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1、,ICU的镇静与镇痛（sedation and analgesia in ICU）,ICU的封闭管理产生幽闭综合症环境陌生、机器设备众多、噪音焦虑、紧张、恐惧有创检查和治疗疼痛,概述,疼痛与焦虑所致的并发症,自主神经系统受到刺激而释放一些体液因子交感神经系统的激活使心率、血压和心肌耗氧量增加，心肌缺血或心肌梗死应激时激素的释放致血凝性增高及纤维蛋白溶解作用受抑制，以及诱发对胰岛素的抗性、代谢率增高和蛋白质加快分解淋巴细胞和粒细胞数量减少而易发生免疫抑制,重症病人获得充分的镇静和镇痛是ICU监护的重要组成部分,解除焦虑、恐惧 减轻生理应激反应 解除疼痛 使机械通气容易进行 完成床边护理、诊断与治
2、疗 恢复患者的昼夜生理节律,对于疼痛评价,“直观模拟量表(visual analogue scale,VAS)”。该量表从“无痛”直到“从未经历过的最剧烈的疼痛分成等级，让患者以手指指着相应的级别。VAS简便易行并有较高的可靠性和确实性，但却忽略了其他的量纲，例如疼痛的性质等。对于危重患者来说，有时无法主观地表达其疼痛程度，从而不得不依赖护理该患者的护士所观察到的一些行为迹象如面部表情、动作、姿势或一些生理学指标如心动过速、血压增高或呼吸加快等来间接评价，但难以做到准确。Elderly patients may have diffi-culty with VAS,NRS is also val
3、id,correlates with VAS,and has been used toassess pain in cardiac surgical patients(21).Because patients can complete the NRS by writing or speaking,and becauseit is applicable to patients in many age groups,NRS may be preferable to VAS in critically ill patients.Multidimensional tools,The level of
4、pain reported by the patient must be considered the current standard for assessment of pain and response to analgesia whenever possible.Use of the NRS is recommended to assess pain.(Grade of recommendation B)Patients who cannot communicate should be assessed through subjective observation of pain-re
5、lated behaviors(movement,facial expression,and pos-turing)and physiological indicators(heart rate,blood pressure,and respiratory rate)and the change in these parameters following analgesic therapy.(Grade of recommendation B),广泛用于评价意识水平的“格拉斯哥昏迷量表Glasgow coma scale)”只对有神经系统缺陷的患者有效而较适用于内科一外科ICU的是钻点拉姆赛量
6、表(6-puint Ramsay scale)。后者是根据镇静深度的增加观察运动反应而制定的一种数字尺度，其缺点是不能用于摄人肌肉弛缓药的患者还有“镇静一激动量表(sedation-agitation scale,SAS),“运动活性评价量表(motor activity assessmentscale,MAAS)等也都具有类似的缺点。,对于疼痛和焦虑的评价,常用于外科手术室的双谱指数(bispectral index,BIS),是借脑电图来提供大脑皮质及皮质下区之间相互作用的信息，从而将意识状态从。0100分加以计分，用以评价患者麻醉时的镇静程度。最近有些学者将BIS扩展到用于ICU患者，但
7、所获结果并不一致,对于疼痛和焦虑的评价,Ramsay镇静分级,1级 病人焦虑、烦躁不安2级 病人合作、清醒入睡3级 病人仅对指令有反应4级 病人入睡、轻叩眉间反应敏捷5级 病人入睡、轻叩眉间反应迟钝6级 深睡或麻醉状态(British Journal of Intensive Care.1992,516),镇静分级评分,Ramsay评分、OAA/S评分、VAS评分充分镇静 Ramsay评分3、4级诊断和治疗性操作 Ramsay评分5、6级,镇静药物,通过影响-氨基丁酸（GABA）与中枢神经系统GABAA受体的亲和力，加强抑制性递质GABA的中枢抑制作用，达到镇静催眠的作用,镇静药物,小剂量：镇
8、静作用，用于治疗焦虑、紧张中等剂量：催眠作用，用于催眠大剂量：麻醉和抗惊厥作用,镇静药物,镇静作用强 对呼吸、循环影响小 一定的镇痛作用 作用时间短 无药物蓄积作用,理想镇静剂,吗啡 哌替啶 芬太尼 阿芬太尼 氟哌利多 安定 咪唑安定 异丙嗪使用最广泛的药物：苯二氮卓类药物 异丙酚,ICU中常用的镇静药和镇痛药,术后镇静 术后24h镇静渡过手术后急性恢复期 机械通气支持 纤维支气管镜检查 PCS-抗焦虑 脑外伤病人预防颅内压升高,镇静药物应用的适应症,地西泮曾广泛用于危重患者。它溶于脂类而发生再分布，对于呼吸或循环系统抑制作用小，但危重患者对其抑制呼吸和降低血压的作用可能很敏感。长期摄人能因活
9、性产物而使镇静作用延长，故不宜于TCU中的镇静使用。地西浮有助于长期住院及不能很快脱离呼吸机的患者的恢复。由于地西洋只溶于有机溶剂，故静注时可引起疼痛及静脉炎。地西浮由肝微粒体系统的酶代谢为两种活性产物去甲地西洋和奥沙西泮。在肝或肾功能不全患者及老年人，地西浮的排除半衰期显著延长，故对这类人使用时需很慎重。,地西泮,劳拉西泮劳拉西浮比地西伴的药效高5一10倍，优选用于长期治疗成人危重患者的焦虑。其作用与地西洋相仿，但摄人后不发生注射部位的疼痛或静脉炎。劳拉西洋的脂溶性较差，故需较长时间才有峰效应它比咪达哇仑的作用持久且较少引起低血压，两者介导相同的顺行性遗忘，但劳拉西伴的价格较低，长期摄人时诱
10、发较能预示的觉醒。由于劳拉西浮是在丙二醇中稀释的，故在溶液中不稳定，并在静脉导管中可发生沉淀。摄人大剂量劳拉西洋或持续滴注时曾发生丙二醇的毒性作用，如急性肾小管坏死、乳酸酸中毒及渗透性过高状态。劳拉西浮也可口服，但丙二醇能使一些患者发生腹泻。劳拉西浮在肝中被葡糖醛酸化为无活性产物。,咪唑安定,咪达哇仑作用时Ail短、溶于水、在生理性pH时嗜脂并迅速跨越血脑屏障。由于其在体内发生快速再分布，故作用时间远短于地西伴。为此它与丙泊酚被推荐用于短期(24 h)治疗危重患者的焦虑。咪达哇仑的药效较地西浮高2一3倍。其不良反应为呼吸抑制和低血压，特别是存在血容量不足和摄人大剂量时。持久滴注有时导致较长时间
11、的作用，特别是在危重患者(由于活性代谢产物蓄积所致)。在肝廓清功能不足的患者，咪达噢仑的排除半衰期可延长到2一4h甚至12 h。在持续滴注时药物间相互作用可能突出，例如由于红霉素、丙泊酚及地西伴都抑制细胞色素P450系统和咪达哗仑的延迟代谢而造成预料不到的镇静作用。,丙泊酚为一种烷基酚，不溶于水，其剂型为豆油、日一油和蛋磷脂中的I%悬液，在体内能提供4 602.4 kJ L-的热量。它有良好的镇静和催眠作用，但不止痛，其作用机制可能涉及中枢神经系统中的GABA受体。滴注时可达到预期的镇静水平，中断用药后可迅速恢复，在ICU中它与咪达噢仑被推4短时间(24 h)使用。它可诱致低血压和心肌抑制。曾
12、报道长期摄人时患者发生高甘油三醋血症和胰腺炎。为了防止感染，盛丙泊酚的瓶子和滴注管道都应侮12 h更换一次，从瓶中抽出的液体也不应保存6h以上。它也可引起注射时疼痛及代谢性酸中毒、横纹肌溶解及循环性虚脱。它在肝中代谢，但由于其廓清超过肝血流速度，故已证明还有肝外代谢通路，为此丙泊酚在肝功能衰竭患者的作用时间仍较短暂。,丙泊酚,氟派啶醇,氟派啶醇为丁酰苯型抗精神病药，已用于治疗危重患者的诺妄。给ICU患者静注的生物利用度较好且可预示其作用程度，但FDA未批准其肠道外给药。控制澹妄的剂量个体间差异很大。对于急性激动的患者开始给予2 mg，继而每隔15一20 mi。将剂量倍增一次。氟娠咙醇有一些重要
13、的不良反应:降低癫痛发作阐、突发锥体外系反应、使QT间期延长等。心律不齐及摄人可延长QT间期的药物如胺碘酮或普鲁卡因胶的患者应慎用。曾报道35 mg的低剂量可引起娜间期明显延长，静注20 mg后几分钟内即可发生。,右美托咪陡为一种a2激动剂型新镇静药，正推荐用于ICU。它比可乐定结合a2受体的亲和力高8倍，且作用时间较短。其优点是有显著镇静作用而只极轻度减少每分钟的换气量。插管和除管时减少血液动力学反应，减轻对外科手术的应激反应，加强止痛药的作用。1999年，MA批准它作为镇静剂短期(24 h)给危重患者滴注右美托咪陡的不良反应包括使血压先升高继而降低和心动过缓。为此对于危重患者不能推注及持续
14、滴注给药。肝功能不全时其清除可能延迟。血容量不足、心动过缓或心输出量低的患者可能易于发生不良反应，故患者的选择极为重要。,右美托咪啶,苯二氮卓类：抗焦虑、镇静、遗忘、抗惊厥1、地西潘（diapezam)：起效时间3-5min，半衰期20-36hrs。2、咪达唑仑（midazolam)：作用快，半衰期短（1.5-2.5hrs)，静脉注射不痛。易引起低血压3、劳拉西泮（lorazepam)：脂溶性,镇静药物,异丙酚(propofol)常作为icu连续静脉用药有遗忘效应外周静脉注射痛对脑外伤患者有脑保护作用抗恶心呕吐作用可控性好，睡-醒转瞬间,镇静药物,氟哌啶醇：强神经安定药，主要用于精神极度兴奋、
15、狂乱、错乱及谵妄。排除疼痛焦虑无呼吸抑制可产生椎体外系综合症可延长QT间期,镇静药物,依托咪酯（etomidate)美索比托(methohexital)右旋美托咪啶（dexmedetomidine),镇静药物,镇痛药,分类：中枢性镇痛药：解热、镇痛、抗炎药,吗啡被推荐为ICU中使用的一线药，它溶于水，与脂溶性阿片类药如芬太尼相比，其峰效应出现晚(30二，而芬太尼为4 ruin).摄人后通过阻滞交感神经及对窦房结的直接作用而导致静脉扩张及心率变慢。其主要不良反应为易于造成呼吸抑制，其他还有镇静、恶心、肠绞痛及奥狄括约肌痉挛，而不依赖于受体的不良反应则为释放组胺而导致的低血压、心动过速，敏感患者可
16、能发生支气管痉挛。吗啡的排除半衰期为2一4 h.其活性代谢产物吗啡-6-葡糖醛酸可发生蓄积而导致肾衰患者发生镇静过度。,吗啡,阿片生物碱类镇痛药,【药动学】吸收：口服吸收，有首过效应，皮下注射可吸收。结合：三分之一 分布：广泛，少量透过血脑屏障进入中枢而发挥作用。代谢：大部分在肝，与葡萄糖醛酸结合，10%成为去甲吗啡 排泄：肾，少量乳汁排泄。注意：可透过胎盘屏障，胎儿血脑屏障功能较差，又能经乳汁分泌，故应用时应注意。【药理作用】1.中枢神经系统 镇痛镇静作用 抑制呼吸 镇咳 催吐、缩瞳 2.消化系统 3.心血管系统 促使组胺释放，抑制中枢使交感神经张力下降 抑制呼吸，使体内CO2升高，使脑血管
17、扩张，颅内压升高。【不良反应】：1.治疗量下引起：恶心、呕吐、便秘、排困难、体位性低血压、呼吸抑制等。2.耐受性和依赖性戒断症状：兴奋、失眠、腺体分泌增加、震颤，呕吐、腹泻焦虑、瞳孔散大,吗啡,对于有血液动力学不稳定性或对吗啡过敏的危重患者，人工合成的阿片类药芬太尼是优选止痛药，它比吗啡的药效高80一loo倍。它与吗啡有类似的基于阿片受体的不良反应，但不释放组胺。它只引起较轻的血液动力学改变，但不影响心肌收缩力的状态。快速摄人大剂量时可引起心动过缓与胸壁僵硬。由于芬太尼溶于脂类，故小剂量时因从脑再分布至其他组织而使作用短暂。较大的蓄积剂量则依赖于排除而非再分布，在此情况下其作用时间延长而与吗啡
18、相似(两者排除平衰期相似)。在肝或肾功能不全的患者，芬太尼的药代动力学无显著改变。芬太尼的代谢产物虽可发生蓄积，但大多无活性、无毒。只有当肝功能严重不全患者摄人大剂量时，芬太尼的药代动力学才可能发生改变。,芬太尼,哌替啶,【作用】1.中枢神经系统：与吗啡相似，较弱。持续时间短。镇痛，镇静 抑制呼吸 催吐：兴奋CTZ 无镇咳作用 可成瘾 眩晕：可增加前庭器官的敏感性,2.平滑肌：类似吗啡，但较弱。肠道：提高张力，不致便秘。也无止泻作用。胆道：平滑肌痉挛，提高胆内压，比吗啡弱。支气管平滑肌：影响小，大剂量可致收缩。子宫：不对抗催产素对子宫的作用。不缩短 产程。3.心血管 体位性低血压：同吗啡 脑血
19、管扩张：抑制呼吸使CO2积蓄。,哌替啶,【不良反应】治疗量与吗啡相似：恶心、呕吐、体位性低血压、眩晕等 久用易成瘾 抑制呼吸 震颤、肌肉痉挛、惊厥：与其代谢产物去甲哌替啶有关。,氢吗啡酮为一种半合成阿片类药，药效为吗啡的5一to倍。其起效时间与作用持续时间均与吗啡相似。它对血液动力学只有轻度作用，不引起组胺释放，而且诱发痉痒、镇静、恶心和呕吐的不良反应也小于吗啡，因而对于不能耐受吗啡的患者是一个良女子的替换药。氢吗啡酮与吗啡相同，也是借与葡糖醛酸着缀合而被代谢的，但也被还原型辅酶I(NADPH)还原酶还原成两种活性代谢物，后者比母体化合物的止痛作用强，但产量很少，只有在肾衰患者或在较长时间内摄
20、人大剂量时才蓄积到有毒性的数量,氢吗啡酮,美沙酮,氯胺酮,阿片类：中枢阵痛，呼吸抑制、欣快吗啡：(morphine)水溶性，起效慢，作用时间长。低血压哌替啶（pethdine)：其代谢产物去甲哌替啶可在体内累积中度引起瞳孔扩大、震颤、惊厥。药物依赖芬太尼（fentanyl),镇痛药物,芬太尼（fentanil)：镇痛效能是吗啡的100倍。高度脂溶性，作用迅速。分布广泛。持续静脉应用时半衰期可从30min逐渐延长至9-16hrs，长时间应用时注意半衰期的变化。对血压影响较小。迷走兴奋，可引起心率减慢舒芬太尼（sufentanil)阿芬太尼(alfentanil),镇痛药物,耐药性、依赖性和撤药反
21、应,耐药性：随时间的延长药效降低，或需加大剂量才能保持药效不减,撤药反应：中枢神经系统紊乱：易激惹、精神狂乱、注意力不集中、打哈欠、肌张力增加等交感神经兴奋：心动过速、血压增高、出汗、发热、气急胃肠道反应,ICU疼痛来源,1.preexisting diseases,invasive procedures,or trauma.2.Monitoring and therapeutic devices3.Routine nursing care and prolonged immobility,后果：inadequate sleep,exhaustion and disorientation.ev
22、okes a stress response characterized by tachycardia,increased myocardial oxygen consumption,hypercoagulability,immunosuppression,and persistent catabolism.pulmonary dysfunction,Recommendation:All critically ill patients have the right to adequate analgesia and management of their pain.(Grade of reco
23、mmendation C),Pain Assessment,The most reliable and valid indicator of pain isthe patients self-report。,Analgesia Therapy,1.Nonpharmacologic：proper positioning of patients,stabilization of fractures,and elimination of irritating physical stimulation；Application of heat or cold therapy,2.Pharmacologi
24、c therapies：include opioids,nonsteroidal anti-inflammatory drugs(NSAIDs),and acetaminophen.,理想：Desirable attributes of an opioid include rapid onset,ease of titration,lack of accumulation of the parent drug or its metabolites,and low cost.Fentanyl has the most rapid onset and shortest duration,but r
25、epeated dosing may cause accumulation and prolonged effects.Morphine has a longer duration of action。hypotension may result from vasodilation and an active metabolite may cause prolonged sedation in the presence of renal insufficiency.,hydromorphone lacks a clinically significant active metabolite o
26、r histamine release.Meperidine has an active metabolite that causes neuroexcitation(apprehension,tremors,delirium,and seizures)and may interact with antidepressants(contraindicated with monoamine oxidase inhibitors and best avoided with selective serotonin reuptake inhibitors),so it is not recommend
27、ed for repetitive use。,Remifentanil has not been widely studied in ICU patients and requires the use of a continuous infusion because of its very short duration of action。Be useful for requiring interruptions for neurologic examination,Adverse effects,patients.Of greatest concern are respiratory,hem
28、odynamic,central nervous system,and gastrointestinal effects.hypotension:the combination of sympatholysis,vagally mediated bradycardia,and histamine release(when using codeine,morphine,or meperidine)central nervous system:hallucinations may increase agitation insome patients.gastrointestinal effects
29、:Routine prophylactic use of a stimulant laxative may minimize constipation.Small-bowel intubation may be needed for enteral nutrition because of gastric hypomotility(45).,Opioid Administration Techniques.,Bolus doses Intravenous administration intramuscular administration.a transdermal patch(on the
30、 permeability,temperature,perfusion,and thickness of the skin).Intramuscular administration is not recommended in hemodynamically unstable patients because of altered perfusion and variable absorption.Daily awakening,The use of a reversal agent,Naloxone,is not recommended because it can induce withd
31、rawal and may cause nausea,cardiacstress,and arrhythmias.,Recommendations:,1.A therapeutic plan and goal of analges(c)2.intravenous doses of an opioid analgesic are required,fentanyl,hydromorphone,and morphine are the recommended agents.(c)3.Scheduled opioid doses or a continuous infusion is preferr
32、ed over an“as needed”regimen to ensure consistent analgesia.A PCA device may be utilized to deliver opioids if the patient is able to understand and operate the device.(b),4.Fentanyl is preferred for a rapid onset of analgesia in acutely distressed patients.(C)5.Fentanyl or hydromorphone are preferr
33、ed for patients with hemodynamic instability or renal insufficiency.(C)6.Morphine and hydromorphone are preferred for intermittent therapy because of their longer duration of effect.(C),NSAIDs,adverse effects,including gastrointestinal bleeding,bleeding secondary to platelet inhibition,and the devel
34、opment of renal insufficiency.NSAIDs should not be administered to patients with asthma and aspirin sensitivity.ibuprofen Ketorolac and naproxen,COX-2 inhibitors,Acetaminophen should be maintained at less than 2 g per day for patients with a significant historyof alcohol intake or poor nutritional s
35、tatus and less than 4 g per day for others,Recommendations:,NSAIDs or acetaminophenmay be used as adjuncts to opioids in selected patients.(B)Ketorolac therapy should be limited to a maximum of five days,with close monitoring for the development of renal insufficiency or astrointestinal bleeding.Oth
36、er NSAIDs may be used via the enteral route in appropriate patients.(B),SEDATION,anxiety and agitation原因：an inability to communicateamid continuous noise(alarms,personnel,and equipment),ontinuous ambient lighting,and excessive stimulation(inadequate analgesia,frequent vital signs,repositioning,lack
37、of mobility,and room temperature).Sleep deprivation and the circumstancesEfforts to reduce anxiety,including frequent reorientation,maintenance of patient comfort,provision of adequate analgesia,and optimizationof the environment。,SEDATION,Agitation can be caused by multiple factors,such as extreme
38、anxiety,delirium,adverse drug effects,and pain处理方法：the first priority is to identify and treat any underlying physiological disturbances,such as hypoxemia,hypoglycemia hypotension,pain,and withdrawal from alcohol and other drugs.,deleterious effect,Ventilator dysynchrony,an increase in oxygen consum
39、ption,and inadvertent removal of devices and catheters。,Sedatives reduce the stress response and improve the tolerance of routine ICU proceduresmaintain patient safety and comfortof restraint and are not to be“used as a means of coercion,discipline,convenience,or retaliation by staff”。follow the int
40、ent of the Centers for Medicare and Medicaid Services regulation regarding restraints.Opioids may produce sedating effects,they do not diminish awareness or provide amnesia for stressful events.,recall their ICU stay report unpleasant or frightening memories,which may contribute to posttraumatic str
41、ess disorder(PTSD)symptoms。Acute PTSD-related symptoms。Sedation of agitated critically ill patients should be started only after providing adequate analgesia and treating reversible physiological causes.(C),(SAS)was the first scale reliable and validScale(MAAS)from the SASRamsay scaleThe Vancouver I
42、nteraction and Calmness Scale(VICS)the Observers Assessment of Alertness/Sedation Scale in the operating roomThe COMFORT scale in children,Subjective Assessment of Sedation and Agitation.,Objective Assessment of Sedation.,Include heart rate variability and lower-esophageal contractilitythe bispectra
43、l index(BIS)uses a digital scale from 100(completely awake)to 0(isoelectric EEG)BIS Limitations in the ICU environment Musclebasedelectrical activity may artificially elevate BIS scores if the patient has not received neuromuscular blockade,Recommendations:,A sedation goal or endpoint should be esta
44、blished and regularly redefined for each patient.Regular assessment and response to therapy should be systematically documented.(C)The use of a validated sedation assessment scale(SAS,MAAS,or VICS)is recommended.(B)Objective measures of sedation,such asBIS,have not been completely evaluated and are
45、not yet proven useful in the ICU.(C),Sedation Therapy,Benzodiazepines,(anterograde amnesia)but do not induce retrograde amnesia.have an opioid-sparing effect by moderating the anticipatory pain responseBenzodiazepines vary in their potency,onset and duration of action,uptake,distribution,metabolism,
46、and presence or absence of active metabolitesPatient-specific factors,such as age,concurrent pathology,prior alcohol abuse,and concurrent drug therapy,affect the intensity and duration of activity of benzodiazepines,Compromised hepatic or renal function may slow the clearance of benzodiazepines or t
47、heir active metabolites.tolerance to benzodiazepines may occur within hours to several days of therapyparadoxical agitation has also been observed during light sedation(drug-induced amnesia or disorientation.)rapid onset and awakening after single doses Its long-acting metabolites,a prolonged durati
48、on of sedative effect may occur withrepeated doses,Lorazepam,Lorazepam has a slower onset but fewer potential drug interactions because of its metabolism via glucuronidation.less useful for the treatment of acute agitation.Lorazepam infusions should be prepared using the 2mg/mL injection and diluted
49、 to a concentration of 1 mg/mL or less and mixed in a glass bottle.Despite these precautions,precipitation may develop.using a PCA device.The lorazepam solvents(PEG)and(PG)have been mplicated as the cause of reversible acute tubular necrosis,lactic acidosis,and hyperosmolar states after prolonged hi
50、gh-dose infusions.exceeded 18 mg/hr and continued forlonger than four weeks and higher doses(25 mg/hr)continuing for hours to days,be administered via the enteral route in tablet or liquid form.Large doses of liquid lorazepam(i.e.,60 mg of 2 mg/mL every six hours)may lead to diarrhea because of the
