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Palliative Medicine Doctors’ Meeting____________________________HKSPM Newsletter 2007 Dec Issue 3 p 16 Management of Excessive Respiratory Secretions: A Sharing of Two Patients’ Stories Dr Lam Wai Man, Haven of Hope Hospital. Correspondence: [email protected] Case histories contributed by Dr Ng Sheung Ching and Dr Ma Chi Ming The Story of Madam C Madam C, a 72-year old retired farmer, had been suffering from right biliary papillomatosis since 2003 with extended right hepatectomy performed. Extensive liver metastases were noted since 2006 and metastatic adenocarcinoma to left lung was detected in 2003. She refused chemotherapy and accepted palliative care. She complained of cough with profuse whitish mucoid sputum which had increased to over 300 ml per day. Oral hyoscine methobromide had been tried with initial improvement. However, the disease progressed and the sputum volume increased to around one liter per day causing dyspnea even at rest. A clinical diagnosis of bronchorrhea was made. Various medications including oral erythromycin 500 mg twice daily and oral indomethacin 50 mg twice daily were tried with no improvement in bronchorrhea but were complicated by nausea with erythromycin and impaired renal function with indomethacin. Continuous subcutaneous infusion of hyoscine hydrobromide up to 1.6 mg per day was given with no improvement in sputum volume but resulted in excessive drowsiness. Continuous subcutaneous infusion of fentanyl and midazolam was needed to control her dyspnea and restlessness. Subsequently, continuous subcutaneous infusion of octreotide was given at a dose of 200-300 micrograms per day. There was significant improvement in the volume of respiratory secretions, dyspnea, and restlessness. Subcutaneous hyoscine and midazolam infusions were stopped due to improvement in symptoms. Her alertness also improved. She subsequently died 10 days after commencement of octreotide infusion. The Story of Madam S Madam Sin, aged 48, was previously a trainer in a cosmetic and fitness center. She had a second marriage. She was diagnosed to have polymyositis in 1997 presenting with weakness. Multiple immunosuppressive therapies had been tried including glucocorticoids, azathioprine, cyclophosphamide, cyclosporin, intravenous immunoglobulins, mycophenolate mofetil, and rituximab, but her disease progressed. She had an episode of severe pneumonia requiring intubation and subsequent tracheostomy. She was then transferred to the rehabilitation ward for convalescence. Upon admission, she was totally dependent in her daily living, and she needed non-oral feeding due to dysphagia. She was just able to move her eyes and fingers. Her main physical symptoms were excessive saliva and sputum affecting her speech and eating, sense of suffocation due to secretions, pain and numbness over pressure points, and pain in multiple joints. Concerning her psychological state, she had a strong sense of helplessness due to repeated treatment failures and loss of independence, fear of dying from suffocation, sense of loneliness due to infrequent visits from her family, and anger and frustration about her physical needs not being promptly addressed by staff. She frequently called for help with dramatic gestures and repeated call bells ringing. The multidisciplinary team attempted to address her multiple needs. The physiotherapist performed vigorous chest physiotherapy and hand function enhancement exercises; the occupational therapist designed a special chair and a foot platform to facilitate her sitting out; the speech therapist provided speech training; the clinical psychologist enhanced her self expression by drawing; the chaplain and some volunteers provided religious, spiritual and social support; and the social worker assisted her in hiring a maid to take care of her in the Palliative Medicine Doctors’ Meeting____________________________HKSPM Newsletter 2007 Dec Issue 3 p 17 and the nurses educated her on performing self suction of saliva. The doctor tried many medications to manage her saliva secretions including oral promethazine, oral amitriptyline, and inhaled ipratropium, but they were not effective. The management of bronchorrhea includes general supportive measures to promote comfort, maintenance of fluid and electrolyte balance, and measures to reduce bronchial secretion production. The following seven entities have been tried in reducing bronchial secretions: Local injection of Botulinum toxin (Botox) 15 Units into each submandibular gland, was performed under ultrasound guidance. It was effective in reducing the volume of saliva secretions by about 70% at one week after injection. The tracheostomy was successfully weaned off. She became less anxious, more talkative and expressive. She survived for six more months after Botox injection with no recurrence of excessive salivation, and she died of acute myocardial infarction and hospital acquired pneumonia. 1. 2. 3. 4. 5. 6. 7. The Management of Bronchorrhea Bronchorrhea is arbitrarily defined as watery sputum production of over 100 ml per day.1 Up to 9 Liters per day has been reported.2 It can be caused by primary lung malignancy especially of bronchioloalveolar cell type and metastases to lung especially from cells of glandular origin (e.g. adenocarcinoma of cervix, colonic adenocarcinoma, and pancreatic cancer). 3, 4, 5 It can also be caused by non-malignant conditions like chronic bronchitis, asthma, and endobronchial tuberculosis. There are three postulated pathophysiological mechanisms for bronchorrhea: 1. Hyper-secretion of mucus-glycoprotein and other glandular products from mucusglycoprotein producing cells – neutrophils accumulating in airway mucosa may stimulate goblet cells secretion. 2. Increased transepithelial chloride secretionthis can be mediated by receptors for prostaglandins (PGE2, PEF2α) or secretin in the bronchial epithelium. 3. Excessive transudation of plasma products into the airway. 6 Bronchorrhea has negative impact on both survival and quality of life. It can cause excessive cough, sleep disturbance and dyspnea. When severe, it may lead to respiratory failure, dehydration and electrolyte disturbance. Radiotherapy and traditional chemotherapy Anticholinergic agents Macrolides Pulsed methylprednisolone Inhaled indomethacin Gefitinib (EGFR-TKI) Octreotide The responses of bronchorrhea to radiotherapy, traditional chemotherapy, and anticholinergic drugs are variable. Macrolides act by affecting neutrophil migration and activities in the lung and inhibiting the synthesis and secretion of a mucus secretogogue from pulmonary macrophages.7 There were case reports of using oral clarithromycin combined with inhaled beclomethasone in managing bronchorrhea in alveolar cell carcinoma,8 pulsed methylprednisolone in a patient with bronchioloalveolar carcinoma (BAC),9 and inhaled indomethacin in patients with chronic airway diseases like chronic bronchitis, diffuse panbronchiolitis and bronchiectasis, presumably by reducing the levels of prostaglandins and its metabolites in sputum.10. Nebulised indomethacin was successful in two patients with BAC suffering from bronchorrhea in reducing the sputum volume, improving the quality of life, and possibly prolonging the survival. 11 Two more recent weapons in treating bronchorrhea are Gefitinib and Octreotide. Gefitinib, an Epidermal Growth Factor Tyrosine Kinase Inhibitor, is thought to reduce bronchorrhea by inhibiting the expression of a major mucin in BAC cells, the MUC5AC mucin, based on findings from animal study and laboratory setting. 12, 13 There were case reports of its successful reduction of sputum volume in BAC patients.14, 15 As the onset of improvement occurred within 24 hours of use, it is likely that its inhibitory action on mucin production is independent of its anti-proliferative effect. Octreotide, a somatostatin analogue, has been reported to significantly reduce the volume of secretions in a lady with the acinar type of Palliative Medicine Doctors’ Meeting____________________________HKSPM Newsletter 2007 Dec Issue 3 p 18 adenocarcinoma of lung at a dose 300-500 micrograms daily.16 It is postulated to have an inhibitory action on the secretin receptors in the bronchial tree. The patient we presented above further substantiates its potential role in bronchorrhea. Surgical techniques are limited by its irreversibility and patients’ fitness for surgery. Anticholinergic drugs and antidepressants are limited by their side effects. Radiation to salivary glands may be complicated by development of head and neck malignancies in the long run. The Management of Sialorrhea There are case reports of the usefulness of local botulinum toxin injection into salivary glands in patients with head and neck cancer, neurodegenerative disorders, and stroke with no reported side effects. 18, 19 Randomized controlled studies have also proven its efficacy. (Table 2)20 Normal adults produce 750 to 1500 ml of saliva per day. Unlike bronchorrhea which is usually the result of excessive secretion, sialorrhea is usually due to oropharyngeal dysphagia and impaired cough effort caused by various neurological diseases, or esophageal dysphagia caused by mechanical obstruction or esophageal dysmotility. Sialorrhea may affect feeding, interfere with speech, lead to social embarrassment, induce sense of suffocation with resultant fear, and increase susceptibility to aspiration pneumonia. The clinical aspects of botulinum toxin injection have also been reviewed.20 It can be injected into parotid glands, submandibular glands, or both. The injections can be guided by anatomical landmarks or ultrasound localization of the salivary glands. Use of ultrasound leads to a higher success rate and fewer side effects, and the dose used can be lower. However, it requires The management of excessive oropharyngeal certain expertise. The dosages reported varied secretions comprises of physical modalities, from 5-75 U into each parotid gland and 5-30 U medications, irradiation to salivary glands and into each submandibular gland. Usually one to various surgical maneuvers.17 (Table 1) 1.5 milliliters of drugs is injected into each gland, and the effect is achieved by diffusion. The 17 onset of reduced saliva production can be Table 1: Management of excessive oropharyngeal secretions rapid within 1-2 weeks, and the effect can Physical Manual suction last from a few weeks to several months. modalities Various respiratory physical therapy techniques: The potential side effects are dry mouth, Postural drainage / Percussion and vibration / dysphagia, jaw weakness and jaw Incentive spirometry / Glossopharyngeal breathing / dislocation. Caution must be exercised in frog breathing / Active cycle of breathing / Forced expiratory maneuvers / Cough assist patients with neuromuscular and muscular disease. Its potential indications in Medications Anticholinergic dugs palliative care lie in the management of Tricyclic antidepressants Botulinum toxin saliva aspiration and drooling in patients with neurological disorders affecting Radiation To salivary glands swallowing, surgery involving upper Surgery On salivary glands aerodigestive tract, laryngeal and upper On neural innervation of saliva production Table 2: Randomized studies on the use of botulinum toxin in sialorrhea 20 Researcher Patient group N Type of study Outcome Mancini 2003 20 Lipp22 2003 Parkinson’s disease Multiple system atrophy Sialorrhea Double blind placebo controlled Dose finding study Ondo23 2004 Parkinson’s disease 16 Jongerius 24 2004 Cerebral palsy 45 Improvement shown at 1 week and 3 months Effect achieved with 75 U into each parotid gland Improved VAS, drooling score and global score Similar effects; fewer side effects Lagalla 25 2006 Parkinison’s disease 32 21 32 Double blind placebo controlled Compared with transdermal scopolamine Double blind placebo controlled Less frequent drooling; less saliva production & improved family and social functioning Palliative Medicine Doctors’ Meeting____________________________HKSPM Newsletter 2007 Dec Issue 3 p 19 aerodigestive tract tumors, as well as patients with saliva fistula after parotid gland surgery, laryngectomy or pharyngectomy. Conclusion We have reported the usefulness of subcutaneous octreotide infusion and local botulinum toxin injection into submandibular glands in the management of bronchorrhea and sialorrhea respectively, and in both patients, a better symptom control and better quality of life had been achieved. Though these two medications are expensive, its use in selected cases should be carefully considered. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Shimura S, Sasaki T, Sasaki H et al. Viscoelastic properties of bronchorrhea sputum in bronchial asthmatics. Biorheology 1988;25:173-179. Hidaka N, Nagao K. Bronchioloalveolar carcinoma accompanied by severe bronchorrhea. Chest 1996;110: 281-282. Epaulard O, Moro D, Langin T et al. Bronchorrhea revealing cervix adenocarcinoma metastatic to the lung. Lung Cancer 2001; 31:331-334. Shimura S, Takishima T. Bronchorrhea from diffuse lymphangitic metastasis of colon carcinoma to the lung. Chest 1994;105: 308-310. Lembo T, Donnelly TJ. A case of pancreatic carcinoma causing massive bronchial fluid production and electrolyte abnormalities. Chest 1995; 108: 1161-1163. Lundgren JD, Shelhamer JH. Pathogenesis of airway mucus hypersecretion. J Allergy Clin Immunol 1990; 85:399-417. Marom ZM, Goswami SK. Respiratory mucus hypersecretion (bronchorrhea): a case discussion – possible mechanism(s) and treatment. J Allergy Clinic Immunol 1991: 87:1050-1055. Hiratsuka T, Mukae H, Ihiboshi H et al. Severe bronchorrhea accompanying alveolar cell carcinoma: treatment with clarithromycin and inhaled beclomethasone. Nihon Kokyuki Gakkai Zasshi 1998;36(5): 482-487. Nakajima T, Terashima T et al. Treatment of bronchorrhea by corticosteroids in a case of bronchioloalveolar carcinoma producing CA 19-9. Internal Medicine 2002;41(3): 225-228. Tamaoki J, Chiyotani A, Kobayashi K. Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis. Amer Review of Resp Disease 1992;145(3); 548-552. Homma S, Kaukabata M, Kishi K et al. Successful treatment of refractory bronchorrhea by inhaled indomethacin in two atients with bronchioloalveolar carcinoma. Chest 1998;115: 1465-1468. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Takeyama K, Dabbagah K, Lee HM et al. Epidermal growth factor system regulates mucin production in airway. Proc Natl Acad Sci USA 1999; 96: 3081-3086 Kitazaki T, Soda H, Doi S et al. Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells. Lung Cancer 2005; 50: 19-24. Milton DT, Kris MG, Gomez JE et al. Prompt control of bronchorrhea in patients with bronchioloalveolar carcinoma treated with gefitinib (Iressa). Support Care Cancer 2005;13:70-72. Kitazaki T, Fukuda M, Soda H et al. Novel effects of gefitinib on mucin production in bronchioloalveolar carcinoma: two case reports. Lung Cancer 2005;49:125-128. Hudson E, Attanoos RL, Byrne A. Successful treatment of bronchorrhea with octreotide in a patient with adenocarcinoma of the lung. J Pain Sympt Manage 2006; 32(3): 200-202. Elman LB, Dubin RM, Kelley M et al. Management of oropharyngeal and tracheobronchial secretions in patients with neurologic diseases. J Pall Medicine 2005; 8(6):1150-1159. Ellies M, Laskawi R et al. Botulinum toxin to reduce saliva flow: selected indications for ultrasound-guided toxin application into salivary glands. The Laryngoscope 2002;112:82-86. Manrique D. Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis. Rev Bras Otorrinolaringo 2005; 71(5):566-569. Tan EK. Botulinum toxin treatment of sialorrhea: comparing different therapeutic preparations. Eur J Neurology 2006;13 (Suppl. 1):60-64. Mancini F, Zangaglia R et al. Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in Parkinsonism. Movement Disorder 2006;18:685-688. Lipp A, Trottenberg T et al. A randomized trial of botulinum toxin A for treatment of drooling. Neurology 2003;61: 1279-1281. Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in parkinson’s disease. Neurology 2004; 62: 37-40. Jongerius PH, van den Hoogen FJ et al. Effect of botulinum toxin in the treatment of drooling: a controlled trial. Pediatrics 2004:114:620-627. Lagalla G, Millevolte M, Capecci M et al. Botulinum toxin type A for drooling in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Movement Disorder 2006; 21: 704-707.