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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 590-599
Copyright © 1997 by The Endocrine Society

Clinical Studies

The Somatotropic Axis in Critical Illness: Effect of Continuous Growth Hormone (GH)-Releasing Hormone and GH-Releasing Peptide-2 Infusion1

Greet Van den Berghe2, Francis de Zegher, Johannes D. Veldhuis, Pieter Wouters, Mariet Awouters, Werner Verbruggen, Miet Schetz, Charles Verwaest, Peter Lauwers, Roger Bouillon and Cyril Y. Bowers

Departments of Intensive Care Medicine (G.V.d.B., P.W., M.A., W.V., M.S., C.V., P.L.), Pediatrics (F.d.Z.), and Medicine, Division of Endocrinology (R.B.), University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; the Department of Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 29908; and the Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Dr. Greet Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Prolonged critical illness is characterized by protein hypercatabolism and preservation of fat depots, associated with blunted GH secretion, elevated serum cortisol levels, and low insulin-like growth factor I (IGF-I) concentrations. In this condition, GH is readily released in response to a bolus of GHRH and GH-releasing peptide-2 (GHRP-2) and, paradoxically, to TRH. We further explored the altered somatotropic axis and cortisol secretion in critical illness by examining the effects of continuous GHRH and/or GHRP-2 infusion.

Twenty-six critically ill adults (mean age ± SEM, 63 ± 2 yr) were studied during 2 consecutive nights (2100–0600 h). According to a weighed randomization, they received one of four combinations of infusions within a randomized cross-over design for each combination: placebo (one night) and GHRP-2 (the other night; n = 10), placebo and GHRH (n = 4), GHRH and GHRP-2 (n = 6), and GHRP-2 and GHRH plus GHRP-2 (n = 6). The peptide infusions (duration, 21 h) were started after a bolus of 1 µg/kg at 0900 h and infused (1 µg/kg/h) until 0600 h. Serum concentrations of GH were determined every 20 min, cortisol every hour, and IGF-I at 2100 and 0600 h on each study night.

The placebo profiles showed pulsatile GH secretion with low secretory burst amplitude [0.062 ± 0.008 µg/L distribution volume (Lv)/min], high burst frequency (6.6 ± 0.4 events/9 h), and detectable basal secretion (0.041 ± 0.009 µg/Lv/min) in the face of low serum IGF-I (106 ± 11 µg/L). IGF-I correlated positively and significantly with the basal component, the pulsatile component, and the total amount of nightly GH secretion.

GHRH elicited a 2- to 3-fold increase in the mean GH concentration (P = 0.006), the GH secretory burst amplitude (P = 0.007), and basal GH secretion (P = 0.03). GHRP-2 provoked a 4- to 6-fold increase in the mean GH concentration (P < 0.0001), the GH secretory burst amplitude (P = 0.002), and basal GH secretion (P = 0.0007), which were associated with a 61 ± 13% increase in serum IGF-I within 24 h (P = 0.02). Compared to GHRP-2 alone, GHRH plus GHRP-2 elicited a further 2-fold increase in the mean GH concentration (P = 0.04) and GH basal secretion (P = 0.02), and an additional 40 ± 6% rise in serum IGF-I (P = 0.04). GHRH and GHRP-2 infusion did not alter elevated cortisol levels.

In critically ill adults, low serum IGF-I levels were positively correlated with diminished pulsatile and increased basal GH secretion. Both basal and pulsatile GH secretion were moderately increased by continuous infusion of GHRH, substantially increased by GHRP-2, and strikingly increased by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elicited a robust rise in circulating IGF-I levels within 24 h without altering serum cortisol levels. These findings open perspectives for GH secretagogues as potential antagonists of the catabolic state in critical care medicine.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INTRAVENOUS or enteral nutrition of patients with prolonged critical illness has been shown to preserve or even enhance fat stores, but appears unable to prevent or reverse protein hypercatabolism (1, 2). The ensuing wasting and malfunctioning of muscles and vital organ systems as well as deficient healing processes prolong the stay in the intensive care unit (ICU). Currently, the potential of exogenous GH to reverse this wasting syndrome is being investigated (3, 4, 5, 6, 7, 8, 9), but the potential of increasing endogenous GH secretion has hitherto not been explored in critical care medicine.

Normal pulsatile GH secretion is thought to depend on at least two hypothalamic regulatory factors, GHRH and SRIH, acting in concert on the somatotropes, and on several neural and hormonal feedback networks that affect pituitary GH synthesis and/or release, either directly or indirectly (10). This complex interaction results in a volleyed burst-like pattern, with intravolley peaks proposed to reflect GHRH bursts during nadirs of SRIH secretion (11).

During critical illness, GH secretion is characterized by reduced pulse amplitude and sometimes by elevated interpulse levels, and is associated with low circulating insulin-like growth factor I (IGF-I) (12, 13, 14). Low levels of circulating IGF-binding protein (IGFBP)-3 and normal or high levels of IGFBP-1 have also been reported (15, 16, 17). The blunted GH secretory pattern appears during prolonged critical illness in the presence of a GH response to GHRH, a paradoxical GH response to TRH, and an exaggerated GH response to GH-releasing peptide-2 (GHRP-2) (18, 19).

The GHRPs are a family of small synthetic peptides acting at the pituitary and the hypothalamus to release GH through activation of a specific, G protein-coupled receptor that has recently been cloned (20, 21, 22, 23, 24). Clinically, the most potent is the hexapeptide GHRP-2 (D-Ala-D-ßNal-Ala-Trp-D-Phe-Lys-NH2) (21, 22, 23, 24). Although the exact mechanism of action of these peptides has not been conclusively elucidated, they seem to act in concert with GHRH, perhaps in part as functional SRIH antagonists (21, 23, 25, 26). In the absence of GHRH, GHRP activity is substantially reduced; in combination with GHRH, the GH response is additive or synergistic in healthy adults (23, 24, 27, 28). Although the receptor for the GHRPs and their analogs has been localized in the hypothalamus and pituitary (20), the endogenous GHRP-like ligand and a postulated hypothalamic U factor (unknown factor) by which GHRPs may affect GH release have hitherto not been identified.

In the current dynamic study, we have further investigated the altered GH secretion during prolonged critical illness and examined the effects of continuous infusion of GHRH and/or GHRP-2 on GH and cortisol secretion in this condition of chronic severe stress.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and concomitant treatment

Patients admitted to the ICU from November 1995 until February 1996 were eligible for participation in this study. Inclusion criteria were intensive care dependency (including mechanical ventilatory support) for at least 1 week, a stable condition without dopamine treatment for at least 48 h (29), together with an expected stay in the ICU for at least another 48 h. Exclusion criteria were age less than 18 yr; preexisting neurological, psychiatric, metabolic, or endocrine disease; intracranial lesions; important liver failure (prothrombin time, <20%); renal failure requiring replacement therapy; and concomitant treatment with glucocorticoids, estrogens, SRIH, thyroid hormones, Ca2+ reentry blockers, clonidine, or dopamine antagonists.

A total of 26 patients (4 women and 22 men) were included (Table 1Go). The mean ± SEM age was 63 ± 2 yr (range, 31–79 yr). The body mass index (BMI) on ICU admission was 26.5 ± 0.9 kg/m2 (range, 17.3–35.5 kg/m2). The Apache II score on the ICU admission day, an indicator of the severity of illness (30), was 17.4 ± 1.1 (range, 7–33).


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  		Table 1. Clinical patient data

 
Patients were critically ill for 18 ± 1 (range, 7–35) days at the time of inclusion in the study. Concomitant treatment included continuous total (n = 17) or partial (n = 5) parenteral nutrition or full enteral feeding (n = 4), with normal caloric intake (a mean of 25 nonprotein Cal/kg/day; range, 16–35 Cal/kg/day) and standard composition (0.8–1.6 g/kg amino acids/day; 2.8–4.3 g/kg glucose/day; 1–1.5 g/kg fat/day covering 25–40% of nonprotein calories) (31); inotropic support with exogenous nondopaminergic catecholamines (n = 14); antibiotics (n = 24); analgesia and sedation with continuously infused opioids (n = 19) and/or benzodiazepines (n = 17); and nonsteroidal antiinflammatory agents (n = 3). Plasma glucose levels were monitored; exogenous insulin was infused when necessary in an attempt to keep the plasma glucose level at 12 mmol/L or less (n = 14) (32). The mean plasma glucose level was elevated at the beginning of the study (8.1 ± 0.4 mmol/L; range, 5.2–14.9). Human albumin was continuously infused when serum levels were low (mean serum albumin concentration at inclusion, 2.9 ± 0.1 g/dL). The mean serum triglyceride level was 188 ± 15 mg/dL (range, 75–429 mg/dL), and the mean C-reactive protein concentration was elevated (14 ± 1.1 mg/dL). Continuous hemodynamic monitoring included electrocardiogram (n = 26), intraarterial blood pressure (n = 26), central venous pressure (n = 26), pulmonary artery pressure (n = 6), and core and peripheral temperatures (n = 26). During the 45-h study period, concomitant ICU therapy remained virtually unaltered in all patients.

The mean total ICU stay was 41 ± 4 (range, 16–107) days. Six patients ultimately died while in the ICU (23%), one patient was discharged from the ICU but died in the hospital, and 73% (19 of 26) of the patients were discharged to the ward, consecutively left the hospital, and are known to be alive 2–6 months after study entry.

Study design and peptide administration (Fig. 1Go)

Patients were studied during a total period of 45 h, with sampling every 20 min during 2 consecutive nights from 2100–0600 h, and received one study compound per night.



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  		Figure 1. Upper panel, Twenty-six patients were allocated by weighed randomization into one of four groups: group 1, placebo vs. GHRH infusion (n = 4); group 2, placebo vs. GHRP-2 infusion (n = 10); group 3, GHRH infusion vs. GHRP-2 infusion (n = 6); and group 4, GHRP-2 infusion vs. GHRH plus GHRP-2 infusion (n = 6). Lower panel, Within these four groups, patients were randomized for the order of peptide infusion into two cross-over subgroups. The duration of each in-fusion was 21 h. Patients were studied during a total period of 45 h, with sampling every 20 min during 2 consecutive nights from 2100–0600 h.

 
The subjects were allocated by weighed randomization to one of four study groups (Fig. 1Go, upper panel): group 1 (n = 4) received placebo vs. GHRH infusion (1 µg/kg bolus at 0900 h, followed by a 1 µg/kg/h continuous infusion until 0600 h) (33), group 2 (n = 10) received placebo vs. GHRP-2 infusion (1 µg/kg bolus at 0900 h, followed by a 1 µg/kg/h continuous infusion until 0600 h) (34), group 3 (n = 6) received GHRH infusion vs. GHRP-2 infusion, and group 4 (n = 6) received GHRP-2 infusion vs. GHRH plus GHRP-2 infusion (1 and 1 µg/kg bolus at 0900 h, followed by a 1 and 1 µg/kg/h continuous infusion until 0600 h). Within these four groups (Fig. 1Go, lower panel), patients were randomized for the order of peptide infusion. The duration of each infusion was 21 h. This randomized cross-over design was applied to minimize possible interference by order of peptide administration or by spontaneous recovery.

By scheduling a GHRP-2 infusion in all patients of groups 2, 3, and 4, the responses to placebo, GHRH, and GHRH plus GHRP-2 could each be compared in a paired fashion to the response to GHRP-2 from the same patient. Therefore, the necessity of administering all four trial drugs in every subject was avoided as were potential difficulties due to the known interindividual variability in the responses of critically ill patients (19).

Placebo (0.9% NaCl), GHRP-2 (50 µg/mL 0.9% NaCl), and/or human GHRH (50 µg/mL 0.9% NaCl; Ferring, Kiel, Germany) infusions were given through a separate lumen of a central venous catheter, inserted for clinical purposes. A PERFUSOR Secura FT pump with a 50-mL PERFUSOR syringe (B. Braun, Melsungen, Germany) permitted precise infusions of small volumes at a constant rate. Inadvertent interruption of the infusion or unanticipated bolus injections of the peptides were thus avoided.

Serum GH concentrations were measured in each sample, serum cortisol concentrations were determined every hour, and serum IGF-I levels were determined in the first and the last sample of each night’s profile.

Blood sampling

All blood samples were collected through an arterial line inserted for clinical purposes independently of this study. The Edwards VAMP system (Baxter Healthcare Corp., Irvine, CA) was used, permitting withdrawal of undiluted blood samples from an indwelling catheter without undue blood loss. The total amount of blood sampled per session was 140 mL. Blood was collected into glass tubes; after clotting and centrifugation, the serum was kept frozen at -20 C until assay.

Assays

All samples of each patient were processed in the same assay run and assayed in duplicate. The serum concentrations of GH in all profiles were measured by RIA, using a polyclonal antibody (35). The intraassay coefficient of variation was 7.3% at 6.7 µg/L and 4.6% at 14.4 µg/L. The detection limit was 1.1 µg/L.

When a GH value within a GH series reached this detection limit, both complete night profiles of the patient concerned were reassayed with a more sensitive immunoradiometric assay (IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA). The detection limit of this IRMA was 0.2 µg/L; the intraassay coefficient of variation was 4.2%. GH concentrations were detectable in all samples. In this way, all GH concentrations that were used for statistical comparison were measured by the same assay.

The regression equation for comparison of both assays was: Nichols IRMA = -0.38 + 0.83 x RIA, with a regression coefficient of 0.83 and a correlation coefficient (r) of 0.93 (r2 = 0.87; n = 218; P < 0.0001).

The plasma concentrations of total IGF-I were measured by RIA after acid-ethanol extraction. The intraassay coefficient of variation was 10.8% at 218 µg/L. The interassay coefficient of variation was 7.6% at 172 µg/L. The detection limit was 10 µg/L. The normal range in healthy adults is 100–300 µg/L.

The serum concentrations of cortisol were measured by RIA after extraction with dichloromethane. The intraassay coefficient of variation was 3.1% at 417 nmol/L. Normal ranges are 276–607 nmol/L at 0800 h, 0–276 nmol/L at 2000 h, and below 50 nmol/L at midnight if asleep.

Data analysis

The sequential serum GH concentrations measured in each profile were transformed into pituitary secretion profiles by eliminating the effect of metabolic clearance, using multiple parameter deconvolution analysis. This method, which was extensively described previously, is designed to compute GH half-life and the number, amplitude, and mass of underlying pituitary secretory GH bursts and to estimate tonic (basal) secretion (36).

The individual GH half-life was determined on each study night and averaged per patient for application to the total data series, which was appropriate, as they were not significantly different between the 2 study nights.

Besides mean serum GH concentrations, the following parameters were calculated for each subject: basal secretion rate [estimated to achieve serum GH concentrations approximating the mean of the lowest 5% of all GH values observed; micrograms per L distribution volume (Lv)/min], amplitudes (maximal secretory rate; micrograms per Lv/min) and temporal positions of all GH secretory bursts, mass of GH secreted per burst (estimated as the area of the resolved secretion burst; micrograms per Lv), and the mean pulsatile GH production (calculated as the product of the number of secretory bursts and the mean GH secretory burst mass over the time interval considered; micrograms per Lv/9 h).

Cortisol profiles were quantified by determining area under the curve, calculated using the trapezoid rule.

Approximate entropy statistic (ApEn)

ApEn is a model-independent statistic for assessing the regularity of time series (37, 38). ApEn measures a logarithmic likelihood that runs on patterns that are similar and remain similar for the next incremental comparisons. It assigns a single nonnegative number to a time series, with larger values corresponding to greater apparent process randomness. ApEn has been demonstrated to be stable to small changes in noise characteristics, and infrequent and significant artifacts. It detects variations in episodic behavior that are not reflected in changes in peak occurrences or amplitudes. Additionally, ApEn provides a direct barometer of feedback system change in many coupled systems. The calculation of ApEn was performed as previously reported (39). As ApEn will generally increase with increasing process noise (and increasing intraassay variation), it is important to compare data sets with similar assay coefficients of variation, as performed here. To this end, we used a tolerance/threshold for ApEn of 0.2 times the series between-sample SD and a window/range of m = 1 consecutive samples over which to test for pattern reproducibility, as is appropriate for time series of fewer than 150 samples, as studied here.

Data were analyzed using paired and unpaired Student’s t test and by multiple comparisons ANOVA, as appropriate. Nonnormally distributed data were logarithmically transformed before analysis. Results are expressed as the mean ± SEM unless indicated otherwise.

Ethical aspects

The study was approved by the institutional review board of the University of Leuven School of Medicine. Informed consent from a first degree relative was obtained before inclusion in the study.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Within each of the four study groups, the GH and cortisol results of the cross-over subgroups were similar (Fig. 1Go, lower panel); accordingly, cross-over results within each study group were pooled.

The releasing peptides were well tolerated. No side-effects were noted during either of the peptide infusions, apart from an increased glucose intolerance in those patients already receiving exogenous insulin infusion (Table 1Go), which was overcome by increasing the dose of insulin.

Somatotropic axis

GH secretion and correlation with circulating IGF-I. Paired analysis vs. placebo (groups 1 and 2); placebo vs. GHRH infusion (n = 4; Fig. 2Go, upper panel): GHRH infusion increased the mean GH concentration 2-fold (P = 0.006), the basal GH secretion rate 2.5-fold (P = 0.03), the secretory burst mass 3-fold (P = 0.007), the secretory burst amplitude 2.7-fold (P = 0.007), and the mean pulsatile production 2.9-fold (P = 0.03). The number of bursts over this nightly 9 h remained unaltered.



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  		Figure 2. Illustrative serum GH concentration profiles from two critically ill men, aged 57 and 64 yr (sampling every 20 min between 2100–0600 h) are shown; profiles with GHRH infusion (1 µg/kg/h) and GHRP-2 infusion (1 µg/kg/h) are compared to that with placebo. Basal and pulsatile components of GH secretion are moderately increased by GHRH infusion and substantially by GHRP-2, whereas the high GH burst frequency is not altered.

 
GHRH infusion over 21 h did not alter serum IGF-I levels significantly compared to placebo values.

Placebo vs. GHRP-2 infusion (n = 10; Fig. 2Go, lower panel, and Fig. 3Go, left panel): GHRP-2 infusion increased the mean GH concentration 4-fold (P < 0.0001), the basal GH secretion rate 6-fold (P = 0.0007), the secretory burst mass 3.2-fold (P = 0.0001), the secretory burst amplitude 6-fold (P = 0.003), and the mean pulsatile production 3.5-fold (P < 0.0001). The number of bursts remained unaltered.



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  		Figure 3. The IGF-I response to a 21-h infusion is depicted as the relative change in the serum IGF-I concentration (percentage) from 0600 h after the first study night until 0600 h after the second study night. Left panel, GHRP-2 infusion after placebo vs. placebo after GHRP-2 infusion (group 2). *, P < 0.05. Right panel, GHRP-2 after GHRH plus GHRP-2 infusion vs. GHRH plus GHRP-2 after GHRP-2 infusion (group 4). *, P < 0.05.

 
The increase in serum IGF-I level induced by a 21-h infusion of GHRP-2 after placebo treatment (61 ± 13%) was higher than that induced by a 21-h infusion of placebo after GHRP-2 (1.7 ± 8.5%; P = 0.02; Fig. 3Go, left panel). The change in serum IGF-I level between 2100–0600 h was 24 ± 7.6% during GHRP-2 vs. -3 ± 4.7% during placebo (P = 0.03).

Correlation of GH secretory variables with circulating IGF-I (n = 14); placebo infusion (Fig. 4Go, left panel): During placebo treatment, the mean GH concentration was 1.5 ± 0.24 µg/L. The basal secretion rate was 0.041 ± 0.009 µg/Lv/min, the burst frequency was 6.6 ± 0.4 bursts/9 h, the secretory burst amplitude was 0.062 ± 0.008 µg/Lv/min, the secretory burst mass was 3.6 ± 0.6 µg/Lv, and the mean pulsatile production was 17.6 ± 2.1 µg/Lv/9 h. The serum IGF-I concentration was 106 ± 11 µg/L at the end of the infusion.



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  		Figure 4. FIG. 4. During placebo (n = 14), serum IGF-I concentration correlated positively and significantly with the mean GH concentration, basal GH secretion, and GH secretory burst amplitude. During GHRH or GHRP-2 infusion (1 µg/kg/h for 21 h) in the same patients, the increased serum IGF-I concentration still correlated positively with the mean GH concentration.

 
The following secretory variables for GH correlated positively and significantly with serum IGF-I concentration: mean GH concentration (r2 = 0.52; P = 0.0039), basal secretion rate (r2 = 0.28; P = 0.05), mean pulsatile production (r2 = 0.35; P = 0.02), and secretory burst amplitude (r2 = 0.48; P = 0.009). The IGF-I correlations with basal secretion rate, mean pulsatile production, and secretory burst amplitude were independent. Neither of the GH secretory variables correlated with age, body mass index, or severity score (Apache II) on admission.

GHRH and GHRP-2 infusions (Fig. 4Go, right panel): During the infusion of GHRH or GHRP-2, the mean GH concentration was 4.1 ± 0.3 µg/L. The basal secretion rate was 0.101 ± 0.013 µg/Lv/min, the burst frequency was 6.8 ± 0.4 events/9 h, the secretory burst amplitude was 0.279 ± 0.046 µg/Lv/min, the secretory burst mass was 8 ± 0.9 µg/Lv, and the mean pulsatile production was 51 ± 5 µg/Lv/9 h. The serum IGF-I concentration was 127 ± 8.5 µg/L at the end of the infusion.

The mean GH concentration still correlated positively and significantly with the serum IGF-I concentration (r2 = 0.57; P = 0.002), whereas the basal secretion rate, secretory burst amplitude, secretory burst mass, and mean pulsatile production were no longer significantly correlated with serum IGF-I.

Paired analysis vs. GHRP-2 (groups 3 and 4); GHRH vs. GHRP-2 infusion (n = 6; Fig. 5Go, middle panel): Compared to GHRH, GHRP-2 infusion induced an increase of approximately 70% in the mean GH concentration (P = 0.006), basal secretion rate (P = 0.03), and secretory burst amplitude (P = 0.02). The number of bursts, secretory burst mass (P = 0.06), and mean pulsatile production (P = 0.07) were not significantly different.



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  		Figure 5. Serum GH concentration profiles of three critically ill men, aged 56, 62, and 69 yr (sampling every 20 min between 2100–0600 h); profiles with placebo, GHRH infusion (1 µg/kg/h), and GHRH plus GHRP-2 infusion (1 and 1 µg/kg/h) are compared to that with GHRP-2 (1 µg/kg/h). These profiles illustrate that, compared to GHRP-2, GHRH induces lower and GHRH plus GHRP-2 induces higher basal and pulsatile components of GH secretion. GH burst frequency is high in all profiles.

 
Between 2100–0600 h, GHRP-2 infusion induced an increase in serum IGF-I of 15 ± 4% compared to 5.5 ± 2.5% during GHRH treatment (P = 0.02).

GHRH plus GHRP-2 vs. GHRP-2 infusion (n = 6; Fig. 5Go, lower panel): Compared to GHRP-2 treatment, GHRH plus GHRP-2 infusion induced a further 2-fold increase in the mean GH concentration (P = 0.04) and a 2.8-fold increase in the basal secretion rate (P = 0.02). The number of bursts over this nightly 9 h, secretory burst mass (P = 0.4), mean pulsatile production (P = 0.5), and secretory burst amplitude (P = 0.1) were not significantly different.

The changes in serum IGF-I levels between 2100–0600 h during GHRP-2 and GHRH plus GHRP-2 infusions were not significantly different. However, a 21-h infusion of GHRH plus GHRP-2 after an infusion of GHRP-2 alone induced a further increase in serum IGF-I levels of 40 ± 6%, whereas this was limited to 1.4 ± 6% when GHRP-2 was infused alone after a 21-h combined infusion of GHRH plus GHRP-2 (P = 0.04; Fig. 3Go, right panel).

Unpaired analysis of all profiles by ANOVA (Fig. 6): Different infusions resulted in significantly different variables of GH secretion, as derived by deconvolution analysis (all P < 0.0001).

ApEn (Fig. 7Go). In group 1 (n = 4), the difference in mean ApEn scores during placebo and GHRH treatments did not reach significance (0.9 ± 0.075 vs. 1.058 ± 0.04; P = 0.1). In group 2 (n = 10), mean ApEn scores during placebo and GHRP-2 were similar (0.874 ± 0.067 vs. 0.919 ± 0.04; P = 0.4). In group 3 (n = 6), the mean ApEn scores during GHRH were a mean 25% higher than those during GHRP-2 infusion (1.007 ± 0.043 vs. 0.803 ± 0.059; P < 0.05). As placebo and GHRP-2 ApEn scores were similar (see group 2), the results from groups 1 and 3 were pooled to evaluate the effect of GHRH in a larger group (n = 10). GHRH increased the ApEn score by 22% (1.027 ± 0.03 vs. 0.842 ± 0.047; P = 0.009). In group 4 (n = 6), the mean ApEn scores during GHRP-2 and GHRH plus GHRP-2 treatments were similar (0.923 ± 0.021 vs. 0.952 ± 0.14; P = 0.6).



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  		Figure 7. Upper panel, Paired ApEn scores (mean ± SEM) of GH secretory patterns during placebo, GHRH infusion (1 µg/kg/h), GHRP-2 infusion (1 µg/kg/h), or GHRH plus GHRP-2 infusion (1 and 1 µg/kg/h) are presented. Lines interconnect data from the same patients. GHRH infusion increases the ApEn score. *, P < 0.05. Lower panel, To assess the effects of placebo (n = 10), GHRH alone (n = 10), and GHRH plus GHRP-2 (n = 6), the respective differences in ApEn scores compared to their paired reference (see Materials and Methods) were analyzed by ANOVA. This revealed that the effects of placebo, GHRH alone, and GHRH plus GHRP-2 were each distinct. GHRH alone induced a rise in ApEn. This rise was attenuated, but not annihilated, by the addition of GHRP-2. Data are presented as the mean ± SEM. *, P = 0.02.

 
Cortisol

Paired analysis vs. placebo (groups 1 and 2). In group 1, who received placebo and GHRH infusions, respectively, similar mean cortisol levels (483 ± 28 and 441 ± 48 nmol/L; P = 0.4) and nightly integrated cortisol values (76,336 ± 4,663 and 70,870 ± 7,712 nmol/L/min; P = 0.4) were observed.

In group 2, who received placebo and GHRP-2 infusions, respectively, mean cortisol was also similar (470 ± 47 and 493 ± 59 nmol/L; P = 0.6), as was nightly integrated cortisol values (75,602 ± 8,346 and 79,078 ± 10,594 nmol/L/min; P = 0.6).

Paired analysis vs. GHRP-2 (groups 3 and 4). In group 3, who received GHRP-2 and GHRH infusions, respectively, similar mean cortisol levels (358 ± 48 and 333 ± 52 nmol/L; P = 0.2) and nightly integrated cortisol values (57,968 ± 7,793 and 53,608 ± 8,774 nmol/L/min; P = 0.2) were observed.

In group 4, who received GHRP-2 and GHRH plus GHRP-2 infusions, respectively, mean cortisol levels were also similar (370 ± 49 and 357 ± 54 nmol/L; P = 0.5) as were nightly integrated cortisol values (59,751 ± 8,397 and 57,889 ± 8,753 nmol/L/min; P = 0.5).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Prolonged critical illness (requiring intensive support of vital functions for >1 week) is known to be associated with blunted GH secretion and low circulating IGF-I levels despite feeding (14). The blunted GH secretion is now further documented to consist of a high number of small secretory bursts superimposed on basal secretion. The low IGF-I levels were shown to correlate positively with GH secretion via GH secretory burst amplitude and basal GH secretion. This finding indicates that a relatively low pulsatile GH secretion may contribute to the low serum IGF-I levels in the chronic phase of critical illness.

This blunted pattern of pulsatile GH secretion in prolonged critical illness does not appear to be due to a limited pituitary capacity to synthesize GH, as the somatotropes readily release large amounts of GH upon stimulation by an iv bolus of GHRP-2 and even more so in response to the combination of GHRH and GHRP-2 (19). These pronounced GH responses are remarkable, as they appear to overcome a number of normally inhibiting factors such as a nonfasting state; high circulating levels of free fatty acids, glucose, insulin, and cortisol; low testosterone levels in males; and sometimes obesity (1, 40, 41, 42, 43, 44, 45). In critical illness, the GH response to a GHRH bolus is not exaggerated to the same extent, suggesting that if a hypothalamic drive of the somatotropic axis is less available, this deficiency is more likely to include the endogenous GHRP-like ligand rather than GHRH (19). A reduced inhibitory SRIH tone would be expected to enhance the responses to both GHRH and GHRP-2 (19) as well as spontaneous GH secretion.

Continuous infusion of GHRH or GHRP-2 increased pulsatile and basal GH secretion without altering the high burst frequency. The responses to GHRH infusion in the reported patients are lower than those in healthy volunteers, and the responses to GHRP-2 in these patients are pronounced compared to the response to GHRP-6 infusion in volunteers (46, 47, 48). GHRH plus GHRP-2 synergistically increased GH secretion in critical illness, essentially through further amplification of basal secretion.

In view of the high doses of continuously administered GHRH and GHRP-2, our observations suggest that the determining event for pulsatility of GH secretion in this condition is neither endogenous GHRH nor the presumed endogenous GHRP-like ligand, but, rather, an intermittent pituitary sensitivity to either or both of these releasing factors. SRIH is a plausible candidate to serve as the principal pacemaker of pulsatile GH secretion. A reduced SRIH inhibitory action on the somatotropes is thought to be involved in the elevated pulsatile and basal GH secretion during starvation (49, 50). However, in contrast to fasting, critical illness is associated with smaller, not larger, GH secretory bursts. Thus, SRIH may be involved, but it is unlikely that alterations in SRIH secretion explain the complete pattern of GH secretion and responsiveness in prolonged critical illness.

The observed GH-releasing effect of GHRP-2 infusion on basal and pulsatile GH secretion is in line with the previously suggested availability of endogenous GHRH to maintain GH synthesis during critical illness (19, 23). The pathophysiological basis for not secreting stored GH during critical illness, in contrast to starvation, is at present unclear. As GHRPs have been shown to act through a specific, G protein-coupled receptor in the hypothalamus and pituitary (20), the endogenous GHRP-like ligand is thought to play a role in the regulation of GH secretion. The lack of this compound in combination with a reduced SRIH tone would provide an explanation for the described findings.

Circulating substances released as a consequence of the inflammatory response to disease or trauma, e.g. tumor necrosis factor-{alpha} and interleukins, are candidates to play a role in the pathogenesis of altered GH secretory control. However, the circulating levels of these cytokines are low to undetectable in the chronic phase of critical illness (51). Alternatively, adaptive mechanisms within the central nervous system, possibly mediated by endogenous dopamine or serotonin, may modulate the regulation of GH secretion in a condition of chronic stress (29, 52, 53). Finally, it seems unlikely that intensive care procedures such as continuous parenteral feeding explain the current findings, as iv infusion of glucose and fat have been shown to suppress rather than stimulate the responses to GHRPs (41).

The 60–100% rise in serum IGF-I levels induced within 24 h by GHRP-2 or GHRH plus GHRP-2 infusion is pronounced compared to the IGF-I response generated by high doses of daily exogenous GH in critical care conditions (9) and compared to the IGF-I response elicited in healthy adults by infusion of GHRP-6 or oral administration of the long acting nonpeptide GH secretagogue, MK-0677 (47, 48, 54). This observation indicates that critically ill subjects can respond to endogenous GH and that the stimulation of endogenous GH release may be at least as effective as the administration of exogenous GH to reverse the catabolic state of critical illness. The persistent positive correlation of elevated IGF-I levels after stimulated GH secretion with mean GH levels, and not with GH secretory burst amplitude, supports the idea that the pulsatile character of GH secretion becomes less relevant for IGF-I generation once GH concentrations remain continuously in the higher range (55, 56). As cortisol levels are not concomitantly increased by the infusion of these peptides, the present findings open perspectives for infusions of GH secretagogues as potential antagonists of the catabolic state in critical care medicine.

The ApEn score of the GH secretory pattern is an indicator of process irregularity and system feedback control. Healthy women secrete GH with more process irregularity than men (57). Aging, starvation, and acromegaly are other conditions associated with an increased ApEn value and, hence, reduced regularity of GH release (39, 57). The ApEn scores in the ICU patients studied were high, especially in view of the low sampling frequency in the profiles, a factor that reportedly lowers the calculated ApEn values (39). The high basal ApEn score suggests increased process randomness of GH release and was further increased by the continuous infusion of GHRH, an effect that was attenuated by the addition of GHRP-2. A GHRH clamp in healthy male volunteers has also been shown to increase the GH ApEn score (58), suggesting that endogenous GHRH release participates in the maintenance of the regularity of GH secretion.

In conclusion, nightly GH secretion during prolonged critical illness was characterized by a high number of small secretory bursts superimposed on some basal secretion in the presence of low circulating IGF-I levels. Both basal and pulsatile GH secretion were increased moderately by continuous infusion of GHRH, substantially by GHRP-2, and strikingly by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elicited a robust rise in circulating IGF-I levels within 24 h without altering serum cortisol levels. The positive and consistent correlation between serum IGF-I levels and GH secretion in both the basal and the stimulated state indicates that some peripheral responsiveness to endogenous GH is maintained during prolonged critical illness. These observations open perspectives for GH secretagogues as potential antagonists of the catabolic state in critical care medicine.



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  		Figure 6. FIG. 6. Summary of deconvolution-derived variables of GH secretion (n = 52) analyzed by ANOVA for the effect of placebo (n = 4), GHRH infusion (1 µg/kg/h; n = 10), GHRP-2 infusion (1 µg/kg/h; n = 22), and GHRH plus GHRP-2 (1 and 1 µg/kg/h; n = 6). The means and upper limits of 95% confidence intervals are depicted.

 

   Acknowledgments
 
Dr. Mehuys (Ferring, Belgium) is acknowledged for organizing the generous supply of GHRH, and Mr. Jean Hellings (Baxter, Belgium) for providing the Vamp systems. We thank Mrs. Martine Ade, Mrs. Viviane Celis, Mrs. Tina Schreurs, and Mr. Eric Van Herck for expert technical assistance. Mrs. G. A. Reynolds is especially acknowledged for coordinating the collaboration between Leuven and Tulane Universities. We thank the medical and nursing staff of the Intensive Care Unit for their invaluable cooperation.


   Footnotes
 
1 Parts of this work have been presented at the International Congress of Endocrinology, San Francisco, CA, 1996, and at the International Pituitary Congress, San Diego, CA, 1996. This work was supported by research grants from the Belgian Fund for Scientific Research (G.0162.96), the University of Leuven (OT 95/24), and the Belgian Study Group for Pediatric Endocrinology. Back

2 Clinical Research Investigator with the Belgian Fund for Scientific Research (G.3c05.95N). Back

Received August 28, 1996.

Revised October 14, 1996.

Accepted October 18, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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