““Woe to the child who tastes salty from a kiss on the brow, for Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die”.he is cursed and soon must die”.

Cystic FibrosisCystic Fibrosis

Overview Definition.

Epidemiology.

Pathophysiology.

Diagnosis and clinical manifestations.

Treatment and outcome.

Anaesthetic implications.

Lung transplant.

Cystic fibrosis

Inherited disease that primarily affects the lungs and digestive tract of about 1200 children and adults in Ireland

Cystic Fibrosis in Ireland

Most common life threatening genetically inherited disease.

Highest proportion of CF population in world.

Carriers of CF gene 1 in 19.

About 50 new cases diagnosed each year.

About 55% of CF patient population aged 18 or older.

Median age of survival 20’S.In 2011 28 patients died aged between 13 and 54 yrs with average age at death of 23.5 yrs.

Demographic data from CFRI 2011.

Year 2011 %

Age range* <1-61

Mean age (yrs)* 19.6

Median age (yrs)* 18.8

Number diagnosed during year 22

Number of males* 612 57.0%

Number of females* 461 43.0%

Number <18 yrs* 514 47.9%

Number ≥18 yrs* 559 52.1%

Number males ≥18 yrs¥ 324 52.9%

Number females ≥18yrs¥ 235 51.0%

Irish ethnicity* 1049 97.8%

Deaths during year ∞ 28

CFRI enrolees alive at the end of 2011 1073

Pathophysiology -Cystic fibrosis

Genetics: Mutations in gene on long arm of chromosome 7 encoding for cystic fibrosis trans-membrane conductance regulator (CFTR) gene which encodes an epithelial chloride channel .

Cystic fibrosis gene mutations

•Commonest mutation – Delta F508

UK and Ireland Caucasians - 75%

UK and Ireland Asians - 29%

•Common mutation found in 1 in 10 UK Asians - Y569D (substitution G - T)

•Delta F508 and 28 others account for 85% mutations in the Northern European Caucasian population

Cystic fibrosis•Gland secretions thicker or more viscous than normal

•Small bowel: obstruction (meconium ileus in the newborn)

•Lungs : thick bronchial mucous, recurrent chest infections, progressive lung damage, heart/lung transplantation

Respiratory Viscid mucous secretion.

Decreased mucous clearance.

Bacterial trapping, proliferation and inflamation.

Chronic colonization of airway with microbes.

Bronchiectasis, cor pulmonale, death.

Cystic fibrosis

Microbiology Nearly half of all patients with CF are infected

with harmful bacteria such as S.aureus and/or P.aerginosa in their lungs.

Prevalance of A.fumigatus,S.maltophilia and MRSA have increased in last few years.

Microbiology S. aureus and H. influenza is more pravelent

in children with CF whereas P. aeruginosa, B. cepacia complex and A. fumigatus is more prevalent in adults with CF.

Antibiotics in trouble!

Gastrointestinal manifestations.

Obstructed pancreatic duct, decreased enzyme secretion, malabsorbtion of vitamin A, D, E, K, elevated fecal fat excretion and steatorrhoea.

CF related DM.

Focal biliary cirrhosis progressing to portal hypertension and multinodular biliary cirrhosis.

Bowel obstruction.

Other clinical manifestations

Nasal pathology

Skin.

Osteoporosis.

Infertility.

DiagnosisHistory and physical examination Clinical manifestations. History of cystic fibrosis in immediate family. Positive newborn screening test.Plus Sweat chloride levels Concentration >60 mEq/l. Genetic testing Documentation of dual CFTR mutation.

Median age at diagnosis in months by

symptom category, 2011.

Treatment Aims Minimize pulmonary infections.

Optimize nutritional status.

Slow disease progress.

Ease symptoms.

Respiratory

Physiotherapy. Inhaled bronchodilators,

hypertonic saline and mucolytics ( DNA ase).

Anti-inflamatory drugs. Oxygen therapy. Antibiotics.

Nutrition Requirements may be difficult to meet as

Increased requirement.

Pancreatic Insufficiency.

Lung disease.

CF Related DM.

Gastrointestinal treatment

Modified Diet

Vitamin supplements

High calorie diet

High Protein diet

Gene Therapy Gene therapy is the use of

normal DNA to "correct" for the damaged genes that cause disease.

In the case of CF, gene therapy involves inhaling a spray that delivers normal DNA to the lungs.

The goal is to replace the defective CF gene in the lungs to cure CF or slow the progression of the disease.

Treatment

•Gene replacement.

•Lung transplant for advanced disease..

•Treating the symptoms does not cure the disease, it can greatly improve the quality of life for most patients and has, over the years, increased the average life span of CF patients to 40 years.

Total number of deaths and median age at

death of PWCF, 1995-2011.

Principal cause of death 2002-2011.

Anesthetic implications

Major or minor surgery.

Site of surgery.

Duration of surgery.

Emergency or elective procedure.

Not suitable for day case surgery usually.

Preoperative assessment

Goal-Optimize patient as much as possible.

History, examination.

Continue regular medications, physiotherapy, nebulized drugs as late as possible pre-op.

Chest radiograph, baseline ABG, bedside spirometry (FEV1),Echocardiography.

Multidisciplionary approach.

Conduct of anaesthesia

Monitoring. Routine plus aterial line, CVC and cardiac output monitoring depending on patient and type of surgery.

Regional or General anaesthesia.

Airway management LMA or oral ETT. Humidified gases and low airway pressures.

TIVA or Volatile anaesthesia.

Limited use of NMB.

Intraoperative physiotherapy.

Post operative managment

Goal –minimize development of postoperative respiratory tract infection.

Good reversal of NMB,s.

Early extubation.

Early NIV.

Chest physiotherapy.

HDU monitoring or ICU ventillation.

Lung transplant in cystic fibrosis

The course of CF is very unpredictable, and that makes the timing for transplant more difficult

About 1600 CF recipients since 1991

120-150 recipients each year

Third largest group to get transplanted

CF recipients do better in general than non-CF recipients

Lung transplant and CF in Ireland

1991-2011-total number of lung transplants on Irish patients 134.(102 in UK and 32 in Ireland)

Total lung transplants-Cystic fibrosis 52%, Emphysema 15% and Idiopathic pulmonary fibrosis 15%.

Matter Lung transplants- 44% IPF, Emphysema 31% and 16% cystic fibrosis.

Transplantation Window of Opportunity—in an

Ideal World

Time

Clin

ical cou

rse

TOO SOON TOO LATE

Marshall SE, et al. Chest.

“Transplant window”

Transplantation Window

of Opportunity—in Reality

Time

Clin

ical cou

rse

TOO SOON? TOO LATE?

“Transplant window??”

Difficult Questions to Ask Before Organ Transplantation

When should a patient be referred for evaluation?

When should a patient be placed on the waiting list?

When should a patient have a transplant?

Referral for Lung Transplant

Patient readiness

Transplant team readiness and comfort level

Local transplant center culture

Wait times (less important now because of LAS)

Lung Allocation Score New scoring system since May 2005

“How bad you need it + How well you’ll do with it”

Applies to transplant candidates > 12 yrs

Scores range from 0-100

Scores can be updated

Lung Allocation Score: Clinical Information

Diagnosis

Age

Height and Weight (BMI)

Diabetes

Use of supplemental oxygen

Six minute walk distance

PASP

PCWP

FVC

Serum Creatinine

Functional Status

Assisted Ventilation

Consensus Guidelines for Referral of Lung Transplant Candidates

with CF FEV1 ≤30% of predicted with rapid, progressive respiratory deterioration Increasing number of hospitalizations Massive hemoptysis Recurrent pneumothorax Increasing cachexia Rapid fall in FEV1

Hypoxemia: PaO2 <7.3 kPa

Hypercapnia: PaCO2 >6.7 kPa

Early referral is recommended for young female patients, who have particularly poor prognosis

American Thoracic Society. Am J Respir Crit Care Med. 1998.Boehler A. Swiss Med Wkly. 2003.

Lung Transplantation in Adult CF Patients with History of Acute

Respiratory Failure

n = 17 (40%) Received lung transplants

n = 14 (82%) Alive at 1 year postoperation

N = 42 Admitted to ICU with hypercapnic respiratory failure

n = 19 (45%) Died in ICU

n = 3 (7%) Died within 6 months of ICU discharge

n = 3 (7%) Alive at 1 year without lung transplant

Sood N, et al. Am J Respir Crit Care Med.

Absolute Contraindications to Lung Transplantation

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997.American Thoracic Society. Am J Respir Crit Care Med. 1998.

LungTransplant

Other major organ dysfunction

Infections affectinglong-term survival

Cardiovascular diseaseHIV

Liver disease: hepatitis CHepatitis B or C

Tuberculosis

Active malignancy <5 years

Renal failure: ClCr <50 mL/min

Other organ damage

Relative Contraindications to Lung Transplantation

Symptomatic osteoporosis

Substance addiction

Psychosocial problems

Nutritional status (<70% or >130% IBW)

High-dose corticosteroid use

Kyphoscoliosis

Invasive ventilation

Fungi or atypical mycobacteria

Pan-resistant organisms

American Thoracic Society. Am J Respir Crit Care Med. 1998.

LungTransplant

CF-relatedarthropathy

Survival of Transplant Recipients by Procedure Type

Trulock EP, et al. J Heart Lung Transplant. 2004.

0

20

40

60

80

100

Su

rviv

al (%

)

0 2 4 6 8 10 12 14 16 18 20

Years

Bilateral lung (N = 6686)

Single lung (N = 8581)

All lungs (N = 15,267)

Potential Surgical Complications of Lung

TransplantationComplication Prevalence (%)

Most serious

•Primary graft failure due to ischemia-reperfusion injury/diffuse alveolar damage

15-35

•Anastomotic complications: vascular or airway

7

Most common

•Phrenic/vocal cord paresis 3-30

•Gastroparesis 25-30

Zuckerman JB, et al. Clin Chest Med.Trulock EP. Am J Respir Crit Care Med.

Akindipe OA, et al. Chest.

Potential Medical Complications Following Lung Transplantation

Obliterative bronchiolitis (BOS/chronic rejection)

Acute rejection

Infection: viral, bacterial, fungal, protozoal

Toxicity of immunosuppressives Nephrotoxicity Hypertension Hirsutism, gingival hyperplasia

Diabetes

Hyperlipidemia

Post-transplant lymphoproliferative disease (EBV)

Zuckerman JB, et al. Clin Chest Med.Kurland G, et al. Curr Opin Pediatr.

Causes of Death in Lung Transplant Recipients

Trulock EP, et al. J Heart Lung Transplant. 2004.

0

10

20

30

40

50

60

70

80

90

0-30 days 31 days-1 year >1-3 years >3-5 years >5 years

Time after transplantation

Perc

en

t of

death

s

Technical complication Graft failure Cardiovascular diseaseInfection – Non-CMV Chronic rejection Malignancy – Non-lymphoma

Early complications Late complications

PROGNOSIS HAS IMPROVED,

BUT LIFE IS STILL SHORTER.