Neutropenic Sepsis – Acute General Management and Support

Ernie MarshallMacmillan Consultant in Medical

OncologyClatterbridge Centre for Oncology

Who Am I ?

• I am– A Medical Oncologist (MCCN)– Site specialist and general remit– Awareness of FN issues across Centre/Unit– Awareness of FN issues at National level (as failed CI

for ORANGE Trial!)– Keen interest in reducing unnecessary hospital stays– Enthusiast for AO

• I am NOT:– Sepsis Expert – or reader of ITU weekly chronicle

Aims

• Overview & Background

• General Principles of management

• Risk Stratification

• Low risk strategies

• FN management in the real world

Why is FN important ?

• Remains a life threatening complication (5% in high risk but 1% in low risk)

• Compromise survival with dose delays, reductions

• FN is not going away– Significant increase in chemo use

– Remains an issue with new therapies

• Well recognised but poorly managed (NCEPOD)

• Increasing burden on DGHs

• Poor patient experience

• Limited high quality research

How Big a Problem?

• We don’t know• Limited data on incidence, mortality, LOS...• No recognised code: current hospital coding uses:

– A41.9 (sepsis)– D70.X (neutropenia)– Y43.3 (‘chemo-related)

• Predominantly Breast/Lung Cancer• Cancer Centre

– CCO audits : 100 over 6mths (4/week)– SWLCN 71 episodes over 3months (6/week)

• DGH data– SH&K FN and AOT Audit: 1-2 per week

Prevention strategies

• Prophylactic Antibiotics

• CSFs: FN risk > 20% in curative cancer where no other regimen available

• Decision to Treat– PT SELECTION

– CHEMO Protocol

NCEPOD:

86% palliative intent

‘20% of cases, decision to treat was assessed as inappropriate’

Background

• Fever ≥ 380C on 2 occasions AND neutrophilcount ≤ 0.5 x 109/l

• Duration in solid tumour 3-5days ( Acute Leukaemia:23-27days)

• 50% of febrile pts have clinically documented infection

Presentation

• Awareness

• Fever, non-specific symptoms

• Usually 7-14days post chemotherapy

• Mucosal damage, catheter-related

• May present with no fever, confusion, (steroids, overwhelming infection)

Investigations

• Immediate FBC and differential

• Urea, creatinine, electrolytes

• Blood cultures– <10% positive*

• Routine cultures unhelpful

• CXR (chest symptoms/signs)

• C –Reactive Protein not routine

• IL-6/IL-8 investigational

Risk Assessment

• Underlying Disease

• Patient Fitness

• Age

• Outpatient episode

• Peak temperature

• Hypotension

• Neutrophil count

• Focus of infection

• Comorbidity

• Duration of neutropenia

• Controlled malignancy

• Fungus

• Gram negative

• Talcot Risk Index*

Multinational Association of Supportive Care in Cancer Risk Index (MASCC)

Characteristics Score

Burden of Illness

no/mild symptoms 5

moderate symptoms 3

No hypotension 5

No COPD 4

Solid tumour/lymphoma 4

No dehydration 3

Outpatient 3

Age over 60yrs 2

Maximum theoretical score is 26:

A score ≥21 denotes low risk

Optimal FN ManagementTemp >38.5 and ANC < 0.5

Prompt assessment & Resuscitation

Calculate MASCC Risk Index

High Risk Low Risk

Antibiotic Protocols

Investigations

High Risk Patients & Sepsis Bundles (www.severesepsis.org)

Job 1: Blood Cultures; FBC U&E

Job 2: Antibiotics

Job 3: Fluid ResuscitationSystolic BP < 90 and/or HR > systolic BP

Job 4: ECGJob 6: Monitor blood glucose

Job 5: Check serum lactate

CVP monitoring and Ventilation

Drug Therapy• Which Antibiotic?

– Beta lactam and aminoglycoside– Monotherapy– Vancomycin only in high risk gram positive

• Time to modification– 72hours or clinical deterioration– Duration of Abs not defined

• Anti-fungals– Rarely required, consider if persistent fever 4-6days

• Growth Factors– Therapy: routine cases not required

Aims and Endpoints?

• Primary Success (response and mortality)– Time to treatment

– Optimal antibiotic (s)

• Secondary Success (benefit)– length of stay

– Toxicity

– Cost

– Quality of life & patient experience

– Hospital acquired infection

Low Risk Strategies

Inpatient Care• Low dose Monotherapy• ‘Step down’ policies

– POCs

• Inpatient oral combination• Inpatient oral monotherapy

– EORTC 46001 moxifloxacin vs co-amoxyclav/Cipro

• Early discharge policiesOutpatient Care• Outpatient parenteral antibiotics• Outpatient oral antibiotics

Inpatient Oral Antibiotics

• 2 International randomised trials*

• Systematic review & metaanalysis (15)

• Low risk inpatients

• Oral co-amoxyclav & ciprofloxacin vs iv standard

• RR, duration of antibiotics and smc rate: equivalence

Freifeld et al NEJM, 1999

Kern et al NEJM, 1999

Vidal et al, J of Antimicro. Chem, 2004

UK Audit of managementInnes et al BJC 2005

• 128 Clinicians from 50 Cancer Departments

• 22% use oral antibiotics from outset

• 38% stratify but variable risk indices

• 51 % of stratifiers use oral antibiotics vs 4% not (p< 0.0001)

• Phillips et al 2007: UK Childrens Cancer Study Group survey: Wide variation in all aspects of care

CCO Experience

• Single Centre oral versus iv trial & sequential audits (1997-)

• Findings (Innes et al 2003, 2008)– Routine clerking proforma incorporating MASCC index

– Majority are low risk patients

– Oral antibiotics safe and effective

– Median duration of stay: Reduced to 2days

– 50% cost savings and reduced nursing time (GRASP)

Do all patients need Antibiotics!Nijhuis et al JCO: 2005

• 36/196 Low risk episodes (clinical and IL-8)

• Standard FN definition

• Median ANC 0.08

• Blood culture negative

• No antibiotics

• Hospitalised until afebrile > 12hrs

• Daily telephone contact

• No episodes of deterioration or readmissions

The Real World

The ORANGE Trial

A Randomised phase III trial evaluating early hospital discharge in low risk patients receiving oral antibiotics

Trial Closed Early April 2007:27 patients registeredNo SMCs, No readmissions, LOS 2 days.

34 sites declined entry due to:Complex admission pathwaysMajority of patients not managed within treating centreInability to carry out MASCCTrial management & out of hours careConflicting local antibiotic policyConflict with C Difficile policies

Patient PathwaysAll familiar with Standards

– Patient information– 24 hour specialist triage– Speedy access to specialist care and antibiotics– FN guidelines

– Compliant with standards BUT does it work in practice?

– NCEPOD• 94% have policies in place BUT• ? Suboptimal patient information• Dislocation of care with many admitted to units under

general physicians

St Helens & Knowsley NHS TrustAudit (2007)

• Snap shot analysis revealed:

– Lack of awareness of care pathways in A&E

– Conflicting triage pathways (FN & Manchester)

– Negative impact of 4hr targets

– No iv antibiotics in A&E

– Delays in first antibiotics up to 12hours

– Delayed antibiotics on Day unit and inpatient Facility due to lack of medical staff and beds.

New pathway • Talk to A&E! (joint working Group)

• Patient alert card introduced• Electronic alert system• Integrated Triage with A&E

pathway• Antibiotics before pt transferred• AO review 24hrs• Re audit 2008:

– 22 patients (9 months) – All received abs < 4hrs– Improved awareness and

communication– High risk LOS 6 days, low risk LOS

4 days

STH&K A&E FN Management Chart

CCO Triage for Suspected FNAudit findings ( Ford, 2009)

• 3 month Triage calls (164 calls)

• 73 attended CCO: majority low risk

• 66 ‘other’: hospital, GP, community nurse

• 50% of cases not neutropenic

• Average Time from triage call to arrival 4 hours (range - 13hours)

• Low risk LOS = 2.7days, High risk LOS = 7days

• Examples of dislocated care at DGH

DGH: Case I

• Cancer Centre Triage call 16.30• Advised to attend local A&E 18.30• ‘Low risk’ : • CCO informed and advice sought• Patient commenced oral antibiotics at 22.00• On call pharmacy input with switch to Imipenem and

G-CSF• Patient continued capecitabine further 24hrs• Hospital LOS : 9days

DGH: Case II

• Cancer Centre Triage call: 9.15

• Advised to attend local A&E 10.20

• ‘Low risk’ :

• CCO informed and advice sought 14.20

• CCO transfer

• Arrived CCO 16.30 – MASCC Score low risk

• IV antibiotics commenced at 18.30

• Hospital LOS 4 days

‘Winning principles’www.improvement.nhs.uk/winning_principles

Transforming Inpatient Cancer Care

• I: Assess before admission: – Improve triage, A&E risk stratification, alerts

• II: Patients should be on a defined inpatient pathway– A&E, AOT review

• III : Daily review– AOT

• IV : Pt information and self management

Summary

• FN is a potentially lethal complication BUT in a minority• We need to improve pathways for all FN patients• Progress requires integrated approach with triage,

Centres, A&E and AOT• Need to improve Pt selection and introduce risk

stratification• AO offers significant opportunities to reduce mortality,

improve pt experience and reduce hospitalisation• AO offers new opportunities to develop real world R&D

and link with NCRN• Forthcoming NICE guidance