hydrocortisone sepsis - World Federation of Pediatric Intensive and ...

BRAZILIAN SEPSIS EPIDEMIOLOGICAL STUDY• Data suggest that sepsis is a major public healthproblem, with an incidence density of about 57 per 1000patients /day;Silva E, et al. Crit Care Med, 2004 8:4;r251-60

PEDIATRIC ICU OF SÃO PAULO UNIVERSITYSeptic shock incidenceMortality30%60%20%40%10%20%0%2002 20030%20022003Sá, Kalil, , Oliveira, Vaz, 2003

SEVERE SEPSIS/SEPTIC SHOCK MORTALITYIN CHILDREN - USA%100908070605040302010097%57%12% 9%1963 1985 1991 1999AnoCrit Care Med 2003; 19

RESUSCITATION OF PEDIATRIC SEPTIC SHOCKPediatric considerationsMargaret M. Parker, MD, FCCM; Jan A. Hazelzet, MD; Joseph A. Carcillo, MDCrit Care Med 2004 Vol. 32

RESUSCITATION OF PEDIATRIC SEPTIC SHOCK – ADAPTEDPARKER MM, HAZELZET JA AND CARCILLO JA - 20040-5minRecognize decreased mental status and perfusion.Maintain airway and establish access according toPALS guidelines.Push 20cc/Kg isotonic saline or colloid boluses upto and over 60cc/Kg.Correct hypoglycemia and hypocalcemia.15minFluid responsive shock(Normalization of bloodpressure and tissueperfusion)Observe in ICUFLUID REFRACTORY SHOCKEstablish central venous access, begin dopamineor dobutamine therapy and establish arterialmonitoring.Fluid refractory-dopamine/dobutamineresistantshockTitrate epinephrine for cold shock andnorepinephrine for warm shock to normalMAP-CVP difference for age and SVCO2saturation > 70%

60minCatecholamine –resistantshockAt risk of adrenal insufficiency?Draw baseline cortisol levelthen give hydrocortisoneNot at risk?Draw baseline cortisol level orperform ACTH stim test.Do not give hydrocortisoneNormal blood pressureCold shockSVCO 2 Sat < 70%Low blood pressureCold shockSVCO 2 Sat < 70%Low bloodpressureWarm shockSVCO 2 Sat 70%Add vasodilator or type IIIPDE inhibitor with volumeloadingTitrate volumeresuscitation andepinephrineTitrate volume andnorepinephrinePersistent Catecholamine-resistantshockStart cardiac output measurement and direct fluid, inotrope, vasopressor,vasodilator, and hormonal therapies to attain normal MAP-CVP and CI >3.3 and < 6.0L/min/m 2 .Refractory shockConsider ECMO

ANTI-INFLAMMATORY INFLAMMATORY PROPERTIES OFCORTICOSTEROIDSSEPSISINFECTIONSEPTIC SHOCKMODS

SCHEMATIC SUMMARY OF GLUCOCORTICOIDPROPERTIESSHOCK, 20(3): 197-207, 2003

What are the criteria to be used in diagnoses ofadrenal insufficiency and relative adrenalinsufficiency in critically ill patients?

DIFFERENT CRITERIA UTILIZED TO DEFINE ADRENALINSUFFICIENCY ACCORDING TO SEVERAL AUTHORSAuthor(Yr)Rothwell et al.(1991)Soni et al.(1995)Hatherill et al.(1999)Menon e Clarson(2002)Loisa et al.(2002)Marik e Zaloga(2003)Pizarro et al.(2005)Increment cortisol < 9 after ACTH stimulated testCortisol < 18 after ACTH stimulated testIncrement cortisol < 7,5 after ACTH stimulated testBaseline Cortisol < 7 and/or cortisol < 18 afterACTH stimulated testBaseline cortisol < 25 and increment 9Increment cortisolCortisol Level( g/dl)Baseline cortisol< 259 after ACTH stimulated test

What are the appropriate plasma cortisolconcentrations in patients with sepsis and septicshock?• The value of baseline cortisol and post corticotropinstimulated test in critically ill patients remains acontroversial issue;• “Normal” or “high normal” plasmacortisolconcentrations may represent relative adrenalinsufficiency or unresponsiveness in sepsis and septicshock and an insufficient response to stress;• The rapid corticotropinstimulation test has beensuggested to be useful in evaluating adrenocorticalfunction and as a predictor of mortality in sepsis;

INCIDENCE OF ADRENAL INSUFFICIENCY ACCORDING TOVARIOUS PUBLISHED DEFINITIONSAuthor(Yr)Rothwell et al. (1991)Soni et al. (1995)Hatherill et al. (1999)Loisa et al. (2002)Menon e Clarson(2002)Marik e Zaloga (2003)Pizarro et al. (2005)Cortisol Level( g/dl)Increment < 9 after ACTH stimulated testCortisol < 18 after ACTH stimulated testIncrement cortisol < 7,5 after ACTHstimulated testCortisol baseline < 25 and increment 9Cortisol baseline < 7 and/or cortisol < 18after ACTH stimulated testCortisol baseline < 25Increment 9 after ACTH stimulated testAccordingbibliographyreferences40%24%52%15%31%61%44%

INCIDENCE OF ADRENALINSUFFICIENCY IN CHILDREN

Summary of published studies on adrenal stimulationtesting in critically ill pediatric patientsStudyPopulationnDose of ACTH forstimulation testDefinition of adrenalinsufficiencyProportionwith AI/RAIClinicalCorrelationHatherill1999PediatricSeptic shock33145 g/ m 2To max 250 gPoststimulationincrease > 9 g/dl525IncreasedvasopressorrequirementsMenon2003PediatricCritical illness13>10Kg: 250 g< 10 Kg: 125 gBasal cortisol < 7 g/dlor Poststimulationcortisol < 18 g/dl31%Not assessedBone2002PediatricSepsis420.5 g/m 2Basal cortisol < 5 g/dlor poststimulatoncortisol < 18 g/dl17%IncreasedvasopressorrequirementsPizarro2005PediatricSetic shock57250 gBasal cortisol< 20 g/dlPoststimulationincrese < 9 g/dlAI – 18%RAI – 26%UnresponsiveshockAdapted by Curr Opin Pediatr 18:448-453453

Absolute and relative adrenal insufficiency in children with septicshock*Cristiane F. Pizarro, MD; Eduardo J. Troster, MD, PhD; Durval Damiani, MD, PhD; JosephA. Carcillo, MDCrit Care Med 2005 Vol. 33, No. 4EditorialsOne step forward: An advance in understanding adrenalinsufficiency in the pediatric critically ill*Michael Agus, MDPediatric Critical Care and EndocrinologyChildren’s Hospital Boston Harvard Medical School Boston, MACrit Care Med 2005 Vol. 33, No. 4Adrenal insufficiency in the critically ill neonate and childMonica Langer, Biren P. Modi and Michael AgusCurr Opin Pediatr 18:448–453. 2006

INCIDENCE OF ABSOLUTE AND RELATIVEADRENAL INSUFFICIENCY IN PATIENTS WITHSEVERE SEPSIS AND SEPTIC SHOCKCristiane F Pizarro; Eduardo Juan TrosterDurval Damiani and Joseph A CarcilloPICU – CHILDREN INSTITUTE – SÃO PAULO -BRAZIL

OBJECTIVES1. To determine the incidence of absoluteadrenal insufficiency and relative adrenalinsufficiency in children with septic shock andsevere sepsis;2. To evaluate their effect on vasopressorrequirements and mortality.

THE PATIENTS WERE CLASSIFIED IN FOUR GROUPSACCORDING TO ADRENAL FUNCTION:GROUP1ABSOLUTE ADRENAL INSUFFICIENCYBaseline cortisol < 20µg/dl andan increment = 9µg/dlGROUP 2RELATIVE ADRENAL INSUFFICIENCYBaseline cortisol 20µg/dl andan increment = 9µg/dlGROUP 3ADEQUATE ADRENAL RESPONSE(with elevated baseline cortisol)GROUP 4ADEQUATE ADRENAL RESPONSE(without an elevated baseline cortisol )Baseline cortisol 20µg/dl and anincrement > 9µg/dlBaseline cortisol < 20µg/dl andan increment > 9µg/dl

100%90%80%70%60%50%40%30%20%10%0%VASOPRESSOR AND FLUIDREQUIREMENTS IN THE FOUR GROUPS100%Group 1 - AAI80%20% 20% 20%Group 2 - RAI60%Group 3 - AAR30% 35% 35%Group 4 - AARFLUID RESPONSIVE SHOCKCATHECOLAMINE REFRACTORY SHOCKDOPAMINE/DOBUTAMINE REFRACTORY SHOCK

MORTALITY RATES IN THE FOUR ADRENAL FUNCTIONGROUPS80%70%60%50%50% 50%47%53%67%76%40%33%30%24%20%10%0%Group 1- AAIGroup 2- RAIGroup 3- AARGroup 4-AARSURVIVORSNON SURVIVORS

SHOULD HYDROCORTISONE BE PREFERREDTO OTHER GLUCOCORTICOIDS IN PATIENTS WITHSEPSIS / SEPTIC SHOCK? YES.

1. MOST OF THE EXPERIENCE WITH LOW-DOSECORTICOSTEROID TREATMENT IN SEPTICSHOCK HAS BEEN WITH THE USE OFHYDROCORTISONE

BEFORE EUROPEAN’S S META-ANALYSISANALYSIS -1995Incluir meta-análise corticóidesMortality rate ~ 11%

BEFORE EUROPEAN’S S META-ANALYSANALYSLar ge, , RCT of High-dosecor t icost er oids in sept ic shcokar eef f ect ive,and might even be...Lefering et al. Crit Care Med. . 1995; 23(7):1294-302.302.Cronin et al. Crit Care Med.1995; 23(8):1430-9.

Summary of study designs - 1966 - 1993Author (Yr)NDrugDose / DurationCooperative Study Group(1963)194Hydrocortisone300mg followed by 50mg/day(6 days)Klastersky et al.85Betamethasone1mg/kg daily(1971)(3days)Schumer172Methylprednisolone30mg/kg(1976)Dexamethasone3mg/kgRepeated after 4hrs (x1) if necessaryThompson et al.60Methylprednisolone30mg/kg(1976)(Up to 4hrs in 24 hrs)Sprung et al.59Methylprednisolone30mg/kg(1984)Dexamethasone6mg/kgRepeated after 4hrs (x1) if necessaryLucas & Ledgerwood(1984)48Dexamethasone2mg, 6mg/kg for 48hrs by continuousinfusionVeterans Administration223Methylprednisolone30mg/kg followed by 5mg/kg(1987)(9hrs)Bone et al.381Methylprednisolone30mg/kg(1987)(24hrs)Luce et al.75Methylprednisolone30mg/kg (x4)(1988)(24hrs)

Annane et al. (2004)meta-analysisanalysis(16 trials 1955 - 2003)1. Short courses of high dose corticosteroids do notaffectmortalityfromseveresepsisandsepticshock;2. Long courses of low dose corticosteroids:a) Improve systematic haemodynamics and reducethe time on vasopressor treatment;b) Reduce mortality at 28 days, , in intensive care units,and in hospital;c) Do not sgnificantily alter risk of gastroduodenal bleeding,superinfections or hyperglycemia.Annane et al. BMJ. 2004, 329:480-9.9.

SUMMARY OF STUDY DESIGNS - 1998 - 2003AuthorNDrugDose(Yr)DurationBollaert et al.41Hydrocortisone100mg EV 8/8h 5 days,(1998)then 50mg 8/8h for 3 day and25mg 8/8h for 3 day forrespondersBriegel et al.(1999)40Hydrocortisone100mg EV then 0,18mg/Kg/h untilshock reversed, then 0.08mg/kg/hfor 6 days, then tapered by24mg/dayChawla et al.44Hydrocortisone100mg EV 8/8hs during 3 days(1999)Annane et al.(2002)299Hydrocortisone50mg EV 6/6hs during 7days plusfludrocortisone 50 g oral tablet 7daysKeh et al.(2003)40Hydrocortisone100mg EV 30min following10mg/h during 3 days

2. Hydrocortisone is thesynthetic equivalent to thephysiologic final active cortisol;3. Hydrocortisonehasintrinsicmineralocorticoidactivity,whereasmethilprednisoloneordexametasone does not;4. 20mg of hydrocortisone is equivalent to 0.05mg offludrocortisone, and 0.05-2mg of fludrocortisone isrecommendedas mineralocorticoidreplacementdosage after treatment of adrenal insufficiency.

SHOULD HYDROCORTISONE BEUSED

Carcillo JA, Task Force Committee Members - 2002• Should be reserved for use in children with cathecolamineresistance and suspected or proven adrenal insufficiency.Patients at risk include:1. Purpura fulminans;HYDROCORTISONE THERAPY2. Children with severe septic shock;3. Children with pituitary or adrenal abnormalities;4. Children who have previously received steroid therapiesfor chronic illness;Dose recommendation vary from1-2mg/kg for stresscoverage to 50mg/Kg for empirical therapy of shock followedby the same dose as a 24-hrinfusion.Crit Care Med.2003;30:1365.2003;30:1365-78

USE OF GLICOCORTICOIDSHildebrandt et al., 2005• There is no agreed consensus for the use of steroids insepsis in UK practice at the moment.- Steroids are regularly used in 76% PICUs;- Only one Unit has a written protocol;- 84% units who use steroids gave as their main indicationpersistent hypotension despite the use of inotropes;- 79% units use hydrocortison / 21% dexamethasone;- 42% units perform a short synacthen test and 25%unitsperforming syacthen tests used low-dosesynacthen.Pediatric Anesthesia.2005 15: 358-365365

• Relativeadrenalinsufficiencyanditsclinicalimplicationshave come in focuswithstudiesdemonstratinga highprevalencein septicshockpatients and a significant associated morbidity;• Thisstateof“relative” adrenalinsufficiencyischaracterized by an inadequate production of cortisol inrelationto anincreaseddemandduringperiodsofsevere stress.

CLINICAL MANIFESTATIONSRELATIVE ADRENAL INSUFFICIENCYCARDIOVASCULAR INSTABILITY, WITHHYPOTENSION AND SHOCK THAT ISUNRESPONSIVE TO FLUID OR VASOPRESSORTHERAPY

RELATIVE ADRENAL INSUFFICIENCY• INCREASED MORBIDITY AND MORTALITY• ASSOCIATION BETWEEN ADRENALINSUFFICIENCY AND A REFRACTORY SEPTCSHOCK

100%90%80%70%60%50%40%30%20%10%0%VASOPRESSOR AND FLUID REQUIREMENTIN THE FOUR GROUPS100%Group 1 - AAI80%20% 20% 20%Group 2 - RAI60%Group 3 - AAR30% 35% 35%Group 4 - AARFLUID RESPONSIVE SHOCKCATHECOLAMINE REFRACTORY SHOCKDOPAMINE/DOBUTAMINE REFRACTORY SHOCK

MORTALITY RATES IN THE FOUR ADRENAL FUNCTIONGROUPS80%70%60%50%50% 50%47%53%67%76%40%33%30%24%20%10%0%Group 1- AAIGroup 2- RAIGroup 3- AARGroup 4-AARSURVIVORSNON SURVIVORS

Relative adrenal insufficiency as a predictor of diseaseseverity,mortality, and beneficial effects of corticosteroid treatment inseptic shockMargriet F. C. de Jong, MSc; Albertus Beishuizen, MD, PhD; Jan-Jaap Spijkstra, MD,PhD;A. B. Johan Groeneveld, MD, PhD, FCCP, FCCMCrit Care Med 2007 vol. 35, 8

CONCLUSIONSDoubts still persist regarding the efficacy of replacementtherapy with low-dosesteroids in children withcatecholamine-resistantseptic shock, and furtherrandomized studies are needed to determine whethertreatment of such patients changes morbidity and/ormortality.