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Febrile Neutropenia in Intensive Care: a Challenge for the Modern Day Intensivist ANAESTHESIA, PAIN & INTENSIVE CARE www.apicareonline.com SPECIAL ARTICLE Febrile neutropenia in intensive care: a challenge for the modern day intensivist Saad Ur Rehman1, Ahsun Waqar Khan1 ABSTRACT 1Consultant Anesthetist and Febrile Neutropenia (FN) is a fairly common complication of cancer chemotherapy. Intensive Care, Shaukat Khanum It leads to delays in cancer treatment and worsens prognosis. Patients with FN are Memorial Cancer Hospital and frequently admitted to intensive care with organ specific complications of FN. The Research Centre (SKMCH&RC), optimal management of critically ill patients with FN necessitates expertise in oncology, Lahore (Pakistan) critical care, and infectious diseases. Intensive care specialists therefore have to be familiar with key principles of care for critically ill patients with cancer and FN. This Correspondence: review provides an overview of the pathophysiology, definition, management and Dr Saad Ur Rehman, Shaukat prognostic factors of critically ill patients with FN. Khanum Memorial Cancer Hospital and Research Key words: Febrile neutropenia; Critical care; Sepsis Centre, Johar Town, Lahore (Pakistan); Phone No. Work: +924235905000, ext 5116; Cell: Citation: Rehman SU, Khan AW. Febrile neutropenia in intensive care: a challenge for +923434545963; Email: saad_ the modern day intensivist. Anaesth Pain & Intensive Care 2018;22 Suppl 1:S102-S105 [email protected] Received: 8 Sep 2018 Reviewed: 16 Sep 2018 Accepted: 15 Oct 2018 INTRODUCTION 1 h”. Neutropenia is defined as “a neutrophil count of < 500 cells per cubic mm or a count of less than 1000 The management of febrile neutropenia (FN) and cell per cubic mm with a predicted decrease of less neutropenic sepsis is difficult and frustrating, so than 500 cells per cubic mm”. much so that just about two decades ago, intensivists were debating whether these patients should even be The incidence of FN varies between 10 and 50% in admitted to the critical care unit.1 According to cur- solid tumors and is reportedly ≥ 80% in hematologi- rent estimates the hospital survival of patients with cal malignancies.4 FN warrants immediate hospital- neutropenic sepsis admitted to intensive care has ization and management. It leads to delays, reduc- improved to 50%.2 As the survival of patients with tion and change of chemotherapeutic agents which cancer increases, more and more patients with ma- adversely affect outcomes and disease free period.5,6 lignancies will be admitted to critical care, hence an understanding of neutropenic sepsis and its manage- PATHOPHYSIOLOGY ment is paramount for intensivists. Neutropenia complicates almost 24% of patients with DEFINITION solid organ tumors and hematological malignancies. It is associated with both chemotherapy and radio- There are several definitions of FN. According to the therapy. Chemotherapeutic drugs kill and suppress European Society for Medical Oncology (ESMO), all the cells that have a high rate of division. Thus FN is defined as: ‘an oral temperature of > 38.5 ᵒC or they affect blood cells, bone cells, and neutrophil two consecutive readings of > 38.0 ᵒC for 2 h and an cells. Actinomycin, asparaginase, cytarabine, busul- absolute neutrophil count (ANC) of < 0.5 x 109 L or fan, cisplatin, daunorubicin, etoposide, fluorouracil, expected to fall < 0.5 x 109 L.3 According to the Infec- ifosfamide, and methotrexate are highly associated tious Diseases Society of America, FN is defined as with neutropenia development. “single oral temperature of ≥ 38.0 ᵒC (101.4 ᵒF) for ≥ S102 ANAESTH, PAIN & INTENSIVE CARE; VOL 22(Suppl) October 2018 febrile neutropenia in intensive care For chemotherapy to be effective it needs to be ad- for development of serious complications, duration ministered on continuous basis. However, chemo- and choice of antibiotics and in hospital mortality. therapy toxicity results in the destruction of all cell Patients at high risk may develop organ failure ne- lines and is stopped for sufficient intervals so as to cessitating intensive care admission. Scoring systems allow normal cells to recover. The duration of che- such as The Multinational Association for Support- motherapy administration is known as chemotherapy ive Care in Cancer (MASCC) risk index score and cycle. Neutropenia incidence is mainly and highly The Clinical Index of Stable Febrile Neutropenia associated with the first cycle of the chemotherapy (CISNE) score are used commonly for risk stratifica- more than the other or subsequent cycles. tion in neutropenic patients.10,11 The majority of causative organisms involved are Antibiotics: bacterial; prolonged neutropenia, hospital stay and In high risk patients, the initial choice of antibiot- antibiotic use predispose to resistant organisms. ics should be broad spectrum beta lactam antibiotics Organisms include gram-positive bacteria, such as like piperacillin/tazobatam, cefipime or carbapen- coagulase-negative staphylococci, Staphylococcus ems. Gram-positive cover is usually not required but aureus, Enterococcus species, and Streptococcus spe- should be considered in patients with indwelling cies. More recently, drug-resistant gram-negative catheters, skin/soft tissue infections and patients go- organisms including pseudomonas aeruginosa, aci- ing into multiorgan failure. netobacter species, stenotrophomonas maltophilia, escherichia coli, and klebsiella species have been In patients with pneumonia, atypical organisms like identified as etiologic agents. In cases of prolonged mycoplasma and Legionella should be covered with neutropenia and persistent infection, fungi like Can- macrolides. Pneumocystis jerovecii and mycobacteria dida species, Aspergillus species or viral infections should be considered in all patients with atypical in- can be seen.7 filtrates and rapid progression to respiratory failure. These patients should undergo a bronchoalveolar la- PRESENTATION vage and started on treatment dose of co-trimoxazole. Presentation is usually to the emergency department Antifungals should be considered when fever does with high grade fevers however atypical presenta- not respond to broad spectrum antibiotics. Liposo- tions with patient feeling generally unwell are also mal amphotericin B or an echinocandin antifungal fairly common.8 Clinical deterioration may be seen in such as caspofungin are appropriate first-line treat- patients admitted to wards as well after administra- ment if the patient has already been exposed to an tion of chemotherapy. Some of these patients are on azole or if the patient is known to be colonized with corticosteroids and clinical signs of overt bacteremia non albicans candida. Fluconazole is not usually used may be masked. but can be given first line provided the patient is at MANAGEMENT low risk of invasive aspergillosis. Once started, anti- fungal treatment should be continued until neutro- The benefits of a detailed history and extensive phys- penia has resolved, or for at least 14 days in patients ical examination cannot be over emphasized. Recent with a demonstrated fungal infection e.g. lung infil- infection, use of previous antibiotics for prophylaxis, trates. treatment and previous culture sensitivities should be reviewed. An extensive review of systems should Intensive Care Management: be done. Any hemodynamic compromise or organ Patients with FN are usually admitted to intensive failure should prompt activation of sepsis pathway care for sepsis, respiratory failure and complications and intensive care involvement. Tonsillar hyper- of neutropenic enterocolitis. Data is scarce on prog- trophy and site of indwelling catheters should be nostic risk factors; however old age, multi organ in- checked. Investigations should include biomarkers volvement and patients with bone marrow transplant of infection including C-reactive protein, at least 2 and hematopoietic stem cell transplant have a poorer sets of blood cultures (both peripheral and indwell- prognosis. Severity of neutropenia usually does not ing catheters) urine, sputum, feces. Swabs from any affect outcomes. skin wounds and broken mucosal membranes should Patients should be admitted to critical care early be taken and chest x-ray ordered.9 rather than waiting for multiorgan failure to develop. Risk Stratification: Delayed ICU admission is associated with worse out- 12 All patients with FN should be stratified for high risk comes. of serious complications. Scoring systems evaluate The management of these patients should be multi- S103 ANAESTH, PAIN & INTENSIVE CARE; VOL 22(Suppl) October 2018 febrile neutropenia in intensive care disciplinary with intensivist taking the lead working signs of neutropenic colitis. This is caused by neu- in consultation with oncologist and microbiologist/ tropenia and breakage of mucosal layer of gut. Radio- infectious disease specialist. Early involvement of logical imaging in form of CT confirms the diagnosis palliative care team should be sought in cases with although USG can be useful as well. Management multi organ involvement. Sepsis and Septic shock is supportive with bowel rest, parenteral nutrition, should be managed according to severe sepsis guide- correction of coagulopathy and antibiotics. Patients lines. Fever trends and markers of infection should should be monitored for signs of peritonitis, perfora- be monitored closely and any sign of clinical deterio- tion or worsening of symptoms which require surgi- ration should prompt an escalation of antibiotic cov- cal intervention.16 er. Source control should take place early; in children
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