management of neutropenic sepsis rebecca frewin consultant haematologist gloucestershire hospitals...

Management of Neutropenic Sepsis

Rebecca FrewinConsultant Haematologist

Gloucestershire Hospitals NHS Foundation Trust

Aims of today

What

• The definition of neutropenic sepsis

Why

• Importance for Emergency Clinicians• Outcomes of Neutropenic sepsis

How

• Assessment of neutropenic sepsis• Guidelines for management of neutropenic sepsis• Spot diagnoses

Definition of Neutropenic Sepsis

Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil countis 0.5 × 109 per litre or lower and who have either:a temperature higher than 38oC orother signs or symptoms consistent with clinically significant sepsis.

NICE Clinical Guideline 151: September 2012

Sepsis or Systemic Inflammatory Response Syndrome (SIRS)

• Patients are often described as being ‘septic’ or in ‘septic shock’• Systemic inflammatory response syndrome (SIRS)

– Temperature >38oC or <36oC– Heart rate >90/min– Respiratory rate >20 or PaCO2 <4.3kPa– White Cell Count >12x 10 9/l

• Sepsis is defined as SIRS in response to infection• Severe sepsis is sepsis associated with:

– Organ dysfunction– Hypotension (systolic BP <90mmHg or >40mmHg from normal)– Organ hypoperfusion (lactic acidosis, oliguria, acute alteration of mental status)

• Septic shock describes sepsis with hypotension despite adequate fluid resuscitation

Deaths from Neutropenic Sepsis• 2 deaths/ day from neutropenic sepsis• 60% increase in chemotherapy between 2002 – 2006• More intensive regimes• Highest death rate is in 65-79 year olds

Neutropenic sepsis: higher risk of dying in young patients

Where do neutropenic sepsis patients present?

SACT Report 2008

Approach to neutropenic sepsis

1. Assessment Initial assessment Investigations More detailed review

2. Treatment Antibiotics Fluid resuscitation Vasopressors Blood product support

Initial assessment

• Brief history– Symptoms– Recent chemotherapy– ‘Normal’ neutrophil count– Late onset neutropenia in rituximab patients

• Limited examination– MEWs – not validated in neutropenic patients– Review of any obvious source

Investigations

• For CXR, probability of pneumonia in a child without respiratory symptoms was 1.9% (Phillips et al (2011)

• Peripheral blood cultures – 28/228 cultures were positive (Sheienmann et al (2010). The differential time to positivity of cultures between central and peripheral cultures can be indicative of catheter related thrombosis NICE Clinical Guideline 151

Early Lactate-Guided Therapy in Intensive Care Unit Patients

Jansen TC. Am J Respir Crit Care Med. 2010;182:752–761.

adjusted HR= 0.61; 95% CI, 0.43-0.87; P= 0.006

Slide 13Copyright 2014 SCCM/ESICM

Treatment: antibiotics

MASCC score in neutropenic sepsis

Initial Resuscitation• During the first 6 hours, the goals of initial

resuscitation of sepsis-induced hypoperfusion should include all of the following as a part of a treatment protocol (Grade 1C): – Central venous pressure 8-12 mm Hg– Mean arterial pressure ≥65 mm Hg– Urine output ≥0.5 mL/kg/h– Central venous (superior vena cava) or

mixed venous oxygen saturation 70% or 65%, respectively


Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock

Control EGDTRelative Risk

(95% Confidence Interval)

P

In-Hospital 46.5 30.5 0.58 (0.38-0.87) 0.009

28-day Mortality 49.2 33.3 0.58 (0.39 – 0.87) 0.01

60-day Mortality 56.9 44.3 0.67 (0.46-0.96) 0.03

Rivers E. N Engl J Med. 2001;345: 1368-1377.


Fluid Therapy• We recommend an initial fluid challenge in

patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. (Grade 1C)


Fluid Therapy• We recommend crystalloids be used as the

initial fluid of choice in the resuscitation of severe sepsis and septic shock. (Grade 1B)

• We recommend against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. (Grade 1B)


Fluid Therapy - Kidney injury• Three multicenter randomized trials showed a significant

increase in the risk of acute kidney injury with hydroxyethyl starch as compared with crystalloids.

Brunkhorst F. N Engl J Med. 2008;358:125-139.Perner A. N Engl J Med. 2012;367:124-134.Myburgh JA. N Engl J Med. 2012;367:1901-

1911.

• One multicenter randomized trial did not find an increase in the risk of acute kidney injury with hydroxyethyl starch as compared with crystalloids.

Guidet B. Crit Care. 2012;16:R94.


Fluid Therapy• We suggest the use of albumin in the fluid

resuscitation of severe sepsis and septic shock when patients require repeated boluses of crystalloids. (Grade 2C)


Meta-analysis: Albumin versus Other Fluids

Outcomes Illustrative comparative risks (95% CI)

Relative effect(95% CI)

No. Of participants(studies)

Quality of the evidence(GRADE)Assumed

riskCorresponding risk

Control Other fluids (may be crystalloid or colloid)

Short-term mortality Study population RR 0.84 (0.73 to 0.97)

1683(11 studies)

⊕⊕⊕⊝moderate342 per

1000287 per 1000(249 to 332)

Short-term mortality(albumin vs crystalloids)

444 per 1000

377 per 1000(324 to 440)

RR 0.85(0.73 to 0.98)

1402 (4 studies)

⊕⊕⊕⊝moderate1

Short-term mortality(albumin vs other colloids)

342 per 1000

195 per 1000(249 to 396)

RR 0.81(0.57 to 1.16)

281(7 studies)

⊕⊕⊕⊝moderate1

1Grade reduced for imprecision.


Vasopressors

• Maintain the MAP >65mmHg (Grade 1C)• Norepinephrine is recommended as first line vasopressin

(Grade 1B)• Epinephrine may be added to and potentially substituted for

norepinephrine when as additional agent is needed to maintain blood pressure (Grade 2B)

• Low dose vasopressin (0.03U/min)may be added to norepinephrine with the intent of raising the MAP to target or reducing the norepinephrine dosage

• Dopamine should be used only as an alternative vasopressor to norepinephrine only in highly selected patients (eg at low risk of arrythmias and/or a low heart rate) (Grade 2C)

Meta-analysis of Norepinephrine versus DopamineOutcomes Illustrative comparative risks* (95%

CI)Relative effect(95% CI)

No. of participants(studies)

Quality of the evidence(GRADE)Assumed risk Corresponding

risk

Dopamine Norepinephrine

Short-term mortality Study population RR 0.91 (0.83 to 0.99)

2043(6 studies)

⊕⊕⊕⊝moderate1,2

530 per 1000 482 per 1000(440 to 524)

Serious adverse events - Supraventricular arrhythmias

Study population RR 0.47 (0.38 to 0.58)

1931(2 studies)


229 per 1000 82 per 1000(34 to 195)

Serious adverse events - Ventricular arrhythmias

Study population RR 0.35 (0.19 to 0.66)

1931(2 studies)


39 per 1000 15 per 1000(8 to 27)

*The assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; RR: Risk ratio;

1 Strong heterogeneity in the results (I squared = 85%), however this reflects degree of effect, not direction of effect. We have decided not to lower the evidence quality.2 Effect results in part from hypovolemic and cardiogenic shock patients in De Backer, NEJM 2010. We have lowered the quality of evidence one level for indirectness.


Inotropic Therapy• We recommend that a trial of dobutamine infusion up to 20

μg/kg/min be administered or added to vasopressor (if in use) in

the presence of:• myocardial dysfunction as suggested by elevated cardiac

filling pressures and low cardiac output, or• ongoing signs of hypoperfusion, despite achieving adequate

intravascular volume and adequate mean arterial pressure.

(Grade 1C)

• We recommend against the use of a strategy to increase cardiac

index to predetermined supranormal levels. (Grade 1B)


Blood product support

• Maintain Hb >70g/l with a target of 70-90 unless extenuating circumstances such as ischaemic coronary artery disease

• Give prophylactic platelet transfusions if platelets <10 or <20 with a significant risk of bleeding.

Spot diagnosis in neutropenic patients

Spot diagnosis

Have we covered it all?

What

• The definition of neutropenic sepsis

Why

• Importance for Emergency Clinicians• Outcomes of Neutropenic sepsis

How

• Assessment of neutropenic sepsis• Guidelines for management of neutropenic sepsis• Spot diagnoses

management of neutropenic sepsis rebecca frewin consultant haematologist gloucestershire hospitals...

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