Prof Michael Levin & Dr David Inwald presentations at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

1. Meningococcal disease
Fluid resuscitation in meningococcal sepsis
:less or more
Michael Levin
Debate MRF conference 2013
© Imperial College London

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4. Where did this protocol come
from?
Is it evidence based ?
Physiological basis vs Evidence
from Randomised Trials

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7. What is the evidence for
hypovolaemia?
• CVP and echocardiography suggests volume depletion
pre fluid resuscitation
• Capillary leak

8. Microvascular Events in Sepsis
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9. Protein leak in
meningococcal sepsis
Controls Mild Moderate Severe Fatal Nephrotics
Meningococcal Disease
Orogui critical care med 1999
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10. 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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13. A delicate balance:
Fluids restore ventricular filling
Capillary leak may lead to pulmonary oedema; tissue
oedema
Early elective ventilation
Early dialysis / haemofiltration

14. What is the role of cardiac failure
• Impaired myocardial contractility
• Inotrope unresponsiveness
• Pulmonary oedema following volume
resuscitation

15. Capillary Leak
Acidosis
Reduced circulating volume
Hypoxia
Reduced preload
Hypoglycaemia
Hypocalcaemia
Hypokalaemia
Hypophosphataemia
TNF, IL1
Nitric oxide
complement
Myocardial
Failure
Hypotension
Reduced coronary
perfusion
Cardiodepressant factors
Bacterial toxins
Neutrophil products
Energy depletion
PAF
Prostaglandins
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Role of IL6 in myocardial depression in
meningococcal septic shock
Pathan et al Lancet 2004

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18. Admissions & mortality from severe
meningococcal disease, St Mary’s PICU, 1992-97
100
predicted death rate (%)
80
30
20
60
observed
death rate (%)
40
Admissions
Death rate (%)
40
10
20
0
0
1992
1993
1994
1995
1996
1997
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19. 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 Africa
1 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 Africa
despite being on antibiotics and quinine
>50% deaths occur within 24 hours of admission
supportive therapies often not considered/unavailable

20. Fluid Expansion As a Supportive Therapy
FEAST Trial
Fluid Expansion As Supportive Therapy in
critically ill African children
FEAST Trial Team (PI Prof Kath Maitland)
m a la r ia
c o n s o r t iu m
D is e a s e
C o n t r o l, B e t t e r H e a lt h
w w w .m a la riac o ns o rtiu m .o rg
Fluid Expansion As a Supportive Therapy

21. FEAST partners
Support:
Funded by
MRC, UK
Albumin and
Saline
donated by
Baxter,
UNITED KINGDOM
MRC Clinical Trials Unit,
London
&
Imperial College,
London (Sponsor)
UGANDA (4
centres)
Mulago Hospial, Kampala
Mbale
Soroti
Lacor Hospital, Gulu
KENYA
Kilifi
TANZANIA
Teule
21

22. Trial Design:
EARLY fluid resuscitation
(FEAST A)
Children with febrile illness
Children with impaired
and impaired perfusion
consciousness and/or
with impaired
respiratory distress
consciousness
and impaired perfusion
and/or respiratory distress
Bolus 5% albumin
20 ml/Kg (40 ml/Kg
after Aug 2010) over 1
hour
Impaired perfusion
Children with respiratory
Any one of:
distress and clinical secs,
•Cap refill 3 or more
•Severe tachycardia,
evidence of impaired
•temperature
perfusion gradient
•weak pulse
Bolus 0.9% saline
20 ml/Kg (40 ml/Kg after
Aug 2010) over 1 hour
Control (No bolus)
Maintenance fluids only
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
Excluded: Fluid loss due to gastroenteritis, burns or trauma. Severe malnutrition

23. Hypotensive Shock
(FEAST Stratum B)
Children eligible for
FEAST A that have
hypotensive shock* on
admission
Bolus 5% albumin
Bolus 0.9% saline
40mls/kg (60mls/kg after
August 2010) per hour
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

24. Typical setting of the trial

25. FEAST(Fluid Expansion As Supportive Therapy) Trial

26. FEAST: Survival in first 48 hours
Percent survived
100%
95%
90%
85%
No
Bolus
92.7%
Boluses
89.4%
3.3% excess mortality in bolus arms (10.6%) vs contro
No difference in mortality between Albumin vs saline
0%
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

27. Response to the trial

28. 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

29. 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

30. Fluid resuscitation in septic shock: between Sylla and
Charybdis

31. Protocolised management is
good
Butbolus may be life savingbe better BUT may
thought may in severe shock
Fluid
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 studiesIncluding further analysis of FEAST Data which
should be open access

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33. Thank you
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