Medicine’s Third: Polypharmacy

The Gist: Polypharmacy, the concurrent use of multiple medications (5+) or use of unnecessary medications, is problematic in medicine.  Consider “medication related problem” on the differential diagnosis and review the patient’s medications.  When prescribing a medication, consider the unwanted reactions and tailor therapy, recalling that medications frequently have subtle or additive effects that may be especially problematic in the elderly. When in doubt, send a communication to a patient's PCP.

The Case: A 58 y/o with a history of hypertension and diabetes presented with weakness, vomiting, and fatigue.  A basic chemistry panel returned with a creatinine of 3.8 mg/dL (last value, 0.9 mg/dL).  While initially it seemed as though the gentleman had prerenal acute kidney injury from vomiting, the patient revealed he had been taking both ibuprofen and naproxen for worsening arthritis, in addition to his prescribed ace-inhibitor and thiazide diuretic.  See another case in this post on medication reconciliation.

Newton's Third Law states:
"For every action there is an equal and opposite reaction.” 

We ponder this frequently looking at collisions or calculating billiard shots but I think this principle can be translated to medicine. In the medical realm we prescribe therapies for the primary action of that medication/intervention.  Yet, unintended consequences abound.  Despite the comically long “disclaimers” of side effects on advertisements, the additive effects, unintended as they may be, are often disguised in a patient’s presenting complaint.  Further, patients are often prescribed medication to mask the side effects of another medication. Struck by this during medical school, I created my own version:
Westafer’s Third Law of Medicine:
 “For every medication action there is an unequal and unintended reaction.” 

This came up recently in a discussion on Twitter regarding a new medication for hyperkalemia, targeted to combat the side effect of elevated potassium in patients on ACE-inhibitors, ZS-9. A medication for a medication side effect (with likely more broad application in reality).

Although prescriptions from the emergency department (ED) are likely a minority of offenders with regard to the volume of inappropriate medications, awareness of the role that medications may play in the patient’s complaint. Studies show that adverse drug events (ADEs) may be responsible for 10-12% of ED visits among patients > 65 years old, although the definition of adverse drug event and determination of causality vary based on the study [1-3].   A more recent Canadian database review demonstrated a lower prevalence of ADEs generating ED visits, 0.8%, but the methods leave something to be desired [4].

A small study by Chin and colleagues identified ED prescriptions for analgesia, notably NSAIDs, muscle relaxants, and narcotics, as an area for future intervention [5].  Interestingly, this paper was published prior to the massive spike in opioid prescriptions; thus, this area may be even more crucial presently [6].  

Polypharmacy, particularly in the elderly, is associated with an increase in the prevalence of falls, mortality, hospital admission, and hospital length of stay.  The elderly are more susceptible to many of these effects as clearance and metabolism change with age, and elderly patients tend to be on more medications. 

Drug-drug interaction - A medication alters the activity of another.  Example: warfarin + ciprofloxacin -> supratherapeutic INR and may lead to increased bleeding.
Drug-disease interaction - Medications that should be avoided in patients with specific medical conditions.  
  • Example: Use of aspirin 325 mg or non-steroid anti-inflammatories in patients with peptic ulcer disease.
Adverse effects - Many medications have more pronounced adverse effects in elderly patients, often because the pharmacokinetics, such as renal excretion, are altered and may predispose patients to acute kidney injury, delirium, or orthostatic hypotension.  Check out this podcast for more.
  • Example: Anticholinergic properties are abundant in medications, including antidepressants, antihistamines, and antipsychotics.  In the elderly these effects are more pronounced and are associated with hallucinations, impaired memory, tachycardia, falls, constipation, etc.
Unnecessary - Medications are frequently initiated and then continued without re-examination for appropriateness. A study of Veterans Association hospital discharges of patients age >65 y/o classified as "frail" found that 44% had at least one unnecessary medication at discharge [8]. These medications contribute to increase cost and may play a role in further drug interactions or adverse effects. 
  • Example: A H2 blocker such as ranitidine may be prescribed for prophylaxis but the anticholinergic effects can contribute to diminished cognition, constipation, etc (see above).
Under-recognized  A prospective observational study by Hohl and colleagues of ED patients > 65 y/o in Canada found ADEs in 8.3%-12.3%, depending on the breadth of the definition of ADEs.  A prospective study by Hohl et al found that many ADEs in the ED were not attributed as medication related, particularly in the older population [9]. 

ED Interventions
  • Consider the Third Law of Medication when pondering the differential diagnosis.  For example, geriatric fall patients should probably be screened for polypharmacy (What medications is the patient on?  Can the problem be explained by a medication?) and while prescribing medications (Is the medication truly necessary? Will it interact with any of their medications?  Does the patient need a bowel regimen or other precautions?)
  • Medication review in the ED.  The ED encounter can serve as an opportunity for an outsider to glance at the patients medications to gain a sense as to whether something may be dangerous or warrant further discussion with their primary physician.
  • Judicious prescription of medications.  In the ED, we often write for short courses of medication and may be lulled into the sense that these prescriptions don't matter, yet they may carry an unintended reaction.  Be familiar with medications that are common offenders.
    • The Beers' List has a long list of medications to avoid in the elderly, but often these aren't the biggest offenders (also note the STOPP criteria). The most common medications associated with ADEs, implicated in 67% of hospital admissions according to a national survey database, were: 
      • warfarin (33.3%)
      • insulins(13.9%)
      • oral antiplatelet agents (13.3%)
      • oral hypoglycemic agents (10.7) [1,4]
  • Targeted feedback to general practitioners regarding potentially problematic medications.  Many health systems and electronic medical records have easy ways to send messages to primary care physicians.  In the ED haste, these communications frequently take a back seat but may be important.  Yet, the ACEP Geriatric ED guidelines recommend referral to PCP for any concern for polypharmacy (>5 medications) or presence of any high risk medication [10].
  • ED pharmacists. Many study authors have called for increasing the role of ED pharmacists in identifying ADE related to medications [2].
1.Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365:(21)2002-12. 
2. Banerjee A, Mbamalu D, Ebrahimi S, Khan AA, Chan TF. The prevalence of polypharmacy in elderly attenders to an emergency department - a problem with a need for an effective solution. Int J Emerg Med. 2011;4(1):22.
3. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:(11)755-65.
4.Bayoumi I, Dolovich L, Hutchison B, Holbrook A. Medication-related emergency department visits and hospitalizations among older adults. Can Fam Physician. 2014;60:(4)e217-22. 
5. Chin MH, Wang LC, Jin L, et al. Appropriateness of Medication Selection for Older Persons in an Urban Academic Emergency Department. Acad Emerg Med. 2007;6(12):1232–1242.
6. Ruscitto A, Smith BH, Guthrie B. Changes in opioid and other analgesic use 1995-2010: Repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland.Eur J Pain. 2015 Jan;19(1):59-66. 
7. Robitaille C, Lord V, Dankoff J, et al. Emergency Physician Recognition of Adverse Drug-related Events in Elder Patients Presenting to an Emergency Department. 2005;12(3). 
8.Hajjar ER, Hanlon JT, Sloane RJ, et al. Unnecessary drug use in frail older people at hospital discharge. J Am Geriatr Soc. 2005;53:(9)1518-23. 
9. Hohl CM, Zed PJ, Brubacher JR, Loewen PS, Purssell RA. Do Emergency Physicians Attribute Drug-Related Emergency Department Visits to Medication-Related Problems? YMEM. 2009;55(6):493–502.e4. 
10.American College of Emergency Physicians. Geriatric emergency department guidelines 2013

Misrepresented: EBM

The Gist: Evidence based medicine (EBM) is misunderstood; it's not a randomized control trial (RCT) or "the literature." Rather, EBM is the intersection of the best available evidence, clinical expertise, and patient values [1-2]. Avoid BARF (Brainless Application of Research Findings), with tips from Emergency Medicine Cases

We have a cultural problem.  Clinicians are increasingly called upon to practice EBM.  Yet, the term EBM does not sit well on the palate of many physicians.  Conversations involving a mention of EBM have resulted in some of the following refrains...
"See, my patients are different..." 
"We'll never get an RCT on that..." 
"The culture is different here, I don't want to get sued." 
"Patients don't understand, but they do hold the power with satisfaction scores." 
"It's cookbook medicine."
With these words and reactionary body language, the dialogue quickly shuts down - by both parties.  First, this is a shame.  We should learn from one another but there seems to be a "hard stop" between many who champion EBM and those who find EBM off-putting. Second, this is a misunderstanding.  EBM is not an RCT.  In fact, EBM is not the best statistical methods or the rationing of care. EBM is not nihilism.  

EBM is the intersection of the best available evidence, clinical expertise, and patient values:
"the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research" [1].
Why, then, the misunderstanding? 
Here are some thoughts...

Misrepresentation. EBM is often used to refer to literature or studies, rather than to the application of research and evidence to particular patients and situations, using one's clinical experience (example and discussion: "EBM is Crap").  As a result, EBM may be misunderstood as a cost-cutting venture or a cookbook for medicine [3]. I have been complicit in perpetuating this misrepresentation of EBM.   As a novice physician-in-training with limited clinical experience, I draw predominantly upon the literature base.  I have unknowingly quoted the literature, thereby proudly proclaiming my practice of EBM, while unconsciously dismissing the other components of EBM.  
  • A remedy:  Remind ourselves and others that the evidence is part of the trifecta of EBM, along with the patient's values and clinical expertise.  We can be clear in what we mean by EBM and refrain from referring to a body of literature as EBM. 
Zeal. A religiosity exists amongst many champions of EBM, or people who believe they are championing EBM.  We tout our pyramids of evidence and may scoff at a lack of evidence or rigorous trials.  This may be off-putting as not all fields are amenable to RCTs and patient populations vary.  Moreover, there's a human tendency to form a reactionary attitude when someone exerts a strong identity [4].  Hence, EBM zeal may engender an anti-EBM attitude and cause people to be wary of solid practice changing evidence.
  • A remedy:  While championing good research and employing the best available evidence, we can balance our enthusiasm with important caveats and understand the importance for tailored approaches for patients.  Gentle education about EBM rather than diatribes may aid individuals in understanding the values of EBM beyond evidence.
Fear.  People like to be right.  We may reflexively become defensive when we are (possibly) wrong. EBM or "literature" can be used in an antagonizing way and, subconsciously, a way to exert a feeling of superiority.  "You haven't read that study?"
  • A remedy: Understand that unlearning in medicine is difficult.  Aggressive assertions may push people further away.  Think of it as a Kubler-Ross like grief cycle, as explained in this post.  This may help us become more cognitively flexible, understand the reticence of others, and perhaps make our points more effectively.  

Confusion.  Historically, researchers, clinicians, physicians in training, and allied health professionals have limited understanding of fundamental statistics [5,6].  As such, we may not understand what we're reading or how it applies to our patient population.  We may have difficulty understanding why something we believed was proper at one time is no longer the case.  Often, this is because the research was, in fact, initially wrong or misleading [7]. 
  • A remedy: Read.  This podcast proffers tips on getting started; however, even the most seemingly rigorous papers published in high impact journals are subject to bias (publication bias and otherwise), which can be difficult to parse through.  For example, the oseltamivir (tamiflu) recommendations from Cochrane changed after they were allotted access to data, demonstrating the profound impact of publication bias [Jefferson et al].  More on this here.
Time. The number of journal articles needed to read (NNR) to obtain valid and relevant information is typically cited as 20-200, an insurmountable task [8].  The process of trolling through the literature is time consuming and may be overwhelming.  Frustration can turn into apathy, confusion, and mistrust.
There are legitimate issues with EBM.  Evidence is often subject to the biases of industry and legislative bodies.  Guidelines or recommendations billed as "EBM" may be hijacked by individuals with conflicts of interest or other agendas. Further, the grading of evidence isn't always objective or consistent, as seen by the grading of evidence for thromboylitics in acute ischemic stroke listed in the ACEP clinical policy.   In addition, guidelines harness EBM and disseminate the body of evidence to practitioners.  For example, the 2008 AHA/ACC guidelines are based largely on low levels of evidence and expert opinion,  many of whom have financial conflicts of interest.  Only 11% of the recommendations were based on high quality evidence [9].  

So, while EBM has imperfections in concept, representation, and implementation, the model incorporates the primary things we, as providers, care about - the evidence, the patient, and clinical experience.  Let's understand what EBM means and apply the term and principles appropriately.

1. Sackett DL, Rosenberg WM, Gray JAM, et al. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–72. 
2. Greenhalgh T, Howick J, Maskrey N. Evidence based medicine: a movement in crisis? BMJ 2014;348:g3725
3. Straus SE, McAlister FA. Evidence-based medicine: a commentary on common criticisms. CMAJ. 2000;163(7):837–41. 
4.  Maalouf A.  In the Name of Identity: Violence and the Need to Belong. New York: Penguin Books, 2000.
5.  Windish D, Huot S, Green M. Medicine residents’ understanding of the biostatistics and results in the medical literature. Jama. 2007;298(9). 
6.  Mavros MN, Alexiou VG, Vardakas KZ, Falagas ME. Understanding of statistical terms routinely used in meta-analyses: an international survey among researchers. PLoS One. 2013;8(1):e47229. 
7.Ioannidis JP a. How many contemporary medical practices are worse than doing nothing or doing less? Mayo Clin Proc. 2013;88(8):779–81.
8. McKibbon KA, Wilczynski NL, Haynes RB. What do evidence-based secondary journals tell us about the publication of clinically important articles in primary care journals? BMC Med. 2004;2:33. 
9.  Tricoci P1, Allen JM, Kramer JM, et al.  Scientific evidence underlying the ACC/AHA clinical practice guidelinesJAMA. 2009 Feb 25;301(8):831-41.

SBO Ultrasound

The GistAs mentioned in this post, the operating characteristics of historical and physical features are suboptimal in small bowel obstruction (SBO).  Bedside ultrasound has better operating characteristics and is one of the easier scans to perform and read.  Assuming others like to make their lives easier, I gave a talk on this; but professionals have created a tutorial at The Ultrasound Podcast tutorial.

I delivered a quick talk at the Controversies and Consensus in Emergency Medicine Conference on ultrasound for SBO, a modality that I've found great utility for in my developing practice. As a believer in Free Open Access Medical education (FOAM) and with hopes that, as a novice I might receive some constructive criticism to help me become better, I have posted the recording.

A Few Tidbits (some redundancy from prior post): 
Time.  Ultrasound for SBO is quick and easy and can be performed in conjunction with the history and physical exam in appropriate patients.  This may alleviate the time to definitive diagnosis (say CT or surgical evaluation), treatment, and/or disposition.*  Furthermore, sometimes we see things we don't expect on ultrasound.  Familiarity with US findings of SBO may make sense of dilated loops of bowel or altered peristalsis encountered during a gallbladder or aorta scan for abdominal pain.  Conversely, there are times when SBO may be suspected and a quick ultrasound may reveal an alternative diagnosis that may grossly change management (examples in talk).

X-rays are out for SBO.  Bedside ultrasound has better operating characteristics than plain films with fewer instances of equivocal results.  Sometimes plain films are crucial to evaluate for pneumoperitoneum but most patients with abdominal pain don't fall in this category.  Indeed, The American College of Radiology conclusion on plain films in suspected SBO
"In light of these inconsistent results, it is reasonable to expect that abdominal radiographs will not be definitive in many patients with a suspected SBO. It could prolong the evaluation period and add radiation exposure while often not obviating the need for additional examinations, particularly CT" [5].
  • Ileus vs. SBO - while US beats plain films with regard to percentage of ambiguous scans, ultrasounds can be equivocal as well.
  • Cause of obstruction/Transition point not well elucidated.  In patients with recurrent SBO from malignancy or adhesions and this may be less important to the managing team and surgeons often stop ordering CT scans if the presentation is consistent with prior presentations. 
  • Consultant access to images obtained at the bedside.
Note:  I have not included surgical consultants requiring a CT scan as part of the limitations.  The surgical literature recognizes the capacity of US to diagnose SBO, although this is not yet widely adopted [6].  However, despite common assumptions, surgeons don't require a CT scan for every recurrent SBO.  As a result, sometimes a positive ultrasound, followed by plain film, may be enough in these patients who will undergo conservative management.  Have a chat with each consultant, they're not always as inflexible as we make them out to be. 

*NCT02190981 pending with LOS as secondary outcome

1.  Carpenter CR, Pines JM. The end of X-rays for suspected small bowel obstruction? Using evidence-based diagnostics to inform best practices in emergency medicine. Acad. Emerg. Med. 2013;20(6):618–20.
2.  Taylor MR, Lalani N. Adult small bowel obstruction. Acad. Emerg. Med. 2013;20(6):528–44.
3. Böhner H, Yang Q, Franke C, Verreet PR, Ohmann C. Simple data from history and physical examination help to exclude bowel obstruction and to avoid radiographic studies in patients with acute abdominal pain. Eur. J. Surg. 1998;164(10):777–84. 
4. Jang TB, Schindler D, Kaji AH.  Bedside ultrasonography for the detection of small bowel obstruction in the emergency department. Emerg Med J. 2011 Aug;28(8):676-8.
5. Katz DS, Baker ME, Rosen MP, Lalani T, et al, Expert Panel on Gastrointestinal Imaging. ACR Appropriateness Criteria® suspected small-bowel obstruction. Reston (VA): American College of Radiology (ACR); 2013. 10 p.
Maung AA, Johnson DC, Piper GL et al. Evaluation and Management of Small-Bowel Obstruction.  J Trauma. 73(5):S362-S369, November 2012