hydrocortisone sepsis - World Federation of Pediatric Intensive and ...
hydrocortisone sepsis - World Federation of Pediatric Intensive and ...
hydrocortisone sepsis - World Federation of Pediatric Intensive and ...
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BRAZILIAN SEPSIS EPIDEMIOLOGICAL STUDY• Data suggest that <strong>sepsis</strong> is a major public healthproblem, with an incidence density <strong>of</strong> 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 SHOCK<strong>Pediatric</strong> 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 <strong>and</strong> perfusion.Maintain airway <strong>and</strong> establish access according toPALS guidelines.Push 20cc/Kg isotonic saline or colloid boluses upto <strong>and</strong> over 60cc/Kg.Correct hypoglycemia <strong>and</strong> hypocalcemia.15minFluid responsive shock(Normalization <strong>of</strong> bloodpressure <strong>and</strong> tissueperfusion)Observe in ICUFLUID REFRACTORY SHOCKEstablish central venous access, begin dopamineor dobutamine therapy <strong>and</strong> establish arterialmonitoring.Fluid refractory-dopamine/dobutamineresistantshockTitrate epinephrine for cold shock <strong>and</strong>norepinephrine for warm shock to normalMAP-CVP difference for age <strong>and</strong> SVCO2saturation > 70%
60minCatecholamine –resistantshockAt risk <strong>of</strong> adrenal insufficiency?Draw baseline cortisol levelthen give <strong>hydrocortisone</strong>Not at risk?Draw baseline cortisol level orperform ACTH stim test.Do not give <strong>hydrocortisone</strong>Normal 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 <strong>and</strong>epinephrineTitrate volume <strong>and</strong>norepinephrinePersistent Catecholamine-resistantshockStart cardiac output measurement <strong>and</strong> direct fluid, inotrope, vasopressor,vasodilator, <strong>and</strong> hormonal therapies to attain normal MAP-CVP <strong>and</strong> CI >3.3 <strong>and</strong> < 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 <strong>of</strong>adrenal insufficiency <strong>and</strong> 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 <strong>and</strong>/or cortisol < 18 afterACTH stimulated testBaseline cortisol < 25 <strong>and</strong> increment 9Increment cortisolCortisol Level( g/dl)Baseline cortisol< 259 after ACTH stimulated test
What are the appropriate plasma cortisolconcentrations in patients with <strong>sepsis</strong> <strong>and</strong> septicshock?• The value <strong>of</strong> baseline cortisol <strong>and</strong> post corticotropinstimulated test in critically ill patients remains acontroversial issue;• “Normal” or “high normal” plasmacortisolconcentrations may represent relative adrenalinsufficiency or unresponsiveness in <strong>sepsis</strong> <strong>and</strong> septicshock <strong>and</strong> an insufficient response to stress;• The rapid corticotropinstimulation test has beensuggested to be useful in evaluating adrenocorticalfunction <strong>and</strong> as a predictor <strong>of</strong> mortality in <strong>sepsis</strong>;
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 <strong>and</strong> increment 9Cortisol baseline < 7 <strong>and</strong>/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 <strong>of</strong> published studies on adrenal stimulationtesting in critically ill pediatric patientsStudyPopulationnDose <strong>of</strong> ACTH forstimulation testDefinition <strong>of</strong> adrenalinsufficiencyProportionwith AI/RAIClinicalCorrelationHatherill1999<strong>Pediatric</strong>Septic shock33145 g/ m 2To max 250 gPoststimulationincrease > 9 g/dl525IncreasedvasopressorrequirementsMenon2003<strong>Pediatric</strong>Critical illness13>10Kg: 250 g< 10 Kg: 125 gBasal cortisol < 7 g/dlor Poststimulationcortisol < 18 g/dl31%Not assessedBone2002<strong>Pediatric</strong>Sepsis420.5 g/m 2Basal cortisol < 5 g/dlor poststimulatoncortisol < 18 g/dl17%IncreasedvasopressorrequirementsPizarro2005<strong>Pediatric</strong>Setic shock57250 gBasal cortisol< 20 g/dlPoststimulationincrese < 9 g/dlAI – 18%RAI – 26%UnresponsiveshockAdapted by Curr Opin Pediatr 18:448-453453
Absolute <strong>and</strong> 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 underst<strong>and</strong>ing adrenalinsufficiency in the pediatric critically ill*Michael Agus, MD<strong>Pediatric</strong> Critical Care <strong>and</strong> EndocrinologyChildren’s Hospital Boston Harvard Medical School Boston, MACrit Care Med 2005 Vol. 33, No. 4Adrenal insufficiency in the critically ill neonate <strong>and</strong> childMonica Langer, Biren P. Modi <strong>and</strong> 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 <strong>and</strong> Joseph A CarcilloPICU – CHILDREN INSTITUTE – SÃO PAULO -BRAZIL
OBJECTIVES1. To determine the incidence <strong>of</strong> absoluteadrenal insufficiency <strong>and</strong> relative adrenalinsufficiency in children with septic shock <strong>and</strong>severe <strong>sepsis</strong>;2. To evaluate their effect on vasopressorrequirements <strong>and</strong> mortality.
THE PATIENTS WERE CLASSIFIED IN FOUR GROUPSACCORDING TO ADRENAL FUNCTION:GROUP1ABSOLUTE ADRENAL INSUFFICIENCYBaseline cortisol < 20µg/dl <strong>and</strong>an increment = 9µg/dlGROUP 2RELATIVE ADRENAL INSUFFICIENCYBaseline cortisol 20µg/dl <strong>and</strong>an increment = 9µg/dlGROUP 3ADEQUATE ADRENAL RESPONSE(with elevated baseline cortisol)GROUP 4ADEQUATE ADRENAL RESPONSE(without an elevated baseline cortisol )Baseline cortisol 20µg/dl <strong>and</strong> anincrement > 9µg/dlBaseline cortisol < 20µg/dl <strong>and</strong>an 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 <strong>of</strong> High-dosecor t icost er oids in sept ic shcokar eef f ect ive,<strong>and</strong> 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 <strong>of</strong> 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 <strong>of</strong> high dose corticosteroids do notaffectmortalityfromsevere<strong>sepsis</strong><strong>and</strong>septicshock;2. Long courses <strong>of</strong> low dose corticosteroids:a) Improve systematic haemodynamics <strong>and</strong> reducethe time on vasopressor treatment;b) Reduce mortality at 28 days, , in intensive care units,<strong>and</strong> in hospital;c) Do not sgnificantily alter risk <strong>of</strong> 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 <strong>and</strong>25mg 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 <strong>of</strong> <strong>hydrocortisone</strong> is equivalent to 0.05mg <strong>of</strong>fludrocortisone, <strong>and</strong> 0.05-2mg <strong>of</strong> fludrocortisone isrecommendedas mineralocorticoidreplacementdosage after treatment <strong>of</strong> adrenal insufficiency.
SHOULD HYDROCORTISONE BEUSED
Carcillo JA, Task Force Committee Members - 2002• Should be reserved for use in children with cathecolamineresistance <strong>and</strong> 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 <strong>of</strong> shock followedby the same dose as a 24-hrinfusion.Crit Care Med.2003;30:1365.2003;30:1365-78
USE OF GLICOCORTICOIDSHildebr<strong>and</strong>t et al., 2005• There is no agreed consensus for the use <strong>of</strong> steroids in<strong>sepsis</strong> 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 <strong>of</strong> inotropes;- 79% units use hydrocortison / 21% dexamethasone;- 42% units perform a short synacthen test <strong>and</strong> 25%unitsperforming syacthen tests used low-dosesynacthen.<strong>Pediatric</strong> Anesthesia.2005 15: 358-365365
• Relativeadrenalinsufficiency<strong>and</strong>itsclinicalimplicationshave come in focuswithstudiesdemonstratinga highprevalencein septicshockpatients <strong>and</strong> a significant associated morbidity;• Thisstate<strong>of</strong>“relative” adrenalinsufficiencyischaracterized by an inadequate production <strong>of</strong> cortisol inrelationto anincreaseddem<strong>and</strong>duringperiods<strong>of</strong>severe 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 <strong>of</strong> diseaseseverity,mortality, <strong>and</strong> beneficial effects <strong>of</strong> 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 <strong>of</strong> replacementtherapy with low-dosesteroids in children withcatecholamine-resistantseptic shock, <strong>and</strong> furtherr<strong>and</strong>omized studies are needed to determine whethertreatment <strong>of</strong> such patients changes morbidity <strong>and</strong>/ormortality.