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.