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Journal Club 8/21/07

Mike Chacey, M.D., Chloe Steinshouer, M.D., Abbie Begnaud, M.D., Amanda Davis, D.O. . Journal Club 8/21/07. Severe Sepsis. Septic Shock. SIRS. Sepsis. The Sepsis Continuum. A clinical response arising from a nonspecific insult, with  2 of the following: T >38 o C or <36 o C

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Journal Club 8/21/07

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  1. Mike Chacey, M.D., Chloe Steinshouer, M.D., Abbie Begnaud, M.D., Amanda Davis, D.O. Journal Club 8/21/07

  2. Severe Sepsis Septic Shock SIRS Sepsis The Sepsis Continuum • A clinical response arising from a nonspecific insult, with 2 of the following: • T >38oC or <36oC • HR >90 beats/min • RR >20/min • WBC >12,000/mm3or <4,000/mm3 or >10% bands SIRS with a presumed or confirmed infectious process Sepsis with organ failure Refractory hypotension SIRS = systemic inflammatory response syndrome Chest 1992;101:1644. Slide modified from Eloise Harman ppt

  3. Sepsis: A Major Cause of ICU Death • More than 750,000 cases of severe sepsis in the US each year • Mortality about 20% (recent decline) • Economic cost of $17 billion each year • Incidence is projected to increase by 1.5% yearly • Although prognosis has improved, because of increased incidence, actual deaths will increase

  4. Goal Directed Therapy Administration of fluids, pressors and transfusion based upon targets for CVP, blood pressure, urine output, mixed venous oxygen saturation and hematocrit.

  5. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Study purpose: to evaluate the efficacy of early goal-directedtherapy in patients presenting to an emergency department with severe sepsis or septic shock (prior to ICU admission) Study design: prospective, randomized controlled, partially blinded, single center trial

  6. Inclusion Criteria • 2 out of 4 criteria for SIRS. • SBP <90 mm of Hg or • Lactate levels 4 mmol/L

  7. Exclusion Criteria • Age <18 • Pregnancy • Acute CVA and seizure • Acute coronary syndrome • Acute Pulmonary edema • Status asthamaticus • Cardiac dysarhythmias(as primary diagnosis)

  8. Exclusion Criteria – cont’d • Acute GI bleeding • Requirement for immediate surgery • Uncured cancer and immunosuppression • DNR • Contraindication to central venous catheter. • Drug over dose • Trauma and Burn injury

  9. Interventions Compared • The study compares the EGDT and standard therapy for sepsis. • EGDT: a definitive resuscitation strategy involves goal directed manipulation of cardiac preload, and contractility to achieve a balance between systemic oxygen delivery and oxygen demand prior to admission. • Standard: protocol for hemodynamic support on the basis of physical findings, vital signs, cvp, and urinary output and admitted to inpatient care asap.

  10. Overview of Patient Enrollment and Hemodynamic Support Rivers E et al. N Engl J Med 2001;345:1368-1377

  11. Protocol for Early Goal-Directed Therapy Rivers E et al. N Engl J Med 2001;345:1368-1377

  12. Base-Line Characteristics of the Patients Rivers E et al. N Engl J Med 2001;345:1368-1377

  13. Outcome Measures • Patients Temp., HR, BP, CVP were measured continuously for first 6 hours of treatment and assessed every 12 hours for 72 hrs. • ABG, Scvo2 by co-oximeter, lactate levels, coagulation-related variables and clinical variables required for APACHE, SAPS, MODS at 0, 3, 6, 12, 24, 36, 48, 60, 72 hours.

  14. Outcome measures contd.. • In-hospital mortality was the primary efficacy end point. • Secondary end points include organ dysfunction scores, treatment administered and health care resource utilization. • Patients were followed for 60 days or until death.

  15. Vital Signs, Resuscitation End Points, Organ-Dysfunction Scores, and Coagulation Variables Rivers E et al. N Engl J Med 2001;345:1368-1377

  16. Early Goal-Directed Therapy Results:28 Day Mortality 60 49.2% P = 0.01* 50 40 33.3% Mortality Sudden CV Collapse 21%vs10% p=0.02 30 20 MODS 22%vs16% P=0.27 10 0 Standard Therapy N=133 EGDT N=130 *Key difference was in sudden CV collapse, not MODS

  17. Kaplan-Meier Estimates of Mortality and Causes of In-Hospital Death Rivers E et al. N Engl J Med 2001;345:1368-1377

  18. Treatments Administered Rivers E et al. N Engl J Med 2001;345:1368-1377

  19. Results • During initial 6 hours: -EGDT group received more fluids, transfusion & inotropic support. -Standard group has lower Scvo2 & high base deficit.

  20. Results Cont • During 7 to 72 hours: - Standard group received more fluid, transfusion, inotropics, underwent mechanical ventilation and PAC. -Standard group has higher APACHE II, SAPS, MODS score and higher lactate, base deficit & lower PH.

  21. Results cont • In-hospital mortality occurred in 38 (30.5%) EGDT and 59 (46.5%) standard. • In the standard group had longer hospital stays.

  22. Readers GuideChoosing Evidence Worksheet • Are the results valid? • Did experimental and control groups begin the study with a similar prognosis? • Were the pt’s randomized? Yes, after eligibility was determined they were assigned to EGT or ST. • 2. Was the randomization concealed? Yes, in computer generated blocks of 2-8 assignments were placed in envelopes to be opened by hospital staff not part of the study. • 3. Were pt’s analyzed in the groups they were assigned? Yes, all 263 were included in intention to tx analysis. • 4. Were pt’s in tx and control groups similar? Yes.

  23. Readers GuideChoosing Evidence Worksheet • Did experimental and control groups retain a similar prognosis after the study started? • Were pt’s aware of group allocation? Not clearly addressed. Would somewhat depend upon medical acumen of pt. • 2. Were clinicians aware of group allocation? Not during the initial assessment, but for a brief period during ED tx (estimated to be 9.9% EGT vs. 7.2% of hospital stay). ICU clinicians were blinded. • 3. Were outcome assessors aware of group allocation? No • 4. Was follow-up complete? 27 pt’s didn’t complete (14 vs 13). Similar reasons in both groups.

  24. Readers GuideChoosing Evidence Worksheet • What are the results? • How large was the treatment effect? • In hospital mortality EGD 30.5% vs ST 46.5% (ARR=16%. NNT = 6pt’s, p=0.009. • 2. Secondary outcomes showed significant differences in favor of EGD at 6hrs for CVP, MAP, CV02, lactate, and APACHE-II. • How precise was the estimate of the treatment effect? • 1. In hospital mortality RR = 0.58 (95% Cl 0.38-0.87). 60 day mortality RR = 0.67 (95% Cl 0.46-0.96)

  25. Readers GuideChoosing Evidence Worksheet • How can I apply the results to patient care? • Were the study patients similar to my patient? Close. Probably a bit more urban and a bit busier ED. Likely comparable. • Were all clnicially important outcomes considered? For the most part. One could look at more long-term sequalae, future clinically significant events. • Are the likely tx benfits worth potential harm and costs? Resource consumption was analyzed and shown to be similar. ST had longer LOS in surviving pts.

  26. Remaining Questions • Not many. A well done study that answered some specific questions. • Just a study of pt’s paid attention to vs. those ignored? • More liberal transfusion limits than in ’99 NEJM article on transfusion.

  27. Current Events in EGDT Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol-based sepsis resuscitation in the emergency department-Results of a national survey. Crit Care Med. 2007 Aug 14 “More than half of all respondents recognized a critical shortage of nursing staff, problems in obtaining central venous pressure monitoring, and challenges in identification of patients with sepsis as the largest roadblocks to overcome in implementing early goal-directed therapy.” Huang DT, Clermont G, Dremsizov TT, Angus DC. Implementation of early goal-directed therapy for severe sepsis and septic shock: A decision analysis. Crit Care Med. 2007 EGDT has important start-up costs, and modest delivery costs, but assuming LOS and mortality are reduced, EGDT can be cost-saving to the hospital and associated with favorable lifetime cost-effectiveness projections. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest. 2007 Aug;132(2):425-32. Implementation of EGDT in our ED was associated with a 9% absolute (33% relative) mortality reduction. Our data provide external validation of the clinical effectiveness of EGDT to treat sepsis and septic shock in the ED. Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. 2007 Apr;35(4):1105-12. Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality. Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP. A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial. Shock. 2006 Dec;26(6):551-7. We evaluated whether a goal-directed protocol, without measurement of central venous oxygen saturation, would improve survival in medical intensive care unit (ICU) patients with septic shock. Implementation of a goal-directed protocol improves survival and clinical outcomes in ICU patients with septic shock.

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