Valproic Acid-Induced Hyperammonemic Encephalopathy

Valproic AcidValproic acid is used for a variety of clinical indications including seizures, migraine prophylaxis and treatment, and bipolar disorder. A metabolite of valproic acid, thought to be propionic acid, has the ability to increase ammonia levels by inhibiting a step in the hepatic urea cycle, which may lead to valproic acid-induced hyperammonemic encephalopathy. As a result, patients treated with valproic acid presenting with signs and symptoms of acute mental status changes, increased seizure frequency, and/or gastrointestinal symptoms should be evaluated for elevated ammonia concentrations.

At Risk Patients [1,2]

Hyperammonemic encephalopathy may occur at any time during therapy with valproic acid. There is NO established relationship between the timing of initiation of valproic acid and symptom onset. In adult patients, age and gender have also been shown to have NO association with the occurrence of  hyperammonemic encephalopathy. Symptoms may occur at pharmacologically therapeutic levels.

While you should have suspicion for this pathology in any patient presenting with altered mental status on valproic acid, the following factors may place the patient at an increased risk for this complication:

  • Anticonvulsant polytherapy and medication interactions
    • Medications such as topiramate, phenytoin, carbamazepine, and phenobarbital have been associated with increased ammonia levels when used in conjunction with valproic acid
  • Renal failure
  • Hepatic failure
  • Carnitine deficiency: Carnitine assists with the elimination of valproic acid and minimizes the formation of harmful valproic acid metabolites.
    • Catabolic states such as trauma or fasting
    • Strict vegetarian diet or malnourishment
    • Long term and/or high dose valproic acid therapy or valproic acid overdose
    • Rare genetic conditions

Treatment: Levocarnitine [1-4]

Levocarnitine is the active isomer of carnitine, an essential cofactor in fatty acid metabolism. In patients with ample supply of carnitine, the majority of valproic acid is metabolized to non-toxic metabolites. In the absence of carnitine, valproic acid metabolism is shifted to an alternate pathway and can result in toxic metabolites, one of which will inhibit the urea cycle resulting in ammonia accumulation. While there are no large, randomized, controlled trials of levocarnitine treatment, numerous case reports and review articles have suggested a benefit with levocarnitine treatment in patients experiencing valproic acid induced hyperammonemic encephalopathy.

One review recommended the following regimen for patients with valproic acid overdose: 100 mg/kg IV loading dose followed by 50 mg/kg (maximum of 3 grams) IV every 8 hours until the ammonia levels are decreasing and the patient is improving [3]. The same loading dosing with lower subsequent doses (50 mg/kg/day) has also been suggested for patients who have developed hyperammonemic encephalopathy with either routine valproic acid therapy or overdose [4].

Take Home Points

  • The usage of valproic acid is increasing, as it is being utilized for a wider variety of indications.
  • Ammonia levels may become elevated in patients treated with valproic acid.
  • Hyperammonemic encephalopathy is possible at any time during treatment and at any valproic acid concentration (including therapeutic levels).
  • Symptoms may include an acute onset of nausea and vomiting, lethargy, cognitive slowing, seizures and decreased levels of consciousness.
  • Treatment for hyperammonemic encephalopathy from valproic acid includes valproic acid cessation +/-  levocarnitine treatment.


  1. Chopra A, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry 2012;34 (3):290-8. PMID 22305367
  2. Lheurex PE, et al. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol 2009;47(2):101-11. PMID 19280426
  3. Perrott J, et al. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmacother 2010;44(7-8):1287-93. PMID 20587742
  4. Mock CM, et al. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. Am J Health Syst Pharm 2012;69(1):35-9. PMID 22180549

Associate Editor: Bryan D. Hayes, PharmD, FAACT (@PharmERToxGuy)
ALiEM-Cord Fellow and Editor: Sam Shaikh, DO (@SynthShaikh)

Author information

Jill Logan, PharmD BCPS

Jill Logan, PharmD BCPS

Clinical Pharmacist

Baltimore Washington Medical Center

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Blunt Chest Trauma: Validation of the NEXUS Chest Rule

Rib fx Chest CTWe commonly see patients who have some form of blunt chest trauma. This is the result of motor vehicle collisions, falls, and a myriad of other traumatic events. The decision to perform thoracic imaging can be difficult. Chest xray (CXR) and/or chest CT? In fact, studies have shown that emergency and trauma physicians often disagree 28-40.9% of the time about which patients require a chest CT following blunt trauma [1, 2].


A recent meta-analysis [3] concluded that patients undergoing whole-body CT (head, neck, chest, abdomen, and pelvis) had a lower overall mortality than trauma patients undergoing selective CT. It is important to note that the results were based on mostly retrospective studies. Also, indiscriminate CTs in low-risk patients have the potential to cause harm from radiation exposure. A 45-year-old who undergoes a whole-body CT has a lifetime attributable risk of cancer mortality of 0.08% [4]. This means that the number needed to harm from a single trauma whole-body CT is approximately 1,250.

The lack of consensus in determining the need for a whole-body CT demonstrates the need for a decision instrument. To address the need for at least chest imaging, Rodriguez et al. have done several studies to develop the NEXUS Chest rule to aid in the decision making process.

The 7 clinical variables in the NEXUS Chest decision instrument are:

  1. Age > 60 years
  2. Rapid deceleration mechanism (fall > 20 ft or MVC > 40 mph)
  3. Chest pain
  4. Intoxication
  5. Abnormal mental status
  6. Distracting painful injury
  7. Tenderness to chest wall palpation

The NEXUS Chest rule was derived in two separate studies [5, 6]. Most recently in 2013, Rodriguez et al. published a validation study of this NEXUS Chest rule [7]. This is what will be reviewed below.


NEXUS Chest Validation of a Decision Instrument for Selective Chest Imaging in Blunt Trauma [7]

Study Design

  • Prospective, observational, diagnostic decision instrument study
  • 9 U.S. Level 1 trauma centers
  • Patients enrolled during 7 am -11 pm via systematic sampling method
  • Inclusion criteria
    1. > 14 years old
    2. Blunt trauma within 24 hours of Emergency department (ED) presentation
    3. Underwent chest imaging (CXR or chest CT) in the ED as part of their evaluation

Outcome Data

The presence or absence of Thoracic Injury seen on Chest Imaging (TICI) was determined on CXRs and Chest CTs, as interpreted by board certified radiologists. Prior to the derivation studies, an expert panel of emergency and trauma physicians defined TICI as any of the following:

  • Pneumothorax
  • Hemothorax
  • Aortic or great vessel injury
  • ≥2 rib fractures
  • Ruptured diaphragm
  • Sternal fracture
  • Pulmonary contusion or laceration

Pericardial tamponade and cardiac contusion were excluded. As part of the NEXUS Chest validation study, an expert panel of 10 physicians classified injuries according to associated clinical interventions.


  • 9,905 patients enrolled prospectively
  • Mean age: 46 years
  • Imaging practices:
    • 43.1% patients had a CXR
    • 42.0% patients had a CXR and chest CT
    • 6.7% patients had a CXR and abdominal CT
    • 5.5% patients had multiple CXRs without CT
    • 2.6% patients had a chest CT without CXR
  • TICI was seen in 1,478 (14.9%) of patients:
    • 363/1478 (24.6%) had MAJOR clinical significance
    • 1079/1478 (73.0%) had MINOR clinical significance
    • 36/1478 (2.4%) had NO clinical significance
  • Operating characteristics of NEXUS Chest Decision Instrument for all TICI:
    • Sensitivity 98.8% (95% CI, 98.1% – 99.3%)
    • Specificity 13.3% (95% CI, 12.6%-14.1%)
    • Negative Predictive Value 98.5% (95% CI, 97.6-99.1%)
    • Positive Predictive Value 16.7% (95% CI, 15.9-17.5%)
    • Negative Likelihood Ratio 0.09 (95% CI, 0.05-0.14)
  • Decision instrument missed 17 TICI (false-negatives).
    • 1/17 of those TICI was clinically significant (pneumothorax which required a chest tube).
    • Therefore, the negative likelihood ratio for TICI with MAJOR clinical significance is 0.02 (95% CI, 0-0.16).

Conclusions and Future Directions

  1. Patients who do not have any of the 7 NEXUS Chest rule clinical variables (score = 0) do not need chest imaging.
  2. This decision instrument is nonspecific and, therefore, would likely not lead to a dramatic decrease in imaging. Future research should focus on delineating the need for a chest CT versus only a CXR. The major concern with only a CXR is the fear of missing aortic and major vessel injuries, which are identifiable on chest CT. However, in the NEXUS study reviewed above, only 15/9905 (0.15%) patients had injuries to the aorta or major vessels. This extremely low rate of aortic injury may NOT justify liberal use of chest CT in low-risk stable patients. Instead, a CXR may be a reasonable screening tool for traumatic aortic injury (TAI), as supported by a decision instrument derived in 2006 [8]. In that study, the following CXR criteria of (1) a displaced left paraspinous line, (2) an abnormal aortic knob, and (3) a widened mediastinum comprised a decision instrument with a negative likelihood ratio of 0.18.
  3. Thoracic ultrasound (US) should be considered in developing future decision rules. In this study, pneumothorax and pulmonary contusion comprised 10/17 of the TICI missed by the decision rule. This included the one missed major injury. A 2010 systematic review [9] concluded that thoracic US has a higher sensitivity (86-98%) versus a supine AP CXR (28-75%) in the setting of blunt trauma. Another systemic review found thoracic US to have a sensitivity of 90.9% when compared to CT [10]. In the same study supine CXR was only 50.2% sensitive. Additionally, thoracic US has good diagnostic accuracy for lung contusion [11]. Ultimately, US may pick up small contusions and pneumothoraces while obviating the need for CT in most stable patients.

Suggested algorithm for thoracic imaging in trauma

  • NEXUS Chest score = 0
    • No thoracic imaging required
  • NEXUS Chest score ≥ 1
    • In well-appearing patient with no evidence of multiorgan injury –> CXR only without chest CT
    • In ill-appearing patients and/or those who will receive workup for other serious injury –> chest CT


  1. Tillou A, Gupta M. Baraff LJ, Schriger DL, Hoffman JR, Hiatt JR, Cryer HM. Is the use of pan-computed tomography for blunt trauma justified? A prospective evaluation. J Trauma. 2009 Oct;67(4):779-87. PMID: 19820586.
  2. Gupta M, Schriger DL, Hiatt JR, Cryer HG, Tillou A, Hoffman JR, Baraff LJ. Selective use of computed tomography compared with routine whole body imaging in patients with blunt trauma. Ann Emerg Med. 2011 Nov;58(5):407-16.e15. PMID: 21890237
  3. Caputo ND, Stahmer C, Lim G, Shah K. Whole-body computed tomographic scanning leads to better survival as opposed to selective scanning in trauma patients: A systematic review and meta-analysis. J Trauma Acute Care Surg. 2014 Oct;77(4):534-9. PMID: 25250591
  4. Brenner DJ, Elliston CD. Estimated radiation risks associated with full-body CT screening. Radiology. 2004 Sep;232(3):735-8. PMID: 15273333
  5. Rodriguez RM, Hendey GW, Marek G, Dery RA, Bjoring A. A pilot study to derive clinical variables for selective chest radiography in blunt trauma patients. Ann Emerg Med. 2006 May;47(5):415-8. PMID 16631976.
  6. Rodriguez RM, Hendey GW, Mower W, Kea B, Fortman J, Merchant G, Hoffman JR. Derivation of a decision instrument for selective chest radiography in blunt trauma. J Trauma. 2011 Sep;7(3):549-53. PMID: 21045745
  7. NEXUS chest: validation of a decision instrument for selective chest imaging in blunt trauma. Rodriguez RM, Anglin D, Langdorf MI, Baumann BM, Hendey GW, Bradley RN, Medak AJ, Raja AS, Juhn P, Fortman J, Mulkerin W, Mower WR. JAMA Surg. 2013 Oct;148(10):940-6. PMID: 23925583. Free article PDF
  8. Ungar TC, Wolf SJ, Haukoos JS, Dyer DS, Moore EE. Derivation of a clinical decision rule to exclude thoracic aortic imaging in patients with blunt chest trauma after motor vehicle collisions. J Trauma. 2006. Nov;61(5):1150-5. PMID: 17099521
  9. Wilkerson RG, Stone MB. Sensitivity of bedside ultrasound and supine anteroposterior chest radiographs for the identification of pneumothorax after blunt trauma. Acad Emerg Med. 2010. Jan;17(1):11-7. PMID: 20078434.
  10. Alrajhi K, Woo MY, Vaillancourt C. Test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis. Chest. 2012. Mar;141(3):703-8. PMID: 21868468
  11. Hyacincthe AC, Broux C, Francony G, Genty C, Bouzat P, Jacquot C, Albaladejo P, Ferretti GR, Bosson JL, Payen JF. Diagnostic accuracy of ultrasonography in the acute assessment of common thoracic lesions after trauma. Chest. 2012. May;141(5):1177-83. PMID: 22016490.


Expert Peer Review: Dr. Robert Rodriguez (lead author)

October 8, 2014

While the rate of traumatic injuries has remained steady, the use of diagnostic imaging for blunt trauma evaluation (especially head to pelvis CT, or “Pan-Scan”) has increased substantially. Indiscriminate use of imaging leads to higher costs, emergency department time, and perhaps most importantly—increased patient radiation exposure. One important measure to quell this explosion in use of imaging, is the development and use of decision instruments (DIs), such as the NEXUS Cervical Spine rule, to safely guide selective imaging.

Our work is directed at decreasing unnecessary thoracic imaging in blunt trauma evaluation. As Dr. Morley summarizes well, we have derived and validated the NEXUS Chest DI that safely guides selective chest/thoracic imaging. It is true that with its relatively low specificity, NEXUS Chest will be able to rule out intra-thoracic injury and spare imaging in a minority of patients (approximately 13%). Our rationale behind developing this low specificity rule is a product of the need to adhere to the overriding principle of maximizing safety, or sensitivity, of the DI. Our expert trauma panel consisting of emergency medicine physicians and trauma surgeons strongly believed that in order to be widely accepted and implemented, a selective chest trauma imaging DI must have near-perfect ability to detect (and rule out) clinically significant injury. Our rule meets that critically important criterion of safety: The sensitivity and negative predictive value of NEXUS Chest for clinically major injury were 99.7% (95%CI, 98.2%-100.0%) and 99.9% (95%CI, 99.4%-100.0%), respectively [1].

It is important to note that NEXUS Chest (and essentially all other directive rule out injury DIs) only tell clinicians when it is safe to forego imaging—they do not mandate imaging in those patients who happen to have one or more of the 7 criteria. Misuse of DIs in this manner can paradoxically lead to increased imaging. For example, when evaluating a geriatric patient who had a minor fall, the fact that the patient is older than 60 years (one of our criteria) does not mean that you have to get a CXR or other chest imaging. NEXUS Chest should not be applied to all adult blunt trauma patients—it should be used in those patients in whom you were already planning to image.

NEXUS Chest will eliminate the need for chest imaging (mostly CXR) upfront in certain blunt trauma patients but where do we go from there in terms of reducing unnecessary diagnostic imaging of the thorax in blunt trauma? The next goal is to reduce chest CT in blunt trauma. We have demonstrated that although chest CT has much higher sensitivity for diagnosing intra-thoracic injury, its indiscriminate use is associated with very high cost and patient radiation exposure. Chest CT in the blunt trauma patient who has a normal or near-normal CXR may be associated with over $200,000 in charges and 593 millisievert effective radiation dose per major injury identified [2].

We are currently in the final stages of developing a DI for selective chest CT in trauma, which we will incorporate into a comprehensive selective chest imaging algorithm.

  1. Rodriguez RM, Anglin D, Langdorf MI, et al. NEXUS Chest: Validation of a decision instrument for selective chest imaging in blunt trauma. JAMA Surg. 2013 Oct;148(10):940-6. PMID: 23925583.
  2. Rodriguez RM, Baumann BM, Raja AS, et al. Diagnostic yields, charges, and radiation dose of chest imaging in blunt trauma evaluation. Acad Emer Med. 2014;6:644-650. PMID: 25039548
Robert Rodriguez, MD, Professor of Clinical Emergency Medicine, UC San Francisco (UCSF)



Author information

Eric Morley, MD

Eric Morley, MD

Associate Residency Director

Assistant Professor of Emergency Medicine

SUNY Stony Brook

Associate Chief of EM, Peconic Bay Medical Center

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I am Dr. Lauren Westafer, Author of The Short Coat: How I Work Smarter

How I Work Smarter LogoI first came to know of Dr. Lauren Westafer (@LWestafer) when she started the amazing The Short Coat blog as a medical student. I feel like such a slacker during medical school… She has quickly risen to the esteemed ranks of online medical education because of both the blog and her podcast, FOAMCast, with Dr. Jeremy Faust. Lauren has kindly agreed to share her tips for working more efficiently.


  • WestaferName: Lauren Westafer, DO MPH
  • Location: Northampton, MA USA
  • Current job: Emergency Medicine PGY-2 at Baystate Medical Center/Tufts University
  • One word that best describes how you work: Happily
  • Current mobile device: iPhone
  • Current computer: MacBook Pro


What’s your office workspace setup like?

As a resident, my office is wherever I am doing work and typically consists of my iPhone and MacBook and/or iPad.  Most of my “work” consists of studying and side-projects; thus, my work often gets done concurrently with activities of daily living. See my home and gym “offices”:

Westafer Laptop

Westafer Gym

My FOAMcast partner and I even pack our microphones whenever we travel to capitalize on free time.

Westafer Suitcase


What’s your best time-saving tip in the office or home?

While multi-tasking is largely a product of our imaginations, I try to work in environments or situations that make the work/studying more appealing. For example, for dedicated studying and complex tasks, I engage in that sole activity. For “extra” reading or projects and less cognitively strenuous tasks, I work while doing cardio at the gym or outdoors. As a result, I work happily while maintaining things in my life that augment my sense of balance (such as exercise, the outdoors, and cooking).

What’s your best time-saving tip regarding email management?

I process it as soon as I can, preferably in bulk, making use of a cornucopia of folders and calendars; however, I do not look at email whilst working clinically.

What’s your best time-saving tip in the ED?

As a resident, I’m still relatively slow and methodical, but two things have helped my efficiency in addition to documenting as I work. I use auto-text for common complaints or practice patterns. For example, if I type .AMA in the chart text, it brings up my auto-text for patients that might be leaving or threatening to leave when I believe work-up/treatment are still warranted.  The auto-texts have fill-in-the-blanks, reminding me to tailor things to that patient but also prompt me to ensure I’ve addressed all of these facets with the patient. Building a good relationship with nurses, technicians, and even the folks who stock the rooms not only makes working more fun but can improve efficiency (getting a patient to x-ray, blood draws, etc).

ED charting: Macros or no macros?

Judicious use of macros, with a personal rule to not use them on sick or medically complex patients. Macros can lead to inaccurate documentation through mindless clicking.  Thus, in my evolving practice, many of mine have fill in the blank sections that remind me to reflect and thereby document key portions.

What’s the best advice you’ve ever received about work, life, or being efficient?

“Early is on-time, on-time is late, and late is unacceptable.” -Rugby Coach, Band Director

“Let the beauty we love be what we do” -Rumi

When we’re passionate about what we do, we tend to work more happily, sustainably, and diligently – choose projects that incite these feelings.

Is there anything else you’d like to add that might be interesting to readers?

Using cloud-based resources such as Google Drive, DropBox, and Mendeley and ensuring pristine organization and systematic use of these resources has been invaluable.

Who would you love for us to track down to answer these same questions?

  • Chris Nickson
  • Haney Mallemat
  • John Greenwood

Author information

Michelle Lin, MD

ALiEM Editor-in-Chief

Editorial Board Member, Annals of Emergency Medicine

UCSF Academy Endowed Chair for EM Education

UCSF Associate Professor of Emergency Medicine

San Francisco General Hospital

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ALiEM Bookclub: When Doctors Don’t Listen

When Doctors Don't Listen

“So what does this ideal medical care look like? The great Tip O’Neill, himself a Boston man, used to say, ‘All politics is local.’ We believe in its corollary, that all medicine is personal. The world of better medicine starts with the individual patient interacting with the individual doctor.”

-The October ALiEM Bookclub Selection:
When Doctors Don’t Listen [1],
by Leana Wen and Joshua Kosowsky




The Rise of Patient-Centered Care

The nature of the patient-physician relationship has seen significant evolution over the past century, for better and for worse. As technology has increased our ability to treat disease, some of the human aspects of delivering medical care–such as keeping the patient at the center of the medical process–have been lost along the way. Today, we find ourselves surrounded by scores of clinical decision making rules, diagnostic algorithms, and smartphones filled with apps. While these tools have a role in helping care for patients, alone they do nothing to improve the delivery of healthcare at the bedside.

Since the Institute of Medicine (IOM) declared patient-centered care as one of its six aims for improvement in healthcare for the 21st century, this approach to the patient-physician relationship has become widely recognized across all domains of medicine. Patient-centered care is defined by IOM as “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”[2]

Patient-centered care seems clear enough on paper, but is far more nebulous to employ in day-to-day practice. In pursuit of this model for healthcare, various approaches to incorporating patients in the delivery of their care have been studied; some familiar strategies include shared decision-making, building engaged communities of patients and providers, and integrating patient data and technology in the care plan for patients. Still, these approaches do not provide a relatable means of reframing our mindset for every clinical encounter.

In examining shared decision-making and participatory medicine through the lens of an element central to all clinical situations– the diagnosis–authors Dr. Leana Wen and Dr. Joshua Kosowsky aim to change the way patients and doctors think when they enter the exam room.

Brief Synopsis

When Doctors Don’t Listen: How to Avoid Misdiagnoses and Unnecessary Tests is, at its core, an argument for the revival of the art of diagnosis through meaningful dialogues with patients. Through a collection of insightful anecdotes, critical analysis of current trends in medicine, and actionable advice for both patients and healthcare providers, Drs. Leana Wen (@DrLeanaWen) and Joshua Kosowsky (@DrKosowsky) make a compelling case for the return of individualized, patient-centered care anchored in the practice of excellent bedside medicine. In addition to the compelling stories of patients helplessly tangled in an algorithmic healthcare system, the authors also provide a stepwise strategy to empower patients each time they interact with the healthcare system and to improve their own health literacy. Drs. Wen and Kosowsky also offer a complementary approach for physicians to improve their communication skills and practice more patient-centered medicine. After a careful dissection of the obstacles to accurate diagnosis and participatory medicine, Drs. Wen and Kosowsky prescribe a ground up approach for reforming healthcare: cut out the “rule-out” mindset and return to a thoughtful, individualized approach to medicine.

Clinical Application

The patient-physician relationship and a skillful diagnosis constitute cornerstones of medicine. This book is directly aimed at improving those cornerstones in a new era of healthcare. Despite being primarily aimed at patients, When Doctors Don’t Listen offers skills that physicians can directly implement at the bedside. In the main text, the authors provide a detailed plan for patients to be more active in their healthcare interactions–the so called 8 Pillars to Better Diagnosis. While understanding these goals for participatory care from the patient’s perspective can easily allow doctors to reconsider their own practices, the book’s appendix includes an entire section that explores the 8 pillars from the perspective of a healthcare provider. Throughout, clinicians can find specific advice, example phrases, and even responses to common criticisms that are immediately employable in daily practice. If nothing else, this book can open physicians’ minds to reconsider some aspects of their care and gain an understanding of the expectations of the 21st-century patient.

On October 8, 2014, Dr. Jordana Haber (Maimonides Medical Center) and I hosted a bookclub discussion featuring Dr. Leana Wen.

Book Club Questions

  1. Participatory medicine requires significant investment from both doctors and patients. Given the huge disparities that exist in health literacy, how much responsibility should patients be expected to take for their role in their healthcare? How can we foster continual growth of this role?
  2. Is shared decision-making and active collaboration between patients and physicians sufficiently well defined to monitor the extent to which it is delivered?
  3. The authors respond to various common criticisms of their approach in the text. What are some challenges you have encountered when trying to individualize care for patients and champion a participatory approach to your practice of medicine? Have you found any solutions to these challenges?
  4. Emergency physicians can often recall stories of close calls–when something just seemed off about a patient, and they were able to catch an insidious presentation of a life-threatening problem. Less often, we hear about situations when an overlooked fact or patient concern led to a change of course in a patient’s care. Tell us about a time you have changed your diagnostic reasoning based on a deeper dialogue with a patient. How did this experience inform your future practice of medicine?


There are two main way to join our ALiEM Book club discussion this month:

  1. You can comment directly below in the comment section.
  2. Tweet us directly at @ALiEMBook, use hashtag #ALiEMbook.




  1. Wen L, Kosowsky J. When Doctors Don’t Listen, How to Avoid Misdiagnoses and Unnecessary Tests. Macmillan; 2013. [Amazon]
  2. Institute of Medicine (US). Committee on Quality of Health Care in America.Crossing the quality chasm: A new health system for the 21st century. National Academies Press, 2001.

Disclaimer: We have no affiliations financial or otherwise with the authors, the books, or Amazon.

Author information

Scott Kobner

Medical student

New York University School of Medicine

ALiEM-EMRA Social Media and Digital Scholarship Fellow


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Carbon Monoxide Poisoning – It’s That Time of Year Again

Screen Shot 2014-09-24 at 9.29.50 PMCarbon monoxide (CO) poisoning may be the most common cause of fatal poisonings worldwide [1]. The majority of poisonings occur in the Fall and Winter. It is that time of year when heaters that have lain dormant all summer are flicked on, sometimes in enclosed areas, introducing CO fumes into homes. The pathophysiology is complex, and not fully understood, but all ED physicians should be aware of the signs and symptoms of CO toxicity, and know how to treat it.


CO affects oxygen delivery through various mechanisms. The most obvious is through formation of carboxyhemoglobin (COHb). Hb binds CO 200 times more tightly than oxygen. About 85% of the CO binds to Hb to form COHb. COHb induces a left shift in the HbO2 dissociation curve, so O2 is not released to the tissues. The remainder of the CO is either dissolved in plasma, or bound to proteins, and wreaks havoc in a myriad of other ways. From the plasma, it can diffuse into cells where, like cyanide, it inhibits cytochrome oxidase, thereby interfering with cellular metabolism and ATP production. CO also causes endothelial damage which then triggers an inflammatory state. CO can also initiate a cascade of events that leads to NO release and vasodilation, causing hypotension. The intracellular toxicity along with hypoxia and hypotension can lead to myocardial infarction, neuron death, and rhabdomyolysis.


student page imageSymptoms and History

The diagnosis is challenging, particularly in more mild cases and in cases of chronic CO poisoning. Symptoms can range from flu-like illnesses (which also conveniently start to crop up around the same time of year), headache, vomiting, confusion, dyspnea, and chest pain, to focal neurologic deficits, seizures, ataxia, syncope, visual changes, and coma.

Obtaining a history, where possible, is key to the diagnosis. Ask about exposure to heaters, fires, or gas or propane-powered motors, particularly in close spaces. If the patient presented from a house fire, it is easy to focus on their burns or trauma, and forget the possibility of CO poisoning. If the exposure occurred at home, then multiple family members may be symptomatic though the symptoms may differ based on their age and underlying health status. Physical findings can also vary. The patient may be tachycardic, dyspneic, and hypotensive due to the physiologic changes described above. In severe cases, they may have cardiac or respiratory failure and arrest.


The first key to diagnosis is to consider CO poisoning in your differential! The next step is to check a COHb level if your ABG/VBG machine has co-oximetry capability or if you have a non-invasive COHb monitor (although these are still under investigation). Routine ABG/VBG machines that lack co-oximetry may give a falsely high O2 sat reading [2]. In addition, you cannot trust your usual O2 sat probe [3]! COHb absorbs at around the same wavelength as HbO2, so the patient may be dyspneic, with very little tissue oxygen delivery, and yet have a very high O2 saturation reading on their finger probe.

The next challenge is in interpreting the co-oximetry result. You have to take into account:

  • The chronicity or duration of exposure
  • The time from exposure to measurement
  • Any intervening treatment (such as supplemental oxygen)
  • The underlying health of the patient

For all these reasons, the percentage of COHb does not always correlate with the patient’s symptoms or their prognosis. A patient may be severely neurologically damaged and have a lower COHb than a less symptomatic patient. This could be because the symptomatic patient had higher levels previously, but did not reach an ED and have a co-oximetry measured until later. Or it may be due to age or co-morbidities. For example, patients with underlying CAD may develop ischemia due to decreased oxygen delivery, have angina, exhibit an elevated troponin, or demonstrate ECG changes at COHb levels as low as 4-6% [4].

Meanwhile, smokers without any additional exposure can have baseline COHb levels as high as 10% [2]. However, as long as physicians take into account duration of exposure, time of measurement, and any intervening treatment (such as supplemental oxygen), the degree of COHb formation is a reasonable marker of the severity of the exposure.

Other lab values that can give a clue to CO poisoning are from the inhibition of intracellular metabolism, which leads to a metabolic, anion gap, lactic acidosis. In addition, an oxygen saturation gap of greater than 5% difference between O2 sat measured from a finger probe and measured on a blood gas sample can give a clue to the presence of aberrant hemoglobin forms [5].


The treatment is oxygen, and lots of it.

On room air, the half-life of COHb is about 200 minutes. If a patient is put on 100% FiO2, that half-life drips to around 80 minutes. The route of administration will depend on the patient’s symptoms and severity. If the symptoms are mild to moderate, then they can be treated with 100% O2 on a facemask. If severe, they may require intubation, and in the most severe cases, hyperbaric oxygen. The indications for hyperbaric oxygen are still under debate. However, it should be considered in patients with “ataxia, seizure, syncope, chest pain, focal neurologic deficits, dyspnea, or EKG changes” or a COHb level over 25% [2]. Some studies recommend hyperbaric oxygen be considered for any acutely symptomatic patient [6]. However, the decision to transfer for hyperbaric oxygen (since most EDs will lack this capability) will also depend on the stability of the patient, and the distance to transfer. For more information about the hyperbaric oxygen therapy debate, read Dr. Repplinger’s nice ALiEM review, which is accompanied by Dr. David Juurlink’s expert peer review comments.

Patients with mild to moderate symptoms, who do not require hospitalization for any other reason, can usually be observed for 4 hours, treated with non-invasive oxygen, counseled regarding exposure and use of CO detectors, and discharged if they have a safe place to go. If there is a concern about home exposure, the fire department can also do a home assessment and check for CO leaks if there are no CO detectors.

Fetal Hb binds even more tightly to CO [7], making CO poisoning even more dangerous for pregnant women. It is therefore recommended that pregnant women be referred for hyperbaric oxygen if there is a COHb level of 15% or higher [4].

Special case: Methylene chloride exposure

A special case is that of COHb formed due to methylene chloride exposure [8]. Methylene chloride is a component in some paint strippers and varnishes. Exposure can occur through ingestion or inhalation. The methylene chloride metabolism forms CO. Therefore, with an ongoing source of CO formation, the half-life can increase to 13 hours.


  • Consider CO poisoning in patients with non-specific symptoms such as headaches and nausea, as well as in those with focal neurologic deficits, syncope, or otherwise unexplained respiratory distress.
  • Ask about CO detectors in people’s homes.
  • Do not trust a finger pulse-oximetry measure in CO poisoning. It will be falsely elevated.
  • Check a VBG or ABG with co-oximetry if concerned.
  • Treat with oxygen, and in severe cases, consider transfer to a hyperbaric oxygen center, particularly in patients with more severe symptoms, higher COHb levels, or in pregnancy.


  1. Raub JA, Mathieu-Nolf M, Hampson NB, Thom SR. Carbon monoxide poisoning–a public health perspective. Toxicology. 2000 Apr 7;145(1):1-14. PMID: 10771127.
  2. Maloney G. Carbon Monoxide. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. New York, NY: McGraw-Hill; 2011. Accessed September 23, 2014.
  3. Bozeman WP, Myers RA, Barish RA. Confirmation of the pulse oximetry gap in carbon monoxide poisoning. Ann Emerg Med. 1997 Nov;30(5):608-11. PMID: 9360570.
  4. Kao LW, Nañagas KA. Carbon monoxide poisoning. Emerg Med Clin North Am. 2004 Nov;22(4):985-1018. PMID: 15474779.
  5. Akhtar J, Johnston BD, Krenzelok EP. Mind the gap. J Emerg Med. 2007 Aug;33(2):131-2. Epub 2007 Jun 5. PMID: 17692762.
  6. Weaver LK. Hyperbaric oxygen therapy for carbon monoxide poisoning. Undersea Hyperb Med. 2014 Jul-Aug;41(4):339-54. PMID: 25109087.
  7. Engel RR, Rodkey FL, O’Neal JD, Collison HA. Relative affinity of human fetal  hemoglobin for carbon monoxide and oxygen. Blood. 1969 Jan;33(1):37-45. PMID: 5763632.
  8. Chang YL, Yang CC, Deng JF, Ger J, Tsai WJ, Wu ML, Liaw HC, Liaw SJ. Diverse manifestations of oral methylene chloride poisoning: report of 6 cases. J Toxicol Clin Toxicol. 1999;37(4):497-504. PMID: 10465248.

Image credit [1 and 2]

Author information

Christina Shenvi, MD PhD

Christina Shenvi, MD PhD

Assistant Professor

Assistant Residency Director

University of North Carolina

The post Carbon Monoxide Poisoning – It’s That Time of Year Again appeared first on ALiEM.

EM Match Advice: Making The Perfect Rank Order List

EM Match iconWith interview season rapidly approaching in a few months (Nov-Feb), we gathered a few more of our favorite program directors to discuss the hot topic of making the rank order list. We feature Dr. Colleen Roche (George Washington), Dr. Jonathan Davis (Georgetown), and Dr. Brian Stettler (Univ of Cincinnati). Thanks again to Dr. Mike Gisondi (Northwestern) for spearheading this innovative and helpful EM Match Advice video series for medical students.

EM Match Advice #4: The Rank Order List


  • 00:00 Dr. Gisondi introduces the expert panel and the five steps in making the rank list. It is important to think of these steps BEFORE interview season starts so that you most efficiently gather information during your interview days.
  • 04:50 Dr. Roche discusses what kind of information that program directors and residents may be presenting to you during interview day. Much of this may not be on the residency website.
  • 08:25 Dr. Roche and Dr. Gisondi comment on what factors the student should focus on in making his/her rank list.
  • 11:10 Dr. Davis follows up discussing information overload and what information may/may not be as important to factor into the rank list. The important elements to focus on the 3 P’s = people, passion, philosophy.
  • 18:30 Dr. Stettler tries to tackle the question of — how do I advise my students on how to make a rank order list?
  • 20:10 Dr. Stettler addresses how to approach “the love note” and whether you can “game” the NRMP match algorithm.
  • 22:30  The panelists discuss two major deciding factors of geography vs programmatic elements.
  • 28:22 Dr. Lin reflects on the comments thus far and then surprises the panelists with a question of her own: What’s your take on the Doximity listing of the best EM programs? The panelists address this question. Here is the official joint response by ACEP, CORD, AAEM, ACOEP, and EMRA.
  • 34:48 The panelists address a case of a student who is at a total loss on how to rank their list of programs. They loved all the sites and now can’t decide. Now what?
  • 47:45 The program directors are challenged to share something that Dr. Gisondi doesn’t know about their program.



  1. Lin M. Top 10 tips on making your rank list, ALiEM (2010).
  2. Joshi N. Making your match rank list, ALiEM (2013).
  3. Deiorio NM, Yarris LM, Gaines SA. Emergency medicine residency applicant views on the interview day process. Acad Emerg Med. 2009 Dec;16 Suppl 2:S67-70. PMID: 20053215.
  4. Yarris LM, Deiorio NM, Lowe RA. Factors applicants value when selecting an emergency medicine residency. West J Emerg Med. 2009 Aug;10(3):159-62. PMID: 19718377
  5. DeSantis M, Marco CA. Emergency medicine residency selection: factors influencing candidate decisions. Acad Emerg Med. 2005 Jun;12(6):559-61.PMID: 15930408.
  6. Love JN, Howell JM, Hegarty CB, McLaughlin SA, Coates WC, Hopson LR, Hern GH, Rosen CL, Fisher J, Santen SA. Factors that influence medical student selection of an emergency medicine residency program: implications for training programs. Acad Emerg Med. 2012 Apr;19(4):455-60. PMID: 22506950.

Author information

Michelle Lin, MD

ALiEM Editor-in-Chief

Editorial Board Member, Annals of Emergency Medicine

UCSF Academy Endowed Chair for EM Education

UCSF Associate Professor of Emergency Medicine

San Francisco General Hospital

The post EM Match Advice: Making The Perfect Rank Order List appeared first on ALiEM.