Cases & Commentaries

Febrile Neutropenia and an Almost Fatal Medication Error
Admitted to the oncology service for chemotherapy treatment, a woman with leukemia was noted to be neutropenic on hospital day 6. She had some abdominal discomfort and had not had a bowel movement for 2 days. The overnight physician ordered a suppository without realizing that the patient was neutropenic and immunosuppressed. Unaware that suppositories are contraindicated in neutropenic patients, the nurse administered the suppository. The patient developed a fever soon after receiving the suppository and required transfer to the intensive care unit for hypotension and management of septic shock. Jennifer Faig, MD, and Jessica A. Zerillo, MD, MPH, both of Beth Israel Deaconess Medical Center, highlight factors that can contribute to medication errors in oncology patients and suggest that adequately trained staff, effective handoffs, a culture of safety, and clinical decision support can reduce risks.

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Cases & Commentaries
Published June 2018

Febrile Neutropenia and an Almost Fatal Medication Error

Commentary by Jennifer Faig, MD, and Jessica A. Zerillo, MD, MPH

The Case

A 33-year-old woman with recently diagnosed acute myelogenous leukemia was admitted to the oncology service for treatment with chemotherapy. She reported feeling relatively well, apart from mild fatigue secondary to anemia. For chronic constipation, she took sennosides daily and polyethylene glycol as needed.

On admission to the hospital, her vital signs were stable, and physical examination was notable only for conjunctival pallor. Chemotherapy was administered as scheduled over 5 days. As expected, her blood counts dropped in response to the chemotherapy, and on hospital day 6 she was noted to be neutropenic with an absolute neutrophil count of 320. That night, she noted some abdominal discomfort. The bedside nurse noted that the patient had not had a bowel movement for the last 2 days despite taking both sennosides and polyethylene glycol daily. The nurse paged the overnight physician, who ordered a suppository without realizing that the patient was neutropenic and immunosuppressed after recent chemotherapy. The nurse administered the suppository as ordered, unaware that suppositories are contraindicated in neutropenic patients.

Several hours later, the patient felt warm and developed shaking chills. Repeat vital signs revealed a fever to 39.7°C and a heart rate of 121 beats per minute, concerning for sepsis. The nurse paged the overnight physician once again. Blood cultures were drawn and broad-spectrum antibiotics were started for febrile neutropenia. The patient worsened clinically and required transfer to the intensive care unit for hypotension and management of septic shock. Her blood cultures ultimately grew Escherichia coli, which may have spread from her bowel to her bloodstream as a result of receiving the suppository. Ultimately, she recovered and was discharged home a week later.

The Commentary

Commentary by Jennifer Faig, MD, and Jessica A. Zerillo, MD, MPH

Medication errors can cause adverse events when an error reaches a patient. In contrast, medication adverse events may be caused not only by errors, but also by an unintended consequence or adverse effect of a drug. Medication errors are a common cause of preventable adverse events in hospitalized patients.(1) Adverse events associated with high-toxicity drugs such as chemotherapy, drug–drug interactions from polypharmacy, and incorrect dosing in patients with decreased renal and hepatic function can lead to significant harm and even fatal outcomes in oncology patients. Antineoplastic drugs were the second most common cause of drug-related deaths in one study that looked at deaths associated with medication errors.(2) One high-risk adverse effect frequently induced by chemotherapy is neutropenia.

Neutropenia is defined as a decrease in the absolute neutrophil count (ANC) and can be subdivided into mild (1000 ≤ ANC < 1500 μL), moderate (500 ≤ ANC < 1000 μL), and severe (ANC < 500 μL).(3) Patients with neutropenia—such as the patient in this case—are at increased risk of developing an infection. Neutrophils are an essential component of the immune system.(4) In addition to chemotherapy, neutropenia can be caused by a number of conditions including nutritional deficiencies, autoimmune conditions, medications, hematologic malignancies, benign ethnic neutropenia, and congenital genetic defects.

A patient's risk of infection depends on a number of factors, such as the severity and duration of neutropenia, integrity of mucosal barriers, and exposure to microbes in the environment.(5) Oncology patients are educated about the signs and symptoms of infection and are instructed to take certain precautions if they develop neutropenia, such as maintaining adequate hand hygiene and avoiding sick contacts, raw or uncooked meat, fruits or vegetables, unpasteurized beverages, and use of suppositories or enemas.(6) To prevent infection, neutropenic patients in the hospital are placed in private rooms on neutropenic precautions.

Infection in a neutropenic patient can be fatal. Importantly, neutropenic patients, especially those on steroids, may not manifest typical signs and symptoms of infection. However, fever remains an important sign that should trigger an infectious workup and empiric antibiotic therapy.(7) Febrile neutropenia occurs in 10% to 50% of solid tumor patients and in greater than 80% of patients with hematologic malignancies.(8) A patient's risk of developing febrile neutropenia depends on the chemotherapy treatment regimen; induction chemotherapy for hematologic malignancies places patients at particularly high risk.(7) The Infectious Diseases Society of America defines febrile neutropenia as an ANC of less than 500 μL or an ANC that is expected to decrease below 500 μL during the next 48 hours and a single oral temperature of 38.3°C or higher or a temperature of 38.0°C or higher sustained over a 1-hour period.(9)

The management of patients with febrile neutropenia includes: (i) obtaining at least two sets of blood cultures (if a central venous catheter is present, a set should be collected from each lumen and from a peripheral site), (ii) obtaining culture specimens from other suspected sources of infection, (iii) performing a chest radiograph if respiratory symptoms are present, and (iv) initiating antibiotics promptly.(9) Because of the high mortality associated with Pseudomonas aeruginosa infection, patients should receive an antipseudomonal antibiotic agent, such as cefepime, a carbapenem or piperacillin–tazobactam.(9) Vancomycin is administered if there is a suspected catheter-related infection, skin or soft-tissue infection, pneumonia, hemodynamic instability, or severe mucositis.(9)

In this case, a patient with chemotherapy-associated neutropenia developed a fever and sepsis soon after receiving a suppository. This mistake could be classified as an adverse drug event due to a medication error, as administering the suppository was contraindicated in this patient because of her neutropenia. While there are no known evidence-based guidelines about the use of suppositories in neutropenic patients, expert recommendations discourage the use of suppositories in these patients due to the potential risk of infection.(10,11)

This case highlights factors that can contribute to medication errors in oncology patients. First, physicians, nurses, and pharmacists who do not have specialized training in oncology may not be aware of the complications associated with chemotherapy regimens. Some hospitals have designated floors for oncology patients with specialized nurses and oncology hospitalists, who are board-certified oncologists or internists with additional oncology training. It is unclear if the care team in this case had such specialized knowledge. Second, this event occurred overnight, a time when likely fewer clinical and pharmacy staff were available. In addition, the physician providing nighttime coverage may not have received a detailed handoff identifying the patient in this case as neutropenic. When handing off an oncology patient to a covering clinician, it's important to communicate the patient's primary disease, chemotherapy regimen, and potential toxicities, which may include cytopenia. Lastly, if a member of the care team suspected that prescribing a suppository was inappropriate for this patient, it is unclear from the case if they would have felt comfortable speaking up. If that were the case, ensuring a culture of safety in which all care team members felt comfortable voicing their concerns may have helped prevent the medication error. Although one must be mindful of alert fatigue, an electronic notification alerting the physician attempting to order a suppository that the patient was neutropenic may have helped prevent the order.

The appropriate management of constipation in this case would include the use of a stimulant laxative and/or a stool softener rather than a suppository. Constipation is a common complaint in oncology patients, and specific supportive care guidelines do exist.(10,12)

Oncology patients are exposed to high-risk medications and are particularly vulnerable to adverse drug events. Even a condition as common as constipation must be treated carefully in oncology patients. Establishing multidisciplinary teams that consist of physicians, pharmacists, and nurses with specialized oncology knowledge is essential for providing high-quality care to these patients. In addition, efforts to build in decision support and appropriate alerts in the electronic health record can help prevent some adverse medication events in oncology patients.

Take-Home Points

Adverse drug events, both those resulting from medication errors and those due to the toxicity of chemotherapy, are common in oncology patients.
Patients with neutropenia are at high risk for infection and should not be prescribed suppositories to treat constipation.
Febrile neutropenia requires prompt evaluation and initiation of broad-spectrum antibiotics.
Adequately trained and available staff, effective handoffs, establishing a culture of safety, and computerized provider order entry with decision support may help to reduce medications errors in oncology patients.

Jennifer Faig, MD
Clinical Fellow in Medicine
SAPPHIRE
Beth Israel Deaconess Medical Center
Boston, MA

Jessica A. Zerillo, MD, MPH
Instructor in Medicine
Hematology/Oncology Division
Beth Israel Deaconess Medical Center
Boston, MA

References

1. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients: results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377-384. [go to PubMed]

2. Phillips J, Beam S, Brinker A, et al. Retrospective analysis of mortalities associated with medication errors. Am J Health Syst Pharm. 2001;58:1835-1841. [go to PubMed]

3. Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program. 2012;2012:174-182. [go to PubMed]

4. Borregaard N. Disorders of Neutrophil Function. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M. eds. Williams Hematology, 9e New York, NY: McGraw-Hill; 2016. [Available at]

5. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med. 1993;328:1323-1332. [go to PubMed]

6. Marrs JA. Care of patients with neutropenia. Clin J Oncol Nurs. 2006;10:164-166. [go to PubMed]

7. Baden LR, Swaminathan S, Angarone M, et al. Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(7):882-913. [go to PubMed]

8. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis. 2004;39(suppl 1):S32-S37. [go to PubMed]

9. Friefeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93. [go to PubMed]

10. Woolery M, Bisanz A, Lyons H, et al. Putting evidence into practice: evidence-based interventions for the prevention and management of constipation in patients with cancer. Clin J Oncol Nurs. 2008;12:317-337. [go to PubMed]

11. Gastrointestinal Complications (PDQ): Health Professional Version. PDQ Supportive and Palliative Care Editorial Board. Bethesda, MD: National Cancer Institute. [go to PubMed]

12. Levy MH, Back A, Benedetti C, et all. NCCN clinical practice guidelines in oncology: palliative care. J Natl Compr Canc Netw. 2009;7:436-473. [go to PubMed]