Guns, Suicide, COPD and Sleep

Within the past year two tragic events, the shootings in Las Vegas and Florida have renewed the debate about guns. The politics and the money that fuels the political debate have sharply divided politicians. As tragic as these mass shootings are, deaths by suicide far outnumber the loss of live in these shootings. In 2014 suicide was the tenth most common cause of death with 42,826 lives lost (1). Half of the suicides were by firearm (21,386).

The medical profession has traditionally been reluctant to speak about politically sensitive issues such as abortion, sexuality, and guns. However, beginning early in this millennium some medical societies such as the American Academy of Pediatrics, the US Preventative Services Task Force and even the Department of Veterans Affairs were suggesting physicians ask patients about gun behavior, but a few patients complained (2-5). There were some anecdotal reports of patients feeling “pressured” to answer questions about guns (5). One grumbled that it was invasion of privacy. The National Rifle Association also viewed the medical community’s gun-related questions as discriminatory and a form of harassment. In 2011, the Republican-controlled Florida legislature, with the support of the then and still state’s Republican governor, Rick Scott, passed restrictions aimed at limiting physician inquiries about gun ownership and gun habits. Under the law, doctors could lose their licenses or risk large fines for asking patients or their families about gun ownership and gun habits. Fortunately, this law was struck down by the 11th U.S. Circuit Court of Appeals (5). The Court ruled in 10-1 decision that the law violated the First Amendment rights of doctors and did nothing to infringe on the Second Amendment right to bear arms.

Eight health professional organizations and the American Bar Association have released a call for action to reduce firearm-related injury and death in the United States (6). Specific recommendations include the following:

• Criminal background checks should be a universal requirement for all gun purchases or transfers of ownership.
• Opposition to state and federal mandates interfering with physician free speech and the patient–physician relationship, such as laws preventing physicians from discussing a patient's gun ownership.
• All persons who have a mental or substance use disorder should have access to mental health care, as these conditions can play a significant role in firearm-related suicide.
• Recognition that blanket reporting laws requiring healthcare providers to report patients who show signs of potentially causing serious harm to themselves or others may stigmatize persons with mental or substance use disorders and create barriers to treatment. The statement urges that such laws protect confidentiality, do not deter patients from seeking treatment, and allow restoration of firearm purchase or possession in a way that balances the patient's rights with public safety.
• There should be restrictions for civilian use on the manufacture and sale of large-capacity magazines and military-style assault weapons, as private ownership of these represents a grave danger to the public.

Our national professional societies including the American Thoracic Society, the American College of Chest Physicians and the Society of Critical Care Medicine have all endorsed this call for action to gun violence (7).

Editors of the Annals of Internal Medicine have recently urged physicians to sign a formal pledge committing to having conversations with their patients about firearms (8). The Annals campaign began in the wake of the Las Vegas shooting and gained momentum after the February 14 school shooting in Parkland, Florida. So far nearly 1000 physicians have signed the pledge (9).

People who commit firearm violence against themselves or others often have notable risk factors that bring them into contact with physicians. We in the pulmonary, critical care and sleep communities are positioned to prevent some of these deaths. Patients with chronic diseases including COPD and sleep deprivation are known to be at higher risks for suicide (10,11). By inquiring about guns during these patients’ clinic visits, we may be able to identify potential problems and prevent some deaths.

It is ironic, but hardly surprising, that Florida, a state known for a series of gun-rights laws and its “Stand Your Ground” self-defense law (5), is the site of the latest mass shooting. The shooter, Nikolas Cruz, by all descriptions could have readily been recognized as a potential threat. Perhaps if he had been identified and an intervention performed before the Florida law banning physicians from discussing guns when the he was 12, a tragedy could have been avoided. As Florida Sen. Marco Rubio recently found out, the times may be changing (12). Politicians should keep their politics out of the clinic, hospital and physician-patient relationship. Those who do not, and especially those who by their actions put our patients in peril, do so at their own political risk.

Richard A. Robbins, MD

Editor, SWJPCC

References

1. Centers for Disease Control and Prevention. Suicide and self-inflicted injury. March 17, 2017. Available at: https://www.cdc.gov/nchs/fastats/suicide.htm (accessed 3/2/18).
2. American Academy of Pediatrics. Gun violence prevention. Available at: https://www.aap.org/en-us/advocacy-and-policy/federal-advocacy/pages/aapfederalgunviolencepreventionrecommendationstowhitehouse.aspx (accessed 3/2/18).
3. United States Preventive Services Task Force. Guide to clinical preventive services. Available at: https://www.ataamerica.com/arc1/users/pdfforms/Guide%20to%20Clinical%20Preventive%20Services.pdf (accessed 3/2/18).
4. Department of Veterans Affairs. Firearms and dementia. August 2017. Available at: https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=2731 (accessed 3/2/18).
5. Alvarez L. Florida doctors may discuss guns with patients, court rules. NY Times. February 16, 2017. Available at: https://www.nytimes.com/2017/02/16/us/florida-doctors-discuss-guns-with-patients-court.html (accessed 3/2/18).
6. Weinberger SE, Hoyt DB, Lawrence HC 3rd, et al. Firearm-related injury and death in the United States: a call to action from 8 health professional organizations and the American Bar Association. Ann Intern Med. 2015 Apr 7;162(7):513-6. [CrossRef] [PubMed]
7. American College of Physicians. More than two dozen organizations join call by internists and others for policies to reduce firearm injuries and deaths in U.S. ACP Newsroom. May 1, 2015. Available at: https://www.acponline.org/acp-newsroom/more-than-two-dozen-organizations-join-call-by-internists-and-others-for-policies-to-reduce-firearm (accessed 3/2/18).
8. Wintemute GJ. What you can do to stop firearm violence. Ann Intern Med. 2017 Dec 19;167(12):886-7. [CrossRef] [PubMed]
9. Frellick M. More than 1000 doctors pledge to talk to patients about guns. Medscape. March 1, 2018. Available at: https://www.medscape.com/viewarticle/893307?nlid=121033_4502&src=wnl_dne_180302_mscpedit&uac=9273DT&impID=1572032&faf=1 (accessed 3/2/18).
10. Goodwin RD. Is COPD associated with suicide behavior? J Psychiatr Res. 2011 Sep;45(9):1269-71. [CrossRef] [PubMed]
11. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Institute of Medicine (US) Committee on Sleep Medicine and Research; Colten HR, Altevogt BM, editors. Washington (DC): National Academies Press (US); 2006. [CrossRef] [PubMed]
12. Associated Press. Sen. Marco Rubio changes stance on high-capacity magazines after Florida school shooting. Time. February 22, 2018. Available at: http://time.com/5171653/marco-rubio-large-capacity-magazine-parkland-shooting/ (accessed 3/2/18).

Cite as: Robbins RA. Guns, suicide, COPD and sleep. Southwest J Pulm Crit Care. 2018;16(3):138-40. doi: https://doi.org/10.13175/swjpcc039-18 PDF

Treatment after a COPD Exacerbation

A couple of years ago I was consulted about a patient at the Phoenix VA who had been admitted for the third time for a COPD exacerbation in two months. Each time the patient was treated with inhaled short-acting bronchodilators, corticosteroids and an antibiotic; rapidly improved; and was discharged after only one or two days in the hospital.  The discharge medications were albuterol, ipratropium, and rapidly tapering doses of prednisone. Apparently, no consideration was given to adding long-acting beta agonists (LABA), long-acting muscarinic antagonists (LAMA), and/or inhaled corticosteroids (ICS). These later medications have been shown to reduce exacerbations in most studies (1,2).

I was reminded of this incident by a recent article published by Melzer et al. in the Journal of Internal Medicine (3). The authors examined 2760 patients with exacerbations of COPD admitted to hospitals in the VA Northwest Health Network (VISN 20) to determine if a LABA and/or glucocorticoid were prescribed at discharge. These medications reduce exacerbations and the best predictor of a future exacerbation is a history of exacerbations (1,2,4). Of the 2760 patients 93% were not receiving a LABA or an ICS at the time of their exacerbation. Of this 93%, two-thirds of the patients had no change in therapy after their exacerbation. The authors state that “among patients treated for COPD exacerbations, there were missed opportunities to potentially reduce subsequent exacerbations by adding treatments known to modify exacerbation risk”. The authors go on to suggest that the VA could develop a Quality Enhancement Research Initiative (QUERI) program to improve delivery of care for some chronic conditions.

So why did the patient at the Phoenix VA and 2/3 of the patients in VISN 20 not receive a LABA, LAMA and/or inhaled corticosteroid after their exacerbations as recommended by the GOLD and ATS guidelines? Are the doctors in the Pacific Northwest and Phoenix unaware of the guidelines as the article and its accompanying editorial imply (5)? The answer probably lies elsewhere. First, the VA does not use the GOLD or ATS guidelines but has developed their own guidelines (6). These guidelines specifically mention consideration of the addition of inhaled corticosteroids and a LAMA but make no mention of a LABA. Rather than encouraging use of these medications, programs were created at the Phoenix VA which restricted Veterans’ access to these more expensive medications. The VA administration empowered the pharmacy to make unilateral decisions based on fiscal considerations with inadequate expert clinician input. These include a requirement to refer all patients for pulmonary consultation for long-acting bronchodilator therapy. This overloaded the pulmonary clinics with patients that did not necessarily need to be seen. In addition, there was a requirement for a trial of ipratropium before beginning tiotropium which took multiple visits further overloading the clinics.

This is another example of administrators meddling in clinical care only to have it blow up in their face and cause something else to go awry wasting money. In this case, the low use of long-acting bronchodilators likely led to an increase in admissions for exacerbation of COPD which are a major determinant of the costs of COPD care (7). Ignorance of the providers is blamed and another program to correct the harm caused by the initial blunder is created. Another example is the control of blood sugar in the ICU. After pushing for tight control of blood sugar for several years, the VA Inpatient Evaluation Center (IPEC) seamlessly converted their program to one examining hypoglycemia when tight control resulting in hypoglycemia was found to be harmful with the publication of the NICE-SUGAR study (8,9).

A QUERI program examining whether a LABA and/or corticosteroid was prescribed at discharge for a COPD patient does not need to be created. What needs to be done is to allow the physicians in the Pacific Northwest and Phoenix to use their best skills and judgment in caring for the patients without interference. If something must be measured, readmissions for exacerbation of COPD could be considered but should be part of a comprehensive program that measures outcomes such as mortality, length of stay, and morbidity. Otherwise, administrative blunders to correct past mistakes will continue.

Richard A. Robbins, M.D.*

References

1. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available at: http://www.goldcopd.org/Guidelines/guidelines-resources.html  (accessed 7/7/13)
2. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, Marciniuk DD, Denberg T, Schünemann H, Wedzicha W, MacDonald R, Shekelle P; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-91. [CrossRef] [PubMed]
3. Melzer AC, Feemster LM, Uman JE, Ramenofsky DH, Au DH. Missing potential opportunities to reduce repeat COPD exacerbations. J Gen Intern Med. 2013;28(5):652-9. [CrossRef] [PubMed]
4. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:1128-38. [CrossRef] [PubMed]
5. Jubelt LE. Capsule Commentary on Melzer et.al., Missing Potential Opportunities to Reduce Repeat COPD Exacerbations. J Gen Intern Med. 2013;28(5):708. [CrossRef] [PubMed]
6. The Management of COPD Working Group. VA/DOD clinical practice guideline for management of outpatient chronic obstructive pulmonary disease. Available at: http://www.healthquality.va.gov/copd/copd_20.pdf (accessed 7/7/13)
7. Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest. 2000;118(5):1278-85. [PubMed] [PubMed]
8. Falciglia M, Freyberg RW, Almenoff PL, D'Alessio DA, Render ML. Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis. Crit Care Med. 2009;37(12):3001-9. [CrossRef] [PubMed]
9. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97. [CrossRef] [PubMed]

*The opinions expressed are those of the author and not necessarily the Southwest Journal of Pulmonary and Critical Care or the Arizona, New Mexico or Colorado Thoracic Societies.  

Reference as: Robbins RA. Treatment after a COPD exacerbation. Southwest J Pulm Crit Care. 2013;7(1):28-30. doi: http://dx.doi.org/10.13175/swjpcc089-13 PDF

Doxycycline and IL-8 Modulation in a Line of Human Alveolar Epithelium: More Evidence for the Anti-Inflammatory Function of Some Antimicrobials

Beta blockers for severe systolic dysfunction; antibiotics for peptic ulcer disease.  These are just a few examples of the many unpredicted consequences of medication intervention.  Rheumatology has known of the disease modifying anti-rheumatic drug (DMARD) capacity of second generation tetracyclines including doxycycline (1). This has actually led to investigations attempting to identify organisms possibly serving as substrates for inflammatory processes including rheumatoid arthritis and even atherosclerosis. Generally, this has been unsuccessful and the conclusion that doxycycline has intrinsic anti-inflammatory properties has become suspect (2,3).

Experience with higher generation macrolides like azithromycin further lends credence to this concept of antibiotics as intrinsically anti-inflammatory (4). There is a body of data suggesting inhibition of cytokine expression by this drug. In diseases like cystic fibrosis where even very high intracellular concentrations of macrolide have no significant activity against pseudomonas species but the drug therapy does appear to modify disease course further supports this anti-inflammatory contention (5). 

Published work has suggested the beneficial anti-inflammatory effect in COPD relating this broadly to doxycycline’s inhibition of matrix metalloproteinases, MMP(s) (6).  MMP(s) have been postulated to rise as a function of the oxidative stress recurrently demonstrated in chronic obstructive pulmonary disease (COPD).  Additionally, doxycycline has demonstrated the ability to impair neutrophil migration in LPS stimulated alveolar macrophages harvested from bronchoalveolar lavage. Hoyt et al. (7) have now nicely demonstrated ex-vivo that doxycycline is capable of inhibiting IL-8 expression in a line of human lung epithelial cells stimulated by a cytomix, a potent combination of inflammatory stimulators. Importantly, this is a demonstration of measureable inhibition of an inflammatory cytokine by the tetracycline in mammalian cells.

The biologic significance of this still remains to be fully determined. In the large ECLIPSE TRIAL, the major discriminator of inflammatory modulators in COPD with inflammation was IL-6 and not IL-8 which actually decreased in the cohort of individuals with evidence of inflammation (8). Further study may reveal that doxycycline also has a suppressive effect on the former cytokine.

Broadly, MAP kinases are a group of protein kinases that participate in the signaling of stress related mediators like cytokines. A finding reported by Hoyt et al. (7) that will require further investigation concerns the decrease in p38 mitogen-activated protein kinase (p38 MAPK) in response to doxycycline. The data in this regard remains conflicting with reports suggesting p38 MAPK is involved in IL-8 transcription in a human monocyte model with exposure to Clostridium difficile toxin (9). Hoyt et al. (7) found a decrease in p38 MAPK along the absence of change in mRNA by reverse transcription-polymerase chain reaction (RT-PCR) suggesting that effect of doxycycline on IL-8 elaboration is post transcriptional. Others have reported data supporting the concept of post transcription modulation of IL-8 by doxycycline as suggested by Hoyt et al. (10). While validation with repeat studies will be necessary, the finding that IL-8 mRNA by RT-PCR was not affected by levels of doxycycline that inhibited IL-8 is noteworthy. One may conclude that IL-8 assembly at the level of the ribosome could be operative.  While it was previously presumed that the tetracyclines specifically targeted bacterial ribosomes, Robbins et al along with all the other studies support the anti-inflammatory effect of tetracyclines in human disease and demonstrates that mammalian cells are also affected by this moiety.

So Hoyt et al. (7) have added to the knowledge base by definitively demonstrating the non-antimicrobial properties of doxycycline by ex-vivo inhibition of IL-8 production in a line stimulated mammalian alveolar epithelial cells. If the RT-PCR data can be further confirmed, this inhibition of IL-8 by doxycycline appears to be a post-transcriptional mechanism. Whether p38 MAPK is a transcriptional or post-transcriptional cytokine modifier remains to be determined.

Jay E. Blum, M.D.

Chief, Pulmonary and Critical Care

Phoenix VA Medical Center

References

1. Stone M, Fortin PR, Pacheco-Tena C, Inman RD. Should tetracycline treatment be used more extensively for rheumatoid arthritis Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol. 2003;30:2112-22.
2. Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation.1999;99:1540-7.
3. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007;25:133-5.
4. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23:590-615.
5. Equi AC, Davies JC, Painter H, Hyde S, Bush A, Geddes DM, Alton E. Exploring the mechanisms of macrolides in cystic fibrosis.  Respir Med. 2006;100:687-97.
6. Greenwald RA, Moak SA, Ramamurthy NS, Golub LM. Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J Rheumatol. 1992;19:927-38.
7. Hoyt JC, Ballering JG, Hayden JM, Robbins RA. Doxycycline decreases production of interleukin-8 in a549 human lung epithelial cells. Southwest J Pulm Crit Care. 2013;6:130-42.
8. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, Lomas DA, Duvoix A, MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agustí A; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065-72.
9. Warny M,  Keates AC, Keates S, Castagliuolo I,  Zacks J,  Aboudola S et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest. 2000;105:1147–56.
10. Li J, Kartha S, Iasvovskaia S, Tan A, Bhat RK, Manaligod JM, Page K, Brasier AR and Hershenson MB.  Regulation of human airway epithelial cell IL-8 expression by MAP kinases.  Am J Physiol Lung Cell Mol Physiol. 2002;283:L690-L699.

Reference as: Blum JE. Doxycycline and IL-8 modulation in a line of human alveolar epithelium: more evidence for the anti-inflammatory function of some antimicrobials. Southwest J Pulm Crit Care. 2013;6(4):184-6. PDF 

COPD, COOP and BREATH at the VA

Reference as: Robbins RA. COPD, COOP and BREATH at the VA. Southwest J Pulm Crit Care 2011;2:27-28. (Click here for PDF version)

The February 2011 Pulmonary Journal Club reviews a study by Rice and colleagues (1) of high-risk COPD patients (click here for Pulmonary Journal Club). This review was authored by Kevin Park who also authored an ACP Journal Club review (2). In Rice’s study a single educational session, an individualized care plan, and monthly case-manager telephone calls, resulted in a 41% decrease in hospitalizations and emergency room visits and a nonsignficant trend toward decreased mortality.

Rice’s study was supported and conducted in the Veterans Integrated Service Network (VISN) 23 (Minnesota, Iowa, Nebraska and the Dakotas). The COPD patients in this study were recruited and followed primarily using the VA computer system. The study represents a potential model of data-based management leading to improved patient outcomes. The authors; Robert Petzel MD, then VISN 23 Director (now Veterans Healthcare Administration Undersecretary); and Janet Murphy, then VISN Primary Care Service Line CEO (now VISN 23 Director) are to be congratulated for their insight into conducting and supporting this study. Unfortunately, many VA administrators are not as far-sighted and restrict or place unreasonable obstacles to investigators’ access to VA data. VA administrators at the National, VISN and local levels should be encouraged to follow Dr. Petzel’s and Ms. Murphy’s lead in utilizing the VA computer system to conduct studies such as Rice’s.

At the time this study was ongoing, a similar study was also being conducted through the VA Cooperative studies program known as Bronchitis and Emphysema Advice and Training to Reduce Hospitalization (BREATH) trial (3). Like Rice’s study, the BREATH study incorporated self-management education, an action plan, and case-management to decrease the risk of hospitalizations due to COPD. However, in contrast to Rice’s study, the patients in BREATH had all been hospitalized within the past year and likely had more severe underlying COPD. Although this multi-center, randomized study which was planned for 5 years was on target for recruitment (425 subjects), it was cancelled after about 2 years. The reasons for the cancellation were never shared with the site investigators (of which this editor was one). It seems unlikely that a behavior study such as BREATH would result in a significant medically adverse outcome to mandate study cancellation. However, if such an outcome occurred in BREATH, it would throw the largely positive results of Rice’s study into question.

Richard A. Robbins MD, Editor, SWJPCC

References

1. Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, Kumari S, Thomas M, Geist LJ, Beaner C, Caldwell M, Niewoehner DE. Disease Management Program for Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial. Am J Respir Crit Care Med 2010;182:890-6.

2. Park K, Robbins RA. ACP Journal Club: A COPD disease management program reduced a composite of hospitalizations or emergency department visits.  ACP Journal Club 2011;154:JC3-5.

3. http://clinicaltrials.gov/ct/show/NCT00395083?order=1. Accessed 2/9/2011.