- Email: [email protected]
Endocrine changes in criticallyill patients
¢
Growth Hormone & IGF Research 1999, 9, 77-81
Short communication
Endocrine changes in critically ill patients G. Van den Berghe Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
A BIPHASlC METABOLIC AND IMMUNOLOGICAL R E S P O N S E TO C R I T I C A L I L L N E S S
The initial, acute phase of the response to critical illness or injury is characterized by gluconeogenesis, proteolysis and lipolysis, which rapidly provide metabolic substrates for organs such as the brain. These processes also allow the synthesis of acute phase proteins and activation of the immune system, with infiltration of affected tissues by leucocytes and systemic release of cytokines, such as turnout necrosis factor a (TNF-a), interferon-7 and other cytokines. At the same time, anabolism in the less vital tissues is 'delayed'. 1 Although certain individuals may under- or over-respond during the acute phase, which could hypothetically be deleterious, these changes have been 'selected' during evolution. Thus, there is reason to believe that these changes are adaptive and beneficial to the defence and survival of the individual. If, despite modem intensive care, recovery does not follow the acute phase of critical illness within a few days, a chronic phase ensues, during which patients often remain dependent on pharmacological and/or mechanical support of vital organ function for weeks or months. This phase is characterized by different metabolic and immunological changes. Although proteolysis is still activated, overall protein synthesis is suppressed and free fatty acid levels are no longer elevated. In fact, fat accumulates in the adipocytes and infiltrates vital organ systems, such as the liver. 2 The immune system becomes relatively paralysed, indicated by T-cell dysfunction and impaired neutrophil chemotaxis. In normal circumstances, the individual would not Correspondence to: G. Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. Tel: +32 16 34 40 21 ; Fax: +32 16 34 40 15; Email: [email protected]
1096-6374/99/0A0077 + 05 $18.00/0
survive this condition, and thus the metabolic and immunological changes observed during the chronic, intensive care unit (ICU)-dependent phase may n o t necessarily be adaptive and beneficial. A B I P H A S I C N E U R O E N D O C R I N E R E S P O N S E TO C R I T I C A L ILLNESS Hypothalamic-pituitary response
It is well known that the anterior pituitary gland plays a crucial role in normal metabolic and immunological homeostasis. There is recent evidence that the hypothalamic-pituitary response to critical illness also follows a biphasic pattern, with an acute and chronic phase. 3 It appears that the acute phase is mainly characterized by an actively secreting anterior pituitary gland and peripheral inactivation or inactivity of anabolic hormones. Clinical recovery is preceded by a rapid normalization of these changes. In contrast, when recovery does not follow within a few days and critical illness becomes protracted, reduced hypothalamic stimulation appears to underlie an impaired pulsatile release of several anterior pituitary hormones (Fig. 1) and the reduced stimulation of the respective target tissues. GH axis response
Acute critical illness or injury initially results in an elevation in circulating levels of growth hormone (GH). 4 The normal nocturnal pattern of GH serum concentrations, which consists of peaks alternating with troughs in which GH levels are virtually undetectable, is altered: the number of GH bursts released by the somatotrophs is increased and the peak GH levels, as well as interpulse concentrations, are high (Fig. 1).5 It is unclear which factor ultimately controls this stimulation
© 1999 Churchill Livingstone
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G. Van den Berghe
of GH release in response to stress. Inhibition of somatostatin release and/or increased levels of stimulatory hypothalamic GH-releasing factors could hypothetically be involved. Serum concentrations of insulin-like growth factor I (IGF-I) are low during the acute phase of critical illness. 6 The concurrence of elevated GH levels and low IGF-I levels has been interpreted as resistance to GH, which may be related to decreased expression of the GH receptor. 7 There are also changes in the circulating levels of IGFbinding proteins (IGFBPs), which regulate the plasma half-life and bioavailability of IGF-I (see also Baxter,
page 67).s The low serum concentrations of IGF-I are associated with low levels of IGFBP-3 and acid-labile subunit (ALS);a,9the synthesis of these three polypeptides is normally increased by GH and, together, they form a 150 kDa ternary complex in the circulation. In acute critical illness, an increased presence of IGFBP-3-protease activity in the plasma has been reported, 9 resulting in an increased dissociation of IGF-I from the ternary complex and a shortening of the plasma half-life of IGF-I. IGFBP-1, which normally binds only a small amount of IGF-I compared with IGFBP-3, remains in the circulation either at normal or elevated concentrations.I° This constellation
Acute critical illness
Healthy individuals
Chronic critical illness
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Fig. 1 Nocturnal serum concentration profiles of GH, thyrotropin and prolactin, illustrating the differences between the acute and chronic phases of critical illness within an intensive care setting. Adapted with permission from Van den Berghe e t al. 3 © The Endocrine Society.
E n d o c r i n o l o g y o f critical illness
of changes in the acute phase of critical illness can be at least partially explained by the release of cytokines, and has been interpreted as contributing to the provision of essential metabolic substrates for survival. The pattern of GH secretion during the chronic phase of critical illness appears to be different from that during the acute phase, displaying generally reduced pulsatile fraction, a non-pulsatile or tonic fraction that is still somewhat elevated and a pulse frequency that remains high. The result is a mean serum GH concentration that is low to normal (Fig. 1).3,11,12This relative suppression of GH release appears to occur only after the patient has been in a critical condition for a certain length of time; it appears to be less dependent on the type or severity of the underlying disease. The reduced amount of GH that is released in the pulses correlates positively with low circulating levels of IGF-I, IGFBP-3 and ALS.n,12 Indeed, it has been shown that when pulsatile GH secretion falls below a critical threshold during the chronic phase of critical illness, circulating levels of IGF-I and ALS progressively decrease over time. As low serum levels of IGF-I and, to a greater extent, low levels of ALS are markers of protein wasting in this type of situation, <8 these findings suggest that the neuroendocrine component of the somatotropic axis participates in the pathogenesis of the wasting syndrome seen in prolonged critical illness. This hypothesis is at least partially corroborated by the fact that the whole somatotropic axis remains readily responsive to the infusion of GH secretagogues, as shown by pulsatile GH secretion (Fig. 2), followed by substantial increases in the circulating levels of IGF-I, IGFBP-3 and ALS.~1,12 This responsiveness to endogenous GH secretion further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the
Placebo
79
acute phase, which is thought to be primarily a condition of GH resistance. The pathogenesis of the impaired pulsatile secretion of GH in prolonged critical illness is thought to be complex. One of the possibilities is a deficiency in the endogenous GH-releasing peptide (GHRP)-like ligand, together with reduced somatostain levels and a maintenance of some of the effects of GH-releasing hormone (GHRH). This would explain both the reduced spontaneous GH secretion and the pronounced responsiveness to GHRPs. 11-13The metabolic efficacy of the administration of GH secretagogues as a strategy to counter the 'wasting syndrome' of protracted critical illness is currently being explored. As the administration of a hypothalamicreleasing factor acknowledges the involvement of pituitary feedback inhibition loops and allows for the peripheral adjustment of metabolic pathways according to the needs determined by the disease, infusion of GH secretagogues may be better tolerated than the administration of high doses of GH and/or IGF-I in the chronic, GH-responsive phase of critical illness, particularly in vulnerable elderly patients. 14 In addition to the changes observed in the levels of GH, IGF-I and IGFBPs during critical illness, the release of prolactin also becomes relatively impaired in the chronic phase of critical illness (Fig. 1), 15 the cause of which remains speculative. Moreover, there is evidence for hypogonadotropic hypogonadism in protracted critical illness. 16-20 Thyroid response The thyroid axis follows a comparable biphasic pattern of responsiveness to critical illness. Within hours of acute injmT or disease, circulating levels of tri-iodothyronine
GHRH
GHRP-2
GHRH + GHRP-2
50 40 30 I
20 10 0 2100
~
I
0600 2100 Time (hours)
I
0600 2100
Time (hours)
I
0600 2100
Time (hours)
0600
Time (hours)
Fig. 2 Nocturnal serum GH profiles in the chronic phase of critical illness, illustrating the effects of continuous infusion of placebo, GHRH (1 pg/kg/hour), GHRP-2 (1 pg/kg/hour), or GHRH + GHRP-2 (1 + 1 pg/kg/hour). Age range of the patients was 62-85 years; duration of illness was between 13 and 48 days; infusions were started 12 hours before the onset of the respective profiles. Adapted with permission from Van den Berghe et aL3 © The Endocrine Society.
80
G. Van den Berghe
rapidly fall, partly because of a decrease in the conversion of thyroxine (T4) to T3 and/or an increase in turnover of the thyroid hormones, whereas mean nocturnal serum levels of thyrotropin remain unaltered. 21 The magnitude of the decrease i n T 3 levels within 24 hours reflects the severity of the illness.22 The cytokines TNF-a and intefleukins-1 and -6 have been suggested as putative mediators of the acute low T3 syndrome. In starvation, these acute changes have been interpreted as an attempt to reduce energy expenditure;23 thus, this is thought to be an appropriate response that does not warrant intervention. Whether this is also applicable to other acute stress conditions, such as the initial phase of critical illness, is still a matter of controversy. 24 During the prolonged phase of critical illness, the pulsatile fraction of thyrotropin secretion is dramatically diminished (Fig. 1) and is positively correlated with the low serum levels ofT3.15 This suggests that the low levels of thyroid hormones in the chronic phase of critical illness may have a neuroendocrine origin. This is supported by the findings that hypothalamic expression of thyrotropin-releasing hormone (TRH) is positively correlated with s e r u m T 3 levels in this condition. Furthermore, an increase in serum thyrotropin levels is a marker for the onset of recovery from severe illness. 2526 The concept of a low T 3 syndrome of neuroendoctine origin has been corroborated by investigating the effect of the administration of TRH: the thyroid axis can be reactivated in the chronic phase of critical illness by TRH infusion, leading to increases in thyrotropin secretion and in circulating levels of T 4 and T 3 (Fig. 3). 12 Interesti@y, the co-infusion of TRH and GH secretagognes appears to be necessary to increase the pulsatile fraction of thyrotropin release and to avoid a rise in circulating levels of r e v e r s e T 3. During TRH infusion in prolonged critical (T3)
Placebo
illness, the negative feedback exerted by thyroid hormones on the thyrotrophs was found to be maintained, thus precluding overstimulation of the thyroid axis. 12 Moreover, TRH infusion allows for peripheral shifts in thyroid hormone metabolism and, accordingly, permits the body to regulate concentrations of thyroid hormones in the circulation and at tissue level, and, therefore, may provide a better tolerated treatment than the administration of T3. Pituitary-adrenal response
The pituitary-adrenal axis also responds differently to acute illness or injury and to the chronic stress of protracted critical illness. Circulating levels of adrenocorticotropin increase during the first few days of critical illness, but decline to subnormal values thereafter, whereas cortisol levels remain elevated throughout critical illness. 27 The elevated levels of cortisol may result from peripheral activation of the adrenal glands in the chronic phase of critical illness. This mechanism may also ultimately fail, as indicated by a 20-fold increase in the incidence of adrenal failure in patients over the age of 55 years, who have been treated in the ICU for longer than 14 days.2s CONCLUSIONS
The acute and chronic phases of critical illness appear to involve different responses, with mostly peripheral changes occurring in the acute phase and primarily neuroendocrine changes occurring in the chronic phase. Thus, these phases should perhaps be approached with different therapeutic strategies. At present, there is no solid pathophysiological basis for hormonal intervention
TRH
TRH + GHRP-2
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Fig. 3 Nocturnal serum thyrotropin profiles in the chronic phase of critical illness, illustrating the effects of continuous infusion of placebo, TRH (1 #g/kg/hour), or TRH + GHRP-2 (1 + 1 pg/kg/hour). Although infusion of TRH alone elevates thyrotropin secretion, the addition of GHRP-2 to the TRH infusion appears necessary to increase its pulsatile fraction. Age range of the patients was 69-80 years; duration of illness was between 15 and 18 days; infusions were started 12 hours before the onset of respective profiles. Adapted with permission from Van den Berghe et al.3 © The Endocrine Society.
Endocrinology of critical illness
d u r i n g t h e acute p h a s e of critical illness. However, t h e d e v e l o p m e n t of m o d e r n i n t e n s i v e care m e d i c i n e h a s l e d to p a t i e n t s u r v i v a l in p r e v i o u s l y l e t h a l c o n d i t i o n s , revealing newly recognized metabolic and neuroe n d o c r i n e disorders. It r e m a i n s to b e e l u c i d a t e d w h e t h e r t h e r e d u c e d h y p o t h a l a m i c s t i m u l a t i o n of t h e anterior p i t u i t a r y gland, w h i c h is d i s t i n c t i v e l y p r e s e n t in t h e c h r o n i c p h a s e of illness in a n i n t e n s i v e care setting, c o n t r i b u t e s to t h e m e t a b o l i c d y s f u n c t i o n t h a t occurs. Infusion w i t h h y p o p h y s i o t r o p i c - r e l e a s i n g p e p t i d e s t h a t are p r e s u m e d to b e d e f i c i e n t h a s b e e n s h o w n to reactivate a n t e r i o r p i t u i t a r y h o r m o n e release in t h e c h r o n i c p h a s e of critical illness, w i t h p r e s e r v e d pulsatility and peripheral responsiveness, regulated by active f e e d b a c k i n h i b i t i o n loops t h a t p r e v e n t o v e r t r e a t m e n t . It r e m a i n s to b e d e t e r m i n e d w h e t h e r this t y p e of tropic e n d o c r i n e i n t e r v e n t i o n will result in beneficial m e t a b o l i c effects and, ultimately, accelerate t h e r e c o v e r y of longstay ICU patients.
ACKNOWLEDGEMENTS S u p p o r t e d b y r e s e a r c h grants from t h e F u n d for Scientific Research Flanders, Belgium ( G . 0 1 6 2 . 9 6 a n d 3C05.95N) a n d t h e Research Council of t h e University of Leuven (OT 95/24).
REFERENCES 1. Kinney JM, Duke JH, Long CL, Gump FE. Tissue fuel and weight loss after injury. J Clin Pathol 1970; 23: 65-72. 2. Streat SJ, Beddoe AH, Hill GL. Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients. J Trauma 1987; 27: 262-266. 3. Van den Berghe G, de Zegher F, Bouillon R. Acute and chronic critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998; 83: 1827-1834. 4. Noel GL, Suh HK, Stone SJG, Frantz AE. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 1972; 35: 840-851. 5. Van den Berghe G, de Zegher E Bouillon R. The somatotropic axis in critical illness: effect of GH-secretagogues. GH IGF Res 1998; 8: 153-155. 6. Hawker FH, Steward PM, Baxter RC et al. Relationship of somatomedin-C/insulin-like growth factor-I levels to conventional nutritional indices in critically ill patients. Crit Care Med 1987; 15: 732-736. 7. Hermansson M, Wickelgren RB, Hammerqvist Fe¢ al. Measurement of human growth hormone receptor messenger ribonucleic acid by a quantitative polymerase chain reactionbased assay: demonstration of reduced expression after elective surgery. J Clin Endocrinol Metab 1997; 82: 421-428. 8. Baxter RC. Acquired growth hormone insensitivity and insulinlike growth factor bioavailability.Endocrinol Metab 1997; 4 (Suppl B): 65-69. 9. Timmins AC, Cotterill AM, Cwyfan Hughes SC et al. Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulinqike
10.
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16. 17.
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19.
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growth factor binding protein 3 protease. Crit Care Med 1996; 24: 1460-1466. Ross RJM, Miell JP, Holly JMP et al. Levels of GH-binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients. Clin Endocrinol 1991; 35: 361-367. Van den Berghe G, de Zegher F, Veldhuis JD et al. The somatotropic axis in critical illness: effect of continuous GHRH and GHRP-2 infusion. J Clin Endocrinol Metab 1997; 82: 590-599. Van den Berghe G, de Zegher F, Baxter RC et al. Neuroendocrinology of critical illness: effect of continuous thyrotropin-releasing hormone infusion and its combination with growth hormone-secretagogues. J Clin Endocrinol Metab 1998; 83: 309-319. Van den Berghe G, de Zegher F, Bowers CY et al. Pituitary responsiveness to growth hormone (GH) releasing hormone, GH-releasing peptide-2 and thyrotropin releasing hormone in critical illness. Clin EndocrinoI 1996; 45: 341-351. Johannsson G, Rosdn T, Bengtsson B-A. Individualized dose titration of growth hormone (OH) during GH replacement in hypopituitary adults. Clin Endocrinol 1997; 47: 571-581. Van den Berghe G, de Zegher F, Veldhuis JD et al. Thyrotropin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone secretagogues. Clin Endocrinol 1997; 47: 599-612. Wang C, Chan V, Yeung RTT. Effect of surgical stress on pitnitary-testicular function. Clin Endocrinol 1978; 9: 255-266. Vogel AV, Peake GT, Rada RT. Pituitary-testicular axis dysfunction in burned men. J Clin Endocrinol Metab 1985; 60: 658-665. Wang C, Chan V, Tse TF, Yeung RT. Effect of acute myocardial infarction on pituitary testicular function. Clin Endocrinol 1978; 9: 249-253. Van den Berghe G, de Zegher E Lauwers P, Veldhnis JD. Luteinizing hormone secretion and hypoandrogenemia in critically ill men: effect of dopamine. Clin Endocrinol 1994; 41 : 563-569.
20. Woolf PD, Hamill RW, McDonald JK, Lee LA, Kelly M. Transient hypogonadotropic hypogonadism caused by critical illness. J Clin Endocrinol Metab 1985; 60: 444-450. 21. Wartofski L, Burman KD. Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome". Endocr Rev 1982; 3: 164-167. 22. Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med 1995; 23: 78-83. 23. Gardner DF, Kaplan MM, Stanley CA, Utiger RD. Effect of triiodothyronine replacement on the metabolic and pituitary responses to starvation. N Engl J Med 1979; 300: 579-584. 24. Utiger RD. Decreased extrathyroidal triiodothyronine production in non-thyroidal illness: benefit or harm? AmJ Med 1980; 69: 807-810. 25. Fliers E, Guldenaar SEE Wiersinga WM, Swaab DE Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with non-thyroidal illness. J Clin Endocrinol Metab 1997; 82: 4032-4036. 26. Bacci V, Schussler GC, Kaplan TC. The relationship between serum triiodothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab 1982; 54: 1229-1235. 27. Vermes I, Bieshnizen A, Hampsink RM, Haanen C. Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 1995; 80: 1238-1242. 28. Barqnist E, Kirton O. Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 1997; 42: 27-31.
Growth Hormone & IGF Research 1999, 9, 77-81
Short communication
Endocrine changes in critically ill patients G. Van den Berghe Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
A BIPHASlC METABOLIC AND IMMUNOLOGICAL R E S P O N S E TO C R I T I C A L I L L N E S S
The initial, acute phase of the response to critical illness or injury is characterized by gluconeogenesis, proteolysis and lipolysis, which rapidly provide metabolic substrates for organs such as the brain. These processes also allow the synthesis of acute phase proteins and activation of the immune system, with infiltration of affected tissues by leucocytes and systemic release of cytokines, such as turnout necrosis factor a (TNF-a), interferon-7 and other cytokines. At the same time, anabolism in the less vital tissues is 'delayed'. 1 Although certain individuals may under- or over-respond during the acute phase, which could hypothetically be deleterious, these changes have been 'selected' during evolution. Thus, there is reason to believe that these changes are adaptive and beneficial to the defence and survival of the individual. If, despite modem intensive care, recovery does not follow the acute phase of critical illness within a few days, a chronic phase ensues, during which patients often remain dependent on pharmacological and/or mechanical support of vital organ function for weeks or months. This phase is characterized by different metabolic and immunological changes. Although proteolysis is still activated, overall protein synthesis is suppressed and free fatty acid levels are no longer elevated. In fact, fat accumulates in the adipocytes and infiltrates vital organ systems, such as the liver. 2 The immune system becomes relatively paralysed, indicated by T-cell dysfunction and impaired neutrophil chemotaxis. In normal circumstances, the individual would not Correspondence to: G. Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. Tel: +32 16 34 40 21 ; Fax: +32 16 34 40 15; Email: [email protected]
1096-6374/99/0A0077 + 05 $18.00/0
survive this condition, and thus the metabolic and immunological changes observed during the chronic, intensive care unit (ICU)-dependent phase may n o t necessarily be adaptive and beneficial. A B I P H A S I C N E U R O E N D O C R I N E R E S P O N S E TO C R I T I C A L ILLNESS Hypothalamic-pituitary response
It is well known that the anterior pituitary gland plays a crucial role in normal metabolic and immunological homeostasis. There is recent evidence that the hypothalamic-pituitary response to critical illness also follows a biphasic pattern, with an acute and chronic phase. 3 It appears that the acute phase is mainly characterized by an actively secreting anterior pituitary gland and peripheral inactivation or inactivity of anabolic hormones. Clinical recovery is preceded by a rapid normalization of these changes. In contrast, when recovery does not follow within a few days and critical illness becomes protracted, reduced hypothalamic stimulation appears to underlie an impaired pulsatile release of several anterior pituitary hormones (Fig. 1) and the reduced stimulation of the respective target tissues. GH axis response
Acute critical illness or injury initially results in an elevation in circulating levels of growth hormone (GH). 4 The normal nocturnal pattern of GH serum concentrations, which consists of peaks alternating with troughs in which GH levels are virtually undetectable, is altered: the number of GH bursts released by the somatotrophs is increased and the peak GH levels, as well as interpulse concentrations, are high (Fig. 1).5 It is unclear which factor ultimately controls this stimulation
© 1999 Churchill Livingstone
78
G. Van den Berghe
of GH release in response to stress. Inhibition of somatostatin release and/or increased levels of stimulatory hypothalamic GH-releasing factors could hypothetically be involved. Serum concentrations of insulin-like growth factor I (IGF-I) are low during the acute phase of critical illness. 6 The concurrence of elevated GH levels and low IGF-I levels has been interpreted as resistance to GH, which may be related to decreased expression of the GH receptor. 7 There are also changes in the circulating levels of IGFbinding proteins (IGFBPs), which regulate the plasma half-life and bioavailability of IGF-I (see also Baxter,
page 67).s The low serum concentrations of IGF-I are associated with low levels of IGFBP-3 and acid-labile subunit (ALS);a,9the synthesis of these three polypeptides is normally increased by GH and, together, they form a 150 kDa ternary complex in the circulation. In acute critical illness, an increased presence of IGFBP-3-protease activity in the plasma has been reported, 9 resulting in an increased dissociation of IGF-I from the ternary complex and a shortening of the plasma half-life of IGF-I. IGFBP-1, which normally binds only a small amount of IGF-I compared with IGFBP-3, remains in the circulation either at normal or elevated concentrations.I° This constellation
Acute critical illness
Healthy individuals
Chronic critical illness
14
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L
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tO
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"d e3
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Fig. 1 Nocturnal serum concentration profiles of GH, thyrotropin and prolactin, illustrating the differences between the acute and chronic phases of critical illness within an intensive care setting. Adapted with permission from Van den Berghe e t al. 3 © The Endocrine Society.
E n d o c r i n o l o g y o f critical illness
of changes in the acute phase of critical illness can be at least partially explained by the release of cytokines, and has been interpreted as contributing to the provision of essential metabolic substrates for survival. The pattern of GH secretion during the chronic phase of critical illness appears to be different from that during the acute phase, displaying generally reduced pulsatile fraction, a non-pulsatile or tonic fraction that is still somewhat elevated and a pulse frequency that remains high. The result is a mean serum GH concentration that is low to normal (Fig. 1).3,11,12This relative suppression of GH release appears to occur only after the patient has been in a critical condition for a certain length of time; it appears to be less dependent on the type or severity of the underlying disease. The reduced amount of GH that is released in the pulses correlates positively with low circulating levels of IGF-I, IGFBP-3 and ALS.n,12 Indeed, it has been shown that when pulsatile GH secretion falls below a critical threshold during the chronic phase of critical illness, circulating levels of IGF-I and ALS progressively decrease over time. As low serum levels of IGF-I and, to a greater extent, low levels of ALS are markers of protein wasting in this type of situation, <8 these findings suggest that the neuroendocrine component of the somatotropic axis participates in the pathogenesis of the wasting syndrome seen in prolonged critical illness. This hypothesis is at least partially corroborated by the fact that the whole somatotropic axis remains readily responsive to the infusion of GH secretagogues, as shown by pulsatile GH secretion (Fig. 2), followed by substantial increases in the circulating levels of IGF-I, IGFBP-3 and ALS.~1,12 This responsiveness to endogenous GH secretion further delineates the distinct pathophysiological paradigm of the chronic phase of critical illness, as opposed to the
Placebo
79
acute phase, which is thought to be primarily a condition of GH resistance. The pathogenesis of the impaired pulsatile secretion of GH in prolonged critical illness is thought to be complex. One of the possibilities is a deficiency in the endogenous GH-releasing peptide (GHRP)-like ligand, together with reduced somatostain levels and a maintenance of some of the effects of GH-releasing hormone (GHRH). This would explain both the reduced spontaneous GH secretion and the pronounced responsiveness to GHRPs. 11-13The metabolic efficacy of the administration of GH secretagogues as a strategy to counter the 'wasting syndrome' of protracted critical illness is currently being explored. As the administration of a hypothalamicreleasing factor acknowledges the involvement of pituitary feedback inhibition loops and allows for the peripheral adjustment of metabolic pathways according to the needs determined by the disease, infusion of GH secretagogues may be better tolerated than the administration of high doses of GH and/or IGF-I in the chronic, GH-responsive phase of critical illness, particularly in vulnerable elderly patients. 14 In addition to the changes observed in the levels of GH, IGF-I and IGFBPs during critical illness, the release of prolactin also becomes relatively impaired in the chronic phase of critical illness (Fig. 1), 15 the cause of which remains speculative. Moreover, there is evidence for hypogonadotropic hypogonadism in protracted critical illness. 16-20 Thyroid response The thyroid axis follows a comparable biphasic pattern of responsiveness to critical illness. Within hours of acute injmT or disease, circulating levels of tri-iodothyronine
GHRH
GHRP-2
GHRH + GHRP-2
50 40 30 I
20 10 0 2100
~
I
0600 2100 Time (hours)
I
0600 2100
Time (hours)
I
0600 2100
Time (hours)
0600
Time (hours)
Fig. 2 Nocturnal serum GH profiles in the chronic phase of critical illness, illustrating the effects of continuous infusion of placebo, GHRH (1 pg/kg/hour), GHRP-2 (1 pg/kg/hour), or GHRH + GHRP-2 (1 + 1 pg/kg/hour). Age range of the patients was 62-85 years; duration of illness was between 13 and 48 days; infusions were started 12 hours before the onset of the respective profiles. Adapted with permission from Van den Berghe et aL3 © The Endocrine Society.
80
G. Van den Berghe
rapidly fall, partly because of a decrease in the conversion of thyroxine (T4) to T3 and/or an increase in turnover of the thyroid hormones, whereas mean nocturnal serum levels of thyrotropin remain unaltered. 21 The magnitude of the decrease i n T 3 levels within 24 hours reflects the severity of the illness.22 The cytokines TNF-a and intefleukins-1 and -6 have been suggested as putative mediators of the acute low T3 syndrome. In starvation, these acute changes have been interpreted as an attempt to reduce energy expenditure;23 thus, this is thought to be an appropriate response that does not warrant intervention. Whether this is also applicable to other acute stress conditions, such as the initial phase of critical illness, is still a matter of controversy. 24 During the prolonged phase of critical illness, the pulsatile fraction of thyrotropin secretion is dramatically diminished (Fig. 1) and is positively correlated with the low serum levels ofT3.15 This suggests that the low levels of thyroid hormones in the chronic phase of critical illness may have a neuroendocrine origin. This is supported by the findings that hypothalamic expression of thyrotropin-releasing hormone (TRH) is positively correlated with s e r u m T 3 levels in this condition. Furthermore, an increase in serum thyrotropin levels is a marker for the onset of recovery from severe illness. 2526 The concept of a low T 3 syndrome of neuroendoctine origin has been corroborated by investigating the effect of the administration of TRH: the thyroid axis can be reactivated in the chronic phase of critical illness by TRH infusion, leading to increases in thyrotropin secretion and in circulating levels of T 4 and T 3 (Fig. 3). 12 Interesti@y, the co-infusion of TRH and GH secretagognes appears to be necessary to increase the pulsatile fraction of thyrotropin release and to avoid a rise in circulating levels of r e v e r s e T 3. During TRH infusion in prolonged critical (T3)
Placebo
illness, the negative feedback exerted by thyroid hormones on the thyrotrophs was found to be maintained, thus precluding overstimulation of the thyroid axis. 12 Moreover, TRH infusion allows for peripheral shifts in thyroid hormone metabolism and, accordingly, permits the body to regulate concentrations of thyroid hormones in the circulation and at tissue level, and, therefore, may provide a better tolerated treatment than the administration of T3. Pituitary-adrenal response
The pituitary-adrenal axis also responds differently to acute illness or injury and to the chronic stress of protracted critical illness. Circulating levels of adrenocorticotropin increase during the first few days of critical illness, but decline to subnormal values thereafter, whereas cortisol levels remain elevated throughout critical illness. 27 The elevated levels of cortisol may result from peripheral activation of the adrenal glands in the chronic phase of critical illness. This mechanism may also ultimately fail, as indicated by a 20-fold increase in the incidence of adrenal failure in patients over the age of 55 years, who have been treated in the ICU for longer than 14 days.2s CONCLUSIONS
The acute and chronic phases of critical illness appear to involve different responses, with mostly peripheral changes occurring in the acute phase and primarily neuroendocrine changes occurring in the chronic phase. Thus, these phases should perhaps be approached with different therapeutic strategies. At present, there is no solid pathophysiological basis for hormonal intervention
TRH
TRH + GHRP-2
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Fig. 3 Nocturnal serum thyrotropin profiles in the chronic phase of critical illness, illustrating the effects of continuous infusion of placebo, TRH (1 #g/kg/hour), or TRH + GHRP-2 (1 + 1 pg/kg/hour). Although infusion of TRH alone elevates thyrotropin secretion, the addition of GHRP-2 to the TRH infusion appears necessary to increase its pulsatile fraction. Age range of the patients was 69-80 years; duration of illness was between 15 and 18 days; infusions were started 12 hours before the onset of respective profiles. Adapted with permission from Van den Berghe et al.3 © The Endocrine Society.
Endocrinology of critical illness
d u r i n g t h e acute p h a s e of critical illness. However, t h e d e v e l o p m e n t of m o d e r n i n t e n s i v e care m e d i c i n e h a s l e d to p a t i e n t s u r v i v a l in p r e v i o u s l y l e t h a l c o n d i t i o n s , revealing newly recognized metabolic and neuroe n d o c r i n e disorders. It r e m a i n s to b e e l u c i d a t e d w h e t h e r t h e r e d u c e d h y p o t h a l a m i c s t i m u l a t i o n of t h e anterior p i t u i t a r y gland, w h i c h is d i s t i n c t i v e l y p r e s e n t in t h e c h r o n i c p h a s e of illness in a n i n t e n s i v e care setting, c o n t r i b u t e s to t h e m e t a b o l i c d y s f u n c t i o n t h a t occurs. Infusion w i t h h y p o p h y s i o t r o p i c - r e l e a s i n g p e p t i d e s t h a t are p r e s u m e d to b e d e f i c i e n t h a s b e e n s h o w n to reactivate a n t e r i o r p i t u i t a r y h o r m o n e release in t h e c h r o n i c p h a s e of critical illness, w i t h p r e s e r v e d pulsatility and peripheral responsiveness, regulated by active f e e d b a c k i n h i b i t i o n loops t h a t p r e v e n t o v e r t r e a t m e n t . It r e m a i n s to b e d e t e r m i n e d w h e t h e r this t y p e of tropic e n d o c r i n e i n t e r v e n t i o n will result in beneficial m e t a b o l i c effects and, ultimately, accelerate t h e r e c o v e r y of longstay ICU patients.
ACKNOWLEDGEMENTS S u p p o r t e d b y r e s e a r c h grants from t h e F u n d for Scientific Research Flanders, Belgium ( G . 0 1 6 2 . 9 6 a n d 3C05.95N) a n d t h e Research Council of t h e University of Leuven (OT 95/24).
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