Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Common raven physiology wikipedia , lookup
Exercise physiology wikipedia , lookup
Neuromuscular junction wikipedia , lookup
Cardiac output wikipedia , lookup
Norepinephrine wikipedia , lookup
Vasopressin wikipedia , lookup
Haemodynamic response wikipedia , lookup
Stimulus (physiology) wikipedia , lookup
Inotropes Áine Duggan 11/04/03 Aims • • • • • • Definition and classification of shock Cardiovascular physiology Classification of inotropic agents Indication for inotropes Specific agents Vasopressin Shock • Failure of the circulatory system to deliver adequate amounts of oxygen and nutrients to the tissues • Inappropriate or inadequate tissue perfusion Categorisation of causes of shock • • • • • Fluid depletion » Hypovolemic Flow restriction » Obstructive Pump failure » Cardiogenic Vascular failure » Distributive Red cell failure » Dissociative Example: major trauma • Hypovolemic shock……..haemorrhage • Obstructive shock……tension pneumothorax • Cardiogenic shock…….cardiac contusion • Distributive shock……..spinal cord injury Example: septicemia • Hypovolemic shock……fluid loss • Cardiogenic shock…..myopathic factors • Distributive shock…..vessel damage Shock: Primary assessment • Airway • Breathing (pneumothorax) • Circulation cardiovascular signs (HR, capillary refill, BP) and effects of circulatory inadequacy (RR, skin colour and temperature, mental status) • Disability • Exposure • Full history and examination and relevant investigations Shock: resuscitation • A open airway • B high flow oxygen and ventilatory support if required • C circulatory access; relevant blood tests; fluid bolus if hypovolaemia suspected and repeated depending on response (HR, BP, UO, CVP,PAWP, peripheral perfusion, MVO2, lactate, ABG); antibiotics; cardioversion, inotropes when intravascular volume replenished; control of haemorrhage Physiology • Blood flow……….systemic blood pressure is monitored as a reflection of local tissue perfusion • Ohm’s law: Pressure = Flow (CO) x Resistance • Organ blood flow = MAP – organ venous pressure/ organ vascular resistance Physiology • Cardiac output is influenced by : heart rate, preload, afterload, contractility, cardiac compliance • Controlled by ANS and humoral mechanisms Physiology • Autoregulation: the ability of an organ or vascular bed to maintain adequate blood flow despite varying blood pressure • Metabolic regulation controls about 75% of local blood flow • Autoregulatory reserve Inotrope • Defined as a drug which increases stroke work at a given preload and afterload • General mechanism: all increase the force of myocardial contraction by increasing the cytosolic calcium concentration, which promotes actin- myosin cross bridge formation and leads to myocyte shortening Drugs • • • • • • • Catecholamines Phosphodiesterase inhibitors Cardiac glycosides (Vasopressin) Glucagon Calcium Thyroid hormone Indications for inotropes • • • • • Cardiopulmonary resuscitation Anaphylaxis Weaning from CPB Cardiac failure post AMI Septic shock Catecholamines • Most frequently used inotropic agent in ICU • All act on adrenergic receptors Adrenergic receptor physiology • Distinguished by response to catecholamines • Receptors demonstrating order of potency such that noradrenaline>adrenaline>isoprenaline are termed alpha receptors • Isoprenaline > adrenaline > noradrenaline are termed beta receptors • Receptors interacting with dopamine are called dopaminergic Adrenergic receptor physiology • Beta receptor occupancy activates adenyl cyclase to increase conversion of adenosine triphosphate to cAMP • Alpha 1 receptor occupancy activates phospholipase C, which increases inositol phosphates IP3 and IP4 and diacyl glycerol. • These second messengers increase Ca release and calcium membrane permeability. Protein kinases then cause phosphorylation of substrate proteins which leads to specific effects Adrenergic receptor physiology • Alpha receptors: α1, α2 • Α1 are located postsynaptically in vascular smooth muscle, smooth muscle of coronary arteries, uterus, skin, intestinal mucosa, iris, splanchnic bed • Activation causes arteriolar and venous constriction, mydriasis, gut relaxation • Cardiac bed α1 receptors increase inotropy and decrease heart rate Adrenergic receptor physiology • α2 receptors are located pre and post synaptically • Activation of presynaptic α2 receptors inhibits noradrenaline, acetylcholine, serotonin, dopamine, and substance P • Activation of postsynaptic α2 receptors causes vasoconstriction, decreased salivation, decreased insulin release Adrenergic receptor physiology • β1 receptors are located in the myocardium, SA node, ventricular conduction system, adipose tissue, renal tissue • Activation causes an increase in inotrophy, chronotrophy, myocardial conduction velocity, renin release, lipolysis Adrenergic receptor physiology • β2 receptors are located in vascular, bronchial, uterine and skin smooth muscle • Stimulation leads to vasodilation, β2 bronchodilation, uterine relaxation, gluconeogenesis, insulin release, K uptake • β3 involved in lipolysis and regulation of metabolic rate Adrenergic receptor physiology • Dopaminergic 1 receptors are located postsynaptically on renal and mesenteric vascular muscle and mediate vasodilation • Dopaminergic 2 receptors are presynaptic and inhibit noradrenaline release Adrenergic receptor physiology • There is an inverse relationship between receptor number and the concentration of circulating adrenergic agonist and the duration of exposure to that agonist • Termed up regulation and down regulation Adrenoreceptor receptor effects • • • • Α1 inotropy, vasoconstriction Α2 inotropy, vasoconstriction B1 chronotropy, inotropy B2 inotropy, vasodilation, bronchodilatation Common agents • Dopamine: low dose DA effects • Dopamine: high dose β1, α1, α2, DA1 and DA2 effects • Noradrenaline: α1, α2, β1, (β2) • Adrenaline: β1, β2 > α1, α2 • Dobutamine: β1> β2, (α1) • Dopexamine: β2 > β1, DA • Isoprenaline: β1, β2 Dopamine • Naturally occuring in humans • Precursor of noradrenaline • Causes release of noradrenaline from nerve endings • Haemodynamic effect varies between individual patients • Dose related effects: low dose DA effects, high dose β, α, DA effects • Neurotransmitter in basal ganglia and CTZ Dopamine • Low dose <4 mcg/kg/min renal and splanchnic vessel DA receptors are activated leading to increased renal blood flow, GFR and Na excretion • Higher doses beta effects of increased myocardial contractility, HR, ABP • >10 mcg/kg/min α1 effects predominate leading to marked increase in ABP, and decreased renal blood flow, increased PVR and PAP Dopamine • Dopamine increases UO, does not prevent of alter course of renal injury • S/E nausea, vomiting, headache, arrhythmias, hypertension, dyspnoea, extravasation may cause sloughing and necrosis, low dose may blunt hypoxic ventilatory drive, increasing shunt fraction, increased myocardial oxygen demand, • Useful for combination of inotropy and vasoconstriction, septic hock, cardiogenic shock (vasodilator) Adrenaline • Direct acting α and β receptor agonist produced by the adrenal medulla • Indications: cardiac arrest, anaphylaxis, bronchospasm, cardiogenic shock, prolongation of regional anaesthesia, nebulized in airway oedema • Beta effects predominate at lower doses, with bronchodilation, vasodilation, increased CO, tachycardia Adrenaline • Fall in diastolic pressure may be seen because of beta 2 effects • Increasing doses α effects predominate and SV may fall as SVR increases • 1-2 mcg/min beta stimulation predominates • 2-10 mcg/min α and β effects, >10 mcg/min mainly α • Effects variable amongst individuals Adrenaline • Effects: tremor, anxiety, restlessness, headache, respiratory stimulation, decreased gut tone and motility, bronchodilation, decreased RBF and GFR, detruser relaxation and increased vesical sphincter tone, increased blood glucose and free fatty acids, hypokalaemia, tachycardia, arrhythmias, myocardial ischaemia, tissue necrosis Noradrenaline • Neurotransmitter of SNS, biosynthetic precursor of adrenaline • Major difference from adrenaline is that α1 effects are apparent at lower doses of the drug, producing an increase in SVR; minimal effects on β2 receptors • Renal, hepatic and cerebral blood flow are decreased • Normally leading to reflex bradycardia, and CO may be decreased; severely hypotensive pxt reflex bradycardia not seen and CO maintained Noradrenaline • Indicated in severe hypotension due to marked reduction in SVR, situations where adequate coronary perfusion pressure needed eg cardiogenic shock due to acute MI, post cardiac surgery • Needs CVL, little bronchodilator effect, slight increase in minute volume, peripheral ischemia • Dose 1-30 mcg/min Isoprenaline • • • • Synthetic catecholamine with pure beta activity Increases HR, contractility, decreases SVR Pulmonary vasodilator and bronchodilator Indications: haemodynamically stable, atropine resistant bradycardia, A-V block until temporary pacing instituted, low CO requiring fast HR eg paediatric, transplant, status asthmaticus, beta blocker overdose, right ventricular failure • Can give through peripheral line; S/E vasodilation, hypotension, tachyarrhythmias, care in coronary artery disease • Dose 0.01-0.1 mcg/kg/min Dobutamine • • • • Synthetic catecholamine Β1, β2, α1 receptor effects Mixture of stereoisomers Increases myocardial contractility, vasodilator, increases HR • Typically increases CO, decreases SVR with minimal effects on HR and ABP • Decreases PVR, useful in RHF Dobutamine • Useful for treatment of low output states caused by myocardial dysfunction secondary to AMI, cardiomyopathy, or myocardial depression post cardiac surgery • Diastolic relaxation even at low dose • S/E hypotension, increased myocardial oxygen consumption, arrhythmias • Dose 2-10 mcg/kg/min Dopexamine • Newish synthetic catecholamine with marked beta 2 activity and also DA1 and DA2 activity • Weak beta 1 and no alpha activity • Mild inotrope, marked vasodilator • Greater renal, gut, and skeletal muscle blood flow than dobutamine but less than renal blood flow and Na excretion than dopamine • S/E arrhythmias, hypotension Phosphodiesterase inhibitors • Amrinone, milrinone, enoxamone • Increases cAMP by inhibiting the conversion of cAMP to AMP • Methylxanthines eg theophylline and caffeine inhibit types 1,2 and 3 PDE • Bypiridines inhibit type 3 eg amrinone, milrinone, enoxamone Phosphodiesterase inhibitors • Increased contractility and increased rate of diastolic relaxation (lusitrophy), vasodilation leading to decreased SVR, MVO2, RAP, LVEDP, PVR • INODILATOR • Minimal effects on HR and BP is patient is euvolemic, have volume available for administration of loading dose Phosphodiesterase inhibitors • No tolerance; place in beta receptor downregulation • Titration kinetics very different to catecholamines • Half lives can be prolonged and excretion is renal • Combined use with catecholamines may be necessary and complementary to maintain MAP Phosphodiesterase inhibitors • Half lives: milrinone 1hr, amrinone 3-4hr, enoxamone 1-20hr (active metabolite) • Risks: hypotension with loading, reversible thrombocytopenia, inhibits platelet PDE 3, ventricular ectopy, abnormal LFTs, fever, GIT upset • Use: moderate to severe ventricular dysfunction with elevated filling pressures Cardiac glycosides • Mechanism: binds and inhibit Na K ATPase leading to increased intracellular Na and then the Na Ca exchanger is activated to remove excess Na resulting in importation of Ca • Vagotonic efects used to control ventricular response in SVTs • Direct and indirect increase in peripheral resistance • Neurohumoral effects eg decreases renin and noradrenaline levels Cardiac glycosides • Narrow therapeutic index • Adverse drug interactions • DIG trial beneficial at serum levels less than 1 ng/ml and detrimental effects at concentrations > 1 ng/ml • Limited role in ICU (Vasopressin) • Arginine vasopressin is a synthetic analogue of ADH, which is produced by posterior pituitary • AVP causes vasoconstriction by direct stimulation of smooth muscle V1 receptors • No increase in myocardial oxygen consumption as no beta effects • Rapid onset with duration of action of 10-20 minutes • Administration through CVL best • Indicated in VF cardiac arrest in dose of 40iu once only Vasopressin • Relative depletion of circulating vasopressin in established septic shock • Immediate and sustained increase in MAP during infusion of vasopressin (0.04U/min) in 14/16 patients in septic shock refractory to traditional vasopressors • Tsuneyoshi et al Crit Care Med 2001: 29 (3) : 487-93 Glucagon • Naturally occurring polypeptide that direcly stimulates adenyl cyclase via receptors to increase cAMP in myocardial cells resulting in positive inotropy with no myocardial excitability • Large doses needed for effect • Obvious metabolic S/E • Severe beta blocker OD Calcium • Essential in myocardial excitation contraction coupling • Role in CPR and shock not established • Deleterious effects on ischaemic brain and myocardium • Unpredictable and variable effects on HR, BP, CO, effect lasts about 5mins: increases SVR • Maybe useful post CPB • Indicated in hyperkalaemia, hypocalcaemia, calcium channel blocker OD Thyroid hormone • Required for synthesis of contractile proteins and expression of beta receptors • Augments myocardial contractility • Indicated in preexisting hypothyroidism; post cardiac transplantation as pxt may have sick euthyroid syndrome • Maybe r ole post routine CPB and in brain dead organ donor Summary • • • • • • Definition and classification of shock Cardiovascular physiology Classification of inotropic agents Indication for inotropes Specific agents Vasopressin