Mechanisms of action, physiological effects, and c……

1、Mechanisms of action, physiological effects, and complications of hypothermiaPresented by R3 柯維琦Supervised by V.S.沈修年 Critical Care Med 2009 Vol. 37, No. 7(suppl)本檔僅供內(nèi)部教學(xué)使用本檔僅供內(nèi)部教學(xué)使用檔案內(nèi)所使用之照片之版權(quán)仍屬於原期刊檔案內(nèi)所使用之照片之版權(quán)仍屬於原期刊公開使用時(shí)公開使用時(shí), 須獲得原期刊之同意授權(quán)須獲得原期刊之同意授權(quán)Definition Core body temperature below 95F (35C)

2、 Classification by temperature is not universal Mild (34-35.9C) Moderate (32-33.9C) Moderate-deep (30-31.9C) Deep (30C)Background 19401960s - Induced hypothermia in cardiac arrest and traumatic brain injury (TBI) Decreased temperature, reduced metabolism, reduced brain demand for oxygen and glucose

3、Deep hypothermia (30C), large efficacy WRONG! Cooling methods slabs of ice, ice pads, refrigerated water on the patient skin, opening windows in winter months Duration 2 to 3 days to up to 10 days Lack of ICUs until 1960sBackground Late 1960s, loss interests Early 1980s, important BREAKTHROUGH neuro

4、logical outcome improved by using mild to moderate hypothermia (31-35C) rather than deep hypothermia (30C)Background Postresuscitation disease, reperfusion injury and secondary brain injury Continue for hours or days A cascade of destructive begin at the cellular level either caused by ischemic or t

5、raumatic Temperature-dependent overall effect rather than single agents (glucocorticoid, thiopental, calcium reentry blocker, NDMA antagonist, N-acetylcysteine) Advent of ICUs manage side effectsMechanisms Speed of induction of hypothermia rapid is better Duration of cooling (depend severity of inju

6、ry and time interval until target temperature) Speed of rewarming slow is better Proper management and prevention of side effectsDifferences and Difficulties Various types of injury (traumatic vs. purely postischemic) Different patients (genetics, comorbidities, gender etc.) Same patient but differe

7、nt time Most data are from animal experiments overestimate and underestimate For example, neuroexcitotoxic cascade, which central to postischemic injury, plays in short time frame (+/- 1-2 hrs) but human showed improvement even hypothermia delayed up to 8 hrsUnderlying Mechanisms,Physiological Seque

8、lae, andConsequences for Patient managementDecrease in Cerebral MetabolismCerebral metabolism decrease by 6-10% for each 1C reduction in body temperature during coolingEarly studies favor deep hypothermia but current understanding is reduction in metabolic rate is only one of the neuroprotective mec

9、hanism. Physiological Consequences and Patient Management (1)When core temperature drops to 32C, the metabolic rate decreases to 50% to 65% of normal, as do oxygen consumption and CO2 production.Change ventilator settings or hyperventilation developed and cause cerebral vasoconstrictionIncrease oxyg

10、en level and cause reperfusion riskCheck ABG during induction phase and adjust feeding rate during maintenance phasePhysiological Consequences and Patient Management (2)Increase fat metabolism (glycerol, free fatty acids, ketonic acids and lactate), cause mild metabolic acidosis, rarely below pH 7.2

11、5.Decease insulin secretion, moderate insulin resistance check glucose frequently during rewarming phase to avoid hypoglycemiaRewarming phase should be slow and controlled, target rewarming rate is 0.25C/hr for post cardiac arrest pts and 0. 1C/hr for patients of TBI Apoptosis, Caplain-Mediated Prot

12、eolysis and Mitochondrial DysfunctionCellular level necrotic, partially or fully recover or enter apoptosis(programmed cell death)Determine by mitochondrial dysfunction, cellular energy metabolism and release of caspase enzymeHypothermia affect early stages of apoptosis,Inhibition of caspase enzyme

13、activationPrevention of mitochondrial dysfunctionDecreased overload of excitatory neurotransmittersModification of intracellular ion concentrationsApoptosis begin late in the postperfusion/posttrauma phase, continuing for a period of 48 to 72 hours or longerIon pumps and NeuroexcitotoxicityHypotherm

14、ia inhibits harmful excitatory processes occurring in brain cells during ischemia-reperfusionNeuroexcitatory cascade (such as calcium influx, accumulation of glutamate, release of its coagonist glycine)Ischemia and reperfusion disrupt the balance of calcium homeostasis at cellular level.How long is

15、the window of opportunity? (start from minutes after injury but last for many hours, even days)As early as possible? Ranging from 30 mins to 6 hrs Combined treatment? Caspase inhibitors or othersImmune response and InflammationIn most brain injuries, inflammation begins about 1hr following a period

16、of ischemia-reperfusionRelease of proinflammatory mediators (TNF- and IL-1), 1 hr to 5 days; stimulates chemotaxis, activate complement systemHappen especially during reperfusion and accompanied with free radicals productionDual role of imflammation neurotoxic or neuroprotective?Time-dependent?Immun

17、e response and InflammationHypothermia Suppress inflammationMitigates reperfusion-related DNA injury, lipid peroxidation and leukotriene productionDecreases the production of nitric oxide, a key to postischemic brain injuryImpairs neutrophil and macrophage function (37.5C) within the first 72 hrs ha

18、s poorer outcome in pts with ICH.In pts with ischemic stroke, 2.4 fold increase of adverse outcome, higher brain infarct volume and increased mortalityCoagulation Activation and Formation of MicrothrombiCPR activate coagulation, leads to intravascular fibrin formation with blockage of microcirculati

19、on in the brain and heart.Heparin and recombinant t-PA improves circulation and survival in animal studiesThrombolysis can improve cerebral tolerance to ischemia, not proved by clinical studies.Hypothermia has mild anticoagulant effects - speculativeMild platelet dysfunction at BT 35CSome inhibition

20、 of coagulation cascade at BT 33C) after resuscitation from cardiac arrest should not be actively rewarmed.PathophysiologyReducing cerebral metabolism (approximately 6-8% per 1C) Reducing excitatory amino acids (glutamate release) Attenuation and/or reversibility of ischemic depolarization of the CN

21、S, leading to membrane stabilization, electrolyte redistribution, and normalization of intracellular water concentration and intracellular pH (stabilization of the blood-brain barrier) Attenuation of oxygen free radical production and lipid peroxidation Restoration of normal intracellular signaling

22、mechanisms (including calcium modulation) and inhibition of deleterious signaling mechanisms, such as apoptotic signaling Restoration of protein synthesis and gene expression Inhibition of deleterious inflammatory products (ie, cytokines, interleukins, arachidonic acid cascade end products) Attenuat

23、ion of CSF platelet-activating factor (PAF) Inhibition of cytoskeletal breakdown Pt selectionInclusion criteria Patients who have been shown to benefit from induced hypothermia include the following:Intubated patients with treatment initiated within a 6-hour post cardiac arrest (nonperfusing ventric

24、ular tachycardia VT or VF) time window Those able to maintain a systolic blood pressure 90 mm Hg, with or without pressors, after cardiopulmonary resuscitation (CPR) Those in a coma at the time of cooling. Coma is defined as not following commands. Brainstem reflexes and pathological/posturing movem

25、ents are permissible. Patients with a Glasgow Coma Score (GCS) of 3 are eligible for hypothermia.Exclusion criteria Exclusion criteria are in part based on theoretical increases in risk. Many studies have reported increased but nonsignificant increases in risk. Patients for whom hypothermia may carr

26、y increased risk include those with the following conditions: Recent major surgery within 14 days - Hypothermia may increase the risk of infection and bleeding. Systemic infection/sepsis - Hypothermia may inhibit immune function and is associated with a small increase in risk of infection. Patients

27、in a coma from other causes (drug intoxication, preexisting coma prior to arrest) Patients with a known bleeding diathesis or with active ongoing bleeding - Hypothermia may impair the clotting system. Check prothrombin time/partial thromboplastin time (PT/PTT), fibrinogen value, and D-dimer value at

28、 admission. (Note: Patients may receive chemical thrombolysis, antiplatelet agents, or anticoagulants if deemed necessary in the treatment of the primary cardiac condition.) Patients with a valid do not resuscitate order (DNR)The Cochrane Database of Systematic Reviews (2007) reports that hypothermia after TBI has not be