Lung Transplant

1
Lung Transplant

• Dave Sweet

2
CASE

• You are currently the fellow working at VGH and
  as you come in Monday morning the charge nurse
  tells you that there are several transplants
  going on today including a lung transplant and
  that we are holding a bed. You have several
  resident working with you that are very excited
  and they start firing questions off.

3
CASE

• What diseases are currently we doing lung
  transplants for?
• Alpha1-antitrypsin
• CF
• COPD
• IPF (UIP and occ NSIP)
• IPAH (including Eisenmengers)
• Sarcoidosis

4
(No Transcript)
5
CASE

• What are the general goals for determining the
  appropriateness of a lung transplant in a
  individual patient?

6
General Principles

• Need to consider the natural history and
  prognosis of primary disease and weigh against
  projected survival post transplant.
• Ultimate goal
• Obtain max mileage from native lung, conferring a
  greater overall survival time with new lung.
• Avoiding death on the waiting list.

7
General Principles

• Consider quality of life while on waiting list
  compared to quality of life with new lung.
• Traditionally, looked at the median 2-year
  posttransplant survival rate and compared this to
  projected survival with underlying condition.
• When formerlonger.patients are transplant
  candidates.

8
General Principles

• 2 year survival rate is not arbitrary number. Two
  reasons why used.
• Average waiting time is around 2 yrs.
• Based on disease the first month mortality varies
  greatly.
• ..but then the mortality decreases relatively
  linearly. This will compensate for this.

9
CASE

• Do the survival rates for different diseases vary
  post transplant? What is the generally quoted
  first month mortality?

10
CASE
First month mortality quoted as 7 to 24
11
CASE

• Which diseases are thought to have the greatest
  survival advantages? Which diseases are
  questionable?

12
Survival advantage?

• Use of time-dependent, nonproportional hazard
  models, equity points, and crossover points.
• Survival benefit demonstrated with
• CF
• IPF
• IPAH
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

13
Survival advantage?

• However, also raised questions about any survival
  benefit for px with
• COPD
• Eisenmener syndrome
• But in addition to survival, quality of life also
  needs to be taken into consideration.
• ie) COPD px changes in quality-adjusted
  life-years may be sufficient to justify
  transplantation.

14
Survival advantage?
15
CASE

• What are the indications for lung transplantation
  for these various diseases based on the ATS 1998
  consensus statement?

16
Indications

• COPD
• FEV1lt 25 (without reversibility)
• And/or PaCO2 gt55 and/or elevated PAP with
  progressive deterioration
• Preference to those px with
• elevated PaCO2 with progressive deterioration
• require long term oxygen therapy.
• Nathan et al. Lung Transplantation
  Disease-Specific Considerations for referral.
  Chest 20051271006-1016

17
Indications

• Interestingthe level of subjective dyspnea my
  be a better predictor of mortality than FEV1.
• ie) grade IV dyspnea stopping to take a breath
  during 100 yrd walk.
• - median survival of 3 yrs, which is comparable
  to 3 yr posttransplant survival rate (61)
• In contrast, FEV1lt35 pred had a median survival
  of 5 yrs.

18
Indications

• Currently several other models being investigated
  which incorporate a number of diff parameters
  such as the BODE index.
• Body weight, Obstruction, Dyspnea level, Exercise
  tolerance.
• Score out of 10.
• 7-1080 mort at 52 months (transplant cand)
• lt7 5 yr mort of lt50 (not transplant cand)

19
Indications

• IPF
• Divided now into UIP and NSIP
• UIPWhen diagnosed should be referred!!!
• Traditionally, break points at FVC of 60-70 and
  DLCO of 50-60 are indicative for poor outcome.
  Very inconsistent.

20
Indications

• Other models look at DLCO and HRCT scan to help
  predict mortality (May see in future!)
• Also, one of the most sensitive markers may be
  desaturation to less than 89 during a 6 min
  walk.
• If able to maintain sats may be able to defer
  transplant referral.

21
Indications

• NSIP
• True NSIP have much better prognosis and majority
  will not need transplant.
• Subgroup which may require include
• 1) DLCO lt35 and/or a dec in DLCO of gt15 have
  shown to have mortality similar to UIP with
  median survival of 2 yrs.

22
Indications

• CF
• FEV1 lt30 or
• Rapid progressive resp deterioration with FEV1
  gt30 (inc hosp, rapid fall in FEV1, massive
  hemoptysis, inc cachexia)
• Room air PaCO2 gt50 or PaO2 lt55.
• Woman whose condition is deteriorating rapidly.

23
Indications

• IPAH
• Medical management has improved greatly.
• 1990 10.5 of all lung transplants.
• 20013.6 of all lung transplants.
• Should exhaust all medical management before
  consider transplant.

24
Indications

• NYHA class III or IV after 3 months of IV
  epoprostenol have 2 yr survival of 46 and should
  be considered for transplant.
• NYHA class I and II 93 and not candidate.

25
Indications

• Sarcoidosis (common disease, rare transplant)
• In 1998 guideline no official recommendation.
• Need to have stage IV. Advanced fibrotic
  changes, honey-combing, hilar retraction, bullae,
  cysts, and emphysema.
• Also reasonable when FVClt50 and/or FEV1 lt40.

26
CASE

• After you clearly describe the answers to the
  above questions your staff speaks up and asks you
  if you are familiar with the Lung Allocation
  Score (LAS).
• What is the LAS? Why was it designed?

27
LAS

• In Canada we determine how organs or allocated
  by
• Size of patient
• ABO matching (Not HLA matching)
• Time on the list.
• Kozower et al. The impact of the lung allocation
  score on short-term transplant outcomes A
  multicenter study. J thorac Cardiovasc Surg
  2008135166-77

28
LAS

• In the US
• Organ procurement and transplantation network
  (OPTN) began allocating lungs in 1990 based on
  size, blood type and amount of time candidate had
  spent on waiting list.
• 1995, minor change when 3 months credit given to
  IPF px to offset their inc mortality. (Not done
  in Canada)
• To better list px according to medical urgency
  and expected benefit the LAS was developed.

29
LAS

• Developed by multivariate modeling and approved
  by OPTN in 2004. Implemented in May 2005.
• Three main objectives are
• Reduce deaths on transplant list
• Inc transplant benefit for lung recipients
• Ensure efficient and equitable allocation of
  organs

30
LAS

• Gives a score between 1-100.
• Weighted combination of predicted risk of death
  during the following year on the waiting list and
  the predicted likelyhood of survival during the
  first year after transplant.

31
CASE

• Is there any evidence that it is working?

32

• First year of implementation compared to previous
  year.
• 170 in each group.
• Dec in waiting times (680 to 445 days).
• Dec death on waiting list (74 to 5130)
• Determined that there was a switch with inc in
  IPF px and dec in COPD and CF.
• Inc in primary graft dysfunction (14.1 to 22.9).
• Inc in ICU stay (5.7 to 7.8 days).
• Hosp mort and 1 yr survival were similar.

33

• Concluded that the LAS is doing what it was
  designed to do.
• Reason why inc in PGD is likely due to higher
  number of retransplants and IPF which both are
  established risk factors for PGD.
• When controlled for Dx, the rates of PGD were no
  longer different.
• This also explains the inc in ICU stay, mech
  vent.
• Most important..no change in mortality.

34
Donor criteria?

• Less than 20 of organ donors possess lungs
  suitable for transplantation

35

• Age lt40 years (heart-lung), lt50 years (lung)
• Smoking history less than 20 pack-years
• Arterial partial oxygen pressure of 140 mm Hg on
  a fraction of inspired oxygen (FIO2) of 40 or
  300 mm Hg on an FIO2 of 100
• Normal chest x-ray Sputum free of bacteria,
  fungi, or significant numbers of white blood
  cells on Gram and fungal staining
• Bronchoscopy showing absence of purulent
  secretions or signs of aspiration
• Absence of thoracic trauma
• Human immunodeficiency virus negative

36
CASE

• You learn that the patient is a 58 yo male with
  severe COPD. Other PMHx includes a NSTEMI 8 yrs
  prev, HTN, hypercholesterolemia. Pre-op ECHO
  results show good biventricular fxn with PAS33
  mmHg via TRJ. Pre-op cath results show clean
  coronaries and right heart cath confirms the
  right sided pressures. Preop PFT show a PEV1 of
  25 and moderate to severe airtrapping. They are
  doing a single right lung transplant and no plan
  for bypass.

37
CASE

• 8) How is the choice for a single vs a double
  lung transplant made? In what situations is a
  double lung preferred?

38
Single vs Double?

• Based on numerous factors such as
• Disease
• Age
• Comorbidities
• Institutional biases
• Organ availability
• Emergency of procedure

39
Single vs Double?

• Majority done in Canada are single lung
  transplants.
• First isolated single lungs were done for
  pulmonary fibrosis and this continues to be the
  norm.
• COPD originally thought not possible to receive
  single lung transplants.
• First done in 1989 by Mal and colleagues
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

40
Single vs Double?

• Currently a standard throughout the country.
• Specifically, in COPD if px is of shorter stature
  and older do better.
• Pulmonary HTN single or double but if choose
  single expect to have more difficulty in first
  few days. Many centers mandate only bilateral.
• Bilateral transplants are mandatory for px with
  CF and bronchiectasis.
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

41
Single vs Double?

• Bilateral lung transplants for mycetomas or other
  chronic fungal or mycobacterial infections
• Many larger centers are now favoring bilateral
  transplants. Specifically the Duke University
  Medical Center.
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

42
Single vs Double?

• Feel do not exclude other patient in many cases.
• If single lung is marginal for transplant,
  taking both will provide adequate function.
• Early post-op management is easier with bilateral

43
Single vs Double?

• Additionally, in 225 px who survive 6 months.
• Single lung transplant (as compared to bilateral)
  was a significant risk for BOS in multivariate
  Cox model (HR2.08, p0.001)
• ? If immunologic advantages of bilateral ?
• Hadjiliadis D et. al. Chest 20021221168-1175.

44
Single vs Double?

• A recent review of the United Network of Organ
  Sharing lung transplant database of 2260
  transplants for emphysema compared single vs
  double lung transplants.
• No difference in 30 day mortality but long term
  survival data favored bilateral lung transplants
  for individuals lt60 yrs of age.
• Bilat were older and more women. ? How to
  interpret?
• Meyer et al. J heart Lung Transplant
  200120935-941.

45
Case

• 9) In what situations will a lung transplant be
  done on bypass? Why if done on bypass is it
  relevant to post-op management?

46
Bypass?

• Most adult transplants can be done without CPB.
  A number of specific situations will necessitate
  CPB.
• Primary or secondary pulmonary htn are most
  safely done on bypass.
• Px with CF likely have such voluminous purulent
  secretions that independent ventilation is
  impossible.
• During bilateral transplant early graft dysfxn of
  the first transplanted lung (reperfusion)
  preventing single lung vent.
• If native lung is unable to sustain patient with
  single lung ventilation.

47
Bypass?

• Why relevant to post-op care?
• 1) If get significant PGD it is unlikely the
  patient can be supported on single lung
  ventilation.
• 2) Bypass is a significant risk factor for PGD!!
• Most recent large study by Dalibon, which
  reviewed 140 LT, confirmed that CPB was
  associated with longer MV, more pulm edema, more
  transfusions and inc early mortality!!
• Dalibon et. al. J Cardiothorac Vasc Anesth
  200620668-672.

48
CASE

• You hear that the case is finishing up. There
  was minimal surgical difficulty the lung was
  implanted using continuous 3/0 polypropylene
  sutures for the bronchial anastomosis
  (end-end-technique), continuous 4/0 polypropylene
  sutures for the pulmonary vein to left atrial
  anastomosis, and continuous 5/0 polypropylene
  sutures for the pulmonary arterial anastomosis.

49
CASE

• Unfortunately you hear that they need to do the
  case on bypass as they were unable to do the
  transplant on single lung ventilation. The
  overall ischemia time was 6 hours and 8 minutes
  for the lung. The post-transplant bronch looked
  pristine and the TEE looked good. The patient is
  brought to ICU post-op stable on AC and FIO2 of
  100 and quickly weaned to 80. CVP12 CI3.5,
  PA40/18. (If the nurse said the PAWP16what
  would you say??)

50
CASE

• 10) Generally what ventilator settings would you
  like post transplant px to be on? What about
  this patient? What is your general plan to wean
  the ventilator?

51
Ventilation?

• Many centers prefer a PC ventilation so as to
  limit peak airway pressures (lt40) and prevent
  barotrauma to the brochial anastomosis.
• Plat pressure should additionally be limited to
  less than 30 to 35 mmHg.
• Minimize Fio2 as quickly as possible.
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

52
Ventilation?

• This patient?
• Due to the very compliant native lung with
  potential for air trapping and the relatively
  stiff transplant lung.need to be aware of
  balance.
• To begin, as long as oxygenation is not a issue.
  Ventilation as if to prevent air trapping in
  native lung.
• Min PEEP, adequate expiratory phase with PC. Can
  still use EEP to determine if airtrapping.
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

53
Ventilation?

• Generally want to get off the ventilator as soon
  as possible.
• Use adequate analgesia via epidural or
  paravertebral (recent metaanalysis and found
  paravertebral block had lower rate of resp
  complications and side effects) .wake and wean.
• If have standard PS weaning protocol it should be
  used as usual.
• Plan to have extubated in 24 to 48 hrs ideally!
• Davies et. al. Br J Anaesth 2006 96418-426.

54
CASE

• 11) Generally discuss your fluid management post
  op. What variables are you balancing with your
  fluid management?

55
Fluid Management

• Careful fluid management is necessary to avoid
  substantial transplant lung edema.
• Usually aim for a negative fluid balance from the
  get go. Def aim for negative balance in the
  first 48hrs.
• Minimal fluid and if require volume use colloid
  or blood.
• Some centers will target a CVP of lt7 mmH20, with
  systemic perfusion supported by pressors.
• Pilcher et. al. A high CVP is associated with
  prolonged mech vent and inc mortality following
  lung transplantation. J Thoracic Cardiovasc Surg
  2005129912-918.

56
Fluid Management

• Retrospective study of 118 px.
• After controlling for CV diz and vasopressors,
  CVP was correlated with duration of MV, with a
  CVP gt7 also being associated with higher ICU and
  hosp mortality.
• Unclear whether a strategy aimed at keeping CVP
  less than 7 would alter outcome or if a marker of
  severity of illness.
• Pilcher et. al. A high CVP is associated with
  prolonged mech vent and inc mortality following
  lung transplantation. J Thoracic Cardiovasc Surg
  2005129912-918.

57
Fluid Management

• Obviously need to balance against the risk of
  renal insufficiency.
• Many of these patient my have CRF.specifically
  the CF px. (why?).
• Additionally cyclosporine or tacrolimus may
  impair renal fxn. Watch levels closely post-op.
  
• Titrate volume to u/o. Previous many centers
  still using renal dose dopamine in this
  setting. No evidence.

58
CASE

• 12)Although our patient remains hemodynamically
  stable. Why is shock in these patients need to
  be quickly identified and diagnosed?

59
CASE

• These patients should not be shocky!!
• NEED TO MAKE DIAGNOSIS (Dr George
  Isac)
• Bleeding? Anastamosis?(watch CTs and hgb)
• Obstructive? Anastamosis?
• Cardiogenic?
• Infection/sepsis?

60
CASE

• Judicious resuscitation (colloid) and
  vasopressors
• STAT ECHO (TEE)
• Notify the Surgeon
• ? Mobilize ECMO early?
• Is their a benign reason why they may be
  requiring increasing vasopressor support?

61
CASE

• After initially settling the patient in and
  continuing on your rounds the RT approaches you
  and states that the FIO2 requirements are back up
  to 100 after a brief period at 50 and hypoxia
  is becoming an issue. A stat CXR was done.

62
CASE
63
CASE

• 13) What is your differential for early
  respiratory failure in the lung transplant? What
  are the risk factors for early respiratory
  failure?

64
Early Respiratory Failure

• DDx
• Reperfusion injury (55)
• Periop cardiovascular(MI, arrhythmia, CHF)
  /haemorrhagic (36)
• Anatomic complications
• Infectious (bacterial and CMV)
• Rejection (hyperacuterare and acutecommon)
• Pneumothorax
• PE
• Chatila el. al. Resp failure after lung
  transplant. Chest 2003123165-173.

65
Early Respiratory Failure

• Risk factors
• Preop pulmonary htn
• Rt vent dysfunction
• Prolonged ischemic time
• CPB
• Chatila el. al. Resp failure after lung
  transplant. Chest 2003123165-173.

66
CASE

• 14) Briefly describe Reperfusion injury, Primary
  Graft failure. What can we do to help prevent
  Reperfusion injury before and after the
  transplant? How do you manage it? (specifically
  in our patient?)

67
Ischemia-Reperfusion Injury

• Typically manifests in the first 72 h after
  transplant.
• Development of airspace disease, progressive
  hypoxemia, and inc in pulmonary pressures
  (reflective both epithelial and endothelia
  injury)
• When PaO2/FiO2 ratio below 200, termed primary
  graft failure.
• Granton, J. Update of early resp failure in the
  transplant recipient. Current Opinion in Critical
  Care 20061219-24.

68
Ischemia-Reperfusion Injury

• Recent 2004 publication identified several risk
  factors
• CPB
• BMI gt25kg/m2
• Immediate elevated PAS
• Trend in oxygenation index over 24hrs
• Elevated APACHE II
• Sekine et al. J Heart Lung Transplant
  20042396-104

69
Ischemia-Reperfusion Injury

• Additionally, a review of 7 French transplant
  centers and 752 px over 12 yrs.
• Found graft ischemic time associated with the
  PaO2/FiO2 ration measured at 6 hrs.
• 30 day mortality was associated with a lower
  PaO2/FiO2 ratio at 6 hrs.
• Identified cold ischemic time of 330 min (5.5hr)
  as distinguishing between px who had a
  uncomplicated course vs those who did not. (Max
  accepted is 6-8hrs)
• Thabu et al. Am J Respir Crit Care Med
  2005171786-791.
• Oto et al. J Thorac Cardiovasc Surg
  2005130180-186.

70
Ischemia-Reperfusion Injury

• Ischemia-Reperfusion Injury also associated with
  long-term consequences.
• Retrospective cohort study of 255 LT px.
• Christie et al reported a 30 day mort of 63.3
  compared to 8.8 in px with and without
  reperfusion injury.
• Median hosp was longer (47 vs 15 days)
• Mech vent longer (15 vs 1 day)
• Lower exercise capacity as assessed by 6 min walk
  distance at 12 months.
• Christie et al. Chest 2005127161-165.

71
Ischemia-Reperfusion Injury

• Pathogenesis
• Variety of perturbations implicated.
• Factors relating to
• Donor
• Method of graft preservation
• Effects of reperfusion following period of
  ischemia

72
Ischemia-Reperfusion Injury

• The Lungs may be made susceptible from
  cytokine-mediated damage in px with elevated ICP
  and compounded following cold preservation of the
  grafts.
• De Perrot et al. Am J Respir Crit Care Med
  2003167490-511

73
Ischemia-Reperfusion Injury

• How can we help prevent ischemia-reperfusion
  injury?
• Can divide into
• Pre-transplant interventions
• Peri-surgical interventions
• Post-surgical interventions

74
Ischemia-Reperfusion Injury
75
Ischemia-Reperfusion Injury

• Pre-Surgical interventions
• Preservation solutionspecifically a
  low-potassium dextran solution provides superior
  preservation over high potassium preservation
  solutions.
• In addition, nitric oxide added to the flush
  during harvest provides a preservation advantage.
  (not well studied)
• Maccherini et al. Transplantation.
  199152621-626
• Yamashita et al. Ann thorac Surg. 199662791-797

76
Ischemia-Reperfusion Injury

• It is known that lung hyperinflation is a
  excellent model of pulmonary edema.therefore
  care should be taken to avoid during harvest and
  storage.

77
Ischemia-Reperfusion Injury

• Peri-Surgical interventions
• Lick and colleagues reported a small series where
  using leukocyte-filtered modified perfusate is
  pumped through the lung at time of reperfusion.
  In case report.no ischemia-reperfusion injury.
• Lick et al. Ann Thorac Surg. 200069910-919

78
Ischemia-Reperfusion Injury

• Post-surgical interventions
• TP-10 inhibitor
• - One of few randomized trials in lung
  transplantation, using soluble complement
  receptor-1 inhibitor led to reduction in duration
  of mech vent.
• - Interestingly, greatest effect in px who
  received bypass.

79
Ischemia-Reperfusion Injury

• NO
• Early preclinical and uncontrolled reports
  suggested that admin of NO either prior to or
  shortly after reperfusion injury could dec
  severity of disease.
• Recent controlled clinical trial failed to show
  benefit when inhaled 10 min after reperfusion.
• Meade et al. Am J Respir Crit Care Med
  20031671483-1489.

80
Ischemia-Reperfusion Injury

• NO
• Another recent trial by Perrin.
• RCT in 30 bilateral lung transplants.
• 20 ppm iNO at time of reperfusion vs control.
• Could not identify any reduction in extravasular
  lung water (p0.61) or improvement in gas
  exchange (p0.61).
• Future studies needed.
• Perrin et al. Chest 20061291024-1030

81
Ischemia-Reperfusion Injury

• ICU management
• Adoption of lung protective strategy would seem
  reasonable. (only one rat study has actually
  looked at this).
• In refractory hypoxemia use of inhaled NO, HFO
  and ECMO may improve gas exchange.
• Granton, J. Update of early resp failure in the
  transplant recipient. Current Opinion in Critical
  Care 20061219-24.

82
Ischemia-Reperfusion Injury

• What about our patient??
• In COPD single lung Tx that develop reperfusion
  injury.dilemmas may arise.
• As px becomes hypoxic and more aggressive
  vent/peep strategies are used.may overdistend
  native lung.
• Cause shunting of blood to dysfunctional
  allograft.
• Futhermore, if worsens still, mediastinal shift
  may result in impaired venous return.

83
Ischemia-Reperfusion Injury

• Better to minimize tidal volumes and lowest PEEP
  to gain acceptable oxygenation and accepting mild
  respiratory acidosis (/- novalung??)
• Place px in lateral decubitus with transplant
  side up, and aggressive chest physiotherapy.
• If this fails.should consider independent lung
  ventilation.
• Be aware that will be more difficult to clear
  secretions and the ease with which the tube may
  be dislodged.
• Gavazzeni et al. Chest. 1993103297-299.

84
Prediction of Independent Lung Vent.

• Prediction of need for single lung ventilation?
• Study looking at 170 px who had single lung
  transplant for COPD.
• 12 required independent lung ventilation.
• Similar in age, sex, ischemic time, and donor
  characteristics to those who required
  conventional ventilation.
• Pilcher et al. Predictors of independent lung
  ventilation an analysis of 170 single-lung
  transplantations. Pilcher J Thorac Cardiovasc
  Surg. 2007 Apr133(4)1071-7

85
Prediction of Independent Lung Vent.

• Patients receiving independent lung ventilation
  had a greater degree of
• Preoperative airflow limitation (FVC1/FVC)
• More hyperinflation
• Lower postoperative PaO2/fraction of inspired
  oxygen ratios
• More radiologic mediastinal shift
• More transplant lung infiltrate on the
  postoperative chest radiograph.

86
Prediction of Independent Lung Vent.

• Multivariate logistic regression analysis showed
  that independent lung ventilation was associated
  with
• Increasing levels of recipient hyperinflation
  (percentage total lung capacity compared with
  predicted value odds ratio 1.04P .032)
• Reduced early postoperative PaO2/fraction of
  inspired oxygen ratio (odds ratio 0.96 P .005)

87
Prediction of Independent Lung Vent.

• Length of ventilation and intensive care unit
  stay and mortality were higher in the independent
  lung ventilation group.
• Among patients who survived to hospital
  discharge, there were no differences in long-term
  mortality between the 2 groups.

88
Prediction of Independent Lung Vent.

• Conclusions Independent lung ventilation
  predicted by the combination of
• Increased hyperinflation measured on recipients'
  preoperative lung function tests
• Low PaO2/fraction of inspired oxygen ratio,
  indicating graft dysfunction in the immediate
  postoperative period.

89
Prediction of Independent Lung Vent.

• Another study looking at predictors of native
  lung hyperinflation.
• Retrospectively analyzed data from 27 patients
  who underwent 31 single lung transplantations for
  emphysema.
• Two groups
• 12 patients with development of acute or chronic
  NLH
• 15 patients without development of hyperinflation
  
• Yonan. Single lung transplantation for emphysema
  predictors for native lung hyperinflation. J
  Heart Lung Transplant. 1998 Feb17(2)192-201

90
Prediction of Independent Lung Vent.

• NLH was defined as
• Radiologic mediastinal shift with
• Flattening of the ipsilateral diaphragm
• Associated with respiratory dysfunction or
  hemodynamic instability

91
Prediction of Independent Lung Vent.

• No differences between the two groups regarding
• age
• preoperative partial pressure of oxygen
• partial pressure of carbon dioxide
• acid-base status
• donor lung size and physiological structure
• side of transplantation
• primary pathologic condition
• rejection score
• infection episodes and obliterative bronchiolitis
  in the transplanted lung after operation.

92
Prediction of Independent Lung Vent.

• Patients with NLH had
• Significantly higher preoperative mean pulmonary
  artery pressure gt 30 mm Hg.
• Lower mean FEV1.
• Higher mean residual volume.

93
CASE

• A quick in and out bronch shows no anatomic abn
  and on TEE the pulmonary veins look good. After a
  short period of time you realize that he is
  deteriorating that the hypoxia is quickly
  becoming refractory. You quickly mobilize ECMO
  and after a short time on ECMO the patient
  stabilizes.
• 15) Your staff asks you if you know of any
  evidence for the use of early ECMO in these
  patients?

94
ECMO

• Several publications looking at ECMO in this
  situation.
• In the setting of pulmonary htn (high risk),
  early ECMO has been advocated (experience based).
• Another review of 17 cases
• ECMO may preserve initial organ function due to
  reduction in use of injurious ventilation
  strategies.
• Dahlberg et al. J Heart Lung Transplant
  200423979-984.
• Pereszlenyi et al. Eur J Cardiothorac Surg
  200221858-863.

95
ECMO

• More recent publication by Oto at Alfred Hosp in
  Melbourne.
• Ten transplant recipients from total of 481
  (2.1) were treated with ECMO.
• Prior to initiation had TEE to exclude lung
  torsion and pulmonary vasc prob, and a
  retrospective crossmatch to exclude humoral
  rejection.

96
(No Transcript)
97
ECMO
Initiate 21 days (7-40days)
Initiated after 0-2 days
98
ECMO
99
(No Transcript)
100
CASE

• One of your keen residents asks if there is
  anyway this could be acute rejection? Are there
  any definitive tests to prove this is not
  rejection?

101
Biopsy!!

• Patients with acute rejection can also have
  alveolar infiltrates, hypoxemia and systemic
  inflammatory response syndrome.
• To rule out hyperacute rejection can do a
  retrospective crossmatch.
• For longer term observation pathologic assessment
  of multiple transbronchial biopsy specimens has
  proven to be the gold standard.
• Debate between transbronchial and surgical
  biopsy.
• Trulock et al. Chest. 19921021049-1054.

102
Open Lung Biopsy

• In 2003 Burns et al looked at 41 patients on mech
  vent with questionable acute rejection that
  received transbronchial and open lung biopsy.
• Surgical biopsy inc dx of rejection by 33 and
  treatment changes in 15 of the 41.
• Currently unresolved debate as previous studies
  contradicted this finding.
• Burns et al. J Heart Lung Transplant
  200322267-275.

103
(No Transcript)
104
Open Lung Biopsy

• The risk of open lung biopsy must be weighed
  against the risk of simple empirical therapy for
  rejection after exclusion of infection.
• Given the consequences of intensification of
  immunosuppression in the intubated, critically
  ill px, open lung biopsy may be justifiable.

105
CASE

• Now that the possibility of rejection has been
  brought up..what are the different types of
  rejection? How are they treated?

106
Rejection

• Hyperacute- humoral based with preformed
  antibodies to the allograft vascular endothelium
• - Only anecdotally reported in the literature
  with lung transplant.
• Cellular immune based rejections
• Acute
• Chronic/bronchiolitis obliterans syndrome (BOS)

107
Rejection

• Standard immunosuppressive management
• Triple drug combocyclosporin, imuran,
  prednisone.
• Methylprednisolone intraop and first 24 hrs. Then
  steroids suspended for 2 weeks, based on
  experimental and clinical evidence they impede
  bronchial anastamotic healing.
• Then oral pred started.
• Some evidence tacrolimus/imuran/steroid may be a
  better combo. (acute and chronic rejection)

108
Rejection

• Acute
• Most common complication following lung
  transplantation.
• Most recipients experience at least 1 episode in
  first year.
• It is clear that there is a association between
  frequency and severity of acute rejection and
  subsequent dev of BOS.

109
Rejection

• Thus, early detection and alteration of
  immunosuppression may have a significant impact
  on subsequent reduction of BOS.
• S/S
• Fever
• Dyspnea
• Dec PaO2
• Fall in vital capacity
• Infiltrates.

110
Rejection

• After first postop month, CXR freq normal during
  episode of acute rejection.
• Obviously, infection can present similarly.
• Need to distinguish with transbronch biopsy and
  BAL.
• Tx
• Methylprednisolone 10-15mg/kg for 3-5 days.
• 2-3 weeks of oral steroid taper.

111
Rejection
Some work by Loubeyre et al, that may be able to
use HDCT to Dx acute rejection and avoid TBB (65
sens for rejection, 85 specific for acute lung
complication.
112
Rejection

• Maintenance immunosuppression regimen should also
  be scrutinized.
• First adjustment from maintenance cyclosporine is
  a switch to tacrolimus in event of cyclosporin
  toxicity or acute rejection episodes despite
  adequate cyclosporine dosage.
• Newer agents such as sirolimus, leflunomide may
  be used more in future.

113
Rejection

• Chronic/bronchiolitis obliterans syndrome(BOS)
• 70 of graft recipients are dx by 5th year.
• Usually presents as a late decline in FEV1 from a
  post-op baseline.
• Pathologic lesion is broncholitis obliterans.

114
Rejection

• Risk Factors
• Episodes of acute rejection
• Primary Graft dysfunction
• CMV pneumonia
• Noncompliance with meds

115
Rejection

• Causes not totally clear.
• Evidence suggests both alloimmune and
  non-alloimmune mech are important (for example
  GERD).
• There is evidence that fundoplication will lower
  BOS scores and even eliminate it in certain
  individuals
• Cantu et al. Ann THorac Surg 2004781142-51

116
Rejection

• Diagnosis- two approaches (definitive proof and
  diagnosis of exclusion)

117
Rejection

• Treatment (no well established protocol)
• Conversion from cyclosporin to tacrolimus may
  stabilize progression.
• ?addition of mycophenolate may be benificial.
• ?sirolimus
• ?azithromycin daily is currently being
  investigated and may show promise.
• Retransplantation?

118
CASE

• 17)Could this be infectious? Where in the
  complications timeline to infectious etiologies
  usually fit? Are there any exceptions?

119
Infection post transplant

• Unlikely in this scenario.
• But infection is one of the leading causes of
  morbidity and mortality.
• Immediate post-op bacterial are the greatest
  threat.
• But candidia or aspergillus or viral (herpies or
  CMV) can also arise.
• Lung transplant procedure and postoperateive
  management. 2008 Uptodate.com.

120
(No Transcript)
121
Bacterial

• Most common pathogen are those that colonized the
  donor or recipient.
• Gram neg such as Pseudomonas, Klebsiella and H.
  flu are most common. Gram positives (staph) are
  also a frequent cause (head injury).
• Most centers use a 7-10 day prophylaxis (eg
  vanco, cefepime) or depending on previous
  colonization.
• We use generally use ceftaz and clox till lines
  and drains are out.

122
Viral

• CMV is most commonly seen infection post-op
  complication (13-75 of transplants).
• Most risk obviously in CMV neg recipient
  receiving CMV pos donor.
• Optimal prophylaxis remains controversial.
• Most centers will supply 12 weeks of IV
  gancyclovir (5 mg/kg qd) for D/-R and CMV
  immunoglobulin.
• If just R get only gancyclovir for 12 weeks.
• If D/-R nothing.

123
Viral

• Patients in the community are also susceptible to
  other viral infections (eg. RSV, adenovirus,
  influenza, parainfluenza).
• Several of these have specific treatments so be
  aware of them (eg. Aerosolized ribavirin)

124
Fungal infections

• Major problem in the long term.
• Aspergillus and Candida account for majority.
• Both can represent colonization but also can be
  life-threatening infections.
• Aspergillus colonization and infection occur
  within first 6 months.
• Mortality for pneumonia/disseminated disease
  approaches 60.
• Critical Care Aspects of Lung Transplantation.
  Journal of Intensive Care Med 19(2) 2004

125
Fungal infections

• Several antifungal prophylactic strategies used.
• Systemic or inhaled or both.
• However, use of systemic antifungal therapies
  limited by lack of in vitro activity against some
  infections, drug interactions, significant
  treatment limiting toxicities.
• Several reports of using inhaled Ampho B lipid
  complex.may see used in future.

126
Fungal infections

• What do we do?
• Candida prophylaxis nystatin swish and swallow.
• PCP septra or aerosolized pentamidine.
• Aspergillusaerosolized ampho B.
• Toxoplasma neg px pyrimethamine for 6 months.

127
Fungal infections

• Although bronchial dehiscence is a rare
  complication due to improved surgical tech and
  lack of steroids for period of time after OR.
• B/c of inherent ischemia occurring at the
  anastomosis fungal infections my develop at this
  site.
• This can lead to life threatening airway
  complicatoins.
• Careful attention should be paid to this area on
  all bronchoscopies.

128
Fungal infections

• In one study by Nunley it was found that 46.7
  with anastamosis infections had airway
  complications where in only 8.7 of patients
  without.
• These included bronchial stenosis,
  bronchomalacia, fatal hemorrhage and dehiscence.
• Nunley et al. Chest 20021221185-1191.

129
Fungal infections

• If on bronchoscopic inspection have
  pseudomembranes should perform biopsy.
• Optimal treatment still unknown.
• Suggested expert opinion is that should use
  combination of systemic and inhaled antifungal
  agents. (eg. Ampho B)
• May need bronchoscopic debridement of the tissue.

130
Fungal infections

• Treatment of systemic infections.
• Albicans still fluconazol.
• Non-albicans caspofungin.
• Ampho B is classic drug of choice for aspergillus
  and fusarium. More utilization of Vori and caspo
  in last several years.
• Careful with Vori as has extensive interactions
  with immunosuppressants.
• Nunley et al. Chest 20021221185-1191.

131
CASE

• The oxygen delivered via ECMO was adjusted
  according to the arterial blood gas results, and
  was successfully reduced to 40 within 4 days.
  After the first 48 hours, the ECMO flow rate was
  maintained at 2.5 L/min, with 3200 RPM. Prior to
  discontinuation of ECMO, the patient was relying
  on his lung for oxygenation with no oxygen given
  through the oxygenator.

132
CASE

• Both the cannulae were successfully removed with
  application of pressure on the site and without
  any problems. The patient did very well there
  after and was discharged to the ward within 8
  days.
• While on the ward several surveillance
  bronchoscopies were performed. There were some
  pseudomembrains seen near the anastomosis and
  they were sampled. They were positive for
  candida sp. and treatment initiated with IV
  caspofungin. The site looked stable during
  repeated bronchoscopy.

133
CASE

• On day 15 you are called to the ward for
  respiratory decline. He is in respiratory
  distress and a CXR is performed.

134
(No Transcript)
135
CASE

• What is high on your differential for the cause
  of the abnormality?
• The patient requires reintubation, independent
  lung ventilation and is taken to the OR for
  repair of his bronchial dehiscence.
• Is there any evidence for the outcomes of Lung
  transplant patients who require readmission to
  the ICU?

136

• All lung transplants at Duke University Medical
  Center discharged from hosp between March 99 and
  Feb 01.
• 51/214 px (23.8) required ICU admissions.
• Of those 27/51 (57.5) required MV.
• Dx
• Resp failure (70)
• Sepsis (6.8)
• Pneumothorax, atrial fib, high-risk bronchoscopy,
  PE, antibiotic desensitization and cardiac arrest
  (2.7 each)

137

• 19/51 (37) died during their ICU admission.
• 16/27 (59) receiving MV died.
• Px who died had lower FEV1 to posttransplant best
  FEV1 ratio prior to ICU admission. (51 vs 75
  p0.001)
• Also, had higher APACHE III scores on ICU
  admission compared to survivors.

138

• Survival rates by Kaplan-Meier
• 1 year 43.1
• 2 year 40.9

139

• Conclusions
• ICU admission and mechanical ventilation, is
  associated with a poor prognosis in lung
  transplant but.
• Is appropriate for selected patients with good
  allograft function.

140
Conclusions

• More immediate ICU complications with IPAH and
  IPF.
• Beware the patient that required by-pass or that
  did poorly on single lung ventilation.
• If become shocky.act quickly and look for the
  diagnosis. (? Bleeding, STAT TEE, contact
  surgeon)
• Reperfusion injury is a diagnosis of exclusion
  and may require independent lung ventilation or
  ECMO.

141
Conclusions

• Predictors of need for independent lung
  ventilation include preoperative airflow
  limitation (FVC1/FVC) and hyperinflation.
• Mobilize ECMO early.
• If questioning diagnosis of acute rejection vs
  infection use open lung biopsy.
• Acute rejection is a marker for future BOS.we
  may be able to make a difference.
• Patients with post-op good allograft function
  should be candidates for readmission to ICU.