Early goal directed therapy (EGDT) aims to balance oxygen delivery and demand through manipulating cardiac preload, afterload and contractility using measures like lactate, base deficit and ScvO2. A study of 263 patients with severe sepsis or septic shock found that those receiving EGDT in the emergency department for at least 6 hours had significantly lower in-hospital, 28-day and 60-day mortality compared to standard therapy. EGDT also resulted in fewer organ dysfunctions, less coagulation abnormalities and cardiovascular collapse.

1. Early goal directed therapy in the treatment of severe sepsis and septic shock Presented by: Dana Darwish PGY1 SICU CCF

2. Introduction There are an estimated 751,000 cases of sepsis or septic shock in the US each year, and they are responsible for as many deaths as acute MI (9.3% of all deaths). In the elderly, the incidence of septic shock and the mortality are substantially higher than younger indiviuals. The present annual cost is estimated at $16.7 billion.

3. Introduction When a systemic inflammatory response develops, it can be self-limited or progress to severe sepsis and septic shock. Intravascular volume depletion, peripheral vasodilation, myocardial depression, and increased metabolism all lead to imbalance between oxygen delivery and demand, resulting in global tissue hypoxia. Global tissue hypoxia precedes multiorgan failure and death .

4. Introduction The transition to tissue hypoxia occurs during the “Golden Hours”, which if recognized and treated early can provide maximum benefit and improve outcome. The golden hours can be in the ED, Hospital ward, or ICU. Physical findings, vital signs, central venous pressure, and urinary output fail to detect persistent global tissue hypoxia.

5. Introduction Mixed venous oxygen sats, lactate concentration, base deficit, and PH vlaues are better resuscitation end points and can be used to manipulate cardiac preload, afterload and contractility to achieve a balance between systemic oxygen delivery and demand. This paper examines whether early goal directed therapy, using the above measures, before admission to the ICU effectively reduces the incidence of multiorgan dysfunction, mortality, and the use of health care resources among patients with severe sepsis or septic shock.

6. Methods Eligibility: Criteria for inclusion: 2 of 4 criteria for SIRS (temp >38 or <36C, HR >90BPM, RR>20 BPM or PCO2<32 mmHg, or WBC>12,000 or < 4000/mm3 or Bands>10%. SBP no higher than 90mmHg (after a crystalloid fluid challenge of 20-30cc/Kg over 30 minutes. Lactate of 4mmol/L or more.

7. Methods Eligibility: Criteria for exclusion: Age < 18 Pregnancy Acute Cerebral vascular event Acute coronary syndrome Acute pulmonary edema Status epileticus Cardiac dysrhythmias Contraindications to central venous cath Active GI hemmorrhage Seizure, drug overdose, burns, trauma, need for immediate surgery, cancer, immunosupression, DNR, or advanced directives limiting treatment.

8. SIRS criteria and SBP<90 or Lactate>4 Assessment and consent Randomization N=263 Standard therapy N=133 Early goal-directed Therapy N=130 Vitals, lab data, cardiac monitoring, Pulse ox, urinary cath, arterial And central venous cath Standard care: CVP 8-12mmHg MAP>65mmHg UO>.5cc/kg/hr Early goal directed therapy>6hrs: CVP 8-12mmHg MAP>65mmHg UO>.5cc/kg/hr SCvO2>70%, SaO2>90%, HCT>30%, CI, VO2. Hospital admission Vitals and lab data Q 12hrs For 72 hrs Follow Up

9. Methods Treatment: Pts were treated in a 9 bed unit in the ED by an emergency physician, 2 residents, and three nurses. Physicians were unaware of the patients study group assignment, double blind. Pts in standard therapy group received hemodynamic support based on CVP, MAP, and UO. Antibiotics were given at the discretion of the physician and admitted for inpatient care ASAP.

10. Methods Treatment Patients in early goal-directed therapy were treated in the ED for at least 6 hrs according to the following protocol: 500cc bolus of crystalloids q 30 minutes to achieve CVP 8-12mmHg. Vasopressors and vasodilators given to achieve a MAP between 65-90mmHg. If ScvO2 <70%, red cells given to achieve HCT>30%. If ScvO2 still <70%, dobutamine 2.5ug/kg/min given to maximum of 20ug/kg/min. Dose was decreased or held for MAP <65mmHg or HR>120BPM. To decrease O2 consumption, pts received sedation and mechanical ventilation if HD optimization was not achieved.

11. Methods Outcome measures The Pts Temp, HR, UO, BP, CVP were measured continously for the first 6hrs, then every 12hrs for 72hrs. Arterial and venous blood gas, lactate, and coagulation related variables and clinical variables recquired for determining APACHE II (sc71), SAPS II (0-174), and MODS (0-24) , with higher scores reflecting more severe organ dysfunction, were obtained at 0, 3, 6, 12, 24, 36, 48, 60, 72 hrs. Patients were followed for 60 days or until death.

12. Methods Statistical Analysis The primary efficacy end point was in-hospital mortality. Secondary end point were resuscitation end points, coagulation-related variables, administered treatments, and the consumption of health care resources. Sample size of 260 pts was required to permit detection of 15% reduction in in-hospital mortality. Assuming 10% refusal or exclusion rate, two sided type I error of 5%, power of 80%. To describe relative risk RR of death, Kaplan-Meier estimates of mortality, risk ratios, and 95% CI were used. Differences between the two groups at base line were tested with students t-test, chi square test, or Wilcoxons rank-sum test The alpha spending function of deMets and Lan was used to determine a P value of 0.04 or less to indicate statistical significance.

13. Results Base line characteristics: 263 pts were randomly assigned to either standard therapy (control), or goal directed therapy. Of the 263 pts, 27pts did not complete the initial 6hr study period (14 in standard and 13 in early goal directed) due to exclusion criteria. There was no significant difference between the groups, including the excluded grps, in baseline characteristics, including adequacy and duration of antibiotics, or base-line vitals, resuscitation end points, organ dysfunction scores, or coagulation related variables.

14. Results Vital signs and resuscitation end points: In the first 6 hrs: No significant difference between the two groups in HR or CVP. MAP was significantly lower in the standard grp, (P<0.001), but goal was met by both grps ScvO2>70 was met by 60.2% in the standard grp vs. 94.9% in the early therapy grp (p<0.001), greater base deficit(p=.006), but similar lactate and pH values. The combined HD goals for CVP, MAP, and UO were achieved in 86.1% in the standard grp vs. 99.2% in the early goal therapy grp.

15. Results Vital signs and resuscitation end points: During the period of 7-72hrs: Pts in the standard grp had significantly higher HR (p=0.04) and significantly lower MAP (P<0.001) than pts in the early goal therapy grp. The two grps had similar CVP (P=0.68). Pts in the standard grp had significantly lower ScvO2 (P<.001), Higher lactate concentration (P=.02), greater base deficit (P<.001), and a lower PH(P<.001).

16. Results Organ dysfunction and coagulation variables: From 7-72 hrs, the APACHE II, SAP II, MODS scores were significantly higher in pts in the standard grp (P<0.001). PT, Fibrin split products, and D-dimers were significantly higher in the standard grp (P=0.001, P<0.001, P=.006 respectively). The two grps had similar pTT, fibrinogen concentration, and platelet counts (p=.06, p=0.21, p=0.51 respectively).

17. Results Mortality: In hospital mortality rate was higher In the standard grp (P=.009), as was the mortality at 28 days (P=0.01), and 60 days (0.03). Similar results were obtained in the 27 pts who were excluded in the first 6 hrs. The rate of in-hospital death due to sudden CV collapse was significantly higher in the standard grp (P=0.02). Death rate due to multiorgan failure was similar in the two grps (P=.27)

18. Results Administered treatment : In the initial 6 hrs: Pts in the early goal directed therapy received significantly more fluids, blood transfusions, and ionotropic support. Similar proportions of patients in both groups required vasopressors and mechanical ventilation.

19. Results Administered treatment: From 7-72 hrs: Pts in the standard group received significantly more fluid, more red cell transfusion, vasopressors, mechanical ventilation, and pulmonary artery cath. The rate of ionotropic agents was similar in both groups.

20. Results Administered treatment: From Base line to 72 Hrs: No significant difference between the two groups in total volume of fluids given (P=.73), or ionotropic agents(P=0.15). Greater portion of pts in the standard grp received vasopressors, mechanical vents, and pulmonary artery cath. Though HCT mean was similar between the two grps at baseline, it was significantly lower in the standard grp at 72 hrs (P<.001).

21. Results Consumption of health care resources: No significant differences between the two grps in mean duration of vasopressor therapy, mechanical ventilation, or mean length stay in the hospital. But, of the patients who survived to hospital discharge, those in the standard grp had stayed a significantly longer time in the hospital (P=0.04).

22. Discussion There is significant benefits with respect to outcome when goal directed therapy is applied at an earlier stage of the disease. In a study by Hayes et al. , higher in-hospital mortality rates with aggressive HD optimization, in pts with septic shock, was observed in the ICU (71%) vs control therapy (52%). In this study, lower mortality rate in septic pts was observed in the early goal directed goal therapy group (42.3%), than in the standard grp (56.8%). The incidence of sudden CV death in the standard group was double that in the early goal directed grp, suggesting that an abrupt transition to severe disease is an important cause of early death.

23. Discussion Among all pts in the study whom goals of CVP, MAP, and UO was achieved in the first 6 hrs, 39.8 % of those in the standard grp were still in the oxygen dependent phase of resuscitation at 6hrs as compared with 5.1% of those in the early goal directed therapy. This was an open, randomized, partially blinded trial with unavoidable interactions in the initial period of the study. As the study progressed, pts in the standard grp may have received some form of goal directed therapy. The potential period of bias was 9.9% in the standard grp and 7.2% in the goal directed grp. This interval is minimal compared to previous studies because clinicians who assumed responsibility for the remainder of the hospitalization were completely blinded to the randomization order.

24. Conclusion Early goal directed therapy at the earliest stages of severe sepsis and septic shock has significant short term and long term benefits. These benefits arise from early identification of patients at high risk for CV collapse and from early therapeutic intervention to restore balance between oxygen delivery and oxygen demand.

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