Early and sustained acute falls in total serum cholesterol

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Early and sustained acute falls in total serum
cholesterol are associated with critical illness
mortality in the setting of tight glycaemic
control
Paul Dark Infection, Injury and Inflammation
Research Group Hope Hospital Intensive Care
Unit The University of Manchester, UK
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Motivation Wellcome Trust Host-Pathogen
Consortium Steve Kemp and Andy Brass T.
congolense infection in mice (Sepsis/CARS
progression) Quantitative trait loci (QTLs)
underlying resistance have been determined and
various congenic mice constructed (C57BL/6
resistant BALB/c susceptible)
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Motivation Micro array Mice tolerant to
infection have a higher expression of important
components of cholesterol biosynthesis (HMGCoA
reductase) and low expression of srb-1, abcg-1,
and apoA-1 genes which are involved in
cholesterol transport compared with the
susceptible strains. Kierstein S, (2007) Genes
and Immunity, In press RXR isoforms/Vit
D3/retinoic acid (? Role in M1 and M2 phenotype)
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• Motivation
• Phenotype (unpublished)
• Mice susceptible (BALB/c) to parasite infection
  have markedly decreased circulating cholesterol
  and shorter survival times, higher mortality
• Mice pre-fed on the high fat diet increased
  significantly in weight had higher plasma
  cholesterol and triglyceride levels, and lower
  parasitaemia, severe anaemia than the low fat-fed
  controls

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Introduction Serum cholesterol is known to be
associated with survival in critical illness, but
this has not been verified in an environment of
tight glycaemic control (a potential
confounder) The effects of changes in
cholesterol levels have not been studied
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Introduction Study question Are serum
cholesterol levels and their early changes
independently predictive of mortality at 28 days
from admission to intensive care, where tight
glycaemic control is normal practice?
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Methods Design Prospective case cohort
study Setting University Hospital level 3 Adult
ICU (mixed trauma/surgical/medical) Population
All critically ill patients (01-April 2006
31-January 2007) Interventions Addition of
lipid testing to routine daily blood analysis
without ICU staff intervention - data reflect
usual ICU practice Total cholesterol,
triglycerides, HDL cholesterol (mmol/l) Roche
Diagnostics Modular Analyser Outcome measure
Alive or dead at 28 days following initial ICU
admission
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• Methods
• Tight glycaemic control
• -nurse delivered (high ratio of nurse/ patient)
• web-based support (insulin dose calculator)
• continuous feed (80-90 enteral delivery)
• upper limit of control 7.1 mmol/l
• extremely low rates of hypoglycaemia
• Ref Thomas A. el al. Anaesthesia 2005 601093 -
  1100

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Results Population characteristics Case cohort
size 607 Male 57 Median Age 56
years Dead within 28 days 33 APACHE II
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Results Population characteristics Case cohort
size 607 Male 57 Median Age 56
years Dead within 28 days 33 APACHE II
median of 16 Severe sepsis on admission 23
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Results Population characteristics Case cohort
size 607 Male 57 Dead within 28 days
33 APACHE II median of 16 Severe sepsis on
admission 23 ICU length of stay
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Results Glycaemic control
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Results Triglyceride responses
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Results Total cholesterol responses
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Results HDL cholesterol responses
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Results Non-HDL cholesterol responses
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Results ICU Day 1 analysis Patients who will
survive to 28 days have a significantly
higher total serum cholesterol on admission (95
CI difference 0.04 to 0.58, P 0.02) Patients
with severe sepsis have significantly lower total
cholesterol on admission (95 CI for difference
0.7 to 1.3, P lt 0.0001)
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Results ICU Day 1 analysis Patients who will
survive to 28 days have a significantly
higher total serum cholesterol on admission (95
CI difference 0.04 to 0.58, P 0.02) Patients
with severe sepsis have significantly lower total
cholesterol on admission (95 CI for difference
0.7 to 1.3, P lt 0.0001) Logistic regression
model Day 1 cholesterol predicts 28 day
mortality OR 0.83, 95CI 0.69-0.87 (p0.03)
Independent of gender but not age, severe sepsis
or APACHE II score
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Results Analysis of early total cholesterol
responses
Survived mean increase in total cholesterol on
second day (0.13 mmol/l) Died mean decrease in
total cholesterol on second day (0.10
mmol/l) P0.001, 95 CI for difference 0.10 to
0.37
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Results Analysis of early HDL cholesterol
responses
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Results Analysis of early non-HDL cholesterol
responses
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Results Analysis of changes over first 72
hours Logistic regression model A fall in
cholesterol between days 2 and 3 of admission to
ICU predicts death within 28 days OR 0.29 95CI
0.14 - 0.60 (plt0.001) Independent of APACHE II
score, severe sepsis or baseline
cholesterol These patterns are not seen for HDL
cholesterol or triglycerides The prognostic
value of total cholesterol change is independent
of glucose
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Conclusions While establishing tight
glycaemia Total cholesterol is associated with
subsequent survival to 28 days Prognostic value
is linked to severe sepsis and APACHE II Not
seen in HDL-cholesterol
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Conclusions While establishing tight
glycaemia Total cholesterol is associated with
subsequent survival to 28 days Prognostic value
is linked to severe sepsis and APACHE II Not
seen in HDL-cholesterol Established tight
glycaemia Switching to cholesterol recovery
(Day 2-3) is associated with survival Prognostic
value independent of severe sepsis, APACHE II and
baseline cholesterol Not seen in
HDL-cholesterol
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Models of tryp. Livestock/human
observation/studies
Models of critical illness Patient
observation/studies
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Infection, Injury and Inflammation Research
Group Prof. Geoff Warhurst
Northwest Institute of Biomedical and Health
Informatics Dr. Iain Buchan Dr. Pat Baker
Wellcome Trust Host-Pathogen Consortium Prof.
Steve Kemp Prof. Andy Brass
Clinical Chemistry Dr. Aram Rudenski
Population and Endocrine Medicine Dr. John
New Dr. Martin Gibson