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t’opyright O 1 ilil 1 try Will iii m.s & Wilkin.s
Lipolytic response to metabolic stress in critically ill
patients
SAMUEL KLEIN, MD; EDWARD J. PETERS, MD; ROBERT E. SHANGRAW, MD, PHD; ROBERT R. WOLFE, PHD
O6,jeciire: To measure whole-body lipolysis
and fatty acid re-esterifieation in critically ill
patients.
Design: The rates of appearance of glycerol
and palmitic acid in blood plasma were mea-
sured by infusing stable isotope tracers
t'H ]glycerol and [1-'°C]palmitic acid, respec-
tively. Energy expenditure was measured by
indirect ealorimetry.
Setting: Medical ICU of The University of
Texas Medical Branch Hospital, a university-
based referral center.
Patients: Five uninjured critically ill pa-
tients. Four patients were hospitalized be-
cause of respiratory insufficiency and one
because of myocardial infarction. Three
patients died during their hospitalization.
Interventions: Metabolic studies were per-
formed in each patient after an overnight
(12-hr) fast.
ñfeasuremento and Main Results: Mean + SE
glycerol and fatty acid rates of appearance
were 4.5 + 1.0 and 11.5 + 0.8 pmol/kg•min, re-
spectively. The ratio of fatty acid to glycerol
rate of appearance was 2.9 + 0.5. Resting
energy expenditure was 132 + 6'7o of predicted.
Coneluaione: A:n accelerated rate of lipoly-
sis is part of the metabolic responGe to severe
stress, regardless of its etiology. Because the
rate of fatty acid release far exceeded energy
requirements, fatty acids that were not
From the Departments of Internal Medicine, Preventive Medi-
cine and Community Health, Surgery and Anesthesiology, The
University of Texas Medical Branch and The Shriners Burns
Institute, Gal veston, TX.
This study was supported, in part, by National Cancer Institute
grant CA50330, National Institutes of Health grant DK38010, and
a grant from The Shriners Hospitals. Dr. Klein is supported by an
American GastroenterologicalAssociation/Merck, Sharp and Dohme
Research Award.
Address requests for reprints to: Samuel Klein, MD, Division of
Gastroenterology, G-64, The University of Texas Medical Branch,
Galve8ton, TX 77550.
0090-3493/91/1906-0776$03.00/0
776
Vol. 18, No.
Printed in U.J.A.
oxidized as fuel were re-esterified to
triglyceride, presumably in the liver. (Crit
Care Med 1991; 19:776)
KcY WORDS: lipolysis; energy expenditure;
stable isotopes; metabolism; critical illness;
substrate cycling; intensive care;lipid metabo-
lism; fatty acid kinetics, glycerol
Adipose tissue constitutes the major fuel reserve
in the body. Adequate mobilization of stored fat is
critical for survival when energy requirements ex-
ceed exogenous energy supply. The regulation of fat
mobilization (lipolysis) is under complex neural,
hormonal, and substrate control. The rate of release
of fatty acids and glycerol represents a dynamic
balance between factors that stimulate and those
that inhibit lipolysis. At all times, the release offatty
acids into the circulation exceeds the body’s rate of
fatty acid oxidation and the excess fatty acids are
recycled back to triglyceride. This phenomenon, the
triglyceride-fatty acid substrate cycle, provides an-
other regulatory level of lipid metabolism and in-
creases the body’s ability to respond rapidly to sud-
den changes in fuel requirements.
During severe illness or injury, energy expendi-
ture frequently increases while food intake is dimin-
ished. Therefore, it is logical that the metabolic
response to stress involves the release of hormones
and sympathetic nervous system stimulation to en-
hance the conversion of stored triglycerides to the
more usable fuels—fatty acid and glycerol—that can
be delivered to other tissues and organs. However,
during stress, other factors such as increases in
plasma lactate (1), free fatty acids(2), and glucose(3)
concentrations, and decreased perfusion of adipose
tissue (4) may enhance fatty acid re-esterification,
thereby decreasing the release of fatty acids, but not
glycerol, into the bloodstream. Enhanced intra-
adipocyte re-esterification of fatty acids, which lim-
its the release of fatty acids into the circulation,
could markedly impair substrate availability for
energy metabolism during critical illness. Increased
rates of fatty acid and glycerol release have been
documented in critically ill patients with burn
injury (5), trauma (6), and sepsis (7), whereas
endotoxemia
Vol. 19, No. 6 Liroi.vSlfi IN
in dogs caused a decrease in fatty acid flux (8). Lipid
kinetics have not been measured in uninjured,
nonseptic critically ill patients, who represent the
majority of patients in the medical ICU.
The purpose of the present study was to measure
the rates of appearance of palmitic acid and glycerol
into the bloodstream, using stable isotope tracers, in
critically ill patients. The rate of appearance of
palmitic acid in plasma represents the fuel made
available by triglyceride hydrolysis. Glycerol rate of
appearance reflects the absolute rate of lipolysis
because, unlike fatty acids, glycerol released during
lipolysis cannot be re-esterified within adipose tis-
sue and must enter the bloodstream t9). Because
three molecules of fatty acids are liberated for each
molecule of glycerol released during lipolysis, the
relationship between fatty acid and glycerol rates of
appearance provides an index of fatty acid re-esteri-
fication within adipose tissue.
MATERIALS AND METHODS
This study was approved by the Institutional
Review Board of the University of Texas Medical
Branch, and informed consent was obtained from
each patient. We studied five patients who were
admitted to the medical ICU of the University of
Texas Medical Branch at Galveston (Table 1). Four
patients required mechanical ventilation because of
respiratory insufficiency, and the fifth patient had
sustained a recent myocardial infarction but was not
in shock. In three patients, pneumonia contributed
to decompensated lung function. No patient had
positive blood culture results, other known infec-
tions, or a hyperdynamic cardiovascular status
(cardiac output 5.05 + 0.49 fsE] L/min). All patients
were critically ill, and three died during their
hospitalization.
The metabolic studies were performed in the
medical ICU. All patients were receiving either
parenteral or enteral nutritional support, which was
stopped 12 hrs before the metabolic studies were
performed. A primed, constant infusion of
f'H,]glycerol (99 atom percent deuterium, MSD Iso-
topes, Montreal, PQ, Canada) dissolved in normal
saline and a constant infusion of[1-' 3C]palmitic acid
potassium salt (99 atom percent 1- i3C, MSD Iso-
topes) bound to human albumin (Cutter Laborato-
ries, Emeryville, CA)( 10) were administered through
an existing iv catheter. The isotopes were infused for
90 mins with a calibrated syringe pump (C. A. Bard,
North Reading, MA). Blood samples were taken
from an existing intra-arterial catheter before start-
ing the isotope infusions and at 60, 70, 80, and 90
mina of the infusion. Oxygen consumption, CO 2
777
Table 1. fi I in icaI characteristics ‹or patit•nts
Sex/Age Mccha n ice1
Patient I yr I Ve nt i I ati‹in II utcom‹'
1 F/49 Myocardial infâ rcti‹in N‹i
2 M/70 Post respiratory arrest Yes
3 F/63
ARDS, pneumonia Yes 11
4 F/31 Asthma, pneumonia Yes
5 M/58 COPD, pneumonia Yes D
Y, female; M, male; S, survived; D, died; AH Uh, adult re.s pi ra-
tory distress synd rome; COPD, chronic obstructive pu I m ona ry
disease.
production, and resting energy expenditure were
measured by indirect calorimetry with a metabolic
me asureme nt cart ( Horizon , Sen sorMe dic s,
Anaheim, CA) with either a T-piece connector fin the
four patients requiring mechanical ventilation) or
face-mask system (in the patient spontaneously
breathing room air).
Blood samples were collected in cold heparinized
tubes. The plasma was promptly separated by cen-
trifugation and stored at —20°C until analysis. Analy-
sis of[1-’"C]palmitic acid enrichment was performed
( 11). The fatty acids were converted to their methyl
esters and separated by gas chromatography, and
isotopic enrichment of [1-’"C]palmitic was deter-
mined by mass spectrometry. Measurement of glyc-
erol isotopic enrichment was performed 112 J. The
trimethylsilyl derivative of glycerol was formed and
isotopic enrichment determined by gas chromatog-
raphy mass spectrometry.
A physiologic and isotopic steady-state was present
during the last 30 mins of isotope infusion, so that
the rate of appearance of palmitic acid and of glycerol
into plasma were calculated using the Steele equa-
tion as it applies to steady-state conditions ( 13). The
Steele equation was corrected for the contribution
made by the stable isotope infusion to the mass of the
substrate pool Ill). The rate of appearance of total
free fatty acids into the bloodstream was calculated
by dividing palmitic acid rate of appearance by the
percentage of total plasma free fatty acid concentra-
tion that was palmitic acid. It was assumed that the
metabolism of palmitic acid was representative of all
fatty acids ( 14, 15).
RESULTS
Mean body weight was 114 + 10 (SE) */c Of ideal,
based on the 1983 Metropolitan Life Insurance Tables
midpoint of the weight range for medium build
(Table 2). However, two of the five patients had
evidence of peripheral edema, which contributed
to their body weight. Measured average resting
778 C RITI CAL PARE
JUNE, 1981

Table 2. Body eize and energy expenditure (mean + sI'.) in patients administration fails to suppress lipolysis and other
catabolic processes to the same degree that it does in
Height (cm) 165 + 5
Weight (kg) 70 + 5
normal volunteers (6, 7).
Percentage of ideal body weight* 114 • 10 The potential energy released by lipolysis (fatty
Resting energy expenditure acids) in our patients was almost double their mea-
kcal/day 1856 + 193 sured rate of energy expenditure. Fatty acids re-
Percent predicted^ 132 + 6
leased during lipolysis, but not oxidized, can be re-
°Based on midpoint of the medium build weight range of the esterified back to triglyceride within adipose tissue,
1983 Metropolitan Life In8ura nce Tables. preventing their release into the bloodstream, or
‘Harris-Benedict equation. they can be released into the circulation and subse-
quently re-esterified within the liver. The mean
Table 3. Lipid kinetics (pmo1/kg per min) in humans studied in our ratio of fatty acid to glycerol rate of appearance in
laboratory during different metabolic conditions (mean + ss) our patients (2.9) was close to the maximum value of
Condition (ref.) Glycerol Ra FFARa 3 mol of fatty acids released for each mole of glycerol.
This observation suggests that blood flow and albu-
Critical illness min delivery to adipose tissue were sufficient to
(current study) 4.5 + 1.0 11.5 • 0.8
Exercise (17) 10.5 + 0.8 30.7 + 2.0
remove and circulate the large mass of fatty acids
Burns (S) 8.2 + 0.7 14.5 • 1.1 released. Therefore, the site for most fatty acid re-
Sepsis (7) 6.3 + 1.1 13.1 • 3.0 esterification is presumably in the liver. Re-esteri-
Trauma (6) 5.3 + 0.5 8.1 + 1.9 fication of unused fatty acids is important for pre-
84-hr fast ( 18) 4.2 + 0.3 13.1 + 0.6
Cancer (7, 19) 2.7 + 0.8—4.1 + 0.4 7.2 + 1.1—11.7 + 1.6
venting free fatty acid accumulation in plasma,
Chronic mal- which could overwhelm albumin binding sites and
nutrition ( 19) 3.1 + 0.3 7.6 + 0.5 have adverse effects (16). However, triglyceride-
Primary hyper- fatty acid cycling requires energy and thus increases
parathyroidism (20) 2.4 + 0.8 6.9:0.8
energy expenditure in critically ill patients (5). In-
12-hr fast (18) 2.4 + 0.2 6.7*0.7
creased hepatic synthesis of triglyceride could also
FFA, free fatty acid; Ra, rate of appearance. cause fatty liver if the rate of triglyceride synthesis
exceeds its rate of export in the form of very low
density lipoproteins.
energy expenditure was -30% greater than that The relationship between different metabolic
predicted by the Harris-Benedict equation (Table 2). states and lipolysis is illustrated in Table 3. The
The rate of appearance of glycerol was 4.5 + 1.0 data are from studies performed in our laboratory
pmol/kg-min and that of free fatty acid was 11.5 + 0.8 (5—7, 17—20), so the techniques for measuring glyc-
pmol/kg-min (Table 3). These rates were slightly erol and fatty acid flux are similar among the stud-
lower than those in other critically ill patients with ies. The patients in the present study were different
trauma, sepsis, or burn injury, but were approxi- from those reported in our other studies of critically
mately twice the values in normal volunteers (Table ill patients. No patient in this study was injured and
3). The ratio of free fatty acid to glycerol rate of none had evidence of severe sepsis. Lipolytic rates
appearance was 2.9 + 0.5. for the patients in the current study are almost twice
those of normal volunteers but less than those of
DISCUSSION critically ill patients with burn injury, sepsis, or
The results of this study support the idea that trauma (Table 3). The rates of lipolysis correlate in
metabolic stress, regardless of its etiology, stimu- general with the rates of energy expenditure and,
lates the release of fatty acids and glycerol from presumably, the level of metabolic stress reported
stored triglycerides. Teleologically, this response for these conditions.
provides advantages for survival by mobilizing a The accelerated rate oflipolysis in our critically ill
fuel source when energy intake is usually limited, medical patients is consistent with the metabolic
rest- ing energy expenditure is increased, and large response to stress observed in other severely ill
amounts of energy may be needed suddenly for patients. Our results support the concept that
“flight" or“fight." However, in hospitalized patients, increased lipolysis represents part of the general-
the lipolytic response to stress may be unnecessary ized response to metabolic stress. Presumably,
and possibly detrimental. Body tissue breakdown sympathoadrenal stimulation is the most important
continues even when energy requirements are met factor responsible for the increased release of glyc-
by enteral or parenteral nutrition because nutrient erol and fatty acids (21). Glycerol is converted to
Vol. 19, No. 6 Al POLYSIS IN CRITICAL I LLNESS
glucose in the liver, whereas fatty acids provide fuel
for cardiac, respiratory, and skeletal muscles. The
rate of fatty acid release far exceeds the rate of
fatty acid oxidation, and most of excess fatty acids
are re-esterified in the liver. Although triglyceride-
fatty acid cycling amplifies the control of lipid me-
tabolism, it is unlikely that this process benefits
hospitalized patients receiving nutritional support.
The resultant increase in energy expenditure and
the possible development of fatty liver caused by
excessive triglyceride-fatty acid cycling could be
detrimental.
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