Growth Hormone in Critical Illness:
Randomized Control Trials
Endocrinology RoundsSeptember 2, 2009
Selina LiuPGY4 Endocrinology
Outline
Background Growth Hormone
Potential Benefits during Critical Illness
Clinical Trials Non-Critical Illness
Critical Illness
Summary
Background
Growth Hormone (GH)
191 amino acid, 22 kd peptide hormone
produced in somatotroph cells of anterior pituitary
Background
Growth Hormone Secretion
secreted in pulsatile patternhealthy adult ~10 pulses/day, longest
~1h after sleep onset
reflects interplay between:
growth hormone releasing hormone (GHRH)somatocrinin
growth hormone release-inhibiting factor, or somatotropin release-inhibiting factor (SRIF)
somatostatin
also affected by physiological factors
Background
physiological factors – can be stimulatory or inhibitory
stimulatory: deep sleep hypoglycemia or fasting
stress
exercise periods of rapid growth (i.e. puberty)
high protein/increased a.a. (especially arginine)
inhibitory: hyperglycemia obesity
advanced age
Background
Background
Growth Hormone Effects
“somatomedin hypothesis” GH exerts effects via IGF (insulin-like growth factor) peptide family
also has effects independent of IGF
multiple sites of action, effects
often unclear which are IGF-dependent vs. independent
Background
Growth Hormone Effects
increased lipolysis & lipid oxidation mobilization of stored
triglyceride
stimulation of a.a. transport (heart, diaphragm), enhancement of protein synthesis (liver)
stimulation of epiphyseal growth, osteoclast, osteoblast activity
antagonism of insulin action
phosphate, water, sodium retention
Background
GH binds to GH receptor (mainly in liver) GH receptor – member of cytokine receptor superfamily
activates JAK/STAT intracellular signalling pathway
JAK (Janus kinases), STAT (signal transducing activators of transcription)
main action: stimulate hepatic IGF-1 synthesis & secretion
Background
Proposed Benefits of GH in Critical Illness:
anabolic properties - protein sparing during hypercatabolism, improved nitrogen balance
improvement of acquired GH resistance
improvement of apparent GH deficiency in prolonged critical illness
related to concept of biphasic GH response
Clinical Trials – Non-Critical Illness studies in stable surgical, burn, trauma patients, and patients on parenteral nutrition
benefits of GH treatment: nitrogen retention
increased IGF-1 levels
decreased duration of mechanical ventilation, hospital length of stay
improved survival reviewed in Taylor BE & Buchman TG. Curr Opin Crit Care 2008;14:438-444
Clinical Trials – Non-Critical Illness effect of GH with hypocaloric nutritional support on relative nitrogen and protein conservation
48 post-op elective abdominal surgery patients
randomized, prospective, double-blind, placebo-controlled
rhGH 0.15 IU/kg daily vs. placebo x 7 days post-op
significant improvement in cumulative nitrogen balance in GH group vs. placebo
also blood glucose
Zhang MM et al. World Journal of Gastroenterology 2007;13:452-456
Clinical Trials - Critical Illness severe sepsis/septic shock
20 ICU patients, randomized placebo-controlled - recombinant GH 0.1mg/kg/d IV infusion vs.
placebo for 3d - GH IGF-1, nitrogen production, improved nitrogen balance- effect did not
persist once GH infusion stopped
Voerman HJ et al. Ann Surg 1992;216:648-655
non-septic ICU patients
18 ICU patients, randomized placebo-controlled- recombinant GH 0.1mg/kg/d IV infusion vs.
placebo for 3d - GH normalized IGF-1, persisted after GH infusion stopped - transient improvement in nitrogen balanceVoerman BJ et al. Crit Care Med 1995;23:665-73
Clinical Trials - Critical Illness
New England Journal of Medicine 1999;341:785-792
Takala J et al. N Engl J Med 1999;341:785-792
Objective:
examine effect of high dose GH on clinical outcomes in critically ill adults receiving prolonged intensive care
Design:
2 parallel prospective multicentre double-blind, randomized placebo-controlled trials
“similar” but not identical protocols
Takala J et al. N Engl J Med 1999;341:785-792
Finnish study:
247 patients from 6 hospitals in Finland
Feb 1994 – June 1997
Multinational study:
285 patients from 12 hospitals in UK, Netherlands, Belgium & Sweden
June 1994 – June 1997
Takala J et al. N Engl J Med 1999;341:785-792
Inclusion criteria:
age 18 – 80 yrs
in ICU for 5-7 days, expected to require ICU for total of at least 10 days
1 of 4 diagnostic groups (1o reason for
admission to ICU)
cardiac surgery, abdominal surgery, multiple trauma, acute respiratory failure
Takala J et al. N Engl J Med 1999;341:785-792
Exclusion criteria:
cancer, Type 1 DM, CKD, burns, organ transplant, acute CNS damage, liver dysfunction, septic shock, on glucocorticoid treatment
Takala J et al. N Engl J Med 1999;341:785-792
Treatment:
recombinant GH vs. placebo (saline) sc daily in am
weight-based GH dosing
< 60 kg = 5.3 mg GH daily > 60 kg = 8.0 mg GH
daily
(range 0.07-0.13 mg/kg body wt/dayfor patients between 40-
120 kg)
Takala J et al. N Engl J Med 1999;341:785-792
Dosing:
Finnish study – dose titrated up from initial dose (1/4 of final dose) to full dose over 3 days
Multinational study – full dose given initially
GH or placebo given for as long as patients were in ICU, but no longer than 21 days
except in multinational study – could be continued on discharge from ICU to floor to a maximum 21 d
Takala J et al. N Engl J Med 1999;341:785-792
Energy intake:
Finnish study – “intended to be equivalent to 80-120% of measured energy expenditure”
Multinational study – based on clinical evaluation
Nitrogen intake:
Finnish study – 1.5 g protein/kg/day
Multinational study – 0.7-1.5 g protein/kg/day
Takala J et al. N Engl J Med 1999;341:785-792 Primary Outcome: duration of ICU stay
Secondary Outcomes: use of ICU resources (as per TISS)
duration of mechanical ventilation, hospital stay
hand grip strength (dynamometer)
level of general fatiuge (fatigue scale)
exercise tolerance (ability to stand/walk, 6 categories)
incidence/clinical course of organ failure (scoring system)
in-hospital mortality (and survival at 6 months, if possible)
Takala J et al. N Engl J Med 1999;341:785-792
other measures:
severity of illness (APACHE II) – on entry, at 24 h
IGF-1, IGF-BP1, IGF-BP3
at baseline, days 4, 7, 14, 21
cause of death (2 independent clinicians)
Takala J et al. N Engl J Med 1999;341:785-792** study design changed before 1st interim analysis due to slow recruitment
previously designed as group sequential trials
1st analysis to be performed when 150 patients received GH or placebo for at least 3d, and survived for at least 2d post-ICU discharge
subsequent analyses after each group of 40 additional patients had completed study, up to max 436 patients
revised to fixed-sample analysis (170 and 190 pts)
intention-to-treat analysis
Takala J et al. N Engl J Med 1999;341:785-792
Takala J et al. N Engl J Med 1999;341:785-792
Takala J et al. N Engl J Med 1999;341:785-792
Difference in mortality persisted at 6 monthsFinnish study: 43% GH vs 23% placebo
Multinational study: 52% GH vs. 25% placebo
Takala J et al. N Engl J Med 1999;341:785-792
Finnish Study
Multinational Study
50% of excess deaths in first
10 d of treatment, rest after GH had
stopped (>21d)
Most of excess
deaths in first 10 d of treatment
Takala J et al. N Engl J Med 1999;341:785-792
Takala J et al. N Engl J Med 1999;341:785-792
No difference in mean daily insulin dose
between survivors and non-survivors
IGF-1 increased to greater extent in GH group than
in placebo.IGF-1 increased in
response to GH more frequently in survivors vs.
nonsurvivors
Baseline IGF-1, IGF-BP1, IGF-BP3 levels similar between groups in
Multinational Study.In Finnish Study, baseline IGF-1 and
IGF-BP3 lower, baseline IGF-BP1 higher in GH group
Nitrogen balance better in GH group (only assessed in Finnish Study) on
days 7, 14, 21
Takala J et al. N Engl J Med 1999;341:785-792
No significant differences in overall frequency of adverse events between groups (both studies)
Increased metabolic/nutritional adverse events in GH vs. placebo – mainly hyperglycemia 71% GH vs 60% placebo (Finnish)
58% GH vs 36% placebo (multinational)
Increased sepsis in GH vs. placebo 13% GH vs 8% placebo (Finnish)
18% GH vs 10% placebo (multinational)
Takala J et al. N Engl J Med 1999;341:785-792
Conclusion:
High dose GH treatment in critically ill patients receiving prolonged intensive care was associated with increased morbidity and mortality
Takala J et al. N Engl J Med 1999;341:785-792
Timing of deaths in 2 studies Difference related to dosing?
(full dose initially in Multinational Study vs. dose titration in Finnish Study)
Mortality rate in placebo group lower than expected (both studies) – related to exclusion criteria ?
Takala J et al. N Engl J Med 1999;341:785-792
Reasons for increased morbidity/mortality in GH group
Modulation of immune function?
Hyperglycemia/insulin resistance?
Prevention of glutamine mobilization?
Stimulation of lipolysis?
Interference with thyroid/adrenal function?
Takala J et al. N Engl J Med 1999;341:785-792
Likely multifactorial
Related to:
Timing
Underlying condition
Dose of GH
Clinical Trials – Critical Illness
Growth Hormone & IGF Research 2008;18:82-87
Duska F et al. Growth Horm IGF Res 2008
Objective:
examine effect of frequent low-dose pulsatile GH treatment with alanylglutamine on IGF-1, glucose, and glutamine levels in multiple trauma patients
Design:
prospective single centre double-blind, randomized placebo-controlled trial with open-label control group
Duska F et al. Growth Horm IGF Res 2008 Inclusion criteria:
multiple trauma patients
expected to require 14 days mechanical ventilation after randomization day 4 post-trauma
Exclusion criteria:
women with hCG > 5 on admission, autoimmune disorders, DM, glucocorticoid treatment in other than substitution doses, age <18 yrs, hypothalamic involvement on CT, DI
Duska F et al. Growth Horm IGF Res 2008
randomized to:
Group 1 – GH (0.05 mg/kg/d IV) and alanylglutamine
Group 2 – placebo and alanylglutamine
Group 3 – isocaloric, isonitrogenous nutrition without glutamine supplementation
GH treatment – IV pulses day 7-17th post injury dilution: 1 ml = 2 mcg/kg body weight GH
alanylglutamine – 0.3g/kg/d continuous IV day 4-17
Duska F et al. Growth Hormone & IGF Research 2008;18:82-87
Duska F et al. Growth Horm IGF Res 2008 Nutrition:
all groups – received 80% of energy expenditure
measured previous day by indirect calorimetry
1.5g/kg body weight amino acids
groups 1 & 2: 1.2g/kg plus 0.3g/kg alanylglutamine
preferably enteral route, but could be supplemented parenterally if needed
IV insulin protocol for hyperglycemia
Duska F et al. Growth Hormone & IGF Research 2008;18:82-87
Duska F et al. Growth Hormone & IGF Research 2008;18:82-87
Over 17 days, IGF-1 level increased in group 1, decreased in group 2, and remained stable in
group 3
IGF-BP1 level decreased in group 1(nonsignficant increase in IGF-BP3 in group 1)
Duska F et al. Growth Hormone & IGF Research 2008;18:82-87
No significant change in glutamine levels with time, in any
of the groups
Duska F et al. Growth Horm IGF Res 2008
Results:
GH treatment increased IGF-1 and IGF-BP3, and decreased IGF-BP1, as compared to placebo or control
No change in glutamine levels seen between groups
GH group had higher blood glucose levels, required more insulin
Duska F et al. Growth Horm IGF Res 2008
Conclusions:
low dose (0.05 mg/kg/day) GH given in intermittent IV pulses was able to normalize IGF-1 levels in multiple trauma patients in the intensive care unit
Clinical Trials – Critical Illness
Crit Care Med 2008;36:1707-1713
Duska F et al. Crit Care Med 2008
intermittent IV pulses of GH IV:
improved nitrogen balance
daily saving of 300 g lean body mass
worsened insulin sensitivity
no change in lipid oxidation
no difference in morbidity, mortality, 6 month outcome
Summary – RCTs of GH in Critical Illness
Voerman et al. Ann Surg 1992, Crit Care Med 1995
IV infusion GH - ? transient effects on nitrogen balance
Takala et al. N Engl J Med 1999 increased morbidity and mortality with high dose daily sc GH
Duska et al. Growth Horm IGF Res, Crit Care Med 2008
low-dose IV pulse GH normalized IGF-1 levels
but – hyperglycemia, insulin resistance
Summary – RCTs of GH in Critical Illness
role of GH in critical illness?
? Acquired deficiency vs. resistance
effect of:
timing
dose
route of administration
underlying patient condition
Outline
Background Growth Hormone
Potential Benefits during Critical Illness
Clinical Trials Non-Critical Illness
Critical Illness
Summary
References
Takala J et al. N Engl J Med 1999;341:785-792 Taylor BE & Buchman TG Curr Opin Crit Care 2008;14:438-444 Zhang MM et al. World J Gastroenterol 2007;13:452-456 Duska F et al. Growth Horm IGF Res 2008;18:82-87 Duska F et al. Crit Care Med 2008;36:1707-1713 Voerman HJ et al. Ann Surg 1992;216:648-655 Voerman BJ et al. Crit Care Med 1995;23:665-73 www.uptodate.com Kronenberg HM et al. Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.
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