Assistant Program Director and Palliative Care guru Dr. Elizabeth Paulk gave an insightful Grand Rounds Lecture today about the history and ethics of physician assisted death (PAD) in this country. She talked in depth about the 1997 Oregon Death with Dignity Act and showed data about the types of patients who seek physician assistance in dying. She highlighted the case of Brittany Maynard, a 29 year old woman with glioblastoma multiforme who became an outspoken advocate for PAD and died by choice in 2014 after moving to Oregon. The Maynard case thrust the issue of PAD into the national spotlight and a 2015 Gallup poll showed an increasingly favorable public perception of PAD with 68% of Americans in favor. Physician assisted death is currently legal in Oregon, Washington, Montana, New Mexico and Vermont. Read more about the controversy and data surrounding PAD and about Brittany Maynard here and here. See Dr. Paulk’s slides for more information about this morally and legally complicated issue.
This morning, Dr. Craig Malloy, Richard A. Lange, M.D. Chair in Cardiology, gave an amazing update for internists on New Therapies fo Atrial Fibrillation. One of the most important topics covered was the noval anticoagulants, or NOACS. Here is a quick review for use in the clinic or hospital!
Dabigatran, rivaroxaban and apixaban are three new drugs that have different mechanisms of action, daily doses, and metabolic and elimination profiles.
Dabigatran (Pradaxa) is a direct thrombin inhibitor (it inhibits factor II) that has a half-life of about 12-14 hours and needs to be administered twice daily. It partially binds plasma proteins and can therefore be partially dialysed. Pradaxa is only eliminated renally: it is therefore contraindicated in patients whose creatinine clearance is
Rivaroxaban (Xarelto) is a direct factor X inhibitor with a half-life of 5-13 hours, but completely binds plasma proteins. It is administered once daily with evening meal in NVAF patients, and twice daily in those with DVT or PE. It is eliminated by the kidney and liver, and can be used at a lower dose if creatinine clearance is15 mL/min in NVAF patients; its use should be avoided in DVT/PE patients whose creatinine clearance is
Apixaban (Eliquis) is a direct factor X inhibitor with a half-life of 9-14 hours, but completely binds plasma proteins. It is administered twice daily and eliminated by kidney and liver. It should not be used if creatinine clearance is
Turiel M, Galaverna S, Colombo C, Gianturco L, Stella D (2015) Practical Guide to the New Oral Anticoagulants. J Gen Pract 3:194. doi: 10.4172/2329-9126.1000I194
This morning, Dr. Una Makris, from the UT Southwestern Division of Rheumatology, gave an excellent talk on the diagnosis and management of chronic low back pain in older adults, a problem that costs more annually than most chronic medical conditions. In her talk, she noted that a multi-modal approach, with physical therapy, cognitive behavioral therapy, pain control, and a host of other methods to deal with this problem. Significant research in the area suggests that we are over-treating and over-spending, without a considerable impact on the burden of this often debilitating condition. In fact, a recent article in the JAMA notes that among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. For more information, check out the articles below:
- Association of Early Imaging for Back Pain With Clinical Outcomes in Older Adults (March 27, 2015) – hint: no improved outcomes
- JAMA: Doctors are Overtreating Back Pain (July 31, 2013)
This morning, Dr. Matthew Leveno, director of the Parkland Medical ICU and youngest winner of the housestaff teaching award, gave an incredible grand rounds presentation about the history, pathophysiology, diagnosis, and management of severe alcohol withdrawal. Take a look below for some important information.
Alcohol abuse is a common problem globally, and it is estimated to result in 2.5 million deaths annually. Of the drugs of abuse, alcohol is the most common, with an estimated 18.3 million individuals dependent on it in the United States. Alcohol abuse has a prevalence of 22.4% in a hospitalised general medical population. In one analysis, alcohol-related admissions accounted for 9% of admissions to a population of mixed medical intensive care unit (ICU) and surgical ICU patients; in addition these patients accounted for 13% of total ICU costs. One population with a particularly high rate of alcohol abuse are trauma patients, with estimates of prevalence ranging from 31% to 70% across centers.
Alcohol-related complications in the ICU affect nearly every organ system (Table 1). Alcohol abuse in patients is associated with increased length of stay, outpatient pneumonia and an almost three times higher incidence of healthcare-associated infections.
Clinical Manifestations and Diagnosis
The gold standard for the diagnosis of alcohol withdrawal syndrome (AWS) is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. It requires that a patient’s alcohol usage is heavy and prolonged, there is a cessation in alcohol intake and also that there is no other general condition that better accounts for the diagnosis.
AWS has four clinical stages: (1) autonomic hyperactivity, (2) hallucinations, (3) neuronal excitation and (4) delirium tremens (Table 2). Patients generally start the withdrawal process at 5 h, with hallucinations at 24 h, and delirium at 48 h; it is rare for this to persist for more than 120 h.
AWS is the result of a disruption of the delicate neurochemical balance that is controlled via inhibitory and excitatory neurotransmitters. The principal inhibitory neurotransmitter is gamma aminobutyric acid (GABA), which exerts its effect on the GABA-A neuroreceptor. A principal excitatory transmitter is glutamate, which affects the N-methyl-D-aspartate neuroreceptor. With chronic alcohol exposure, the brain has a tolerance to the effects of the alcohol due to down-regulation of the GABA-A receptor over time. This down-regulation may occur by modification of the GABA-A receptor in the alpha 1 subunit to make the receptor less susceptible to the effects of alcohol exposure.
The severity of the symptoms of AWS should direct the appropriate pharmacotherapeutic interventions. The patient’s comorbidities, other active diagnoses as well as exposure to any other drug of abuse should also be factored into the development of their treatment plan.
Benzodiazepines have historically been the mainstay pharmacologic intervention of AWS; they are generally considered to be the ‘gold standard’ treatment. It has been shown that sedative-hypnotic agents such as benzodiazepines, in comparison with other agents, reduce mortality and control the symptoms of AWS. All benzodiazepines have the same mechanism of action on the GABA receptor. Several agents have been used for AWS including chlordiazepoxide, lorazepam, valium, oxazepam and midazolam. Lorazepam is suggested as the benzodiazepine of choice for AWS due to its intermediate half-life, which balances a smooth withdrawal, with the potential for delayed metabolism in those with impaired hepatic function such as geriatric or cirrhotic patients.
Benzodiazepines were traditionally administered to AWS patients in a fixed dose regimen. There has now been over two decades of experience accumulated with the use of on demand or ‘symptom-triggered’ dosing of benzodiazepines for AWS treatment. This method of symptom-triggered dosing relies on the Clinical Institute Withdrawal Assessment for Alcohol [CIWA-A or CIWA-Ar (revised)]. In studies, the symptom-triggered dosing method results in both a decrease in the amount of benzodiazepines administered and a shortened duration of withdrawal symptom. While the symptom-triggered approach has these advantages, there is quite limited experience of the use of this approach in critical care settings, and it has not shown the same benefit across all studies.
The alpha-2-agonist, clonidine, has traditionally been used to blunt the sympathomimetic effects of AWS. This has been done outside critical care settings. While intravenous clonidine is available in Europe, it is not currently available for use in the United States. This has resulted in intensivists to turn to dexmedetomidine, a drug derived from clonidine. Dexmedetomidine is not FDA-approved for AWS, but rather for procedural conscious sedation and sedation for mechanical ventilation
Beta-blockers have been used as an adjunctive agent in AWS. Given the sympathetic outflow associated with autonomic hyperactivity, betablockers are a direct antagonist. This medication can be administered either orally or intravenously, and it serves to normalise tachycardia and hypertension in non-agitated patients that are otherwise comfortable. In a randomised trial by Gottlieb, atenolol in patients with AWS served to make a more rapid resolution of their vital sign abnormalities and clinical signs such as tremor. Betablockers serve an important role as part of a multimodal pharmacological plan, but they should never be used without a GABA agent.
Haloperidol is a phenothiazine that is commonly prescribed in ICUs for acute agitation. It has the benefit of haemodynamic neutrality, and the possible complications of an elevation in the QTc interval and tardive dyskinesia. While haloperidol is an adjunctive agent in AWS setting, it is particularly useful for the symptoms related to delirium. Most frequently, it is used in patients with underlying psychiatric disorders.
AWS continues to challenge clinicians in critical care settings. Keys to good outcomes in this area include early recognition of the disorder and rapid implementation of appropriate pharmacologic treatment. The range of symptoms represents a spectrum; the pharmacologic strategy needs to match the severity that the patient is experiencing. While some patients have a good therapeutic response to a single benzodiazepine agent, more severe cases may require a multimodality therapy. The current protocol used at our institution is presented in Table 3. With a stepwise protocol-driven plan, intubation and mechanical ventilation can be avoided except in the more severe cases, contributing to better outcomes in terms of length of stay and VAP.
Modified from: DeMuro JP. Alcohol withdrawal syndromes in the critically ill. OA Alcohol 2013 Feb 01;1(1):1. Under the terms of the Creative Commons Attribution License (CC-BY).
This morning, Dr. Sharon Inouye gave us an excellent overview of delirium, with a focus on acute delirium in the elderly. She is the director of the Aging Brain Institute and Professor of Medicine at the Harvard School of Medicine and Beth Isreal Deaconess Medical Center. As a leading expert in the field, Dr. Inouye developed the Confusion Assessment Method (CAM), an internationally recognized method for identifying delirium. Here is a synopsis of her talk, with salient points that directly apply to our clinical practice.
Risk Factors for Delirium
- Underlying dementia
- Older age
- Co-morbid illness
- Severity of medical illness
- ‘High-risk’ medication use (see below!)
- Diminished activities of daily living
- Sensory impairment (vision, hearing)
- Urinary catheterization
- Urea and electrolyte imbalance
Potentially Inappropriate Medications for the Elderly
In 2012, the American College of Geriatrics released the Beers criteria for medications with potential harm (including risk for delirium) in the elderly – mant of the medications we most commonly use populate this list!
- 1st generation antihistamines (diphenhydramine, chlorpheniramine, etc.)
- Anti-parkinson agents (benztropine)
- Anti-spasmodics (dicyclomine, hyoscyamine, etc.)
- Anti-microbials (Nitrofurantoin – pulm toxicity)
- CNS medications
- Tricyclics (amitriptyline, imipramine, doxepin – very antichol)
- Conventional and Atypical Anti-psychotics
- Benzos (increased risk of cognitive impairment)
- Sedative/Hypnotics (zolpidem, eszopiclone, etc.)
- Anti-arrhythmics (disopyramide, etc.)
- Antitussives (dextromethorphan, etc.)
- Anti-vertigo meds (meclizine, etc.)
- H2-blockers (famotidine, etc.)
- Mydriatics (atropine, etc.)
The list goes on, for more information, click here.
Diagnosis/Identification of Delirium
The Confusion Assesment Method
(to use the CAM, click the image above to visit the HELP website)
- Non-pharmacologic measures are best! Guidelines do not recommend pharmacologic management as a first line, except for a few specific situations.
- Reduce medications
- Reduce length of stay
- Maintain day-night cycle
- Familar surroundings and people
- Remove catheters!
- Maintain nutritional balance
- Drug treatment may reduce agitation, but may prolong delirium duration and cognitive decline.
- Pearl – reserve for patients with severe agitation which will:
- Cause interruption of essential medical therapy (i.e. intubation)
- Pose potential harm to the patient or staff
- Recommended Approach:
- Haloperidol 0.25-0.50 mg PO or IM (avoid IV – short acting and can precipitate torsades de pointes)
- Repeat dose q30 minutes until patient is manageable (maximum dose 3-5mg/24 hours)
- Maintenance: 50% of loading dose divided over the next 24 hours
- Taper dose of the next several days
- Pearl – reserve for patients with severe agitation which will:
Dr Holick, endocrinologist and mineral metabolism specialist from Boston University, gave us a rousing Grand Rounds about vitamin D deficiency. The recommendations for vitamin D supplementation, which Dr. Holick notes afflicts almost everyone, are below:
However, these dosing recommendations change for patients with obesity, as increased body weight can increase the need for vitamin D up to 2-3 fold. Dr. Holick’s research is prolific, so take a look at a recent article about the need for increased vitamin D dosing in obese patients.
The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers
This morning, Dr. Zea Borak presented an interesting talk on idiopathic pulmonary fibrosis at Grand Rounds. Perfect time for a quick primer on this rare condition!
Idiopathic pulmonary fibrosis (IPF) is a nonneoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known cause. IPF is a rare disease that affects approximately 5 million people worldwide. The prevalence is estimated to be slightly higher in men (1/5000) than in women (1/7700).
The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathlessness and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease and classic signs of right heart failure may be present.
The etiology is not yet completely understood. Environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock).
IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that have been published in guidelines endorsed by several professional societies.
includes other idiopathic interstitial pneumonias, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures.
Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medications. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. However, IPF is typically progressive and leads to significant disability.
The median survival is 2 to 5 years from the time of diagnosis.
Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1997. Available on http://www.orpha.net. Accessed (3.13.15).
Excellent Grand Rounds presentation today by Dr. Joseph Garcia, focused on HIF-2 signaling and the use of acetate to increase epo production in treatment of anemia. In his slides, he discussed the use of biomarkers beyond traditional iron studies (ferritin, transferrin, iron, etc.) to determine the etiology of a patient’s anemia. Among these, the soluble transferrin receptor (sTfR), is useful because it does not change in response to acute inflammation, making it useful in the diagnosis of anemia of chronic disease. The chart below summarizes the changes in sTfR levels in different settings of anemia:
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Dr. Saad Khan, from the UTSW division of Hematology/Oncology, presented an update on the diagnosis and treatment of thyroid cancer. A point important for general internists is the evaluation of incidentally discovered thyroid nodules. The algorithm below may help clarify the diagnostic process:
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This past Friday Dr. Ruggiero, Assistant Professor in the Division of Pulmonary and Critical Care at UT Southwestern, gave grand rounds and talked about chronic critical illness. She referred to the “ProVent” score which is a prognostic model for 1-year mortality in patients ventilated for 21 days or more. This was a prospective cohort study and identified 4 independent predictors of 1-year mortality with 1 point assigned to each variable:
1. Vasopressor requirement
3. Age greater than or equal to 50 years
4. Platelets < 150,000
A score of 0 is associated with 15% mortality compared to a score of 3 and 97% mortality. Click on the link below to review this 2008 study!