A 17-year-old Black adolescent presents to a family medicine clinic with a 1-day history of acute-onset chest discomfort, palpitations, and abdominal pain. The patient denies aggravating or alleviating factors as well as shortness of breath, activity intolerance, hematemesis, or melena. Two weeks prior, she was prescribed naproxen 500 mg twice daily for knee pain that was precipitated by squatting exercises at physical therapy (PT). She was completing PT after a right anterior cruciate ligament (ACL) repair several months prior. The family medicine provider who prescribed naproxen instructed her to take it with food and to avoid all other nonsteroidal anti-inflammatory drugs (NSAIDs). She was not taking any other known gastric mucosa irritants.
Since sustaining the ACL tear, the patient took 3 separate courses of ibuprofen and naproxen without incident. She experienced improved mobility and denied any additional trauma to the right knee. Up until the PT visit, the patient had been well managed with nonpharmacologic pain treatments. The care for this patient occurred over several visits; a timeline of the progression of care is shown in the Figure.
The patient is a refugee from South Sudan who moved to the United States in 2017. She is currently enrolled at a local high school. She denies alcohol, tobacco, or drug use and is not participating in any organized sports. The patient has regular menstrual cycles that last 5 to 6 days and are moderately heavy for 2 to 3 days.
The patient’s medical history includes Helicobacter pylori infection, an isolated episode of syncope with negative cardiology workup, ACL tear of the right knee, and stress fracture of the right tibia. Her medical history is limited by lack of documentation prior to 2017. Her family history is notable for maternal hypertension and diabetes. The patient has no known coagulation disorders, liver disease, or other chronic conditions.
Physical examination findings are normal except for tachycardia (112 beats/min) and hypertension. (142/82 mm Hg and 134/74 mm Hg upon recheck); other vital signs are stable. Abdominal examination is normal with active bowel sounds, no tenderness to palpation, guarding, rigidity, organomegaly, masses, or costovertebral angle tenderness. Blood work for complete blood cell count (CBC) and comprehensive metabolic panel (CMP) is taken and electrocardiography is ordered.
The patient is instructed to discontinue naproxen immediately and begin omeprazole 20 mg once daily. She is scheduled for a follow-up visit in 5 days to discuss the laboratory results.
Laboratory Evaluation and Follow-Up Visit
Findings from CBC show various abnormalities consistent with anemia (Table 1). Her CMP results are within normal limits except for a glucose level of 103 mg/dL and carbon dioxide of 19 mmol/L. The patient did not present to the local medical center to have the electrocardiography completed.
During the first follow-up visit, the patient denies symptoms; however, when a more specific review of systems is taken, the patient notes exercise intolerance and shortness of breath when participating in her physical education class. She also experiences dizziness that she attributes to not “drinking enough water.” The patient has improved abdominal pain following naproxen discontinuation. Currently, she is not experiencing syncope or near syncope, appetite changes, sleep changes, nose bleeds, melena, or hematuria. However, she does report melena associated with episodes of abdominal pain earlier in the week.
Her vitals are somewhat improved with a heart rate of 98 beats per minute and blood pressure of 128/72 mm Hg; other vital signs are stable. A physical examination reveals generalized abdominal tenderness and is otherwise normal with no tachycardia, respiratory abnormalities, organomegaly, or changes to bowel sounds. Because of the patient’s recent hemoglobin of 9.0 g/dL, blood work is ordered to recheck CBC and evaluate iron studies including ferritin, iron, total iron binding capacity (TIBC), and reticulocyte count (Table 2). Fecal occult studies, H pylori antibodies, and hematopathology smear review are also ordered (Table 3).
The differential diagnosis includes gastrointestinal (GI) bleed, peptic ulcer disease, H pylori infection, acute gastritis, coagulopathy, and angiodysplasia. Considering the recent naproxen use and anemia, omeprazole 20 mg daily is continued to treat acute gastritis and suspected GI bleeding.
The day 5 laboratory evaluation confirms that the patient has anemia. The patient’s low mean corpuscular volume (MCV) indicates smaller than usual red blood cell (RBC) size and low mean corpuscular hemoglobin concentration (MCHC) indicates decreased hemoglobin concentration within the RBC (Table 2). The findings indicate microcytic hypochromic anemia. The differential diagnosis for a patient with microcytic hypochromic anemia suggest iron-deficiency anemia, anemia of chronic disease, thalassemia, lead poisoning, and x-linked sideroblastic anemia.1
The elevated reticulocyte count indicates that the patient is producing immature RBCs to compensate for acute blood loss. The low iron saturation indicates that the body is depleting iron stores too quickly through blood loss. The total iron binding capacity, unsaturated iron binding capacity, iron, and serum ferritin levels are all within normal limits. Additionally, acute blood loss from the GI tract is confirmed by the 3 positive fecal occult blood tests. The hematopathologist’s review confirms the presence of microcytic hypochromic anemia with anisocytosis most likely representing iron-deficiency anemia.
The patient is started on ferrous sulfate 325 mg daily and continues omeprazole 20 mg once daily
After further discussion with the patient’s mother regarding the results, she reports that the patient had previously been treated for an H pylori infection. It is unsure if a test of cure was completed. If this information was available during the initial workup, it would have been preferred to order the H pylori fecal antigen test to evaluate for active infection as serologic levels do not differentiate between active and past infection.2 A breath test would not be appropriate as the patient had already been started on a proton pump inhibitor (PPI) and this may cause false-negative results.2
A consultation is scheduled with a pediatric GI provider at a local academic medical center. In the meantime, the patient continues to experience intermittent symptoms of dizziness, shortness of breath, and dark tarry stools.
At the time of the pediatric GI consultation, her symptoms have stabilized on omeprazole therapy and iron supplementation. After consultation, the plan is to continue treating the microcytic anemia that is suspected to be caused by an NSAID-induced upper GI bleed. The shortness of breath and tarry stools have resolved. The pediatric GI provider orders a repeat CBC with differential (Table 1, Day 17) and adds erythrocyte sedimentation rate and C-reactive protein. The CBC shows improving anemia with hemoglobin and hematocrit trending upward. The inflammatory markers are within normal limits.
The patient and her mother are counseled on avoidance of over-the-counter or prescription NSAIDs including aspirin, ibuprofen, and naproxen because of their suspected role in this patient’s GI bleed. The omeprazole dose is increased to 40 mg daily on an empty stomach 20 minutes prior to breakfast to help suppress acid production and allow for healing of the gastric mucosa. No additional imaging or procedures are completed at this time because of the improvement in the patient’s status.
Outcome and Discussion
Overall, the patient stabilized well after an acute GI bleed. However, she will require close monitoring and follow-up with both her primary care provider and pediatric GI provider. Approximately 2 months after identification of GI bleeding, elimination of the cause and initiation of ferrous sulfate led to an increase in hemoglobin to 11.9 g/dL and hematocrit to 40.8%. She is asymptomatic and has no abnormal findings on physical examination. The patient has a repeat laboratory evaluation 7 months later, which shows stable levels. However, the patient continues to have microcytic hypochromic anemia and requires ongoing ferrous sulfate supplementation.
If this patient had shown hemodynamic instability, including a hemoglobin less than 7 mg/dL, possible interventions would have included inpatient hospitalization, administration of blood products, fluid resuscitation, urgent endoscopy after stabilization, vasopressors, intravenous acid suppression, and trending of CBC.3 Depending on the severity of bleeding, more invasive procedures including arterial embolization, balloon tamponade, and surgical intervention may be necessary.3
Most NSAIDs work by nonselectively blocking cyclooxygenase (COX) 1 and COX 2, which play integral factors in blocking pain signals to the brain and inhibiting the synthesis of prostaglandins.4 NSAIDs work to inhibit prostaglandin synthesis in the pain pathway, while concurrently blocking prostaglandin synthesis in the stomach where COX 1 provides gastric mucosal protection.5 This may lead to NSAID-induced GI bleeding, which is caused by a breakdown in the gastrointestinal lining secondary to nonselective COX inhibition in the gastric mucosa.4
Ibuprofen is a more commonly used NSAID in pediatric patients for management of pain and fevers. In this patient’s case, naproxen was appropriately initiated for management of musculoskeletal knee pain but resulted in GI bleeding. One study found that the median time between NSAID initiation and onset of GI bleeding was 4 days.6 Therefore, practitioners prescribing or recommending NSAID medications should be aware that adverse effects and significant complications are not limited to long-term use.
One study suggests that 36% of upper GI bleeds in children were secondary to NSAID use.7 While GI side effects are a well-known risk of NSAID use in children, management techniques for GI bleeding often stem from those used in the management of adult GI bleeding.8 In the setting of upper GI bleeding, acid suppression with the use of higher doses of a PPI at 1 to 3 mg/kg/d in children or 40 mg twice daily in adults is recommended as initial PPI management.8 No significant benefit is found in choosing one PPI over another and PPI therapy has shown to be more beneficial than histamine 2 antagonists.8 Initially, this patient was started on omeprazole 20 mg daily; because the patient weighed 80 kg, the care team could have initiated omeprazole at up to 80 mg per day.
This case also demonstrated that H pylori can precipitate peptic ulcer disease, gastric and duodenal ulcerations, and gastritis with an unexplained link between H pylori infection and iron-deficiency anemia.2 Testing for H pylori should be considered in the workup.2
The patient remained hemodynamically stable but if her status had deteriorated, she would have required additional intervention for stabilization and consideration of procedural interventions such as endoscopy.4 Continued counseling of patients and parents on the risks associated with short-term use of NSAIDs is essential, as well as the signs and symptoms they should monitor for. Although this patient was a young, healthy female, she experienced a significant adverse reaction to NSAIDs that may not typically be expected. Providers should continue to use caution and close monitoring when prescribing NSAIDs to any population, especially children.
Amalia Gedney-Lose, DNP, ARNP, FNP-C, is a clinical assistant professor and family nurse practitioner at the University of Iowa College of Nursing and University of Iowa Hospitals and Clinics in Iowa City, Iowa.
- Chaudhry HS, Kasarla MR. Microcytic hypochromic anemia. In: StatPearls [Internet]. StatPearls Publishing; 2022 Jan. Updated May 2, 2022. Accessed July 29, 2022. https://www.ncbi.nlm.nih.gov/books/NBK470252/
- Saleem N, Howden CW. Update on the management of Helicobacter pylori infection. Curr Treat Options Gastroenterol. 2020;18(3):476-487. doi:10.1007/s11938-020-00300-3
- Al Duhailib Z, Dionne JC, Alhazzani W. Management of severe upper gastrointestinal bleeding in the ICU. Curr Opin Crit Care. 2020;26(2):212-218. doi:10.1097/MCC.0000000000000699
- Qureshi O, Dua A. COX Inhibitors. In: StatPearls [Internet]. StatPearls Publishing; 2022 Jan-. Updated April 29, 2022. Accessed July 29, 2022. https://www.ncbi.nlm.nih.gov/books/NBK549795/
- Flower RJ. The development of COX2 inhibitors. Nat Rev Drug Discov. 2003;2(3):179-91. doi:10.1038/nrd1034
- Cardile S, Martinelli M, Barabino A, et al. Italian survey on non-steroidal anti-inflammatory drugs and gastrointestinal bleeding in children. World J Gastroenterol. 2016;22(5):1877-83. doi:10.3748/wjg.v22.i5.1877
- Grimaldi-Bensouda L, Abenhaim L, Michaud L, et al. Clinical features and risk factors for upper gastrointestinal bleeding in children: a case-crossover study. Eur J Clin Pharmacol. 2010;66(8):831-837. doi:10.1007/s00228-010-0832-3.
- Romano C, Oliva S, Martellossi S, Miele E, et al. Pediatric gastrointestinal bleeding: Perspectives from the Italian Society of Pediatric Gastroenterology. World J Gastroenterol. 201;23(8):1328-1337. doi:10.3748/wjg.v23.i8.1328