1. Growth Hormone in Critical Illness: Randomized Control Trials Endocrinology Rounds September 2, 2009 Selina Liu PGY4 Endocrinology

2. Outline  Background  Growth Hormone  Potential Benefits during Critical Illness  Clinical Trials  Non-Critical Illness  Critical Illness  Summary

3. Background  Growth Hormone (GH)  191 amino acid, 22 kd peptide hormone  produced in somatotroph cells of anterior pituitary

4. Background  Growth Hormone Secretion  secreted in pulsatile pattern healthy 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

5. 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

6. Background

7.  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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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 balance Voerman BJ et al. Crit Care Med 1995;23:665-73

14. Clinical Trials - Critical Illness New England Journal of Medicine 1999;341:785-792

15. 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

16. 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

17. 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 (1 o reason for admission to ICU)  cardiac surgery, abdominal surgery, multiple trauma, acute respiratory failure

18. 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

19. 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 = 8.0 mg GH daily (range 0.07-0.13 mg/kg body wt/day for patients between 40-120 kg)

20. 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

21. 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

22. 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)

23. 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)

24. Takala J et al. N Engl J Med 1999;341:785-792 ** study design changed before 1 st interim analysis due to slow recruitment  previously designed as group sequential trials  1 st 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

25. Takala J et al. N Engl J Med 1999;341:785-792

27. Difference in mortality persisted at 6 months Finnish study: 43% GH vs 23% placebo Multinational study: 52% GH vs. 25% placebo

28. 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

29. Takala J et al. N Engl J Med 1999;341:785-792

30. 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

31. 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)

32. 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

33. 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 ?

34. 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?

35. Takala J et al. N Engl J Med 1999;341:785-792  Likely multifactorial  Related to:  Timing  Underlying condition  Dose of GH

36. Clinical Trials – Critical Illness Growth Hormone & IGF Research 2008;18:82-87

37. 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

38. 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

39. 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 7-17 th post injury dilution: 1 ml = 2 mcg/kg body weight GH  alanylglutamine – 0.3g/kg/d continuous IV day 4-17

40. Duska F et al. Growth Hormone & IGF Research 2008;18:82-87

41. 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

42. Duska F et al. Growth Hormone & IGF Research 2008;18:82-87

43. 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)

44. 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

45. 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

46. 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

47. Clinical Trials – Critical Illness Crit Care Med 2008;36:1707-1713

48. 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

49. 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

50. 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

51. Outline  Background  Growth Hormone  Potential Benefits during Critical Illness  Clinical Trials  Non-Critical Illness  Critical Illness  Summary

52. 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.comwww.uptodate.com  Kronenberg HM et al. Williams Textbook of Endocrinology. 11 th edition. 2008 Saunders Elsevier.