7.6 Denervated Heart

Question 1

A 65-year-old man is listed on the emergency list for incision and
drainage of perianal abscess. He gives history of a heart transplant 3 years ago

Where does the heart get its nerve
supply?

Answer 1

Autonomic innervation

• Sympathetic—T1–4 segment of the spinal cord—
  postganglionic cardio accelerator fibres
  form a cardiac plexus
• Parasympathetic—branches of the Vagus

Question 2

What is the effect of sympathetic
stimulation on the heart?

Answer 2

• Positive chronotropy –
  increased heart rate
• Positive inotropy –
  increased contractility
• Positive dromotropy –
  increased electrical conductivity across
  atrioventricular node

Question 3

What are the indications a heart
transplant is in order?

Answer 3

The indication is end stage heart disease not remediable
by conservative measures.

The primary disease could be any of the following:

• End stage cardiac failure
• Cardiomyopathy
• Congenital defects
• Valvular heart disease

Question 4

.According to the UK guidelines for referral and assessment of adults for
heart transplantation, the conventional criteria for heart transplantation are as
follows

Answer 4

1. • Impaired LV systolic function
2. • NYHA III/IV symptoms
3. • Receiving optimal medical treatment
     (beta blockers, ACE inhibitors/
     angiotensin receptor blocker and aldosterone antagonists)
4. • Resynchronisation and/or defibrillator implanted (if indicated)
5. • Evidence of a poor prognosis, defined as:
     ° Vo2 max <12 ml/kg/min if on β-blockade,
     <14 ml/kg/min if not on β-blockade,
     ensuring respiratory quotient ≥1.05

° Elevated B-type natriuretic peptide levels
despite full medical treatment

° A poor prognosis indicated by the
Heart Failure Survival Score (HFSS)
or Seattle Heart Failure Model (SHFM)

Question 5

The contraindications are (cardiac transplant)

Answer 5

• Significant pulmonary hypertension
  (pulmonary arterial pressure > 60 mmHg).
• Severe, irreversible end organ damage—
  lung (FEV1< 50%),
  liver (bilirubin > 43 μmol/L),
  kidney (eGFR < 40 mL/min/1.73m2).
• Diabetes mellitus with end organ damage.
• Active smoking, alcohol and other substance misuse.

Question 6

Explain the physiology of a denervated (transplanted) heart.

Answer 6

1. Absent sympathetic and parasympathetic innervation
2. Absent sensory innervation
3. Dependent on intrinsic regulation of cardiac output

Sympathetic neuronal reinnervation commences within 12 months after the
transplant but the parasympathetic innervation is less extensive.

Question 7

1. Absent sympathetic and parasympathetic innervation

Answer 7

Absent sympathetic and parasympathetic innervation

° Loss of vagal tone—resting heart rate at 90–100/min.

° No response to direct autonomic influence or
drugs that act via autononomic nervous system (atropine).

° Absent rate response to baroreceptors, valsalva,
carotid sinus stimulation, hypovolaemia, light anaesthesia.

° Stimulated only through directly acting agents such as catecholamines.

° Lack of catecholamine stores in myocardial neurons

loss of response to laryngoscopy/intubation.

Question 8

• Absent sensory innervation
• Dependent on intrinsic regulation of cardiac output

Answer 8

• Absent sensory innervation
  ° Increased incidence of silent myocardial ischaemia;
  hence the need for
  routine regular angiogram.
• Dependent on intrinsic regulation of cardiac output
  ° Stroke volume is preload dependent;
  hence the need to maintain
  ventricular filling pressures.

Question 9

How does a denervated heart respond to direct and indirect sympathomimetics?

Answer 9

Direct sympathomimetics
(adrenaline, noradrenaline, isoprenaline, dobutamine)

• Inotropic effects of adrenaline and noradrenaline are augmented;
  dobutamine and isoprenaline have normal response.

Indirect sympathomimetics (ephedrine)

• There is no catecholamine store in the myocardial neurones,
  so there is a decreased response

Question 10

What effect does atropine have?

Answer 10

Atropine and glycopyrollate (and digoxin) have no effect on the transplanted
heart due to absence of vagal connection.

Its use is still warranted as a neuromuscular reversal agent

along with neostigmine to counteract the
peripheral muscarinic effects such as miosis, nausea, bronchospasm,
increased bronchial secretions, sweating and salivation.

Question 11

What are the concerns when you are anaesthetising a patient with a heart transplant for a noncardiac surgery?

Answer 11

• Problems with physiology of denervation – as above.
• Related to progressive primary disease.
• Presence of defibrillator or pacemaker.
• Complications of transplant procedure such as
  leaky valves and conduction defects.
• Problems with rejection.
• Problems due to immune suppressants—
  nephrotoxicity, hepatotoxicity,
  hypertension, electrolyte imbalance,
  enhanced cytochrome P450.
• Infection - Cytomegalovirus,
  Pneumocystis carinii, fungal and protozoal
  opportunistic infections.

° Need for meticulous aseptic technique.

° Routine prophylactic antibiotics.

° Use of irradiated, leucocyte depleted,
CMV negative blood products if indicated.

Question 12

What are the concerns when you are anaesthetising a patient with a heart transplant for a noncardiac surgery?

Answer 12

• Difficult venous and arterial access— avoid right internal jugular venous
  cannulation as this is the recommended route for endomyocardial biopsy.
• Need for extensive preoperative investigations and intraoperative
  monitoring.

° Preoperative— ECG: beware of a double ‘P’ wave.
Coronary angiogram might be indicated to rule out ischaemic heart disease.

° Intraoperative—
5 lead ECG to monitor ischaemia and arrhythmias,
cardiac output monitoring to evaluate cardiac function,
volume status and aid fluid resuscitation,
peripheral nerve stimulator to assess
the neuromuscular function.

Question 13

Choice of technique

Answer 13

Both general and regional anaesthesia have been used successfully in
these patients

in the absence of significant
cardiorespiratory,
hepatic or
renal dysfunction,

there is no absolute contraindication to any anaesthetic technique.

Titration of anaesthetic agents to avoid drastic reduction
in preload and afterload is necessary due to the changes to normal
physiological responses.

Question 14

What are the problems with rejection?

Acute

Answer 14

Acute rejection:

This is a cellular or antibody mediated response
characterised by
arrhythmias,
fluid retention,
dyspnoea, and
pyrexia

and happens in the first 3 months after transplant.

Surveillance is by endomyocardial biopsy
and the treatment is by augmenting the
maintenance dose of immunosuppressants,
high dose steroids and occasionally
plasmapheresis and total lymphoid tissue irradiation.

Question 15

What are the problems with rejection?

Chronic

Answer 15

Chronic rejection:

otherwise termed as allograft vasculopathy,

it is immune mediated
and leads to an accelerated concentric intimal proliferation of
the donor coronary vessels.

It is a leading cause of late death in transplant recipient.

Surveillance is by routine invasive angiogram and there is no
specific treatment but the incidence is reduced by regular statin use.

Question 16

What are the implications of the patient’s immunosuppressant therapy for perioperative care?

Answer 16

Immunosuppression is usually achieved with the following drugs.

Calcineurin inhibitor

Steroids

Target of Rapamycin (TOR) inhibitors

Antiproliferative drugs

Question 17

Calcineurin inhibitor

Answer 17

Eg. Cyclosporin and Tacrolimus

Prevents T-cell activation and cell-mediated
immune reactions such as delayed
hypersensitivity and allograft rejection

• Metabolised by hepatic cytochrome P450—care with anaesthetic drugs
• Nephro- and neuro-toxicity, dyslipidaemia, diabetes, pancreatitis, and
  hypertension
• Hyperkalaemia, hypomagnesaemia, and hyperuricaemia
• Enhances effects of neuromuscular blockers

Question 18

Steroids

Answer 18

Eg. Methylprednisolone

Inhibition of T- cell lymphokines production

• Hypertension, cushingoid features,
  psychosis, hyperglycaemia,
  hyperkalaemia, osteoporosis
• Adrenal suppression—
  need for intraoperative supplementation

Question 19

Target of Rapamycin (TOR) inhibitors

Answer 19

Eg. Sirolimus

Prevention of T- and B- cell activation

• Minimal nephrotoxicity—so used in patients with renal dysfunction
• Peripheral oedema, hypertension, dyslipidaemia, and diarrhoea

Question 20

Antiproliferative drugs

Answer 20

Eg. Azathioprine and mycophenolate mofetil

Nonspecific inhibition of T- and B- lymphocytes

• Myelosuppression leading to pancytopaenia
• Reduces effects of nondepolarising neuromuscular blocking agents
• Hepatotoxicity and gastrointestinal side effects
• Pulmonary infiltrates

Question 21

General Side effects of transplant drugs

Answer 21

In addition, all the drugs increase the incidence of

skin and lymphoproliferative malignancy
propensity to infections.

The implications of immunosuppressant therapy are:

• Need for continuation intraoperatively to maintain the plasma levels.
• Steroid requires supplementation to account for stress response.
• Preoperative blood tests to rule out
  haematological, renal, and electrolyte impairment.

Question 22

General Side effects of transplant drugs

Intraoperative

Answer 22

• Strict asepsis and appropriate antibiotic prophylaxis
  as these patients are at risk of infections—
  bacterial, viral, fungal, and protozoal.
• Careful positioning due to presence of
  steroid induced osteoporosis and skin fragility.

Question 23

• Drug interactions:

Answer 23

° Cyclosporin enhances and azathioprine reduces
aminosteroid neuromuscular blocking action.

° Cytochrome P450 interactions of anaesthetic drugs

° Avoid nephrotoxic drugs such as non-steroidal anti-inflammatory drugs
and aminoglycoside

Question 24

What long-term health issues may occur in these patients?

Answer 24

Between 85 and 90% of recipients live for at least a year
after the transplant.

The proportion decreases with around 50% survival rate at 10 years.

There is also increased risk of infection,
skin and lymphoproliferative
malignancies, hepatic and renal impairment,
allograft vasculopathy, diabetes
mellitus, osteoporosis, etc.

Health related quality of life is usually good,
and improves rapidly after transplantation.

Question 25

What are the issues associated with anaesthetising a lung transplant patient for subsequent
surgery?

Answer 25

The control of breathing is usually preserved and hence there is little or no
change in the pattern of breathing. Also the response to ventilation to Co2 is
normal. `

The goal is to maintain oxygenation with minimal airway pressures,
optimal PEEP and Fio2.

• Complete transection of nerve supply with absent or very little
  reinnervation—
  loss of cough reflex and neurally mediated changes in
  bronchomotor tone.
• Decreased mucociliary clearance—
  in the presence of impaired cough and immunosuppression,
  there is increased risk of perioperative chest infection.

Strict asepsis, prophylactic antibiotics, incentive spirometry and
physiotherapy in the immediate postoperative period is necessary.

• Interruption of lymphatic drainage increases the susceptibility of
  pulmonary oedema stressing the importance of judicious fluid
  administration.
• Drug-induced muscle weakness (steroid myopathy) can affect the
  muscles of respiration;
  hence the need for careful titration and monitoring
  of neuromuscular blocking drugs.
• In single lung transplants, knowledge of underlying lung disease is
  important.
  In restrictive diseases of the native lung, increased airway
  pressures might be required to ventilate them, which can cause
  barotrauma and volutrauma in the transplant lung.
• Hypoxic pulmonary vasoconstriction (HPV) response is
  intact in native and grafted lung.

Positive pressure ventilation improves oxygenation to
the native lung and obliterates HPV.

This sudden increase in blood flow to the native lung
can result in haemodynamic instability and problems
with gas exchange.

Also in case of allograft rejection blood flow to the
transplant lung is reduced.