Myocardial Protective Effects of Shenfu Injection after Mitral Valve Replacement Surgery; A Systematic Review and Meta Analysis

Bong-Jin Shin; Ji-Ho Kim; Mu-Hyeok Ahn; Jung-Nam Kwon; Shin, Bong-Jin; Kim, Ji-Ho; Ahn, Mu-Hyeok; Kwon, Jung-Nam

doi:10.13048/jkm.22038

JKM > Volume 43(3); 2022 > Article

Shin, Kim, Ahn, and Kwon: Myocardial Protective Effects of Shenfu Injection after Mitral Valve Replacement Surgery; A Systematic Review and Meta Analysis

Review Article

The Journal of Korean Medicine 2022; 43(3): 164-180.

Published online: September 1, 2022

DOI: https://doi.org/10.13048/jkm.22038

Myocardial Protective Effects of Shenfu Injection after Mitral Valve Replacement Surgery; A Systematic Review and Meta Analysis

Bong-Jin Shin¹

, Ji-Ho Kim¹

, Mu-Hyeok Ahn¹

, Jung-Nam Kwon¹^{, 2}^{, *}

¹Pusan National University School of Korean Medicine

²Department of Internal Medicine of Korean Medicine, Pusan University Korean Medicine Hospital

Correspondence to: Jung-Nam Kwon, School of Korean medicine, Pusan National University 49, Busandaehak-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, Republic of Korea., Tel: +82-55-360-5956, Fax: +82-55-360-5509, E-mail: jnkwon@pusan.ac.kr

BJS and JHK contributed equally to the work.

Received February 11, 2022 Revised June 30, 2022 Accepted July 15, 2022

Abstract

Objectives

The purpose of this study was to evaluate the effects of shenfu injection on myocardial protective effects after mitral valve replacement surgery.

Methods

We searched four international databases (PUBMED, Embase, Web of Science and CNKI) and three domestic electronic databases (OASIS, RISS and NDSL) for relevant studies. We used following keywords ‘shenfu’, ‘valve replacement’, ‘mitral valve’ at PUBMED, Embase and Web of Science; ‘二尖瓣’, ‘参附注射液’, ‘瓣膜’ at CNKI and ‘이첨판’, ‘판막’, ‘삼부’ at domestic databases. The search range included randomized controlled trials. When appropriate, meta-analyses were performed.

Results

Seven randomized controlled trials were selected. All studies used Shenfu injection after mitral valve replacement surgery. We analyzed myocardial damage, cardiac function, patients’ recovery rate, with various evaluation indicators. We also used meta-analysis for CK-MB, cTnI, MDA and voluntary recovery of heartbeat. CK-MB was analyzed in two subgroups: 8 hours and 24 hours after surgery. Std was −2.34(95% CI −4.10, −0.58) for 8 hours and −1.95(95% CI −4.79 to 0.88) for 24 hours. 8 hours showed statistically significant difference. cTnI appeared significant decrease with Std of −2.13(95% CI −2.60, −1.66). MDA showed significant decrease with Std of −0.95(95% CI −1.43 to −0.47). Voluntary recovery of heartbeat significantly increased with the odd ratio of 4.34(95% CI 1.76, 10.70).

Conclusions

We suggest that Shenfu injection after Mitral valve replacement surgery may have significant myocardial protective effects in terms of reducing myocardial damages, reactive oxygen species, increasing cardiac function and patients’ recovery after surgery. However, the evidence is limited, further research is required.

Keywords: Mitral valve replacement, Myocardial protection, Shenfu injection

Fig 1

PRISMA flow chart.

Fig 2

The meta results of CK-MB in 8 hours (SFI vs Control goup).

Fig 3

The meta results of CK-MB in 24 hours (SFI vs Control goup).

Fig 4

The meta results of cTnI in 8 hours (SFI vs Control goup).

Fig 5

The meta results of MDA in 24 hours (SFI vs Control goup). (502)

Fig 6

The meta results of Voluntary recovery of heartbeat (SFI vs Control goup).

Fig 7

Risk of bias summary.

Fig 8

Risk of bias graph.

Table 1

Characteristics of Selected studies

First author (year)	Subject size (n)		NYHA Class II: Class III (n : n)	Male : Female (n : n)	Age (M±SD)	Criteria
First author (year)	Subject size (n)		NYHA Class II: Class III (n : n)	Male : Female (n : n)	Age (M±SD)	Inclusion criteria	Exclusion criteria
Qing yong (2006)16)	E	20	15:5	8:12	39.0±10.4	Patients undergoing mitral valve replacement with cardiopulmonary bypass	Not mentioned
Qing yong (2006)16)	C	20	13:7	9:11	37.0±9.3		Not mentioned
Li kai (2009)17)	E	20	17:3	10:10	66.8±5.6	Patients undergoing mitral valve replacement surgery	Not mentioned
Li kai (2009)17)	C	20	15:5	7:13	65.6±5.1	Patients undergoing mitral valve replacement surgery	Not mentioned
Zhen Chuandong (2009)18)	E	10	All patients are NYHA Class II or III	Not mentioned	Not mentioned	Patients undergoing mitral valve replacement with cardiopulmonary bypass	Not mentioned
Zhen Chuandong (2009)18)	C	10	All patients are NYHA Class II or III	Not mentioned	Not mentioned		Not mentioned
Wang Fangjun (2010)19)	E	30	All patients are NYHA Class II or III	13:17	34.5±6.1	Patients undergoing mitral valve replacement with cardiopulmonary bypass	Not mentioned
Wang Fangjun (2010)19)	C	30	All patients are NYHA Class II or III	14:16	36.5±5.7		Not mentioned
Wu Jun (2018)20)	E	8	6:2	4:4	46.4±6.3	Patients undergoing mitral valve replacement surgery	Not mentioned
Wu Jun (2018)20)	C	8	6:2	3:5	46.1±6.1	Patients undergoing mitral valve replacement surgery	Not mentioned
Song Zhi-bin (2020)21)	E	39	20:19	26:13	67.37±12.68	Patients with NYHA Grade 2, 3 Patients with severe mitral stenosis by pulsation treatment echocardiography (<1.5cm²)	Need of aortic balloon reverse Treated with antiplatelet drugs, anticoagulants or other drugs within 1 week before the study Patients with severe vascular disease Patients with severe coagulopathy and immunodeficiency Complications of liver and kidney dysfunction Patients with infections and malignancies.
Song Zhi-bin (2020)21)	C	39	18:21	23:16	66.91±13.04
Feng Yi (2020)22)	E	30	Not mentioned	54:66	62.19±0.28	Patients undergoing mitral valve replacement with cardiopulmonary bypass	Not mentioned
Feng Yi (2020)22)	C	30	Not mentioned	54:66	62.19±0.28		Not mentioned

C: Control group, E: Experimental group, M: Mean, SD: Standard Deviation SFI : Shenfu Injection

* Specific number of patients was not mentioned in both groups.

Table 2

Characteristics of Selected studies

First author (year)	Interventions		Results /Time of examination & Results		Adverse events
Qing yong (2006)16)	E	1.0 mL/kg SFI^* was injected before the surgery, after induction of anesthesia, 12hours, 36hours, and 60hours after surgery, respectively.	CK (10^4U/L) HR (beats/min) / T2^†, T3^† MAP (mmHg) / T2^†, T3^†	CK-MB (ug/L) / T1^†, T8^†, T10^†, T11^†,T12^†, T13^† The amount of dopamine used. [mg/kg] / T15^† The amount of amrinone used. [mg/kg] / T15^†	Not mentioned
Qing yong (2006)16)	C	250 mL saline was injected before the surgery, after induction of anesthesia, 12 hours, 36 hours, and 60 hours after surgery, respectively.			Not mentioned
Li kai (2009)17)	E	1.5 mL/kg SFI was transfused through central vein before operations and pumped via CPB, respectively.	HR (beats/min) MAP (mmHg) PAWP (mmHg) CI, SVI, LVSWI (kg*min) CK-MB (U/L)	cTnI (ng/mL) MYO (ng/mL) MDA (nmol/mL) Voluntary recovery of heartbeat (%) The amount of dopamine used. [mg/(kg*min)]	Not mentioned
Li kai (2009)17)	C	No additional treatment.			Not mentioned
Zhen Chuandong (2009)18)	E	1.5 mL/kg SFI was injected in pre-filling via CPB.	Detached from ventilator (h) Duration of ICU (h) VAFS	Hospitalization period after surgery (d) / T16^† MDA (nmol/mL) / T4^†, T9^†, SOD (nU/mL) / T4^†, T9^†, T11^†	Not mentioned
Zhen Chuandong (2009)18)	C	No additional treatment.	Detached from ventilator (h) Duration of ICU (h) VAFS		Not mentioned
Wang Fangjun (2010)19)	E	1 mL/kg SFI was injected 60sec before unclamping aorta via CPB.	Voluntary recovery of heartbeat (%) ST change from aortic opening to heart rate^† ST segment normalization time^†	Parallel cycle time The amount of dopamine used [mg/kg] / T5^†, T6^†, T7^†, T15^† Ventricular fibrillation rate^†	Not mentioned
Wang Fangjun (2010)19)	C	1 mL/kg saline was injected 60sec before unclamping aorta via CPB.			Not mentioned
Wu Jun (2018)20)	E	1.5 mL/kg SFI was transfused through central vein before operations and pumped via CPB, respectively, as soon as clamped aorta was unclamped.	CKMB (U/L) cTnI (ng/mL) MDA (nmol/mL)	Voluntary recovery of heartbeat (%) The amount of dopamine used. [mg/(kg*min)]	Not mentioned
Wu Jun (2018)20)	C	No additional treatment.	CKMB (U/L) cTnI (ng/mL) MDA (nmol/mL)		Not mentioned
Song Zhi-bin (2020)21)	E	5.0 mL/kg SFI was injected intravenously with 250mL of 5% glucose solution	Urine discharge 24 hours after surgery (mL/h) Duration of ICU (h) / T16^† Detached from ventilator (h) / T16^† sICAM-1(pg/mL) / T14^†	cTnI (μg /L) / T14^† CKMB (μg /L) / T14^† LVEF (%)/ T14^†	Nausea 2 Dizziness and headache 12 Tachycardia 1
Song Zhi-bin (2020)21)	C	Same amount of saline as Group E.		cTnI (μg /L) / T14^† CKMB (μg /L) / T14^† LVEF (%)/ T14^†	Headache 1 Weakness 1 Tachycardia 1
Feng Yi (2020)22)	E	1.5 mL/kg SFI was injected during prefilling and opening of the aorta via CPB	cTnI (ng/mL) / T10^† CKMB (U/L) / T10^†		Not mentioned
Feng Yi (2020)22)	C	No additional treatment.	cTnI (ng/mL) / T10^† CKMB (U/L) / T10^†		Not mentioned

* SFI:Shenfu injection,

† p<0.05

†† p<0.01

C: Control group, CI: Cardiac index, CK:Creatine kinase, CK-MB: Creatine kinase MB Fraction, CPB:Cardiopulmonary bypass, cTnI: Cardiac troponin, DBP: Diastolic Blood Pressure, E: Experimental group HR: Heart rate, ICU: Intensive care unit, IPC:Ischemic preconditioning, LVEF: Left ventricular ejection fraction, LVSWI:Left ventricular stroke work index, MAP: Mean arterial pressure, MDA: Malondia ldehyde, MYO: Myogloblin, PAWP: Pulmonary capillary wedge pressure, SBP: Systolic Blood Pressure, :sICAM-1: Soluble intercelluelar adhesion molecule-1, SOD: Superoxide dismutase, SpO2:Saturation of percutaneous oxygen, SVI: Stroke volume index, VAFS:Visual analog Fatigue Scale

T1: Before operation or clamping aorta or anesthesia. T2 : Before ascending aorta occlusion.T3 : 30minutes after heart beat. T4: Immediately after operation. T5: Up to 30minutes after surgery. T6: 1 hour after the opening of the ascending aorta or 30minutes to 1hour after surgery. T7: 1 hour to 90minutes after surgery. T8: 2 hours after operation or opening of the ascending aorta T9: 3 hours after operation. T10 : 8hours after operation or opening of the ascending aorta T11 : 24hours after operation or opening of the ascending aorta T12 : 48hours after operation T13 : 3days after operation T14: 4days after operation T15 : During the period of residence in ICU T16 : After surgery

참고문헌

1. Kim M.S., Cho S.J., Park S.J., Cho S.W., Choi S.H., Kim H.S., & Park S.W.(2019). Frequency and clinical associating factors of valvular heart disease in asymptomatic Korean adults. Scientific reports;9(1):1-8.

2. Kil A.R., & Shin Y.S.(2020). Relationship between Warfarin Related Knowledge, Self Efficacy and Medication Adherence of Patient with Prosthetic Heart Valve Replacement. 21(1):584-592.

3. Book publishing Jungdam Editorial department steps to internal Medicine 3. Seoul. JDB;(2013). p. 243-6.

4. Kim J.H., Jung S.H., Kim N.H., Jung J.H., Soh J.E., Lee S.J., & Hwang H.K.(2002). A Case Report on the Inflation Failure of Distal Portion of Inoue Balloon during Percutaneous Mitral Valvuloplasty in a Patient with Rheumatic Mitral Stenosis. Korean Circulation Journal;32(10):906-910.

5. Shin D.K., Kim M.H., Cho J.K., & Kim K.S.(1996). Evaluation of the Surgical Treatment for Mitral Stenosis. The Korean journal of thoracic and cardiovascular surgery;29(10):1095-1101.

6. Asmar B.E., Perrier P., Couetil J., & Carpentier A.(1991). Failures in reconstructive mitral valve surgery. J Med Liban;397-11.

7. Zheng C.(2004). Cardioprotection of Shenfu on the Ischemia-Reperfusion Injury In Mitral Valve Repalcement with Cardiopulmonary Bypass and Its Effect on Postoperative Fatigue Syndrome. 重庆医科大学.;

8. Cho H.J., Lee J.W., Jung S.H., Je H.G., Choo S.J., Song H., & Chung C.H.(2008). Midterm Results of the Bioprosthesis in Mitral Position. Journal of Chest Surgery;41695-702.

9. Kim H.Z., Lim S.H., Park S.W., Kim N.S., & Lee M.K.(2007). Iatrogenic Aortic Dissection Following Mitral Valve Replacement - A case report -. Korean Journal of Anesthesiology;53(4):524-527.

10. Kim S.H., Kim C.S., Lee N.J., Gil N.S., Lee J.H., Yoon S.Z., & Bahk J.H.(2008). Left Ventricular Rupture immediately after Mitral Valve Replacement -A case report-. Korean Journal of Anesthesiology;;54(3):363-365.

11. Na K.J., Kim S.H., & Kim G.H.(1995). Clinical Results of Mitral Valve Replacement. The Korean journal of thoracic and cardiovascular surgery;28(12):1113-1121.

12. Shin H.R., Kim C.H., & Chu H.M., et al(2020). A Case Report of a Mitral Stenosis Patient Treated with Korean Medicine. J Int Korean Med.;41(3):457-466.

13. Ryu H.C., Seo C.H., & Kim I.G., et al(2005). Clinical Report of Cerebral Infarction Patient with Mitral Regurgitation. Korean J Oriental Physiology & Pathology.;19(4):1082-1087.

14. Wang Y.Y., Li Y.Y., Li L., Yang D.L., Zhou K., & Li Y.H.(2018). Protective Effects of Shenfu Injection against Myocardial Ischemia-Reperfusion Injury via Activation of eNOS in Rats. Biological & pharmaceutical bulletin;41(9):1406-1413.

15. Song W.T., Cheng F.F., Xu L., Lin C.R., & Liu J.X.(2012). Chinese medicine shenfu injection for heart failure: A systematic review and meta-analysis. Evid Based Complement Alternat Med;(2012). 71314910.1155/2012/713149

16. Qing Y., Dong L., & Wei T.(2006). Effects of Shenfu injection on perioperative myocardial enzymes and hemodynamics in patients with mitral valve replacement. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery;04284-285.

17. Li K., Zheng S.Y., & Chen Z.Y.(2009). Study of protective effect of Shen-fu injection on myocardial ischemia-reperfusion injury in mitral valve replacement. Practical Geriatrics;23(01):30-34.

18. Zheng C.D., & Min S.(2009). Effect of Shenfu injection in improving fatigue syndrome after open heart surgery. Journal of Clinical and Experimental Medicine;8(07):110-111.

19. WANG Fang-jun, CHEN Bing, TU Fa-ping, YANG Guang, QIN Jiao, & HE Hong-xia. (2010). Effects of shenfu injection on recovery of heartbeat in patients undergoing mitral valve replacement surgery. Chinese Journal of Experimental Traditional Medical Formulae;(04):170-173. 10.13422/j.cnki.syfjx.2010.04.064

20. Wu J., Mo S., Luo Y., Guo Y., Ding Y., Yang X., & Wei Y.(2018). Myocardial Protection of Shenfu Injection and Non-invasive Limb Ischemic Preconditioning in Mitral Valve Replacement. Chinese Journal of Integrative Medicine on Cardio-/Cerebrovascular Disease;16(05):574-576.

21. Song Z.B., Sun D., Ma Y.F., Wei L.J., & Wang Y.S.(2020). Effects of Shenfu Injection on Postoperative Assisted Respiration and Serum s ICAM-1, CK-MB and cTnI in Patients Undergoing Mitral Valve Replacemen with Cardiopulmonary Bypass. Chinese Journal of Rational Drug Use;17(05):52-55.

22. Feng Y.(2020). To evaluate the perioperative myocardial protective effect of different doses of Shenfu injection (SFI) in patients undergoing mitral valve replacement (MVR) with cardiopulmonary bypass. Journal of North Pharmacy;17(04):82-83.

23. Iliodromitis E.K., Lazou A., & Kremastinos D.T.(2007). Ischemic preconditioning: Protection against myocardial necrosis and apoptosis. Vascular health and risk management;3(5):629-637.

24. Shin H.R., Kim C.H., Chu H.M., Lee Y.U., Kim K.H., Won J.H., & Song B.K.(2020). A Case Report of a Mitral Stenosis Patient Treated with Korean Medicine. Korean J. Orient. Int. Med;41(3):457-466.27).

25. Jeong G.S., Jeon J.C., Kam C.W., & Park D.I.(2001). One case treated cerebral Infarction with rheumatic mitral stenosis. Korean Journal of Internal Medicine;22(3):463-9.

26. Nationwide college of Korean Medicine Faculty Council of Cardiology Internal Medicine. (2016). Cardiovascular and Neurological Medicine in Korean Medicine I, II. Seoul. Wooripub;p. 119-44,275. p. 178-9,196,370.

27. Ryu H.C., Seo C.H., Kim I.G., Choi C.W., Lee Y.S., Kim J.S., & Kim H.C.(2005). Clinical Report of Cerebral Infarction Patient with Mitral Regurgitation. Journal of Physiology & Pathology in Korean Medicine.;191082-1087.

28. Wei W.K., & Mo S.Q.(2005). Clinical Observation on Chinese Herbal Medicine in Preventing the Attack of Rheumatic Feverin Patients with Chronic Rheumatic Valvular Heart Disease. Journal of Guangzhou university of traditional chinese medicine;22(3):167-9.

29. Chen Y.M.(2008). Yiyuan Qiangxin Decoction in the Treatment of 56 Cases of Rheumatic Heart Valve Disease with Heart Failure. Chinese medicine modern distance education of China;6(1):46-7.

30. Jeong D.Y., Lee B.K., Hong J.W., & An W.G.Study of Membrane Potential Analysis According to Applying Doksam-tang to a Human Heart Failure Model. Herbal Formula Science [Internet];(2015). Jun. 30. 23(1):121-31. Available from: https://doi.org/10.14374/HFS.2015.23.1.121

31. Beijing College of Traditional Chinese Medicine. (1983). Practical Chinese Medicine. Beijing. Beijing Press;p. 744p. 747

32. Song W.T., Cheng F.F., Xu L., Lin C.R., & Liu J.X.(2012). Chinese Medicine Shenfu Injection for Heart Failure: A Systematic Review and Meta-Analysis. Evidence-Based Complementary and Alternative Medicine;1741-4288.

33. Zhao F.; The second people’s Hospital of Chengdu. (2021). Clinical study of Shenfu Injection combined with mechanical ventilation in treatment of severe asthma with type II respiratory failure. Journal of Hubei University of Chinese Medicine;30-3338.

34. Yu S.(2021). Study on the “dose-effect-toxicity” relationship of Shenfu injection on Gemcitabine combined with cisplatin in the treatment of advanced lung cancer. Contemporary Medicine;172-173.

35. Seo S.P.(2002). Serum Cardiac Markers. KOREAN JOURNAL OF INSURANCE;2111-18.

36. Lee J.H., & Choi Y.C.(2016). Rhabdomyolysis. Korean Journal of Neuromuscular Disorders;8(1):22-27.

37. Yoon Y.S., Kang H.S., Choue C.W., Kim K.S., Song J.S., & Bae J.H.(1998). The Significance of Serum Cardiac Troponin I Concentration in the Patients with Acute Myocardial Infarction. Korean Circulation Journal;28(10):1717-1726.

38. Kim M.W., Seo S.W., Kim S.G., & Kwon Y.J.(1986). Serum Myoglobin in the Early Phase of Acute Myocardial Infarction. Korean Circulation Journal;16(3):373-378.

39. Kim E.Y.(2011). Pharmacotherapy in Critical Care for Adults. J. Kor. Soc. Health-Syst. Pharm;285(2):169

40. Heo J.H., Jeong C.H., Jang J.M., Kim W.S., Jang W.I., & Lee Y.S.(2003). Relationship of Hemodynamic Changes during Off-Pump Coronary Bypass Grafting and Their Effects on Postoperative Outcome. Journal of Chest Surgery;36(8):576-582.

41. Kim Y.K., Lee D.H., Jin S.H., Lee W.G., & Song K.E.(2006). Relationships among Oxidative Stress Markers, Lifestyle Factors and Biochemical Findings. Annals of Laboratory Medicine;26(5):343-350.

42. Witkowska A.M., & Borawska M.H.(2004). Soluble intercellular adhesion molecule-1 (sicam-1): An overview. Eur Cytokine Netw;15(2):91-98.