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Managing neutropenia and neutropenic complications

Managing neutropenia and neutropenic complications. The impact of infection in patients with cancer. Increased in-hospital mortality. Infection & sepsis. Increased morbidity. Increased healthcare costs. 8% increase in mortality with each hour that sepsis treatment is delayed.

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Managing neutropenia and neutropenic complications

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  1. Managing neutropenia and neutropenic complications

  2. The impact of infection in patients with cancer Increased in-hospital mortality Infection & sepsis Increased morbidity Increased healthcare costs 8% increase in mortality with each hour that sepsis treatment is delayed Effective prevention and management of infection is essential • Klastersky (ESMO Guideline), 2016; Oakley, 2016; Danai, 2006; Williams, 2004

  3. Preventing anti-cancer treatment-induced neutropenic complications

  4. Granulocyte colony-stimulating factor (G-CSF) reduces FN incidence G-CSF prophylaxis results in fewer patients developing FN • Meta-analysis of 15 trials (3182 patients) • Prospective cohort study • (3638 patients) 39.5% RR of 0.54(95% CI, 0.43 to 0.67; p=0.0001) 22.8% 22.4% 6.4% Primary CSF prophylaxis(n=772) No CSF(n=2866) Primary CSF prophylaxis No CSF • Lyman, 2011; Kuderer, 2007

  5. G-CSF and neutrophil production • + Therapeutic G-CSF • Endogenous G-CSF • Stem cells • Neutrophil progenitors • 5–7 days • 7–10 days • Precursor cells • ↑ number of precursor cells • 1 day Shorter time to differentiation • 4–5 days • Response is greater and more rapid than with endogenousG-CSF alone • Post-mitotic cells • Adapted from Scarffe and Kamthan, 1990; Wan, 2015; Paul, 2013; Bohlius, 2008

  6. Side effects of G-CSF • Mild/moderate medullary bone pain • most common side effect attributed to G-CSFs • refer to individual product label for prevalence • successfully treated with mild analgesics • Rare cases of splenic rupture • Allergic reaction • Other warnings: • Acute respiratory distress syndrome, alveolar haemorrhage, haemoptysis • Fever and bone pain due to abrupt increase of leucocytes • NCCN (myeloid growth factors), 2016; Kawano, 2016; Product SmPCs

  7. Commercial growth factor formulations • Short-acting G-CSF • Half-life 3-4 hours • Long-acting G-CSF • Same therapeutic protein as short-acting G-CSF, but contains an additional modification called “pegylation” or “glycopeylation”, resulting in a larger therapeutic protein • Half-life 15 to 80 hours because rapid renal elimination is reduced due to larger size • Simplification of management of neutropenia and reduction of nursing time needed • †See individual SmPCs for dosing details

  8. Biopharmaceuticalsandbiosimilars • G-CSF is a biopharmaceutical • Biopharmaceuticals • Are produced using recombinant DNA technology • Are larger and more complex than traditional drugs • Cannot be replicated exactly and even small differences in manufacturing processes can affect efficacy and safety • Strictly regulated manufacturing process are required • Biosimilars • Are replicas of complex biopharmaceuticals, also using recombinant DNA technology • However, they are not exact replicas - the name biosimilars indicates that they are highly similar (but not identical) to patented biopharmaceuticals • European Medicines Agency, 2017

  9. Secondary prophylaxis with G-CSF • Secondary prophylaxis: if a patient develops FN in the first chemotherapy cycle, prophylactic G-CSF should be given for subsequent cycles • 25% • 20% 13% • 15% Primary G-CSF prophylaxis is recommended in high risk patients • Percentage of patients developing FN* • 10% 3% • 5% • 0% High risk patients treated with primary G-CSF prophylaxis High risk patients treated with secondary G-CSF prophylaxis *Madry et al, 2016; NCCN (myeloid growth factors), 2016; Aapro, 2011 (EORTC Guidelines); Rivera, 2003

  10. FOR Can reduce the number of patients who become febrile during neutropenia Can be cost-effective Survival advantage demonstrated for specific populations and with certain antibiotics AGAINST Extensive use of antimicrobials selects for microbial resistance, which may affect Prophylactic efficacy Ability to treat subsequent infections Prophylactic use of antimicrobials precludes their use in standard empirical treatment Antimicrobial prophylaxis: the arguments • NCCN (prevention and treatment of cancer-related infections), 2016

  11. Useofantimicrobialprophylaxisshouldbebased on riskidentification Low risk Anticipated neutropenia ≤7 days High risk Anticipated duration of neutropenia >7 days and profound neutropenia (ANC <100 cells/mm3) and/or other high-risk factors such as HCT advanced age, poor performance status, co-morbidities, high risk chemotherapy regimens and high risk malignancies Antimicrobial prophylaxis not routinely recommended Antimicrobial prophylaxis (fluoroquinolone) should be considered • NCCN (prevention and treatment of cancer-related infections) 2016; Flowers, 2012 (ASCO guidelines); Freifeld, 2011 (IDSA guidelines)

  12. The nursesrole in reducingtheriskof febrile neutropenia • Awareness of riskfactors • Use correct hand washing protocols • Appropriate precautions during invasive procedures and intravenous catheter care • Educate patients and caregivers on protectivemeasures, daily monitoring practicesandsignandsymptomsofinfection • Hand washing, skin protection, oral care, gastrointestinal protection, genitourital protection, foodhygiene • Educatepatientsaboutuseandadministrationof G-CSF Hand washing is the single most important protective measure for preventing infection in neutropenic patients Dalen, 2016;Elad, 2015; Mize, 2014; Schlesinger, 2009; Coughlanand Healy, 2008; Friese, 2007

  13. Management of Febrile Neutropenia (FN)

  14. Careful patient assessment is important • Signs of infection are not always obvious • Temperature > 38.3 °C and ANC <0.5 ×109/L clearly indicate febrile neutropenia • Increased vigilance is required when patients: • Present unwell • Show changes in behaviour (e.g. disorientation, confusion) • Are hypotensive compared to previous BP readings • Are receiving corticosteroids • Present low grade fever Patients should be evaluated by a healthcare provider as soon as possible • Klastersky (ESMO Guideline), 2016; Marrs, 2006

  15. Role of nurses in evaluating patient risk Step 1: Assess the FN risk of planned chemotherapy regimen Step 2: Evaluate presence of individual patient risk factors Step 3: Define overall risk • O’Brien, 2014; Aapro et al, 2011 (EORTC Guidelines)

  16. Clinical pathway for neutropenic patients • Is the patient on anticancer therapy? When did patient last receive chemotherapy? • How have they been feeling? • Are there any specific symptoms of infection? History Examine • Temperature, pulse, quick SOFA criteria? • Urgent full blood count, kidney and liver function tests, CRP, lactate, and blood culture. • Refer urgently to local acute provider. Action • Treat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately (aim: within one hour of admission time, the “GOLDEN HOUR”). Treat • Wingard, 2017; Klastersky (ESMO guideline), 2016; NCCN (prevention/treatment of cancer-related infections), 2016; Singer, 2016

  17. Patient-related risk factors for FN • Age* • Advanced disease • History of prior FN • Mucositis • Poor performance status • Cardiovascular disease • Comorbid conditions * Patients >65 y are twice as likely to experience FN. Prophylactic G-CSF should be used in all elderly patients receiving myelotoxic chemotherapy Because chemotherapy regimens are standardized by cancer type, patient-related risk factors are particularly important in any given treatment setting Klastersky(ESMO Guideline), 2016;Lustberg, 2012; Lymann, 2011

  18. MASCC FN Risk Index: risk of infectious complications in FN patients • Overall score: ≥21 • At low risk of complications • Patients can often be treated with oral antibiotics and possibly as outpatients, if adequate follow-up available • Overall score: <20 • At high risk of complications • Patients should be hospitalised and commenced on broad spectrum i.v antibiotics, due to high risk of bacterial sepsis In FN patients, risk of infectious complications should be assessed promtly and managed accordingly MASCC – Multinational Association of Supportive Care in Cancer Klastersky (ESMO guideline), 2016; NCCN (prevention/treatment of cancer-related infections), 2016

  19. Example of algorithm to guide patient management after risk assessment Chemotherapy Risk assessment for neutropenic complications Low- or moderate-risk patient* High-risk patient ANC ≥500/mm3 and afebrile ANC <1,000/mm3 and febrile or ANC ≤500/mm3 Chemotherapy cycle ≤14 days Chemotherapy cycle >14 days Continue monitoring Prophylactic G-CSF indicated: e.g., G-CSF SC starting >24 h after chemotherapy and continuing until ANC ≥10,000/mm3 Prophylactic G-CSF indicated: e.g., G-CSF SC starting >24 h after chemotherapy and continuing until ANC ≥10,000/mm3 Prophylactic G-CSF indicated: e.g., longacting G-CSF SC starting >24 h after chemotherapy * A patient who is considered low or moderate risk and then becomes febrile with an ANC <1,000/mm3 will be considered high risk in all subsequent cycles. Klastersky(ESMO Guideline), 2016; Aapro (EORTC Guidelines), 2011; Donohue, 2006

  20. Initial management of FN Klastersky (ESMO Guideline), 2016

  21. Neutropenia-related IV line infections • Risk factors • Multiple IV lines • Type of device used • Duration of placement • Extent and duration of neutropenia • Previous bacteraemia • IV line inserted after onset of aplasia • Management • If catheter-related infection is suspected, obtain skin swabs and blood cultures • Administer appropriate treatment • Remove catheter in cases of serious infection • Follow international guidelines • NCCN (prevention and treatment of cancer-related infections), 2016; NCCN (patient guidelines, fever and neutropenia), 2006; Mermel, 2001 .

  22. Blood cultures • When possible, take all cultures before starting the patient on antimicrobials from all relevant sites (i.e. iv lines, wounds, urine, nose and throat) • The cycles of fever and chills generate cytokines that can affect the culture yield • The best time to culture seems to be when a modest fever is increasing • Two blood samples should be cultured:1,2 • Preferred option: one obtained from peripheral blood and one from a central venous catheter • Clearance of infections should be documented with repeat blood cultures1 • A repeat of cultures after 72 h is usually appropriate • 1NCCN, (prevention and treatment of cancer-related infections), 2016; 2Klastersky, 2016 (ESMO Guideline); Hughes, 2002

  23. The “GOLDEN HOUR” • Early recognition of sepsis and initiation of appropriate interventions in the “golden hour” of patient arrival at the hospital are associated with improved outcomes. • The cornerstones of successful management include: • Early haemodynamic optimization • Administration of appropriate antimicrobial therapy • Effective source control of infection • Specific written sepsis protocols, early stabilization and aggressive resuscitation in the emergency department with early transfer to the ICU may aid in improving outcome. Forde, 2017

  24. Clinical criteria to identify patients with sepsis and septic shock Quick SOFA criteria are a useful tool to promptly identifyinfected patients likely to have poor outcomes • Singer, 2016

  25. SOFA score: qSOFA variables qSOFA (quick SOFA) score • Identification adult patients with in ICU suspected infection who are likely to have poor outcomes • Fulfillment of any two of these three clinical variables has same predictive validity than full SOFA score outside of the ICU • Respiratory rate ≥22/min • Altered mentation • Systolic blood pressure ≤100 mm Hg • No requirement for laboratory tests and can be assessed quickly repeatedly • Can be used to prompt further investigations, initiation or escalation of therapy, referral to critical care or increase frequency of monitoring • Regarding in-hospital mortality, full SOFA score is a significantly better discriminant than qSOFA (Eamon, 2017) • Singer, 2016

  26. SOFA score: full SOFA variables Sequential Organ Failure Assessment (SOFA) score • Singer, 2016

  27. Potential antimicrobial strategies • IV monotherapy • Imipenem/cilastatin • Meropenem • Piperacillin/tazobactam • Cefepime • Ceftazidime * • Fever + Neutropenia(single oral temp. 38.3oC or 38.0oC over 1h) +(ANC <0.5 x 109/L or ANC <1.0 x 109/L and predicted decline to ≤0.5 x 109/L over the next 48 h) • Low risk • High risk • Oralfor some low risk patients • IVChoice of antibiotic may depend on local antibiotic susceptibilitypatterns and individual patient syndromes. Ciprofloxacin + amoxicillin/clavulanate Moxifloxacinmonotherapy * • IV combination therapycould be considered, especially in cases of resistance If empiric vancomycin (or other agents for gram-positive resistant infection) is initiated, reassess its use within 2– 3 days. Reassess after 3 – 5 days • *Examples • NCCN (prevention and treatment of cancer-related infections), 2016

  28. Summary • A proactive nursing strategy involves • risk assessment • implementing protective measures • educating patients to minimise the risk of infection • being aware of signs and symptoms of complications of neutropenia • Primary prophylaxis with G-CSF for high risk patients • secondary prophylaxis should be employed in subsequent cycles following a neutropenic event • Caution when considering prophylactic antibiotics • Prophylactic antimicrobials should be used only when indicated by risk assessment

  29. Summary • Febrile neutropenia has a significant impact on morbidity and mortality • Initial antibiotic treatment should be administered within 1 GOLDEN hour of triage • Management of febrile neutropenia requires • Continuous monitoring • The prompt removal of the source of infection

  30. Test question 1 What is the clinical presentation of a neutropenic patient with infection A: Hypotension, sweating, low urinary output B: Fatigue, tachypnoea C: No signs D: All of the above

  31. Test question 1 What is the clinical presentation of a neutropenic patient with infection A: Hypotension, sweating, low urinary output B: Fatique, tachypnoea C: No signs D: All of the above

  32. Test question 2 Infections in FN patients can be prevented by A: Using the MASSC risk index for FN patients B: Start antimicrobial agents C: Temperature <38,5C D: Handwashing protocols by staff

  33. Test question 2 Infections in FN patients can be prevented by A: Using the MASSC risk index for FN patients B: Start antimicrobial agents C: Temperature <38,5C D: Handwashing protocols by staff

  34. Test question 3 Recovery time after HSCT takes A: < 7 days B: < 14 days C: < 21 day D: > 28 days

  35. Test question 3 Recovery time after HSCT takes A: < 7 days B: < 14 days C: < 21 day D: > 28 days

  36. Test question 4 The Golden Hour improves not the A: Administration of appropriate antimicrobial therapy B: Effective source control of infection C: Total serum neutrophil level D: Early haemodynamic optimization

  37. Test question 4 The Golden Hour improves not the A: Administration of appropriate antimicrobial therapy B: Effective source control of infection C: Total serum neutrophil level D: Early haemodynamic optimization

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