Quality Corner – Crohn’s Disease, Tachycardia, Thrombocytosis; Angioedema – Treatment and Disposition

Author: Christine Kulstad, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Welcome to Quality Corner, an emDocs series evaluating tough cases and potential areas for improvement. The cases described below are based on ED bouncebacks, with all identifying details removed, and are limited to what was documented in the medical record.

Case 1 – Crohn’s Disease

A 25-year-old male with a past medical history of Crohn’s disease and anemia presented with diffuse abdominal pain, vomiting, and diarrhea for 2 days. He had a heart rate of 130 on arrival, but otherwise normal vital signs. His abdominal exam did not show focal tenderness or peritonitis. A CBC, CMP, lipase, UA, and lactate were ordered. He was given 2 L of IVF. His labs were unremarkable except for a hemoglobin of 9.3 and a platelet count of 615. He was discharged with iron supplementation and instructed to keep his upcoming appointment with his gastroenterologist in 10 days.

He returned 16 hours later with persistent pain. At that point, it was noted that his heart rate at the time of discharge was 115. Repeat blood work showed a hemoglobin of 6.5 and an elevated ESR and CRP. He was given more IVF, 2 units of pRBCs, ciprofloxacin, and metronidazole, and then admitted with a GI consult.

There are several things to consider in this case, from documentation to systems problems to knowledge review.

1. Crohn’s patients often have GI bleeding, but this was not documented (history or exam) on the first visit. His second visit note says he had been having blood in stool x 3 days. We all know history can change from one provider to another, but get in the habit of asking and documenting this. No doubt his history of anemia provided false reassurance that his hemoglobin of 9.3 was not serious.

2. Next a common system issue – he was discharged with tachycardia. It frequently happens that vitals are measured after the order to discharge and are not always seen by the responsible provider. Check that abnormal vitals have normalized prior to discharge, or explain why you think they don’t need to.

3. It’s also advisable to have at least 2 exams documented on every patient you see with abdominal pain. If the patient is being discharged, the second documented exam should say he/she is better and tolerating PO.

4. Last, knowledge review – This patient had platelets > 600 on the first visit. Thrombocytosis occurs in infections, postsurgical states, malignancy, post-splenectomy state, acute blood loss, iron deficiency, or as a side effect of certain medications (Tefferi, 2017). Think of it as an even less specific inflammatory marker – something to explain if you’re sending someone home.

For Crohn’s flares, there is no agreed upon scoring system to determine severity. Reviewing the medications list can provide some clue to baseline severity- none vs sulfasalazine vs immunomodulators or biologics. Checking an ESR and CRP can assist, though these are not always included in the standard abdominal pain work-up (AS., 2013). Physical exam remains critical – tender masses or peritonitis suggest more severe flare.

Ideally, management of this chronic disease would be initiated with the input of your friendly local gastroenterologist, but this may not easy to obtain at all hours in every ED. In the patient with mild to moderate disease, treatment has traditionally started with medications like sulfasalazine or mesalamine, although they are no longer recommended by the American College of Gastroenterology due to lack of effect. For an acute flare, start steroids such as prednisone 40-60 mg daily (Lichtenstein GR, 2009). Be generous with supportive care, as IVF and anti-emetics may keep them from bouncing back. Outpatient care is appropriate, assuming they have follow-up or that it can be arranged. For those who have more severe disease including a concerning exam, elevated inflammatory markers, or fever, order a CT with IV contrast. Start antibiotics (ciprofloxacin/metronidazole or rifaximin if allergic) and steroids (Lichtenstein GR, 2009) (AS., 2013). These patients should be admitted with a GI consult.

Highlights:

• Make sure abnormal vitals have normalized, or explain why they didn’t need to.
• Thrombocytosis is non-specific but may be found with blood loss and infection.
• Check ESR/CRP on most Crohn’s flares to help determine severity.
• Consult GI for further input regarding evaluation and management.

Additional reading:

Tefferi, A (2017). Approach to the patient with thrombocytosis. In L. K. Leung (Ed.), UpToDate. https://www.uptodate.com/contents/approach-to-the-patient-with-thrombocytosis

Cheifetz AS. Management of active Crohn disease. JAMA. 2013 May 22;309(20):2150-8. doi: 10.1001/jama.2013.4466.

Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009 Feb;104(2):465-83; quiz 464, 484. doi: 10.1038/ajg.2008.168.

Case 2 – Angioedema

A 53-year-old woman presented with right sided facial swelling to her lips and lower face but without airway obstruction. She had a history of hypertension and had been taking lisinopril for 7 months. She was treated with methylprednisolone, diphenhydramine, and ranitidine. After a brief observation in the ED, it was documented that her swelling improved and that she was tolerating PO. She was told to stop lisinopril, start losartan, and was discharged. She returned 4 hours later with worsening swelling and was admitted to the MICU for airway monitoring.

1. How do we treat angioedema? Many people start with the treatments for anaphylaxis with H1 and H2 blockers, steroids, and possibly IM epinephrine. These medications will likely have no effect if the cause is angioedema, but if the cause is not clear cut, they are relatively benign medications to try. The biggest downside may be the delay to using more effective therapies. First a brief review: ACE-I’s inhibit the angiotensin converting enzyme (ACE) which degrades bradykinin. The excess bradykinin is thought to lead to edema in susceptible individuals. Two medications have been developed to treat hereditary angioedema and have been tried in ACE-I induced angioedema (Riha HM, 2017). The first, ecallantide, inhibits production of bradykinin. Mechanistically, it seems unlikely to reverse the edema that is already in place, and low quality studies show mixed results (Riha HM, 2017). The second medication, icatibant, is a bradykinin receptor antagonist, so it sounds more promising. A small study published in the NEJM in 2015 did show a positive effect, but the drug’s expense limited its adoption (Baş M, 2015). That was probably a good thing as a larger RCT by Sinert et al published in 2107 showed no effect (Sinert R & group., 2017).

So what can you use? FFP. It contains the ACE enzyme which degrades existent bradykinin and improves edema in 2-4 hours. Give 2 units, if your patient can tolerate the volume (Guyer, 2017). Although there has not been an RCT to demonstrate its effectiveness, it is widely available, relatively inexpensive, and has case reports to support its use. The only problem is the delay inherent in administering FFP, which typically requires typing and time to thaw.  It can also worsen the condition due to the presence of several other factors associated with angioedema, thus warranting close monitoring of the patient.

2. The next question (assuming immediate airway intervention is not needed) that complicates management of these patients is disposition. Can you ever send them home from the ED? Do all have to go to the MICU? It helps to know that the swelling peaks over minutes to hours. If the patient started noticing lip swelling 24 hours ago and finally gave into their significant other nagging them to get it checked out, it’s unlikely to progress to airway closure. The swelling will typically last 24-72 hours, but can persist for up to 5 days (Guyer, 2017). When/where to admit will depend on the practice patterns in your hospital, how long the patient has been affected, and the risk tolerance of both you and your patient.

3. Discharge instructions – Foremost, advise the patient to avoid ACE-I in the future. Update their EMR to reflect the involved medication as an allergy. Secondly, the patient will likely need another medication to treat their hypertension. In the ideal setting, the patient’s primary care provider will choose the agent. However, many of our patients lack timely access to a PCP and may need you to prescribe something. Two systematic reviews suggested the recurrence of angioedema with an ARB was up to 10%, making it seem a risky choice (Haymore BR, 2008)(Beavers CJ, 2011).  Another meta-analysis found the risk of angioedema related to ARB use to be equal to that of placebo (Makani H, 2012), justifying their use in patients in whom this class may be superior to other anti-hypertensive medications. This is another time when shared decision making will help.

Highlights:

• Angioedema peaks in hours and can last for days.
• FFP is the most reliable treatment, which may work in 2-4 hours.
• Disposition depends on length of symptoms and available monitoring.
• Instruct your patient to avoid ACE-I in the future. ARBs can be used in this patient population, but have some risk.

Additional reading:

Riha HM, Summers BB, Rivera JV, Van Berkel MA. Novel Therapies for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review of Current Evidence. J Emerg Med. 2017 Nov;53(5):662-679.

Baş M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, Veit J, Schossow B, Hapfelmeier A, Kehl V, Kojda G, Hoffmann TK. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015 Jan 29;372(5):418-25.

Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, Schranz J, Baptista J, Kimura A, Nothaft W; CAMEO study group. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017 Sep – Oct;5(5):1402-1409.e3.

Guyer, A. B. (2017, Oct). ACE inhibitor-induced angioedema. (S. Saini, Ed.) Retrieved from UptoDate: https://www.uptodate.com/contents/ace-inhibitor-induced-angioedema

Haymore BR, Y. J. (2008, Nov). Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol, 101(5), 495-9.

Makani H, M. F.-P. (2012, Aug). Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol, 110(3), 383-91.

Beavers CJ, D. S. (2011, Apr). The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother, 45(4), 520-4.