Question 28

College answer

Respiratory failure in a cardiopulmonary transplant patient is most commonly due to infection, rejection or a combination of the two and has a high mortality. A multi-disciplinary approach with quaternary level consultation is warranted including the transplant unit and infectious diseases. 
 
Issues related to pneumonia 
Causative organisms- Opportunistic infections e.g. PJP, CMV, Aspergillus, Scedosporium as well as other bacterial, viral or atypical causes of community-acquired pneumonia. 
Early aggressive investigation – appropriate specimens/nasopharyngeal swabs and PCR testing, CXR, CT scan, bronchoscopy and consideration of lung biopsy 
Early aggressive antimicrobial therapy – To cover standard CAP organisms and likely opportunistic organisms eg co-trimoxazole, ganciclovir, antifungal agents. Steroid therapy if severe PJP 
 
Issues related to respiratory function 
Need to rule out rejection (cellular or antibody mediated)- often treated empirically for both infection and rejection. Enhanced antibody response developed to combat infection may result in concurrent antibody mediated rejection (AMR).  
Impaired cough and clearance of secretions. 
Impaired lung function due to obliterative bronchiolitis (a manifestation of chronic rejection)- small airway disease 
Bronchial or tracheal stenosis relating to the original anastomotic site may be present- large airway disease 
 
Issues related to immunosuppression 
On-going immunosuppression will need to be carefully managed in consultation with the transplant unit  
Stress dose steroids if associated shock 
Therapeutic drug monitoring of immunosuppression 
 
Issues related to cardiac function 
The transplanted heart is denervated. It is only responsive to directly acting drugs/hormones present in the circulation.  
Normal compensatory cardiac autonomic reflexes are not present and therefore the heart is more sensitive to directly acting drugs and less able to rapidly respond to changes in intravascular volume.  
Careful titration of fluid boluses needed- likely diastolic dysfunction. 
Difficult to clinically assess response to and adequacy of therapy 
Premature diffuse obliterative coronary atherosclerosis occurs resulting in impaired ventricular function 
 
Issues related to other organ function 
Renal – altered renal function secondary to calcineurin inhibitors 
Altered adrenal function secondary to steroid use. Consider need for steroid cover 
Glycaemic control with increased steroid dose 
Other co-morbidities and issues related to reason for heart-lung transplant, e.g. vascular disease, diabetes 
 
Other 
Early referral to transplant centre  
Involvement of multi-disciplinary team – transplant unit, ID, respiratory, cardiology, physiotherapy Psychological support of patient and next of kin 
 
Valid points not mentioned in the template were given credit 
 
Additional Examiners' Comments: 
Candidates who did not pass had knowledge gaps in this area. 

Discussion

This question is almost identical to Question 22 from the first paper of 2009.  Therefore, the discussion section from this previous question can be safely reproduced here with virtually no modification. For a broader overview of complications following heart-lung transplantation, and specifically sepsis in the heart-lung transplant recipient, there are dedicated chapter in the Required Reading section:

• Sepsis in the heart and lung transplant recipient
• Perioperative care of the cardiac transplant recipient
• Perioperative care of the lung transplant recipient

Anyway: a systems-based approach to discussing the "key clinical issues":

Airway:

• This patient may require intubation;
• The risk of intubation in the immunocompromised patient must be weighed, as it places them at considerable risk of VAP.
• On the other hand, clearance of secretions may not be satisfactory, and effort of breathing may be so great that the cardiac reserve is exhausted (as these people tend to have a rather fixed cardiac output).

Ventilation:

• Respiratory function will be impaired because of the pneumonia.
• The college also mentions obliterative bronchiolitis, which is a common feature of lung transplantation (it is a host vs graft chronic rejection syndrome)- in fact its the major cause of morbidity and mortality in long-term transplant patients. Obliterative bronchiolitis manifests as an obstructive respiratory disease, featuring an irreversible decrease in FEV₁ which progressively worsens.

Circulation:

• Myocardial ischaemia: the myocardia of these people tend to also be subjected to chronic rejection, and the consequence of this looks like an accelerated rate of coronary vascular disease. This is a mixture of normal coronary athersclerosis and a uniquely transplant-associated distal obliterative disease, which looks totally different histologically. A seriously unfortunate feature of this unique obliterative process is the fact that collateral circulation doesn't seem to form, in contrast to normal atherosclerotic narrowing. The upshot of all this is the predisposition of relatively young hearts to relatively severe ischaemic heart disease.
• Increased responsiveness to infused inotropes: The denervated heart, in the absence of sympathetic stimulus, will grow vast numbers of catecholamine receptors. This is analogous to the skeletal muscle in the denervated legs of a spinal patient, which will overexpress acetylcholine receptors. Thus, inotropes will have an exaggerated effect on the transplanted heart.
• Insensitivity to normal autonomic stimuli: Severed from the autonomic nervous system, the heart will no longer respond normally to changes in blood pressure, posture, or volume. There will not be a compensatory tachycardia when the patient is hypovolemic.

Renal and electrolyte abnormalities:

• These patients like have been receiving steroids or cyclosporine-like drugs. 
• The use of steroids will result in a hypernatremia, fluid retention, and hypokalemia.
• Alternatively, the barupt withdrawal of steroids may produce hyponatremia and hyperkalemia
• Renal function may be very poor, and drug clearance may be affected.
• Cyclosporine may also cause a distal renal tubular acidosis.

Infectious agents:

• In 60% of cases, pneumonia in the heart-lung trasplant recipient is due to an opportunistic pathogen.
• The pathogens are as follows:
  • Opportunistic:
    • CMV
    • Aspergillus
    • Pneumocystis
    • Nocardia
  • Community-acquired
    • H.influenzae
    • S.pneumoniae
    • Moraxella catarrhalis
  • Hospital-acquired
    • Acinetobacter
    • Pseudomonas
    • Stenotrophomonas
    • Klebsiella
    • Legionella
    • E.Coli

Note how weirdly the range of bugs is arrayed. The community pathogens are fairly bog-standard, but the Stanford people found that gram-negatives dominated the hospital-acquired infectious lung flora.

Immunesuppression in the context of an acute infectious illness may have to be continued, because its cessation may result in catastrophic rejection.

• Autonomic disconnection:
  • No cardiovascular response to hypotension; thus, sepsis or spinal/epidural anaesthesia result in massive hypotension
  • Atropine has no effect on heart rate
  • Digoxin has no effect on heart rate
  • There is no bradycardia in response to cholinergic drugs, eg. neostigmine
  • There is no reflex tachycardia in response to GTN
• Adenosine has an exaggerated effect, and one should use 1mg doses
• Inotropes have an exaggerated effect, perhaps with the exception of isoprenaline (?)
• Coronary artery disease is accelerated in these people

Cisneros, J. M., et al. "Pneumonia after heart transplantation: a multiinstitutional study." Clinical infectious diseases 27.2 (1998): 324-331.

Reichenspurner, Hermann, et al. "Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation." The Annals of thoracic surgery 62.5 (1996): 1467-1473.

Gao, Shao-Zhou, et al. "Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings." Journal of the American College of Cardiology 12.2 (1988): 334-340.

Yusuf, S. A. L. I. M., et al. "Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade."Circulation 75.4 (1987): 696-704