assessment of adipose tissue metabolism by means of subcutaneous microdialysis in patients with...

Assessment of adipose tissue metabolism by meansof subcutaneous microdialysis in patients with sepsisor circulatory failureAlexandre Martinez1, Rene Chiolero1, Marc Bollman1, Jean-Pierre Revelly1, Mette Berger1, Christine Cayeux1

and Luc Tappy2

1Surgical Intensive Care Unit, University Hospital, Lausanne, and 2Institute of Physiology, School of Medicine, University of Lausanne, Lausanne, Switzerland

CorrespondenceProf. L. Tappy, Institut de physiologie, 7 rue du

Bugnon, 1005 Lausanne, Switzerland

E-mail: [email protected]

Accepted for publicationReceived 23 January 2003;

accepted 10 June 2003

Key wordslactate production; lipid oxidation; lipolysis; shock

Summary

To evaluate the role of adipose tissue in the metabolic stress response of critically illpatients, the release of glycerol and lactate by subcutaneous adipose tissue wasassessed by means of microdialysis in patients with sepsis or circulatory failure andin healthy subjects. Patients with sepsis had lower plasma free fatty acidconcentrations and non-significant elevations of plasma glycerol concentrations,but higher adipose-systemic glycerol concentrations gradients than healthy subjectsor patients with circulatory failure, indicating a stimulation of subcutaneous adiposelipolysis. They also had a higher lipid oxidation. Lipid metabolism (adipose-systemicglycerol gradients, lipid oxidation) was not altered in patients with circulatoryfailure. These observations highlight major differences in lipolysis and lipidutilization between patients with sepsis and circulatory failure. Hyperlactataemia waspresent in both groups of patients, but the adipose-systemic lactate concentrationgradient was not increased, indicating that lactate production by adipose tissue wasnot involved. This speaks against a role of adipose tissue in the development ofhyperlactataemia in critically ill patients.

Introduction

In individuals acutely submitted to major aggressions such as

systemic infection, haemodynamic failure, or severe trauma, a

set of relatively stereotyped neuroendocrine and metabolic

responses is activated. These include an activation of the

sympathetic nervous system and of the hypothalamo-pituitary

adrenal axis, resulting in enhanced peripheral sympathetic

nerve discharge and increased secretion of adrenaline and

glucocorticoid from the adrenal glands. In addition, numerous

cytokines and inflammatory mediators are released (Wilmore &

Robinson, 1993; Chiolero et al., 1997; Kim & Deutschman,

2000).

From a metabolic standpoint, severe aggressions lead to an

inhibition of spontaneous feeding (anorexia) associated with a

major redistribution of energy substrate fluxes. Gluconeogenesis

from aminoacids and lactate is stimulated to ensure a continuous

supply of glucose to the brain and inflammatory tissues; muscle

insulin resistance develops and impairs glucose metabolism in

skeletal muscle while preferential oxidation of fat occurs in

tissues other than nervous cells and inflammatory/immune cells.

There is evidence that this redistribution of substrate fluxes is

associated with an increased rate of adipose tissue lipolysis and

of non-esterified fatty acid turnover (Chiolero et al., 1997;

Wolfe, 1997).

Hyperlactataemia is a hallmark of the metabolic stress

response. Its severity increases with that of the initial injury

and shows a positive correlation with mortality (Rashkin et al.,

1985; Lind & Lithell, 1994). Both an increased rate of lactate

production (Chiolero et al., 2000) and a decreased lactate

utilization (Levraut et al., 1998) have been proposed to

contribute to the increase in plasma lactate concentrations.

The mechanisms underlying alterations of lactate fluxes remain

incompletely understood, but may involve alterations of the

sympathoadrenal axis activity, inflammatory mediators and

changes in glucoregulatory hormones. The contribution of

individual tissues to hyperlactataemia remains an open question

(Stacpoole et al., 1992; Leverve, 1999).

Adipose tissue has long been considered as a mere energy

storage compartment. Adipocytes indeed synthesize triglycer-

ides in the presence of excess energy substrate fluxes and release

the stored lipids as non-esterified fatty acids when energy

balance is negative (Frayn, 1996). However, a large body of

observations indicates that adipose tissue plays an active role in

the regulation of whole body energy homeostasis. The control

of lipolysis in subcutaneous fat is complex, being under the

Clin Physiol Funct Imaging (2003) 23, pp286–292

� 2003 Blackwell Publishing Ltd • Clinical Physiology and Functional Imaging 23, 5, 286–292286

control of stimulatory b-adrenergic mediators and inhibitory,

presynaptic a-adrenergic nerve fibres in addition to systemically

and locally produced mediators such as adenosine and peptide

hormones or cytokines (Lafontan & Berlan, 1995; Arner,

1999). This results in an integrated release of fatty acid from

adipose stores to meet systemic metabolic demands. In

addition, we (Henry et al., 1996) and others (Jansson et al.,

1990, 1994; Lovejoy et al., 1992) have observed that adipose

tissue can contribute substantial amounts of lactate in the

systemic circulation.

Very few studies have directly evaluated adipose tissue

metabolism in severely ill patients. It was therefore the aim of

this study to assess the role and regulation of subcutaneous

adipose tissue to the metabolic stress response in critically ill

patients. For this purpose, we studied whole body substrate

utilization and adipose tissue lactate and glycerol release (the

latter being an index of adipose tissue lipolysis) in healthy

human volunteers and in two groups of critically ill patients:

one with severe sepsis or septic shock, the other with circulatory

failure after cardiac surgery. In all subjects, adipose tissue lactate

and glycerol release was assessed by continuous subcutaneous

microdialysis (Lonnroth & Smith, 1990; Binnert & Tappy,

2002).

Methods

Subjects

Five patients with severe sepsis or septic shock and six patients

with acute circulatory failure were included in the study. Their

anthropometric and clinical characteristics are shown in Table 1.

We did not attempt to match the two groups of patients for

severity of illness as the major aim of the study was merely to

observe adipose tissue lipolysis in critically ill patients at large.

Seven healthy male subjects (mean age 36Æ6 ± 5Æ9 years, weight

80Æ2 ± 5Æ8 kg and height 1Æ77 ± 0Æ03 m were included as a

control group.

The study was approved by the University of Lausanne Faculty

of Medicine research ethic board. Patients or relatives and

healthy volunteers gave written informed consent.

Inclusion criteria

General criteria: Medical management in surgical intensive care

unit, arterial lactate concentration ‡1Æ5 mmol l)1. In patients

with severe sepsis or septic shock the criteria of the American

College of Chest Physicians/Society of Critical Care Medicine

were fulfilled. Severe sepsis documented infection with two or

more of the following manifestations: (i) temperature >38�C or

<36�C, (ii) heart rate >90 beats min)1, (iii) respiratory rate

>20 breaths min)1 or PaCO2 <32 mmHg, and (iv) white blood

cell count >12 000 or <4000 mm)3 or >10% immature forms

associated with acute organ dysfunction. Septic shock: sepsis-

induced hypotension despite adequate fluid resuscitation.

Patients with circulatory failure met the following criteria: (i)

early postoperative period after cardiac surgery under extracor-

poreal bypass, (ii) cardiac failure requiring inotropic drugs after

full fluid resuscitation, and (iii) pulmonary catheter already in

place.

Experimental protocol

Healthy subjects were studied in the morning after a 10–12-h

fast. Patients were studied after a minimal fast of 10 h. In

healthy subjects, a venous cannula was inserted into an

antecubital vein of one arm. A primed (4 mg kg)1) continu-

ous (40 lg kg)1 min)1) infusion of 6,6 2H2 glucose

(Cambridge Isotope Laboratory, Cambridge, MA, USA) was

administered through this cannula. A second cannula was

inserted into a wrist vein of the controlateral arm for

withdrawing blood samples. This hand was maintained in a

thermostabilized box heated at 56�C to achieve partial

arterialization of blood samples. In critically ill patients, 6,62H2 glucose was infused through a central venous catheter, and

blood samples were obtained from an arterial line. In both

groups of subjects, one microdialysis catheter (CMA 60; CMA/

Microdialysis, Stockholm, Sweden; dialysing membrane length

30 mm, cut off 30Æ000 Da) was inserted into the subcutaneous

periombilical tissue under local anaesthesia and was infused

with a Ringer’s solution.

Whole body energy expenditure and net substrate oxidation

were assessed with indirect calorimetry (using a hood system

throughout the experiment) (Jallut et al., 1990). Patients were

subjected to the same experimental protocols as healthy subjects

with the differences that: (i) 6,6 2H2 glucose was directly

infused through a central venous catheter and blood samples

were collected from an arterial line, and (ii) indirect calorimetry

was performed by collecting expired air at the expiratory valve

of the ventilator. Blood and dialysate samples and indirect

calorimetry measurements were obtained after allowing a 180-

min period for tracer equilibration to reach a steady-state.

Indirect calorimetry and dialysate collections were obtained

continuously over 1 h. Three blood samples were taken at

intervals of 30 min for the determination of plasma 6,6 2H2

glucose.

Analytical procedure

Plasma glucose concentrations were measured with the glucose

oxidase method, using a Beckman glucose analyser II (Beck-

man Instruments, Brea, CA, USA), plasma lactate concentra-

tions were measured enzymatically using a Yellow Spring

Instrument (YSI lactate analyser, Yellow Spring, OH, USA).

Plasma free fatty acid concentrations were measured with a

colorimetric method, using a kit from Wako (Freiburg,

Germany). Plasma insulin concentrations were measured by

radioimmunoassay using a kit from Linco (St Charles, MO,

USA). Lactate and glycerol concentrations in the dialysates

were measured by means of a CMA microdialysis analyser

(CMA, Stockholm, Sweden). Plasma 6,6 2H2 glucose

Adipose tissue metabolism in shock, A. Martinez et al.


287

enrichment was measured by gas chromatography–mass

spectrometry, as described by Tappy et al. (1997). For this

analysis, plasma glucose was derivatized to pentacetyl glucose

and spectrometric analysis was performed after chemical

ionization, with selective monitoring of m/z 333 and 331.

Calculations

Net rates of substrate oxidation were calculated with the

equations of Livesey & Elia (1988). Whole body glucose

turnover was calculated with Steele’s equation for steady-state

conditions (De Bodo et al., 1963). Under such conditions,

glucose production is equal to glucose utilization.

Non-oxidative glucose utilization was calculated as (glucose

production) ) (net glucose utilization). For microdialysis meas-

urements, tissue substrate production is reflected by a positive

gradient of concentration between the dialysate and the systemic

circulation (Binnert & Tappy, 2002). This gradient was

calculated as (dialysate concentrations) ) (systemic plasma

concentrations), assuming a near complete substrate recovery

at the low flow rate (0Æ3 ll min)1) used in these experiments.

All results in text, tables and figures are shown as median

(range). Comparison between groups was performed by

unpaired t-test with Bonferroni’s adjustment.

Results

The chemical conditions, anthropometric parameters of the

patients, plasma C-reactive protein (CRP) and cortisol concen-

trations and doses of vasopressors in the morning of the test are

shown in Table 1.

The two groups of critically ill patients had marked elevations

of plasma glucocorticoids and inflammatory markers compared

with reference values, indicating severe stress. All patients with

circulatory failure had a cardiac index <2Æ8 l m)2 and received

intravenous inotropic agents and vasopressors (see Table 1).

Plasma glucose, lactate and insulin concentrations were signi-

ficantly increased in both groups of critically ill patients

compared with healthy subjects. Hyperinsulinaemia was more

important in patients with circulatory failure. In contrast, plasma

free fatty acids were somewhat lower in both groups of critically

ill patients (Tables 2 and 3).

Net substrate oxidation rates, glucose turnover and energy

expenditure are shown in Table 4. There was no significant

difference between groups in energy expenditure and glucose

oxidation rates, but there was a large interindividual variability

in these parameters in the two groups of critically ill patients.

Net lipid oxidation rate was significantly higher in septic

patients than in healthy subjects (P<0Æ05). Whole body glucose

Table 2 Plasma glucose, insulin and free fattyacid concentrations.Glucose (mmol l)1) Insulin (pmol l-1) Free fatty acids (mmol l-1)

Healthy subjects 5Æ2 (4Æ5–5Æ7) 46Æ8 (40Æ8–57Æ0) 0Æ49 (0Æ33–0Æ80)Sepsis/septic shock 8Æ9 (5Æ7–12Æ4)* 83Æ4 (67Æ2–179Æ4)* 0Æ34 (0Æ20–0Æ58)Circulatory failure 10Æ0 (8Æ9–11Æ4)* 285Æ0 (168Æ6–594Æ0)*,** 0Æ34 (0Æ16–0Æ44)

*P<0Æ05 or less versus healthy subjects.**P<0Æ05 or less versus sepsis/septic shock.

Table 1 Patients� characteristics.

DiagnosticSex(M/F)

Weight(kg)

Age(years)

Temperature(�C)

Cardiacindex (l m-2)

CRP(mg l-1)

Cortisol(lmol l-1)

Noradrenaline

infusion(ng min-1)

Dobutamine

infusion(lg min-1)

Sepsis/septic shockHemicolectomy afteropen abdominal trauma

F 62 19 38Æ2 5Æ32 268 584 – –

Peritonitis M 70 72 36Æ7 3Æ3 216 882 14 –Peritonitis F 66 42 38 3Æ4 126 566 4 –Infection with enterobacter F 62 67 37Æ8 3Æ3 233 (1803)a 24 300Intestinal perforation M 68 78 36Æ6 3Æ73 264 1013 – –

Circulatory failureAorto-coronary grafting F 59 73 38 2Æ31 75 (2034)a 80 1000Aorto-coronary grafting F 52 70 37Æ8 1Æ84 50 451 45 800Aorto-coronary grafting M 73 66 37Æ9 1Æ94 118 264 42 1000Mitral valve replacement M 49 64 37Æ2 2Æ56 224 (2472)a – 500Ruptured thoraco-abdominal aneurysm

M 78 77 37Æ4 2Æ45 71 1250 17 300

Mitral valve replacement M 73 66 36Æ9 2Æ18 66 691 22 400

aPatients having received hydrocortisone.



288

production and utilization were significantly increased in

patients with circulatory failure and with sepsis/septic shock

compared with healthy subjects. As net glucose oxidation was

not significantly altered, non-oxidative glucose disposal repre-

sented the major portion of the increase in glucose utilization in

the two groups of critically ill patients (Table 4).

Tables 3 and 5 show plasma and interstitial lactate and

glycerol concentrations (measured in the dialysate collected

from subcutaneous microdialysis probes). The interstitial lactate

concentration was significantly higher than systemic concentra-

tions (P<0Æ05) in healthy subjects, confirming that adipose

tissue produces lactate in resting healthy individuals. The

difference between interstitial and systemic lactate concentration

was however not significant in patients with cardiac surgery,

and was virtually zero in patients with sepsis/septic shock.

Interstitial adipose glycerol concentrations were significantly

higher than plasma concentrations in all groups of subjects

(P<0Æ05). In sepsis/septic shock patients, there was a 66%

increase in interstitial glycerol compared with healthy subjects

(P<0Æ05) and a 71% increase in the adipose-systemic gradient

(P<0Æ05). In patients with circulatory failure, there was 1Æ6-fold

increase in interstitial glycerol concentrations compared with

healthy subjects (n.s.) which was essentially secondary to a 3Æ7-

fold increase in systemic glycerol concentrations (P<0Æ05) while

the adipose-systemic gradient was comparable with the one

measured in healthy subjects.

Discussion

General patient characteristics

The two groups of critically ill patients studied had elevated

plasma cortisol and CRP concentrations. CRP was, on average,

more elevated in sepsis/septic shock, indicating a large

inflammatory component in this population of patients. From

a metabolic standpoint, the two groups displayed several

features of the expected metabolic stress response (Wilmore &

Robinson, 1993), including hyperlactataemia and hypergly-

caemia. The magnitude of these responses was similar in the two

groups. Hyperinsulinaemia was observed in both groups, but

was markedly higher in patients with circulatory failure. The

latter finding may be attributed to the administration of

vasoactive amines which are known to further decrease insulin

sensitivity (Chiolero et al., 2000).

Glucose metabolism

Both groups of patients had markedly increased glucose

turnover rates. Care was taken, when measuring glucose

kinetics, to adjust the bolus dose of labelled glucose to the

prevailing glycaemia and to let sufficient time (4 h) for tracer

equilibration. It is therefore unlikely that the values observed

were overestimated. In spite of this marked stimulation of

glucose production and utilization, net glucose oxidation did

Table 4 Energy expenditure and substrates oxidation rates.

Energy expenditure

(kcal day-1)

Net glucose oxidation

(lmol kg-1 min-1)

Lipid oxidation

(mg kg-1 min-1)

Glucose turnover

(lmol kg-1 min-1)

Non-oxidative glucose disposal

(lmol kg-1 min-1)

Healthy subjects 1640 (1478–2259) 6Æ1 (1Æ7–8Æ7) 0Æ89 (0Æ64–1Æ15) 10Æ2 (9Æ8–11Æ4) 4Æ4 (2Æ0–5Æ8)Sepsis/septic shock 1710 (1250–1731) 1Æ75 (0Æ0–7Æ0)* 1Æ26 (0Æ30–1Æ26) 20Æ7 (10Æ4–29Æ1)* 18Æ0 (5Æ0–31Æ9)*Circulatory failure 1390 (1000–1500) 4Æ3 (1Æ6–15Æ7) 0Æ60 (0Æ00–1Æ09) 20Æ7 (12Æ1–32Æ4)* 14Æ2 (7Æ2–18Æ0)*

*P<0Æ05 or less versus healthy subjects.

Table 5 Glycerol concentrations.Plasma glycerol

(lmol l-1)

Adipose interstitial

glycerol (lmol l-1)

D Adipose-systemic

glycerol gradient (lmol l-1)

Healthy subjects 50 (27–73) 229 (100–483) 211 (73–429)Sepsis/septic shock 66 (46–115) 402 (115–627)* 356 (136–534)*Circulatory failure 174 (142–226)* 280 (192–1105) 131 (10–872)


Table 3 Lactate concentrations.Plasma lactate

(mmol l-1)Adipose interstitiallactate (mmol l-1)

D Adipose systemiclactate gradient (mmol l-1)

Healthy subjects 1Æ05 (0Æ84–1Æ51) 1Æ70 (1Æ06–4Æ47) 0Æ85 (0Æ07–3Æ17)Sepsis/septic shock 2Æ56 (1Æ16–8Æ48)* 3Æ23 (1Æ12–7Æ36) 0Æ04 ()1Æ11–1Æ08)Circulatory failure 2Æ88 (2Æ41–3Æ67)* 3Æ32 (2Æ54–6Æ26) 0Æ84 (0Æ15–3Æ47)




289

not differ significantly from those observed in healthy subjects.

In fasting conditions, net glucose oxidation, as measured with

indirect calorimetry, reflects essentially hepatic glycogen break-

down (Tappy et al., 1995). It can therefore be concluded that

glycogenolysis was not markedly increased and that an increased

rate of gluconeogenesis was mainly responsible for the increase

in glucose production (Shaw et al., 1985; Wilmore & Robinson,

1993).

Fat metabolism

An increased adipose tissue lipolysis and an enhanced reliance

on lipids as energetic substrates are often considered hallmarks

of the metabolic stress response, particularly in septic patients

(Samra et al., 1996). There were however marked differences in

lipid metabolism between septic patients and patients with

circulatory failure: in sepsis, whole body lipid oxidation was

significantly increased and represented the major source of

energy during failure, whereas glucose oxidation tended to be

lower than in healthy subjects. In contrast, the contribution of

lipids and glucose to overall energy expenditure was unchanged

in patients with circulatory failure compared with healthy

subjects.

An increased lipid oxidation in sepsis/septic shock implies

an increased rate of lipolysis. The plasma concentrations of free

fatty acids were however not increased. This suggests that the

turnover rates of plasma free fatty acids were increased, and

hence that plasma free fatty acid levels provide an unreliable

estimate of adipose tissue lipolysis in such condition. This has

indeed been documented in critically ill patients using labelled

palmitate to measure fatty acid turnover (Nordenstrom et al.,

1983). In contrast, with these normal plasma free fatty acid

concentrations, the plasma concentrations of glycerol were

somewhat higher, and the gradient between adipose interstitial

and systemic glycerol concentrations was significantly

increased by 62% in sepsis which is consistent with an

increased adipose tissue lipolysis. This suggests that monitoring

of adipose tissue glycerol release represents a suitable substitute

to the use of labelled fatty acids to evaluate adipose tissue

lipolysis.

Our observation of increased adipose tissue lipolysis and lipid

oxidation together with normal plasma free fatty acid concen-

trations in septic patients compared with both healthy subjects

and patients with circulatory failure suggests that plasma free

fatty acid clearance is increased in sepsis. The mechanisms

remain largely unexplained (Samra et al., 1996). It appears likely

that plasma free fatty acid transport into muscle, and possibly

into other tissues, is altered in sepsis. It has indeed been

observed that endotoxin and cytokines alter fatty acid transport

protein and FAT/CD36 gene expression in liver cells of Syrian

hamsters (Memon et al., 1998). This suggests that the transport

and intracellular trafficking of fatty acid is remodulated by

cytokines. The relationship between fatty acid transporters and

lipid oxidation both in normal conditions and during sepsis

remains to be established.

In contrary to the classical description of the metabolic stress

response, we failed to observe indications of an increased

lipolysis and lipid oxidation in patients with circulatory failure.

Plasma free fatty acid concentrations were not increased, but

were even somewhat lower in patients than in healthy subjects.

Furthermore, net lipid oxidation rates were not increased. This

certainly speaks against increased rates of lipolysis and lipid

utilization in these patients. Surprisingly, plasma glycerol

concentrations were markedly elevated in patients with circu-

latory failure but the gradient between adipose interstitial and

systemic concentrations was not increased. This indicates that

the rise in glycerol concentrations was not secondary to a

stimulation of subcutaneous adipose tissue lipolysis (Binnert &

Tappy, 2002). Plasma glycerol concentrations depend on the

balance between glycerol production (essentially lipolysis) on

the one hand, and glycerol utilization on the other. Glycerol

utilization is known to take place mainly, but not exclusively, in

liver cells (Landau et al., 1996; Jensen et al., 2001). We have

recently reported that whole body glycerol clearance was

decreased 2 days after a major liver resection (Tappy et al.,

2002). We therefore propose the hypothesis that circulatory

failure may have altered glycerol clearance, possibly through a

reduction of splanchnic blood flow. The primary condition of

the patients (i.e. cardiac pump failure) and the high rate of

catecholamine infusion may both have contributed to reduce

splanchnic blood flow and hence glycerol clearance. Whatever

the cause of this alteration of glycerol kinetics, our data clearly

indicate that plasma glycerol concentrations represent an

unreliable indicator of lipolysis in critically ill patients.

Patients with circulatory failure were undoubtedly under

significant sympathomimetic stimulation secondary to endo-

genous and/or exogenous catecholamines. This would be

expected to stimulate adipose tissue lipolysis and secondarily

to increase lipid oxidation rate. There is no clear explanation as

to why adipose tissue lipolysis was not increased in these

patients although sympathetic activation was certainly intense.

Hyperinsulinaemia may contribute to suppress adipose tissue

lipolysis in critically ill patients. Numerous other mediators,

including adenosine and prostaglandins (Lafontan & Berlan,

1995) are involved in the control of adipose tissue lipolysis and

may possibly counteract the stimulatory action of catecholamine

under these conditions. In addition, the sympathetic control of

lipolysis is complex, with both b stimulatory and a, presynaptic,

inhibitory influences of catecholamines (Lafontan & Berlan,

1995), and there is no indication as to how critical illness affects

this intricate balance. Finally, there is evidence in healthy

humans that catecholamines, whether endogenously produced

or exogenously administered, produce significant stimulation of

whole body free fatty acid appearance rates at low to moderate

doses. An inhibition of adipose tissue blood flow is however

expected to occur at high rates of catecholamine infusion and

may secondarily lead to a low rate of systemic fatty acid release

together with increased adipocytic fatty acid re-esterification

(Spitzer et al., 1988; Romijn et al., 1993). Our observation

indicates that the release of fatty acids from subcutaneous



290

adipose tissue is not stimulated in patients with circulatory

failure.

Hyperlactataemia and adipose tissue

There is still controversy regarding the mechanism at the

origin of hyperlactataemia in critically ill patients. Both an

increased lactate production and a decreased lactate utilization

may be involved to various extents (Leverve, 1999). We have

recently reported, using a pharmacokinetic model to calculate

lactate kinetics after administration of a bolus of exogenous

lactate, that lactate clearance was little altered in patients with

circulatory failure after cardiac surgery (Chiolero et al., 2000).

This tended to indicate that an increased lactate production was

primarily responsible for the hyperlactataemia observed in

these patients. Other investigators reported, however, using the

same approach, that a decreased lactate clearance was at work

in patients with sepsis (Levraut et al., 1998). Although we do

not report direct measurements of lactate kinetics in these

patients, our observation of an increased glucose production

without a proportional increase in glucose oxidation indicates

that non-oxidative glucose disposal was enhanced in critically

ill patients. Increased non-oxidative glucose disposal under

fasting conditions strongly suggests that non-oxidative glyco-

lysis was stimulated and hence that lactate production was

increased in both groups of patients. There is presently little

information regarding the tissues involved in lactate produc-

tion in critically ill patients. Several investigators have

suggested that splanchnic organs, skeletal muscle, the lungs

or inflammatory cells might all participate in lactate production

under such conditions (Cain & Curtis, 1992; Vallet et al., 1994;

Bellomo et al., 1996; James et al., 1996; Tamion et al., 1997).

Other investigators (Jansson et al., 1990; Lovejoy et al., 1992)

and ourselves (Henry et al., 1996) have shown that adipose

tissue contributes significantly to whole body lactate produc-

tion in healthy subjects at rest and during hyperinsulinaemia.

Adipose tissue is now recognized to be a highly active tissue

which synthesizes and releases various metabolically active

peptides such as cytokines and leptin (Ailhaud, 2000).

Furthermore, it was reported that lactate production by

adipose cells was increased during surgical stress in patients

undergoing cholecystectomy (Fellander et al., 1996). Surpris-

ingly, this production of lactate could be inhibited by

a-adrenergic blockers indicating not only that sympathetic

activation was involved, but also that it was mediated by

a-adrenergic receptors (Fellander et al., 1996). Our present

data, however, do not support the hypothesis that adipose

tissue plays a major role in the increased lactate production

during severe sepsis or circulatory failure. Interstitial adipose

lactate concentrations were indeed slightly higher than

systemic lactate concentrations, which is consistent with a

net lactate efflux from adipose tissue to the blood in patients

with circulatory failure. The adipose-systemic gradient of

lactate concentrations was, however, very small, and was not

enhanced or decreased in critically ill patients compared with

healthy subjects. This observation is clearly not consistent with

the hypothesis that adipose tissue lactate production was

stimulated.

Conclusions

In summary, our present observations indicate that the metabolic

responses associated with sepsis/septic shock differ markedly

from that associated with circulatory failure. Sepsis is associated

with a stimulation of adipose tissue lipolysis and whole body

lipid oxidation, while circulatory failure does not induce such

effects in spite of major adipose tissue stimulation by endogenous

and exogenous catecholamines. Our observations were essen-

tially focused on adipose tissue metabolism as assessed using

subcutaneous microdialysis. They indicate that systemic concen-

trations of plasma free fatty acids and glycerol are poor indicators

of lipid metabolism in septic patients, and that monitoring of the

difference between systemic and adipose glycerol concentrations

may provide a useful index to evaluate in vivo lipolysis.

Acknowledgment

This study was supported by a grant from the Swiss Science

Research Foundation (# 3200-061582, Rene-Louis Chiolero).

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