Meningococcal disease

Fluid resuscitation in meningococcal sepsis :less or more

Michael Levin

Debate MRF conference 2013© Imperial College London

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Where did this protocol come from?

Is it evidence based ?

Physiological basis vs Evidence from Randomised Trials

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What is the evidence for hypovolaemia?

• CVP and echocardiography suggests volume depletion pre fluid resuscitation

• Capillary leak

Microvascular Events in Sepsis

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© Imperial College London© Imperial College London

Fra

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ance

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al b

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0-5

Controls Mild Moderate Severe Fatal Nephrotics

Meningococcal Disease

Orogui critical care med 1999

Protein leak in meningococcal sepsis

What are the consequences of volume replacemeent if there is a generalised capillary leak

• Pulmonary Oedema• Cerebral Oedema• Tissue oedema and ascites• Compartment synbdrome

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A delicate balance:

Fluids restore ventricular filling

Capillary leak may lead to pulmonary oedema; tissue oedema

Early elective ventilation

Early dialysis / haemofiltration

What is the role of cardiac failure

• Impaired myocardial contractility• Inotrope unresponsiveness• Pulmonary oedema following volume

resuscitation

Capillary Leak

Reduced circulating volume

Reduced preload

Acidosis

Hypoxia

Hypoglycaemia

Hypocalcaemia

Hypokalaemia

HypophosphataemiaTNF, IL1

Nitric oxide complement Hypotension

Reduced coronary perfusion

Cardiodepressant factors

Bacterial toxins

Neutrophil products

PAF

Prostaglandins

Energy depletion

Myocardial Failure

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Role of IL6 in myocardial depression in meningococcal septic shockPathan et al Lancet 2004

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De

ath

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%)

Ad

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40

30

20

10

0

100

80

60

40

20

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predicted death rate (%)

1992 1993 1994 1995 1996 1997

Admissions & mortality from severemeningococcal disease, St Mary’s PICU, 1992-97

observeddeath rate (%)

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If Fluid reuscitation improves outcome in sepsis in PICU, would it improve outcome of sepsis/Malaria in Africa ?

Highest rates of child mortality are in Africa1 in 8 children dies before age 5 (20-fold the mortality in industrialized countries)

15-30% mortality among children admitted to hospitals in sub-Saharan Africadespite being on antibiotics and quinine>50% deaths occur within 24 hours of admissionsupportive therapies often not considered/unavailable

FEAST Trial Fluid Expansion As Supportive Therapy in critically ill African children

Fluid Expansion As a Supportive TherapyFluid Expansion As a Supportive Therapy

malaria

consortium

Disease Control, Better Health www.malariaconsortium.org

FEAST Trial Team (PI Prof Kath Maitland)

Fluid Expansion As a Supportive TherapyFluid Expansion As a Supportive Therapy

21

KENYAKilifi

TANZANIATeule

UGANDA (4 centres)Mulago Hospial, KampalaMbale SorotiLacor Hospital, Gulu

UNITED KINGDOM

MRC Clinical Trials Unit, London&Imperial College, London (Sponsor)

Albumin and Saline donated by Baxter,

Funded by MRC, UK

FEAST partners

Support:

Trial Design: EARLY fluid resuscitation (FEAST A)

Children with impaired consciousness and/or

respiratory distress and impaired perfusion

Bolus 5% albumin

20 ml/Kg (40 ml/Kg after Aug 2010) over 1

hour

Bolus 0.9% saline

20 ml/Kg (40 ml/Kg after Aug 2010) over 1 hour

Control (No bolus)

Maintenance fluids only

Children with respiratory distress and clinical evidence of impaired

perfusion

Follow-up to 4 weeks (24 weeks if developed neurological sequelae by 4 weeks)Clinical assessments at 1, 4, 8, 24, 48 hours and at 4 weeks

Impaired perfusionAny one of: • Cap refill 3 or more

secs, • Severe tachycardia, • temperature gradient• weak pulse

Excluded: Fluid loss due to gastroenteritis, burns or trauma. Severe malnutrition

Children with febrile illness and impaired perfusion with impaired consciousness and/or respiratory distress

Hypotensive Shock (FEAST Stratum B)

Children eligible for FEAST A that have hypotensive shock* on admission

Bolus 5% albumin

40mls/kg (60mls/kg after August 2010) per hour

Bolus 0.9% saline

40mls/kg (60mls/kg after August 2010) per hour

Follow-up to 4 weeks (24 weeks if developed neurological sequelae by 4 weeks)Clinical assessments at 1, 4, 8, 24, 48 hours and at 4 weeks

*Hypotensive shock defined as severe hypotension plus signs of impaired perfusion. Severe hypotension: <1yr sbp <50mmHg; 1-5 yrs sbp <60mmHg; >5yrs: sbp <70mmHg

Typical setting of the trial

FEAST(Fluid Expansion As Supportive Therapy) Trial

0%

85%

90%

95%

100%P

erce

nt

surv

ived

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Hours from admission

No Bolus 92.7%Boluses89.4%

FEAST: Survival in first 48 hours

3.3% excess mortality in bolus arms (10.6%) vs control (7.3%)No difference in mortality between Albumin vs saline boluses

Response to the trial

Should FEAST result in changes to UK meningococcal sepsis algorhythm ??

• Why did Fluids cause Harm in FEAST• Are the findings applicable to Developed countries• How does availability of ventilation;inotropes; PICU

alter findings from FEAST

• All subgroups showed harm in FEAST• Anemia/non anemic; acidosis/non acidosis; malaria/non

malaria

A personal perspective

• FEAST should not be ignored by developed country PICUs

• Fluids may have caused pulmonary deterioration or cerebral oedema

• The broad inclusion criteria might have resulted in patients with pneumonia and heart failure being included.

• The availability of ventilation and inotropes may mitigate the pulmonary / cardiac/ cerebral effects of fluids

• BUT it is the only RCT of fluids with a control arm

Fluid resuscitation in septic shock: between Sylla and Charybdis

Protocolised management is good

But thought may be better

Fluid bolus may be life saving in severe shock BUT may be associated with pulmonary and cerebral oedema

Fluids should be used with more thought; and continual re evaluation to detect adverse effects

Less may be more- and we need further studies- Including further analysis of FEAST Data which should be open access

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Thank you

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