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Neuroprotective strategies for patients with acute myocardial infarction combined with hypoxic ischemic encephalopathy in the ICU
Accepted Manuscript The Neuroprotective Strategic Analysis for Patients with Acute Myocardial Infarction Combined with Hypoxic Ischemic Encephalopathy in ICU Yali Chao, Weiwei Hu, Dr. Xiaojuan Geng PII:
S1109-9666(16)30345-1
DOI:
10.1016/j.hjc.2016.12.006
Reference:
HJC 104
To appear in:
Hellenic Journal of Cardiology
Received Date: 3 December 2016 Revised Date:
30 December 2016
Accepted Date: 30 December 2016
Please cite this article as: Chao Y, Hu W, Geng X, The Neuroprotective Strategic Analysis for Patients with Acute Myocardial Infarction Combined with Hypoxic Ischemic Encephalopathy in ICU, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2016.12.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The Neuroprotective Strategic Analysis for Patients with Acute Myocardial Infarction Combined with Hypoxic Ischemic Encephalopathy in ICU
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Yali Chao#, Weiwei Hu#, Xiaojuan Geng Intensive Care Unit,the Affiliated Hospital of Xuzhou Medical University Correspondence to:Dr.Xiaojuan Geng,Intensive Care Unit,the Affiliated Hospital of Xuzhou Medical UniversityNo.99,West Huaihai Road,Xuzhou,Jiangsu,221002,PR China. Email:[email protected] #Yali Chao and Weiwei Hu contributed equally to this article.
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Abstract Background: We conducted this study to investigate the neuroprotective treatment strategies for patients with acute myocardial infarction (AMI) complicated with hypoxic ischemic encephalopathy (HIE) in the ICU. Methods: A total of 83 cases that were diagnosed with secondary AMI for the first time were selected and divided into observation group (n=43) and the control group (n=40). All of patients underwent emergency or elective PCI. Patients in the control group were treated with mannitol to reduce intracranial pressure, cinepazide maleate to improve microcirculation in the brain and also given comprehensive treatments of oxygen inhalation, fluid infusion, acid-base imbalance correction, electrolyte disturbance, etc. Patients in the observation group underwent conventional treatment combined with neuroprotective therapeutic strategies. The treatment effects were compared. Results: Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group (P < 0.05). After treatment, jugular vein oxygen saturation (SjvO2) and blood lactate (JB-LA) levels of the two groups were lower than those before treatment, cerebral oxygen utilization rate (O2UC) increased, with significantly higher increase in the observation group (p<0.05). After treatment, the activities of daily living (ADL) scores of both groups were higher than those before treatment and the neural function defect score (NIHSS) scores was decreased. Conclusion: The adoption of neuroprotective strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen to treat the AMI with HIE patients had a better application effect and me be worth clinical promotion. Key words: ICU; acute myocardial infarction; hypoxic ischemic encephalopathy; neural protection Introduction Acute myocardial infarction (AMI) is the acute myocardial necrosis induced by the persistent and serious coronary artery ischemia and hypoxia [1,2]. Brain tissue is very sensitive to hypoxia, which can lead to irreversible hypoxic injury, necrosis or apoptosis within 6min. Coronary artery and cerebral artery have a common basis in
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the mechanism of thrombosis, atherosclerosis, inflammation, oxidative stress, ischemia and hypoxia injury, reperfusion injury and so on [3]. Except for irreversible myocardial injury and myocardial remodeling, the occurrence of AMI plays an important role in hypoxic ischemic injury of brain tissue. Early revascularization can significantly improve the short-term and long-term prognosis of AMI, but epidemiological studies have found that [4] cognitive dysfunction incidence rate of the patients with an AMI history of 5-10 times was about 10-15%, which is 3-5 times than patients without coronary heart disease. At the early stage of AMI, cardiogenic shock, cardiac arrest and sudden death could occur, and with an increase of rescue success rate of primary cardiopulmonary resuscitation and the improvement of the advanced life support technologies, prevalence rate of AMI secondary to hypoxic ischemic encephalopathy (HIE) increased gradually, which was about 0.5-2.0%, and the success rate of the treatment increased gradually, which was about 60-85% [5]. The cause of HIE is the decrease of acute severe cerebral perfusion, which makes hypoxic-ischemic damage, promotes inflammation, necrosis or apoptosis of nerve cells, and forms the nerve function disorder. Currently, the theoretical studies and animal models of neural protection have strongly supported their roles in neural protection with HIE [6,7]. But, there are few clinical studies, and its mechanism remains to be further analyzed. Theoretical investigations and experimental studies on animal models of neuroprotection have strongly supported its role in neuroprotection of HIE [7,8], but still lack of in vivo clinical studies, further studies are still needed to elucidate the mechanism. Based on previous results, this study aims to discuss the neuroprotective strategies for patients with AMI secondary to HIE in ICU, and to provide a reference for the clinical treatment. 1. Materials and Methods 1.1 Sample Selection A total of 83 cases that were diagnosed with AMI secondary to AMI for the first time at the Affiliated Hospital of Xuzhou Medical University from January 2012 to January 2016 were selected, with the inclusion criteria: ①Diagnosed with AMI according to the following criteria: acute chest pain symptoms, typical ischemic electrocardiographic changes and dynamic evolution characteristics, and myocardial necrosis markers（cTnI or cTnT or CK-MB）are positive; ② Within 72h of the occurrence of AMI, different levels of consciousness or new nerve dysfunction occurs, such as adverse physical activity, slurred speech, agnosia, memory disorder and so on; ③ Through the head MRI or CT examination, early intracranial hemorrhage, cerebral edema, unclear grey matter margin, cortical laminar necrosis and so on will be detected; at the end, neuronal death, obvious brain atrophy and extensive injury of brain function are visible; ④ Family members sign the informed consent. Exclusion criteria: ① The disease condition is serious, and the expected survival time is less than one month; ②The presence of primary brain lesions, brain trauma, brain tumors and so on; ③ Neurological and psychiatric diseases caused by other reasons, such as Alzheimer disease, severe anxiety or depression, etc.; ④ Poor compliance and incomplete clinical data. Patients were divided into the control group with 40 cases and the observation
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group with 43 cases according to the parity number method of the last numeral of admission numbers. In the control group, there were 23 males and 17 females aged 40-75 years, with an average age of （58.6±12.5）. There were 23 cases with transmural myocardial infarction and 17 cases of subendocardial myocardial infarction. The AMI time was 4-30h, and (10.5 + 4.2) on average and the time of PCI was 50-83min, (62.8 + 14.9) min on average. There were 5 cases of cardiogenic shock, 4 cases of malignant arrhythmia and 2 cases of cardiopulmonary resuscitation. In the observation group, there were 25 males and 18 females aged 40-70 years, with an average age of （57.7±15.4）. There were 24 cases of transmural myocardial infarction and 19 cases of subendocardial myocardial infarction. The AMI time was 3~36h, and （11.2±4.6） on average; the time of PCI was 55-90min, （65.7±13.6）min on average. There were 6 cases of cardiogenic shock, 3 cases of malignant arrhythmia and 3 cases of cardiopulmonary resuscitation. The general information of the patients in the two groups were compared, and the differences were not statistically significant (P>0.05). 1.2 Research Methods All patients underwent emergency or elective PCI, which were performed by the same operation and nursing team according to standard medical procedure. The patients were all placed in ICU during the preoperative and postoperative periods. The absolute bed rest were ensured and the vital signs were closely monitored by continuous ECG monitoring. Patients in the control group were treated with 100ml mannitol intravenous drip for 2-3 times per day to reduce intracranial pressure and were administered 320mg of Cinepazide Maleate Injection per day to improve microcirculation in the brain as well as comprehensive treatments of Oxygen inhalation, rehydration, acid-base imbalance correction and electrolyte disturbance and so on. Patients in the observation group were given conventional treatment combined with neuroprotective therapeutic strategies, which in this particular case are: ① hypothermia: a brain cooling device (GE company, Fairfield, Connecticut, USA) was used to make the patients wear ice caps, and at the same time, ice bags were placed in the areas of armpits and groin to reduce the temperature; temperature data in the brain cooling device were monitored to prevent frostbite and to make sure brain tissue and cells of the patient were at a low temperature, which reduced the oxygen consumption of the brain cells effectively and protected the damaged brain cells. ② the ganglioside injection treatment (produced by Harbin Medical Pharmaceutical Co. Ltd. of Hei Longjiang province): a treatment course of 20mg intravenous drip per day for one week, blood pressure, pulse rate, respiratory rate, bleeding tendency, etc. of the patients were observed during the intravenous drip period and were recorded every 4 hours. ③ the hyperbaric oxygen therapy: when the patients were in stable condition, they were treated with hyperbaric oxygen chamber treatment with a pressure of 0.24Mpa, the pressure was increased to 15min and kept stable for 1h and then reduced to 15min, while mask oxygen inhalation was given twice during the stable pressure period, with 10 min intervals. The treatment frequency was once per day for a 5 day course of treatment; a rest of two days was given after 2 days of each treatment, and then the next course of treatment was administered. ④the dietary strategy: a gastric
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tube was inserted into the stomach through the nasal cavity of patients by the medical workers, in which fish oil food and enteral nutrition suspension liquid containing n-3 polyunsaturated fatty acid were injected, and gastric juice was extracted every 4h. 1.3 observation indicators and evaluation methods Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the two groups were compared. Arterial cerebral oxygen metabolism indicators before treatment and after one week were compared, including jugular venous bulb oxygen saturation (SjvO2), blood lactate (JB-LA) and cerebral oxygen utilization rate(O2UC)，O2UC=SaO2－SjVO2 /SaO2. The Seldinger method was used to puncture the right internal jugular vein of the patients and jugular vein blood was extracted as samples to conduct blood gas analysis. Activities of daily living (ADL) before treatment and after one-month treatment were compared. Barthel scoring method and neural function defect score (NIHSS score) were used to evaluate brain function. Barthel scoring method standard: 0 score indicates that patients do not have the independent ability of daily life, various functions are performed poorly and they need to rely on others absolutely. 100 scores show that patients have the independent ability to deal with the daily life, they can control their bladder and bowel, and they have good physical functions and do not need the help of others. NIHSS score was evaluated from eleven aspects of consciousness level, gaze, vision, upper limb movement, facial paralysis, ataxia, lower limbs movement, language and feeling, dysarthria and neglect, scores were accumulated to get the final score, and the higher the score, the worse neural function. 1.4 Statistical methods SPSS19.0 software was used to conduct statistical analysis; measurement data was expressed by the mean ± standard deviation. Comparison between observation and control groups was tested by the independent sample t-test. Percentage (%) was used to express the enumeration data and chi-square test was used for data analysis. P＜ 0.05 indicated that the differences were statistically significant. 2 Results 2.1 Comparisons of the consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay between patients of the two groups The consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group, and the differences were statistically significant (P < 0.05). See Table I. Table I. Comparisons of the consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay between the two groups (d) Groups Consciousness Reflex Muscle Duration of recovery time recovery time tension ICU stay recovery time 7.3±1.5 7.8±1.6 23.3±4.7 The control 6.5±1.7
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5.5±1.4
15.5±3.2
5.304 0.024
5.319 0.025
5.328 0.023
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group 3.7±1.2 The observation group t 5.263 P 0.026
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2.2 Comparison of arterial blood cerebral oxygen metabolism indicators After treatment, the SjvO2 and JB-LA levels of the two groups were lower than before, while the O2UC increased; the observation group improved more significantly, and the differences were statistically significant (p<0.05). See Table II. Table II. Comparisons of arterial blood cerebral oxygen metabolism indicators SjVO2 (%) O2UC After Before After Before treatment treatment treatment treatment 60.5±5.2 0.17±0.03 0.20±0.04 The control 68.2±5.6 group 70.3±5.7 54.3±5.4 0.16±0.04 0.28±0.05 The observation group t 0.425 4.628 0.123 4.238 P 0.546 0.030 0.935 0.036 Note: SjVO2 is jugular vein oxygen saturation: JB-LA is blood cerebral oxygen utilization rate
JB-LA (mmol /L) Before After treatment treatment 3.5±0.7 2.6±0.5 3.6±0.8
2.0±0.4
0.152 4.527 0.867 0.032 lactate; O2UC is
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2.3 Comparisons of ADL and NIHSS scores before and after treatment After treatment, the ADL scores of the both groups increased more than those before treatment and NIHSS scores decreased; the observation group improved more significantly, and the differences were statistically significant (p<0.05). See Table III. Table III. Groups
Comparisons of ADL and NIHSS scores before and after treatment Barthel scores NIHSS scores Before After Before After treatment treatment treatment treatment 75.3±7.4 5.2±0.8 3.8±0.6 control 67.2±6.5
The group The observation group
65.8±6.8
82.4±7.6
5.3±0.7
3.4±0.5
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0.326 0.649
5.234 0.022
0.248 0.765
5.102 0.025
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3 Discussion Hypothermia therapy on patients in the temperature range of 28-35℃ is usually divided into three stages of induction, maintenance and rewarming [9] At the induction phase, an intravenous drip of ice salt water can be used to decrease the temperature and the brain cooling device can be used to make patients wear ice caps for hypothermia. At the the maintenance phase, the former can be combined with water circulating ice blanket for sustentation, and the latter can be combined with changing the ice cubes in the ice caps for sustentation through monitoring the temperatures showed in the brain cooling device. Hypothermia therapy can inhibit the apoptosis of brain cells, reverse the nerve cells function, improve the blood brain barrier, and effectively inhibit the influx of Calcium ions [10] . Hypothermia treatment can also effectively inhibit the release and activation process of various inflammatory factors, which leads to a blocking of the cascade amplification reaction [11], effectively inhibit the expression of neuron specific enolase (NSE), block apoptosis process of nerve cells, reduce brain edema as well as promote nerve functional recovery [12]. Ganglioside is a glycosphingolipid, which is a component of the nerve cell membrane. Ganglioside administration can promote the differentiation of brain nerve cells, help the form synapses, make the plastic regulation for nerve cells[13], and at the same time, interact with neurotrophic factors and commonly inhibit the occurrence of nerve cell apoptosis. Ganglioside can be embedded into the nerve cell membrane through the blood brain barrier (BBB) to effectively reduce the Ca2 + influx, alleviate cerebral edema and reduce the damage of free radicals to brain cells [14,15]. Hyperbaric oxygen therapy is a type of treatment method with positive pressure ventilation and intermittent high concentration oxygen supply. Through high pressure oxygen supply, arterial oxygen content and oxygen partial pressure can be increased and oxygen tension can be improved, which can achieve brain oxygen content improvement, hypoxia metabolism process correction, brain edema alleviation, the effective blocking of the apoptosis process of brain cells so as to make the damaged brain cells restore normal function [16]. n-3 polyunsaturated fatty acids are usually rich in fish oil and fatty fish, which can be supplemented and intervened by diet to add the required components for the structure formation and function play of exogenous neural tissue and cells [17] and to enhance the phosphorylation activation of Akt neurons, improve the survival rate of neurons and directly produce the protective effect [18]. At the same time, n-3 polyunsaturated fatty acid have a good inhibitory effect on the release of inflammatory factors and activation of microglia to indirectly reduce the damage of neurons [19]. Our results demonstrate that consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group. After treatment, for the observation group, the jugular venous bulb oxygen saturation (SjvO2) and blood
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lactate (JB-LA) levels were lower than those of the control group, cerebral oxygen utilization rate (O2UC) increased, ADL scores were higher than that of the control group, NIHSS scores decreased, and the differences were statistically significant. In summary, the adoption of neuroprotective protection strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen to treat the AMI combined with HIE patients in ICU has a better application effect and that is worthy of clinical application. However, there are many points about the neuroprotective effect that remain to be studied in vivo, such as the best treatment time for hypothermia, the adjustment of the specific parameters, the application dose and the courses of ganglioside, the application security of hyperbaric oxygen and so on. In addition, the number of samples and the observation indicators should be increased, and the follow-up period should be extended to observe the application security and the observation efficiency of the neural protection.
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In conclusion, the adoption of neuroprotective protection strategies of mild hypothermia and ganglioside treatment assisted with hyperbaric oxygen treatment to treat AMI patients with HIE as a complication in ICU is safe and efficient for application. It provided strong evidences for the application of neuroprotection, broadened indications of neuroprotection, and also improved the prognosis of patients with AMI complicated by HIE.
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References 1. Tousoulis D: New modalities assessing left and right ventricular function: How they apply to myocardial infarction. Hellenic J Cardiol 2016; 57: 143-144. 2. Andrikopoulos G, Terentes-Printzios D, Tzeis S, Vlachopoulos C, Varounis C, Nikas N, Lekakis J, Stakos D, Lymperi S, Symeonidis D, Chrissos D, Kyrpizidis C, Alexopoulos D, Zombolos S, Foussas S, Kapparanidis A, Oikonomou K, Vasilikos V, Andronikos P, Dermitzakis A, Richter D, Fragakis N, Styliadis I, Mavridis S, Stefanadis C, Vardas P: Epidemiological characteristics, management and early outcomes of acute coronary syndromes in Greece: The PHAETHON study. Hellenic J Cardiol 2016; 57: 157-166. 3. Lipovetskiĭ BM. About dyslipidemic states characteristic for various forms of ischemic heart disease and cerebrovascular damages. Kardiologiia. 2007;47(8):8-11. 4. Böhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R, Custodis F, Diener HC, Laufs U, Lonn E, Sliwa K, Teo K, Fagard R, Redon J, Sleight P, Anderson C, O'Donnell M, Yusuf S. Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension. 2015 Mar;65(3):651-61. 5. Koenig MA. Brain resuscitation and prognosis after cardiac arrest. Crit Care Clin. 2014 Oct;30(4):765-83. 6. Demarest TG, Schuh RA, Waddell J, McKenna MC, Fiskum G. Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of
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neonatal hypoxic-ischemic encephalopathy. J Neurochem. 2016 Jun;137(5):714-29. 7. Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, Van Meurs KP, Rogers EE, Gonzalez FF, Comstock BA, Juul SE, Msall ME, Bonifacio SL, Glass HC, Massaro AN, Dong L, Tan KW, Heagerty PJ, Ballard RA.High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics. 2016 Jun;137(6). 8. Zhang X, Zhang Q, Li W, Nie D, Chen W, Xu C, Yi X, Shi J, Tian M, Qin J, Jin G, Tu W. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy. J Neurosci Res. 2014 Jan;92(1):35-45. 9. Frymoyer A, Bonifacio SL, Drover DR, Su F, Wustoff CJ, Van Meurs KP. Decreased Morphine Clearance in Neonates with Hypoxic Ischemic EncephalopathyReceiving Hypothermia. J Clin Pharmacol. 2016 May 26(3):15-16. 10. Elbahtiti A, Aly NY, Abo-Lila R, Al-Sawan R. Therapeutic hypothermia for infants with hypoxic ischemic encephalopathy: A five years' single center experience in Kuwait. J Neonatal Perinatal Med. 2016 May 19(3):14-15. 11. Saito J, Shibasaki J, Shimokaze T, Kishigami M, Ohyama M, Hoshino R, Toyoshima K, Itani Y. Temporal Relationship between Serum Levels of Interleukin-6 and C-Reactive Protein in Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. Am J Perinatol. 2016 May 11(3):12-13. 12. Nespeca M, Giorgetti C, Nobile S, Ferrini I, Simonato M, Verlato G, Cogo P, Carnielli VP. Does Whole-Body Hypothermia in Neonates with Hypoxic-Ischemic EncephalopathyAffect Surfactant Disaturated-Phosphatidylcholine Kinetics? PLoS One. 2016 Apr 12;11(4):e0153328. 13. Zhu XY, Ye MY, Zhang AM, Wang WD, Zeng F, Li JL, Fang F. Influence of one-year neurologic outcome of treatment on newborns with moderate and severehypoxic-ischemic encephalopathy by rhuEP0 combined with ganglioside (GM1).Eur Rev Med Pharmacol Sci. 2015 Oct;19(20):3955-60. 14. Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Rabionet M, Dere E, Dörmann P, Sandhoff K, Willecke K.Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem. 2012 Dec 7;287(50):41888-902. 15. Ariga T. Pathogenic role of ganglioside metabolism in neurodegenerative diseases. J Neurosci Res. 2014 Oct;92(10):1227-42. 16. Zhou BY, Lu GJ, Huang YQ, Ye ZZ, Han YK. [Efficacy of hyperbaric oxygen therapy under different pressures on neonatal hypoxic-ischemic encephalopathy]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Apr;10(2):133-5. 17. Cheng P, Huang W, Bai S, Wu Y, Yu J, Zhu X, Qi Z, Shao W, Xie P. BMI Affects the Relationship between Long Chain N-3 Polyunsaturated Fatty Acid
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Intake and Stroke Risk: a Meta-Analysis. Sci Rep. 2015 Sep 15;5:14161. 18. Zhang W, Liu J, Hu X, Li P, Leak RK, Gao Y, Chen J. n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling. Stroke. 2015 Oct;46(10):2943-50. 19. Allam-Ndoul B, Guénard F, Barbier O, Vohl MC. Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages. Lipids Health Dis. 2016 Apr 5;15(1):69.
S1109-9666(16)30345-1
DOI:
10.1016/j.hjc.2016.12.006
Reference:
HJC 104
To appear in:
Hellenic Journal of Cardiology
Received Date: 3 December 2016 Revised Date:
30 December 2016
Accepted Date: 30 December 2016
Please cite this article as: Chao Y, Hu W, Geng X, The Neuroprotective Strategic Analysis for Patients with Acute Myocardial Infarction Combined with Hypoxic Ischemic Encephalopathy in ICU, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2016.12.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT The Neuroprotective Strategic Analysis for Patients with Acute Myocardial Infarction Combined with Hypoxic Ischemic Encephalopathy in ICU
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Yali Chao#, Weiwei Hu#, Xiaojuan Geng Intensive Care Unit,the Affiliated Hospital of Xuzhou Medical University Correspondence to:Dr.Xiaojuan Geng,Intensive Care Unit,the Affiliated Hospital of Xuzhou Medical UniversityNo.99,West Huaihai Road,Xuzhou,Jiangsu,221002,PR China. Email:[email protected] #Yali Chao and Weiwei Hu contributed equally to this article.
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Abstract Background: We conducted this study to investigate the neuroprotective treatment strategies for patients with acute myocardial infarction (AMI) complicated with hypoxic ischemic encephalopathy (HIE) in the ICU. Methods: A total of 83 cases that were diagnosed with secondary AMI for the first time were selected and divided into observation group (n=43) and the control group (n=40). All of patients underwent emergency or elective PCI. Patients in the control group were treated with mannitol to reduce intracranial pressure, cinepazide maleate to improve microcirculation in the brain and also given comprehensive treatments of oxygen inhalation, fluid infusion, acid-base imbalance correction, electrolyte disturbance, etc. Patients in the observation group underwent conventional treatment combined with neuroprotective therapeutic strategies. The treatment effects were compared. Results: Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group (P < 0.05). After treatment, jugular vein oxygen saturation (SjvO2) and blood lactate (JB-LA) levels of the two groups were lower than those before treatment, cerebral oxygen utilization rate (O2UC) increased, with significantly higher increase in the observation group (p<0.05). After treatment, the activities of daily living (ADL) scores of both groups were higher than those before treatment and the neural function defect score (NIHSS) scores was decreased. Conclusion: The adoption of neuroprotective strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen to treat the AMI with HIE patients had a better application effect and me be worth clinical promotion. Key words: ICU; acute myocardial infarction; hypoxic ischemic encephalopathy; neural protection Introduction Acute myocardial infarction (AMI) is the acute myocardial necrosis induced by the persistent and serious coronary artery ischemia and hypoxia [1,2]. Brain tissue is very sensitive to hypoxia, which can lead to irreversible hypoxic injury, necrosis or apoptosis within 6min. Coronary artery and cerebral artery have a common basis in
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the mechanism of thrombosis, atherosclerosis, inflammation, oxidative stress, ischemia and hypoxia injury, reperfusion injury and so on [3]. Except for irreversible myocardial injury and myocardial remodeling, the occurrence of AMI plays an important role in hypoxic ischemic injury of brain tissue. Early revascularization can significantly improve the short-term and long-term prognosis of AMI, but epidemiological studies have found that [4] cognitive dysfunction incidence rate of the patients with an AMI history of 5-10 times was about 10-15%, which is 3-5 times than patients without coronary heart disease. At the early stage of AMI, cardiogenic shock, cardiac arrest and sudden death could occur, and with an increase of rescue success rate of primary cardiopulmonary resuscitation and the improvement of the advanced life support technologies, prevalence rate of AMI secondary to hypoxic ischemic encephalopathy (HIE) increased gradually, which was about 0.5-2.0%, and the success rate of the treatment increased gradually, which was about 60-85% [5]. The cause of HIE is the decrease of acute severe cerebral perfusion, which makes hypoxic-ischemic damage, promotes inflammation, necrosis or apoptosis of nerve cells, and forms the nerve function disorder. Currently, the theoretical studies and animal models of neural protection have strongly supported their roles in neural protection with HIE [6,7]. But, there are few clinical studies, and its mechanism remains to be further analyzed. Theoretical investigations and experimental studies on animal models of neuroprotection have strongly supported its role in neuroprotection of HIE [7,8], but still lack of in vivo clinical studies, further studies are still needed to elucidate the mechanism. Based on previous results, this study aims to discuss the neuroprotective strategies for patients with AMI secondary to HIE in ICU, and to provide a reference for the clinical treatment. 1. Materials and Methods 1.1 Sample Selection A total of 83 cases that were diagnosed with AMI secondary to AMI for the first time at the Affiliated Hospital of Xuzhou Medical University from January 2012 to January 2016 were selected, with the inclusion criteria: ①Diagnosed with AMI according to the following criteria: acute chest pain symptoms, typical ischemic electrocardiographic changes and dynamic evolution characteristics, and myocardial necrosis markers（cTnI or cTnT or CK-MB）are positive; ② Within 72h of the occurrence of AMI, different levels of consciousness or new nerve dysfunction occurs, such as adverse physical activity, slurred speech, agnosia, memory disorder and so on; ③ Through the head MRI or CT examination, early intracranial hemorrhage, cerebral edema, unclear grey matter margin, cortical laminar necrosis and so on will be detected; at the end, neuronal death, obvious brain atrophy and extensive injury of brain function are visible; ④ Family members sign the informed consent. Exclusion criteria: ① The disease condition is serious, and the expected survival time is less than one month; ②The presence of primary brain lesions, brain trauma, brain tumors and so on; ③ Neurological and psychiatric diseases caused by other reasons, such as Alzheimer disease, severe anxiety or depression, etc.; ④ Poor compliance and incomplete clinical data. Patients were divided into the control group with 40 cases and the observation
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group with 43 cases according to the parity number method of the last numeral of admission numbers. In the control group, there were 23 males and 17 females aged 40-75 years, with an average age of （58.6±12.5）. There were 23 cases with transmural myocardial infarction and 17 cases of subendocardial myocardial infarction. The AMI time was 4-30h, and (10.5 + 4.2) on average and the time of PCI was 50-83min, (62.8 + 14.9) min on average. There were 5 cases of cardiogenic shock, 4 cases of malignant arrhythmia and 2 cases of cardiopulmonary resuscitation. In the observation group, there were 25 males and 18 females aged 40-70 years, with an average age of （57.7±15.4）. There were 24 cases of transmural myocardial infarction and 19 cases of subendocardial myocardial infarction. The AMI time was 3~36h, and （11.2±4.6） on average; the time of PCI was 55-90min, （65.7±13.6）min on average. There were 6 cases of cardiogenic shock, 3 cases of malignant arrhythmia and 3 cases of cardiopulmonary resuscitation. The general information of the patients in the two groups were compared, and the differences were not statistically significant (P>0.05). 1.2 Research Methods All patients underwent emergency or elective PCI, which were performed by the same operation and nursing team according to standard medical procedure. The patients were all placed in ICU during the preoperative and postoperative periods. The absolute bed rest were ensured and the vital signs were closely monitored by continuous ECG monitoring. Patients in the control group were treated with 100ml mannitol intravenous drip for 2-3 times per day to reduce intracranial pressure and were administered 320mg of Cinepazide Maleate Injection per day to improve microcirculation in the brain as well as comprehensive treatments of Oxygen inhalation, rehydration, acid-base imbalance correction and electrolyte disturbance and so on. Patients in the observation group were given conventional treatment combined with neuroprotective therapeutic strategies, which in this particular case are: ① hypothermia: a brain cooling device (GE company, Fairfield, Connecticut, USA) was used to make the patients wear ice caps, and at the same time, ice bags were placed in the areas of armpits and groin to reduce the temperature; temperature data in the brain cooling device were monitored to prevent frostbite and to make sure brain tissue and cells of the patient were at a low temperature, which reduced the oxygen consumption of the brain cells effectively and protected the damaged brain cells. ② the ganglioside injection treatment (produced by Harbin Medical Pharmaceutical Co. Ltd. of Hei Longjiang province): a treatment course of 20mg intravenous drip per day for one week, blood pressure, pulse rate, respiratory rate, bleeding tendency, etc. of the patients were observed during the intravenous drip period and were recorded every 4 hours. ③ the hyperbaric oxygen therapy: when the patients were in stable condition, they were treated with hyperbaric oxygen chamber treatment with a pressure of 0.24Mpa, the pressure was increased to 15min and kept stable for 1h and then reduced to 15min, while mask oxygen inhalation was given twice during the stable pressure period, with 10 min intervals. The treatment frequency was once per day for a 5 day course of treatment; a rest of two days was given after 2 days of each treatment, and then the next course of treatment was administered. ④the dietary strategy: a gastric
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tube was inserted into the stomach through the nasal cavity of patients by the medical workers, in which fish oil food and enteral nutrition suspension liquid containing n-3 polyunsaturated fatty acid were injected, and gastric juice was extracted every 4h. 1.3 observation indicators and evaluation methods Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the two groups were compared. Arterial cerebral oxygen metabolism indicators before treatment and after one week were compared, including jugular venous bulb oxygen saturation (SjvO2), blood lactate (JB-LA) and cerebral oxygen utilization rate(O2UC)，O2UC=SaO2－SjVO2 /SaO2. The Seldinger method was used to puncture the right internal jugular vein of the patients and jugular vein blood was extracted as samples to conduct blood gas analysis. Activities of daily living (ADL) before treatment and after one-month treatment were compared. Barthel scoring method and neural function defect score (NIHSS score) were used to evaluate brain function. Barthel scoring method standard: 0 score indicates that patients do not have the independent ability of daily life, various functions are performed poorly and they need to rely on others absolutely. 100 scores show that patients have the independent ability to deal with the daily life, they can control their bladder and bowel, and they have good physical functions and do not need the help of others. NIHSS score was evaluated from eleven aspects of consciousness level, gaze, vision, upper limb movement, facial paralysis, ataxia, lower limbs movement, language and feeling, dysarthria and neglect, scores were accumulated to get the final score, and the higher the score, the worse neural function. 1.4 Statistical methods SPSS19.0 software was used to conduct statistical analysis; measurement data was expressed by the mean ± standard deviation. Comparison between observation and control groups was tested by the independent sample t-test. Percentage (%) was used to express the enumeration data and chi-square test was used for data analysis. P＜ 0.05 indicated that the differences were statistically significant. 2 Results 2.1 Comparisons of the consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay between patients of the two groups The consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group, and the differences were statistically significant (P < 0.05). See Table I. Table I. Comparisons of the consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay between the two groups (d) Groups Consciousness Reflex Muscle Duration of recovery time recovery time tension ICU stay recovery time 7.3±1.5 7.8±1.6 23.3±4.7 The control 6.5±1.7
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5.5±1.4
15.5±3.2
5.304 0.024
5.319 0.025
5.328 0.023
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group 3.7±1.2 The observation group t 5.263 P 0.026
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2.2 Comparison of arterial blood cerebral oxygen metabolism indicators After treatment, the SjvO2 and JB-LA levels of the two groups were lower than before, while the O2UC increased; the observation group improved more significantly, and the differences were statistically significant (p<0.05). See Table II. Table II. Comparisons of arterial blood cerebral oxygen metabolism indicators SjVO2 (%) O2UC After Before After Before treatment treatment treatment treatment 60.5±5.2 0.17±0.03 0.20±0.04 The control 68.2±5.6 group 70.3±5.7 54.3±5.4 0.16±0.04 0.28±0.05 The observation group t 0.425 4.628 0.123 4.238 P 0.546 0.030 0.935 0.036 Note: SjVO2 is jugular vein oxygen saturation: JB-LA is blood cerebral oxygen utilization rate
JB-LA (mmol /L) Before After treatment treatment 3.5±0.7 2.6±0.5 3.6±0.8
2.0±0.4
0.152 4.527 0.867 0.032 lactate; O2UC is
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2.3 Comparisons of ADL and NIHSS scores before and after treatment After treatment, the ADL scores of the both groups increased more than those before treatment and NIHSS scores decreased; the observation group improved more significantly, and the differences were statistically significant (p<0.05). See Table III. Table III. Groups
Comparisons of ADL and NIHSS scores before and after treatment Barthel scores NIHSS scores Before After Before After treatment treatment treatment treatment 75.3±7.4 5.2±0.8 3.8±0.6 control 67.2±6.5
The group The observation group
65.8±6.8
82.4±7.6
5.3±0.7
3.4±0.5
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0.326 0.649
5.234 0.022
0.248 0.765
5.102 0.025
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3 Discussion Hypothermia therapy on patients in the temperature range of 28-35℃ is usually divided into three stages of induction, maintenance and rewarming [9] At the induction phase, an intravenous drip of ice salt water can be used to decrease the temperature and the brain cooling device can be used to make patients wear ice caps for hypothermia. At the the maintenance phase, the former can be combined with water circulating ice blanket for sustentation, and the latter can be combined with changing the ice cubes in the ice caps for sustentation through monitoring the temperatures showed in the brain cooling device. Hypothermia therapy can inhibit the apoptosis of brain cells, reverse the nerve cells function, improve the blood brain barrier, and effectively inhibit the influx of Calcium ions [10] . Hypothermia treatment can also effectively inhibit the release and activation process of various inflammatory factors, which leads to a blocking of the cascade amplification reaction [11], effectively inhibit the expression of neuron specific enolase (NSE), block apoptosis process of nerve cells, reduce brain edema as well as promote nerve functional recovery [12]. Ganglioside is a glycosphingolipid, which is a component of the nerve cell membrane. Ganglioside administration can promote the differentiation of brain nerve cells, help the form synapses, make the plastic regulation for nerve cells[13], and at the same time, interact with neurotrophic factors and commonly inhibit the occurrence of nerve cell apoptosis. Ganglioside can be embedded into the nerve cell membrane through the blood brain barrier (BBB) to effectively reduce the Ca2 + influx, alleviate cerebral edema and reduce the damage of free radicals to brain cells [14,15]. Hyperbaric oxygen therapy is a type of treatment method with positive pressure ventilation and intermittent high concentration oxygen supply. Through high pressure oxygen supply, arterial oxygen content and oxygen partial pressure can be increased and oxygen tension can be improved, which can achieve brain oxygen content improvement, hypoxia metabolism process correction, brain edema alleviation, the effective blocking of the apoptosis process of brain cells so as to make the damaged brain cells restore normal function [16]. n-3 polyunsaturated fatty acids are usually rich in fish oil and fatty fish, which can be supplemented and intervened by diet to add the required components for the structure formation and function play of exogenous neural tissue and cells [17] and to enhance the phosphorylation activation of Akt neurons, improve the survival rate of neurons and directly produce the protective effect [18]. At the same time, n-3 polyunsaturated fatty acid have a good inhibitory effect on the release of inflammatory factors and activation of microglia to indirectly reduce the damage of neurons [19]. Our results demonstrate that consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay of the observation group were significantly shorter than those of the control group. After treatment, for the observation group, the jugular venous bulb oxygen saturation (SjvO2) and blood
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lactate (JB-LA) levels were lower than those of the control group, cerebral oxygen utilization rate (O2UC) increased, ADL scores were higher than that of the control group, NIHSS scores decreased, and the differences were statistically significant. In summary, the adoption of neuroprotective protection strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen to treat the AMI combined with HIE patients in ICU has a better application effect and that is worthy of clinical application. However, there are many points about the neuroprotective effect that remain to be studied in vivo, such as the best treatment time for hypothermia, the adjustment of the specific parameters, the application dose and the courses of ganglioside, the application security of hyperbaric oxygen and so on. In addition, the number of samples and the observation indicators should be increased, and the follow-up period should be extended to observe the application security and the observation efficiency of the neural protection.
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In conclusion, the adoption of neuroprotective protection strategies of mild hypothermia and ganglioside treatment assisted with hyperbaric oxygen treatment to treat AMI patients with HIE as a complication in ICU is safe and efficient for application. It provided strong evidences for the application of neuroprotection, broadened indications of neuroprotection, and also improved the prognosis of patients with AMI complicated by HIE.
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