Early and sustained acute falls in total serum cholesterolare associated with critical illness mortalityin the setting of tight glycaemic control

Paul DarkInfection, Injury and Inflammation Research GroupHope Hospital Intensive Care UnitThe University of Manchester, UK

Motivation

Wellcome Trust Host-Pathogen ConsortiumSteve 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)

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)

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Phenotype (unpublished):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

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

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?

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

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 60:1093 - 1100

ResultsPopulation characteristics:

Case cohort size = 607Male = 57%Median Age = 56 yearsDead within 28 days = 33%APACHE II

APACHE II score

4035302520151050

Fre

qu

en

cy

100

80

60

40

20

0

ResultsPopulation characteristics:

Case cohort size = 607Male = 57%Median Age = 56 yearsDead within 28 days = 33%APACHE II = median of 16Severe sepsis on admission = 23%

ResultsPopulation characteristics:

Case cohort size = 607Male = 57%Dead within 28 days = 33%APACHE II = median of 16Severe sepsis on admission = 23%

ICU length of stay

Length of stay on ICU (days)

80757065605550454035302520151050

Fre

qu

en

cy

300

200

100

0

Results

Glycaemic control

0 1 2 3 4 5 6 7 8 9 100

1

2

3

4

5

6

7

8

9

10Survived

Died

ICU Day

Plas

ma

gluc

ose

(mm

ol/l)

Results

Triglyceride responses

0 1 2 3 4 5 6 7 8 9 100

1

2

3Survived

Died

ICU Day

Ser

um tr

igly

cerid

es (

mm

ol/l)

Results

Total cholesterol responses

2

2.2

2.4

2.6

2.8

3

3.2

3.4

0 2 4 6 8 10ICU day

Tot

al c

hole

ster

ol (

mm

ol/l)

Died Survived

Results

HDL cholesterol responses

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 2 4 6 8 10

ICU day

HD

L ch

oles

tero

l (m

mol

/l)

Died Survived

Results

Non-HDL cholesterol responses

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

0 2 4 6 8 10

ICU day

Non

-HD

L ch

oles

tero

l (m

mol

/l)

Died Survived

Results

ICU Day 1 analysis:

Patients who will survive to 28 days have a significantly highertotal serum cholesterol on admission (95% CI difference = 0.04 to 0.58, P = 0.02)

Patients with severe sepsis have significantly lower total cholesterolon admission (95% CI for difference = 0.7 to 1.3, P < 0.0001)

Results

ICU Day 1 analysis:

Patients who will survive to 28 days have a significantly highertotal serum cholesterol on admission (95% CI difference = 0.04 to 0.58, P = 0.02)

Patients with severe sepsis have significantly lower total cholesterolon admission (95% CI for difference = 0.7 to 1.3, P < 0.0001)

Logistic regression model

Day 1 cholesterol predicts 28 day mortalityOR = 0.83, 95%CI 0.69-0.87 (p=0.03) Independent of gender but not age, severe sepsis or APACHE II score

Results

Analysis of early total cholesterol responses

-0.60

-0.50

-0.40

-0.30

-0.20

-0.10

0.00

0.10

0.20

0.30

Day 1 to 2 Day 2 to 3

Cha

nge

in t

otal

cho

lest

erol

Died

Survived

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)P=0.001, 95% CI for difference = 0.10 to 0.37

Results

Analysis of early HDL cholesterol responses

-0.30

-0.25

-0.20

-0.15

-0.10

-0.05

0.00

0.05

0.10

Day 1 to 2 Day 2 to 3

Cha

nge

in H

DL

chol

este

rol

Died

Survived

Results

Analysis of early non-HDL cholesterol responses

-0.50

-0.40

-0.30

-0.20

-0.10

0.00

0.10

0.20

0.30

Day 1 to 2 Day 2 to 3

Cha

nge

in n

on-H

DL

chol

este

rol

Died

Survived

Results

Analysis of changes over first 72 hours:

Logistic regression model

A fall in cholesterol between days 2 and 3 of admission to ICUpredicts death within 28 days OR 0.29 95%CI 0.14 - 0.60 (p<0.001)

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

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

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

Models of tryp.Livestock/human observation/studies

Models of critical illnessPatient observation/studies

Infection, Injury and Inflammation Research GroupProf. Geoff Warhurst

Population and Endocrine MedicineDr. John NewDr. Martin Gibson

Clinical ChemistryDr. Aram Rudenski

Northwest Institute of Biomedical and Health InformaticsDr. Iain BuchanDr. Pat Baker

Wellcome Trust Host-Pathogen Consortium Prof. Steve KempProf. Andy Brass