【作者】 马宏仲；

【导师】 王俊科；

【作者基本信息】 中国医科大学 ， 麻醉学， 2007， 博士

【摘要】 机械通气在医疗实践中发挥越来越大的作用,其涉及到临床麻醉、重症监测治疗和复苏。早在1832年Dalziel就成功研制成第一台负压呼吸机;1928年Driker-Shaw成功研制成的“铁肺”（iron lung）,从而开创了机械通气的新纪元。此后近一个世纪里,机械通气成功地解救了无数患者生命。同时,过度通气所致呼吸性碱中毒作为机械通气的一个并发症,对机体产生的重要影响也日益受到人们的重视。过度通气是指通气超过生理所需而引起的一组症候群,若血浆H₂CO₃原发性减少低于正常值下限（PaCO2＜35mmHg）且PH＞7.45则称为呼吸性碱中毒。呼吸性碱中毒在24h内发生者则称为急性呼吸性碱中毒。多年来,医学界对呼吸性酸中毒的研究报导较多,而关于呼吸性碱中毒的报道却很少,因为呼吸性碱中毒多见于机械控制通气和癔病综合征。临床上过度通气常常用于全麻诱导、气管拔管、腹腔镜手术和外伤所致的颅内高压等。尤其在外伤性颅内高压中,常采用过度通气降低颅内压。过度通气降低颅内压是利用CO₂化学调节作用,低CO₂可使脑血管收缩,减少脑灌注,从而降低颅内压,为手术创造相对清晰的视野。Morno-Kellie原理认为由脑组织、脑血容量、脑脊液三者组成的颅腔内容物中,产生调节作用的只有依赖脑血流量和脑脊液。但是过度通气导致的脑血管收缩却使原本处于缺血水平的脑细胞供血进一步减少。已有大量研究证实,过度通气不仅仅涉及到大脑的血供问题,而且有着广泛的生理效应,如引起低钾血症,酸碱平衡失调等。目前医学界认同重度过度通气引起的脑缺血,但对于过度通气是如何导致脑循环障碍及临床实践中过度通气的时程仍缺乏一致性,另外过度通气对于脑外伤颅内高压患者所致重要电解质的变化规律知之甚少,因此本课题带着这样的疑问,建立犬急性硬膜外血肿颅内高压模型,就相关问题进一步深入研究。方法一、资料及分组健康雄性家犬25只,年龄为2～4岁,体重13～15.5kg,常规饲养一周。禁食10h,禁饮6h。随机分为5组（A、B、C、D和E组,每组5只）,采用硬膜外球囊膨胀法建立犬急性颅内高压模型,各组先机械通气30min,维持P_ETCO₂在32-45mmHg之间:其中A组仅放置硬膜外球囊和颅内压力传感器,不膨胀球囊。二、麻醉和建立监测犬腹腔注射3%戊巴比妥钠30mg/Kg麻醉,气管插管,在保留自主呼吸下颈内静脉逆行穿刺连接三通管用于监测CVP、输液及采血。股动脉穿刺连接压力传感器连续测量MAP和采血,连接多参数监护仪,连续检测肛温、P_ETCO₂、HR、ECG、iBP和SPO₂等指标。三、犬颅内高压模型建立犬俯卧位,双外耳道连线距中线1cm处分别钻孔。左顶钝头细套管针脑室穿刺深约6mm接压力传感器。右顶硬膜外置乳胶球囊。术中充分止血,骨蜡密封骨孔。匀速向球囊内注入37℃生理盐水3～5ml,60sec内颅内压升至60±3mmHg后停止注射。判定颅内高压标准为:犬一侧瞳孔扩大、呼吸变缓及CT显示硬膜外占位。四、监测指标颅内高压3h后,维库溴铵0.8mg/kg静脉注射打断犬自主呼吸,连接呼吸机通气。A组家犬为空白对照组,硬膜外球囊内不注射液体,仅机械通气维持P_ETCO₂在32-45mmHg。B（正常通气组）、C（轻度通气组）和D（中度通气组）和E组（重度通气）建立硬膜外血肿颅内高压模型,机械通气30min后(P_ETCO₂范围在32-45mmHg)。调节呼吸机参数,B、C、D、E组P_ETCO₂分别维持在32-45、25-32、25-20及20mmHg以下持续通气60min。各组在术前及所设P_ETCO₂数值段内每10min采集颈静脉和股动脉血各0.5ml血气分析。另外测动静脉血血糖（BS）和乳酸（Lac）。在硬膜外球囊膨胀前（T₁）、过度通气后2h（T₂）、6h（T₃）、12h（T₄）、24h（T₅）和48h（T₆）各采集颈静脉血4mL,应用酶联免疫吸附法测定S100B和CRP含量。过度通气结束后排空球囊液体,此后2h（P₂）、6h（P₆）和12h(P₁₂)分别进行神经功能缺损评分。48h后处死,取犬不同部位脑组织病理分析。五、犬脑血流动力学检测经颅多普勒超声仪（TCD）,探头置于球囊同侧颞窗,调整探头获得最佳大脑中动脉（CMA）血流信号,记录收缩期峰值血流速度（Vs）、舒张期末血流速度（Vd）、平均血流速度（Vm）、搏动指数（PI）和阻力指数（RI）。同时计算脑氧利用率（O₂Ucc）、动静脉氧含量差（A-VDO₂）、脑氧耗量（CRO₂）、动静脉乳酸含量差（Da-juL）、脑氧摄取率（ERO₂）、脑氧耗量（Da-jvO₂）和动静脉糖含量差（Da-juglu）。结果除A组外,余20条家犬均成功建立急性硬膜外血肿颅内高压模型,按照预定时间完成过度通气。球囊膨胀时犬心率减慢、血压升高、呼吸减慢、单侧瞳孔扩大,与膨胀前比较有显著性差异（P＜0.05）。一、随着过度通气的进行,动脉血中K⁺、Ca²⁺、PaCO₂和HCO₃^-进行性降低,pH逐渐升高,PaCO₂下降与K⁺呈现正相关,相关系数r=0.9196（P＜0.01）。PaCO₂与血钙的相关系数为0.1973（P＜0.05）,CL^-和Na⁺基本保持不变。各组过度通气前后SaO₂维持不变（P＞0.05）。颈内静脉血气在中度过度通气后PH进行下降,严重过度通气则降到低点达到7.11±0.04（P＜0.05）。球囊扩张后,轻中度过度通气SjvO₂不变,D组和E组SjvO₂降至最低达到（42±6）%。二、与A组相比,球囊扩张后,动脉和静脉血中BS及Lac急剧升高,以静脉增加明显,动静脉BS浓度差增加（P＜0.05）,轻度过度通气Lac轻微降低,重度过度通气则使二者浓度更加升高（P＜0.05）,重度过度通气组脑动静脉Lac含量差（Da-juL）增加,与A组比较差异显著（P＜0.05）。三、球囊扩张后,犬心率减慢,血压和颅内压急剧升高,颅内压由术前的13±3.4 mmHg增加到60±3.0mmHg,与术前比较有显著性差异（P＜0.05）。当P_ETCO₂在25-35mmHg范围测得的PaCO₂与ICP呈现高度正相关r=0.9958,P＜0.01。轻度过度通气使颅内压轻微降低,但仍然高于术前。重度过度通气(P_ETCO₂＜20mmHg)时颅内压改变不大。四、脑氧供需:球囊扩张后,SjvO₂逐渐降低,过度通气P_ETCO₂的下降伴随SjVO₂也下降,当P_ETCO₂＜20mmHg时降到最低点。Da-jvO₂随着过度通气加深而降低,但当中度过度通气时Da-jvO₂则增加明显,与手术前和球囊扩张后比较有显著性差异（P＜0.05）。轻度过度通气时氧摄取率改变不大,但重度过度通气使氧摄取率明显降低,与术前比较有显著性差异（P＜0.05）。五、经颅多谱勒超声监测:硬膜外球囊扩张后大脑中动脉出现Vs和Vd显著减慢,PI和RI增大,与创伤前相比有显著性差异（P＜0.05）。轻度过度通气时,Vs有一定回升,但仍然处于低水平。当P_ETCO₂＜25mmHg时,Vs、Vd值达到最低,随过度通气的加深其值改变不大。六、S100B和CRP含量变化:所有犬硬膜外球囊扩张后S100B和CRP的含量不同程度升高（P＜0.05）。各组S100B蛋白6h后开始升高,12h达到峰值（2.08±0.32μg/L）,24h轻微下降,D组升高尤明显,与术前比较差异显著（P＜0.05）;CRP在实验组中2h后迅速增高,6h达到峰值（21.8±2.5mg/L）一直持续到48h,与球囊扩张前比较差异显著（P＜0.05）,D组CRP增加更高,6h达到29.4±5.7mg/L,与其余各组比较有显著性差异（P＜0.05）。七、神经功能评分:所有犬在过度通气后2h内神经功能评分较高,6h段分值降低,且随时间延长分值降低。重度过度通气组在手术后2h和6h的分值较高,与其余各组比较有显著性差异（P＜0.05）。而在12h后则与其它各组比较无显著性差异（P＞0.05）。在同一时间点A组、B组、C组和E组的神经功能评分并无显著性差异（P＞0.05）。八、病理分析:实验组球囊受压处脑组织软化、肿胀、色泽变暗,对侧脑组织结构基本正常。高倍光镜下皮质受压处大量脑细胞坏死,坏死带向脑组织深部延伸逐渐减轻,并伴脑实质部压迫性出血。周围皮质脑细胞坏死散在分布,脑细胞肿胀。D组较其它各组坏死细胞分布更广泛,脑组织肿胀明显。电镜下见坏死脑细胞结构模糊,脑细胞内线粒体空泡化以及溶解改变。结论一、急性过度通气影响体电解质、酸碱的变化,使动脉血中PH值升高、K⁺、Ca²⁺降低。PaCO₂每降低10mmHg,K⁺降低0.5mmol/L,Ca²⁺降低0.05mmol/L。二、当P_ETCO₂在25-35mmHg范围时,PaCO₂与ICP呈正相关关系,大于该范围,则颅内压降低不显著;小于该范围,会导致脑血液供应减少。严重通气引起脑氧供需失衡。三、急性过度通气影响血流动力学的变化,轻中度过度通气利于改善颅内高压引起的高血压作用。四、S100B和CRP浓度变化能够反映大脑受损的程度,其变化与神经功能受损评分具有一致性。五、重度过度通气对硬膜外血肿犬引起脑缺血可能因为脑血管过度收缩,脑细胞利用氧障碍、氧供需失衡等诸多因素综合作用的结果。六、重度过度通气延迟颅内高压犬麻醉苏醒时间。更多还原

【Abstract】 Mechanical ventilation plays an important role in medical practice,which involves in clinical anesthesia,ICU and resuscitation.Mechanical ventilation experenced a long time.In 1832,Dalziel developed a negative pressure breathing machine;In 1928, Driker-Shaw developed"iron lung".From then on,a new epoch of mechanical ventilation developed.Within about one century,mechanical ventilation successfully saved a lot of patients’lives.At the same time,more and more doctors thought highly of hyperventilation,but,a new problem occurred,a complication of mechanical ventilation, could produce some important effects on organisms.Hyperventilation means a series of syndrome that ventilation produces once its role surpasses physiological need.When H₂CO₃ level of blood plasma decreased lower limit of normal（PaCO₂＜35mmHg） and PH＞7.45,as called respiratory alkalosis.Acute respiratory alkalosis means respiratory alkalosis takes place within 24 hours.About one century,medical scholars placed much energy to respiratory acidosis,but they paid little attention to respiratory alkalosis because respiratory alkalosis often existed mechanical ventilation and Hysteria Syndrome.At present clinical practice,hyperventilation is frequently used in induction of general anesthesia,extubation,laparoscopic operation,acute intracranial hypertension of trauma and so on,Especially in the traumatic intracranial hypertension.Hyperventilation is often used to reduce intracranial hypertension.Its role of lowering ICP depends on CO₂ chemical regulation in CNS.low CO₂ in blood makes Cerebral vessels constrict,which can reduce cerebral perfusion and ICP,thus,hyperventilation is frequently used to reduce bleeding during operation. Morno-Kellie’s principle points out that cranium content consists of brain tissue, cerebral blood volume and cerebrospinal fluid（CSF）.Only both cerebral blood volume and CSF is spontaneously regulatable.The alteration of cranium content pressure mainly depends on cerebral blood volume and CSF.But,severe cerebral vasoconstriction does much harm to brain cells.Meanwhile,many studies demonstrated that hyperventilation not only induced cerebral ischemia but also brought wide physiological role such as kaliopenia,acid-base disturbance,etc.Even though many doctors agree on the fact that severe hyperventilation can produce cerbral ischemia,few doctors know how circulatory disorder of brain takes place and how suitable time of hyperventilation is.In addition,they really don’t know how electrolytics alter when given hyperventilation.So we establish the intracranial hypertension model of extradural hematoma to make deep study on these problems.Methods25 healthy male dogs,received retro-grade jugular bulb venous catheterization and arterial catheterization,were randomly divided into 5 groups;A,B,C,D and E group（each=5）.Dogs but A group were hyperventilated after epidural balloon inflation set up and built up animal model of introcranial hypertention by injecting 3-5ml 0.9%NS into lactoprene balloon of epidura.Dogs’P_ETCO₂ in B,C,D and E group will be maintained 32-45,25-32,25-20 and below 20 mmHg respectively for 60min by adjusting breathing parameters.0.5ml jugular jugular blood and femoral artery blood was taken suction respectively at different P_ETCO₂ period for measuring blood gas,VO₂,DO₂,ERO₂,lactic acid and blood sugar every 10 min when dogs’P_ETCO₂ chalks numerical value Booked.Vs,Vd,Vm,Pi and RI in MCA will be recorded by using Transcranial Doppler（TCD）.Meanwhile,cerebral oxygen delivery/supply will be calculated according to blood gas analysis results.1、Data and Grouping25 Healthy male dogs,age from 2 to 4 years,body weight from 13 to 15.5Kg,will raise for one week,fasting for 12hrs,no drinking for 6hs.before experiment,are randomly divided into 5 groups（A、B、C、D and group E,each=5）.Dogs in group A were placed a sacculus into epidural cavity but no inflatiing.The sacculus of dogs in any other groups was all inflated as the model of acute intracranial hypertension.All dogs were given 30min normal ventilation and P_ETCO₂ kept 32-45mmHg.2、Anesthetizing and Monitoringsodium pentobarbital according to 30mg/Kg was injected into abdominal cavity for anesthetizing dogs,and afterward intubation was operated.Internal jugular vein punctured under spontaneously breathing for monitoring CVP,infusing fluit and collecting blood.Femoral artery punctured for monitoring blood pressure and collecting blood.Multiparameter monitors continuosly detected body temperature, P_ETCO₂,HR,ECG,iBP and SPO₂.3、Establishing dog’s model of intracranial hypertensionEstablish dog’s model of intracranial hypertension by adopting epidural sacculus inflation.Place dogs to prone position,ambi-outer ear line 1cm distance between median line was drilled respectively.A trochar in left brain would be intubated to side ventricula to monitor ICP,and a foam rubber sacculus was placed into epidural cavity. Then,3～5ml 37℃physiological saline was injected into the sacculus within 60 seconds and kept ICP 60±3mmHg range.The symptoms of acute intracranial hypertension were as follows:side corediastasis,breathing alleviated or CT Image of occupyed Epidural.4、Targets monitoredAfter kept acute intracranial hypertension for 3hs,0.8mg/kg vecuronium bromide I.v.then given mechanical ventilation.The dogs of group A,control group,without inflation.P_ETCO₂ in group A will be kept from 32 to 45mmHg under ventilatiing.Group B（normal breathing）,group C（mild hyperventilation）,group D（midrange hyperventilation） and group E（severe hyperventilation）set up the model of intracranial hypertension.After kept P_ETCO₂ normal level for 30min,P_ETCO₂ of B,C,D and group E would be kept 32-45,25-32,25-20 and below 20mmHg respectively for 60min by adjusting breathing parameters.0.5ml jugular blood and femoral artery blood was taken suction respectively every 10min in different P_ETCO₂ period for measuring blood gas,blood lactic acid and blood sugar.Meanwhile,4mL jugular blood will be collected in pre-inflation（T₁）,post hyperventilation 2h（T₂）,6h（T₃）,12h（T₄） 24h（T₅） and 48h（T₆） for measuring content of S100B and CRP.drawn out hydatid fluid from balloon after hyperventilation.Neurological deficits scoring was evaluated at post hyperventilation 2h,6h and 12h.dogs would be put to death for pathological analysis at 48h.5、Monitoring CBFput detecting head of TCD to temple and adjust detecting head untill getting best signal of CMA.Vs、Vd、Vm、Pi and RI in MCA were recorded by using Transcranial Doppler in differently time.meanwhile O₂Ucc,A-VDO₂,Da-juL,ERO₂,Da-jvO₂ and Da-juglu will be calculated by blood gas value.ResultsExcept group A,other any dogs were all established the model of intracranial hypertension and finished this experiment sucessfully.when sacculus inflated,Heart rate got slow,blood pressure increased,respirary frequency reduced and side pupil dilatated （P＜0.05） when compared with pre-inflation.1、Blood gas analysisWith the hyperventilation development,K⁺,Ca²⁺,PaCO₂ and HCO₃^-in arterial Blood decreased gradually.PH increased gradually,there existed a positive correlation between PaCO₂ and K⁺.its coefficient correlation r=0.9196（P＜0.01）.Coefficient correlation between PaCO₂ and Ca²⁺ r=0.9196（P＜0.01）.CL^-,SaO₂ and Na⁺ kept changeless（P＞0.05）.PH decreased with hyperventlation,and got the lowest point 7.11±0.04（P＜0.05） when given severe hyperventilation.SjvO₂ in mild and midrange hyperventilation group kept changeless.But SjvO₂ in group D and group E got lowest point（42±6）%.2、Blood Sugar and Lactic AcidWhen compared with group A,Blood Sugar and Lactic Acid in experimental groups increased rapidly after inflation especially BS and Lac of jugular blood. Da-juglu increased（P＜0.05）,Lactic acid in group mild hyperventilation decreased slightly,but severe hyperventilation makes BS and Lac increase（P＜0.05）.Da-juL in group D increased sharply,there is significant difference between group A and group D （P＜0.05）.3、ICP and HemodynamicsAfter balloon inflated,all dogs’HR decreased quickly,blood pressure and ICP increased.ICP increased from 13±3.4 mmHg in pre-operative to 60±3.0mmHg,there is significant difference when compared with pre-operation（P＜0.05）.when value of P_ETCO₂ kept from 25 to 35mmHg,it revealed a positive coefficient correlation of PaCO₂ and ICP r=0.9958（P＜0.01）.mild hyperventilation can reduce ICP slightly but its value is much higher than pre-opration.With severe hyperventilation development (P_ETCO₂＜20mmHg),ICP still kept changeless.4、DO₂ and VO₂When inflated,SjvO₂ dcreased quickly with P_ETCO₂.when P_ETCO₂＜20mmHg, SjvO₂ reached the lowest point.Da-jvO₂ decreased gradually with hyperventilation.but Da-jvO₂ in midrange hyperventilation increased significantly when compared with pre-operation or post-inflation（P＜0.05）.ERO₂ in mild hyperventilation group changed slightly,but severe hyperventilation made ERO₂ decrease significantly when compared with pre-operation（P＜0.05）.5、Transcranial Doppler sonography（TCD）After inflation,TCD showed Vs and Vd got slow greatly after epidural balloon expanded（P＜0.05）.PI and RI increased significantly when compared with pre-trauma（P＜0.05）.Athough Vs increased in mild hyperventilation,the value of PI and RI in B,C,D and E group grew higher than A group（P＜0.05）.when P_ETCO₂＜25mmHg,Vs and Vd got its slowest point and showed much significant difference（P< 0.05） with P_ETCO₂ lowering.When P_ETCO₂＜25mmHg,Vs and Vd got its lowest point and kept changeless when hyperventilation deepened.6、S100B and CRPWhen inflated,S100B and CRP in experimental group increased at different degree （P＜0.05）.S100B started to grow in 6h,peaked in 12h（2.08±0.32μg/L）,decreased slightly in 24h.The value of S100 in group D grew more than pre-operation and other any groups（P＜0.05）.CRP grew rapidly in 2h,peaked in 6h（21.8±2.5mg/L） untill 48h, there was significant difference when compared with pre-inflation（P＜0.05）.CRP in group D grew most quickly of all groups,its value reached 29.4±5.7mg/L in T₅（P＜0.05）.7、Neurological Deficits Scoring（NDS）After 2h hyperventilation,Neurological Deficits Scoring of all dogs was much high.their score decreased from time to time.NDS in severe hyperventilation group was higher in 2h and 6h than any other groups（P＜0.05 ）but no significant difference in 12h（P＞0.05）.There was no significant difference between group A,B and C at the sametime（P＞0.05）.8、Pathological analysisDogs’s brain tissue of area compressed in experimental groups sofetened,swollen and blackened but other side brain tissue kept normal.Under light microscope,brain tissue in compressed area got necrosed mostly.and necrosis band extended to deep brain tissue and got lessened gradually in deep brain area.Necrosis cells in brain of group D diffused distribution.Necrosis was more wider than any other groups.Under electronical microscope,we can see the structure of the necrosis cells get blurred.Mitochondrium vacuolizated and dissolved.Conclusions1、Acute hyperventilation have much important effect on electrolytics and acid base,and it makes PH increase,K⁺ and Ca²⁺ decrease.Blood K⁺ reduced 0.5mmol/L and Blood Ca²⁺ reduced 0.05mmol/L when PaCO₂ reduced every 10mmHg.2、When P_ETCO₂ kept from 25 to 35mmHg,ICP decreased with PaCO₂.when PaCO₂ exceed 35mmHg,ICP dcreased slightly;when PaCO₂ was reduced to 25 mmHg,cerebral ischemia could take place.Severe hyperventilation results in Disequilibrium of O₂ Supply/Need.3、Acute hyperventilation have an important effect on hemodynamics of organism.mild and midrange hyperventilation alleviated hypertension brought about by acute intracranial hypertension. 4、Density of S100Band CRP shows the extent and level of injuried brain,their change have coincidence with NDS.5、Severe hyperventilation resulted in cerebral ischemia lies in Cerebral vessels constricted exceptionally,and obstacle of brain’s oxygen intaking plays an important role in cerbral ischemia also.6、Severe hyperventilation delayed palinessthesia time of dogs with acute intracranial hypertension.更多还原