Erythropoietin & other inflammatory modulator
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Associate Professor Craig French: Erythropoietin & other inflammatory modulators. From CICM ASM PROGRAM 2019. Supported by Donate Life.
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Erythropoietin & other inflammatory modulator
- 1. Erythropoietin and other Hormonal Inflammatory Mediators in Trauma Craig French Director of Intensive Care, Western Health Chair ANZICS CTG
- 2. Disclosures
- 3. Disclosures • Industry Funding – Western Health received payment for the conduct of clinical trials Takeda • Government Funding – NHMRC – MRFF – National Blood Authority • Professional – Chair ANZICS Clinical Trials Group – Australian Red Cross Blood Service • Academic – University of Melbourne – Monash University
- 5. Trauma Global Problem • Trauma 10 percent of global burden of disease • 56 million people were admitted to hospital following trauma • 4.8 million died – Road Injury (29%) Falls (12%) • Transport Injury Global DALY per 100000 population is 1103
- 7. Hormone Therapy In Trauma Patients • Corticosteroids • Sex Steroid Hormones – Progesterone • Erythropoietin
- 9. Corticosteroids • Traumatic Brain Injury (pharmacological) • Spinal Cord Injury (pharmacological) • General Trauma Patients (supraphysiological)
- 11. CRASH
- 19. Corticosteriods
- 20. Sex Hormones
- 21. Sex Hormones
- 22. Progesterone
- 23. Progesterone
- 24. Progesterone
- 25. Progesterone
- 26. Why EPO?
- 28. EPO PREVENTS APOPTOSIS It can also increase the proliferation of erythroid cells and induce the entry of erythroid progenitors into the cycle
- 30. Hypoxia stimulates EPO production
- 31. Brines and Cerami Mol Med 2012
- 32. Brines and Cerami Mol Med 2012
- 34. Mechanism of Action Established Supportive Pre-Clinical Data
- 35. Clinical Studies
- 37. French et al, Annals of Surgery, 2017
- 40. Skrivars et al, J Trauma 2017
- 41. Nine percent absolute increase “Good Outcome” 58% vs 49%
- 42. • Global Problem with high mortality and disability • Strong Basic Science Rationale • Strong Preclinical Evidence • Best data for mortality benefit of any intervention proposed by ANZICS CTG Why another EPO study?
- 43. EPO-TRAUMA
- 44. EPO-TRAUMA • 2500 participants • 90% power 6% ARR in primary outcome • 90% power to detect 4%ARR in six month mortality
- 45. Team EPO • Australia MRFF • Ireland HRB • Finland
Notes de l'éditeur
- Good Morning Thank you to the organising committee for inviting to speak. You will observe the title of my presentation differs a little from the program. In the time available I will present an overview of hormonal inflammatory mediators not all
- While I am a cyclist who aspires to be competitive again I have never used EPO and declined all requests to supply EPO. And yes there have been such requests.
- My disclosures are listed here. I am a chief investigators on NHRMC and MRFF funded research in this area
- Trauma prevention has been incredibly successful over the last two decades. Some of the most impactful initiatives are displayed here. List them. Despite such measures the global burden remains incredibly high
- This article published in 2016 highlights the impact of global trauma. 28 causes of injury, 67 risk factors, 20 age groups, both sexes and 187 countries in 21 world regions from 1990 to 2010.
- Today I will briefly overview the use of these hormonal therapies in trauma patients
- Many parallels regarding the use of steroids in sepsis and in traumatic injury First they may used in pharmacological doses where the effect is to reduce inflammation and oedema Second they have been evaluated in supraphysiological doses where the basic science rationale is similar to that supports their use in sepsis in that a state of relative adrenocortcoid insufficiency exists. And that this insufficiency is associated with excessive inflammation, hemodynamic instability and risk of death
- CRASH STUDY Prior tot the CRASH study Corticosteroids were widely used in patients with head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1–2%. Despite this over 50% of US ICUs used steroids for this indication.The CRASH trial—a multicentre international collaboration—aimed to confirm or refute such an effect by recruiting 20 000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment.
- Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21·1%] vs 893 [17·9%] deaths; relative risk 1·18 [95% CI 1·09–1·27]; p=0·0001).
- The jury is still out .They are still suggested in a recent cochrane review. However the trial results are inconsistent and the clinical significance of the small benefit observed in some trials uncertain. For these reasons and concern of harm ( in particular sepsis) their routine use has largely disappeared in Aus and NZ. In the US the debate is more vocal and practice less uniform.
- As mentioned earlier the use of supraphysiological doses of steriods was postualted to be of benefit in trauma patients Hypolyte Study
- 150 patients with severe trauma were included in 7 intensive care units in France 200mg hydrocortisone
- Well Why EPO what do we know about it that might make it an effective adjunctive agent in the management of trauma?
- Within hours, certain tissue factors, including tumor necrosis factor (TNF), are released by the damaged cells into their surroundings. These factors attract macrophages, white blood cells specialized in cleaning up damaged tissues. Furthermore, the nutrient flow between affected and healthy tissue is interrupted in order to isolate the injured area. As a result, cells within the affected region begin to die, predominantly via programmed cell death, or apoptosis. Moderate inflammatory reactions ensue, helping to clean up the damaged tissue. As the inflammation abates, repair mechanisms become activated and ultimately lead to the formation of a scar. To limit the uncontrolled expansion of tissue damage after activation of the innate immune system, a counterregulatory response is simultaneously triggered by inflammation or hypoxia. So we also see the simultaneous up regulation of Tissue protective receptors within the penumbra. Tissue protective cytokines produced at the lesion periphery,, and diffuses inward, engaging the TPR, rescues cells within the penumbra from apoptosis. The lesion size is contained at the boundary defined by the effective inhibition of apoptosis and unrescuable cellular destruction.
- A small pool of erythrocyte precursors (burst-forming unit erythroids and colony-forming unit erythroids) in the bone marrow continuously become responsive through the expression of the EPO receptor, but are programmed to undergo apoptosis unless EPO is present (21). In this way, the continuous loss of senescent erythrocytes (~1% each day) is precisely replaced by newly matured red cells so as to maintain equilibrium and avoid tissue hypoxia
- The molecular mechanism of action is now well understood and distinct tissue protective receptors for which EPO is the agonist exist. Model of erythroid EPO/EpoR signaling. The homodimeric EpoR molecule with Janus kinase 2 (JAK2) bound to its cytoplasmic domain is primed for EPO stimulation. EPO binding to the extracellular domain of EpoR results in conformational changes that bring JAK2 bound sites in close proximity to each other. This results in transphosphorylation of JAK2 and activation, which in turn increases other downstream signaling through three pathways signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways.
- Hypoxia inducible factor 1 seen within minutes of hypoxia HIF 1 binds to the enhancer of EPO gene and increases EPO production within hours
- Evolution of tissue injury and its modulation by endogenous erythropoietin or exogenous non-erythropoietic tissue-protective cytokines. After a primary insult (for example, a vascular infarct) a penumbra develops around necrotic cells in a region where the oxygen tension falls below a critical limit (time point 1; T1). Cells around the core are stressed and at risk of undergoing apoptosis and form the penumbra (T2). Cells within the penumbra and immune cells recruited from a distance by the products of necrosis begin to secrete pro-inflammatory cytokines. These cytokines induce the expression of TPR erythropoietin receptors (EPORs) by cells in the penumbra, with the highest activity at the lesion epicentre where the cytokines are most concentrated (T3) and expression of EPOR is highest (T4). The hypoxic conditions in the penumbra also induce the expression of hypoxia-inducible factor (HIF) in some cell types (such as astrocytes), which initiates increased erythropoietin (EPO) production. However, pro-inflammatory cytokines can also directly inhibit erythropoietin synthesis, thereby producing a gradient that is the inverse (T5, left) of that of EPOR (T4). This results in diminished salvage of the penumbra. The apoptotic programme in EPOR-expressing cells can be terminated by the binding of erythropoietin within a few hours of injury. Application of exogenous erythropoietin or other tissue-protective cytokines to the injury site can substitute for endogenous erythropoietin (if it is suppressed) and protect EPOR-expressing cells from apoptosis (T5, right), so reducing the degree of tissue loss by terminating the apoptotic programme (T6).
- EPO improves outcome in rodent models of TBI Administration of EPO rescues the penumbra after cerebral ischemia. An ischemic core (IC; panel E) is caused by a 1-h occlusion of the middle cerebral artery distal to the rhinal artery in a rat, followed by reperfusion (stage 1 injury). TNFα and other proinflammatory cytokines are produced within this central volume of injury corresponding to the circulatory territory of the middle cerebral artery (MCA) and diffuse into the adjacent cerebral cortex to the right of IC (stage 2 injury response). Microglia (the macrophage equivalents of the nervous system) are recruited into the penumbra (right panels) and amplify injury. Within the penumbra, the TPR is subsequently upregulated (stage 3 injury response), but upregulation of its ligand EPO is suppressed. Therefore, EPO does not penetrate very far into the penumbra from the unsuppressed periphery, producing a large lesion when evaluated 24 h later (light gray area, panel S). However, parenteral administration of EPO (panel E) rescues the penumbra by delivering TPR ligand into this region primed for TPR activity but deficient in endogenous EPO
- We had a number of prespecified sensitivity analyses. When adjusted for illness severity according to the IMPACT TBI predicted probability of a poor outcome, 6-month mortality was lower in patients who received erythropoietin than in those who received placebo (adjusted odds ratio 0・58 [95% CI 0・34–0・99], p=0・04; adjusted hazard ratio 0・62 [0・39–0・97], p=0・04). First large RCT to do so
- Meta analysis Describe – registered with prospero predefined protocol 9 RCTs identifed eight reported mortality – use the latest reported mortality ( as now recommended) Analysis of TBI only patients Excluding high risk trials
- Mention trial sequential analysis- 95% confidence limit crossed for at least a 20% reduction in mortality Trial Sequential Analysis (TSA) is a methodology that combines an information size calculation (cumulated sample sizes of all included trials) for a meta-analysis with the threshold of statistical significance. TSA is a tool for quantifying the statistical reliability of data in the cumulative meta-analysis adjusting significance levels for sparse data and repetitive testing on accumulating data.
- There was another major difference about 50% had coexisting multiple trauma
- EPO-TRAUMA is a multicentre, concealed, blinded, parallel group randomised controlled trial evaluating the effect of epoetin alfa (EPO) compared to placebo in critically patients following trauma. The proposed protocol and analytical methods are similar to those of the successfully completed EPO-TBI study The primary aim of the study is to determine the efficacy of EPO compared to placebo in reduce death and disability at six months in critically ill trauma patients This study will be the first adequately powered randomised trial evaluating EPO in critically ill trauma patients. It will confirm or refute an effect of EPO on mortality. The results will be applicable to patients in Australia and internationally and generalizable to the military population. If effective EPO may save the lives of two hundred people under the age of 65 year in Australia alone. EPO-TRAUMA will impact clinical practice: only a large randomised controlled trial can answer critical questions such as this and provide a trusted evidence base to guide clinicians. The successful completion of EPO-TRAUMA is of the highest priority. It will objectively resolve the uncertainty about EPO in critically ill trauma patients and may lead to the saving of thousands of young Australian lives in the future.
- 2,500 patients, Critically ill trauma patients requiring mechanical ventilation admitted to participating centres This study will have 90% power (2 sided p-value of 0.05) to detect a 6% reduction (31% vs 25%) in the primary outcome. This figure includes inflation for a loss to follow up rate of 3% and one planned interim analysis at 50% recruitment. This sample size will further enable a 91% power (2 sided p-value of 0.05) to detect a 30% relative reduction in 6-month mortality (15.3% vs 10.7%).