Protracted Critical Illness Research Articles

Quasi-torpor for long-duration space missions

Innovative solutions are required to make long-duration space missions feasible. Crew performance and health is paramount to the success of anticipated Moon and Mars missions. Metabolic reduction via a quasi-torpor state is a possible mitigation strategy that can reduce consumable payload, which is necessary given the lack of available resupply options, and to reduce psychological stress, which is a risk for such lengthy missions. Even in lunar or cis-lunar missions, a quasi-torpor state could be implemented as an emergency countermeasure for critical situations where life support becomes limited. However, to date no studies have tested a quasi-torpor state in humans, and the impacts of intentional prolonged metabolic reduction on physiological and psychological parameters are unknown. To this end, we planned a three-phase study to provide proof-in-principle of the tolerability, feasibility, and side effects of a non-intravenous alpha-2-adrenergic receptor agonist for moderate sedation. This was accomplished by 1) determining the dosing and metabolic effects for different non-intravenous routes of alpha-2-adrenergic receptor agonist drugs; 2) assessing the degree of metabolic reduction and side effects during a 24-h quasi-torpor protocol; and 3) evaluating participant performance and total metabolic reduction achieved over a 5-day quasi-torpor protocol. We also aim to determine how skeletal muscle health and performance are affected by this quasi-torpor state. Quasi-torpor induced changes in skeletal muscle health and performance, as well as impacts on cognition and psychological stress, also have implications for terrestrial situations that result in prolonged confinement (e.g., austere environments such as submarine or remote scientific or military deployment and protracted critical illness). The findings of this three-phase study will be immediately applicable as a rescue strategy for emergencies during current or upcoming space missions. They will also identify key physiological and practical questions that need to be addressed for future deployment in long-duration space missions. This paper reviews the relevant literature that informed our rationale and approaches for this three-phase study.

Can functional electrical stimulation-assisted cycle ergometry replace insulin infusion in patients? A nested substudy in a randomized controlled trial with 6 months' follow-up.

Functional electrical stimulation-assisted cycle ergometry (FESCE) can deliver active exercise to critically ill patients, including those who are sedated. Aerobic exercise is known to stimulate skeletal muscle glucose uptake. We asked whether FESCE can reduce intravenous insulin requirements and improve insulin sensitivity in intensive care unit (ICU) patients. We performed an a priori-planned secondary analysis of data from an outcome-based randomized controlled trial (NCT02864745) of FESCE-based early-mobility program vs standard of care in mechanically ventilated patients. We analyzed glucose profile, glucose intake, and insulin requirements during ICU stay in all enrolled patients. In a nested subgroup, we performed hyperinsulinemic (120 mIU/min/m2 ) euglycemic clamps at days 0, 7, and 180 (n = 30, 23, and 11, respectively). We randomized 150 patients 1:1 to receive intervention or standard of care. Seventeen (23%) patients in each study arm had a history of diabetes. During ICU stay, patients received 137 ± 65 and 137 ± 88 g/day carbohydrate (P = .97), and 31 vs 35 (P = .62) of them required insulin infusion to maintain blood glucose 8.61 ± 2.82 vs 8.73 ± 2.67 mM (P = .75, n = 11,254). In those treated with insulin, median daily dose was 53 IU (interquartile range [IQR], 25-95) vs 62 IU (IQR, 26-96) in the intervention and control arm, respectively (P = .44). In the subgroup of patients undergoing hyperglycemic clamps, insulin sensitivities improved similarly and significantly from acute and protracted critical illness to 6 months after discharge. The FESCE-based early-mobility program does not significantly reduce insulin requirements in critically ill patients on mechanical ventilation.

Mitochondrial Function in an In Vitro Model of Skeletal Muscle of Patients With Protracted Critical Illness and Intensive Care Unit-Acquired Weakness.

Functional mitochondria in skeletal muscle of patients with protracted critical illness and intensive care unit-acquired weakness are depleted, but remaining mitochondria have increased functional capacities of respiratory complexes II and III. This can be an adaptation to relative abundancy of fatty acid over glucose caused by insulin resistance. We hypothesized that the capacity of muscle mitochondria to oxidize fatty acid is increased in protracted critical illness. We assessed fatty acid oxidation (FAO) and mitochondrial functional indices in vitro by using extracellular flux analysis in cultured myotubes obtained by isolating and culturing satellite cells from vastus lateralis muscle biopsy samples from patients with ICU-acquired weakness (n = 6) and age-matched healthy controls (n = 7). Bioenergetic measurements were performed at baseline and after 6 days of exposure to free fatty acids (FFAs). Mitochondrial density in myotubes from ICU patients was 69% of healthy controls ( P = .051). After adjustment to mitochondrial content, there were no differences in adenosine triphosphate (ATP) synthesis or the capacity and coupling of the respiratory chain. FAO capacity in ICU patients was 157% of FAO capacity in controls ( P = .015). In myotubes of ICU patients, unlike healthy controls, the exposure to FFA significantly ( P = .009) increased maximum respiratory chain capacity. In an in vitro model of skeletal muscle of patients with protracted critical illness, we have shown signs of adaptation to increased FAO. Even in the presence of glucose and insulin, elevation of FFAs in the extracellular environment increased maximal capacity of the respiratory chain.

Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.

BackgroundMitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors. It has been hypothesized that bioenergetics failure of skeletal muscle may contribute to the development of ICU-acquired weakness. The aim of the present study was to determine whether mitochondrial dysfunction persists until protracted phase of critical illness.MethodsIn this single-centre controlled-cohort ex vivo proof-of-concept pilot study, we obtained vastus lateralis biopsies from ventilated patients with ICU-acquired weakness (n = 8) and from age and sex-matched metabolically healthy controls (n = 8). Mitochondrial functional indices were measured in cytosolic context by high-resolution respirometry in tissue homogenates, activities of respiratory complexes by spectrophotometry and individual functional capacities were correlated with concentrations of electron transport chain key subunits from respiratory complexes II, III, IV and V measured by western blot.ResultsThe ability of aerobic ATP synthesis (OXPHOS) was reduced to ~54 % in ICU patients (p<0.01), in correlation with the depletion of complexes III (~38 % of control, p = 0.02) and IV (~26 % of controls, p<0.01) and without signs of mitochondrial uncoupling. When mitochondrial functional indices were adjusted to citrate synthase activity, OXPHOS and the activity of complexes I and IV were not different, whilst the activities of complexes II and III were increased in ICU patients 3-fold (p<0.01) respectively 2-fold (p<0.01).ConclusionsCompared to healthy controls, in ICU patients we have demonstrated a ~50 % reduction of the ability of skeletal muscle to synthetize ATP in mitochondria. We found a depletion of complex III and IV concentrations and relative increases in functional capacities of complex II and glycerol-3-phosphate dehydrogenase/complex III.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1160-x) contains supplementary material, which is available to authorized users.

Endocrine Responses to Critical Illness: Novel Insights and Therapeutic Implications

Critical illness, an extreme form of severe physical stress, is characterized by important endocrine and metabolic changes. Due to critical care medicine, survival from previously lethal conditions has become possible, but many patients now enter a chronic phase of critical illness. The role of the endocrine and metabolic responses to acute and prolonged critical illness in mediating or hampering recovery remains highly debated. The recent literature on changes within the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-adrenal axis and on hyperglycemia in relation to recovery from critical illness was critically appraised and interpreted against previous insights. Possible therapeutic implications of the novel insights were analyzed. Specific remaining questions were formulated. In recent years, important novel insights in the pathophysiology and the consequences of some of these endocrine responses to acute and chronic critical illness were generated. Acute endocrine adaptations are directed toward providing energy and substrates for the vital fight-or-flight response in a context of exogenous substrate deprivation. Distinct endocrine and metabolic alterations characterize the chronic phase of critical illness, which seems to be no longer solely beneficial and could hamper recovery and rehabilitation. Important novel insights reshape the current view on endocrine and metabolic responses to critical illness and further clarify underlying pathways. Although many issues remain unresolved, some therapeutic implications were already identified. More work is required to find better treatments, and the optimal timing for such treatments, to further prevent protracted critical illness, to enhance recovery thereof, and to optimize rehabilitation.

AKI patients have worse long-term outcomes, especially in the immediate post-ICU period

Acute kidney injury (AKI) is associated with worse outcome in the acute phase of acute illness but also in the chronic phase. In a large Danish study in this issue of Critical Care, 1-year mortality was higher in patients with AKI than in patients without AKI. Mortality was most important during the first 50 days after admission to the intensive care unit (ICU), whereas after 2 months the survival curves of patients with AKI and those of patients without AKI were similar. The reasons for this observation are not clear, but protracted critical illness and fragility after acute critical illness probably play important roles. Because we see more and more of these patients, they should be the focus of ICU research. Consequently, ICU and post-ICU care for these patients requires focus and a more integrated approach to the specific problems of these survivors of acute critical illness.

Hormonal status in protracted critical illness and in-hospital mortality

IntroductionThe aim of this study was to determine the relationship between hormonal status and mortality in patients with protracted critical illness.MethodsWe conducted a prospective observational study in four medical and surgical intensive care units (ICUs). ICU patients who regained consciousness after 7 days of mechanical ventilation were included. Plasma levels of insulin-like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured on the first day patients were awake and cooperative (day 1). Mean blood glucose from admission to day 1 was calculated.ResultsWe studied 102 patients: 65 men and 37 women (29 of the women were postmenopausal). Twenty-four patients (24%) died in the hospital. The IGF-1 levels were higher and the cortisol levels were lower in survivors. Mean blood glucose was lower in women who survived, and DHEA and DHEAS were higher in men who survived.ConclusionsThese results suggest that, on the basis of sex, some endocrine or metabolic markers measured in the postacute phase of critical illness might have a prognostic value.

Hormonal status and ICU-acquired paresis in critically ill patients

The pathogenesis of intensive care unit-acquired paresis (ICUAP), a frequent and severe complication of critical illness, is poorly understood. Since ICUAP has been associated with female gender in some studies, we hypothesized that hormonal dysfunction might contribute to ICUAP. To determine the relationship between hormonal status, ICUAP and mortality in patients with protracted critical illness. Prospective observational study. Four medical and surgical ICUs. ICU patients mechanically ventilated for >7 days. None. Plasma levels of insulin growth factor-1 (IgF1), prolactin, thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and cortisol were measured on the first day patients were awake (day 1). Mean blood glucose from admission to day 1 was calculated. ICUAP was defined as Medical Research Council sum score <48/60 on day 7. We studied 102 patients (65 men and 37 women, 29 post-menopausal), of whom 24 (24%) died during hospitalization. Among the 86 patients tested at day 7, 39 (49%) had ICUAP, which was more frequent in women (63% versus men 36%, p = 0.02). Mean blood glucose was higher in patients with ICUAP. Estradiol/testosterone ratio was greater in men with ICUAP. ICUAP 7 days after awakening was associated with increased blood glucose and with biological evidence of hypogonadism in men, while an association with hormonal dysfunction was not detected in women.

Adiponectin, retinol-binding protein 4, and leptin in protracted critical illness of pulmonary origin

IntroductionCritically ill patients requiring intensive care uniformly develop insulin resistance. This is most pronounced in patients with sepsis. Recently, several hormones secreted by adipose tissue have been identified to be involved in overall insulin sensitivity in metabolic syndrome-related conditions. However, little is known about these adipokines in critical illness.MethodsWe studied circulating levels of the adipokines adiponectin, retinol-binding protein 4 (RBP4), and leptin during critical illness, and the impact of intensive insulin therapy, a therapy shown to affect insulin sensitivity, in serum samples from prolonged critically ill patients with a respiratory critical illness (n = 318). For comparison, we studied healthy subjects (n = 22) and acutely stressed patients (n = 22).ResultsDuring acute critical illness, circulating levels of adiponectin, RBP4, and leptin were low. Patients with sepsis had lower levels of leptin and RBP4 than did nonseptic patients. When critical illness was sustained, adipokine levels returned to normal reference values. Insulin therapy enhanced adiponectin, blunted the rise of RBP4, and did not alter leptin levels.ConclusionsAcute critical illness is associated with immediate, but transiently low serum adipokine levels. Adiponectin and RBP4 are associated with altered insulin resistance in critical illness.

Systemic illness

Systemic illnesses are associated with alterations in the hypothalamic-pituitary-peripheral hormone axes, which represent part of the adaptive response to stressful events and may be influenced by type and severity of illness and/or pharmacological therapy. The pituitary gland responds to an acute stressful event with two secretory patterns: adrenocorticotropin (ACTH), prolactin (PRL) and growth hormone (GH) levels increase, while luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyrotropin (TSH) levels may either decrease or remain unchanged, associated with a decreased activity of their target organ. In protracted critical illness, there is a uniformly reduced pulsatile secretion of ACTH, TSH, LH, PRL and GH, causing a reduction in serum levels of the respective target-hormones. These adaptations are initially protective; however, if inadequate or excessive they may be dangerous and may contribute to the high morbidity and mortality risk of these patients. There is no consensus regarding the type of approach, as well as the criteria to use to define pituitary axis function in critically ill patients. We here provide a critical approach to pituitary axis evaluation during systemic illness.

Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness.

To establish the prevalence, clinical characteristics, and electrophysiologic features of residual neuromuscular dysfunction after prolonged critical illness. Prospective follow-up study of survivors of prolonged critical illness. A university hospital and two district general hospitals in the UK. The study occurred for a period of 5 yrs. All patients during that time who were in the intensive care unit for >28 days were entered in the study. At follow-up, length of intensive care unit and hospital stay, duration of mechanical ventilation and admission Acute Physiology and Chronic Health Evaluation II score were recorded from the case notes. A clinical history was obtained, a Barthel Index disability score was calculated, and a full neurologic examination was performed. Nerve conduction studies, needle electromyography, single-fiber electromyography and thermal thresholds were performed. A total of 195 patients were identified. There were 86 survivors, of whom 47 could be contacted and 22 consented to be studied. The median time from intensive care unit discharge to follow-up was 43 months (range, 12-57 months). All gave a clear history of severe weakness and functional impairment after hospital discharge and, in all, recovery was prolonged. Motor or sensory deficits were present on clinical examination in 59% of the patients studied. Common peroneal nerve palsy was present in two patients. A total of 21 of 22 (95%) patients had electromyographic evidence of chronic partial denervation at follow-up, findings indicative of a preceding axonal neuropathy. The single-fiber electromyographic studies were also consistent with a preceding motor neuropathy. Severe weakness requiring prolonged rehabilitation and abnormal clinical neurologic findings are extremely common in survivors of protracted critical illness. Neurophysiologic evidence of chronic partial denervation of muscle consistent with previous critical illness polyneuropathy is almost invariable and can be found up to 5 yrs after intensive care unit discharge in >90% of these long-stay patients. Evidence of myopathy is unusual. These findings have important implications for the management and rehabilitation of intensive care survivors.

Role of growth hormone, insulin-like growth factor-I, and insulin-like growth factor binding proteins in the catabolic response to injury and infection

The erosion of lean body mass resulting from protracted critical illness remains a significant risk factor for increased morbidity and mortality in this patient population. Previous studies have documented the well known impairment in nitrogen balance results from both an increase in muscle protein degradation as well as a decreased rate of both myofibrillar and sacroplasmic protein synthesis. This protein imbalance may be caused by an increased presence or activity of various catabolic agents, such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 or glucocorticoids, or may be mediated via a decreased concentration or responsiveness to various anabolic hormones, such as growth hormone or insulin-like growth factor-I. This review focuses on recent developments pertaining to the importance of alterations in the growth hormone-insulin-like growth factor-I axis as a mechanism for the observed defects in muscle protein balance.

Adrenal function in protracted critical illness: evaluation with the low-dose (1 μg) corticotropin stimulation test

To investigate the adrenocortical function in protracted critical illness, 43 patients (29 men and 14 women), having a mean (± SD) age of 55 ± 21 years were studied. First, a morning blood sample was obtained to determine baseline plasma cortisol. Subsequently, 1 μg of corticotropin (ACTH, synacthen) was injected intravenously and a second blood sample was drawn 30 min following the injection to measure stimulated plasma cortisol. Patients having a stimulated cortisol level of at least 18 μg/dl were defined as responders. In 36 patients, morning interleukin-6 (IL-6) concentrations were also measured. Mean baseline and stimulated plasma cortisol were 16.8 ± 4.1 μ/dl and 21.2 ± 5.1 μg/dl respectively. The median increment in cortisol was 4.1 μg/dl. Median IL-6 was high (39.3 pg/ml, interquartile range 24.9–86.6 pg/ml). There was a negative correlation between IL-6 and stimulated plasma cortisol (r = -0.40, P = 0.01). Of the 43 patients, 31 patients (72%) were responders, and 12 patients (28%) were non-responders to the low-dose synacthen test. Non-responders had significantly higher IL-6 levels compared to responders (76.6 vs 37.3 pg/ml, P = 0.01). Overall, 18 patients died and 25 patients survived to hospital discharge. Non-survivors had significantly lower baseline (15.1 ± 2.9 vs 18.0 ± 4.5 μg/dl, P = 0.02) and stimulated (19.1 ± 3.3 vs 23.0 ± 5.6, P = 0.01) cortisol levels compared to survivors. In conclusion, patients with protracted critical illness may have an altered adrenal responsiveness to stimulation by ACTH. This finding is in part explained by an increase in the production of IL-6 and carries a poor prognosis.

The neuroendocrine response to stress is a dynamic process.

The initial neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function, the peripheral anabolic pathways being inactivated. This response presumably provides metabolic substrates, establishes the host's defences and is thus considered to be adaptive and beneficial. It was previously assumed that the acute stress response persisted throughout the course of critical illness, but this assumption has now been disproved. Indeed, a uniformly reduced pulsatile secretion of growth hormone, thyroid-stimulating hormone, prolactin and luteinizing hormone has been observed in protracted critical illness, impairing the function of target organs. A reduced availability of thyrotropin-releasing hormone, gonadotropin-releasing hormone, the endogenous ligand of the growth hormone-releasing peptide receptor (possibly ghrelin) and, in very long-stay critically ill men, also growth hormone-releasing hormone seems to be involved. The pulsatile secretion of growth hormone, thyroid-stimulating hormone, prolactin and luteinizing hormone can be re-established by relevant combinations of releasing factors, which also substantially increase the circulating levels of insulin-like growth factor-1, growth hormone dependent binding proteins, thyroxine, tri-iodothyronine and testosterone. Active feedback inhibition loops prevent the target organs being overstimulated. The metabolism is altered in a beneficial way when growth hormone-secretagogues, thyrotropin-releasing hormone and gonadotropin-releasing hormone are administered together, whereas the effect of single-hormone treatment is minor and accompanied by side-effects. This new concept of a selectively reduced stimulation of pituitary function in the chronic phase of critical illness unveils new therapeutic perspectives to reverse the paradoxical wasting syndrome' and intensive care dependency.

Management of background pain and anxiety in critically burned children requiring protracted mechanical ventilation.

Optimal control of pain and anxiety is an elusive but important goal in children with protracted critical illness. This review represents an effort to document the doses of background medication required to achieve this goal in a group of children managed under a pain and anxiety protocol that adjusts background infusions to comfort. The course of children with wounds involving at least 10% of the body surface and coincident respiratory failure requiring mechanical ventilation for more than 7 days managed 1 Jan 97 to 31 Dec 98 was reviewed. A pain and anxiety protocol was used, including background infusions of morphine and midazolam adjusted to comfort. These 28 children had a mean (+/- standard deviation) age of 5.3 +/- 4.6 years, wound size of 48.3 +/- 28.4%, and were intubated for 25.0 +/- 23.9 days. Neuromuscular blocking drugs were administered for 65 of 447 (14.5%) ventilator days. To maintain comfort, drugs were required at doses substantially above standard dosing schemes. The highest daily background infusion of morphine sulfate averaged 0.40 mg/kg/hr +/- 0.24 mg/kg/hr (usual starting dose was 0.05 to 0.1 mg/kg/hr) and was reached 14.1 +/- 12.8 days after admission. The highest daily background infusion of midazolam averaged 0.15 +/- 0.07 mg/kg/hr (usual starting dose was 0.04 mg/kg/hr) and was reached 14.0 +/- 3.8 days after admission. Morphine infusions at extubation averaged 0.22 +/- 0.17 mg/kg/hr and midazolam infusions 0.10 +/- 0.12 mg/kg/hr. All children survived to discharge and there was no perceived morbidity related to these high doses of medication. Children with serious burns and respiratory failure will require high doses of background opiates and benzodiazepines to remain comfortable, because they develop drug tolerance during protracted critical illness. Infusions can be continued at a reduced dose through extubation, do not result in addiction or other apparent morbidity if adjusted to desired level of comfort, and may contribute to a reduced incidence of treatment-related stress disorders.

Novel insights into the neuroendocrinology of critical illness.

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically accrued. This 'wasting syndrome' often persists after the underlying disease has been resolved and thus perpetuates intensive care dependency. Although the crucial role of an intact hypothalamus-pituitary axis for homeostasis during stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recently described. Novel insights in this area are reviewed here. The initial endocrine stress response consists primarily of a peripheral inactivation of anabolic pathways while pituitary activity is essentially amplified or maintained. These responses presumably provide the metabolic substrates and host defense required for survival and to delay anabolism, and thus should be considered as adaptive and beneficial. Persistence of this acute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been observed in protracted critical illness, causing diminished stimulation of several target organs. Impaired pulsatile secretion of anterior pituitary hormones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing factors evoked immediate and pronounced pituitary hormone release. A reduced availability of TRH, one of the endogenous ligands of the GH-releasing peptide (GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay critically ill men, also of GHRH, appear to be involved. This hypothesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of GH, TSH and PRL was re-amplified by relevant combinations of releasing factors which also substantially increased circulating levels of IGF-I, GH-dependent binding proteins, thyroxine and tri-iodothyronine (T3) while avoiding a rise in reverse T3. Active feedback-inhibition loops prevented overstimulation of target organs and metabolic improvement was noted with the combined infusion of GHRP and TRH. Whether this novel endocrine strategy will also enhance clinical recovery from critical illness remains to be explored.

A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness

A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness

Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness

Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness

Leptin Levels in Protracted Critical Illness: Effects of Growth Hormone-Secretagogues and Thyrotropin-Releasing Hormone

Leptin Levels in Protracted Critical Illness: Effects of Growth Hormone-Secretagogues and Thyrotropin-Releasing Hormone

Leptin levels in protracted critical illness: Effects of GH-secretagogues and TRH

Leptin levels in protracted critical illness: Effects of GH-secretagogues and TRH