Effects Of Uitra-early Intensive Blood Pressure-Lowering Treatment On Hematoma Expansion,Plasma Matrix Metalloproteinase 9 And Neurologic Function In Intracerbral Hemorrhage

Studying background:Intracerebral hemorrhage(ICH) is a familiar emergency in Department of Neurology, the high rate of death and disability associated with this illness had taken the lead in all types of stroke. At present,owing to lack of effective therapy based evidence improving the neurological function of patients with ICH, this brought high financial burden to the society and families of patients. Researches showed that the pathophysiological three-stage process of ICH mainly included hematoma formation and hematoma enlargement and perihematomal edema. Hematoma enlargement and perihematomal edema in spontaneous ICH are important factors affecting severity and prognosis of patients. Elevated blood pressure,especial systolic blood pressure are closely related to hematoma enlargement and brain edema. After ICH elevated blood pressure is very common.To control the rapid early elevated blood pressure is a key clinical intervention.Through more than ten years of exploration,more and more scholars have changed the concept of managing blood pressure in acute cerebral hemorrhage from initial cautiously lowering blood pressure to intensive reduction in current international multi center, prospective trials.The safety of antihypertensive treatment was gradually accepted,but there have been still many problems to be solved of its effectiveness and optimal blood pressure control range and mechanisms of clinical benefit.The intensive blood pressure reduction in acute cerebral hemorrhage trial (INTERACT-2) announced in may 2013 showed the primary outcome(the proportion of patients with a poor outcome,defined as death or major disablity) were not significantly different. In addition to the delayed time for treatment(within 6 hours of symptom onset)、inclusion and exclusion criteria and the choice of antihypertensive drugs,other pathophysiological mechanisms of brain injury after ICH such as perihematomal edema、blood brain barrier disruption and upregulation of inflammatory medium would have important impacts on the clinical prognosis. MMP-9(matrix metalloproteinase-9) plays an important role in the inflammatory reaction and perihematomal edema formation.The hematoma enlargement in spontaneous intracerebral hemorrhage is related to MMP-9 or not, the intensive blood pressure lowering treatment influences the expression of MMP-9 or not,this kind of research is seldom seen.In this study, we controlled the patients blood pressure at level of 130 140mmHg by mainly intravenously dripping nitroglycerin within 1 hours,and maintained for 24 hours,we observed the effects of ultra-early intensive antihypertensive treatment (within 4 hours of onset) on hematoma expansion、plasma MMP-9、brain edema and neurological function of patients with basal ganglia ICH. We investigated the clinical outcome and possible mechanisms of clinical benefit of ultra early intensive antihypertensive treatment on patients after 90 days.Objective:We performed this study to investigate the effects of ultra-early intensive blood pressure-lowering treatment on the enlargement of hematoma, plasma matrix metalloproteinase 9,brain edema and neurological function in acute basal ganglia intracerebral hemorrhage.Methods:This study was a prospective study, approved by the medical ethical committee of our hospital.134 patients who had a spontaneous ultra-early basal ganglia intracerebral hemorrhage within the previous 4 hours and who were recruited from Department of Neurology of our Hospital during January 2012 and February 2014 were randomly divided into strengthening antihypertensive group(with a target systolic blood pressure level among 130～140 mmHg within 1 hours) consisted of 67 patients, overall 60 patients had completed the brain CT scans and treatment, and normal antihypertensive group(with a target systolic blood pressure level among 160～180 mmHg within 1 hours) consisted of 67 patients, overall 62 patients had completed the brain CT scans and treatment. There were no significant difference in baseline datas of 122 patients, such as age,gender. Eligible patients were aged≥18 years and were consistent with the revised standards of Chinese Fourth Academic Conference on cerebrovascular disease with CT-confirmed spontaneous basal ganglia or thalamus ICH and NIHSS score≥ 4 points and elevated systolic BP(≥ 2 measurements of≥ 160 mmHg and≤220 mmHg recorded≥ 5 minutes apart) with the capacity to start randomly assigned BP-lowering treatment with 4 hours of ICH and hematoma volume<30 ml or>30 ml and disagreed with surgical operation and<60 ml. Exclusion criteria included ICH secondary to a structural cerebral abnormal with strong evidence such as brain tumor,cerebral arteriovenous malformation or secondary to trauma, cerebral infarction,or the use of a thrombolytic agent; severe intracranial artery stenosis; ischemic stroke within 30 days; secondary intraventricular hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles;coagulation dysfunction; platelet count less than 50×109/L;known sensitivity to nitroglycerin; a candidate for immediate surgical intervention; serious patient is likely to die after 24 hours in hospital;or deep coma; consent by patients or representative cannot be obtained.(1)Nitroglycerin would be administered as a continuous infusion in the strengthening antihypertensive group, concentration of 40 ug/ml,with a starting dose of 5ug/min,and then increased by 5ug/min every 3～5 minutes as needed, and increased by 10～20ug/min at 20ug/min, SBP was reduced to 130～140 mmHg in 1 h, then maintained for 24h. In the normal antihypertensive group,if SBP was less than 180 mmHg,antihypertensive drugs would not be used, or performed intravenously drip nitroglycerin in 1 h, SBP was less than 180 mmHg,if SBP failed below 160 mmHg,nitroglycerin would be stopped or reduced untill SBP returned to 160-180 mmHg, then maintained for 24h. ECG was monitored immediately after the patient was admitted to hospital, blood pressure was monitored continuously(5 min per time until it reached BP standards,then 15 min per time). ECG changes were observed during treatment, with or without headache, dizziness, palpitation, chest tightness, chest pain and other symptoms.After 24 h treatment,the treatment of all patients was replaced by oral or nasal feeding enalapril or felodipine to reach the target BP of 160/90 mmHg, according to 2011 Chinese guidelines for the management of acute cerebral hemorrhage.(2) Neurological function score We performed U.S. National Institutes of Health neurological deficit (NIHSS) score before and after 24h and 14d of treatment.If patients NIHSS score were not performed on admission 14d,we replaced it with one on 13d or 12d or follow-up score.Patients were followed up in outpatient clinic or by telephone on fourth weeks after discharge and in outpatient clinic or home visits at 90 days. We performed modified Rankin scale (mRS) score,mild or moderate disability was defined as a score of 0 to 2, major disability was defined as a score of 3 to 5, a score of 6 indicating death.(3) Cranial CT was performed on admission or when disease aggravated or after 24h、5d of admission and diagnosed by more than two physicians of neurology or radiology,known nothing about the group and treatment of patients.After 5d of admission,60 patients cranial CT examination were completed in strengthening antihypertensive group,and 62 patients in normal antihypertensive group. If patient brain CT scan were not performed on admission 24h or 5d,we replaced it with one most recently from 24h((no more than 48 hours of admission)or from 5d (no more than 6 days of admission).We calculated the volume of hematoma and edema of cerebral hemorrhage.Hematoma volume=1/2(A×B×C×D),A:the longest diameter in the largest sectional area of hematoma(cm),B:at the same area, vertical maximum diameter width of A line(cm),C:the number of hematoma layers,D:thickness of CT slice(cm).The calculation method of lesion volume:taken length and width in the largest sectional area and slice numbers, lesion volume (range of peripheral edema edge) was valued at the same formula above. Edema volume(surrounding edema volume)=lesion volume - hematoma volume.The hematoma expasion was according to Kazui standard.Hematoma brain CT scans were calculated twice and defined as V1 and V2. If V2/V1>1.4 or V2-V1>12.5ml, we considered it as hematoma expansion.(4) Plasma MMP-9 level We determined it by ELISA. The procedure was followed by instruction of ELISA Kit (R&D Systems American company). Venous blood of patients was obtained before and after 5d of the treatment. Venous blood of 2-3ml were taken, anticoagulated by heparin, and were centrifugated for 15 minutes within 30 minutes. The supernatant (plasma) was extracted, preserved in the -80℃ refrigerator, detected altogether.(5) Statistical methods SPSS13.0 statistical software was used for statistical analysis. Measurement data were described as x±s and were analysed by t test, if accorded with normal distribution. If accorded with skew distribution,measurement data were described as median (M) and quantile (P25,P75) and were analysed by Mann-Whitney U test. Enumeration data were analysed by x2 test.P<0.05 had significant difference.Results:(1) For patients allocated to the strengthening antihypertensive group mean SBP was 145.35±10.54mmHg(with 46.7% of patients achieving the target SBP of 130-140mmHg) at 1 hour as compared with 163.08±9.96mmHg(with 74.2% of patients achieving the target SBP of 160-180mmHg)in the normal group,the difference was statistically significant (t=-9.552, P=0.000).The mean SBP in strengthening antihypertensive group was 139.77±8.40mmHg(with 70.0% of patients achieving the target SBP) after 24 hours treatment as compared with 160.05±10.64mmHg(with 69.4% of patients achieving the target SBP)in the normal group,the difference was statistically significant (t=-11.668, P=0.000).Cerebral infarction or other strokes did not occurred in two groups of patients, and so did severe hypotension.(2)There was no significant difference at 24h after treatment according to NIHSS score[Median:10.0(8.0,12.8),10.5(8.0,14.0),Z=-0.524,P=0.600], suggesting that early strengthening antihypertensive treatment were safe and tolerant. The NIHSS score of patients in strengthening antihypertensive group was significantly lower than it in normal group at 14d after treatment[Median:5.5(3.0,10.0),8.0 (5.0,12.0), Z= -2.140,P=0.032],suggesting that ultra-early strengthening antihypertensive treatment could improve the early neurological function of patients with cerebral hemorrhage. At 90d after treatment,1 patient was lost to follow-up in two groups respectively, the proportion of severe disability or death(mRS score 3～6) in strengthening antihypertensive group was significantly lower than it in normal group (22.03%, 13/59;39.34%,24/61, x2=4.214, P=0.040),suggesting that the ultra-early strengthening antihypertensive therapy could improve the self-care ability of patients with basal ganglia intracerebral hemorrhage.(3) The hematoma volume (12.23±7.01ml,14.66±6.22ml,t=-2.022,P=0.045)and proportion of patients with hematoma enlargement (8.33%,24.19%, x2=5.596, P=0.018) in strengthening antihypertensive group were less than those in normal group,the difference was statistically significant. At 5d after treatment the edema volume in strengthening antihypertensive group was significantly less than it in normal group (5.01±4.18ml,7.26±6.23ml, t=-2.339,P=0.021), the difference was statistically significant, suggesting that the ultra-early strengthening antihypertensive therapy could relieve the hematoma expansion of patients with basal ganglia intracerebral hemorrhage after 24 hours treatment,alleviate the brain perihematomal edema after 5 days of onset.(4)There were no significant difference in MMP-9 plasma level between the two groups before treatment (53.37±10.79ng/ml,54.29±10.35ng/ml,t=-0.481,P=0.632).The MMP-9 plasma level in the two groups both increased at 5d after treatment,suggesting that MMP-9 would play an important role in cerebral injury after ICH.The plasma MMP-9 level was significantly lower than that of normal group (102.57±14.26ng/ml, 110.33±23.58ng/ml,t=-2.179, P=0.031),the difference was statistically significant, suggesting that ultra-early strengthening antihypertensive therapy could decrease the level of plasma MMP-9 after 5 days of onset,and reduce the injury of brain tissue.Conclusions:(1) Intravenously dripping nitroglycerin could reduce and control the blood pressure of patients with ultra-early basal ganglia intracerebral hemorrhage quickly and effectively and safely.(2)Ultra-early(within 4h of symptom onset) strengthening antihypertensive therapy could relieve the hematoma expansion of patients with basal ganglia intracerebral hemorrhage after 24 hours of treatment.(3)Ultra-early(within 4h of symptom onset) strengthening antihypertensive treatment could alleviate the brain perihematomal edema of patients with basal ganglia intracerebral hemorrhage after 5 days of onset.(4)Ultra-early(within 4h of symptom onset) strengthening antihypertensive treatment could decrease the level of plasma MMP-9 of patients with basal ganglia intracerebral hemorrhage after 5 days of onset.(5)Ultra-early(within 4h of symptom onset) strengthening antihypertensive treatment could improve the early neurologic function and self-care ability after 90 days of onset in patients with basal ganglia intracerebral hemorrhage.