Κριτική ανάλυση άρθρου

1. Κριτική ανάλυση άρθρου ΕΚΠΑΙΔΕΥΤΙΚΟΠΡΟΓΡΑΜΜΑ ΑΚΑΔΗΜΑΪΚΟΥ ΕΤΟΥΣ 2011-2012 ΤΗΣ ΠΑΝΕΠΙΣΤΗΜΙΑΚΗΣ ΚΛΙΝΙΚΗΣ ΕΝΤΑΤΙΚΗΣ ΝΟΣΗΛΕΙΑΣ (ΠανΜΕΘ) του ΓΟΝΚ «Οι Άγιοι Ανάργυροι» Τρίτη 1Νοεμβρίου 08.00-09.00 Οι Άγιοι ΑνάργυροιΒοήθεια μας!! Γ. Μπαλτόπουλος

2. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Key words-Λέξεις κλειδιά • Δεν έχει !! • Early Sepsis Therapy, Lactate Clearance, Central VenousOxygen Saturation Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)Investigators.JAMA. 2010;303(8):739-746

3. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Τι γνώριζαν Ι: • Blood lactate concentrations reflect the balance between lactate production and clearance. • Failure of oxidative mechanisms can affect both production and clearance of lactate. • Lactate concentrations >5 mmol/ litre with severe metabolic acidosis predicts high mortality. • Impaired lactate clearance, rather than hypoxic tissue production of lactate, is the cause of hyperlactaemia in stable septic patients. • Basal lactate production: is 0.8 mmol/kg/h (1300 mmol/day). • Phypers B, JMT Pierce .Lactate physiology in health anddisease. Continuing Education in Anaesthesia, Critical Care & Pain 2006;6(3): 128-132 Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

4. Glycolysis, Kreb’s cycle and oxidative phosphorylation Phypers B, JMT Pierce .Lactate physiology in health anddisease. Continuing Education in Anaesthesia, Critical Care & Pain 2006; 6 (3) : 128-132

5. Ερώτηση 1Τι είναι το 2-hydroxypropanoic acid ? • Το οξύ του ξυνόγαλου • Το οξύ του ξυδιού • Το επιστημονικό όνομα του γαλακτικού οξέως • Το επιστημονικό όνομα του οξικού οξέως Carl WilhelmScheele 1780

6. Ερώτηση 2Ποιος είναι ο Archibald V. Hill;Ο άλλος είναι ο Otto Meyerhof 1 2 1 2 Τι έκαναν αυτοί; • Πήραν Nobel το 1922 • Ανακάλυψαν το γαλακτικό οξύ • Περιέγραψαν το τρόπο δημιουργίας γαλακτικού στον οργανισμό • Το 1 & 3 είναι σωστά

7. Ερώτηση 3Η πρώιμη στοχευμένη αντιμετώπιση της σήψης και του σηπτικού shock βελτιώνει την επιβίωση; • Ναι • Όχι • ΔΓ/ΔΑ

8. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Τι γνώριζαν ΙΙ: • Severe sepsis and septic shockinvolves a myriad of pathogenic changes, includingcirculatory abnormalities that result in global tissuehypoxiawhich is reflected in mixed venous oxygen saturation. • Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med 1996;14:218-25 • ScvO2 and SvO2 are closely related and are interchangeable for the initial evaluation of critically ill patients even if cardiac indices are different. SvO2 can be estimated with great accuracy by ScvO2 in 92% of the patients using a power model. • Ladakis C, Myrianthefs P, Karabinis A, Karatzas G, Dosios T, Fildissis G, Gogas J, Baltopoulos G. Central venous and mixed venous oxygen saturation in critically ill patients. Respiration. 2001;68(3):279-85. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

9. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Τι γνώριζαν ΙΙI: • Goal-directed resuscitation for severe sepsis and septic shock has been reportedto reduce mortality when applied in the emergency department. • Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377 • The quality of reporting of those that are published isoften inadequate. In this article, we present an adapted CONSORT checklistfor reporting noninferiority and equivalence trials and provide illustrativeexamples and explanations for those items amended from the originalCONSORT checklist. The intent is to improve reporting of noninferiority andequivalence trials, enabling readers to assess the validity of their results andconclusions. • Piaggio G,Elbourne DR,Altman DG,Pocock SJ,Evans SJW,for the CONSORT Group.Reporting of Noninferiorityand Equivalence Randomized Trials.An Extension of the CONSORT Statement. JAMA, 2006; 295: 1152-1160 Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

10. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Τι στόχο έβαλαν (Υπόθεση): • To test the hypothesis of noninferiority between lactate clearance and centralvenous oxygen saturation (ScvO2) as goals of early sepsis resuscitation. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

11. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Πως το σχεδίασαν: • Design, Setting, and Patients:Multicenter randomized, noninferiority trial involvingpatients with severe sepsis and evidence of hypoperfusion or septic shock whowere admitted to the emergency department from January 2007 to January 2009 at1 of 3 participating US urban hospitals • Approved by the local institutional review boards and performed in accordance with GoodClinical Practice guidelines Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

12. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Πως το έκαναν: • We randomly assigned patients to 1 of 2 resuscitation protocols. • TheScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure,and ScvO2 of at least 70%; and • the lactate clearance group was resuscitated tonormalize central venous pressure, mean arterial pressure, and lactate clearance of atleast 10%. • The study protocol was continued until all goals were achieved or for up to6 hours. Clinicians who subsequently assumed the care of the patients were blindedto the treatment assignment. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

13. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Participants • Inclusion criteria: • Pts >17yrs with severe sepsis or septicshock with confirmed or presumedinfection, (≥ 2 SIRS criteria),and • hypoperfusion • either a SBP< 90mmHg after a minimum of 20mL/kg rapid volume challenge or • ablood lactate concentration of at least36 mg/dL (4 mmol/L) • informed consent • Exclusion criteria • pregnancy • any primary diagnosis other than sepsis • suspected requirement for immediate surgery within 6 hours of diagnosis • an absolute contraindication to chest or neck central venous catheterization • cardiopulmonary resuscitation • transfer from another institution with a sepsis-specific resuscitative therapy underway • advanced directive orders that would restrict the study procedure Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

14. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Main Outcome Measure • The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at equal to −10%. • Secondary end points were ICU length of stay, hospital length of stay, ventilator-free days, and new onset multiple organ failure. • Other end points assessed were the number of resuscitative goals achieved, administered treatments, and predefined protocol-related serious adverse events. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

15. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • ScvO2 group • First, isotonic crystalloid was administered in boluses to achieve a central venous pressure of 8 mm Hg or higher. • Second, the mean arterial pressure goal of 65 mm Hg or higher, • if not achieved with fluid administration, was targeted by initiating and titrating vasopressors (dopamine or norepinephrine) to achieve this desired blood pressuregoal. • Finally, the ScvO2 goal of 70% or higher was targeted after central venous and mean arterial pressure goals were met. • If the ScvO2 was lower than 70% and the hematocrit was lower than 30%, packed red blood cells were transfused to achieve a hematocrit of at least 30%. • If the ScvO2 remained lower than 70% after the hematocrit was 30% or higher, dobutamine was initiated and titrated in attempts to achieve an ScvO2 of at least 70%. • Central venous catheter  ScvO2 Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

16. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Lactate clearance group • First, isotonic crystalloid was administered in boluses to achieve a central venous pressure of 8 mm Hg or higher. • Second, the mean arterial pressure goal of 65 mm Hg or higher, • if not achieved with fluid administration, was targeted by initiating and titrating vasopressors (dopamine or norepinephrine) to achieve this desired blood pressure goal. • Finally, the lactate clearance of at least 10% goal was targeted after central venous and mean arterial pressure goals were met. • Lactate clearance = [(lactate initial −lactate delayed)/ lactate initial] x 100%, for which lactate initial was the measurement at the start of the resuscitation and lactate delayed was another measurement after a minimum of 2 hours after resuscitation was initiated • If the lactate clearance was not at least 10% at the first delayed measurement and the hematocrit was less than 30%, packed red blood cells were transfused to achieve a hematocrit of at least 30%. • If the lactate clearance remained lower than 10% after the hematocrit was at least 30%, dobutamine was initiated and titrated in attempts to achieve a lactate clearance of at least 10%. • When treatment was continued due to lactate clearance less than 10%, subsequent lactate measurements were performed at a minimum of 1-hour intervals and repeat lactate clearance calculated. • Central venous catheter ScvO2 Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

17. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Study patients were treated in the emergency department during the entire study treatment period, from randomization to either of the 2 study termination criteria: all treatment goals were achieved or 6 hours had elapsed. • Patients were then transferred to an ICU where the critical care physicians, unencumbered by the study protocol in any way, assumed the care of all patients. The study investigators did not provide care for the patients or influence their care in the ICU. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

18. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • As a safety measure, clinical physicians could elect study group crossover. • For patients assigned to the ScvO2 group, clinicians could order a second lactate concentration to calculate the lactate clearance. In the lactate clearance group, the clinician could request to connect the central venous catheter to monitor ScvO2. • To execute 1 of these options, the clinician was required to indicate clinical deterioration based on 1 of the following criteria: • (1) falling systolic blood pressure or inadequate urine output (0.5mL/kg per hour); • (2) worsening ventilatory status based on either clinical (respiratory rate, oxygen saturation, or oxygen requirement), arterial blood gas, or mechanical ventilator parameters; or • (3) worsened mental status Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

19. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Assessments and Outcome Measures • During the study resuscitation treatment period, the patient’s physiological parameters were measured routinely. • All data needed to calculate the Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, and the Mortality in Emergency Department Sepsis were collected. • After ICU admission, patients were assessed daily for 72 hours and detailed data were collected. • Patients were followed up until hospital discharge or death. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

20. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Study Flow Diagram Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

21. Ερώτηση 4 Πως θα συγκρίνεται τις 2 ομάδες ασθενών; • Με το paired t-test • Με το unpaired t-test • Με το Mann-Whitney U test • Με το x2 test

22. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Patient Demographics and Clinical Characteristics NS Continuous data are compared using an unpaired t test; categorical data, using the x2 test. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

23. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Systemic Inflammatory Response Criteria and Dysfunctional Organ Systems NS Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

24. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Physiological and Severity of Illness Measurements Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

25. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Administered Treatments and Resuscitation Goals Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

26. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial Hospital Mortality and Length of Stay Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

27. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Patients in the group resuscitated to a lactate clearance of 10% or higher had 6% lower in-hospital mortality than those resuscitated to an ScvO2 of at least 70% (95% CI for this difference, −3% to 15%) exceeding the −10% predefined noninferiority threshold. • These data support the substitution of lactate measurements in peripheral venous blood as a safe and efficacious alternative to a computerized spectrophotometric catheter in the resuscitation ofsepsis Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

28. Ερώτηση 5 Τι είναι τα 95% διαστήματα αξιοπιστίας (CI) μιάς διαφοράς αναλογιών; • Η διαφορά της αναλογίας Α από την αναλογία Β • Η % διαφορά των αναλογιών • Τα διαστήματα μέσα στα οποία θα βρεθεί το 95% των διαφορών

29. Έτσι υπολογίζονται τα διαστήματα αξιοπιστίας!95% CI for this difference, −3% to 15% na and nb =the total numbers of observations in two samples, A and B ka and kb=the numbers of observations within each sample that are of particular interest pa= ka/naand pb= kb/nb http://faculty.vassar.edu/lowry/prop2_ind.html

30. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Author Contributions: • Dr Jones had full access to allof the data in the study and takes responsibility forthe integrity of the data and the accuracy of the dataanalysis. • Study concept and design: Jones, Shapiro, Trzeciak, Kline. • Acquisition of data: Jones, Shapiro, Trzeciak, Arnold,Claremont, Kline. • Analysis and interpretation of data: Jones, Shapiro,Trzeciak, Kline. • Drafting of the manuscript: Jones, Kline. • Critical revision of the manuscript for important intellectualcontent: Jones, Shapiro, Trzeciak, Arnold,Claremont, Kline. • Statistical analysis: Jones, Kline. • Obtained funding: Jones, Kline. • Administrative, technical, or material support: Jones,Shapiro, Arnold, Claremont, Kline. • Study supervision: Jones, Kline Trial Registration clinicaltrials.gov Identifier: NCT00372502 Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

31. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Financial Disclosures: • Dr Jones reports receiving research support from Critical Biologics Corp and Hutchinson Technology and having served on an advisory board for Brahms and Siemens in 2009. • Dr Trzeciak reports that he receives research support from Ikaria, Novo Nordisk, serves as a consultant to Spectral Diagnostics, and has received 3 honoraria from Edwards Lifesciences prior to 2005, but has not received any personal remuneration from any commercial interest since 2005. • Dr Shapiro reports that he has received research support from Biosite, Hutchinson Technology, and Eli Lilly. • Dr Kline reported that he is the inventor on US patent 7,083,574, a breathbased device that monitors patient response to resuscitation. • Dr Arnold and Ms Claremont reported no financial conflicts Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

32. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Funding/Support: This project was supported by grant GM76652 from the National Institutes of Health (NIH), National Institute of General Medical Sciences (Dr Jones). • Dr Trzeciak was supported by grant GM83211 from the NIH. Dr Shapiro was supported by grants HL091757 and GM076659 from the NIH. • Role of the Sponsors: The sponsor of this study reviewed and approved the study design but had no role in the conduct of the study; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the article. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

33. Lactate Clearance vs Central VenousOxygen Saturation as Goalsof Early Sepsis TherapyA Randomized Clinical Trial • Additional Contributions: We thank • J. Lee Garvey, MD, who functioned as the study monitor; • Jackeline Hernandez, MD, and Nikita Young, BS (all from Carolinas Medical Center, Charlotte, North Carolina), and DavidLundy,MD (Cooper University Hospital, Camden, New Jersey), for their invaluable assistance with monitoring the study and enrolling patients; • Charlie Johnson, BS (paid consultant from Studymaker LLC, Newton, Massachusetts) for assistance with database management. • We also thank • R. Phillip Dellinger, MD (Cooper University Hospital, Camden, New Jersey), for his thoughtful critique of this report and who received no remuneration. • We are indebted to the emergency department and ICU nurses and physicians at Carolinas Medical Center, Beth Israel Deaconess Medical Center, and Cooper University Hospital who willingly assisted in the care of the study patients. • Finally, we humbly express our deepest gratitude to the patients who so willingly participated in this study. Jones AE, Shapiro NI, Trzeciak S,Arnold RC, Claremont HA,Kline JA, for the Emergency Medicine ShockResearch Network (EMShockNet)InvestigatorsJAMA. 2010;303(8):739-746

34. Και μετά και μετά ;; • Puskaricha MA, Trzeciak S, Shapiro NI, Heffner AC, Kline JA,JonesAE, On behalf of the Emergency Medicine Shock Research Network (EMSHOCKNET). • Outcomes of patients undergoing early sepsis resuscitation for cryptic shockcompared with overt shock. Resuscitation 2011; 82:1289– 1293

35. Συμπέρασμα Πολύ καλά δομημένη επιστημονική δουλειά Πολύ καλός σχεδιασμός Πολύ καλή στατιστική επεξεργασία των δεδομένων Η κάθαρση του γαλακτικού > 10% είναι εξίσου αξιόπιστο εργαλείο για την παρακολούθηση της ανάνηψης των σηπτικών αρρώστων τις πρώτες 6 ώρες στο ΤΕΠ, όπως ο ScvO2 Χρόνια πολλά Ευχαριστώ για την προσοχή σας