Presentation on theme: "Noncardiac surgery in Heart Transplanted Patients Speaker: Dr Rakesh Garg Dr Praveen Dr Praveen Moderator: Dr Bhalla"— Presentation transcript:
Noncardiac surgery in Heart Transplanted Patients Speaker: Dr Rakesh Garg Dr Praveen Dr Praveen Moderator: Dr Bhalla www.anaesthesia.co.in firstname.lastname@example.org
Indications of Heart Transplant: Idiopathic or ischemic cardiomyopathy Viral cardiomyopathy Systemic diseases such as amyloidosis and complex congenital heart disease
Factors associated with reduced 1 year survival…… older donors, older recipients, longer preservation times, repeat transplantation, and poor preoperative status of the recipient –requiring mechanical ventilation, –Intraaortic balloon pump, –left ventricular assist device, or –intensive care Smits et al.Clin Transpl.2003;82:89-100
Subsequent Surgical intervention…… disease acquired as a consequence of immunosuppression such as malignancy, infection, and steroid induced osteoporosis or unrelated problems pertaining to ENT, urologic, ophthalmic, orthopaedic, dental procedures etc Shaw et al. Br J Anaesth.1991;57:772-78 Steib et al. Ann Fr Anesth Reanim.1993;12:27-37.
Preoperative evaluation and intraoperative management of the patient with prior cardiac transplant requires an understanding of some of the unique features inherent to transplantation. denervation, vasculopathy, rejection, and arrhythmias. Physiological concerns and pharmacological interactions Kostopanaglotou et al. Paediatr Anaesth.2003;13:754-63. Musci et al. Thorac Cardiovasc Surg.1998;46:268-74 Schmid et al. Ther Umsch. 1990;47:122-28
Anatomy and Physiology of the Transplanted Heart: Portions of both native and donor right atria present, two P waves on the ECG. Native sinus activity not transmitted across the midatrial suture line. Asynchronous contraction occurs between the native and allograft atria, reducing the usual 15-20% atrial contribution to ventricular stroke volume, the “atrial kick” MR is common because of alterations in LA geometry caused by transplantation. Mod to severe TR is often present.
Denervation During transplant, –sympathetic postganglionic, –parasympathetic preganglionic and –afferent nerves to the heart are transected. The recipient atrium remains innervated, but haemodynamically unimportant, while the donor atrium is denervated and is responsible for the electrophysiological responses of the transplanted heart.
Denervation: HR is determined by the donor SA node. Loss of vagal effects on both the sinus and AV nodes results in an increased resting heart rate of 90-110 bpm which reflects the intrinsic rate of depolarization at the donor sinoatrial.
Denervation: The denervated heart retains its intrinsic control mechanisms which include: –a normal Frank-Starling Effect demonstrated with volume loading and in response to exercise, –normal impulse formation and conductivity and –intact and adrenoceptors responding normally to circulating catecholamines without evidence of denervation hypersensitivity to exogenous and endogenous catecholamines. But the normal variations or response to physiologic compensatory responses such as carotid massage and valsalva maneuvers are absent.
Loss of efferent sympathetic innervation prevents the heart from rapidly changing rate and contractility in response to exercise, hypovolemia, or vasodilatation. Afferent nerve interruption impairs rennin angiotensin-aldosterone regulation, vasoregulatory responses to changes in cardiac filling pressures, and eliminates the afferent signals perceived as angina.
Other effects associated with heart denervation include loss of cardiac baroreflexes and loss of sympathetic response to laryngoscopy and intubation. The denervated heart may have a more blunted heart response to inadequate anaesthetic depth or analgesia
Normal heart increases it’s CO via neural stimuli - ↑ in HR and contractility. Denervated heart lacks the ability to respond acutely to hypovolemia or hypotension with reflex tachycardia but responds to stress primarily by an ↑ in stroke volume in a twofold sequential manner. –Initially the denervated heart relies upon the Frank Starling mechanism of increased venous return to augment LVEDV and increase CO. –Following that, the ↑ in LVEDV and pressures are not sustained, but the increased CO is maintained by a HR which slowly increases over 5-6 minutes in response to increasing circulating catecholamines. This reflects dependence of the SA node on direct stimulation by endogenously released catecholamines and the absence control via neural mechanisms. heart transplant patients are said to be “preload dependent”.
In transplanted heart …. ANREP effect acts in addition to Frank Starling Effect. Failing heart Impaired length dependent force generation. Increased Aortic Pressure abruptly + inotropic effect within 1-2 min. HOMEOMETRIC AUTOREGULATION.
Increasing preload is useful before anaesthetic manoeuvres such as rapid thiopentone induction or spinal anaesthesia.
With exercise, the time to peak HR is prolonged as is duration of increase HR after exercise is stopped. This finding implies that the response to surgical response surgical stress or stimulation may be delayed and may persist after adequate drug therapy has been administered to control the stress. This increase in HR in response to exercise or stress is markedly diminished by beta blocker therapy. Nonselective beta blockade will lower endurance and peak BP response to exercise.
The absence of meaningful cardiac autonomic input to the heart has imp implications for pharmacologic responses perioperatively. Drugs with cardiac actions that depend on autonomic reflexes (e.g. atropine, digoxin, pancuronium) are ineffective in altering HR. for same reason, opioid induced bradycardia is absent. Drugs that are direct agonist to beta adrenergic receptors (e.g. epinephrine isoproteronol) are chosen when treating bradycardia.
HR responses to vasodilatation and vasoconstriction are also absent. Therefore, the normal increase and decrease in HR caused respectively by afterload reduction (e.g. with sod nitroprusside, nicardipine) or increased BP (e.g. with phenylephrine) don’t occur. Similarly, CO may be reduced more than usual when isoflurane is administered because the negative inotropic effects of this drug are not offset by reflex tachycardia. Beta adrenergic supersensitivity changes the response of the transplanted heart to epinephrine, NE, isoproteronol, and dobutamine, whereas drugs whose effects rely on the release of catecholamines from adrenergic nerves (indirectly acting drugs such as ephedrine and dopa) may have reduced efficacy.
To summarize…….. The HR shows no response to drugs like –muscle relaxants (pancuronium, gallamine), –anticholinergics (atropine, glycopyrolate, and scopolamine), –anticholinestrases (neostigmine, edrophonium, pyridostigmine, and physostigmine) and –digoxin, nifedipine, phenylephrine, or nitroprusside, but will respond to –isoproterenol, ephedrine, dopamine, or glucagons.
Cardiac innervation may occur over time. –Incomplete and unpredictable sympathetic reinnervation Clinical determinants of reinnervation include –time from transplant, –young age of the donor, –fast uncomplicated surgery, and –low rejection frequency. The restoration of sympathetic innervation is associated with improved contractility and HR response to exercise. Sympathetic reinnervation may occur before, or in absence of parasympathetic reinnervation. –However, while parasympathetic reinnervation has been demonstrated in animals, only sympathetic reinnervation has been demonstrated in human cardiac transplants. Many long term studies – reinnervation – absent/partial/incomplete in humans Am J Cardiol 1974
Cardiac function following transplantation: Ventricular function: Myocardial metabolism normal Ventricular function slightly reduced Contractile reserve normal Frank-Starling mechanism intact Left ventricular mass/end diastolic wall thickness are normal Diastolic relaxation abnormal Preload dependence for ventricular output Exercise response –Cardiac output increases owing to increased venous return –HR increases owing to catecholamine increases
Coronary Circulation: Changes in Coronary Circulation following transplantation: –Resting coronary flow increased by absence of -adrenergic tone –Coronary flow regulated by pH and PCO2 with intact autoregulation –Vasospasm and vasoconstriction in response to acetylcholine possible (responsive to adrenoceptor agonist and antagonist) –Coronary atherosclerosis accelerated and silent ischemia likely.
Accelerated Coronary atherosclerosis: Allograft coronary vasculopathy remains the greatest threat in long term survival. Allografts are prone to the accelerated coronary atherosclerosis, characterized by circumferential, diffuse involvement of entire coronary arterial segment, as opposed to the conventional form of the coronary atherosclerosis with focal plaques often found in eccentric positions in proximal coronary arteries. Etiology of coronary vasculopathy is multifactorial, recurrent graft rejection is a major contributing factor. Pathophysiologic basis remains elusive, but it is likely due to an immune cell mediated activation of vascular endothelial cells to up regulate the production of smooth muscle cell growth factors. Traditional risk factors for coronary artery disease may exacerbate the problem. Collateral formation is uncommon.
The criterion standard for evaluating coronary artery disease has been Angiography. However, this modality may underestimate the degree of diffuse intimal hyperplasia in the transplanted patients with coronary vasculopathy Coronary IVUS useful and reliable modality for evaluating coronary vasculopathy. Although it is often combined with angiography, IVUS is more sensitive in detecting early intimal disease. DSE safe and reliable screening method for coronary vasculopathy.
In pediatric transplant pts, it has been noted to have baseline regional wall motion abnormalities at rest in the absence of coronary vasculopathy, that resolves during DSE. This may imply subclinical coronary insufficiency in these patients.
Silent Ischemia: Because afferent cardiac innervation is rare, substantial portions of recipient with accelerated vasculopathy have silent ischemia. Silent coronary disease sec to accelerated atherosclerosis due to disruption of afferent nerve fibers responsible for ischaemic pain. Thus, the presenting signs are those resulting from ischemia such as left ventricular dysfunction, ventricular arrhythmias, or even sudden death.
Detection of intraoperative MI may be problematic. Monitoring ECG for ST changes consistent is of some value. Unexplained hypotension should raise the suspicion of MI. TEE is a more sensitive monitor for changes in cardiac function than hemodynamic changes undergoing, and may be of benefit for high risk pts with previous cardiac transplant undergoing surgical procedures. Treatment of suspected of intraoperative MI is directed at improving the balance of myocardial oxygen supply and demand. The use of CB (diltiazem) and NTG may be indicated.
Evaluation for rejection: Cardiac transplant recipients usually experience 2-3 episodes of rejection within the first year after transplant. Rejection is most likely in the first 3-6 months and decreases after that time. Rejection no specific clinical signs in its early stages. Usual presentation includes: –Fatigue, –Relative hypotension (decrease in systolic pressure >20 mm Hg below control), –S3 gallop, –Elevated JVP, –Other symptoms of left ventricular dysfunction. Findings: –Pericardial effusion, –ECHO- worsening systolic/diastolic function –Atrial / ventricular arrhythmias.
Arrhythmias are more prominent during episodes of rejection, and this can compound the intraoperative morbidity in pts undergoing noncardiac surgery. Graft failure associated with rejection is another risk factor for pts undergoing noncardiac surgery. This is particularly true when anaesthetic agents used may contribute to myocardial depression. Pts with scrupulously evaluated for the presence of graft failure and treated appropriately before GA is considered. Adequate level of immunosupression should be maintained in the perioperative period Bradycardia and small ECG complexes should also alert the physician to the possibility of impending rejection, as should an increased frequency of transient ischemic attacks. These signs and findings should prompt emergent myocardial biopsy.
The gold standard for determining the presence of acute rejection is Endomyocardial biopsy. Because this is an invasive procedure, new efforts are directed to developing a noninvasive method to detect rejection, including MR imaging with MR spectroscopy, changes in atrial electrophysiology, and serial dobutamine stress echocardiography.
Acute vascular rejection results in a greater incidence of mortality, tenfold increase in allograft coronary artery disease, hemodynamic compromise, and decreased long-term survival. In paediatrics rejection may present with progressive deterioration of organ function or with minimal symptoms from the transplanted organ and present with nonspecific symptoms such as poor appetite, irritability or fatigue. It has been shown that pts who undergo surgery during a period of rejection may have a higher morbidity.
Chronic rejection is usually manifested as diffuse, concentric stenosis of the graft’s coronary arteries. This process, termed allograft arteriopathy or vasculopathy, can be demonstrated in 42% of transplant recipients by angiography and in 75% of recipients by ivus (intracoronary artery us). Early diagnosis of the condition may allow for more effective treatment. Allograft vasculopathy is believed to be secondary to immunologically mediated endothelial injury, but other recipient factors (dyslipidemia, diabetes, HTN) and donor factors (eg older donor, age, donor HTN) may also play a role.
Cardiac dysrhythmias: Cardiac dysrhythmias in adult heart transplant recipients are common and have been used as a predictor of rejection. Cardiac dysrhythmias may occur in heart transplanted patients, probably due to lack of vagal tone, rejection, and increased endogenous catecholamine concentrations. Onset of arrhythmias should prompt a search for coronary vasculopathy or rejection. If rejection is the underlying cause it must be treated.
The SA node may have an increased refractory period and atrial conduction may be prolonged. Thus, 1st AV block is common. A 5-10% incidence of incomplete and complete right bundle branch block has been noted and as many as 20% of heart transplanted patients requires a pacemaker for bradyarrhythmias. The type of pacemaker present and likely response to electrocautry must be determined before induction of anaesthesia. Bradyarrhythmic therapy in these patients should be a direct β-adrenergic stimulating agent (ephedrine, isoproterenol). Glucagons is also useful as a positive chronotrope and inotrope. Lidocaine should be used cautiously in treating ventricular dysrhythmias because of its negative inotropic action.
Antiarrhythmics.. Atropine ordinarily blocks the effects of acetylcholine, which is released from the vagus; in the denervated heart, atropine has no effect. Class IA antiarrhythmics, like Procainamide, normally act via a combination of indirect, atropine like properties and direct suppression of Purkinje system automaticity. While these agents remain useful in the treatment of SVT or Atrial flutter, the absence of ameliorating tachycardia unmasks their potent negative inotropy after heart transplantation. Class IB drugs like lidocaine or phenytoin, suppress ventricular automaticity independently of the ANS, and are thus equally effective in the denervated heart.
class II - blocking drugs,, retain their usual activity. Bretylium exhibits mixed direct and indirect effects through the autonomic system. The net effect on the denervated heart remains poorly understood, thus limiting its use to refractory VT or VF. class IV -CCBs, directly suppress the sinus and AVnodes - retain their usual efficacy after heart transplantation. These drugs, however, possess potent negative inotropic actions as well. Class V comprised of other agents (e.g. digoxin and adenosine) must be considered individually. Digoxin acts in a biphasic manner. Early reduction in AV conduction that characterizes the response to digoxin is largely vagally mediated. Later in the course of digoxin therapy, direct action will influence AV conduction in the transplant recipient. Adenosine retains its efficacy in terminating SVTs via a direct SA node depression and slowing of Atrial HIS conduction.
Immunosuppressive drugs: All transplant pts who come for surgical procedures will be on some antirejection protocol. It is important for anaesthesiologists to know how these drugs interact with our anaesthetic drugs and also what side effects immunosuppressive drugs may exhibit. Immunosuppressive drugs may modify the pharmacological effects of many drugs used in anaesthesia.
Azathioprine Mechanism of action Decreased synthesis / utilization of RNA/ DNA precursors, Blocks lymphocyte proliferation Interactions: Allopurinol slows its metabolism Toxicity: Anemia,Leukopenia(bone marrow suppression), Cholestatic jaundice, Hepatitis, Pancreatitis Comments : Acute increased NDMR requirements antagonize competitive neuromuscular blocking drugs by phosphodiesterase inhibiting properties Clinically relevant doses of azathioprine do not antagonize NMB drugs in humans. However, it may prolong the effect of Sch
Steroids Mechanism of Action: Inhibition of release/ action of leukotrienes; interference with antigen receptor interactions Toxicity: Pituitary-adrenal axis suppression with cushingoid features Psychoses Glucose intolerance HTN Skin fragility Ulcers Osteoporosis Comments: commonly reduced to minimal levels as time from transplantation progresses. However, augmented doses of corticosteroids are the mainstay for treating rejection episodes. They may also be used as “pulse therapy” during rejection episodes. An additional bolus of steroid is usually given in the perioperative period.
Cyclosporine Mechanism of action: Inhibits synthesis of IL1 and other lymphokines; causes lymphocytolysis, selectively activates suppressor T cells while inhibiting B cells and cytotoxic T cell proliferation. Interactions: Metab dec by metoclopramide, cimetidine, verapamil, diltiazem, alcohol Toxicity: HTN Nephrotoxicity Hepatotoxicity Neurotoxicity Comments: Affects renal function – drugs excreted by kidney are not readily cleared. Potentiation of NDMR -Enhance NMB from atracurium and vecuronium. Potentiate the effect of barbituratres, fentanyl, and muscle relaxants particularly vecuronium and atracurium. Thus a smaller dose of NDMR may be needed and recovery time is prolonged.
Tacrolimus Mechanism of action: Inhibits production of IL2 and other lymphokines, calcineurin inhibitor. Inhibits T cell lymphocyte proliferation but is 100 times more potent than cyclosporine. Interactions: Similar to cyclosporine, Drugs that increase Tacrolimus and cyclosporine levels are verapamil, diltiazem, (not nifedipine), (via cyt P450 inhibition), ketokonazole, fluconazole, itraconzole, erythromycin, clarithromycin, imepenem, ciplox, steroids, perinorm. Drugs with synergistic nephrotoxicity are genta, tobra, ampho B, vanco. Toxicity: Nephrotoxicity Glucose intolerance HTN Neurotoxicity Comments: Newer immunosuppressive drugs like tacrolimus, which has been found to be effective in rescue therapy for intractable cardiac rejection as a substitute for cyclosporine.
Mycophenolate mofetil Mechanism of action: Inhibition of inosine monophosphate dehydrogenase Interactions: Increases levels of acyclovir Toxicity: Irritation of GIT(diarrhoea, ulcers, perf, bleed) Nephro / hepatotoxicity Bone marrow suppression Comments: used as substitute for azathioprine. One tentative advantage may be reduced coronary atherosclerosis.
Muromonab CD3 antibody (OKT3) Mechanism of action: Inhibits antigen recognition by binding to the CD2 surface antigen of lymphocytes, lymphocyte opsonization Toxicity: GI problems, Cytokine release syndrome (fever, Chills, hypotension, pulmonary edema)
Antithymocyte globulin Mechanism of action: Opsonization of lymphocytes Toxicity: Allergic reactions Serum sickness Fever Chills
Side effects of immunosuppressive that have a direct impact on Anaesthetic and perioperative management. To summarize……
Effects of specific drugs in Transplanted Hearts: Denervation has important implications in the choice of pharmacologic agents used after cardiac transplantation. The response of the transplanted heart to cardiovascular drugs depends on their mechanism of action. Drugs that act indirectly on the heart via the sympathetic (ephedrine) or parasympathetic (atropine, pancuronium, edrophonium) nervous system will generally be ineffective. Indirect drugs that depend on autonomic pathways are absent e.g. the chronotropic effects of atropine, panc, or opioids are absent. Rundquist et al. Blood Press.1993:2:252-61.
Drugs with a mixture of direct and indirect effects will exhibit only their direct effects (leading to the absence of the normal increase in refractory period of the atrioventricular node with digoxin, tachycardia with NE infusion, and bradycardia with neostigmine). Thus, agents with direct cardiac effects (such as epinephrine or isoproteronol) are the drugs of choice for altering cardiac physiology after cardiac transplantation. However, the chronically high catecholamine levels found in cardiac transplant recipients may blunt the effect of adrenergic agents, as opposed to normal responses to adrenergic agents.
Denervated hearts also respond normally to glucagons, NE, EPI, and propranolol. Phenylephrine, a direct vasoconstrictor is also effective and should be readily available when anaesthetizing cardiac transplant recipients. Acute administration of digoxin has no electrophysiological effects, but chronic administration depresses atrioventricular conduction. Quinidine slows atrioventricular conduction and sinus rate in transplanted hearts. The vagotonic effects of neostigmine would not be expected in transplanted hearts. However few reports has been reported of bradycardia with the use of neostigmine.
Vagolytic drugs such as atropine would not be expected to be effective in transplanted hearts. However, atropine reversed the neostigmine induced bradycardia in few reports. Infusions of isoproteronol should be available to treat bradycardia unresponsive to atropine. Ephedrine may also be used to treat bradycardia or hypotension. Propranolol blocks the effects of isoproteronol and norepinephrine at the SA node. Pancuronium does not exert its vagolytic effect in a transplanted heart. Atropine may not reverse Sch induced bradycardia in the transplanted hearts, so Sch is usually avoided.
Effects of specific drugs in Transplanted Hearts: To summarize……
Agent Sinus rate AV conduction Hemodynamic effect comment 1 Atropine ---+ muscarinic effect 2 CCB ↓↓↓ SVR may not change BP 3 Digoxin -Initial- chronic↓ No effect on AV nodal refractory period 4 Dobutamine ↑↑↑CO ↑BPHR effect greater than in normal heart; useful in detecting coronary insufficiency 5 Dopamine ↑↑↑CO may ↑BPOften useful during separation from CPB and early ICU Decrease in central BP sec to decrease in PVR 6 Epinephrine ↑↑↑BP & CO 7 Isoproteronol ↑↑↓BP may ↑CO 8 NE ↑↑↑BP may ↑CO no signs of super sensitivity 9 Nitroprusside --↓BP may ↑CO 10 Phenylephrine --↑BP variable effect on CO 11 Procainamide ↓↓ 12 Propranolol ↓↓Usually ↓CO ↓BP
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