Top Sepsis Studies

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1 A75M233/A75M529 Monday 08:00-09:15 Wednesday 14:45-16:00 Maureen A Seckel APRN, ACNS-BC, CCRN, CCNS, FCCM Critical Care CNS and Sepsis Leader Christiana Care Health Services, Newark, DE Top Sepsis Studies

2 Disclosure National Association for Continuing Education/La Jolla Pharmaceuticals Grant Project

3 Objectives 1. Review new research pertinent to sepsis care 2. Apply knowledge of current sepsis guidelines with current pertinent case studies 3. Analyze appropriateness of how to apply research clinically

4 Live Content Slide When playing as a slideshow, this slide will display live content Poll: NameONE top barrier in your care of sepsis patients?

5 2 Quick Updates About Sepsis.

7 VS Levy M, et al. Intensive Care Medicine.

8 NEW 1 Hour Bundle Measure lactate (remeasure if > 2) Obtain blood cultures prior to antibiotics Administer broad-spectrum antibiotics Rapid administration of 30ml/kg crystalloid for BP or lactate 4 Vasopressors if BP during or after fluid resuscitation to maintain MAP 65

9 9 TOP SEPSIS STUDIES

10 1 Angiotensin II Angiotensin II for the Treatment of High- Output Shock (ATHOS-3)

11 What is Angiotensin II Octa-peptide hormone that is a potent but labile vasoconstrictor Produced in the kidney from angiotensin I after the removal of two amino acids by angiotensin converting enzyme (ACE) in the lung, endothelial cells, kidney, and brain Acts on the central nervous system to regulate renal sympathetic nerve activity, renal function, and, therefore, blood pressure

12 RASS

NEJM Angiotensin II RCT, double-blind, placebo controlled Eligibility 18 with vasodilatory shock after min 25 ml/kg volume resuscitation AND high-dose vasopressors N=321

13 NEJM Angiotensin II RCT, double-blind, placebo controlled Eligibility 18 with vasodilatory shock after min 25 ml/kg volume resuscitation AND high-dose vasopressors N=321 patients (163 A, 158 placebo) North America, Australasia, Europe 80.7% sepsis Vasodilatory Shock CI > 2.3 l/min, OR ScvO2 > 70%, AND CVP > 8 mmhg MAP > 0.2 mcg norepinephrine

14 Treatment Angiotensin II OR Saline (Placebo) Initiated 20 ng/kg/min, max 200 Hours 1-3: adjusted to MAP to minimum 75 mmhg; vasopressors were constant Hours : adjusted to MAP mmhg; vasopressor could be adjusted

15 Results

16 Primary and Secondary End Points MAP response 3 hours 69.9% vs 23.4% p < Mean Change in NE equivalent dose vs P <0.001 Khanna, et al. NEJM. 2017;377:

17 Angiotensin II Angiotensin II increased BP and reduced vasopressor dose in patients with vasodilatory shock who were receiving high dose vasopressors FDA approved 12/21/17 Available 3/18 GIAPREZA

18 A Word About Giapreza Starting dosage 20 nanograms ng/kg/min Central venous line is recommended Monitor blood pressure response and titrate GIAPREZA every 5 minutes by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure Do not exceed 80 ng/kg/min during the first 3 hours of treatment Maintenance doses should not exceed 40 ng/kg/min Once the underlying shock has sufficiently improved, down-titrate every 5 to 15 minutes by increments of up to 15 ng/kg/min based on blood pressure

Calculator Fluid Restricted Drug Added IV bag Final Concentration No 1-2.5 mg/ml 500 ml 5,000 ng/ml Yes 1 2.5 mg/ml 250 ml 10,000 ng/ml 2 2.

19 Calculator Fluid Restricted Drug Added IV bag Final Concentration No mg/ml 500 ml 5,000 ng/ml Yes mg/ml 250 ml 10,000 ng/ml mg/ml 500 ml 10,000 ng/ml 1 mg = 1,000,000 (1 million) nanograms 1 mg = 1,000 microgram 8.4 = 20 ng/kg/min X 70 kg X 60 min/hr 10,000 ng/ml

20 2 Vitamin C

21 Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock

22 Vitamin C Retrospective 7 month before-after study 1 facility IV Vitamin C 1.5 g Q 6 hours over 4 days Hydrocortisone 50 mg IV Q 6 hours over 7 days Thiamine 200 mg IV Q 12 hours over 4 days N=47 patients in both arms No significant differences between groups; primary diagnosis, comorbidities, vasopressor use, APACHE scores, etc. Marik, et al. Chest. 2017;151:

23 Results Hospital mortality (p<0.001) Treatment 4(8.5) Control 19 (40.4) ICU LOS Treatment 4 (3-5) Control 4 (4-10) Vasopressors (p<0.001) Treatment Control

IV shortages Remember tight glucose control VICTUS is coming Caution: point of care blood glucose testing in

24 Vitamin C Vitamin C with steroids and thiamine may prove to be effective in preventing progressive organ dysfunction and reducing mortality of patients with sepsis and septic shock Can it hurt? IV shortages Remember tight glucose control VICTUS is coming Caution: point of care blood glucose testing in patients who are receiving intravenous therapy may falsely elevate results. Please send bloodwork to the lab for optimal interpretation.

25 Live Content Slide When playing as a slideshow, this slide will display live content Poll: Which statement is INCORRECT about the 2 previous studies (1,2)?

26 3 NY Mandated Emergency Care

Background 2013 Rory s Regulations 405.2, 405.

27 Background 2013 Rory s Regulations 405.2, Required reporting 3-hour and 6-hour bundle measures

28 NY Mandated Emergency Care Retrospective study patients with sepsis and septic shock that were reported to NY State Department of Health from 4/1/14 to 6/30/16 N=49,331 patients at 149 hospitals Sepsis protocol in ED within 6 hours All 3-hour bundle components within 12 hours Seymour, et al. NEJM. 2017;376:

29 Results Results 40,696 (82.5%) 3 hour bundle completion within 3 hours In hospital mortality (p=0.05) 9,213 (22.6%) vs 2038 (23.6%) Each hour to completion of 3-hour bundle was associated with higher mortality 1.04 per hour, 95% CI, ; p<0.001 Bundle completion hours % higher odds of in-hospital death Seymour, et al. NEJM. 2017;376:

30 Results

Results 1-3 hours 1.04 per hour, 95% CI, 1.03-1.

22, p=0.001 1-3 hours 1.04 per hour, 95% CI, 1.03-1.

31 Results 1-3 hours 1.04 per hour, 95% CI, ; p< hours 1.14 per hour, 95% CI, , p= hours 1.04 per hour, 95% CI, ; p< hours 1.14 per hour, 95% CI, , p=0.001

32 NY Mandated Emergency Care Association between time to treatment and outcomes among patients treated in a NY ED 82% EDs compliance with 3-hour bundle in 1 st 3 hours A longer time to treatment for the 3-hour bundle and antibiotics were associated with higher riskadjusted in-hospital mortality No association between time to completion initial fluid bolus and in-hospital mortality Authors: Fluid data should not be interpreted as evidence in favor of abandoning early fluid resuscitation. Causal inference will require RCTs.

33 4 Antibiotics

34 Antibiotics Retrospective study to evaluate association between antibiotic timing and mortality Eligibility N=35,000 randomly selected inpatients with sepsis Treated at 21 EDs between Northern California

35 Treatment Adults 18 with sepsis diagnosis codes Medical record review Calculated time from ED registration to administration of 1 st IV or enteral antibiotic

36 Results Observed Mortality Sepsis N=12, (3.9%) Severe Sepsis N=18,210 1,595 (8.8%) Septic Shock N=4,668 1,215 (26%)

37 Results - Mortality Each lapsed hour was associated with a 9% increase in mortality

38 Antibiotics In patients with sepsis admitted through ED, each lapsed hour between presentation and antibiotic administration was associated with 9% increase in odds of mortality in patients with sepsis, severe sepsis, and septic shock Although antibiotics given within 1 st hour were associated with greatest benefit, antibiotics given between hours 2-5 were associated with similar odds of mortality

39 Live Content Slide When playing as a slideshow, this slide will display live content Poll: Which statement is INCORRECT about the 2 previous studies (3,4)?

40 Steroids (ADRENAL) trial 5

41 Steroids International double-blind, parallel-group, RCT Eligibility Adults with septic shock with mechanical ventilation Treated with vasopressors or inotropes for minimum of 4 hours Australia, UK, New Zealand, Saudi Arabia, Denmark N=3658 (1832 H, 1826 placebo)

42 Treatment IV Hydrocortisone OR Placebo IV infusion hydrocortisone at 200 mg/day Continuous infusion over 24 hours for a maximum of 7 day Endpoints ICU discharge or death

43 Results - Survival

44 Results

45 Results - Secondary Outcomes Median time to resolution of shock p<0.001 Hydrocortisone 3 (2-5) vs Placebo 4 (2-9) Median time to ICU discharge p<0.001 Hydrocortisone 10 (5-30) vs Placebo 12 (6-42) Median time to cessation ventilator days p<0.001 Hydrocortisone 6 (3-18) vs Placebo 7 (3-24) Blood transfusions p=0.004 Hydrocortisone 683/1848 (37%) vs Placebo 773/1855 (41.7%)

46 Steroids In patients with septic shock and mechanical ventilation, the administration of continuous infusion of hydrocortisone did not result in lower mortality at 90 days than placebo There were some secondary outcomes that were better for the hydrocortisone treatment arm however; no difference in shock reoccurrence number of days out of ICU or hospital Duration and reoccurrence rate mechanical ventilation Rate or renal replacement therapy Rate of new-onset bacteremia or fungemia

47 Steroids Activated PROtein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial 6

48 Steroids Multicenter, double-blind, RCT Eligibility Adults with indisputable or probable septic shock Infection + SOFA score (min 3-4) + vasopressors for minimum 6 hours 34 centers N=1241 (614 T, 627 placebo)

49 Randomization Treatment Steroid Placebo + DAA Placebo Steroids + DAA Placebo Steroids Placebo + DAA Steroids + DAA Hydrocortisone 50 mg IV Q 6 hr, + Fludrocortisone 50 mcg per ng/og

50 Results (264)43% vs (308)49.1%

51 Secondary Outcomes ICU mortality (217)35.4% vs (257)41% Hospital discharge (239)39% vs (284)45.3% Shorter weaning from mechanical ventilation P=0.006 Shorter weaning vasopressors P<0.001 Time to reach SOFA score < 6 P<0.001 Vasopressor free days P<0.001 Organ-failure free days P=0.003

52 Steroids 90 day all cause mortality was lower among ICU patients with septic shock who received Hydrocortisone + Fludrocortisone vs placebo Secondary outcomes were better for the treatment arm however; No significant difference in GI bleeding No significant increase in superinfection Higher risk of hyperglycemia; P=0.002 Steroids appear safe and generally beneficial for patient with septic shock

53 Live Content Slide When playing as a slideshow, this slide will display live content Poll: Which statement is INCORRECT about the 2 previous studies (5,6)?

54 7 Sepsis Survivors

55 Sepsis Survivors Retrospective cohort study Eligibility Random 5% Medicare discharges for severe sepsis N=135,370 United States Quantify cognitive and physical functional impairment in Medicare patients with severe sepsis and were discharged to a SNF

56 Results Survival by Discharge Location 1 year Mortality 35.6% not SNF 43.2% SNF 52.8% return SNF

57 Results Survival and Cognition Median Survival Very severe: 2.6 months Severe: 7 months Moderate: 14.3 months Intact: 24.2 months

58 Results Survival and ADLs Median Survival Total Dependent: 2.3 months Dependent: 8.7 months Independent: 39.9 months

59 Sepsis Survivors Discharge to SNF was associated with shorter survival in this cohort of Medicare patients surviving hospitalization with severe sepsis Cognitive impairment and ADL dependence were each strongly associated with shortened survival Suggest future studies for associations with longer term outcomes New cognitive impairment and ADL dependence vs preexisting May help target prognostication and decision making

60 8 Fluid Responsiveness

61 Fluid Responsiveness Secondary analysis; prospective, multisite, observational, consecutive-sample cohort 9 hospitals in NY from 10/1/14-3/31/16 N= 3,686 hypotensive sepsis patients 1,241 Responsive, 773 Refractory 1. Determine the prevalence of fluid responsiveness in initially hypotensive sepsis patient 2. Determine baseline clinical variables 3. Assess timeliness of fluid responsiveness

62 Definitions Hypotensive SBP < 90 mmhg > 40% baseline MAP < 65 mmhg Fluid responsive Initially hypotensive; sustained BP without vasopressor titration for 24 hours after initiation of fluid resuscitation Refractory SBP/MAP did not reach target, was transient, or required vasopressor titration Fluids 0.9% normal saline

$Results Fluid Responsiveness Model 1: Patient identified predictors Refractory 1. CHF 2.$

63 Results Fluid Responsiveness Model 1: Patient identified predictors Refractory 1. CHF 2. Temp < Initial lactate 4 4. Immunocompromised 5. Coagulopathy 6. Altered gas exchange

64 Model 1 Patient Risk Factors The greater number of risk factors, higher % of Refractory

65 Model 2: Intervention factors Fluid resuscitation > 120 minutes (delayed) strong predictor of Refractory

66 Patient Outcomes

67 Fluid Responsiveness 2350/3688 (64%) were fluid responsive Refractory predictors include; CHF, immunocompromised, hypothermia, hyperlactemia, coagulopathy Late initiation (> 2 hours) of fluid resuscitation was stronger than any other factor for refractory Mortality, mechanical ventilation, ICU utilization and LOS were all increased in refractory patients

68 Fluids Isotonic Solutions and Major Adverse Renal Events Trial (SMART) trial 9

69 Fluids Pragmatic, cluster-randomized, multiplecrossover trial 5 ICUs at academic center from 6/1/15-4/30/17 N= 15,802 Adult ICU patients 7942 balanced crystalloid vs 7860 saline Balanced crystalloid Lactated Ringers or Plasma Lyte A Saline 0.9% NS

70 Methods Relative contraindications balanced crystalloids Hyperkalemia Brain injury Saline Option Advisor CPOE Relative Risk? YES NO Assigned Balanced Crystalloid

71 Results Outcomes Balanced Crystalloids MAKE (14.3%) Saline 1211 (15.4%) P value P=0.04 Mortality 10.3% 11.1% P=0.06 Sepsis Mortality 25.2% 29.4% P=0.02 New RRT 2.5% 2.9% P=0.08 Renal dysfunction 6.4% 6.6% P=0.60

72 Results Major Adverse Kidney Events

73 Results - Mortality

74 Results Hazard Ratio BC to saline 0.93 (95% CI ); P= (95% CI ); P=0.03

75 Fluids In critically ill adults, balanced crystalloids resulted in lower mortality, lower new RRT, and lower persistent renal failure than saline Patient with sepsis had improved outcomes (mortality and RRT)with balanced crystalloids vs saline No information regarding LR vs Plasma Lyte A

76 Live Content Slide When playing as a slideshow, this slide will display live content Poll: Which statement is INCORRECT about the 3 previous studies (7,8,9)?

77 Conclusions The Science of Sepsis is continually evolving It is important to keep updated on the research and to ask those why questions

78 Late Breaking

79 SIRS Sepsis-1 VS SOFA Sepsis-3 Retrospective analysis 21, 491 infected patients Medical Information Mart for Intensive Care-III data base SOFA had higher AUC mortality prediction SIRS had higher sensitivity (96% vs 91%) Suggestion that may be not appropriate to compare predictive performance Fang, et al. CHEST 2018;153(5):

80 PCT use effects No difference ICU LOS, Hospital LOS, recurrent infections Initiation/mixed no effect mortality Cessation mortality duration antibiotics Lam, et al. Crit Care Med 2018; 46: )

81 PCT is effective biomarker in guiding antibiotic discontinuation antibiotic duration No adverse effects ICU LOS or mortality Iankova, et al. Crit Care Med;2018;46:

82 Thank You

83 References 1. Khanna, et al. Angiotensin II for the treatment of vasodilatory shock. NEJM. 2017;377: Marik, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151: Seymour, et al. Time to treatment and mortality during mandated emergency care for sepsis. NEJM. 2017;376: Liu, et al. The timing or early antibiotics and hospital mortality in sepsis. Am J Resp Crit Care Med. 2017;196: Venkatesh, et al. Adjunctive glucocorticoid therapy in patients with septic shock. NEJM DOI: /NEJMoa Annane, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. NEJM. 2018;378: Ehlenbach, et al. Sepsis survivors admitted to skilled nursing facilities: cognitive impairment, activities of daily living dependence, and survival. Crit Care Med. 2018; Leisman, et al. Predictors, prevalence, and outcomes of early crystalloid responsiveness among intially hypotensive patients with sepsis and septic shock. Crit Care Med : Semler, et al. Balanced crystalloids versus saline in critically ill adults. NEJM. 2018;378:

CORTICOSTEROID USE IN SEPTIC SHOCK THE ONGOING DEBATE DIEM HO, PHARMD PGY1 PHARMACY RESIDENT VALLEY BAPTIST MEDICAL CENTER BROWNSVILLE

CORTICOSTEROID USE IN SEPTIC SHOCK THE ONGOING DEBATE DIEM HO, PHARMD PGY1 PHARMACY RESIDENT VALLEY BAPTIST MEDICAL CENTER BROWNSVILLE 1 ABBREVIATIONS ACCP = American College of Chest Physicians ARF =