Febrile Neutropenia

Neutropenia in oncology patients often results due to chemotherapy. The lowest neutrophil count is generally seen 5 -10 days after the last chemotherapeutic dose and the risk of developing an infection primarily depends on the severity and duration of neutropenia, comorbidities, use of in-dwelling catheters. 

The absolute neutrophil count (ANC) normal range is 1500 to 8000/mm3 (1.5 to 8.0 × 109/L).  Fever is defined as a temperature of 38.3°C on one occasion or 38.0°C persisting >1 hour.


Definitions
Neutropenia is defined as an absolute neutrophil count <1000/mm3(<1.0 × 109/L)
Severe neutropenia is defined as an absolute neutrophil count <500/mm3 (<0.5 × 109/L) Profound neutropenia is defined as an absolute neutrophil count <100/mm3 (<0.1 × 109/L).

Fever is the most common finding seen with bacterial infections in the neutropenic patient. Common symptoms and signs are often absent in the neutropenic patient because impaired inflammatory response. 



Examination (Head to toe to look of any signs of infection)

Lungs
Skin
Urine
Abdomen
CNS

Oral cavity
Perianal area
Intravascular catheters (Thrombophlebitis, Infective Endocarditis)

Avoid doing a Digital Rectal Examination in neutropenic patients. Id necessary, do only after antibiotic administration. 

Work up

• Blood cultures
• Urinalysis, Urine culture,
• CXR
• Sputum, stool, and wound drainage Gram stains and culture 
• FBC, Renal and Liver function  

Treatment 

Known source - Guided Antibiotics
Unknown source and ill patient - Empiric Broad Spectrum Antibiotics

Gram-positive bacteria currently account for more than half of microbiologically confirmed infections in febrile neutropenic patients. Monotherapy with an appropriate broad-spectrum agent is as effective as dual-agent treatment in most circumstances. Consider adding vancomycin if:

• Hemodynamic instability
• Radiographic pneumonia
• Catheter-related infection
• Skin or soft tissue infection
• Known colonization with a resistant gram-positive organism
• Severe mucositis (recent use of fluoroquinolone prophylaxis)

Discussion with patient's treating oncologist should happen simultaneously about the choice of Antibiotics (unless there are agreed existing protocols) and plan for admission v/s discharge since hospitalization may lead to drug-resistant infections. 

A subgroup of patients with febrile neutropenia may appear well with no signs of infection. They are expected to settle their neutropenia within a week have a low risk of severe infection and can be considered for outpatient care in liaison with the Oncologist.        Ensure early follow up for them prior to discharge. 

Decision Rules to risk stratify Neutropenic Patients

Clinical Index of Stable Febrile Neutropenia 

MASCC Risk Index for Febrile Neutropenia 

Clinical evidence supports the benefits of empiric antibiotics only with ANC ≤500/mm. There is little evidence for empiric antibiotics when the ANC >1000/mm. Abx are continued until the infection has clinically resolved and/or the ANC is >500/mm3 (>0.5 × 109/L).

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic

Chemotherapy Induced Emetogenecity

Cancer is one of the top three killers today and Emergency Departments are expected to  see more and more Oncological Emergencies in future. CINV i.e. Chemo Induced Nausea and Vomiting is one such complication of chemotherapy. 

Few patients receiving chemotherapy rank CINV as the most severe side effects and in the past, about half of the patients postponed or refused, potentially curative treatments due to the fear of CINV. With the correct use of antiemetics, CINV can be prevented in almost 70% to up to 80% of patients. Though over the past 25 years, steady improvements in the control of chemotherapy-induced nausea and vomiting (CINV) have been achieved but it still remains a significant issue of concern. 

Pathophysiology of CINV

CINV happens due to noxious reactions along the neuronal pathways. Chemoreceptor trigger zone, which is outside the blood-brain barrier senses emetic stimuli through receptors such as 5HT3, NK1, D2 and muscaranic. Chemicals bind to these receptors and initiate a response. Additionally, activation of these receptors may also occur through GI irritation. 

CLASSIFICATION OF CINV

CINV is differentiated into the following categories: 

1. Acute onset: within 24 hours of initial administration of chemotherapy
2. Delayed onset: occurring 24 hours to several days after initial treatment
3. Anticipatory: emetic episodes are triggered by taste, odor sight, thoughts, or anxiety secondary to a history of poor response to antiemetic agents 
4. Breakthrough: occurring despite prophylactic treatment
5. Refractory: occurring during subsequent cycles when antiemetics have failed in earlier cycles

Risk of CINV with Chemotherapy medications 

Patient-related risk factors, including young age, female gender, experience of emesis during pregnancy, impaired quality of life, and previous experience with chemotherapy, are also known to increase the risk for CINV. Conversely, patients with a history of high alcohol consump- tion have a lower risk of chemotherapy-induced nausea and vomiting.

Management

5-HT3RAs (Receptor Antagonists)

• High therapeutic index for prevention of CINV, most effective antiemetics in the prophylaxis of acute CINV. 
• Generally safe, with a favorable side effect profile (low grade headache, malaise, and constipation). High-dose (24-32mg) Ondansetron appears to be more effective  
• Some literature reports suggest a potential link between 5-HT3 receptor antagonists and the serotonin syndrome, QTc prolongation esp with a single IV dose of 32mg

Steroids, Dexamethasone/Methylpresdnisolone 

• Steroids can be effective when administered as a single agent in patients receiving chemotherapy of low emetic potential. Most beneficial, when used in combination with other antiemetic agents.
• When corticosteroids are administered with aprepitant, doses should be reduced by half.

NK1RAs, Aprepitant

• Aprepitant is the first representative of this new group that blocks the NK1 receptor in the brainstem emetic center and gastrointestinal tract
• Aprepitant is a moderate inhibitor of CYP3A4; therefore, the dexamethasone dose has to be reduced if used concomitantly.

Adjunctive therapy 

1. Metoclopramide

• In the past, metoclopramide was used alone or in combination with a corticosteroids
• Now, it is reserved for those who are intolerant to 5-HT3RAs or steroids
• May cause extrapyramidal side effects including acute dystonic reactions, akathisia  

2. Olanzapine  

• An atypical antipsychotic drug with potential antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting.

3. Benzodiazepines

• Used in certain circumstances, to cut anxiety and risk of anticipatory CINV or in patients with refractory and breakthrough emesis.

4. Antihistamines

5. Cannabinoids

• Possess beneficial side effects (sedation, euphoria) in addition to weak antiemetic efficacy but usefulness is limited by the high incidence of toxic effects, such as dizziness and hallucinations.
• Advised in patients intolerant or refractory to 5-HT3RAs or steroids and aprepitant. 

Key Points

First Line for CINV - 5HT3 Antagonists, Steroids, NK1RA
Adjuncts - Benzodiazepines, D2 RA, Olanzapine, Anti-Histaminics, Cannabinoids 


References: 

1. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. The oncologist. 2007 Sep 1;12(9):1143-50.
2. WHO Pharmaceuticals newsletter. Ondansetron and serotonin syndrome. 2012; 3:16.
3. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuro psychopharmacology. 1996 Feb 29;14(2):87-96.
4. WarrDG, HeskethPJ, GrallaRJetal. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in pa- tients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005;23:2822–2830. 
5. www.uspharmacist.com
6. Hesketh, Paul J. "Chemotherapy-induced nausea and vomiting." New England Journal of Medicine 358.23 (2008): 2482-2494.

Author:

              

     Lakshay Chanana

     @EMDidactic