1. Description of the problem
Cystic Fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients.
Severe bronchiectasis
Obstructive pulmonary disease
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Viscous and tenacious secretions
Hemoptysis
Pneumothorax
Pancreatic insufficiency
Liver disease
Malnutrition
Digital clubbing
Diabetes
Pancreatitis (if pancreatic sufficient)
Bowel obstruction (distal intestinal obstruction syndrome)
Salt loss
Male infertility (absence of the vas deferens)
Airway clearance
Control of infection
Nutritional support
Diabetes control
Hydration
Relief of respiratory obstruction
CFTR modifier medications
2. Emergency Management
Airway clearance
Control of infection
Nutritional support
Diabetes control
Hydration
Clinical assessment of respiratory status with provision of adequate oxygenation
Immediate assessment for pneumothorax and hemoptysis should be made (latter is evident)
Bronchodilators (beta-agonists); use of anticholinergics not well established
Arterial blood gas assessment
Chest X-ray
Chest tube placement in cases of pneumothorax
Chemistry and CBC with differential
PT/INR, type and screen with avoidance of excitement should be sought in cases of hemoptysis
Intravenous steroids to be considered in cases where asthmatic component predominates (no fever, few crackles, prominent wheezing, impending respiratory failure); use methylprednisolone 60-125 mg (expert opinion)
Anxiolytics
Intravenous hydration with isotonic solution (normal saline commonly used); goal is to decrease viscosity of secretions (dehydration is a major finding of exacerbations)
If significant hemoptysis and bleeding site is known, position patient to keep that side dependant
Add vitamin K to medical therapy (if hemoptysis)
Consider aminocaproic or tranexamic acid in massive hemoptysis (>400cc)
In respiratory failure with hypercapnea/acidosis, consider BiPAP or intubation
Intravenous antibiotics covering the patient’s prior cultures; if unknown, cover most common bacteria including Pseudomonas aeruginosa and Staphylococcus aureus
If massive hemoptysis (> 400 cc and it does not stop), prepare for bronchial artery embolization or resection (rarely used); bronchoscopy has limited utility in such settings
Airway clearance in the form of manual chest physical therapy to mobilize and remove secretions should be initiated using manual chest physical therapy (in critically ill patients), supplemented by percussion VEST or other PEP devices
Use of mucous active agents by nebulization, including dornase-alpha (1 or 2 times daily), hypertonic saline (3-10%, up to 4 times daily) and N-acetylcysteine (no good evidence to support its use)
Nebulized antibiotics including tobramycin for inhalation, colistin or aztrenam lysinate for inhalation.
Some patients with specific mutations (most common are G551D and R117H) benefit from the oral medication ivacaftor, which improves CFTR function and as a result ameliorates most of the disease manifestations. Ivacaftor should be continued in these patients.
Another CFTR modifier for patients with the most common mutation combination (DF508 homozygotes; 40-45% of all adults with CF) is lumacaftor/ivacaftor and has the same benefits in modifying CFTR function, although not as pronounced as ivacaftor for the patients in the previous paragraph. It should also be continued.
3. Diagnosis
CF remains primarily a clinical diagnosis. The main organ systems being affected are as follows:
Sinopulmonary disease, characterized by:
1. Obstruction of the sinuses with nasal polyps;
2. Bronchiectasis;
3. Small airway disease with obstruction;
4. Chronic cough with sputum production;
5. Infection with characteristic bacteria non-typeable H. influenzae, S. aureus, Pseudomonas aeruginosa (including mucoid phenotypes), B. cepacia and non-tuberculous mycobacteria.
Gastrointestinal disease, characterized by:
1. Pancreatic insufficiency in > 90% of patients with destruction of the exocrine pancreas at birth; this leads to fat and fat-soluble vitamin malabsorption leading to malnutrition;
2. Recurrent acute pancreatitis with minimal “insults” in pancreatic sufficient patients (mainly seen in adults);
3. Meconium ileus in newborns and distal intestinal obstruction (DIOS) in adults leading to bowel obstruction.
Endocrine and other manifestations:
1. CF-related diabetes (with features of both type 1 and 2); 2. Salt loss syndrome (easier dehydration); 3. Congenital absence of the vas deferens (CBAVD) in males
Manifestations as side effects of treatment:
1. Renal stones (due to dehydration);
2. Renal failure (as a result of frequent aminoglycosides);
3. Hearing loss (as a result of frequent aminoglycosides).
Gold standard for diagnosis is sweat chloride; values over 60 are consistent with CF, values between 40 and 59 are borderline.
Genetic testing provides confirmation. There are 23 CF-causing known CFTR mutations and when two of these are found CF can be diagnosed; there are more than 2000 non-CF-causing CFTR mutations. If two of these or one of them is found with the 23 mutations, CF can only be confirmed by the sweat test and highly suggestive clinical manifestations.
These 1900+ mutations are either too rare to be 100% certain of their clinical manifestations or do not always cause severe enough alterations in CFTR to cause CF.
Isolated elevations in alkaline phosphatase can be seen in patients even without significant liver disease (up to 20% of patients).
During exacerbations, elevations in WBC, CRP and ESR are common.
Insulin resistance with high blood sugars and high insulin requirements are common during acute exacerbations; however, ketoacidosis almost never occurs.
PT and INR can be normal, but may still have vitamin K deficiency.
In patients with ABPA, high eosinophil levels and IgE can occur.
After a period of antibiotic therapy it is not uncommon to see modest elevations in eosinophilia; its clinical significance is unknown.
CXR shows bronchiectasis.
In patients with abdominal obstruction syndrome, DIOS is the most common and manifests with mild or no obstructive signs on abdominal X-ray, but large amounts of stool are seen in the right colon and terminal ileum.
In patients with pneumothorax it can be seen on CXR, although frequently it is loculated because of adhesions.
In patients with hemoptysis findings similar to exacerbation with or without alveolar infiltrates can be seen.
CT chest is useful in hemoptysis in assessing laterality and can be useful in respiratory exacerbation to assess extent of the disease.
Figure 1
Figure 1.
Figure 2
Figure 2.
A CF exacerbation is by far the most common reason for respiratory problems requiring ICU admission. The typical presenting finding sinclude subacute onset of dyspnea, increased sputum, low-grade fevers, weight loss, fatigue and generalized malaise.
Hemoptysis with > 30 cc per day is also a common presenting sign, particularly in those with advanced disease. CF exacerbations are more common in patients who have more severe baseline disease and in those who have a history of poor adherence to therapies.
Sudden onset of symptoms accompanied by chest pain suggests pneumothorax as a cause. This is also more common in patients with severe disease.
If the patient presents with abdominal pain the most likely cause will be distal intestinal obstruction syndrome (DIOS), which is a meconium ileus of the adult. The patient will have abdominal pain, which can be severe, decreased but not necessarily absent bowel movements, nausea, decreased appetite and occasionally vomiting.
The abdominal exam might even show rebound, but bowel sounds will be present. Labs will not point to a liver or pancreatic source and the white blood cell count is often mildly elevated. The abdominal x-ray will show a large amount of stool, especially in the right colon, with or without features of obstruction (not-infrequently, radiology fails to recognize this condition).
The condition occurs in pancreatic-insufficient patients, usually in the setting of changes in pancreatic enzyme supplementation, or poorly controlled diabetes or relative dehydration (for example, being out in the summer heat).
Other diagnoses that need to be entertained include pulmonary embolism, especially in debilitated patients with indwelling catheters,and in those with catheters – septic emboli. These are not as common. Cardiac causes, especially left-sided heart failure, would be highly unlikely in this population and fluid overload would be a likely cause only if there is concomitant renal failure.
Other gastrointestinal causes that can lead to ICU admission include appendicitis, cholecystitis (sometimes without obvious stones, but with significant biliary sludge) and acute pancreatitis in pancreatic-sufficient patients. In children and young adults intussusception can also occur, it can occur in setting of colon cancer which is more common in patients with CF. The first two issues are difficult to recognize and require further testing; pancreatitis is easy to identify by an elevation in pancreatic enzymes.
For patients who present with pulmonary symptoms and signs requiring ICU care need a chest x-ray and sometimes a CT chest with contrast to assess for pulmonary embolism; upper and lower extremity ultrasound can also help confirm DVT.
For patients with GI presentations an abdominal x-ray is needed and appropriate labs. If a diagnosis cannot be established, then an ultrasound of theg allbladder would help and occasionally a HIDA scan might be needed. CT abdomen or US could also help determine the diagnosis of appendicitis.
4. Specific Treatment
Pulmonary exacerbations require the following:
1. Aggressive hydration to help hydrate the secretions and make them easier to mobilize;
2. Chest physical therapy: manual or with devices (either mechanical like high-frequency oscillation vest or positive end-expiratory devices like A-capella or EZ PEP);
3. Medications for mucous clearance;
4. IV antibiotics that are directed towards the patient’s prior pathogens; usually these include Pseudomonas aeruginosa and Staphylococcus aureus.
5. Continue CFTR modifiers, ivacaftor or ivacaftor/lumacaftor if appropriate
If significant hemoptysis is present treatment should also include the following:
1. Try to keep the patient calm and avoid coughing;
2. Place affected side (if known) in dependent position;
3. DISCONTINUE airway clearance and airway clearance or nebulized medications (Pulmozyme, saline, tobramycin, etc.) except for albuterol as needed;
4. Give vitamin K orally or IV to correct occult vitamin K deficiency (can happen even if INR is normal);
5. Consider bronchial artery embolization if persistent hemoptysis; bronchoscopy may have limited value in establishing which side is bleeding.
6. Consider elective intubation, but with anesthesia help, as cough can be lethal
If patient presents with pneumothorax treatment should include the following:
1. Discontinuation of mechanical and positive end-expiratory airway clearance techniques;
2. Decompression of the pneumothorax by appropriate means (small-bore vs. large-bore chest tube; emergent decompression in cases of tension);
3. Increased laxatives in view of probable narcotic need;
4. Prepare for pleurodesis in most cases, since pneumothoraces tend to recur; for appropriate method need to consider disease severity and local surgical preference (since pleurodesis is a relative contraindication for lung transplant in most situations).
DIOS treatment requires the following:
1. Aggressive hydration;
2. Use of Miralax or other PEG solutions by mouth or NG tube or G-tube if available in sufficient amount to induce stooling (usually more than a gallon needed) if patient not vomiting;
3. Enemas with tap water, Fleet or gastrografin till bowel movements if the patient cannot tolerate fluids by mouth;
4. Surgical consultation if the obstruction is severe.
Cholecystitis requires:
1. IV hydration;
2. Antibiotics
3. Surgical, GI or IR consultation if significant, especially if obstruction is unrelieved.
Pancreatitis requires:
1. NPO or clear liquid diet;
2. Pain control;
3. Use of pancreatic enzymes (might suppress pancreas secretions).
Appendicitis requires:
1. Studies to rule it in;
2. Surgical consultation for removal.
Respiratory medications used for airway clearance (commonly used bronchodilators not listed)
1. Pulmozyme (dornase-alpha) 2.5 mg nebulized daily or twice daily (evidence against its use in non-CF bronchiectasis exists)
2. Hypertonic saline 3%, 7% or 10% 4-5 cc daily to four times daily
3. Mucomyst 20% 1 cc nebulized one to four times daily (no evidence for efficacy in CF except for anecdotal long-term experience)
Nebulized antibiotics used to treat infection
1. TOBI (tobramycin inhalation solution) 300 mg nebulized twice daily
2. Colistin 150 mg nebulized twice daily
3. Cayston (aztreonam lysine for inhalation) 75 mg nebulized three times daily (requires its own proprietary nebulizer)
IV/oral antibiotics
1. Levofloxacin 750 mg orally or IV daily
2. Ciprofloxacin 750 mg twice daily orally
3. Meropenem 2 g IV every 8 hours
4. Ceftazidime 2 g IV every 8 hours
5. Cefepime 2 g IV every 8 hours
6. Zosyn 4.5 g IV every 6 hours
7. Aztreonam 2 g IV every 8 hours
8. Tobramycin 7-10 mg/kg IV daily (aim for high dose after hydration if renal function OK)
9. Vancomycin 1-1.5 g IV twice daily
10. Linezolid 600 mg once or twice daily (IV or oral)
11. Doxycycline or minocycline 100 mg twice daily by mouth
12. Azithromycin orally or IV 500 mg three times per week or 250 mg daily
13. Bactrim DS 1-2 tablets twice daily (usually oral)
Steroids
Oral (prednisone) or IV (methylprednisolone) from 1 mg/kg one to four times per day depending on the clinical status.
Pancreatic enzymes
1. Creon
2. Zenpep
3. Pancreaze
4. Ultresa
5. Pertzye
6. Viokace
FOR ALL ENZYMES, number refers to lipase units per pill; usually patients take 1500-2000 U/kg/meal daily; beware of doses above 3000 U/kgmeal, as this can cause fibrosing colonopathy.
If patients need to be fed via nasojejunal or G-tube, pancreatic enzymes should be opened and dissolved in bicarbonate prior to administration, unless the patients can swallow them.
Diabetes
Insulin is the preferred medication; however, beware of correction sliding scale because of a high incidence of hypoglycemia due to deranged pancreatic function.
DIOS
1. Golytely 4-8 L by mouth until bowels clear
2. Miralax 1 box in 1 gallon of fluid until bowels clear (might need more)
3. Gastrografin: dissolve the equivalent of what is needed for CT study in 200-300 cc of fluid and use by mouth or rectally as needed
4. May also need Mucomyst and Fleet enemas.
What do you do if the patient fails to improve?
If a patient fails to improve within 3-5 days from a respiratory exacerbation:
1. Reculture and consider changing antibiotics to cover other pathogens like mycobacteria and fungi;
2. Switch current antibiotics, using the current antibiogram only as a guide (i.e., resistant bacteria can still respond to antibiotics).
3. Consider Bronchoscopy, especially in intubated patients, to improve secretion clearance with instillation of Pulmozyme and hypertonic saline locally.
4. Consider allergic bronchopulmonary aspergillosis as the diagnosis and treat with steroids.
For refractory hemoptysis, including after repeated bronchial artery embolization, consider surgery (lobectomy or pneumonectomy) if there is adequate pulmonary reserve.
For refractory pneumothorax with persistent air leak and no resolution of the pneumothorax, additional chest tubes and/or pleurodesis should be attempted. Pleurodesis can be attempted using a combination of mechanical and chemical means.
For refractory pancreatitis, investigate for pseudocysts or other complicating factors and consider prolonged TPN.
For DIOS consider using interventional radiology for gastrografin enemas (similar process to barium enemas), where the gastrografin can be placed close to the obstruction, avoiding the need for surgical exploration; and surgery should be a last resort.
5. Disease monitoring, follow-up and disposition
Respiratory failure due to a typical CF exacerbation will usually respond to aggressive care with improvement in hypercapnea, decrease in sputum production and thickness, and coughing intensity. The best determinant of success is pre-respiratory failure lung function.
Respiratory failure due to pneumothorax usually has a good prognosis; however, in advanced disease, the prognosis is worse.
Hemoptysis usually has a good prognosis, once the problem is resolved; however, in severe disease the hemoptysis might be recurrent and sometimes lethal.
DIOS has a good prognosis, but recurrence is common.
Pancreatitis has a good prognosis, but it can recur. Note, patients can become pancreatic insufficient after recurrent episodes.
Once the respiratory failure is resolved, patients will no longer typically require ICU level care. If unable to be discharged to home, transfer to a lower-level inpatient unit or a rehabilitation facility. Follow-up should occur in a CF clinic. The same is true for most cases of respiratory failure due to pneumothorax or hemoptysis. When appropriate, in severe disease without any obvious contraindications to lung transplant, a referral to the transplant center should also be considered.
Pathophysiology
CF is caused by dysfunction of a protein named CFTR (cystic fibrosis transmembrane conductance regulator), which is a large chloride channel. The disease is inherited in autosomal recessive fashion and there are multiple genetic defects that can lead to CFTR dysfunction to differing degrees. Inadequate transport of chloride leads to viscous secretions in every exocrine gland in the body, including lungs, gastrointestinal tract, pancreas, liver, sinuses and the vas deferens.
Thick secretions lead to dysfunction of many organs; in the majority ofpatients the exocrine pancreas is fibrosed and destroyed at birth. Inapproximately 10% of patients the exocrine pancreas functions, but theyare prone to recurrent bouts of pancreatitis.
Epidemiology
Cystic fibrosis is the most common life-limiting genetic disease in the Caucasian population
It is an autosomal recessive disease, so the CFTR (cystic fibrosis transmembrane regulator) gene must have mutations on the copies of both parents for the disease to be evident
The gene is present in 1/30 persons of European descent; it is present but less common in African Americans and Hispanics, but even less common in Asian Americans.
There are approximately 30,000 patients in the United States; the vast majority are diagnosed in early childhood (now they are mainly diagnosed via newborn screening), but a small percentage with milder symptoms can be diagnosed as adults, including geriatric age.
Over 90% of the patients are Caucasian.
The disease can have very different degrees of severity across the patient population.
Certain genotypes predispose to more severe disease, but other not-yet-identified genetic modifiers, environmental factors and adherence can play a significant role in the disease phenotype (lung disease, pancreatic sufficiency vs. insufficiency, presence of diabetes, liver disease).
Patients are frequently infected with Pseudomonas (mucoid and non-mucoid phenotype) and with Staphylococcus aureus (MSSA and less frequently MRSA), Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, non-tuberculous mycobacteria (mainly MAC and M. abscessus) are increasing in prevalence, but are less common.
Diabetes is present in 35% of patients over the age of 30.
Liver disease is rare and only present in approximately 5% of severe cases.
Other problems include osteoporosis, severe sinus disease with nasal polyps and recurrent episodes of acute pancreatitis in pancreatic-sufficient patients.
Most patients have pancreatic insufficiency at birth and their exocrine pancreas is destroyed, requiring oral enzymes to digest food.
In children, thick mucus can lead to meconium ileus at birth.
In adults, especially in cases of dehydration, thick inspissated secretions can lead to distal intestinal obstruction syndrome (DIOS), which is characterized by significant amounts of stool in the terminal ileum and requires special attention to avoid surgery. Hydration, PEG solutions (Miralax or Golytely are examples) and use of enemas can help avoid surgery.
Prognosis
Patients with CF admitted with respiratory failure have a poor to fair prognosis; this is influenced by their level of lung function prior to respiratory failure; however, prognosis improves as lung function improves.
The prognosis for patients admitted with a pneumothorax and hemoptysis depends primarily on the severity of the underlying lung function prior to admission.
Presence of diabetes can complicate the prognosis.
Malnutrition and other organ dysfunction can also influence the prognosis.
The expected median survival of all current patients in the US Registry is 40.7 years.
The mean age of patients who die is 27.5 years.
Special considerations for nursing and allied health professionals.
Respiratory therapy plays an integral role in providing nebulized medications and airway clearance in a timely fashion.
Nursing needs to coordinate medication, pancreatic enzymes (when needed), pain control and nebulizer administration.
Physicians, Nurses and social work should ensure that the patient’s wishes about end-of-life care are honored.
What's the evidence?
Flume, PA, Mogayzel, PJ, Robinson, KA. “Cystic Fibrosis Pulmonary Guidelines: Pulmonary Complications: Hemoptysis and Pneumothorax”. Am J Respir Crit Care Med. vol. 182. 2010. pp. 298-306.
Flume, PA, Mogayzel, PJ, Robinson, KA. ” Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations”. Am J Respir Crit Care Med. vol. 180. 2009. pp. 802-808.
Flume, PA, Robinson, KA, O’Sullivan, BP . ” Cystic Fibrosis Pulmonary Guidelines: Airway Clearance Therapies”. Respir Care. vol. 54. 2009. pp. 522-537.
Yankaskas, JR, Marshall, BC, Sufian, B . “Cystic Fibrosis Adult Care: Consensus Conference Report”. Chest. vol. 125. 2004;. pp. 1S-39S.
Kremer, TM, Zwerdling, RG, Michelson, PH . ” Intensive Care Management of the Patient with Cystic Fibrosis”. J Intens Care Med. vol. 23. 2008. pp. 159-177.
Farrell, PM, Rosenstein, BJ, White, TB . ” Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report”. J Pediatr. vol. 153. 2008. pp. 4S-14S.
“Patient Registry Report: Annual Data Report 2013”. 2014.
Wainright, CE, Elborn, JS, Ramsie, BW . ” Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR”. N Engl J Med. vol. 373. 2015. pp. 220-231.
Mogayzel, PJ, Naureckas, ET, Robinson, KA . ” Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for Maintenance of Lung health”. Am J Respir Crit Care Med. vol. 187. 2013. pp. 680-689.
Maisonneuve, P, Marshall, BC, Knapp, EA . ” Cancer Risk in Cystic Fibrosis: a 20-year Nationwide Study from the United States”. J Natl Cancer Inst. vol. 105. 2013. pp. 122-129.
Ramsey, BW, Davis, J, McElvaney, NG . ” A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation”. N Engl J Med. vol. 365. 2011. pp. 1663-72.
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