CONCISE CLINICAL REVIEW

On the Neuroendocrinopathy of Critical Illness

Perspectives for Feeding and Novel Treatments
Greet Van den Berghe
Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University and
Hospitals, Leuven, Belgium

Abstract accentuated by the concomitant fasting. Accepting the lack of

Typical for critical illnesses are substantial alterations within the
hypothalamic–anterior pituitary–peripheral hormonal axes that are
proportionate to the risk of poor outcome. These neuroendocrine
responses to critical illness follow a biphasic pattern. The acute phase
(first hours to days) is characterized by an increased release of
anterior pituitary hormones, whereas altered target-organ sensitivity
and hormone metabolism result in low levels of the anabolic
peripheral effector hormones and contribute to the substantially
elevated levels of the catabolic hormone cortisol. The prolonged
phase of critical illness is hallmarked by a uniform suppression of the
neuroendocrine axes, predominantly of central/hypothalamic origin,
which contributes to the low (or insufficiently high in the case of
cortisol) circulating levels of the target-organ hormones. Several
of the acute-phase adaptations to critical illness are due to or
macronutrients as well as the neuroendocrine responses to such
fasting in the acute phase of critical illness has shown to beneficially
affect outcome. In contrast, the neuroendocrine alterations that
occur in the chronic phase of illness while patients are fully
fed contribute to bone and skeletal muscle wasting and impose risk
of adrenocortical atrophy. The combined administration of those
hypothalamic releasing factors, which have been identified as
suppressed or deficient during prolonged critical illness, may be a
promising strategy to enhance recovery. The potential impact of
treatment with such hypothalamic releasing factors on recovery from
critical illness as well as on long-term rehabilitation should be
investigated in future randomized controlled clinical trials.
Keywords: growth hormone; cortisol; adrenocorticotropic
hormone; thyrotrophin-releasing hormone; ghrelin

Thanks to the development of modern
intensive care medicine over the past
7 decades, patients nowadays survive
previously lethal trauma or illnesses. The
majority of patients treated in ICUs
worldwide recover within a week. About
25% of ICU patients, however, enter the
chronic phase of critical illness, during
which they require vital organ support
often for weeks, sometimes months. On
average, between 15% and 20% of those
prolonged critically ill patients do not
survive the ICU phase, and the risk of not
leaving the hospital alive is even higher.
Irrespective of the type of the initial disease
for which patients required vital
organ support, ICU-acquired weakness
develops in the chronic phase. Ongoing
hypercatabolism despite the provision of
artificial nutrition is believed to result
in ongoing loss of lean body mass, which is
assumed to contribute to the weakness
and frailty and to prolong the dependency
on intensive medical care.
The hypothalamic–anterior pituitary
axes play a central role in the endocrine
regulation of metabolic homeostasis.
Outside the context of critical illness, it is
well known that growth hormone (GH)
deficiency causes loss of muscle and bone
mass and induces weakness, whereas
acromegaly results in an inappropriately
large bone and muscle mass with loss
of body fat. Normal availability of thyroid
hormone is also crucial for the balance
between anabolism and catabolism.
Hypothyroidism causes weakness and
cognitive and organ dysfunction,
and hyperthyroidism results in increased
energy expenditure, hypercatabolism, and
wasting. Also, the pituitary–adrenocortical
axis is a major switch in controlling the
metabolic balance, as evidenced by the
phenotype of patients with Addison disease
and those with Cushing syndrome. Lack

( Received in original form July 26, 2016; accepted in final form September 8, 2016 )
Supported by the Research Foundation Flanders grant G041712N, the Methusalem Program of the Flemish Government grant METH/14/06, and the
European Research Council under the European Union’s Seventh Framework Program grant FP7/2013-2018 ERC Advanced Grant Agreement 321670.
Correspondence and requests for reprints should be addressed to Greet Van den Berghe, M.D., Ph.D. Intensive Care Medicine, UZ Leuven, Herestraat 49,
B-3000 Leuven, Belgium. E-mail: greet.vandenberghe@kuleuven.be
CME will be available for this article at www.atsjournals.org
Am J Respir Crit Care Med Vol 194, Iss 11, pp 1337–1348, Dec 1, 2016
Copyright © 2016 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201607-1516CI on September 9, 2016
Internet address: www.atsjournals.org

Concise Clinical Review 1337


of cortisol causes weakness and impaired
cognition, and hypercortisolism causes
muscle and bone wasting, with
inappropriate fat storage.
Critical illness is characterized by
profound alterations within these normally
tightly feedback-controlled neuroendocrine
systems. Research performed over the last
2 decades has revealed that these changes
follow a biphasic pattern, with the
neuroendocrine responses to acute and
prolonged critical illness being distinct
(1, 2). Recent research has shed some light
on which of these neuroendocrine
alterations are likely adaptive and beneficial
at a certain time point in the course of
critical illness and which may represent a
therapeutic opportunity that should
be further explored in clinical trials.
In this concise review, the new insights
are integrated with the previous
knowledge on the alterations within
the neuroendocrine system observed
during the acute and the chronic phases of
critical illness, with a special focus on the
GH axis, the pituitary–thyroid axis and
the pituitary–adrenocortical axis.
Opportunities for research are highlighted.
The GH Axis
GH is released into the circulation by the
somatotrope cells of the anterior
pituitary gland in a pulsatile fashion, with
peak GH levels alternating with virtually
undetectable troughs. The regulation of
pulsatile GH secretion is complex, with
hypothalamic GH-releasing hormone
(GHRH) stimulating, and somatostatin
inhibiting, the synthesis and secretion of GH
(3). In addition, ghrelin, a highly conserved
hormone expressed in the hypothalamus
and in the gut, is a third key driver
of pulsatile GH release (4, 5). The
hypothalamic and pituitary G-protein–
coupled ghrelin receptor can also
be activated by several synthetic
GH-releasing peptides (GHRPs) (6, 7).
GH exerts direct and indirect effects, the
latter exerted by insulin-like growth factor-I
(IGF-I), of which the bioactivity is
regulated via a series of IGF-binding
proteins (IGFBPs) (8, 9).
The GH Axis in the Acute Phase of
Critical Illness
Within hours up to days after onset of
acute illnesses, the GH secretion pattern
1338 American Journal of Respiratory and Critical Care Medicine Volume 194 Number 11 | December 1 2016
changes substantially (Figure 1A). More GH
is released into the circulation, with high
GH peaks and interpulse concentrations
and an increased GH pulse frequency
(1, 10). Concomitantly, in part triggered by
proinflammatory cytokines, peripheral
GH resistance develops, with loss of
functional GH receptors as revealed by low
circulating levels of GH-binding protein,
and as a consequence enhanced GH
secretion in the face of low levels of IGF-I,
GH-dependent IGFBP-3, and acid-labile
subunit (8, 10–12). Enhanced clearance
of IGF-I, due to changes in its binding
proteins, further lowers its circulating
levels. Reduced expression of the GH
receptor (12, 13), whereby low-circulating
IGF-I and thus loss of negative feedback
inhibition is believed to drive the abundant
release of GH in the acute phase of illness.
This constellation is also evoked by
fasting, where it results in amplified direct
lipolytic and insulin-antagonizing effects
of GH, leading to a release of endogenous
fatty acids and glucose into the circulation,
whereas indirect, IGF-I–mediated effects
of GH are switched off. As a result, energy-
consuming anabolism, mediated by IGF-I,
is postponed. From an evolutionary
viewpoint, such a GH-axis response to
acute illnesses appears appropriate for
survival.
The GH Axis in the Prolonged Phase
of Critical Illness
Unlike in the acute phase of illness, the
pulsatile release of GH is suppressed in
prolonged (fed) critically ill patients
(Figure 1A) (14–16). Although it was
previously assumed that GH resistance
persists throughout critical illness, GH
responsiveness was later shown to recover
in the chronic phase when patients are
receiving nutrition. In this chronic phase,
the pulsatile fraction of GH release
correlates positively with circulating IGF-I,
IGFBP-3, and acid-labile subunit levels
(14–16), which suggests that the loss of
pulsatile GH release contributes to these
low levels of IGF-I and binding proteins in
prolonged critical illness. Furthermore,
the infusion of a ghrelin-like GH-releasing
peptide (GHRP-2) was found to reactivate
pulsatile GH secretion back to the level
of activation seen in the acute phase of
illness and to proportionally increase
IGF-I and GH-dependent IGFBP levels
(Figure 1B) (14, 15). The higher-than-
normal release of GH in response to
CONCISE CLINICAL REVIEW
GHRP-2 reveals that the somatotropes
are more than able to synthesize GH.
Hence, it is more likely that the cause of
the relative hyposomatotropism in the
chronic phase of illness lies within the
hypothalamus. With GH release in
response to GHRH that is much lower than
that to GHRP-2 in prolonged critical
illness (9), a hypothalamic inactivity of
ghrelin is likely to play a key role. This
“hyposomatotropism,” with loss of
pulsatile GH secretion, contributes to
muscle and bone wasting typically present
in prolonged critical illness (16).
The Pituitary–Thyroid Axis
Thyrotrophin-releasing hormone (TRH)
secreted by the hypothalamus stimulates
the pituitary thyrotropes to produce
thyrotrophin (TSH) in a pulsatile fashion,
which in turn regulates the thyroidal
synthesis and secretion of thyroid
hormones. Although the thyroid gland
predominantly produces thyroxin (T4), the
biological activity of thyroid hormones is
largely exerted by triiodothyronine (T3)
(17). Different types of deiodinating
enzymes control the peripheral activation
of T4 to T3 or the alternative conversion
of T4 into the biologically inactive reverse
T3 (rT3) (18). Thyroid hormones enter
cells through specific monocarboxylate
transporters, and T3 acts on thyroid
hormone nuclear receptors that
heterodimerize with the Retinoid-X
Receptor and control gene expression in
various peripheral tissues (19). Circulating
and local thyroid hormones exert
feedback control on both hypothalamic
TRH and pituitary TSH secretion.
The Pituitary–Thyroid Axis in the
Acute Phase of Critical Illness
The initial response of the thyroid axis to
illness in humans consists of a rapid decline
in the circulating levels of T3 and an
increase in rT3 levels (Figure 2). This is
explained by an immediately decreased
type 1 deiodinase (D1) activity and an
increased type 3 deiodinase (D3) activity
(18,19), whereby T4 is converted to rT3
rather than to T3 (20, 21). TSH and
T4 levels are transiently elevated but
subsequently return to normal (Figure 2)
(22). Low T3 levels without an increase
in TSH is referred to as “the low T3
syndrome.” Such a low T3 syndrome is also
CONCISE CLINICAL REVIEW

A Health Acute Critical Illness Prolonged Critical Illness

14 14 14
GH (μg/l)

7 7 7

0 0 0
21:00 06:00 21:00 06:00 21:00 06:00
Time Time Time

B
50 50 50 50
Placebo GHRH GHRP-2 GHRH + GHRP-2
40 40 40 40
GH (μg/l)

30 30 30 30
20 20 20 20
10 10 10 10
0 0 0 0
21 06h 21 06h 21 06h 21 06h
Time Time Time Time

150
IGF-1 R2= 0.67

100 ALS R2= 0.76

concentration (%)
Change in

IGFBP-3 R2= 0.57

50

–50
0 100 200 300 400 500 600
Pulsatile GH
(μg/lv over 9h)
Figure 1. Illustration of the growth hormone (GH) axis responses to acute and prolonged critical illness as compared with the healthy control condition.
(A) Nocturnal GH plasma concentration time series during health and during acute and prolonged critical illness. Pulsatile GH secretion is activated
during acute critical illness and suppressed during prolonged critical illness. (B) The suppressed pulsatile GH secretion during prolonged critical illness can
be reactivated. As compared with placebo, continuous infusion of GH-releasing hormone (GHRH; 1 mg/kg/h) was only partially able to reactive GH
secretion, whereas infusion of GH-releasing peptide 2 (GHRP-2; 1 mg/kg/h) and even more so the combination of GHRH and GHRP-2 (1 1 1 mg/kg/h)
could restore the increased pulsatile GH secretion as observed in the acute phase of critical illness. Unlike during acute illness, primarily a condition of
GH resistance, reactivated pulsatile GH secretion in the prolonged phase of critical illness is able to generate peripheral GH responses. This is illustrated by
the regression lines between pulsatile GH secretion and the changes in circulating insulin-like growth factor I (IGF-I), acid-labile substrate (ALS), and
IGF-binding protein-3 (IGFBP-3). These lines indicate that GH responses during prolonged critical illness are proportionate to GH secretion up to a
certain point, beyond which a further increase in GH secretion has apparently little or no additional effect. This point corresponds to a pulsatile GH
secretion that can be evoked by the infusion of GHRP-2 alone. lv = liter of distribution volume. Adapted by permission from Reference 2.

Concise Clinical Review 1339

 CONCISE CLINICAL REVIEW

A effects (27). Recent indirect evidence from

Health Acute Critical Illness Prolonged Critical Illness two large randomized controlled trials
7 (RCTs), the EPaNIC (Early versus Late
Parenteral Nutrition in Critically Ill Adults)
trial and the pediatric PEPaNIC trial,
TSH (mlU/l)

supports this possibility. It was shown that

tolerating the substantial macronutrient
deficit that occurs during the first week in
the ICU improves outcomes as compared
with preventing it via early initiation of
0 parenteral nutrition (29, 30). Accepting
21h 06h 21h 06h 21h 06h such “relative fasting” early during critical
illness reduced nosocomial infections,
B prevented liver function abnormalities,
Acute Critical Illness Prolonged Critical Illness prevented muscle weakness, and enhanced
changes in peripheral + neuroendocrine component recovery (29–33). The clinical “harm” by
metabolism and binding
giving parenteral feeding early coincided
with a reversal of the decrease in plasma
TRH TRH ↓ TSH and T3 as well as of the increase in
rT3 (34). Such an effect of early parenteral
nutrition was also shown in an animal
model of critical illness, where it prevented
TSH (↑) = the suppressed expression and activity of
TSH ↓
liver D1 and the activated expression and
activity of D3 and reversed the plasma
phenotype of the low T3 syndrome
(Figure 3) (35). Statistically, part of the
T4 (↑) = T4 ↓ clinical benefit of not feeding patients early
D1
+ D3, D1 D1
+
D3, D1 was explained specifically by the steeper
acute decrease in T3 and in the T3/rT3
ratio. Hence, part of the immediate
↑ T3 rT3 ↑ ↓↓ T3 rT3 (↑)= decrease in T3 and increase in rT3
concentrations during acute critical illness
D3, D1 + D1 D3, D1 + D1 is in fact elicited by the concomitant fasting
rather than the illness and is likely
T2 T2
beneficial (34). Besides less energy
Figure 2. Illustration of the pituitary–thyroid axis responses to acute and prolonged critical illness as expenditure with low T3 availability evoked
compared with the healthy control condition. (A) The nocturnal pulsatile thyroid-stimulating hormone by the shortage of macronutrients,
(TSH) secretion is suppressed during prolonged critical illness. (B) In the acute phase of critical illness, optimized bacterial killing capacity via a
the peripheral changes in thyroid hormone metabolism predominate, whereas in the chronic phase, direct impact of high D3 activity locally
a hypothalamic suppression is superimposed, with (partial) recovery of the peripheral changes.
within granulocytes (36, 37) could also
Adapted by permission from Reference 2. D1–3 = iodothyronine deiodinase type 1–3; rT3 = reverse
T3; T2 = diiodothyronine; T3 = triiodothyronine; T4 = thyroxin; TRH = thyrotropin-releasing hormone.
explain fewer nosocomial infections (29, 30).

The Pituitary–Thyroid Axis in the

present when healthy subjects are fasted.
In critical illness, the severity of the
disease is reflected by the degree of the
acute decrease in serum T3 (23), and
nonsurvivors have lower T3 levels than
survivors (24).
Cytokines have been proposed to
trigger the low T3 syndrome, although
cytokine antagonists administered after an
endotoxemic challenge cannot restore
normal thyroid function (25). Other factors
contributing to the acute low T3 syndrome
are decreased concentrations of thyroid
hormone–binding proteins and inhibition
of hormone binding, transport, and
metabolism by free fatty acids and
bilirubin (26).
The immediate decrease in circulating
T3 that occurs when otherwise healthy
subjects fast protects the organism against
hypercatabolism (27, 28). Patients with
illnesses requiring intensive medical care
cannot normally feed by mouth and often
are not yet given artificial nutrition.
Inferentially, at least part of the decrease
in circulating thyroid hormone levels in
response to acute illness could thus be
fasting induced and hence could represent
an adaptation to the low availability of
nutrients and could mediate beneficial
Prolonged Phase of Critical Illness
In prolonged critically ill patients who for
weeks or longer receive, among other
vital support, also full enteral and/or
parenteral nutrition, different changes
within the thyroid axis are present (1).
In this later phase, low plasma T4
concentrations accompany the low
T3 levels, tightly linked with a virtually
complete loss of pulsatile TSH secretion
(Figure 2) (38). Also, TRH gene expression
in the hypothalamic paraventricular nuclei
of patients who died after a prolonged
critical illness was found to be much lower
than in patients who died suddenly (39).

1340 American Journal of Respiratory and Critical Care Medicine Volume 194 Number 11 | December 1 2016
CONCISE CLINICAL REVIEW

TSH d7
2.5 12 P = 0.001
2.0 11
1.5 10
Δ TSH (mlU/l)

1.0 9
Fasted

mlU/l
0.5 Fed 8
0.0 7 **
–0.5 6
–1.0 5
P = 0.03
–1.5 4
d0 d3 d5 d7 Fasted Fed

T4
T4 d7
5.0 80
P = 0.1
0.0 70
–5.0 60
ΔT4 (nmol/l)

–10.0 50 *

Nmol/l
Fasted
–15.0 40
Fed
–20.0 30
–25.0 20
–30.0 10
P = 0.7
–35.0 0
d0 d3 d5 d7 Fasted Fed

T3 T3 d7

1.0 3.5 P = 0.0001

0.8 *
3.0
0.6
Fasted 2.5
ΔT3 (nmol/l)

0.4 Fed
2.0
Nmol/l

0.2
1.5 *
0.0
1.0
–0.2
–0.4 0.5
P = 0.007
–0.6 0.0
d0 d3 d5 d7 Fasted Fed
Figure 3. Effect of feeding during critical illness, as compared with fasting, on the “low T3 syndrome” in a rabbit model. Feeding critically ill rabbits
intravenously reversed the phenotype of the low T3 syndrome as compared with full fasting for 7 days after onset of illness. The gray areas indicate the
normal reference ranges for healthy rabbits. Asterisks indicate significant differences from values in healthy rabbits. Adapted by permission from Reference
35. d = day; T3 = triiodothyronine; T4 = thyroxin; TSH = thyrotrophin.

In this post mortem study, the suppressed
TRH mRNA expression correlated
positively with the low plasma T3 (39).
Thyroidal production and/or release of
thyroid hormones thus appears reduced in
prolonged critical illness because there is
lack of hypothalamic TRH-mediated
stimulation of the thyrotropes with
suppressed TSH-mediated activation of
the thyroid gland as a result. The finding of
a supranormal TSH that precedes onset
of recovery further supports this concept
of a reversible central hypothyroidism in
prolonged critical illness (40).
It remains obscure which molecules
drive the hypothalamic suppression in
prolonged critical illness. Suspects other
than cytokines must be involved, as plasma

Concise Clinical Review 1341


cytokine concentrations are usually much
lower in this late phase (41). High
hypothalamic concentrations of dopamine
or cortisol are candidate mediators (42–44).
An altered set point for feedback
inhibition within the hypothalamus could
be due to locally increased type-2
deiodinase (D2) expression and activity,
which can elevate local thyroid hormone
availability (45, 46). Increased pituitary D2
could also be possible (47) but was not
confirmed in an experimental model (48).
In contrast with the apparent adaptive
nature of the low T3 syndrome present
during acute illness, substantial evidence
from human and animal studies indicates
that peripheral tissues of patients suffering
from prolonged critical illness show signs
of adaptation to the low production of
thyroid hormones by increasing thyroid
hormone transporters, local activation of
thyroid hormone, and increasing the
expression of the active thyroid hormone
receptor isoform. For example, in skeletal
muscle and liver biopsies from prolonged
critically ill patients, the monocarboxylate
transporter-8 was shown to be
overexpressed (49). In an animal model,
such up-regulation of the thyroid hormone
transporters in liver and kidney could be
reversed with thyroid hormones (49, 50).
Furthermore, local activation of D2 in
tissues such as skeletal muscle and lungs
was documented, which could represent
an adaptive attempt to increase thyroid
hormone activity locally in these tissues (50,
51). And in liver biopsies of prolonged
critically ill patients, an inverse correlation
was observed between on the one hand the
ratio of active thyroid hormone receptor
TRa1 over the ligand-insensitive isoform
TRa2, a surrogate marker of thyroid
hormone sensitivity, and on the other hand
the ratio of T3 over rT3 (52). These data
suggest that in the chronic phase of critical
illness, several tissues seem to require a
higher thyroid hormone availability.
In line with such an interpretation, low
T3 levels have been found to correlate
inversely with markers of muscle
breakdown and of bone loss in prolonged
critical illness (15). In itself, such an
association cannot differentiate between
cause and consequence (16, 53), but the
causality question was addressed by
investigating the effect of TRH treatment.
A continuous infusion of TRH given to
prolonged critically ill patients was shown
to increase plasma T4 and T3, but also rT3
1342 American Journal of Respiratory and Critical Care Medicine Volume 194 Number 11 | December 1 2016
concentrations were elevated (15, 53).
However, in combination with GHRP-2,
TRH infusion was capable of normalizing
plasma T4 and T3 without an increase in
rT3 (53), which was explained by a GH-
mediated suppressive effect on the thyroid
hormone-inactivating D3 (Figure 4) (54).
This combined releasing factor treatment
for 5 days also induced an anabolic
response (Figure 4) that was not present
with GHRP-2 alone. Hence, a causal
relationship between the central
hypothyroidism and the impaired
anabolism during prolonged critical illness
was suggested (53). A great advantage of
treatment with hypothalamic releasing
factors is that the negative feedback
inhibition by thyroid hormones at the
pituitary level is maintained during critical
illness, which prevents overstimulation of
the pituitary–thyroid axis (15, 53).
The Pituitary–Adrenocortical
Axis
During health, cortisol is diurnally secreted
in pulses from the adrenal cortex, with
the highest levels in the early morning hours
and lower levels at night. Cortisol release
is controlled by adrenocorticotropic
hormone (ACTH, corticotrophin) produced
by the pituitary corticotrophes, in turn
driven by hypothalamic corticotrophin-
releasing hormone (CRH) and to a lesser
extent vasopressin (55, 56). ACTH
stimulates steroidogenesis by binding to
the melanocortin-2 receptor in the
adrenocortical cell membrane. ACTH up-
regulates the expression of this receptor,
drives cholesterol release from the lipid
droplets, and increases the expression
of proteins required for cholesterol
uptake (such as the low-density
lipoprotein–receptor and scavenger-
receptor class B member-1) and for
cholesterol synthesis (3-hydroxy-3-
methylglutaryl-CoA reductase) (56–61).
ACTH also increases expression of key
steroidogenic enzymes, such as
steroidogenic acute regulatory protein and
the cytochrome P450 cholesterol side-chain
cleavage enzyme CYP11A1 (56–61).
Besides this feed-forward activation of
cortisol synthesis/secretion, feedback
inhibition of CRH and ACTH by cortisol
tightly controls its own release.
Ninety percent of circulating cortisol is
bound to binding proteins, predominantly
CONCISE CLINICAL REVIEW
corticosteroid-binding globulin and
albumin, but only free cortisol exerts
biological activity. Cortisol acts via the
glucocorticoid receptor, a 90-kD
intracellular receptor protein virtually
expressed in all cells. Considering the fact
that glucocorticoid receptor protein levels
and glucocorticoid bioavailability are
largely similar in most cell types, the striking
cell-specific and sometimes even opposite
effects of cortisol require a complex
differential intracellular regulation (62).
The molecular basis of cell-specific
glucocorticoid responsiveness involves
glucocorticoid receptor splice variants and
differential expression of coreceptor
proteins functioning as coactivators and
corepressors of transcription. Also,
differences in chromatin structure and
DNA methylation status of glucocorticoid
receptor target genes determine variable
cortisol effects in different tissues (63). The
physiological actions of cortisol range from
the complex regulation of the immune
system and metabolism to effects on the
cardiovascular and central nervous system.
The Pituitary–Adrenocortical Axis in
the Acute Phase of Critical Illness
Circulating cortisol increases substantially
in response to acute illness or trauma,
assumed to be driven by a several-fold
increased adrenocortical cortisol production
evoked by increased CRH and ACTH
release (55, 64, 65). Briefly, increased
plasma ACTH concentrations have indeed
been reported after trauma or sepsis (66).
Several cytokines can also directly modulate
cortisol production and the glucocorticoid
receptor number and/or affinity (67). As
albumin and corticosteroid-binding
globulin levels are substantially decreased,
the latter in part due to elastase-induced
cleavage (68, 69), a proportionally much
higher increase in circulating free cortisol
is present (70, 71). The diurnal variation
in cortisol secretion disappears with
acute illnesses or trauma (55, 65). An
appropriate activation of the
hypothalamic–pituitary–adrenal axis and
cortisol response to acute critical illness is
vital (72–77). The vital stress-induced
hypercortisolism in critically ill patients
improves the hemodynamic status through
fluid retention and vasopressor
sensitization; provides energy via shifting
carbohydrate, fat, and protein metabolism;
and protects against excessive inflammation
by suppressing inflammation (1, 67).
CONCISE CLINICAL REVIEW

IGF-I (µg/L) T4 (nmol/L) T3 (nmol/L)

p < 0.0001 p < 0.0001 2.0 p < 0.0001

200

140
160 1.6

120 110
1.2

80
80 .8

40
50 .4
d0 d5 d10 d0 d5 d10 d0 d5 d10

GHRP-2 +TRH / placebo

placebo / GHRP-2 +TRH

Δ % OC over 5 days Δ % urea / creatinine ratio serum

100 p = 0.03

30 p < 0.0001

–80 –30
GHRP-2 placebo d0 d5
+ TRH
Figure 4. Effect of the combined infusion of thyrotropin-releasing hormone (TRH) and the growth hormone–releasing peptide-2 (GHRP-2) on the
“low T3 syndrome” during prolonged critical illness. A continuous infusion of TRH in combination with GHRP-2 in prolonged critically ill fed patients
reversed the hyposomatotropism and the low T3 syndrome, as evidenced via a crossover design with 5 days infusion of GHRP-2 1 TRH followed by
5 days placebo (red symbols) or vice-versa (blue symbols). Five days of GHRP-2 1 TRH infusion was shown to increase a marker of anabolism in bone
and to suppress ureagenesis, suggesting reduced catabolism in skeletal muscle. Adapted by permission from Reference 16. d = day; IGF-1 = insulin-like
growth factor I; OC = osteocalcin; T3 = triiodothyronine; T4 = thyroxin.

The Pituitary–Adrenocortical Axis in
the Prolonged Phase of Critical Illness
In most patients, hypercortisolism is still
present in the chronic phase of critical
illness, but given that ACTH levels are now
low, this must be brought about by
alternative, non–ACTH-mediated pathways
(78, 79). Indeed, a steep decrease in
plasma ACTH occurs after a short-lasting
elevation (Figure 5), whereas plasma
cortisol concentrations remain high
(66, 80). This “ACTH-cortisol dissociation”
of critical illness is not what one would
expect in the context of an ongoing
activation of the pituitary–adrenocortical
axis in response to such a high and
sustained level of physical stress. It remains
unclear what is driving the low ACTH
levels in the face of high plasma cortisol.
Reduced ACTH mRNA levels have been
reported in nine human pituitary glands
harvested post mortem from patients who
died after septic shock as compared with
patients who died suddenly from other
diseases, in the absence of a compensatory
increase in the expression of CRH or
vasopressin in the hypothalamus (81). Also,
in experimental models of sepsis, pituitary
ACTH expression levels were found to be
suppressed in the more chronic phase
of critical illness (82), which could be
evoked by nitric oxide or by suppressed
orexin (81, 82). However, if such sepsis-
induced suppression of pituitary ACTH
expression was a sign of organ failure, this
would inferentially cause abnormally low
plasma cortisol concentrations, which in
patients is usually not the case. Although
increased adrenocortical sensitivity to
ACTH has been suggested as an alternative
explanation (83), the cortisol response to
any given endogenous plasma ACTH level

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 CONCISE CLINICAL REVIEW

HPA axis during CI HPA axis during recovery HPA axis during prolonged CI

Hypothalamus CRH ? CRH ? CRH ?

ACTH ↑→↓↓ ACTH ↑→nl ACTH ↓↓

Anterior
pituitary
Feedback inhibition

Feedback control
Adrenal cortex Cortisol availability ↑ Cortisol availability nl Cortisol availability low?
- Production nl / ±↑/ ±↓ - Production ↑→nl - Production ↓↓
due to adrenal
Cytokines, toxins, atrophy
low ACTH (loss of ACTH signaling)
Liver/Kidney
- Clearance ↓↓ - Clearance ↑→nl - Clearance ↓↓

A-ring reductases ↓↓
11β-HSD2 ↓
Circulation

Elevated plasma cortisol Normal plasma cortisol Risk of low plasma cortisol
Predominantly driven by
suppressed cortisol clearance
with suppressed ACTH
Figure 5. Schematic overview of the pituitary–adrenocortical axis changes during critical illness (CI) followed by either recovery or prolonged critical illness.
During critical illness, after an initial brief increase in plasma corticotrophin (ACTH), elevated plasma cortisol in the face of paradoxically low plasma ACTH is
explained predominantly by reduced cortisol breakdown in liver and kidney. When recovery follows after a short-lasting illness, the normalization of cortisol
breakdown allows for a rapid normalization of the circulating ACTH and cortisol levels within a tightly feedback-controlled system. When ACTH remains
suppressed for weeks during prolonged critical illness, there is a potential risk of adrenocortical atrophy. 11b-HSD2 = 11b-hydroxysteroid dehydrogenase 2;
CRH = corticotropin-releasing hormone; HPA = hypothalamic–pituitary–adrenocortical; Nl = normal.

is not elevated during critical illness (84),
and in response to exogenous ACTH it
is quite often low. Furthermore, ACTH
signaling in human adrenal glands was
found to be unaltered in the acute phase
and substantially suppressed in the chronic
phase of illness (85). Therefore, another
more plausible explanation for high plasma
cortisol concentrations and low plasma
ACTH levels, with low ACTH-regulated
gene expression in the adrenal cortex
during critical illness, is negative feedback
inhibition exerted by plasma cortisol that is
elevated through alternative, non–ACTH-
driven, pathways.
Although clinicians always assumed
that cortisol production rate must be about
sixfold higher than normal to generate and
maintain hypercortisolemia during critical
illness, it was quantified in ICU patients only
recently. Using stable isotopes, a study
showed that morning cortisol production
rate was only moderately increased, less
than doubled, in critically ill patients with
hyperinflammation and unchanged in other
critically ill patients as compared with
the cortisol production rates of healthy
matched control subjects, in the face of
several-fold higher plasma total and free
cortisol levels in all patients (80). The stable
isotope technique also showed that cortisol
plasma clearance was substantially
suppressed in all patients irrespective of
the degree of inflammation. With three
subsequent studies, this finding was further
explored (80). Cortisol half-life and plasma
clearance during critical illness was also
quantified after the administration of a 100-mg
bolus of hydrocortisone. Similar results
were obtained: plasma cortisol clearance
reduced to 40% of that in matched control
subjects and a cortisol half-life that was a
median fivefold longer in patients. This
suppressed cortisol breakdown was due to
reduced expression and activity of the
cortisol-metabolizing enzymes,
predominantly the A-ring reductases
in liver and 11b-hydroxysteroid
dehydrogenase-2 in kidney, as suggested by
urinary steroid ratios, tracer kinetics, and
assessment of human liver-biopsy samples
(80). Reduced cortisol clearance was
present irrespective of type and severity
of illness and irrespective of ICU stay
and prognosis. This suggested that a
pronounced suppression of cortisol
breakdown may be the key mechanism that,
together with ongoing normal (or slightly
elevated) cortisol production, brings about
the high plasma cortisol in prolonged
critical illness.
The new insight that the plasma half-
life of cortisol is so much longer during
critical illness necessitated another detailed
analysis of ACTH and cortisol secretion
rates and their interaction via time series of
plasma concentrations measured every
10 minutes overnight in critically ill patients
and in healthy control subjects (84). With

1344 American Journal of Respiratory and Critical Care Medicine Volume 194 Number 11 | December 1 2016
CONCISE CLINICAL REVIEW

deconvolution analysis, which takes into
account elimination half-life of the
hormone, the plasma concentration time
series were transformed into hormonal
secretion profiles (86). This technique
unveiled that in the presence of high total
and free plasma cortisol concentrations,
both the nocturnal ACTH and cortisol
pulsatile secretion rates were reduced
rather than increased in critically ill
patients (87), but the normal feedback
control was active. Thus, beyond the
very acute phase of critical illness, high
nocturnal plasma cortisol concentrations
seem to be predominantly maintained by
reduced cortisol breakdown. With only
slightly increased daytime and suppressed
nighttime cortisol secretion rates, it also
seems that 24-hour cortisol production
rates during critical illness are not, or are
only moderately, higher than during health.
When the adrenal cortex is deprived of
adequate ACTH signaling for an extended
period of time, as with sustained low
circulating ACTH that is present in the
prolonged phase of illness, its integrity
may become impaired (Figure 5). A study
of adrenal cortex biopsies harvested
immediately post mortem from acute and
prolonged (>7 d) critically ill patients and
from sudden out-of-hospital deaths
showed a very pronounced depletion
of cholesterol esters and suppressed
expression of ACTH-regulated genes in
adrenal glands from prolonged, but not
above, offers a conceptual frame to better
understand the results of RCTs that have
investigated endocrine and metabolic
interventions and to improve the design of
future trials.
First, a large multicenter RCT
investigated the impact on outcome of high
doses of GH, started on ICU admission
and continued into the chronic phase of
critical illness (91). Instead of showing
the anticipated improved outcome via
induction of anabolism, this treatment
doubled mortality. Suppression of cell
damage removal and overdosing of GH in a
condition of recovered GH sensitivity in the
chronic phase of illness possibly played a
role. Second, although only investigated
in a few small studies, administration of
either substitution doses or high doses of
thyroid hormones also showed no clinical
outcome benefit, and one was stopped early
for potential harm (92). Again, dosing
issues of the peripherally active hormones
and timing of treatment initiation may have
been important. Third, studies on the
potential impact of hydrocortisone in
patients with sepsis, administered at a dose
that represents six times the equivalent of
the cortisol production during critical
illness, revealed conflicting results (67, 93,
94). Such high doses in the context of a
Hormone plasma concentration
substantially reduced breakdown of steroids
during critical illness could explain why any
expected benefits may have been offset by
potential harm. In contrast, multicenter
RCTs performed in critically ill adults
and children showed that withholding
parenteral nutrition during the first week of
critical illness, and thereby accepting virtual
fasting and its neuroendocrine responses,
reduced organ failure, prevented weakness,
and accelerated recovery (29–32, 34).
Accepting the fasting responses rather than
forcefully feeding patients early in the
course of illness was most beneficial for the
sickest patients, who were at the highest
risk. Such a benefit was at least partially
explained by a better preservation of
autophagy during fasting, which is
important for an optimal innate immune
response and for cell damage removal in
vital organs and in skeletal muscle (32).
The findings of these studies also shed new
light on the controversial issue of insulin
treatment during critical illness. Benefits
were initially shown with very strictly
lowering blood glucose levels to the healthy
fasting ranges, both in adults and children,
an intervention that also accentuated the
acute fasting-like neuroendocrine responses
to illness in the context of early parenteral
feeding (95–98), but risk of harm was

cortisol
or hormone secretion rate

acute, critically ill patients (85). These

results are quite reminiscent of the
phenotype of proopiomelanocortin-
deficient mice and thus suggest that a
sustained lack of ACTH effect could indeed
predispose prolonged critically ill patients
to adrenal atrophy (88). Such risk of
adrenal atrophy in patients with a
prolonged ICU stay also helps to explain
the reported 20-fold higher incidence of
symptomatic adrenal insufficiency in
critically ill patients being treated in the
intensive care unit for more than 14 days
(89). It remains to be investigated whether
CRH or ACTH could offer a potential to
prevent or treat adrenal failure in the
prolonged phase of critical illness (90).
Reconciliation with Results
from Intervention Trials
The biphasic nature of the neuroendocrine
responses to critical illness, as described
? Level
observed
during health
GH, TSH, ACTH
T3 (and T4), IGF-I
ACUTE PROLONGED RECOVERY (?)
illness illness
Figure 6. Simplified cartoon of anterior pituitary–dependent changes during the course of critical
illness. In the acute phase of illness (first hours to few days after onset), the growth hormone (GH),
thyrotrophin (TSH), and corticotrophin (ACTH) secretory activity (red) is amplified, whereas levels of
active thyroid hormone (triiodothyronine, T3) and insulin-like growth factor-I (IGF-I) (green) are low,
and cortisol levels (yellow) are elevated. In prolonged critical illness (intensive care dependency for
weeks), pulsatile secretion of GH, TSH, and ACTH is uniformly suppressed, which drives the low
circulating levels of IGF-I and thyroid hormones. In the prolonged phase of critical illness, plasma
cortisol remains elevated in the presence of low ACTH, largely because of suppressed cortisol
breakdown. With sustained ACTH deficiency, however, adrenal atrophy may ensue, which may
cause inappropriately low cortisol availability. The onset of recovery after acute illness is characterized
by increased TSH. Whether this is also the case for GH and ACTH currently remains unclear. Whether
recovery of the anterior pituitary axes after prolonged critical illness is complete in the long term or not
also remains to be investigated. Adapted by permission with new insights from figures in References
1 and 2.

Concise Clinical Review 1345

 CONCISE CLINICAL REVIEW

shown in subsequent pragmatic
multicenter trials (99). The role of tight
blood glucose control versus no blood
glucose control should thus be
reinvestigated in the context of not giving
parenteral nutrition during the first week
in the ICU.
Conclusions
The hypothalamic–anterior pituitary
axes respond biphasically to severe illness
and trauma (Figure 6). The acute
adaptations represent at least partial
responses to fasting, which is beneficial and
thus should not be interfered with. In
contrast, the uniform suppression of the
neuroendocrine axes observed in the
prolonged fed state of critical illness
might be harmful. Treatment with
hypothalamic releasing factors in the
prolonged phase of illness can reactivate
the anterior pituitary, which may be more
effective and safer than administration of
the peripherally active hormones (GH,
thyroid hormones, hydrocortisone),
which have been shown to be either not
effective or even to cause harm. Indeed, a
particular advantage of releasing
factors is that overstimulation of the
respective hormonal axes, and thus
toxic side effects of high peripheral
hormone levels, is avoided by intact
negative feed-back control and by
the ability to adaptively change
peripheral hormonal metabolism
(15, 16, 53). Future intervention studies
should focus more on patients with
prolonged critical illness and investigate
the potential of combined administration
of the hypothalamic releasing factors that
have been identified as suppressed or
deficient. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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