Nauseated and Breathless: Nobody’s Preferred Way to Die Annie Massart, MD [email protected] Twitter: @Annie_Massart_ Disclosures • None Objectives • Describe the prevalence of dyspnea in advanced COPD and lung cancer • Identify therapeutic options for managing dyspnea • Name the mechanisms of action for common antiemetics • Tailor antiemetic regimens to nausea triggers Case 1 • 37.6, HR 95, BP 130/80, RR 20, O2 sat 94% on RA. • Normal work of breathing, decreased air movement throughout, no wheezes. While speaking, some pursed lip breathing and has to pause intermittently to breathe. • Normal bowel sounds, LLQ TTP, no rebound/guarding • CT abdomen: uncomplicated diverticulitis • CXR: stable emphysema, no infiltrate Case 1 How would you address his breathing concerns? A. Start supplemental oxygen and monitor response B. Treat for COPD exacerbation with steroids and nebulized bronchodilators C. Start him on Morphine Extended Release 30 mg po q12h and monitor response D. Provide him with a hand-held fan and monitor response E. Remind him he’s here for diverticulitis and you’ll refer him to pulmonary clinic Kamal, A.H., et al. J Palliat Med. 2011 Oct;14(10):1167-72 Dyspnea • 50-80% of patients with advanced cancer • 90-95% of patients with advanced COPD • Dyspnea and distress both higher in COPD than lung cancer Dyspnea • Decreased activity level • Deconditioned patients become dyspneic more easily • Increased dependence on their caregivers • Decreased quality of life Assessing Dyspnea O’Donnell, D.E., et al. Can Respir J. 2007 Sep;14 Suppl B:5B-32B. Management Options • Disease optimization • Oxygen • Non-pharmacologic therapies • Pharmacologic therapies Disease Optimization Tailored to patient • Endobronchial lesion→ Bronch with tumor destruction vs stent • Lesion compressing airway → XRT • Emphysema with large bullae → Surgery • Malignant effusion → Thoracentesis Case courtesy of Dr Mohammad Osama Yonso, Radiopaedia.org, rID: 25128 Oxygen Oxygen Helps Hypoxemic Patients Continuous oxygen Nocturnal oxygen Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med.1980 Sep;93(3). Oxygen for Dyspnea Abernathy, A.P., et al. Lancet. 2010 Sep 4;376(9743):784-93. Too Much is Harmful Chu, D.K., et al. Lancet. 2018 Apr 28;391(10131):1693-1705. Non-pharmacologic Therapies Kako, J., et al. J Pain Symptom Manage 2018 Oct;56(4):493-500. Favors usual care Favors pulm rehab Pharmacologic Therapies Dyspnea Improves with Opioids A-L Jennings et al. Thorax 2002;57:939-944 Opioid-Naive Opioid-Tolerant Mild Dyspnea Severe Dyspnea Morphine 5 mg po q4h Increase baseline Hydrocodone 5 opioid dose 25-50% mg q4h Oxycodone 5 mg po q4h Hydromorphone 1 mg po q4h Titrate 50-100% every 24 hours as needed *In severe lung disease, start at 50% of above, titrate <25% per 24 hours Thomas, J., von Guten. C.. Lancet Oncol. 2002 Apr;3(4):223-8. Benzodiazepines • Not 1st line therapy • 2nd line if opioids alone insufficient • Don’t relieve dyspnea, but anxiety associated with dyspnea Dyspnea Summary • Dyspnea is highly prevalent in COPD and advanced cancer patients • Impacts QOL and functional status • First line management is nonpharmacologic • Opioids are an option for those with persistent dyspnea • Supplemental oxygen only benefits hypoxemic patients The Emetogenic Pathway Harris, D.G. British Medical Bulletin, Volume 96, Issue 1, 30 September 2010, Pages 175–185 Receptor site affinities of commonly used antiemetics Glare, P., et al. Treating nausea and vomiting in palliative care: a review. Clinical interventions in aging. , 2011, Vol.6, p.243-259 Nausea and Vomiting • 1. Investigate! Nausea and Vomiting Relevant history: • Colicky abdominal pain, nausea better after voluminous emesis→ obstruction • Bloating, nausea improves with small volume emesis → gastric stasis • Vertigo, worsening of nausea with movement → Vestibular problem • Morning nausea and headaches → Increased ICP • Associated with anxiety → Cortex • New medications, opioids, polypharmacy → med activation of CTZ • Radiation treatment? Nausea and Vomiting • 1. Investigate! • 2. Choose antiemetic based on involved pathway Receptor site affinities of commonly used antiemetics Glare, P., et al. Treating nausea and vomiting in palliative care: a review. Clinical interventions in aging. , 2011, Vol.6, p.243-259 Nausea and Vomiting • 1. Investigate! • 2. Choose antiemetic based on involved pathway • 3. Schedule and titrate up • 4. If no improvement, ADD another medication with a different mechanism QTc is 510 msec Case 1 What do you do? A. Order ondansetron 4 mg IV x 1. B. Order ondansetron 4 mg IV x 1 and telemetry. C. Provide the patient with isopropyl alcohol wipes. D. Repeat the EKG and hope the QTc is better. Medication Studied Dose(s) Impact on QTc Haloperidol 15 mg/day po +7.1 msec ~34 mg/day IV +41 msec Olanzapine 20 mg/day po +1.7 msec 1.25-10 mg IV +11 msec Promethazine 25 mg IV +20-25 msec Ondansetron 4 mg IV x 1 +16-20 msec Palonosetron 0.25-2.25 mg po No significant effect* Fosaprepitant 200 mg IV No significant effect *Palonosetron has not demonstrated QTc prolongation in CINV. Two studies in PONV demonstrated QTc prolongation but this may have been related to anesthesia. Inhaled Alcohol vs IV Ondansetron Nausea reported on a 0-10 scale, 0 for no nausea and 10 indicating worst nausea imaginable. Winston, A.W., et al. AANA journal. , 2003, Vol.71(2), p.127-132 Inhaled Alcohol vs Oral Ondansetron April, M.D., et al. Annals of Emergency Medicine : Journal of the American College of Emergency Physicians. , 2018, Vol.72(2), p.184-193 Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 50327 Case 2 Does she need prophylactic anti-emetics? A. I don’t know, I’ll have the fellow call you. B. She’s not nauseated now, but I can throw on some ondansetron prn to be safe. C. If she is receiving moderately or highly nauseating chemo, she definitely needs scheduled antiemetics. D. It’s probably not a big deal, let’s see how she does without them. Chemotherapy Induced Nausea and Vomiting (CINV) • 83% of patients in 1979 → 35% of patients in Emetogenic Risk of 2004 Chemotherapy Category Risk • Huge impact on quality of life! High >90% • 2014: Antiemetics listed as one of the top 5 Moderate 30-90% advances in oncology over the last 50 years Low 10-30% • Untreated CINV can be a trigger for future nausea Minimal <10% Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Navari RM, Aapro M. N Engl J Med 2016;374:1356-1367. Acute CINV Delayed CINV Olanzapine Works on multiple receptors - Dopamine: D1, D2, D3, D4 - Serotonin: 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 - Acetylcholine: Muscarinic receptors - Histamine: H1 Olanzapine for the Prevention of CINV Navari RM et al. N Engl J Med 2016;375:134-142. Trigger Mechanism of Typical 1st Line Nausea/Vomiting Antiemetics Opioid-induced Stimulation of CTZ Metoclopramide, (D2),Gastroparesis (D2) haloperidol, and Constipation (H1, AchM), prochlorperazine Sensitization of labyrinth (H1,AchM) Malignant bowel Stimulation of CTZ (D2), Stimulation Metoclopramide (if obstruction of peripheral pathways (H1, AchM) partial), haloperidol, and dexamethasone Impaired GI Gastroparesis (D2) Metoclopramide motility of advanced cancer Wood, G. J., et al. JAMA 2007, Vol.298(10), p.1196-1207 Trigger Mechanism of Nausea/Vomiting Typical 1st Line Antiemetics Radiation- 5HT3 released in gut, vagal nerve 5HT3 antagonists induced activates vomiting center Brain tumor ↑ ICP or meningeal irritation activate Dexamethasone meningeal mechanoreceptors which stimulate the vomiting center. Motion- Stimulation of vestibulocochlear Scopolamine, associated nerve (H1, AchM). promethazine, diphenhydramine Wood, G. J., et al. JAMA 2007, Vol.298(10), p.1196-1207 Nausea and Vomiting Summary • Choose antiemetics based on the likely involved pathways • Schedule antiemetics! • Combine antiemetics with different mechanisms of action. References • Glare, P., et al. Treating nausea and vomiting in palliative care: a review. Clinical interventions in aging. , 2011, Vol.6, p.243-259 • Wood, G. J., et al. Management of intractable nausea and vomiting in patients at the end of life: "I was feeling nauseous all of the time . nothing was working". JAMA 2007, Vol.298(10), p.1196-1207 • Harris, D.G. Nausea and vomiting in advanced cancer. Br Med Bull. 2010;96:175-85. • Adel,N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manag Care. 2017 Sep;23(14 Suppl):S259-S265. • Alese, O.B., et al. Management patterns and predictors of mortality among US patients with cancer hospitalized for malignant bowel obstruction. Cancer. 2015 Jun 1;121(11):1772-8. • Arezzo, A., et al. Stent as bridge to surgery for left-sided malignant colonic obstruction reduces adverse events and stoma rate compared with emergency surgery: results of a systematic review and meta-analysis of randomized controlled trials. Gastrointest Endosc. 2017 Sep;86(3):416-426. • Chouhan, J., et al. Retrospective analysis of systemic chemotherapy and total parenteral nutrition for the treatment of malignant small bowel obstruction. Cancer Med. 2016 Feb;5(2):239-47. • Rath, K.S. , et al. Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer. Gynecol Oncol. 2013 Apr;129(1):103-6. • Hoda, D., et al. Should patients with advanced, incurable cancers ever be sent home with total parenteral nutrition? A single institution's 20-year experience. Cancer. 2005 Feb 15;103(4):863-8. • Tiep, B., et al. Oxygen for end-of-life lung cancer care: managing dyspnea and hypoxemia. Expert Review of Respiratory Medicine. 2013 7:5, 479-490 • Currow, D.C., et al. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage.