two groups. GOS in the trial group
was superior to that of the control group (po0.05).
Adverse reaction
No abnormal changes in blood routine examination,
liver or renal functions were seen in all patients. Only
one patient reported a mild rash which resolved without
symptomatic therapy. Apart from this, no other obvious
adverse reaction occurred.
Discussion
TICH belongs to the category of blood stasis in
traditional Chinese medicine (TCM). When the brain
suffers from external force, its blood vessels are injured.
According to TCM theory, blood stasis may block
the upper orices, resulting in qi and blood disorders,
which is basically in accordance with the recognition of
modern medicine (brain edema and cerebral circulation
disturbance are secondary to the compression of brain
tissue by hematoma). Extensive clinical application of
Chinese materia medica known to activate blood circu-
lation and resolve stasis can improve microcirculation,
eliminate toxic products, and attenuate cerebral edema,
thus promoting the absorption of intracranial hemato-
ma and improving the functions of the nervous system
(You et al. 2003).
DHI consists of the well known Chinese material
medica herbal Radix Salviae miltiorrhizae and Flos
Carthami. As the principal agent, Radix Salviae
miltiorrhizae (bitter taste) promotes blood circulation
and dissipates stasis; while as the assist agent, Flos
Carthami (pungent taste) resolves blood stasis and
unblocks collaterals. The two herbs act in combination
to promote blood stasis and unblock collaterals,
removing stasis and regenerating with scientic compat-
ibility according to TCM theory. Some studies show
that DHI plays a role in dilating vessels, clearing oxygen
free radicals, and inhibiting lipid oxidization, and may
protect blood vessel endothelium, improve microcircu-
lation, anticoagulate, and inhibit thrombopoiesis (Jin
2003). DIH may lower the cerebral capillary perme-
ability, cerebral index, and cerebral water content in rats
with cerebral ischemia, thus attenuating brain edema
induced by brain ischemia (Zhang et al. 2007). DIH
may lower total and activities of nitric oxide synthase,
thus reducing the production of nitrogen monoxide
and attenuating tissue injury, showing signicant anti-
oxidative injury. It has a protective effect on brain cells
secondary to local cerebral ischemia (Den et al., 2006).
According to the mechanism of action, the clinical
therapeutic efcacy of DHI was observed in this study.
Routine treatment of TICH in combination with DHI
was proved able to promote the early absorption of
intracranial hematomas, shorten the course of disease,
and improve the prognosis. Its mechanism of action
may be achieved by lowering whole blood viscosity and
brinogen content, promoting brolysis, and improving
microcirculation. No obvious adverse reaction occurred
during the whole therapeutic course. No abnormal
intracranial hematoma expansion or rehemorrhage was
detected during the therapeutic course. No abnormality
was found in the dynamic observation of the patients
coagulation spectrum, indicating DHI was effective
and safe in treatment of TICH, with no possibility
of hemorrhage. These results indicate that DHI maybe
considered as an effective agent in the treatment of
TICH.
Brain injury requires comprehensive treatment. The
importance of routine medicinal treatment cannot be
ignored. Although our study indicates that DHI is
effective in the treatment of TICH, further, randomized,
double-blind and multi-centered studies are still neces-
sary to conrm our conclusions. Further studies are also
needed to verify its precise mechanism of action, the
therapeutic dose and course, and opportunities for
medical use.
References
Cao, M., Hou, Z.M., Yan, Y.S., et al., 2002. Clinical study
of microcirculation alterations after brain injury. Chin. J.
Clin. Neurosurg. 7, 3638.
Chen, W., Shao, J., 2005. Clinical observation of Xuesaitong in
treatment of severe brain injury. J. Emerg. Tradit. Chin.
Med. 14, 443444.
Den, F., Hu, C.L., Xie, Y.L., 2006. Effect of Danghong
Injection on nitrioxide synthase in rats after local cerebral
ischemia. Chin. J. Integr. Med. Cardio-/Cerebrovasc. Dis.
4, 880881.
Daniel, F.K., Neil, A.M., Rouzbeh, K., et al., 1997. Cerebral
blood ow as a predictor of outcome following traumatic
brain injury. J. Neurosurg. 86, 633641.
Holm, L., Cassidy, J.D., Carroll, L.J., et al., 2005. Summary
of the WHO collaborating centre for neurotrauma task
force on mild traumatic brain injury. J. Rehabil. Med. 37,
137141.
Jennett, B., Snoek, J., Bond, M.R., et al., 1981. Disability after
severe brain injury: observations on the use of the Glasgow
Outcome Scale. J. Neurol. Neurosurg. Psychiat. 44,
285293.
Jin, J.Z., 2003. Observation of the therapeutic effect of
Danhong Injection in treatment of bertebrobasilar arterial
insufciency. Chin. J. Gerontol. 23, 839.
Li, C., Liu, W.G., et al., 2003. Comparison of standard large
craniotomy with routine craniotomy in treatment of acute
subdural hematoma. Chin. J. Traumatol. 6, 305308.
 ARTICLE IN PRESS
M. Sun et al. / Phytomedicine 16 (2009) 683689
Liu, Y.X., Gao, J.Z., Wang, G.W., et al., 2007. Clinical
observation of ligustrazine in early treatment of acute brain
injury. Chin. J. Clin. Neurosurg. 12, 755.
Philipp, T., Hans, R.W., Jukka, T., Javier, F., 2008. Outcome
after acute traumatic subdural and epidural haematoma in
Switzerland: a single-centre experience. Swiss Med. Wkly.
138, 281285.
Tada, A., Hisada, K., Suzuki, T., et al., 1981. Measurement
volume of intracranial hematoma by computed tomogra-
phy. No Shinkei Geka 9, 251256.
Tai, M.H., Liu, L.M., Ma, R.Q., 2005. General pharmacology
of Danhong Injection. J. First Mil. Med. Univ. 25, 335338.
Teasdale, G., Jennett, B., 1974. Assessment of coma and impaired
consciousness. A practical scale. Lancet 7872, 8184.
689
Wang, Z.C., 2005. Neurosurgery, vol. 26. Hubei Science and
Technology Press, Wuhan, pp. 435436.
Xin, Q., Li, X.F., Si, D.Y., 2004. Protective effects of
Danshen Honghua Injection on experimental
cerebral ischemia in rats. Chin. Tradit. Patent Med. 26,
222224.
You, H.X., Qiu, J.D., Yang, W., et al., 2003. Clinical study of
ultra-early application of dongshen root injection in
treatment of brain injury. Chin. J. Clin. Neurosurg. 8,
118119.
Zhang, M.L., JIN, J.W., DU, X.F., 2007. Effects of Danhong
Injection on cerebral capillary permeability and cerebral
water content in the experimental rats with cerebral
ischemia. Hebei Med. J. 29, 204205.