5.2.

1 The metabolic and nutritional response to critical illness

G. Lavery
Effects of starvation
Metabolic response to stress

Sympathetic nervous system activity and catecholamine release

Adrenal lucocorticoids in critical illness

Glucaon in critical illness

!uman ro"th hormone in critical illness

Thyroid function in critical illness

The role of cyto#ines

Eicosanoids $lipid metabolites%

&rolactin in critical illness
The effect of critical illness on the ut
'mplications for nutritional support in critical illness

Structural chanes in the ut miht promote translocation

!ypermetabolism( increased catabolism( and nitroen loss

The tendency to hyperlycemia and lucose intolerance

)se of nutrients for non*nutritional effects
+hapter ,eferences
-ey messaes
The nutritional and metabolic chanes "hich occur in critical illness are driven by any
combination of lac# of nutrient inta#e $starvation%( the endocrine.mediator response to the
/stress0 of critical illness( and physioloical insult to the astrointestinal tract.
The metabolic response to critical illness is typified by catabolism( protein loss( and
immunosuppression.
1utritional support of the critically ill patient should supply ra" material for protein
anabolism( "ound healin( and oran repair( supply enery and other substances needed
to maintain cellular function( and( if possible( attenuate harmful aspects of the metabolic
response.
Effects of starvation
The initial response to starvation is lycoenolysis to maintain blood lucose
concentration. !o"ever( lycoen stores become e2hausted "ithin 2 to 3 days( and an
alternative source of lucose is re4uired to fuel tissues such as the brain "hich enerates
enery e2clusively from lucose. Structural body protein is bro#en do"n to provide
amino acids as a substrate for luconeoenesis. This protein brea#do"n is halted by an
adaptive process by "hich the brain uses #etones as its metabolic fuel. 'n addition( the
body0s basal enery re4uirement is reduced and is supplied mainly by o2idation of lipid
stores $fat%. 5nly "hen the fat stores are almost depleted does protein brea#do"n and
luconeoenesis aain become sinificant.
Thus the result of proloned starvation is a reduction in muscle mass $and strenth% "ith
a less mar#ed reduction in visceral protein mass. The muscle "ea#ness is accentuated by
deficiencies in electrolytes and trace elements $e.. calcium( manesium( phosphate( and
selenium%. These factors have sinificant effects on diaphramatic function( s#eletal
muscle function( and even myocardial performance.
The immune response is also enerally impaired by malnutrition( althouh conventional
mar#ers $"hite cell count( immunolobulin levels% are usually normal. There is atrophy
of the spleen and lymph nodes( and an attenuation of the response to immunoloical
challene.
Metabolic response to stress
+ompared "ith the starvin patient( the critically ill patient has a very different /internal
milieu0 and e2hibits reater and more proloned neative nitroen balance due to protein
brea#do"n $luconeoenesis%. There is no adaptation to enery production from fat
stores( and the basal metabolic rate is increased by 26 to 76 per cent. Metabolic and
endocrine responses include stimulation of the sympathetic nervous system( release of
epinephrine $adrenaline%( lucocorticoids( and lucaon( suppression of prolactin( ro"th
hormone( and thyroid hormone release( metabolic resistance to the effects of insulin(
production of cyto#ine mediators( and release of eicosanoid precursors from membrane*
bound phospholipids $8i. 1%.
8i. 1 1utritional and metabolic imbalance in critical illness9 T18( tumor necrosis factor:
!G!( human ro"th hormone.
The body0s initial response to stress is primarily controlled by the locus ceruleus in the
brainstem and the paraventricular nucleus of the hypothalamus $Michelson et al. 1;;<%.
=hen stimulated( the former releases norepinephrine $noradrenaline%( stimulates the
autonomic nervous system( and increases arousal. The latter produces corticotropin*
releasin hormone "hich activates the hypothalamo>pituitary>adrenal a2is. The locus
ceruleus and corticotropin* releasin hormone systems e2hibit mutual feedbac# in that
stimulation of either system "ill lead to activation of both path"ays.
Sympathetic nervous system activity and catecholamine release
Most physioloical insults occurrin in critical illness stimulate the sympathetic nervous
system $e.. pain( hypotension( hypoperfusion( hypo2ia( hypercarbia( acidosis%. This
causes stimulation of the adrenal medulla by preanlionic sympathetic fibers and "ithin
minutes leads to increased plasma epinephrine levels. 1orepinephrine levels are also
increased since neuronal re*upta#e does not #eep pace "ith the increased release of this
sympathetic neurotransmitter "hich therefore enters the plasma. This mechanism
complements the release of norepinephrine and the sympathetic activity conse4uent on
stimulation of the locus ceruleus.
The effects of the catecholamines( althouh comple2( are often summari?ed as the
promotion of the fiht or fliht response. These include stimulant effects on heart rate(
cardiac contractility( and blood pressure. ,eional blood flo" is altered( "ith increased
flo" to s#eletal muscle and decreased flo" to s#in and viscera $includin the ut and
#idneys%. Sodium retention is promoted by a direct tubular effect and by the renin>
aniotensin mechanism. This is a protective mechanism aainst actual or potential
hemorrhae.hypovolemia. Epinephrine is a ma@or catabolic hormone( promotin
lycoenolysis( luconeoenesis( and lipolysis. This causes an increase in blood lucose
"hich is further compounded since epinephrine promotes lucaon secretion and inhibits
the release of insulin.
Adrenal lucocorticoids in critical illness
+orticotropin*releasin hormone from the paraventricular nucleus is carried in the
hypophyseal>portal circulation and stimulates release of A+T! from the anterior
pituitary. The result is an increase in plasma cortisol levels "ith a loss of the normal
circadian rhythm. Aurin this period of sustained and increased cortisol synthesis there
may be a reduction in the production of other adrenal steroid hormones. +onversely(
adrenal insufficiency durin critical illness is bein reported more fre4uently( particularly
in cases of systemic sepsis "ith shoc#.
Glucaon in critical illness
Glucaon is a peptide hormone produced in the a cells of the pancreatic islets in response
to decreasin plasma lucose( e2ercise( and protein loadin. 't stimulates lycoenolysis(
luconeoenesis( and #etone production( and inhibits lipoenesis. Thus its ma@or effect is
to raise plasma lucose and promote catabolism.
'n health( lucaon is inhibited by hyperlycemia( increased plasma insulin( and free fatty
acids. 'n critical illness( ho"ever( lucaon levels are increased despite the presence of
the above( and this is thouht to be a response to increased catecholamines
!uman ro"th hormone in critical illness
!uman ro"th hormone is a 1;1*amino*acid protein produced by the anterior pituitary.
'ts effects can be summari?ed as a protein*sparin effect "hich protects lean body mass( a
reduction in body fat $lipolysis%( improvement in immunocompetence( sodium and "ater
retention( hyperlycemia( and $potentially% increased incidence of neoplasia.
!uman ro"th hormone is stimulated by the hypolycemic state and also by e2ercise(
sleep( hih protein inta#e( and increased levels of leucine and arinine. !uman ro"th
hormone secretion is inhibited by lon*term lucocorticoid administration and plasma
free fatty acids $plasma free fatty acids are increased by epinephrine and lucaon%. 't is
thouht to e2ert its effects partially by direct action on tissues and partially throuh
stimulation of the liver to produce insulin*li#e ro"th factor '( a B6*amino*acid chain.
Caseline human ro"th hormone is elevated and diurnal variation is reduced in many
stressed individuals. !o"ever( continuin hih levels of stress( as typified by critical
illness( may be associated "ith reduced human ro"th hormone levels and insulin*li#e
ro"th factor ' is also usually decreased. This attenuates anabolic processes.
Thyroid function in critical illness
Laboratory measurements of thyroid function in critically ill patients are fre4uently
abnormal and are al"ays difficult to interpret. The most common abnormality is lo" T3
syndrome. Most patients e2hibitin this condition have a normal total thyro2ine level and
should be considered euthyroid. Lo" T3 is probably due to deficient T< upta#e by the
tissues and thus reduced peripheral conversion of T< to T3 $responsible for 76 per cent of
total T3 production%. The en?yme "hich cataly?es the conversion $50*monodeiodinase% is
inhibited by lucocorticoids. 'n lo" T< and T3 syndrome those e2hibitin the lo"est
plasma T< levels have the hihest mortality. Aespite normal levels of free hormone(
postmortem analysis has sho"n lo" tissue T< levels in brain( lun( liver( and #idney( but
normal T< levels in myocardium and s#eletal muscle. These abnormalities are commonly
rouped toether under the term /sic# euthyroid syndrome0 $,olih and 5ber 1;;5%.
The role of cyto#ines
These naturally occurrin mediators are produced by monocytes( macrophaes( and
related cell lines. +yto#ine production increases durin critical illness and has effects
"hich complement the counter*reulatory hormones $epinephrine( lucaon( and
lucocorticoids%. The presence of invadin Gram*neative bacteria( circulatin
endoto2in( or "idespread tissue in@ury are all potential triers. The responses associated
"ith cyto#ine action are pyre2ia( loss of lean body mass( stimulation of acute phase
protein synthesis( and chanes in vascular tone and permeability.
'ncreased levels of the cyto#ine tumor necrosis factor have been found in patients "ith
trauma( burns( and sepsis. 't increases neutrophil and monocyte activation and
lympho#ine production. 8ever and amino acid mobili?ation from s#eletal muscle are also
due( in part( to tumor necrosis factor. 't also encouraes vascular proliferation and
collaen production and so enhances "ound healin. =hen e2cessive production occurs(
tumor necrosis factor causes e2cessive muscle "astin and nitroen loss. 't triers the
subse4uent release of other cyto#ines $interleu#ins 1 and D% as "ell as prostalandins and
the counter*reulatory hormones.
Eicosanoids $lipid metabolites%
Specific fatty acids derived from dietary lipids are incorporated into the structure of the
phospholipid cell membranes. These phospholipids represent a reservoir of potential
metabolic mediators( the nature of "hich depends on the fatty acids inested $or infused%.
)nder en?ymatic action( the phospholipid membranes release fatty acid molecules "hich
are converted to a number of eicosanoids. The inta#e of omea*D fatty acids causes the
release of arachidonic acid "hich produces thrombo2ane A2 and prostalandin E2 via the
cyclo*o2yenase path"ay. The former is a potent vasoconstrictor "hile the latter is an
immunosuppressant. The substitution of omea*3 for omea*D fatty acids in the diet
ultimately results in the production of eicosapentanoic acid( thrombo2ane A3( and the 3
series prostanoids. Thrombo2ane A3 is a less potent vasoconstrictor than A2( and the 3
series prostanoids are less immunosuppressant than the 2 series.
&rolactin in critical illness
&rolactin( "hich is secreted by the anterior pituitary to promote lactation( also has an
immunoreulatory role. Coth T and C lymphocytes have prolactin receptors. The
immunosuppressive effect of cyclosporin is probably due( in part( to the fact that it
competes for the prolactin bindin site on T cells.
&rolactin concentrations increase in acute stress but are normal or reduced in lon*term
stress such as that associated "ith critical illness. This may be e2plained by the proloned
increase in lucocorticoid production "hich is thouht to inhibit prolactin release. This
prolactin deficiency state "ould impair immune function( particularly cell*mediated
immunity( althouh the physioloical sinificance is unclear.
The effect of critical illness on the ut
The mucosal cells of the astrointestinal tract have one of the hihest turnover rates of
any body tissue. Endothelial rene"al depends on the division and miration of stem cells
"ithin the mucosal crypts. Therefore an intact ut mucosa depends on a balance bet"een
cell rene"al and e2foliation. The intact mucosal layer( tiht @unctions bet"een cells(
lymphocytes( macrophaes( and neutrophils in the submucosa and &eyer0s patches( and
ut*enerated 'A all contribute to barrier function of the ut $Thompson 1;;5%.
A fall in perfusion and tissue o2yenation( "hich occurs in many forms of critical illness(
is a sinificant insult to the ut. Splanchnic hypoperfusion may persist after apparently
ade4uate fluid resuscitation( and even short periods of circulatory compromise may result
in proloned ut ischemia.hypo2ia. This may cause cell in@ury( necrosis( and loss of
mucosal interity( a state "hich may be e2acerbated by coe2istin malnutrition( bacterial
overro"th of the ut( and $possibly% reperfusion in@ury follo"in periods of
hypovolemia and hypotension.
Cacterial translocation $the miration of viable bacteria across the intestinal barrier to the
liver( spleen( or mesenteric lymph nodes% and endoto2in translocation may occur
follo"in loss of barrier function. =hen such processes occur to a limited e2tent( "hich
may be an everyday event( the -upffer cells in the liver prevent spill*over into the
systemic circulation. =hen there is a ma@or deficiency in ut barrier function( systemic
spill*over occurs because $i% the liver is over"helmed by the amount of bacteria and.or
endoto2in presented to it and $ii% often the cause of ut barrier failure $e..
hypoperfusion% "ill also induce hepatic dysfunction( preventin efficient phaocytosis of
bacteria and removal of endoto2in in portal blood.
5ranisms "hich breech the mucosal element of the ut barrier may be phaocytosed by
macrophaes and transported to the mesenteric lymph nodes. Aain( if the microbial load
is e2cessive( these micro*oranisms may reach the circulation via the lymph system. The
presence of circulatin endoto2in has itself been found to increase intestinal permeability
in healthy humans.
Cacterial translocation has been implicated in the pathoenesis of multiple oran
dysfunction in animal models of critical illness( but the clinical sinificance in humans is
less clear. The overro"th of pathoens in the upper astrointestinal tract of critically ill
patients may be follo"ed by multiple oran failure in the ma@ority. !o"ever( other "or#
suests no sinificant portal bacteremia after ma@or trauma and no correlation bet"een
increased intestinal permeability and infective complications.
'mplications for nutritional support in critical illness
5ur current incomplete vie" of the response to critical illness is only of value if "e use it
constructively. =hen attemptin to optimi?e nutritional support "e should consider the
follo"in.
Structural chanes in the ut miht promote translocation
=henever possible the enteral route should be used for nutritional support. Early enteral
nutrition helps to preserve intestinal mucosal mass( barrier function( and $possibly%
intestinal immune function.
!ypermetabolism( increased catabolism( and nitroen loss
't "ould appear that( at least after trauma( optimally resuscitated patients have an
increased metabolic rate "ithin the first 2< h. The practice of supplyin e2cess calories to
avoid underfeedin has been sho"n to increase mortality in septic rats.
The tendency to hyperlycemia and lucose intolerance
!ih lucose inta#e is associated "ith hepatic lipoenesis and dysfunction. The hih
circulatin levels of epinephrine( lucaon( and cortisol and the resistance to insulin
mean that the critically ill patient is unli#ely to tolerate a lucose load "ithout sinificant
hyperlycemia and its associated problems.
)se of nutrients for non*nutritional effects
Some substances have metabolic benefits "hich o beyond their nutritional value
$Minard and Eanu 1;;D%. The amino acid lutamine is an important nutrient for
enterocytes and prevents mucosal atrophy in e2perimental models of starvation. =hen
administered enterally lutamine reduces bacterial translocation in rats( and "hen
administered parenterally it appears to enhance ut immune function. Glutamine is also a
natural buildin bloc# for the reducin aent lutathione( and this may increase
protection aainst cellular in@ury in ischemia>reperfusion.
Arinine is another conditionally essential amino acid involved in the process of protein
synthesis( the production of nitric o2ide $"hich has beneficial effects on ut
microvascular responses to in@ury%( and the secretion of human ro"th hormone and
insulin. 't stimulates immune function enerally and has been associated "ith improved
bactericidal activity and "ound healin.
1utritional benefit may also sprin from manipulation of metabolic path"ays. )tili?ation
of omea*D fatty acids $common in =estern diet% results in the production of dienoic
prostalandins such as prostalandin E2 "hich has an immunosuppressive effect due to
its effect on T cells. 'n contrast( if omea*3 fatty acids $found in abundant amounts in fish
oil% are substituted( prostalandin synthesis is s"itched from dienoic to trienoic
path"ays( thus reducin prostalandin E2 levels.
1ucleotides are the structural subunits for A1A and ,1A synthesis. Aietary nucleotides
are bro#en do"n in the small bo"el lumen into nucleosides and purine or pyrimidine
bases. These may be absorbed by the enterocytes. Aurin metabolic stress( "ith rapid cell
turnover( intestinal mucosal health may become dependent on( and limited by( the supply
of nucleotides. Thus nucleotide supplementation may maintain or improve ut barrier
function and therefore reduce septic complications.
+orrection of specific nutrient and hormone deficiencies
'n 1;D1( the administration of pituitary land e2tract to a roup of severely burned
patients "as found to reduce urinary nitroen e2cretion and improve other nutritional
parameters. Cy the 1;76s( recombinant human ro"th hormone "as available and had
been sho"n to improve nitroen balance( even at lo" caloric inta#es in normal sub@ects.
A similar improvement in nitroen balance associated "ith the use of human ro"th
hormone "as demonstrated in patients receivin total parenteral nutrition after ma@or
astrointestinal surery. =hen administered to children "ith burns( human ro"th
hormone reduces the healin time of s#in donor sites and total time in hospital. !uman
ro"th hormone increases plasma levels of insulin*li#e ro"th factor '. 'ndeed( the
benefit of human ro"th hormone administration is partly due to the action of insulin*
li#e ro"th factor ' "hich( iven alone( has been sho"n to improve ut mucosal atrophy
and reduce intestinal permeability in septic animals. !o"ever( 4uestions about optimum
dose( re4uired duration of treatment( other effects( and indications for the use of human
ro"th hormone and insulin*li#e ro"th factor ' remain. They do not yet constitute
therapies of proven benefit and so should not be used routinely.
5ther factors may influence the metabolic and nutritional response. Since dopamine
appears to depress pituitary function and thus inhibits prolactin and human ro"th
hormone release $van den Cerhe and de Feher 1;;D%( it may be prudent to avoid its
use( at least in severe sepsis. Gut barrier function appears to be important in the overall
response( and so maintenance of astric acidity( aressive cardiovascular resuscitation(
and monitorin.optimi?ation of splanchnic blood flo" may be helpful. The presence of
bile in the ut is important( since bile salts bind endoto2in in the astrointestinal tract.
5ther strateies to prevent or attenuate the cyto#ine cascade have been less successful(
althouh antibodies to endoto2in( tumor necrosis factor( and receptor antaonists have
been $or are at present% under investiation.
+hapter ,eferences
Michelson( A.G.( Gold( &.=.( and Sternber( E.M. $1;;<%. The stress response in critical
illness. 1e" !ori?ons( 2( <2D>31.
Minard( G. and Eanu( &. $1;;D%. Status and clinical utility of pharmaconutrients. +urrent
5pinion in +ritical +are( 2( 253>;.
,olih( +.A. and 5ber( -.&. $1;;5%. The endocrine response to critical illness. Medical
+linics of 1orth America( B;( 211>2<.
Thompson( E.S. $1;;5%. The intestinal response to critical illness. American Eournal of
Gastroenteroloy( ;6( 1;6>266.
van den Cerhe( G. and de Feher( 8. $1;;D%. Anterior pituitary function durin critical
illness and dopamine treatment. +ritical +are Medicine( 2<( 1576>;6.