Febrile Neutropenia and Sepsis Management in Chemotherapy: A Case Study
Introduction
Mrs Zoe is a 58 year old Australian female of Dutch heritage got admitted to the hospital with mild confusion and disorientation, pale and diaphoretic. On examination her BP was 92/56 mmHg, pulse regular at 106 beats per minute, tachypnoeic and had temperature 38C.On auscultation, she has crackles and poor air entry into the left lower lobe with widespread end expiratory wheezes and inflamed mucosal ulceration.
Zoes blood reports include white blood cells -0.5x10/ Neutrophils- 0.2x10/L, Haemoglobin- 85g/dl. Her clinical findings reveals that she has developed neutropenia and pancytopenia.febrile neutropenia is defined as an oral or tympanic membrane temperature of 38C on two occations, at least one hour apart within a 12h period or a single temperature of > 38.5C with an absolute neutrophil count of 0.5 x10/ 1 or 1.0 x10/1 with a predicatble decline to 0.5 x10/ 1 in 24- 48h (according to J wringley, TV Ajithkumar, in special training in oncology, 2011). The cytotoxic agents associated with the highest risk of neutropenia include cyclophosphamide, taxanes, ifosfamide,platinums and cytarabine. (C.J Coyne and Rahul. N-2021). Mrs. Zoe received cytotoxic agent cyclophosphamide one week ago.
As Zoe had increased body temperature and low neutrophil count she was diagnosed to have febrile neutropenia.Mrs Zoe also has inflamed mucosal ulceration and mouth ulcers.
Her past medical history includes stage 111 triple negative breast cancer two months ago.For which she underwent a wide local excession and axillary lymph node dissection. Initially she has experienced a seroma formation that caused her considerable pain and restricted function in her right upper limb, but the area is now almost healed and pain free. She also had anorexia, cachexia, and fatigue.
Her medical report reveals that she is on Cycle 2 Day 8 chemotherapy regimen known as adjuvant AC-T and received doxorubicin,cyclophosphamide, and paclitaxel. She verbalized that she was suffering from mouth ulcers, felt too unwell to eat and drink, also had nausea, anorexia, cachexia and fatigue and also reported that she passed urine earlier in the day.
Body
Febrile neutropenia is one of the most common complications of chemotherapy in almost all types of malignancy. Any fever (T >100.4F or 38C) after receiving myelosuppressive chemotherapy requires urgent evaluation.Physical examination of mouth, chest, abdomen, and perianal area are needed to asses for focal signs of infection. Standard laboratory evaluation includes evaluation of all central venous lines for a bloodstream infection by obtaining a blood culture and a CBC with differential to assess for degree of neutropenia. Empiric broad spectrum antibiotic therapy with coverage for gram negative organisms immediately after obtaining a blood Culture is the standard of care. If CBC shows severe neutropenia (ANC less than 0.5 x10 cellsL-1), then admission for continued intravenous antibiotics is usually recommended until neutropenia improves.( according to Avani Mangoli, Michael D. Deel in Encyclopedia of child and Adolescent Health (First Edition),2023).
Neutropenic fever can be dangerous and is considered a medical emergency, as a severe decrease in the absolute neutrophil count (ANC) comprises the immune systems ability to fight against opportunistic infections. Morbidity and mortality depend on severity and duration. Fever and neutropenia that last for less than seven days are associated with a more positive prognosis. Conversely, higher risk of infection- related morbidity and mortality is seen in individuals with persistent neutropenia that lasts for more than seven days, or the presence of profound neutropenia with a neutrophil count lower than 100 cells/mm3.( According to Jennifer Cheung , RN Editors:Antonella Melani, MD, Lisa Miklush,PhD, RN,CNS Illustrator:Abbey Richard). Zoe has received chemotherapy one week ago which is the cause for the development of neutropenia.
On admission , Zoe had signs and symptoms of sepsis such as altered mental status. Hypotension,heart rate 106bpm, increased body temperature, respiratory rate 26 breaths per minitue, poor oral intake, cough, mottled skin, decreased urine output and difficulty in breathing. One of the complications in immunocompromised cancer patients is Sepsis which leads to high mortality and morbidity rate.
According to National Library of Medicine Neutropenic sepsis(NS) is a common and predictable complication of bone marrow disorders and cytotoxic chemotherapy, with an estimated incidence of 70-100% during the neutropenic phase after intensive chemotherapy. Patients with neutropenia are vulnerable to invasive infection,which can be rapidly overwhelming, causing septic shock and death. There is widespread recognition that neutropenic sepsis, as with all forms of sepsis, is a medical emergency in which urgent administration of intravenous fluid and antibiotics have proven benefits on outcome. Despite this, neutropenic sepsis remains a major complication of cancer chemotherapy, with an associated mortality rate ranging from 2% to 21%.'
'Severe sepsis (in which signs of organ dysfunction or hypoperfusion complicate sepsis) and septic shock (in which hypotension persists despite adequate fluid resuscitation.), frequently and sometimes devastatingly complicate the prognosis of patients with neutropenic sepsis. Cardiovascular insufficiency in patients with neutropenic sepsis as indicated by refractory hypotension or signs of inadequate oxygen delivery to end organs, such as confusion and oliguria- mandates early involvement of the critical care team, because these patients are likely to require advanced monitoring and cardiorespiratory support. The mortality from severe sepsis in patients with haematological malignancies has been estimated at 36%, using data from disease registries in the USA.'
Zoe exhibits the signs and symptoms of sepsis which includes increasingly short of breath, tachycardiac,looking peripherally cyanosed with SPO2 84% on 6L/min o2 via simple face mask, mildly confused and disoriented , pale and diaphoretic,hypotensive,tachycardiac tachypnic and has increased body temperature. The medical emergency team call is activated. An arterial blood gas on room air reveals PH 7.32,Pao2 54mmHg, PaCO2 52mmHg, HCO3 18 mmol/L, BE-3, lactate 3.6 mmol/L which indicates she has a mixed respiratory and metabolic acidosis. She was transferred to intensive care unit for further treatment.
Mucosities
Zoe says that she has mouth ulcers that are causing some pain and limiting her ability to eat and drink. According to the journal of experimental & clinical cancer Research 39, Article number 210(2020) Inflammation response of epithelial mucosa to chemo-radotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of the patients treated with chemotherapy develop mucosits;this percentage rises to about 90% for head and neck cancer patients(HNC)treated with both chemo-and radiotherapy. 19% of the latter will be hospitalized and will experience a delay in antineoplastic treatment for high-grade mucositis management, resulting in a reduction of the quality of life, a worse prognosis and an increase in patient management costs.
According to the journal of experimental clinical & cancer Research 39, Article number 210(2020). "Mucositis development consists of a cascade of events that can be divided in five stages occurring consecutively and mechanistically linked. The injury of mucosa membranes,named mucositis initiation phase, is caused by either radio- and/ or chemotherapy. This stage occurs concurrently with chemo- or radiotherapy administration. Systemic chemotherapy and radiotherapy induce tissue damage causing reactive oxygen species(Ros)release, DNA damage thereby leading to cell death of the basal and suprabasal epithelial cells. In particular, DNA strands breaks lead to the activation of the apoptotic process which is regulated by p53 activation and increased caspase 3. As a direct consequence of it, dead cells release endogenous damage-associated pattern molecules(DAMPs). This primary damage response characterizes the second stage of mucositis development. During this stage cells of the injured mucosa promote the transcription of several genes involved in the mucositis process. In this molecular scenario, the nuclear factor kB(NF-kB) represents the main transcriptional mediator modulating over 200 genes associated with pro-inflammatory cytokines (tumor necrosis factor /TNF-; interleukin -6/IL-6; interleukin-1/IL-1), cell adhesion molecules, stress responders and cytokine modulators. The presence of pro-inflammatory cytokines is,also,reported within the mucosa, where they seem to induce early damage of connective tissue and endothelium, as well as to inhibit tissue oxygenations and to favor epithelial basal cell death. During this phase the activation of the immediate response genes, as well as the activation of c-JUN and the c-JUN aminoterminal kinase.(JNK)takes place; thereby following the release of cell membrane bound molecules lead to activation of other transcription factors involved in the process(9). Among them, the nuclear factor erythroid 2-related factors to(NRF2) is a basic leucin zipper protein that promotes the expression of antioxidant proteins as consequence of injury and inflammation process (10). Moreover, anticancer treatment damages also fibroblast, thus leading to the activation of protein -1(AP1) and the consequence secretion of metalloproteinases (MMPs), such as MMP1 and MMP3 which degrade collagenous sub-epithelia matrix and disaggregate the epithelial basement membrane respectively.
Anemia is a common side effect of chemotherapy is myelosuppression, including the onset of anemia.Anemia can impair a patients functional status, diminish physiologic reserve, and result in significant fatigue. ( According to Maryam B Lusterg, MD, MPH). In zoes case her haemoglobin 85g/L and she feels unwell.
Zoe also has mild nausea.Although significant progress has been made, chemotherapy induced nausea and vomiting remains an important adverse effect of treatment. The dose-dense combination of doxorubicin and cyclophosphamide is considered highly emetogenic (experienced by >90 percent of patients),whereas regimens containing either docetaxel, paclitaxel, or carboplatin are moderately emetogenic(experienced by 60 to 90 percent of patients). All patients receiving adjuvant chemotherapy require antiemetic therapy tailored to the risk of the specific treatment regimen. (Maryam B Lustberg, MD MPH).
How to prevent Neutopenic fever
Preventing neutropenic fever begins by taking steps to limit exposure to opportunistic pathogens. Measures include daily baths, oral hygiene, routine inspection of the skin and other portals of entry. Cleaning and cooking food well, as well as avoiding contact with pets, plants, and visitors with active infections.Additionally, with hospitalized patients, heathcare workers and caregivers should practice standard precautions, including regular hand hygiene and utilizing personal protective equipment, as well as limiting skin breaks or injury by avoiding rectal thermometers, enemas, suppositories, digital rectal examinations, and invasive procedures.
Additional measures can involve giving preventive therapy with colony-stimulating factors that stimulate the bone marrow to increase the production of white blood cells like neutrophils. These agents are administered according to clinical practice guidelines developed by the American society of clinical oncology as a prophylactic treatment in high risk patients for primary prophylaxis or secondary prophylaxis, or as a combination with antibiotic therapy during active infection with neutropenic fever.
Prophylactic use of antibiotics, antifungal, or antiviral therapy can be beneficial for high-risk patients undergoing procedures that may further compromise the immune system, like hematopoietic stem cell transplantation (HSCT) or induction therapy for leukemia and conditions like high grade graft-versus-host-disease(GVHD). These individuals may also get screening for herpes simplex virus(HSV),hepatitis, and influenza infections, in order to assess for active or latent infections and initiate prophylactic antivirals. (According to Jennifer Cheung, RN Editors Antonella Melani, MD Lisa Miklush, Phd,RN, CNS Illustrator:Abbey Richard).
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