Xuebijing Treatment for Novel Coronavirus Pneumonia, the Applicable Population and Theoretical Basis of Integrative Medicine
2020-03-23
The National Health Commission and the National Administration of Traditional Chinese Medicine successively have issued many versions of the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Diagnosis and Treatment Protocol) after the outbreak of Novel Coronavirus Pneumonia (NCP). The trial version 5 is in operation. In both trial versions 4 and 5, Xuebijing (XBJ) injection is recommended for severe and critical cases in western medicine treatments, whilst for moderate cases with epidemic toxin blocked internally in lung syndrome and severe cases with inner blocking causing collapse syndrome in TCM treatment. In the corresponding period, led by Academician Nanshan Zhong, a research group of respiratory and intensive care medicine experts urgently launched a prospective multicenter clinical trial to study the efficacy of XBJ in NCP treatment. First recommended by the Diagnosis and Treatment Protocol as a Chinese medicine injection, then put into a clinical trial led by authoritative experts combating NCP, XBJ certainly has attracted extensive attention both inside and outside the medical and pharmaceutical community.
Since the release of the Diagnosis and Treatment Protocol Trial Version 4 on Jan.27th, over 1000 NCP-designated hospitals in various provinces and cities had purchased XBJ urgently to treat patients in the past two weeks. Many hospitals had never administrated XBJ before, and a lot of clinical and pharmaceutical professionals were not familiar with its application and clinical safety. Therefore, there could be some incorrect and unreasonable drug administration which might lead to the potential increase of clinical risks and jeopardize the treatment for NCP patients. According to the Diagnosis and Treatment Protocol, which stage of NCP is the best time to introduce XBJ for treatment? What issues should be noted in medication? Professor Yuanlin Song, director of the respiratory and intensive care medicine department of Zhongshan Hospital affiliated to Fudan University, and Professor Zhijun Li, co-chairman of the first aid committee of the Chinese Association of Integrative Medicine, member of integrative medicine department of Tianjin First Central Hospital, share their opinions.
Professor Yuanlin Song: XBJ should be administrated as soon as possible after the diagnosis of severe and critical cases to take the full advantage of integrative medicine.
NCP is community-acquired pneumonia caused by virus infection. Currently, there is no cure nor treatment for this disease. Hoping for an original drug as a solution is doomed in vain. The aid is too slow to be helpful. Therefore, there is a need to rapidly screen all promising and listed drugs based on evidence to find those can be repurposed for NCP complications treatment. Even if those drugs could not kill the virus, they should be introduced as essential drugs for clinical treatment as long as they prevent deterioration and work for complications.
Due to the pathological characteristics of NCP and the innate function problems of human beings, some patients may suffer from dysimmunity and inflammatory responses losing control, and strike by cytokine storm, which leads to the rapid and uncontrollable deterioration. It doesn’t matter in what sequence those factors affect the human body. The correlation and causation between them create a vicious circle and the process is complicated and fast-changing. Once it occurs, the treatment becomes more difficult, which has been a clinical challenge for the international medical community to overcome for decades. Yet up to now, none of the single-target drugs in existence has been proved useful. In fact, dysimmunity, cytokine storm, and even coagulation storm are common pathological processes of severe pneumonia, sepsis, and other critical diseases. There is nothing new for professionals to deal with. Most respiratory and intensive care medicine experts have a clear understanding and response strategy.
Severe cases of NCP show evident pulmonary exudation, respiratory distress, a significant drop of oxygen saturation and oxygenation index, mainly caused by infection-induced systemic inflammatory response syndrome (SIRS) Without effective control, severe cases deteriorate into critical cases. Patients may develop acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), septic shock and multiple organ dysfunction syndromes (MODS) involving heart, liver and kidney damage, which means more challenging treatment and even death. These clinical features are consistent with the definition of sepsis as life-threatening organ dysfunction resulting from maladaptive response to infection, as well as the diagnostic criteria for severe community-acquired pneumonia and sepsis.
If the logic stands, cytokine storm and coagulation storm are not daunting in severe and critical cases of NCP. The clinical characteristics of NCP have been described in many published articles. Treatment for NCP may be established bearing anti-virus in mind, and with the reference of domestic and international guidelines for the diagnosis and treatment of severe community-acquired pneumonia and sepsis.
The best treatment strategy is "prevention before disease onset", which means timely detecting the sign and preparing the next step in advance. To achieve this, it requests a thorough understanding of the pathological process and clinical features of the cytokine storm. Once patients show signs of aggravation of inflammatory reaction, XBJ can be administrated with the conventional treatment in combination, which contributes to targeted-prevention of cytokine storm with its multi-target effects, such as antagonism of endotoxin, inhibition of inflammatory factors and protection of vascular endothelial cells. In case of patients with cytokine storm, XBJ should be administrated on the concept of "preventing the disease from exacerbating", which may prevent the deterioration into critical cases with its effects, including blocking pathway of cytokine storm, reducing the acute lung injury induced by pulmonary capillary leakage, and protecting the coagulation function and organ function. In this stage, a small dose of glucocorticoids may also be introduced for anti-inflammatory and its therapeutic effects should be monitored. However, the pros and cons remain debatable.
For critical cases, life supports such as mechanical ventilation, continuous renal replacement therapy (CRRT), and extracorporeal membrane oxygenation (ECMO) are necessary. Yet they cannot completely solve endogenous pathological changes, only temporarily replace the function of organs to sustain life. Targeted drug treatment should also be given. XBJ may save patients’ lives by preventing further aggravation of ARDS, easing the microcirculation disorder and coagulation dysfunction caused by microthrombus, and alleviating the degree of organ dysfunction.
In-depth clinical data analysis of XBJ treatment for severe pneumonia shows that XBJ demonstrates more evident efficacy with critical cases in pneumonia severity index (PSI) Ⅳ-Ⅴ level. In the light of no specific antiviral drug available, the advantage of integrative medicine should be brought into full play. Given their unique therapeutic effects, including multi-target anti-inflammatory, improving coagulation function and protecting organ function, TCM treatments such as XBJ should be administrated for severe and critical cases to reduce the incidence and fatality as low as possible. In short, NCP has its own characteristics and we have no established experience in treating it. It is highly suggested that XBJ should be administrated following the instruction of the Diagnosis and Treatment Protocol, and taking the treatment experience from a randomized controlled trial of XBJ in the treatment of severe community-acquired pneumonia into consideration. The dosage used in "Efficacy Study of XBJ in NCP Treatment", the clinical trial led by Academician Nanshan Zhong, is 100ml each time, twice a day, with 7 days or more in a course. XBJ should be administrated as soon as possible after the diagnosis of severe and critical cases to seize the best timing.
Professor Zhijun Li: XBJ was developed based on the "three syndromes and three methods" theory which demonstrates "Chinese Wisdom" or "Chinese Method" in the treatment of acute and critical diseases.
Learning from the TCM theory, Professor Jinda Wang, one of the founders of Chinese acute and critical disease medicine, has systematically put forward the "three syndromes and three methods" theory, which combines the "toxic heat syndrome and clearing away heat and toxic materials method", "blood stasis syndrome and promoting blood circulation and removing blood stasis method", and "acute deficiency syndrome and supporting the healthy energy method" together. XBJ is a successfully developed product under the guidance of this theory, with the functions of promoting blood circulation and removing blood stasis, cooling blood and nourishing blood, and combating the toxins. The modern integrative medicine elaborates on the connotation of the "three syndromes and three methods". The early stage of infection is often manifested as toxic heat syndrome (SIRS). If the toxic heat gets into the blood, it may damage the pulmonary capillary endothelium, causing capillary leakage, and lead to ARDS, also, capillary microthrombus can cause microcirculation disturbance, destroy coagulation balance, and lead to blood stasis syndrome (DIC). If the heat damage body energy, it may cause ischemia and anoxia in various tissues and organs, and lead to acute deficiency syndrome (septic shock, MODS).
The application of TCM in treating NCP mainly focuses on two aspects. One is prevention, which means "prevention before disease onset" and "preventing disease from exacerbating". The other is the integrative treatment for severe cases.
1. The TCM syndrome of NCP is dampness syndrome. As the disease progressing, the damp evil may generate heat and become damp and hot. According to the TCM theory of "defensive Qi and nutrient blood" in the treatment of heat diseases, the breaking point for mild cases deteriorating into severe cases is when the damp evil goes into blood aspect from the Qi aspect. According to the TCM theory of "preventing disease from exacerbating" and "blocking and reversing", the crucial part of treatment is to block the deterioration into severe cases, which means to block the transformation of the toxic heat syndrome to blood stasis syndrome, as well as to prevent the damp evil entering blood aspect from Qi aspect. Therefore, drugs treating blood aspect syndrome should be administrated as soon as possible to prevent the heat from transferring to the blood aspect in the heat toxin syndrome stage. In the stage of heat toxin syndrome and blood stasis syndrome, it is essential to protect the functions of all organs at all times and support Qi properly in time to prevent acute deficiency syndrome. It is also one of the academic viewpoints of "three syndromes and three methods" theory.
2. Recently, with the accumulation of experience in NCP treatment, doctors in the frontline have observed the presence of a cytokine storm, which means that patients are deteriorating, hard to treat, indicating a bad prognosis. Many popular science articles regarding the correlation of cytokine storm and systemic inflammatory response syndrome are available on the Internet, discussing the causes, progresses, and consequences. XBJ, mentioned in the Diagnosis and Treatment Protocol of NCP, one of its approved indications back in 2004 is SIRS. Judging from this, XBJ was aiming to treat this syndrome, i.e. cytokine storm, when Professor Jinda Wang developed it over 20 years ago. Therefore, China does have a drug for cytokine storm. The question is whether the public embraces and welcomes it. Introducing XBJ in the early stage can protect the vascular endothelial cells damaged by SIRS and reduce capillary leakage. It also can reduce capillary microthrombus, lower the incidence of coagulation disorders, and block the transformation of the toxic heat syndrome to blood stasis syndrome, which is the "three syndromes and three methods" theory in practice.
All doctors in critical care are well aware that the malignant interaction between cytokine storm and coagulation storm is the sign of deterioration, which indicates DIC, shock, organ failure, and the increasing fatality. Therefore, it is crucial to block the cytokine storm induced by infection to avoid triggering the coagulation storm, which is another valid reason for the administration of XBJ. In recent years, a randomized controlled trial on XBJ treatment for severe pneumonia, led by respiratory experts and completed in combination with the emergency and intensive care departments, showed XBJ reduced the case fatality of severe pneumonia by 8.8%. The recently completed randomized controlled trial on XBJ treatment for sepsis, a multidisciplinary collaboration led by intensive care specialists, also showed a reduction in sepsis fatality. It has formed an evidence-based evidence chain, which validates the transformation of the "three syndromes and three methods" from a theoretical system to an evidence-based one.
The characteristic of TCM is focusing on people all the time. Most of the time, diseases are caused by disturbed homeostasis failed to self-recovery after the invasion of external factors. TCM treats diseases based on the reactions of the human body. It doesn't have much to do with the pathogen, old or new. The same TCM treatment can be applied as long as the reactions to the disease remain alike. That is the vital root for the "three syndromes and three methods" theory to deal with various critical diseases. It should be known as "Chinese Wisdom" or "Chinese Method" in treating acute and critical diseases.
This article is reviewed by Professor Yuanlin Song and Professor Zhijun Li.
