10 years ago, 55-year-old Professor Chengnan Ota led the research group to complete the research on the treatment of animal cerebral ischemia by inhaling hydrogen, which proved the therapeutic effect of a small amount of hydrogen for the first time. This paper was published in Natural Medicine in June 2007, which opened the research direction of hydrogen medicine. Now, Professor Naruto Ota, who has retired at the age of 65, continues to fight in the front line of hydrogen medical research and transferred to Shuntian University to participate in the clinical controlled trial of hydrogen inhalation in the treatment of human cerebral ischemia. 10 year is a sword, but the clinical research of new medicine is obviously not completed in 10 year. Although we see that hydrogen, as an extremely safe therapeutic gas, has a very broad clinical application prospect, the progress of clinical research is still unsatisfactory. The main reason is that the strength and team size of relevant researchers are not strong enough, the state and the government have no big investment and key support, and the hydrogen academic and health industry fields have not really risen. But I firmly believe that hydrogen, as a true, effective and safe new therapeutic gas, must have strong vitality, and no difficulty or obstacle can stop the progress of hydrogen medicine.
The core contents of this research paper include:
1. The results of brain magnetic resonance imaging showed that the relative signal intensity of brain tissue necrosis in hydrogen treatment group was significantly better than that in control group.
2. The NIHSS clinical score for judging the severity of patients' illness is obviously better than that of the control group;
3. Physical therapy with Barthel index is also obviously superior to the control group.
Of course, the research scale is not large enough to reach the standard of using hydrogen as a clinical drug to treat cerebral ischemia, but today there is a lot of human evidence that hydrogen is safe and effective in treating cerebral ischemia.
I. Introduction
Preface is the introduction of the research paper, which mainly tells readers how necessary this research is and how meaningful it is to study it. The author arouses readers' interest by introducing the research background and explaining the purpose in the preface.
As a therapeutic antioxidant, inhaling hydrogen 1-4% can significantly improve the cerebral infarction injury in rats, and inhaling hydrogen under normal oxygen can also promote the recovery of brain function in rats after cardiac arrest. A large number of animal experiments and more than 20 clinical studies have proved the therapeutic effect of hydrogen on human clinical diseases. Inhalation of hydrogen has been proved to be safe for human patients with acute cerebral ischemia and brain injury caused by cardiac arrest and cardiopulmonary resuscitation. Therefore, it is necessary to carry out a randomized controlled clinical study to evaluate the therapeutic value of hydrogen on cerebral ischemia and other diseases.
This study adopts a randomized controlled clinical study to explore the safety and effectiveness of hydrogen therapy in patients with mild to moderate acute cerebral infarction. The purpose of the study is to judge the safety and effectiveness of hydrogen therapy by more extensive safety inspection and more objective clinical evaluation indicators, and the purpose of the study also includes accelerating the clinical application of hydrogen therapy.
Second, research methods.
1, research design and research object
In this study, 50 patients with acute cerebral infarction were recruited, 25 of them were treated with hydrogen, and the other 25 were the control group. The ID numbers of these patients were used for random grouping. This study was not completely blind, mainly because there was no placebo hydrogen absorber. However, data collection and analysis are blind. Nursing staff and other related personnel, such as radiologists and physiotherapists who participated in the study, also don't know the details.
The criteria for patients' enrollment include: 1) the treatment time is 6-24 hours; 2) The neurological dysfunction score NIHSS is 2-6; 3)MRI showed mild to moderate brain injury. In any image of diffusion-weighted magnetic resonance imaging, the maximum diameter of brain injury is 0.5-3.0 cm. Cerebral ischemia was classified according to the acute stroke treatment organization 10 172 test. The experiment of acute stroke treatment institution 10 172 mainly classifies the causes according to the clinical manifestations, CT, MRI, color Doppler ultrasound, TCD, MRA and other imaging and laboratory examination results of stroke patients.
Exclusion criteria: Obvious main artery occlusion and multiple lesions scattered in multiple cerebral artery perfusion areas were excluded. Other exclusion criteria are as follows: severe uncontrollable diabetes, liver and kidney dysfunction, severe heart disease, especially atrial fibrillation, severe lung disease, pneumonia, asthma and pleural effusion (Figure 1). Evidence of any acute bleeding in the patient's brain tissue was also excluded, and the patient received plasminogen activator therapy or anticoagulant therapy. According to this standard, 50 subjects were selected from 1 176 patients with clinical cerebral infarction.
Flowchart of topic selection
Why should patients be screened? The main purpose is to unify the patients' conditions and avoid the individual differences of patients from covering up the treatment effect. Imagine that if some people have heart disease and some people have completely normal heart and lungs, the former may recover slowly under the same degree of cerebral ischemia. Of course, the final clinical application depends entirely on whether there are indications, because as long as it is proved to be effective, even patients with other diseases such as diabetes can use it as long as they are not contraindicated. Moreover, if a certain treatment method can produce therapeutic effects on a variety of diseases, the final benefits will be even greater.
2. Treatment methods
All patients in this group began to receive daily physical therapy and evaluation on the second day after admission. The hydrogen treatment group inhaled 3% hydrogen 1 hour twice a day, and the hydrogen treatment lasted for 7 days. Non-re-inhaled ordinary masks are used to inhale hydrogen. Hydrogen is produced by Nishima Hydrogen Generator (Numazu, Shizuoka Prefecture, Japan) (note that this is different from the method used by Japanese scholars to prepare high-pressure gas cylinders in the past). The hydrogen concentration was analyzed by gas chromatography. In order to ensure adequate inhalation, venous blood was collected before the end of hydrogen inhalation, and the hydrogen concentration in blood was detected by gas chromatography. Patients in the hydrogen inhalation group were not given edaravone because doctors thought that hydrogen had neuroprotective and antioxidant effects, which were similar to edaravone. However, from the next day, ozagrel was regarded as a class B drug, and ozagrel was a selective thromboxane A2 synthase inhibitor.
The control group did not inhale hydrogen, but did not restrict any drug treatment, including class B drugs. In addition, edaravone 30 mg was injected intravenously every 12 hours for 14 days. Edaravone is a free radical scavenger with neuroprotective effect. Ozagrel was given 80 mg intravenously every 12 hours for 14 days. Agatraban was injected with 60 mg on the first day, and then injected with 1 0 mg every hour for 4 consecutive days. Agatraban is an anticoagulant. All patients in the control group used edaravone, 19 patients used ozagrel, and 6 patients used argatroban.
3. Evaluation indicators
Evaluation serves research purposes. The first is to study the safety of using hydrogen, mainly monitoring the most routine physiological indicators such as blood pressure, pulse and body temperature. The second is to study the effect of hydrogen therapy, which is analyzed by MRI and neurological function score. The original text is divided into evaluation, blood test and nuclear magnetic resonance, all of which have the same purpose, mainly considering the classification and convenient writing.
Routine indicators include blood pressure, pulse, body temperature, daily food intake, and blood oxygen saturation detection three or more times a day. NIHSS score was measured blindly every day for 2 weeks. Barthel index, Brunnstrom classification, Rankin score and functional independent measurement were performed in physiotherapy department every day. Blood biochemical analysis Venous blood was collected on the first 1, seventh 14 days of hospitalization, and blood biochemical analysis was carried out, including liver, kidney, pancreas, myocardial enzymes, electrolyte levels and blind blood cell count. Electrocardiogram was recorded on admission and on demand during hospitalization.
Magnetic resonance imaging. Brain MRI scans were performed on the day of hospitalization and on the 3rd, 5th, 7th, 10 and 14 days respectively. Diffusion-weighted imaging marks the location, volume and signal intensity of cerebral infarction to evaluate abnormal lesions. By using the software combining image analysis software (DICOM) and ROI, the infarct volume is manually circled around the core infarction. And then automatically calculate. The signal intensity of the core infarction area (B) and the normal brain tissue (C) in the corresponding part of the control side is compared as a reference to calculate the severity, which is also automatically calculated by DICOM software. Pathological signal density is expressed by B/C ratio.
The diffusion-weighted imaging data are compared with the relative magnetic signal strength, which is expressed as A × B/C, where a represents the infarct volume and B/C is the signal strength ratio. Perform the same calculation on all images. If there are multiple infarct sites, calculate each infarct site separately, and the data collection is repeatable and reliable.
4. Clinical information registration and informed consent
This is a prescribed action in clinical research, which must be carried out before the research is carried out according to the regulations, otherwise many clinical journals will not accept it.
5. Statistical analysis
Statistics adopt corresponding analysis methods according to data types. Statistics plays a very important role in academic research, and it is generally a necessary option when describing research methods, and it is often ranked at the end of the method.
Third, research results.
In academic papers, research results are the most important part, which is the key to determine the new findings and level of the paper. For example, the results of this study are now effective evidence to prove the safety of hydrogen in treating cerebral ischemia. So, be sure to read and experience this part carefully.
1, basic information of patients
The patient was hospitalized during 20 14, 10, 1 to 20 16, 18. The average age of the hydrogen treatment group was 76 years old, and that of the control group was 73.3 years old, including 2 cases of hydrogen treatment group/kloc-0 and 9 cases of control group over 80 years old. There is no statistical difference in age (of course there is no difference, and the hydrogen treatment group is older, which is obviously a disadvantage). Other indicators were similar between the two groups.
Comments: The randomized experimental group and the control group are equally divided, but there are still differences, especially when the sample size is relatively small. In this experiment, the average age of the control group is 73.3 years old, while the average age of the hydrogen treatment group is 76 years old, which is very different between the two groups. For cerebral ischemia, a difference of three years may have a great influence on the prognosis. Of course, from the analysis of more indicators, there is no statistical difference between the two groups. As far as this study is concerned, all you need to know is that according to this set of data, the grouping is fair.
2. Laboratory inspection
/kloc-Life indicators were tested every day for 0/4 days. The blood oxygen saturation of the two groups was higher than that of the control group (P = .03) (Figure 2), and there was no significant difference in other indexes. On the first 1, seventh and 14 days of hospitalization, there was no difference in blood biochemical tests. These results show that hydrogen therapy is safe for patients with acute cerebral infarction.
Except that the oxygen saturation shown in the last picture has not changed.
Comments: The biological safety of hydrogen has long been very clear, but as a disease treatment tool or drug, the safety of specific patients still needs to be verified. The evaluation of safety here is based on the most basic physiological data. For this study, although a small dose of hydrogen is used in a short time, the special risk is that patients themselves, patients with cerebral infarction whose average age is over 70 years old, and elderly patients with poor health level try to use a new treatment method, which should have higher requirements for determining safety.
After inhaling hydrogen, the blood hydrogen concentration measured by gas chromatography is 24.5mM, which is consistent with the theoretical speculation of inhaling 3% hydrogen. Under normal pressure, the saturated dissolved concentration of pure hydrogen (100%) in water is 800mM, while 3% is 24 mm. After inhaling 1 hour, the blood is saturated. Note: The solubility of hydrogen in blood is theoretically much higher than that in water, because there are not only water in blood, but also many nonpolar molecules, such as fat, protein and other biomolecules. These molecules are more easily combined with hydrogen, which can increase the solubility of blood in hydrogen. So the original author's theoretical calculation method here is not accurate enough.
3. MRI results
No magnetic resonance signal of cerebral hemorrhage was found in the cerebral infarction area of all patients, and the severity of cerebral infarction area was expressed by relative signal intensity. On the first 1 day after admission, there was a big difference between the two groups, and there was no statistical difference. Among them, the hydrogen treatment group was 28 ~ 855, with an average of 241; The control group ranged from 18 to 1896, with an average of 272 (Figure 4a). On the 7th day and14th day, the situation changed, and the hydrogen treatment group was obviously better than the control group (P=.025 and .028). After logarithmic transformation, it was found that the difference between the two groups was more obvious (P = .002) (Figure 4b). The relative signal intensity decreased to 152% on the first 10 day and to 12 1% on the first 10 day, while the control group remained at a very high level above 2 19%. The results show that hydrogen therapy is helpful to the recovery of brain tissue injury in patients with cerebral infarction.
This is the most important research achievement! Difference degree of two lines
Comments: MRI vibration is the core achievement of this research paper, which proves that hydrogen inhalation has therapeutic effect on brain injury in patients with cerebral infarction, and it is also the most objective and painstaking achievement. It can be seen from the vibration of nuclear magnetic resonance that hydrogen therapy can reduce the severity and scope of brain injury. Note that the hydrogen therapy in this study is after the best clinical treatment window (6 hours). Theoretically, it is rare and commendable to think that brain injury is irreversible and still get therapeutic effect. Of course, more and more scholars in the field of cerebral ischemia believe that cerebral infarction is not irreversible without the best treatment time, but still has therapeutic value. This study also coincides with this new view.
For the latest viewpoint about cerebral ischemia, please see the latest explanation of Stroke Cafe.
After apoplexy tea (48), walk out of the shadow of apoplexy penumbra.
4. Nerve function recovery
The NIHSS score showed that both groups recovered with time, especially the hydrogen treatment group (Figure 5). On the third to fifth day of hospitalization, the NIHSS score in the control group increased slightly, suggesting that the neurological function deteriorated at this time, while the score in the hydrogen treatment group did not increase significantly at the same time. After the fifth day, the NIHSS scores of the two groups all improved, and there was a significant difference between the two groups. The hydrogen treatment group improved obviously every day, and on the 5th, 6th, 5th, 7th and 9th day, P < 0. 0 1.
Blue is the hydrogen treatment group, and the smaller the value, the lighter the condition.
5, physical therapy to improve the situation
Barthel index, Brunnstrom classification, Rankin score and functional independent measurement were performed in physiotherapy department every day.
The Barthel index of ADL was designed and formulated by Dorother Barthel and Floorence Mahney in 1965, which is a common method for evaluating ADL in American rehabilitation institutions. Barthel index evaluation is very simple, with high reliability and sensitivity, and it is a widely used and most studied ADL evaluation method.
Brunnstrom's evaluation of motor function of hemiplegia is an indispensable theoretical basis for determining the goal of rehabilitation treatment, making rehabilitation treatment plan and evaluating rehabilitation effect. Brunnstrom divides the functions of upper limbs, hands and lower limbs into 1 ~ 6 stages according to the occurrence and development law of the above diseases in patients with brain injury and hemiplegia, and each stage has a clear judgment standard table.
Rankin score can evaluate the completely independent living ability of stroke patients. Evaluate the ability of independent living, and take walking ability as a clear scoring standard. * * * Seven grades, 0 is asymptomatic, the higher the score, the worse the prognosis, and 6 is death.
Physical therapy data were evaluated every day for 2 weeks (Figure 6), because 9 patients, including 3 patients in the hydrogen therapy group and 6 patients in the control group, did not receive physical therapy every day, so the data of 9 patients were not included.
During the physical therapy, no complications were found in the two groups, and all the evaluation indexes were improved, especially mRS, BRS and FIM in the hydrogen therapy group. BI index between the two groups was also statistically different (P
The conclusion of this paper is that according to this small-scale clinical study, hydrogen therapy is safe for patients with cerebral ischemia, and some research indicators also show that hydrogen therapy can promote the recovery of brain injury in patients, and hydrogen has certain therapeutic value for cerebral ischemia. In my opinion, the results of this study show that hydrogen inhalation therapy has a significant effect on brain tissue recovery, neurological function improvement and quality of life in patients with acute cerebral ischemia. Hydrogen therapy for cerebral ischemia deserves larger-scale clinical research, and perhaps hydrogen therapy will become a routine treatment for patients with cerebral ischemia in the future.
discuss
The exposition of the paper is a theoretical analysis conducted by the author according to the research results, representing the author's views and ideas, often reflecting the author's theoretical height and level, and it is also worth reading. Some time ago, the background, research methods and research results of this paper were introduced respectively. In order to give you an overall understanding and grasp of the article, I will explain the discussion part of the paper to you today.
Anyway, the significance of studying hydrogen is that it may have application value: a large number of studies show that hydrogen has potential value in the prevention and treatment of many diseases. There are many ways to use hydrogen, such as breathing hydrogen, drinking hydrogen water, injecting hydrogen water, bathing with hydrogen water, eye drops and so on. Inhalation of hydrogen can quickly ingest hydrogen, which is more suitable for emergency patients. Injecting and drinking hydrogen water is also possible, but emergency patients have higher requirements for liquid dosage and oral administration is often limited. Therefore, from the perspective of safety and feasibility, inhaling hydrogen is the best choice.
Most patients in the study are over 75 years old, including over 90 years old. Hydrogen inhalation therapy has not found any obvious side effects and complications, and can improve oxygen saturation. These results show that inhaling hydrogen is very safe and can be used by most people, including the elderly. This study adopts random grouping, which is ideal, and there is no significant difference in the basic situation between the two groups. Therefore, when analyzing the final research results, the factors that need to be adjusted are not considered.
A variety of pathophysiological processes will occur in cerebral infarction tissues, such as energy exhaustion, cell membrane integrity damage, inflammatory reaction, excitotoxicity, oxidative stress, cell necrosis and apoptosis, and tissue edema caused by blood-brain barrier damage, which will eventually lead to irreversible damage to brain tissues. Besides being an antioxidant, hydrogen can also regulate the expression of many signal molecules and many inflammation-related genes. The mechanism of how low-dose hydrogen regulates various signal molecules is still unclear. Recent studies believe that oxidative stress can make phospholipids produce bioactive molecules through free radical chain reaction, which may be an important reason for affecting the expression of signal molecules and genes.
Both hydrogen and edaravone can neutralize hydroxyl radicals, and it has been reported that hydrogen is better than edaravone in the treatment of animal cerebral ischemia. In this study, all patients in the control group received edaravone, while 24% patients in the control group received argatroban, and 76% patients in the control group and 100% patients in the hydrogen treatment group also received ozagrel. Agatraban and ozagrel have similar effects, so judging the effect of hydrogen will not be affected by the use of these drugs. The results of this study show that inhaling hydrogen is more effective than using edaravone in human patients with cerebral ischemia.
The results of magnetic resonance imaging showed that the histopathological damage of cerebral infarction area in hydrogen treatment group was lighter and the recovery speed was faster than that in control group. After treatment 14 days, the relative injury index returned to near normal level, and there was still slight injury after treatment 10 days, which was usually inflammatory vasogenic brain edema after blood-brain barrier destruction. The degree of tissue injury in the control group was significantly higher than that in the hydrogen treatment group at the peak of injury and during recovery. The results suggested that the hydrogen treatment group began to recover on the fifth day after cerebral ischemia. The results of nuclear magnetic resonance show that hydrogen not only affects the penumbra of cerebral ischemia tissue, but also affects the ischemic core tissue. It shows that if hydrogen can be used earlier, the treatment effect will be better (treatment will start after 6 hours in this study).
As an evaluation index of the effect of hydrogen therapy, NIH stroke score was also significantly improved compared with the control group. Especially after 3 days of treatment, the hydrogen treatment group has been significantly better than the control group. The daily living ability of patients was evaluated by physical therapy data, and the results showed that many indexes of hydrogen therapy group were better than those of control group.
Conclusion: Hydrogen inhalation is a safe and effective treatment for patients with acute cerebral ischemia. Hydrogen inhalation can be used as a potentially feasible new therapy for acute cerebral ischemia.
The discussion in this paper only analyzes the results one by one, without in-depth discussion. This is probably the characteristic of clinical research, which does not pay attention to theory, and the key lies in the effect.