Presentation on theme: "Karyn L. Butler, MD, FACS, FCCM Chief, Surgical Critical Care"— Presentation transcript:
1 CRITICAL ILLNESS RELATED CORTICOSTEROID INSUFFICIENCY CIRCI: Current Status 2013 Karyn L. Butler, MD, FACS, FCCMChief, Surgical Critical CareHartford HospitalAssociate Professor of SurgeryUniversity of ConnecticutHartford, CT
2 Background1940’s:‘Relative Adrenal Insufficiency”: activation of adrenal response, inadequate for magnitude of insult Pollak H. Lancet 1940Adrenalectomised animals exposed to shock had high mortality (Seyle et al.)1980’sEtomidate impairs cortisol synthesisIncreased mortality 28 to 77% in trauma patients (Watt et al. Anesthesia 1984)1990’sPatients with MSOF improve after GC treatment (Arch Surg 1993)
3 ….Hydrocortisone did not improve survival or reversal of shock in patients with septic shock.
9 ACCM ConsensusCritical Illness-Related Corticosteroid Insufficiency (CIRCI)Absolute or Relative adrenal insufficiency should be avoidedInadequate cellular corticosteroid activity for the severity of the patient’s illnessDynamic / ReversibleCrit Care Med 2008
10 ….the evidence to support its existence as a relevant clinical entity is currently not compelling….We therefore suggest that the terms “RAI” and “critical illness related corticosteroid insufficiency” be abandoned….
11 Key questions Terminology? How is the diagnosis established? When / How to treat?Does therapy make a difference?
12 Result of stress response? Potentiate organ dysfunction? CIRCIResult of stress response?Potentiate organ dysfunction?
13 The Stress ResponseActivation of hypothalamic-pituitary-adrenal (HPA) axis essential to maintenance of cellular and organ homeostasisHPA axis failure common in systemic inflammationIncidence ~ 20%60% in septic shock (Anane et al Am J Resp Crit Care Med 2006)“Adrenal failure”CAPTraumaHead InjuryBurnsLiver Failures/p Cardiac Surgery
15 Cortisol physiology Increases blood pressure Increases sensitivity to vasopressor agents (increases transcription and expression of receptors)Increases endothelial nitric oxide synthetase (maintaining microvascular perfusion)Reduces number and function of immune cells at sites of inflammationDecreases the production of cytokine/ chemokinesEnhances macrophage migration inhibitory factor
16 Cortisol physiology Major endogenous GC secreted by adrenal cortex > 90% bound to CBGDecreased CBG during acute illness free cortisolCortisol binds to intracellular receptorsActivates or represses gene transcriptionInhibit NFB by increasing IB transcription
18 Cortisol physiology Cortisol binds to intracellular receptors Activates or represses gene transcriptionInhibits NFB by increasing IB transcription
19 How to establish diagnosis? Measure cortisolFree vs. totalTiming (random vs. other)Association with severity of illnessGender differencesMeasure provoked cortisol productionACTH ‘stim’ test (low vs. high dose)Threshold for mortality?
21 How to establish diagnosis? ACTH stimulation test SHOULD NOT be used to identify those patients with septic shock or ARDS who should receive GC’s (2B)Normal range of free cortisol is unclearNo test is able to measure GC resistance at the tissue levelUnclear what level of circulating cortisol is needed to overcome tissue resistanceACCM consensus Crit Care Med 2008
22 Key questions Terminology? How is the diagnosis established? When / How to treat?Does therapy make a difference?
23 When / How to treat?Hydrocortisone should be considered in patients with septic shock who have responded poorly to fluid resuscitation and vasopressors (2B)Meta-analysis of 6 RCTHydrocortisone mg/dayGreater shock reversal at day 7No change in mortalityMethylprednisolone 1 mg/kg/day x 14 days for early severe ARDS (pO2/FIO2 < 200)ACCM consensus Crit Care Med 2008
24 When / How to treat?Dose should be adequate to down-regulate the pro-inflammatory response without causing immune-paresis or interfering with wound healingGC dose reduced slowly to avoid rebound inflammationDexamethasone NOT indicatedImmediate and prolonged HPA axis suppressionACCM consensus Crit Care Med 2008
25 When / How to treat?IV hydrocortisone 200 mg/day if hemodynamically unstable despite fluid resuscitation and vasopressor support (2C)Do not use ACTH ‘stim’ test to identify who receives GC therapy (2B)Taper GC when vasopressors no longer required (2D)Do not use in sepsis if no shock (1D)Continuous infusion (2D)
26 Key questions Terminology? How is the diagnosis established? When / How to treat?Does therapy make a difference?
27 Methylprednisolone infusion in early severe ARDS Results of a Randomized Controlled TrialMeduri GU, Golden E, Freire AX,Umberger R et al.Memphis Lung Research ProgramChest 2007; 131:
28 Study design Randomized, double blind, placebo controlled Five ICU’s in Memphis91 patients with severe early ARDS (<72h)Randomized to MP x 28 days (1mg/kg/d) vs. placeboOutcomesReduction in lung injury scoreSuccessful extubation by day 7
29 Results MP n=63, Placebo n= 28 Reduction of LIS: 69.8% vs. 35.7%; P=0.002Extubation: 53.9% vs. 25%; P=0.01MP: lower CRP levels, decreased MV LOS, decreased ICU LOSMortality: 20.6% vs. 42.9%; P= 0.03
30 Conclusions Down regulated SIRS Improved pulmonary and extrapulmonary organ dysfunctionReduced duration of MV and ICU length of stayAssociated with decreased mortality
31 Glucocorticoids and CPB 1966: “…it is conceivable that such [glucocorticoid] administration before prolonged cardiopulmonary bypass in humans would be of value.”–Moses ML et al. J Sur Res
32 Glucocorticoids and CPB 1966: High dose dexamethasone attenuates lysosomal enzyme release after CPBBeneficial effects of methylprednisolone mg/kg prior to CPB prevented pulmonary vascular and alveolar architectural changes (early 1970’s)Initial studies from 1970’s to early 2000 not promising
33 Kilger E, Weis F, Briegel J, Frey L et al. Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgeryKilger E, Weis F, Briegel J, Frey L et al.University of MunichCrit Care Med 2003; 31:
34 Study designProspective noninterventional trial to identify patients at high risk for SIRSProspective randomized interventional trial of prophylactic hydrocortisone in target populationExclusions:Renal insufficiency Cr > 2 mg/dLInsulin dependent diabetes mellitusBody mass index > 30 kg/m2
35 Risk Factors Duration of CPB > 97 minutes EF < 40% CABG with 4 or more graftsPlanned valve + CABG
36 Methods High risk patients randomized to: Stress dose hydrocortisone: 100 mg bolus before anesthesia, continuous infusion 10 mg/hr tapered over 4 daysPlaceboSerum Il-6 levels before anesthesia and 6 hours after CPBHemodynamic variablesLength of stay data
37 ConclusionsPreoperative risk stratification is pivotal to provide effective anti-inflammatory prophylactic treatmentPeri-operative continuous hydrocortisone reduces systemic inflammationStudy not powered to detect reduction in mortality rate at 30 days
38 Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized studyWeiss F, Kliger E, Roozendaal B. et al.University of Zurich, University Munich, UCSF-IrvineJ Thorac Cardiovasc Surg 2006; 131:
39 Background High stress exposure Increased catecholaminergic activityDecreased HPA activityPost-operative chronic stress symptoms (PTSD?)Impairments in mental healthDecrease HRQL
40 Study design 36 High risk patients EF < 35%CPB > 97 minutesProspective, randomized, double blind trialRandomized to stress dose hydrocortisone (4 days) or placeboHRQL questionnaire 6 months post-opTraumatic memoriesChronic stress symptoms
42 Conclusions (6 months post-op) Stress dose hydrocortisone in high-risk cardiac surgical patients:Reduces peri-operative stress exposureDecreases chronic stress symptomsImproves Health-related quality of life
43 Cardiopulmonary and systemic effects of methylprednisolone in patients undergoing cardiac surgery Liakopoulos OJ, Schmitto JD, Kazmaier S. et al.University of Gottingen, GermanyAnn Thorac Surg 2007; 84:
44 Study design Elective CABG Exclusion: Emergency or concomitant cardiac surgical proceduresAge > 80 yearsEF < 30%AMI < 4 weeksRenal dysfunctionMethylprednisolone 15 mg/kg 30 minutes before CPB
45 Main outcome measures Hemodyanmic parameters Cytokine, troponin and CRP levelsMechanical ventilation, LOS
46 Conclusions Glucocorticoid treatment before CPB: Attenuates perioperative release of systemic and myocardial inflammatory mediatorsImproves myocardial functionPotential cardioprotective effect in patients undergoing cardiac surgerySurgical practice changed
47 Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trialHalonen J, Halonen P, Järvinen O. et al.Kuopio University Hospital, FinlandJAMA 2007; 297:
48 Study design 3 University hospitals 241 patients (age 30-85 years) Exclusion:AF or flutterUncontrolled DMInfectionCr >2 mg/dLRandomized to Hydrocortisone (100 mg) or placeboFirst dose post- op, then q8h x 3 daysAll patients received metoprolol according to HRSample size based on reduction of AF 30% to 15%
49 Outcome measuresOccurrence of AF during the first 84 hours after cardiac surgeryStudy protocol discontinued after first episode of AFMeta-analysis of RCT of primary outcome of AF (2 + present study)
52 ConclusionsIntravenous hydrocortisone reduced the relative risk of post-op AF by 37%Meta-analysis confirmed beneficial effect of corticosteroid treatment over placeboNo serious complications associated with steroid use
53 Modifiable Risk Factor? Marker of Illness Severity? CIRCIModifiable Risk Factor?Marker of Illness Severity?
54 Summary ACCM Consensus 2008 Surviving Sepsis 2012 Hydrocortisone ( mg/day) for patients with septic shock despite fluid resuscitation and vasopressors (2B)ACTH stimulation test SHOULD NOT be used to identify who should receive GC’s (2B)GC dose reduced slowly to avoid rebound inflammationMethylprednisolone 1 mg/kg/day x 14 days for early severe ARDS (pO2/FIO2 < 200)IV hydrocortisone 200 mg/day if hemodynamically unstable despite fluid resuscitation and vasopressor support (2C)Do not use ACTH ‘stim’ test to identify who receives GC therapy (2B)Taper GC when vasopressors no longer required (2D)Do not use in sepsis if no shock (1D)Continuous infusion (2D)