Guidelines on Brain Protective Drugs for Craniocerebral Trauma in China
I. Purpose
In order to guide the neurosurgeons in China to correctly use brain-protective drugs to treat patients with craniocerebral injury, reduce brain dysfunction, promote brain function recovery, reduce toxic side effects, improve the treatment effect of patients with craniocerebral trauma, and reduce the medical burden of the country and patients.
II. Scientific basis
Through collecting and analyzing the Evidence Class I clinical evidence on the efficacy of brain-protective drugs in treating patients with craniocerebral injury, and after careful discussion and analysis by the Chinese Association of Neurological Surgeons and the Chinese Neurological Injury Expert Committee, we made a more objective scientific conclusion.
Class I clinical evidence-based medicine
1, hormone: domestic and international clinical medical centers have carried out steroid hormone treatment of patients with craniocerebral injury clinical research, its efficacy is more controversial, most of the clinical research results are disappointing. 2004 British journal “The Lancet” published high-dose hormone treatment of 10008 patients with acute craniocerebral injury prospective randomized double-blind clinical control study results were shocking. 5007 cases of acute craniocerebral injury Patients (GCS <14) were treated with high-dose methylprednisolone within 8 hours of injury (total methylprednisolone dose of 21.2 g at 48 hours), and another 5001 patients with the same injury were given placebo as a control group, which showed a 21.1% mortality rate in the methylprednisolone group and a 17.9% mortality rate in the control group, significantly increasing patient mortality
(P=0.0001). The main causes of increased mortality were infection and gastrointestinal bleeding. The findings call for the use of high doses of hormones in patients with acute craniocerebral injury (1). The efficacy of conventional doses of hormones in the treatment of patients with acute craniocerebral trauma is highly controversial and no definite conclusion has been reached.
2. Calcium antagonists: A 12-year, four-phase prospective, randomized, double-blind, controlled European and international multicenter study of the calcium antagonist nimodipine (nimotop) in the treatment of craniocerebral injury and traumatic subarachnoid hemorrhage (tSAH) was conducted.
Phase I was a prospective randomized, double-blind, controlled clinical study of 351 patients with acute craniocerebral injury and was found to be ineffective. This was followed by a phase II prospective randomized double-blind study in 852 patients with acute craniocerebral injury, which also proved to be ineffective in patients with craniocerebral injury, but after analyzing the clinical data, it was found that nimotop was effective in patients with traumatic arachnoid hemorrhage (tSAH). In order to demonstrate its definitive efficacy in tSAH patients, another phase III prospective randomized double-blind clinical control study of nimodone in 123 tSAH patients was conducted in Europe, and the results also showed effectiveness. Subsequently, a phase IV prospective randomized double-blind clinical control study with a large sample of 592 tSAH patients in 35 hospitals in 13 countries was conducted, with disappointing results and no therapeutic effect of nimodone. Because of the controversial clinical effects of nimodipine, nimodipine has been internationally excluded from the treatment of patients with acute craniocerebral injury and tSAH patients (study results are publicly unpublished) (2, 3).
3, albumin: albumin is currently a commonly used drug in the clinical treatment of acute craniocerebral injury brain edema. In 2007, the New England Journal of Medicine published the results of a prospective randomized, double-blind controlled study of albumin versus saline in patients with acute craniocerebral injury. 460 patients were enrolled based on the following criteria: acute craniocerebral injury, GCS ≤13, and CT scan confirmation of craniocerebral injury. 460 patients were randomly divided into two groups: 231 patients ( 50.2%) albumin treatment group, all treated with 4% albumin liquid for 28 days or until death; 229 patients (49.8%) were saline control group. There was no statistical difference in the clinical indexes (age, injury, CT scan) between the two groups before treatment. 460 patients with heavy craniocerebral injury (GCS 3-8 points): 160 cases (69.3%) in the albumin treatment group and 158 cases (69.0%) in the saline control group. At 24 months post-injury, there were 71 deaths (33.2%) in the albumin group and 42 deaths (20.4%) in the saline group (P = 0.003). Among patients with severe craniocerebral injury, 61 (41.8%) died in the 146 albumin-treated group and 32 (22.2%) in the 144 saline control group (P<0.001). Among patients with moderate craniocerebral injury, 8 deaths (16.0%) occurred in the 50 albumin-treated group and 8 deaths (21.6%) in the 37 saline control group (P = 0.50). The study found that albumin increased mortality in patients with heavy cranial injury (4).
4, magnesium ion: in 2007, the British “Lancet Neurology” published a group of seven U.S. medical centers using magnesium sulfate treatment 499 cases of prospective randomized double-blind clinical control study results. Study grouping: low-dose group (plasma magnesium ion concentration 1.0-1.85mmol/l), high-dose group (1.25-2.5mmol/l) and the control group. The results of the study found that the mortality rate of patients: control group (48%), low dose group (54%) (p=0.007), high dose group (52%) (p=0.7). Studies have shown that magnesium sulfate for acute craniocerebral trauma patients is not effective, and even harmful (5).
5, glutamate antagonist: Selfotel is the world’s first synthetic glutamate receptor antagonist in 1988. Phase I volunteer trial, found that it will cause psychiatric/psychological side effects; Phase II 108 acute craniocerebral injury patients in clinical studies show a role in reducing intracranial pressure; Phase III clinical trials on 860 heavy craniocerebral injury patients in a large-scale prospective randomized double-blind clinical control study, the results of the study proved ineffective. cerestat is a non-competitive antagonist of glutamate, which binds Cerestat is a non-competitive antagonist of glutamate that binds to the magnesium binding site on the glutamate receptor channel and exerts pharmacological effects only when the receptor is activated by high glutamate concentrations. Phase III clinical trials of 340 patients with craniocerebral injury in 70 centers in Europe and the United States were conducted in a prospective randomized, double-blind, controlled clinical study and showed ineffective results. The glutamate antagonist CP101-606 has fewer side effects than the first two. It is four times more concentrated in brain tissue than in plasma and can reach therapeutic concentrations very quickly. A phase III clinical trial was conducted in a prospective randomized double-blind clinical control study of 400 patients with craniocerebral injury, and the results of the study showed ineffectiveness. The glutamate antagonist D-CPP-ene was studied in a prospective randomized double-blind clinical control study in 51 centers in Europe, treating 920 patients with acute craniocerebral injury. Follow-up results at 6 months post-injury showed that the prognosis of patients in the treatment group was worse than in the placebo group, but not statistically significant. dexanabinol is not only a non-competitive NMDA inhibitor, but also a free radical scavenger, antioxidant and inhibitor of the inflammatory effects of alpha tumor necrosis factor. A prospective randomized, double-blind, controlled clinical study in patients with acute craniocerebral trauma was conducted in six neurosurgical centers in Israel. 101 patients were randomized to different doses of Dexanabinol or placebo. The results showed that it reduced hypotension and mortality in patients with craniocerebral trauma, but there was no statistical difference (6).
6. Free radical scavenger:Tirilazad is a very powerful free radical scavenger. It is considered to be more effective than traditional steroids in combating cerebral edema and does not have the side effects of glucocorticoids. It has been shown to have no significant efficacy in patients with acute craniocerebral trauma through a prospective randomized double-blind clinical control study of 1700 patients with heavy craniocerebral injuries in the United States and worldwide. Polyethylene-coated superoxide dismutase (PEG-SOD) is another powerful free radical scavenger. Muizelaar of the American College of Medicine of Virginia reported the results of a phase II clinical study that PEG-SOD was effective in treating patients with craniocerebral injury. However, this was followed by a prospective randomized double-blind clinical controlled study of 463 patients with severe craniocerebral injury in 29 centers in the United States. Follow-up results at 3 months post-injury showed a 7.9% improvement in GOS scores in the 10,000 units/kg PEG-SOD treatment group and a 6% improvement at 6 months post-injury, but neither reached statistical significance. Other doses of treatment did not differ from the control group. There are other types of free radical scavengers currently in clinical trials with efficacy to be evaluated (6).
7. Bradykinin antagonists:The prospective randomized double-blind clinical controlled study of Bradycor, a bradykinin antagonist, was conducted at 39 centers in the United States, treating 139 cases with ICP as the primary observation target. The results showed no significant differences between the treatment and control groups. The clinical study of the project was discontinued due to the poor safety profile of the drug (6).
8. Mitochondrial function protector: A clinical multicenter study of SNX-111, a mitochondrial function protector, for the treatment of patients with acute craniocerebral injury. 160 patients were treated with disappointing results, with a mortality rate of 25% in the treatment group and 15% in the placebo group.
This trial was stopped when the mortality rate was higher in the drug administration group than in the placebo group (6).
9. Other neurotrophic drugs: Nerve growth factor, brain activator and other peptide-based nutritional drugs have not been studied in a strictly randomized double-blind multicenter prospective controlled study, and their efficacy cannot be judged yet (2, 5-9).
Fourth, the expert guidance of drug treatment
1, mega-dose hormones, magnesium preparations and mega-dose albumin have the risk of increasing mortality in patients with acute craniocerebral injury, and are strongly discouraged;
2, calcium antagonists (Nimodipine), glutamate receptor antagonists (Selfotel, Cerestat, CP101-606, D-CPP-ene, Dexanabinol), free radical scavengers (Tirilazad, PEG-SOD), bradykinin antagonists (Bradycor) and mitochondrial function protectors (SNX- 111) are ineffective in the treatment of patients with acute craniocerebral injury and are not recommended;
3, a variety of peptide neurotrophic drugs in the treatment of patients with craniocerebral injury, the lack of class I clinical evidence-based medical evidence, it is recommended to use with caution;
4. Although ATP, CoA, vitamin B6 and vitamin C are also lack of Class I clinical evidence for the treatment of acute craniocerebral trauma patients, they have been proved to be non-toxic, inexpensive and have clear pharmacological effects through long-term clinical application, and their use is recommended. In view of the design of international multicenter clinical studies, there are still some irrationalities, such as: the drug doses of international prospective randomized double-blind multicenter clinical control studies obviously exceed the actual clinical use doses in China (continuous intravenous drip of 4% albumin liquid for 28 days, 48-hour intravenous drip of mega-dose methylprednisolone 21.2 grams, etc.). Therefore, Chinese neurosurgeons should take into account the actual situation of patients with craniocerebral injury and choose the use of brain-protective drugs reasonably according to the Chinese Pharmacopoeia.
V. Explain that due to the continuous progress of clinical medicine, the level I evidence-based medical evidence for drug treatment of patients with craniocerebral injury will continue to increase, and the Chinese Guidelines for the Treatment of Brain Protective Drugs in Craniocerebral Injury will continue to be revised and improved, and we will reflect the most authoritative scientific conclusions in the field of neurosurgery and neuroscience in a timely and objective manner for the benefit of patients with craniocerebral injury in the future. Chinese neurosurgeons should join hands with relevant pharmaceutical companies to actively carry out prospective randomized double-blind multi-center clinical control studies (evidence-based medicine level I evidence), develop effective brain-protective nutritional drugs for the treatment of craniocerebral injury patients, and really improve the treatment effect of craniocerebral injury patients.
The Guidelines for the Treatment of Brain Protective Drugs in Craniocerebral Injury in China are recommended by neurosurgeons and are for the clinical reference and guidance of neurosurgeons in China only and do not have legal effect.