1. Management of Neutropenic Sepsis Rebecca Frewin Consultant Haematologist Gloucestershire Hospitals NHS Foundation Trust

2. 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

3. Definition of Neutropenic Sepsis Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5 × 109 per litre or lower and who have either: a temperature higher than 38 o C or other signs or symptoms consistent with clinically significant sepsis. NICE Clinical Guideline 151: September 2012

4. Sepsis or Systemic Inflammatory Response Syndrome (SIRS) Patients are often described as being ‘septic’ or in ‘septic shock’ Systemic inflammatory response syndrome (SIRS) – Temperature >38 o C or <36 o C – Heart rate >90/min – Respiratory rate >20 or PaCO 2 <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 40mmHg from normal) – Organ hypoperfusion (lactic acidosis, oliguria, acute alteration of mental status) Septic shock describes sepsis with hypotension despite adequate fluid resuscitation

5. 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

6. Neutropenic sepsis: higher risk of dying in young patients

7. Where do neutropenic sepsis patients present? SACT Report 2008

10. Approach to neutropenic sepsis 1.Assessment  Initial assessment  Investigations  More detailed review 2.Treatment  Antibiotics  Fluid resuscitation  Vasopressors  Blood product support

11. 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

12. 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

13. 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 13 Copyright 2014 SCCM/ESICM

14. Treatment: antibiotics

16. MASCC score in neutropenic sepsis

17. 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 Slide 17 Copyright 2014 SCCM/ESICM

18. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock ControlEGDT Relative Risk (95% Confidence Interval) P In-Hospital 46.530.5 0.58 (0.38-0.87) 0.009 28-day Mortality 49.233.3 0.58 (0.39 – 0.87) 0.01 60-day Mortality 56.944.3 0.67 (0.46-0.96) 0.03 Rivers E. N Engl J Med. 2001;345: 1368-1377. Slide 18 Copyright 2014 SCCM/ESICM

19. 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) Slide 19 Copyright 2014 SCCM/ESICM

20. 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 hydroxy- ethyl starches for fluid resuscitation of severe sepsis and septic shock. (Grade 1B) Slide 20 Copyright 2014 SCCM/ESICM

21. 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. Slide 21 Copyright 2014 SCCM/ESICM

22. 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) Slide 22 Copyright 2014 SCCM/ESICM

23. 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 risk Corresponding 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) ⊕⊕⊕⊝ moderate 342 per 1000 287 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) ⊕⊕⊕⊝ moderate 1 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) ⊕⊕⊕⊝ moderate 1 1 Grade reduced for imprecision. Slide 23 Copyright 2014 SCCM/ESICM

24. 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)

25. Meta-analysis of Norepinephrine versus Dopamine Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Assumed risk Corresponding risk DopamineNorepinephrine Short-term mortality Study population RR 0.91 (0.83 to 0.99) 2043 (6 studies) ⊕⊕⊕⊝ moderate 1,2 530 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) ⊕⊕⊕⊝ moderate 1,2 229 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) ⊕⊕⊕⊝ moderate 1,2 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. Slide 25 Copyright 2014 SCCM/ESICM

26. 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) Slide 26 Copyright 2014 SCCM/ESICM

27. 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.

30. Spot diagnosis in neutropenic patients

31. Spot diagnosis

33. 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