Controversies in the Diagnosis and Management of Cellulitis

Journal Club Podcast #37: July 2017

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A brief discussion of several of the controversies that have popped up in the last few years regarding the diagnosis and management of cellulitis...

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Articles:

Article 1: Peterson D, McLeod S, Woolfrey K, McRae A. Predictors of failure of empiric outpatient antibiotic therapy in emergency department patients with uncomplicated cellulitis. Acad Emerg Med. 2014 May;21(5):526-31. Answer Key.

Article 2: Pallin DJ, Camargo CA Jr, Schuur JD. Skin infections and antibiotic stewardship: analysis of emergency department prescribing practices, 2007-2010. West J Emerg Med. 2014 May;15(3):282-9. Answer Key.

Article 3: Weng QY, Raff AB, Cohen JM, Gunasekera N, Okhovat JP, Vedak P, Joyce C, Kroshinsky D, Mostaghimi A. Costs and Consequences Associated With Misdiagnosed Lower Extremity Cellulitis. JAMA Dermatol. 2016 Nov 2. Answer Key.

Article 4: Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, Rothman RE, Karras DJ, Hoagland R, Pettibone S, Talan DA. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. JAMA. 2017 May 23;317(20):2088-2096. Answer Key.

Vignette:

You're moonlighting in a local ED one afternoon, when you encounter Mrs. X, a 40-year-old woman with rheumatoid arthritis, for which she takes Methotrexate. She was gardening three days prior to presentation when she suffered a small cut to her left ankle from a misplaced spade. The following day, there was some mild erythema around the wound, which has progressed. She now has redness, warmth, and mild swelling to the lateral ankle and distal calf, with no signs of lymphangitis and no fluctuance. The ankle joint moves easily and without pain. As she is afebrile and well appearing, you discuss with her PMD and send her out on Bactrim and Keflex, to cover both Strep species and MRSA.

The very next patient you meet is Mr. Y, a 50-year-old obese male with CHF. He has had swelling in both his legs for quite some time, chalked up in the past to chronic lymphedema and CHF, but now has redness and pain to both ankles and lower legs. Given the severity of the redness and swelling, you elect to treat the patient for cellulitis and order vancomycin, then place an admission order. The hospitalist muses that perhaps the patient has venous stasis dermatitis, but admits that it's probably worth treating for potential cellulitis.

Thinking back to both patients later in the day, you begin to worry about your treatment plans. Should the immunosuppressed woman have been admitted for her cellulitis? What factors make patients more prone to treatment failure? Do you always need to prescribe both Bactrim and Keflex for cellulitis (see IDSA guidelines for SSTIs)? And finally, could the second patient have had stasis dermatitis, and if so, did he really need antibiotics and admission? You decide to look into the evidence to try to answer these questions, and dive right into the literature...

PICO Question:

Given the nature of the journal club this month, no specific PICO questions was devised. Instead, we looked at several controversial issues surrounding the management of cellulitis, including diagnostic accuracy, antibiotic selection, risk factors for treatment failure, and prescribing practices.

Search Strategy:

Again, due to the nature of the journal club, no specific search strategy was undertaken. Recent high-impact articles were selected from the medical literature, some due to their highly controversial nature.

Bottom Line: Cellulitis, a common skin infection, results in around 2.3 million ED visits in the US annually. This number has risen over the years with the increasing prevalence of community-acquired MRSA (CA-MRSA) (Pallin 2008). Despite these rising numbers, there remains significant controversy regarding the diagnosis and management of this common condition, in part due to the lack of objective diagnostic criteria, the presence of several hard to distinguish mimics (Weng 2016), and difficulties in determining the bacterial etiology in the majority of cases (Jeng 2010).

The most recent guidelines from the Infectious Diseases Society of America (IDSA) do not recommend adding MRSA coverage for the management of mild or moderate non-purulent skin and soft-tissue infections (i.e. cellulitis and erysipelas). The PGY-4 paper (Moran 2017) found that among patients treated as an outpatient for cellulitis, cephalexin alone resulted in similar cure rates to cephalexin plus trimethroprim-sulfamethoxazole, supporting the IDSA recommendations. However, it should be noted that this recommendation does not apply to patients with fever or leukocytosis, or in immunocompromised patients. In our PGY-2 paper (Pallin 2014), the authors determined, among other things, that 63% of patients with cellulitis were given antibiotic regimens that included CA-MRSA coverage. Unfortunately, they did not attempt to determine how many of these patients had criteria that would exclude them from the IDSA recommendation, but instead insinuate that nearly all of them were being treated inappropriately. They even go so far as to recommend using this as a reported quality measure for Medicare’s Physician Quality Reporting System, a suggestion that is both premature and potentially dangerous.

Our PGY-3 article (Weng 2016) went a step further, attempting to determine the costs associated with misdiagnosis of lower extremity cellulitis in the US. They report that 30.5% of patients admitted to the hospital with lower extremity cellulitis in their study were misdiagnosed, and that the majority of these patients did not require hospital admission. Using a literature review, they therefore determined that such misdiagnoses cost between $195 and $515 million dollars annually throughout the US. Unfortunately, all of these conclusion are based on a highly methodologically flawed retrospective study in which final diagnosis was determined by chart review out to thirty days post-discharge. It is quite likely that the retrospective conclusion of misdiagnosis was, in many cases, itself a misdiagnosis. Additionally, the authors offer no direction on how to avoid such proposed misdiagnosis, failing to consider the amount of data available 30 days after presentation that would not be available to the ED physician at the time of presentation (e.g. response to treatment), and fail to note that among misdiagnosed patients who were deemed not to require hospital admission at all (determined retrospectively by dermatologists), the mean length of stay was over 4 days! This information suggests that either these patients did, in fact, need to be admitted, or that the ability to differentiate cellulitis from “pseudocellulitis” did not become evident until several days of observation had passed. An editorial written in response to this review notes many of these issues, but also calls for improved diagnostic capabilities and discussion between the ED and admitting physicians (Moran 2017), which seems more than reasonable.

Our PGY-1 paper (Peterson 2014) found that fever (odds ratio [OR] 4.3), chronic leg ulcers (OR 2.5), chronic edema or lymphedema (OR 2.5), prior cellulitis in the same area (OR 2.1), and cellulitis at a wound site (OR 1.9) were all predictors failure of outpatient management of cellulitis.

All of this evidence suggests that cellulitis can be a difficult diagnosis fraught with controversy. Care should be taken when diagnosing lower extremity cellulitis, as there are many mimics that do not require antibiotics. Care should also be taken in those patients with risk factors for failed outpatient therapy, with close follow-up and good return precautions given to such patients. Additionally, improved adherence to current IDSA guidelines would likely result in use of fewer antibiotics with fewer adverse effects.

Diagnosis of Atraumatic Subarachnoid Hemorrhage

Journal Club Podcast #36: June 2017

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Dr. Chris Carpenter and Marco Sivilotti bridge the US-Canada border to bring us a new podcast on the diagnostic approach to atraumatic SAH...

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Articles:

Article 1: Sensitivity of early brain computed tomography to exclude aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis, Stroke 2016; 47: 750-755). (http://pmid.us/26797666) Answer Key.

Article 2: False-negative interpretations of cranial computed tomography in aneurysmal subarachnoid hemorrhage, Acad Emerg Med 2016; 23: 591-598. (http://pmid.us/26918885) Answer Key.

Article 3: Spontaneous subarachnoid hemorrhage: A systematic review and meta-analysis describing the diagnostic accuracy of history, physical examination, imaging, and lumbar puncture with an exploration of test thresholds, Acad Emerg Med 2016; 23: 963-1003. (http://pmid.us/27306497) Answer Key.

Article 4: Determination of a testing threshold for lumbar puncture in the diagnosis of subarachnoid hemorrhage after a negative head computed tomography: A decision analysis, Acad Emerg Med 2016; 23: 1119-1127. (http://pmid.us/27378053) Answer Key.

Vignette: Mrs. Z. is a healthy 30-year-old female who presents to your emergency department 2-hours after onset of “the worst headache of my life” which peaked within 1 minute of onset but was not “thunderclap”. She describes the headache as diffuse with associated nausea, but no photophobia, neck stiffness, vomiting, focal motor-sensory deficits, or fever. She reports no recent viral or febrile illness, blunt trauma, travel history, or sick contacts. Nobody else at home or work has had a headache recently. Her immunizations are up-to-date and she denies any significant PMH including no history of migraine (or other) headache disorders, cerebral aneurysm, stroke, HIV or other immunocompromising disorder, pseudotumor cerebri, malignancy, bleeding diatheses, or meningitis. She denies recent alcohol use or any history of intravenous or illicit substance abuse. She has not tried any medications for her headache. She is a secretary and lives at home with her husband and 3 year old child.

In the ED, her vitals are BP 106/55, P 58, RR 18, T 37.2°C, and 100% oxygen saturation on room air. She is in no acute distress, and her exam is unremarkable.

As you consider the diagnosis of subarachnoid hemorrhage and await her CT, you weigh the value of a post-CT lumbar puncture. You recall a recent meta-analysis discussed on your favorite “podcast” Emergency Medical Abstracts (listen here) as well as an episode of McMaster’s Textbook of Internal Medicine (watch here) and wonder how other researchers and specialties interpret the best evidence. Realizing that there are two distinct questions for the ED diagnosis of SAH, you develop two PICO questions.

PICO Question:

PICO Question #1

Population: ED patients with sudden onset severe headache concerning for aneurysmal SAH (aSAH)

Intervention: Computed tomography within 6 hours of symptom onset

Comparison: No comparator

Outcome: CT sensitivity, specificity, positive/negative likelihood ratio for aSAH

PICO Question #2

Population: ED patients with sudden onset severe headache concerning for aneurysmal SAH (aSAH)

Intervention: Lumbar puncture following unremarkable CT

Comparison:No comparator

Outcome: LP sensitivity, specificity, positive/negative likelihood ratio for aSAH

Search Strategy:

Using these PICO questions, you devise a PubMed search using Clinical Queries (diagnosis/broad) and the search term “aneurysmal subarachnoid hemorrhage” which identifies 2891 studies (see http://tinyurl.com/zrvgc3s) from which you select the 4 studies below from last year.

Bottom Line:

Needle in a Haystack

Headaches represent about 2% of emergency department (ED) visits annually. While severe headache patients presenting with altered mental status, fevers, or associated trauma usually generate sufficient concern to justify further diagnostic evaluations, most other sudden onset headache cases ultimately prove to result from benign, non-life threatening causes like migraine headache. The myriad causes of sudden onset headaches include cough, exertion, and post-coital, but can also include potentially life-threatening conditions like sinus thrombosis, vascular dissection, intracerebral hemorrhage, vasospasm, and aneurysmal subarachnoid hemorrhage. [Landtblom 2002, Delasobera 2012, de Bruijn 1996, Pascual 1996, Dodick 1999] Observational studies indicate that migraine headaches are at least 50-times more common than SAH amongst ED headache patients, so SAH represents a needle in a haystack for a very common chief complaint. [Edlow 2003] Missed SAH diagnosis occurs between 12%-53% of cases with ED providers estimated to miss 5% of them. [Edlow 2000, Vermeulen 2007]

Up to 80% of SAH cases result from a ruptured cerebral aneurysm. Other causes of SAH include low-pressure perimesencephalic bleeds, cerebral amyloid angiopathy, vasculitis, sickle cell disease, and cocaine or amphetamine abuse. [Carpenter 2016] One-fourth of aneurysmal SAH victims die within one-day and 50% of SAH survivors never return to work. Correctly identifying SAH early can reduce these adverse outcomes if subsequent neurosurgical interventions (coiling or clipping) occur emergently. [Schievink 1997] Therefore, the possibility of aneurysmal SAH must be considered in ED patients presenting with severe headaches. Understanding the SAH diagnostic evidence available for bedside evaluation, advanced imaging, and the role for lumbar puncture (LP) is therefore essential and the landscape is shifting.

Non-Contrast Cranial CT

Computed tomography (CT) became widely available for the evaluation of headache patients about 30 years ago. Early CTs were 4-slice and radiologists’ interpretative learning curves were steep. These early CTs were imperfect (sensitivity ~90%) for identifying small amounts of blood in the subarachnoid space, so textbooks, guidelines, and several generations of emergency medicine trainees advised against a CT-only approach to rule-out aneurysmal SAH. Instead, SAH could only be ruled out when a negative CT was followed immediately by a LP demonstrating cerebrospinal fluid (CSF) without either red blood cells or (at least 12 hours post-headache onset) xanthochromia. However, in 2017 there are three problems with that approach: (1) contemporary CTs are far better at identifying blood in the subarachnoid space; (2) LP’s frequently identify blood that is not in the subarachnoid space (traumatic LPs); and (3) CSF xanthochromia is not an accurate diagnostic test for SAH.

A rule of thumb to define sufficient diagnostic accuracy to rule-in a disease as positive is likelihood ratio (LR+) > 10 or negative likelihood ratio (LR-) < 0.1 to rule-out a disease. Both Perry 2011 and Backes 2012 demonstrate acceptably safe CT accuracy for SAH when imaging is obtained within 6-hours of headache onset (summary LR+ 235, summary LR- 0.01). Beyond 6-hours CT is still accurate to rule-in SAH (summary LR+ 223) but less impressive to rule out SAH (summary LR- 0.07, 95% CI 0.01-0.61). These studies used neuro-radiologists to interpret the CT, which opens the question as to whether general radiologists’ accuracy would equate these studies. Recent studies indicate that general radiologists’ are just as accurate for the diagnosis of SAH as neuro-radiologists.

Post-CT LP– Quantifying Benefits and Harms

Most European hospitals use spectrophotometry to evaluate the presence or absence of xanthochromia, whereas 99% of North American hospitals use visible inspection. Recent meta-analyses indicate that visible xanthochromia can rule-in SAH (LR+ 25) but is less accurate to rule it out (LR- 0.22). At least four spectrophotometric methods to evaluate xanthochromia exist and most ED headache studies report different methods, but spectrophometry using any method doesn’t appear to be significantly better than visible xanthochromia to rule-in or rule-out SAH. [Carpenter 2016, Chu 2014] At a threshold of 2000 x 106 red blood cells per liter in the final tube of CSF collected, the LR+ is 10.3 and the LR- is 0.07 (95% CI 0.01-0.49). [Perry 2015] Importantly, up to 30% of patients experience worsening post-LP headache, in addition to the risks of post-LP back pain, epidural bleeding, and introduction of skin flora into the central nervous system. [Seupaul 2005] Patients are not the only reluctant participants in this exercise; physician barriers to routine post-CT LP include inadequate time in the busy ED and expectation of normal or non-diagnostic results in most patients (low diagnostic yield). In fact, up to 1 in 6 LPs are traumatic (blood detected from skin or superficial soft tissue, not from the subarachnoid space). Consequently, LP is not performed in over half of acute headache patients in whom a CT is obtained. [Perry 2010, Perry 2013]

The ultimate objective is not to understand test accuracy; instead, the goal is to deliver the appropriate care to the right patients. How is a busy ED physician supposed to interpret all of these numbers and communicate with patients meaningfully to allow shared decision making? One approach to balance the harms and benefits of post-CT LP is to hypothesize test- and treatment-thresholds. The test-threshold describes the probability of a diagnosis (aneurysmal SAH) below which continuing to test for the diagnosis will harm more patients than it will help, whereas above the threshold additional testing will benefit more patients than will be harmed. This threshold is derived from the test accuracy (CSF xanthochromia or RBC), risk of the test (post-LP headache, infection, or epidural bleed), benefit of the treatment for those with disease, and harms of the treatment for those without disease (since false-positives will receive the treatment and have no possibility of benefit since they don’t actually have the disease). Based upon one recent diagnostic meta-analysis, the threshold at which post-CT LP would benefit patients is quite narrow (2-4% for CSF RBC or 2%-7% for visible xanthochromia). Doubling the risk of benefit and halving the risk of harm was used to further evaluate these thresholds and the thresholds didn’t change significantly. Still not convinced? Thinking about the benefit of LP alone (and neglecting the potential for harms associated with LP), the Number Needed to LP (NNLP) to identify one CNS infection in acute onset headache patients is 227 [Brunell 2013] while the NNLP to identify one additional aneurysmal SAH upon which neurosurgical intervention occurs and which was missed by CT within 6 hours ranges from 250 [Perry 2011, Sayer 2015] to 15200! [Blok 2015]

Journal Club Discussion Between Neurosurgery & Emergency Medicine

Here is the synopsis of the Journal Club discussion between Neurosurgery and Emergency Medicine, including Dr. Sivilotti the senior author of the PGY-III meta-analysis.

PGY-I

CT within 6 hours of thunderclap headache onset is sufficiently sensitive to rule out SAH without LP, if the CT is 16 slice or greater with cuts < 5mm.

PGY-II

Non-contrast head CT is an excellent test for ED headache patients in whom SAH is a concern, but like every other test that exists it is not 100% sensitive. Scenarios in which false negative CTs occur include imaging more than 6 hours after the onset of the headache, less severe bleeds (as measured by Hunt-Hess classification), anemia (Hg <10), and non-neuro-radiologists readers. In those scenarios, patient shared decision making about additional testing (CTA or LP) is warranted but should include informed consent about anticipated benefits and potential harms.

PGY-III

Less than one in 10 headache patients concerning for SAH are ultimately diagnosed with SAH in recent studies. While certain symptoms and signs increase or decrease the likelihood of SAH, no single characteristic on history/physical exam is sufficient to rule in or rule out SAH. Within 6 hours of symptom onset, noncontrast cranial CT is highly accurate, while a negative CT beyond 6 hours substantially reduces the likelihood of SAH. Based on anticipated treatment benefit of 80% with immediate aneurysmal SAH (aSAH) diagnosis, LP risk of 1% (including significant post dural headache, discomfort, and infection), and total (cancer + other) risk for angiography of 2%, LP would only be helpful in a pre-LP probability of aSAH range of 2-7% (if using visible xanthochromia) or 2-4% (if using CSF RBC > 1000). Therefore, LP appears to benefit relatively few patients within a narrow pretest probability range. Scenarios in which false negative CTs occur include imaging more than 6 hours after the onset of the headache, less severe bleeds (as measured by Hunt-Hess classification), anemia (Hg <10), and non-neuro-radiologists readers. In those scenarios, patient shared decision making about additional testing (CTA or LP) is warranted but should include informed consent about anticipated benefits and potential harms. With improvements in CT technology and an expanding body of evidence, test thresholds for LP may become more precise, obviating the need for a post-CT LP in more acute headache patients. Existing SAH clinical decision rules await external validation, but offer the potential to identify subsets most likely to benefit from post-CT LP, angiography, or no further testing.

PGY-IV

Decision analysis using accepted methods but sparse, low quality evidence-basis demonstrates post-CT LP test threshold that is significantly higher than the majority of ED headache patients in whom SAH is considered. Nonetheless, the similar test-threshold point-estimate for post-CT LP in comparison to Carpenter et al (which used very different methods to derive a test-threshold), indicates that current textbook and guideline recommendations (which advocate post-CT for everyone) merit revision.

The discussion amongst the Journal Club attendees focused around two issues.

1) Some neurosurgeons expressed concerns about the risk of aneurysmal re-bleeding within 24 hours, which has been recognized to be about a 6% risk since observational studies were conducted in the 1950’s. Some of the neurosurgeons also noted that no test is perfect, so their traditional approach has been that more testing is generally better for patients and providers. Dr. Sivilotti made the point that attempts to attain diagnostic perfection (0% miss rate) leads to operational inefficiencies for the hospital and at eventually harms some patients.

2) Some noted uncertainty about how to derive the initial pre-test probability estimate by which to guide post-CT decision-making about the benefits vs. harms of LP. It was noted that the PGY-III meta-analysis included weighted average prevalence of SAH of 7.5% in recent prospective studies of headache patients in whom SAH is a concern. This meta-analysis prevalence is one evidence-based estimate of pre-test probability. The point was then made that the 7.5% probability of SAH falls within the 2%-7% range for which LP benefits outweigh risks, but the meta-analysis authors noted that the 7.5% prevalence estimate is pre-CT. Whether a CT is obtained less than 6-hours post-headache onset (summary LR- = 0.01 so post-CT probability of SAH = 0.1%) or later than 6-hours (summary LR- = 0.07 so post-CT probability of SAH = 0.6%). Either way, the post-CT probability of SAH is far below the lower margin of benefit (2%). The issue with CT diagnostic accuracy beyond 6-hours is the 95% Confidence Interval which extends to 0.61, so these situations require more careful contemplation and perhaps offer a role for CT angiography – a proposal to which neurosurgery eagerly agreed requires additional research at Washington University.

Future Research Priorities

Carpenter et al. was grounds for practice-change for many ED diagnosticians, but has also received criticism – mainly based on philosophical grounds. Is the role of emergency medicine to definitively rule-in or rule-out particular diagnoses or simply to exclude (or minimize) life-threats without putting a label of certainty on symptom etiology? Based upon the personal observations that thunderclap headache represents a potential life-threat that is not SAH in over half of cases and that a CT/LP approach alone will fail to identify other life-threats without consulting Neurology and/or Neurosurgery with additional advanced imaging at the discretion of these consultants, some argue that diagnostic research based upon ruling-in or ruling out SAH alone is inherently flawed and not worthy of altering the long-standing practice paradigm of CT then LP if CT is non-diagnostic. However, this approach neglects to consider the potential harms of LP, the number of additional studies required to save one additional life or avert one bad outcome, or the role for shared decision-making. It is worth noting that the perspective that thunderclap headache more commonly represents a non-SAH life-threatening diagnosis than SAH or migraine is counterintuitive to most ED research. This phenomenon likely reflects spectrum bias in that sicker patients with more likelihood of life-threatening disease and poor outcomes are being labeled as “thunderclap headache” than is the norm in published research and common practice. Indeed, a subset of acute headache patients who do benefit from post-CT LP almost certainly exists, including those with hemoglobin less than 10 g/dL (increased risk of false-negative CT), significant delay between headache onset and CT, and those in whom diagnoses like CNS infection or pseudotumor cerebri are being contemplated. The art of medicine is identifying the individual patients who are more likely to benefit from additional testing rather than applying a one-size fits all that mandates routine post-CT LP.

Many questions remain unanswered. Can general radiologists rule-out aneurysmal SAH as well as neuro-radiologists? Will clinical decision aids provide an additional risk-stratification mechanism by which to identify subsets more likely to benefit from post-CT LP? Is there a role for CT angiography (CTA) following a non-diagnostic non-contrast CT? If so, which patients would benefit from CTA?

Bottom Line: The decades old dogma that acute headache patients in whom SAH is a consideration must uniformly undergo an LP following a non-diagnostic CT appears is unnecessary for a large subset of these patients and may leads to harms via additional downstream testing that results from the imperfect, non-specific findings in CSF.

Risk of Delayed Traumatic ICH in Patients on Anticoagulation

Journal Club Podcast #32: May 2017

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After a brief interlude where I shamelessly self-promote my new novel, I talk about the risks of delayed bleeding in head injury patients on warfarin...

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Articles:

Article 1: Menditto VG, Lucci M, Polonara S, et al. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med 2012;59:451-455. Answer Key.

Article 2: Swap C, Sidell M, Ogaz R, Sharp A. Risk of Delayed Intracerebral Hemorrhage in Anticoagulated Patients after Minor Head Trauma: The Role of Repeat Cranial Computed Tomography. Perm J. 2016 spring;20(2):14-6. Answer Key.

Article 3: Chauny JM, Marquis M, Bernard F, Williamson D, Albert M, Laroche M, Daoust R. Risk of Delayed Intracranial Hemorrhage in Anticoagulated Patients with Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis. J Emerg Med. 2016 Nov;51(5):519-528. Answer Key.

Article 4: Nishijima DK, Offerman SR, Ballard DW, et al. Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and pre-injury warfarin or clopidogrel use. Ann Emerg Med2012;59:460-468. Answer Key.

Vignette:

You are working a moonlighting shift at a local level II trauma center when you meet Mr. X, a 68 year old gentleman with a history of atrial fibrillation, for which he takes diltiazem for rate control and warfarin for anticoagulation. He sees his primary care physician on a regular basis and has his international normalized ratio (INR) checked once a week. It has been between 2.0 and 3.0 consistently for the last 6 months. This morning, while walking his dog, a rare crossbreed known as a great doodle (a cross between a great Dane and a poodle), he was tripped up by the leash and fell forward, striking his forehead on the concrete. He suffered no loss of consciousness, has a mild headache, and has had no nausea or vomiting. His wife states that he has had no altered mental status since the fall.

On exam he has a GCS of 15, a superficial abrasion to his forehead with a small 4 cm hematoma, no cervical spine pain or tenderness, and a normal neurologic examination. His INR today is 3.2. Being an astute reader of the literature, you remember that the studies on the Canadian Head CT rules excluded patients on anticoagulation, and proceed to order a head CT, which is read as normal by the attending radiologist (not a neuroradiologist).

After updating the patient’s tetanus booster you discharge him home in the care of his wife. That night after your shift, you begin to worry about your patient and his risk of delayed intracranial hemorrhage given his anticoagulant use. You also wonder if his risk would be higher if he were on one of the novel anticoagulants (rivaroxaban, apixaban, etc). Unable to sleep, you head online and begin to search the literature for answers.

PICO Question:

Population: Patients on anticoagulation therapy suffering minor head injury

Intervention: Observation and/or repeat CT scan of the head CT

Comparison: Discharge after normal initial head CT

Outcome: Risk of delayed intracranial hemorrhage leading to a change in management

Search Strategy:

A previous journal club covering delayed intracranial bleeding in the setting of anticoagulation was conducted in 2012 (http://emed.wustl.edu/Journal-Club/Archive/August-2012). The online archive was searched and two of the articles were chosen for inclusion. PubMed was searched using the terms anticoagulation AND “delayed intracranial hemorrhage”, resulting in 7 articles (http://tinyurl.com/y9yjn3go). Among these, a systematic review and meta-analysis was chosen as well as one of the articles included in the systematic review.

Bottom Line:

Traumatic brain injury results in just over 1.3 million emergency department (ED) visits, 275,000 hospitalizations, and 52,000 deaths annually in the United States alone, with an increase in the combined rate of ED visits, hospitalization, and death from 521 per 100,000 in 2001 to 823.7 per 100,000 in 2010 (CDC TBI Report). In elderly patients suffering a fall, long-term anticoagulation has been shown to increase not only the incidence of intracranial hemorrhage (ICH) compared to those not on anticoagulation (8.0% vs. 5.3%, p < 0.0001), but to also increase mortality in those with ICH (21.9% vs. 15.2%, p = 0.04) (Pieracci 2007). Additionally, the use of warfarin prior to blunt head trauma has been shown to increase mortality compared to those not taking anticoagulants, with an odds ratio of 2.008 (95% CI 1.634-2.467) (Batchelor 2012). Unfortunately, the rate of pre-injury warfarin use has been increasing in trauma patients in the US, from 2.3% in 2002 to 4.0% in 2006 (P < .001); in patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (P < .001) (Dossett 2011).

Given the increasing number of head injury patients seen in the ED, and the increase in concomitant anticoagulant use, the clinical dilemmas surrounding these patients have become more and more relevant. Studies in patients taking warfarin who suffer minor head injury have shown incidences of ICH ranging from 6.2%-29% (Li 2001, Gittleman 2005, Brewer 2011), leading some authors to conclude that most, if not all, such patients should undergo routine cranial CT scanning on presentation (Brewer 2011, Cohen 2006, Fabbri 2004). One important question surrounds the prognostic implications of a normal cranial CT in head injury patients on anticoagulant therapy. While some European guidelines suggest that all anticoagulated patients with head injury should be admitted for a period of routine observation (Vos 2002, Ingebrigtsen 2000), these recommendations are not based on studies of the prevalence of delayed ICH.

In the three primary studies reviewed, the incidence of delayed ICH following normal CT scan in patients taking warfarin ranged from 0.6% to 6%; the meta-analysis revealed a pooled risk of 0.6%. However, if a diagnosed ICH has no affect on the patient’s outcome or treatment, then it would be considered a surrogate outcome, which is often “used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives (Thomas 1995).” As such outcomes are often found to be clinically insignificant, their use has been questioned in the literature (Guyatt 2011, Fleming 1996), and the incidence of patient important outcomes should be considered instead. In these studies, the majority of patients found to have delayed ICH required no neurosurgical intervention and had no adverse outcome documented. The incidence of death or neurosurgical intervention ranged from 0 to 1.1%, with a pooled incidence of 0.13% in the meta-analysis.

The authors of one of the articles reviewed suggest that “our data support the general effectiveness of the European Federation of Neurological Society’s recommendations for 24-hour observation followed by a repeated head CT scan for anticoagulated patients with a minor head injury” (Menditto 2012). However, this conclusion is based on the incidence of delayed ICH (6%) rather than the incidence of clinically important outcomes (1.1%). In this study, only one patient out of 87 suffered clinically significant delayed ICH. It is mentioned in the study that one patient showed signs of neurologic deterioration, however they do not say if this was the same patient who required neurosurgical intervention. If so, this would suggest that observation alone would suffice to detect any clinically significant delayed ICH.

Additionally, the authors do not perform a cost-effectiveness analysis to support their conclusion. In a subsequent editorial appearing in the same journal, it is suggested that a protocol of 24-hour observation and routine repeat CT scanning would cost an average of just over $1 million per patient saved (Li 2012). The author of the editorial suggests that home observation and phone call follow-up would be more cost-effective, and likely as safe, though this has not been studied.

While the current literature does not support routine hospital observation for 24 hours or repeat cranial CT scans in all anticoagulated patients with head injury, this may be warranted in those at increased risk of delayed bleeding, such as those with supratherapeutic INR levels or concomitant antiplatelet therapy. Further studies are needed to identify these higher risk patients for delayed bleeding to determine appropriate management. Furthermore, as newer anticoagulants enter the market and begin to replace warfarin, such as apixaban, dabigatran, and rivaroxaban, further studies on the risk of delayed hemorrhage may be necessary to determine the best management strategy for patients on these medications.