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Noncardiac surgery in Heart Transplanted PatientsSpeaker: Dr
Rakesh Garg Dr PraveenModerator: Dr Bhallawww.anaesthesia.co.in
[email protected]
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Indications of Heart Transplant:
Idiopathic or ischemic cardiomyopathy
Viral cardiomyopathy
Systemic diseases such as amyloidosis and complex congenital
heart disease
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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
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Subsequent Surgical intervention
disease acquired as a consequence of immunosuppression such
asmalignancy, infection, and steroid induced osteoporosis or
unrelated problems pertaining to ENT, urologic, ophthalmic,
orthopaedic, dental procedures etc
Shaw et al. Br J Anaesth.1991;57:772-78Steib et al. Ann Fr
Anesth Reanim.1993;12:27-37.
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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
interactionsKostopanaglotou et al. Paediatr
Anaesth.2003;13:754-63.Musci et al. Thorac Cardiovasc
Surg.1998;46:268-74Schmid et al. Ther Umsch. 1990;47:122-28
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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 kickMR is common because of
alterations in LA geometry caused by transplantation. Mod to severe
TR is often present.
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Denervation During transplant, sympathetic
postganglionic,parasympathetic preganglionic andafferent 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.
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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.
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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 andintact 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.
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Loss of efferent sympathetic innervation prevents the heart from
rapidly changing rate and contractility in response to exercise,
hypovolemia, or vasodilatation.Afferent nerve interruption
impairsrennin angiotensin-aldosterone regulation,vasoregulatory
responses to changes in cardiac filling pressures, and eliminates
the afferent signals perceived as angina.
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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
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Normal heart increases its 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.
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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.
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Increasing preload is useful before anaesthetic manoeuvres such
as rapid thiopentone induction or spinal anaesthesia.
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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.
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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.
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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) dont
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.
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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.
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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
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Cardiac function following transplantation:Ventricular
function:Myocardial metabolism normalVentricular function slightly
reducedContractile reserve normalFrank-Starling mechanism
intactLeft ventricular mass/end diastolic wall thickness are
normalDiastolic relaxation abnormalPreload dependence for
ventricular outputExercise response Cardiac output increases owing
to increased venous returnHR increases owing to catecholamine
increases
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Coronary Circulation:Changes in Coronary Circulation following
transplantation:Resting coronary flow increased by absence of
-adrenergic toneCoronary flow regulated by pH and PCO2 with intact
autoregulationVasospasm and vasoconstriction in response to
acetylcholine possible (responsive to adrenoceptor agonist and
antagonist)Coronary atherosclerosis accelerated and silent ischemia
likely.
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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.
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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.
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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.
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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.
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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.
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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 functionAtrial / ventricular arrhythmias.
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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.
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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.
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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.
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Chronic rejection is usually manifested as diffuse, concentric
stenosis of the grafts 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.
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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.
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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
-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.
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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.
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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.
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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.
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AzathioprineMechanism 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 requirementsantagonize 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
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SteroidsMechanism of Action:
Inhibition of release/ action of leukotrienes; interference with
antigen receptor interactions
Toxicity:
Pituitary-adrenal axis suppression with cushingoid
featuresPsychosesGlucose intoleranceHTNSkin
fragilityUlcersOsteoporosis
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.
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CyclosporineMechanism 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:HTNNephrotoxicityHepatotoxicity 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.
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TacrolimusMechanism 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:
NephrotoxicityGlucose intoleranceHTNNeurotoxicity
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.
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Mycophenolate mofetilMechanism of action:
Inhibition of inosine monophosphate dehydrogenase
Interactions:
Increases levels of acyclovir
Toxicity:
Irritation of GIT(diarrhoea, ulcers, perf, bleed)Nephro /
hepatotoxicityBone marrow suppressionComments:
used as substitute for azathioprine.One tentative advantage may
be reduced coronary atherosclerosis.
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Muromonab CD3 antibody (OKT3)Mechanism of action:
Inhibits antigen recognition by binding to the CD2 surface
antigen of lymphocytes, lymphocyte opsonizationToxicity:
GI problems,Cytokine release syndrome (fever, Chills,
hypotension, pulmonary edema)
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Antithymocyte globulinMechanism of action:
Opsonization of lymphocytes
Toxicity:
Allergic reactionsSerum sicknessFever Chills
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Side effects of immunosuppressive that have a direct impact on
Anaesthetic and perioperative management.To summarize
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Cyclosporin ATacrolimusAzathioprineSteroidsMycophenolate
mofetilAnti-thymocyte
globulinOKT31Anaemia2Leucopenia3Thrombocytopenia4HTN5DM6Neurotoxicity7Renal
Insufficiency8Anaphylaxis9Fever
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Cyclosporin ATacrolimusAzathioprineSteroidsMycophenolate
mofetilAnti-thymocyte
globulinOKT31Anaemia--+-+--2Leucopenia--+-+++3Thrombocytopenia--+-+--4HTN+++-+---5DM+++-++---6Neurotoxicity++-+---7Renal
Insufficiency+++-----8Anaphylaxis-----++9Fever-----++
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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.
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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.
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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.
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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.
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Effects of specific drugs in Transplanted Hearts:To
summarize
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Agent Sinus rate AV conductionHemodynamic
effectcomment1Atropine2CCB3Digoxin4Dobutamine5Dopamine6Epinephrine7Isoproteronol8NE9Nitroprusside10Phenylephrine11Procainamide12Propranolol
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Agent Sinus rate AV conductionHemodynamic
effectcomment1Atropine---+ muscarinic effect2CCB SVR may not change
BP3Digoxin-Initial-chronicNo effect on AV nodal refractory
period4DobutamineCO BPHR effect greater than in normal heart;
useful in detecting coronary insufficiency5DopamineCO may BPOften
useful during separation from CPB and early ICUDecrease in central
BP sec to decrease in PVR6EpinephrineBP & CO7IsoproteronolBP
may CO8NEBP may COno signs of super sensitivity9Nitroprusside--BP
may CO10Phenylephrine--BP variable effect on
CO11Procainamide12PropranololUsually CO BP
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Anaesthetic Management to be continued..
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