INVESTIGATIONAL TREATMENTS FOR SEPSIS AN OVERVIEW

Transcription

1 INVESTIGATIONAL TREATMENTS FOR SEPSIS AN OVERVIEW

2 THE GLOBAL BURDEN OF SEPSIS Mortality rate estimated to be 30-50% Rates estimated to be as high as 80% in developing nations One third to one half of all hospital deaths are related to sepsis Post Sepsis Syndrome: Survivors have significant long term physical, psychological, and cognitive disabilities 63% will be re-hospitalized within 1 year 1/3rd will die within the first year 24 billion spent annually in the US $325 million spent annually in Canada 45.1% of sepsis patients in Canada require ICU

3 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

4 SEPSIS: DEFINITION Life-threatening organ dysfunction caused by a dysregulated host response to an infection Three elements: Infection, Host response, Organ dysfunction Shaped by host, and pathogen factors Inflammatory mediators, clotting, anti-inflammatory mediators Characteristics can change over time Septic shock is considered a subset of sepsis Patients in which underlying circulatory, cellular, and metabolic abnormalities are profound enough to substantially increase mortality Lactate greater than 2 mmol/l and hypotension requiring vasopressors

5 SCREENING TOOLS Sequential Organ Failure Assessment score (SOFA) and Multiple Organ Dysfunction Syndrome score (MODS) Measure severity of organ dysfunction Describes how a patients status changes over time Acute Physiology and Chronic Health Evaluation II score (APACHE II score) Measure severity of disease in patients admitted to ICU Describes morbidity and can be used to predict mortality Simplified Acute Physiology Score II (SAPS II) Measure severity of disease in patients admitted to ICU Predicts mortality

6 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

7

8 INFLAMMATION AND CLOTTING Both an integral part of a normal immune response Immune system and coagulation system are evolutionarily linked Activate, and interact with each other Clotting restricts the spread of infection Inflammation increases blood flow to the site of infection (vasodilation), and allows for leakage of fluid from the blood vessels into damaged/infected tissue (vascular permeability) During a normal immune response, these processes are highly regulated and balanced to maintain localized effects and homeostasis Pro and anti-inflammatory mediators Coagulants and anticoagulants In Sepsis, there is a dysregulation of the normal immune response

9 Inflammation and coagulation

10 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

11 UNCOMPLICATED INFECTION VS SEPSIS The exact reason why uncomplicated infections turn in to sepsis is unknown, but likely multifactorial Pathogen factors: toxin production (exotoxins), bacterial structure (endotoxin) Host factors: age, gender, susceptibility to infection, genetic susceptibility, site of infection, etc. Pneumonia is the most common source accounting for 50% of cases Organisms involved in sepsis have changed over time In many cases an organism cannot be identified on cultures

12 SEPSIS AND ORGAN DYSFUNCTION Caused by direct cellular injury or impairment of tissue oxygenation Impaired tissue oxygenation Macrovascular causes: vasodilation results in hypotension and less oxygenated blood getting to organs Microvascular causes: imbalance in coagulation pathways results in clot formation in the microvasculature Direct cellular injury Nitric oxide released by endothelium can result in free radical production Anaerobic metabolism results in less ATP formation Critical point is reached where energy production doesn t meet demand Cell Death Lactate associated with anaerobic metabolism

13 SEPSIS: GENERAL APPROACH TO TREATMENT Time = Life For each hour therapy is delayed mortality increases 8% Source control Drain abscess, remove infected hardware, etc. Broad spectrum antibiotics Narrow regimen as cultures return Supportive care Fluids and Inotropes Ventilation Continuous Renal Replacement Therapy (CRRT)

14 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

15 ANTICOAGULATION Sepsis represents a pro-coagulant state with profound deficiencies in circulating endogenous anticoagulants Clots formed in the microvasculature can contribute to organ failure Certain anticoagulants have been shown to have anti-inflammatory properties Eg. Heparin neutralizes endotoxin, and inhibits TNF-alpha (increases protein binding)

16 ACTIVATED PROTEIN C One of the first agents that showed a mortality benefit in patients with septic shock (2001) Activated protein C (drotecogin alpha, APC) In its activated form, Protein C has antithrombotic, pro-fibrinolytic, and anti-inflammatory properties In sepsis, protein C levels are depleted, and conversion to activated form is impaired PROWESS study (2001)- consistent mortality benefit, regardless of age, sex, site of infection, severity of illness, etc. Subsequent studies failed to reproduce results, and showed an increase risk of bleeding APC voluntarily withdrawn from market by manufacturer in 2011

17 ACTIVATED PROTEIN C: NEW BEGINNINGS? SCARLET-2 a phase 3, randomized, double blind, placebo controlled study Still in approval process. Hope to start enrolling patients early 2019, and complete trial by 2022 Will study mortality benefits of ART-123 (Thrombomodulin alpha) vs placebo in septic shock Thrombomodulin is a cofactor in the process of converting protein C to its activated form Previous trials have compared ART-123 vs Heparin for Disseminated Intravascular Coagulopathy (DIC) Statistically significant increase in resolution of DIC

18 HEPARIN Early Intravenous Unfractionated Heparin and Mortality in Septic Shock Published 2008 Retrospective study on adult patients admitted for septic shock to Winnipeg ICU s between During this time period total patients were admitted Of these 2912 met 1991 criteria for septic shock Patients were further excluded if they died within 48 hours, received heparin > 48 hours after admission, or had mixed shock states (cardiogenic, hemorrhagic, obstructive, etc) Final study cohort was 2326 patients 1604 did not receive therapeutic heparin Control 722 received therapeutic heparin Intervention

19

20 HEPARIN Baseline characteristics: Treatment group: lower APACHE II scores, older, more likely to have COPD, CHF, diabetes Control group: higher APACHE II scores, higher incidence of liver failure, neutropenia, and lower platelet counts Propensity matching was performed to attempt to eliminate baseline bias between the two groups Suitable matches were found for 695(96%) of treatment group

21

22 HEPARIN Baseline characteristics: Treatment group: lower APACHE II scores, older, more likely to have COPD, CHF, diabetes Control group: higher APACHE II scores, higher incidence of liver failure, neutropenia, and lower platelet counts Propensity matching was performed to attempt to eliminate baseline bias between the two groups Suitable matches were found for 695(96%) of treatment group Primary outcome was 28 day mortality Reduction in mortality treatment group (40.1%) vs control (44.2%) Hazard ratio 0.85, 95% CI: P: 0.05 For patients with the highest APACHE II scores absolute reduction in mortality of 13% Hazard raio 0.70, 95% CI: , P: 0.01

23 HEPARIN Secondary outcomes Statistically significant reduction in vasopressor requirements, and were more likely to be liberated from mechanical ventilation, but median length of hospital stay was longer Safety: no significant difference in rate of GI bleed, CNS bleed, or need for transfusions Conclusions: Early administration of therapeutic doses of heparin may be associated with reduced mortality over 28 days. Reduction in mortality is more pronounced with increasing severity of illness

24 HEPARIN: HETRASE TRIAL Unfractionated Heparin for Treatment of Sepsis: A Randomized Clinical Trial HETRASE Trial Published in 2009 Single center, randomized, double blind, placebo control study with 319 patients Intervention Unfractionated heparin infusion at 500 units/hr for 7 days Control Placebo infusion Primary outcomes: Length of hospital stay (discharged alive) Change from baseline Multiple Organ Dysfunction (MOD) score

25 HEPARIN: HETRASE TRIAL Inclusion Criteria Adult patients coming in to ER Main reason for admission was suspected or confirmed infection Exclusion Criteria Pregnancy Increased risk of bleeding Requirement for anticoagulation Transplantation > 24 hours of admission to the hospital No significant differences between treatment and control groups at baseline

26

27 HEPARIN: HETRASE TRIAL Primary outcomes Median length of stay was 12.5 days for treatment group, and 12 days for placebo No statistically significant difference Hazard ratio 1.04, 95% CI: No statistical difference in decline in MOD score Secondary outcomes 28 day mortality: no statistically significant difference Safety 2 episodes of minor bleeding in each group 1 episode of serious bleeding (GI bleed)

28

29 HEPARIN Difference between retrospective Winnipeg study and HETRASE Dose used: Treatment dose vs. 500 Units/hr HETRASE patients had less severe illness Lower APACHE II score, younger, 50% had no comorbidities Future/Current study: Heparin Anticoagulation to Improve Outcomes in Septic Shock: HALO study Multi center, randomized, open label study (phase 2) IV heparin infusion at 18 units/kg/hr vs. Control of standard DVT prophylaxis Will include patients with a high severity of illness Primary outcome: Number of vasopressor free days Secondary outcome: 90 day mortality, ICU mortality Hopes to be completed by 2020

30 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

31 STEROIDS IN SEPSIS The use of steroids in sepsis has several theoretical benefits Increase transcription of anti-inflammatory cytokines Decrease transcription of pro-inflammatory cytokines Inhibit platelets Inhibit Nitric Oxide Enhances vasculatures responsiveness to vasopressors However, the evidence supporting the use of steroids in sepsis is controversial Studies dating as far back as the 1960 s Wide range of results (significant improved outcome vs. potential harm) Steroid use has fallen in and out of favour as a result

32 STEROIDS IN SEPSIS: HISTORY Early trials done in the 1960 s-1970 s Used large doses of methylprednisolone (30mg/kg) or dexamethasone (3mg/kg) Bolus dose at time of diagnosis. Could be repeated in 4 hours Mortality rates 10.4% in steroid groups vs 38.4% in placebo group Based on this evidence, high dose methylpred administered at the onset of septic shock became standard practice High dose methylpred revisited in the 1980 s (various trials) No difference in mortality/higher mortality seen in steroid groups Potential adverse effects and higher rate of secondary infections High dose steroid use fell out of practice

33 STEROIDS IN SEPSIS: HISTORY Series of trials in the 1990 s Used hydrocortisone instead of methylpred Much smaller doses ( mg/day of hydrocortisone) Showed quicker reversal of shock, potentially showed improvement in mortality Small studies (40 patients) that prompted larger studies in the 2000 s Annane trial (French trial) in 2002 Multicenter, double-blind, placebo controlled trial with 300 patients Treatment arm: hydrocortisone 50mg IV q6h + Fludrocortisone 50 mcg po daily for 7 days

34

35 STEROIDS IN SEPSIS: HISTORY Annane trial ctd. All patients given ACTH stim test, classified as either having adequate or inadequate adrenal reserve (non responders) Adequate adrenal reserve: change in cortisol > 248 nmol/l Non-responders: change in cortisol <248 nmol/l No mortality difference noted 28 day mortality (53% v 63%), ICU mortality (58% vs 70%), and hospital mortality (61% vs 72%), and duration of shock all lower in non responders receiving hydrocortisone No difference in mortality at 1 year No difference in adverse effects Conclusion: Low dose corticosteroids reduced mortality rates in patients with evidence of relative adrenal insufficiency (non responders in ACTH stim test)

36 STEROIDS IN SEPSIS: HISTORY CORTICUS trial 2008 Multicenter, randomized, double-blinded, placebo controlled study with 499 patients Underpowered: only 499 out of the intended 800 Treatment arm: Hydrocortisone 50mg IV q6h for 5 days, then tapered off over 6 days (11 days total) No statistical difference in 28 day mortality ACTH stim test done on all patients No statistical difference even for ACTH non-responders CORTICUS vs French trial French trial had patients that were more sick French trial enrolled patients within the first 8 hours of diagnosis, vs 72 hours in CORTICUS missed window of opportunity?

37

38 STEROIDS: ADRENAL TRIAL Adjunctive Glucocorticoid Therapy in Patients With Septic ShockADRENAL trial Published in March of 2018 Multicenter, randomized, double-blind, placebo controlled trial with 3658 patients 3800 patients enrolled, 142 (3.7%) withdrew/lost to follow up Primary outcome was 90 day mortality with an intention-to-treat analysis Intervention Hydrocortisone 200mg/day administered as a continuous infusion for 7 days or until ICU discharge Control Placebo infusion No statistical difference in baseline characteristics of control group and treatment group

39

40 STEROIDS: ADRENAL TRIAL Inclusion Criteria Age 18 years Mechanical ventilation Strong clinical suspicion of infection 2 SIRS criteria Continuous vasopressor for SBP 90mmHG or MAP 60mmHG for 4 hours Exclusion Criteria Met all inclusion criteria >24 hours ago Corticosteroid use for other indication Treatment with Etomidate or Amphotericin B Death deemed inevitable or imminent, or death from underlying disease likely within 90 days Cerebral malaria or strongloides infection

41 ADRENAL: RESULTS Primary outcome: no statistical difference in 90 day mortality (OR: 0.95, CI: , p = 0.50) Six subgroups were also analyzed: 1. admission type (surgical vs medical), 2. Site of sepsis (pulmonary vs non pulmonary) 3. Sex 4. Duration of shock before enrollment 5. APACHE II score 6. Dose of vasopressors No significant differences in mortality between subgroups

42 ADRENAL: RESULTS Primary outcome: no statistical difference in 90 day mortality (OR: 0.95, CI: , p = 0.50) Six subgroups were also analyzed: 1. admission type (surgical vs medical), 2. Site of sepsis (pulmonary vs non pulmonary) 3. Sex 4. Duration of shock before enrollment 5. APACHE II score 6. Dose of vasopressors No significant differences in mortality between subgroups Secondary outcomes: Treatment group had faster reversal of shock, time to initial extubation, and discharge from ICU No significant difference in rate of shock recurrence, total time alive off ventilator, and hospital discharge Treatment group needed fewer blood transfusions

43 ADRENAL: RESULTS Secondary outcomes: No statistical difference between groups in 28 day mortality, need for renal replacement therapy, and incidence of new-onset bacteremia/fungemia Adverse events: Significantly greater in treatment group (1.1% vs 0.3%) Hyperglycemia 6 vs 3, Hypernatremia 3 vs 0, Encephalopathy 3 vs 0 Serious adverse events 4 events in treatment group: 2 myopathy, 1 Ischemic bowel, 1 Circulatory shock 2 events in placebo group: 1 bleeding, 1 wound dehiscence

44

45 ADRENAL CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo Criticisms: Antibiotic therapy was recorded but appropriateness based on culture results was not Infusion vs intermittent dosing of hydrocortisone Some patients received open label steroids (7.4% and 8.8%) Clinician reported adverse events Didn t monitor for secondary infections other than bacteremia/fungemia Did not check for long term neuromuscular weakness

46 APROCCHSS TRIAL Hydrocortisone Plus Fludrocortisone for Adults With Septic Shock APROCCHSS TRIAL (French 2, Annane 2) Published March of 2018 Multicentre, randomized, double-blinded, placebo controlled study 1241 patients enrolled Intervention/Control Originally, study was designed to have 4 parallel groups to evaluate benefits/risks of steroids and APC given alone or in combination via 2 by 2 factorial design Steroids + APC Steroids + Placebo APC + Placebo Placebo + Placebo

47 APROCCHSS TRIAL Intervention/Control APC was withdrawn from the market during the trial Subsequent analysis was performed to show no interaction between APC and other treatment elements Use of APC was suspended and groups were combined Intervention Infusion 1: Hydrocortisone 50 mg IV q6h x 7 days Infusion 2: Placebo or APC Enteral: Fludrocortisone 50 mcg daily x 7 days Control Infusion 1: Placebo Infusion 2: Placebo or APC Enteral: Placebo Primary outcome was 90 day mortality with an intention to treat analysis

48 APROCCHSS TRIAL No statistical differences in baseline criteria between groups Inclusion criteria Admitted to ICU for < 7 days Indisputable or probable septic shock <24 hours Presence of clinically or microbiologically documented infection Sofa Score of 3-4 for 2 organ systems for 6 consecutive hours Vasopressor therapy for 6 hours Exclusion criteria Septic shock > 24 hours High risk of bleeding (eg. Recent surgery) Pregnancy or lactation Previous treatment with corticosteroids Underling conditions that could affect short-term survival Known hypersensitivity to activated drotrecogin alfa (APC)

49

50 APROCCHSS: RESULTS Primary outcome: Statistically significant reduction in 90 day mortality with intervention Intervention 43% vs Control 49.1% Relative Risk: 0.88, 95% CI: , p: 0.03 Absolute Risk Reduction: 6.1% CI: 0.6% %, p: 0.03 NNT: 17 Secondary outcomes: Statistically significant reduction with intervention for: mortality at ICU/hospital discharge, mortality at 180 days, vasopressor free days, organ failure free days, weaning from vent and vasopressors at 28 days No statistical difference: 28 day mortality, safety outcomes/incidence of serious adverse events

51

52 APROCCHSS: CONCLUSIONS In critically ill patients with septic shock, the addition of hydrocortisone and fludrocortisone compared to placebo was associated with a significant improvement in mortality at 90 days. Criticisms Fragility Index = 3 No survival benefit at 28 days, but benefit at 90 days Withdrawal of APC Underpowered Used old sepsis guidelines to guide treatment

53 APROCCHSS VS. ADRENAL Patients in the APROCCHSS (French 2) trial were more ill at time of enrollment Higher vasopressor requirements and higher SAPS II scores ADRENAL trial used continuous infusion of hydrocortisone APROCHSS trial used Fludrocortisone APROCHSS trial had fewer surgical patients More pneumonia related sepsis rather than intraabdominal sepsis in ADRENAL Benefit of steroids depending on cause/source of infection?

54 STEROIDS: WHAT HAVE WE LEARNED? High dose steroids are likely not beneficial and potentially harmful Low dose steroids result in faster resolution of shock and liberation from mechanical ventilation does this even matter? Weak evidence to suggest benefit of steroids in patients who have a non surgical source of infection Weak evidence to suggest benefit of steroids in patients with septic shock who have a high severity of illness (high mortality risk) Surviving Sepsis Guidelines Avoid steroids in the absence of shock Avoid steroids if fluids/vasopressors can restore hemodynamic stability Hydrocortisone 200 mg/day if this is unachievable Kitchen Sink scenarios Acknowledges low quality of evidence to support this practice

55 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

56 VITAMIN C: A CURE FOR SEPSIS? Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock Published February of 2017 (Marik Trial) Theory: Vitamin C acts as an anti-oxidant, and down regulates the production of pro-inflammatory mediators. Prevents free radical related organ damage Acts synergistically with steroids on the anti-inflammatory cascade Thiamine helps prevent oxalate crystallization, a by-product of high dose Vitamin C (can lead to renal failure) Critically ill patients are often deficient in vitamin C and thiamine

57 VITAMIN C: A CURE FOR SEPSIS? Single center, unblinded, retrospective before-after study, with historical controls (Eastern Virginia Medical School ICU) 47 patients in treatment arm compared to 47 historical controls Intervention Vitamin C 1.5 g IV q6h for 4 days or ICU discharge Dosage devoid of any complications or side effects Thiamine 200 mg IV q12h for 4 days Hydrocortisone 50 mg IV q6h for 7 days or ICU discharge, followed by 3 day taper Control Standard sepsis treatment Of note, 60% of historical controls had received hydrocortisone as part of standard treatment

58 VITAMIN C: A CURE FOR SEPSIS? Primary outcome: hospital survival Inclusion criteria Consecutive patients admitted to Eastern Virginia Medical School Critical Care Unit Primary diagnosis of severe sepsis or septic shock Procalcitonin level 2 ng/ml Exclusion criteria <18 years of age Pregnant Patients with limitations of care No statistical differences between treatment group and controls

59

60 VITAMIN C: RESULTS Primary outcome: Statistically significant decrease in hospital mortality in treatment group 8.5% (4 of 47) vs 40.4% (19 of 47) Odds ratio of 0.13, 95% CI: , p: Per the Authors: Of the 4 patients that did pass away, they all died from underlying disease and NOT sepsis Advanced dementia, heart failure, sarcoidosis, COPD All survived ICU care Secondary outcomes: Treatment group had significantly lower duration of vasopressor therapy, and requirement for renal replacement therapy Treatment group had greater improvement in SOFA score, and procalcitonin clearance in the first 72 hours

61

62 VITAMIN C Conclusion: The early use of IV vitamin C with corticosteroids and thiamine may prove to be effective in preventing progressive organ dysfunction, and reducing mortality of patients with severe sepsis and septic shock Criticisms Potential bias: Single centre study, historical controls, unblinded Treatment and Control period not concurrent and not during same season (Late winter-summer vs Fall-early winter) Small Sample size 60%Control group received part of treatment (steroids) Multiple interventions used A hypothesis generating study at best with further need for RCTs

63 VITAMIN C Study in Korea using Marik protocol (2018) Single center, unblinded, retrospective before-after study, with historical controls Patients admitted to ICU with community acquired pneumonia (treatment = 53 patients, control = 46) No statistical difference in mortality between groups Propensity matching was performed to help eliminate bias from baseline group characteristics 17% (6 of 36) mortality in treatment group vs 39% (14 of 36) mortality in propensity matched historical controls OR 0.31, 95% CI , p = 0.04 No statistical difference in change in SOFA score Majority of the same criticisms apply as to the original Marik trial

64 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

65 OTHER THERAPIES BEING INVESTIGATED Beta-blockade Patients with sepsis often remain tachycardic can result in myocardial damage, inefficient pump Tachycardia associated with mortality Esmolol has been shown to increase survival, while not influencing hemodynamics Cytokine and endotoxin inactivation or removal Hemoperfusion through adsorptive materials eg. Polymixin B fiber column Plasma exchange IVIG Inhibition of innate immune system Eg. Eritoran, TLR-4 antagonist Statins

66 FAILED TREATMENT APPROACHES Inhibition of innate immune system TLR-4 (PRR) antagonist TAK-242 Anti-endotoxin antibody HA-1A TNF-alpha antibody, IL-1 receptor antagonists Preventing Organ Failure Nitric oxide inhibitors prevent vasodilation and free radical production N-acetylcysteine antioxidant Therapeutic Hypothermia Ibuprofen Activated protein C

67 OUTLINE Review Definition of Sepsis Immune System Sepsis Pathophysiology Anticoagulation Steroids: The Great Debate Vitamin C: A Cure for Sepsis? Other Therapies Being Investigated Failed Treatment Approaches Example Case/Questions

68 EXAMPLE CASE Patient L.S. is a 75 year old African American male with a past medical history of ESRD requiring renal transplant, diabetes, and hypertension. He presents to the ER with a 3 day history of productive cough, fever, chills, and shortness of breath. L.S. is diagnosed with community acquired pneumonia and admitted. What are some L.S. s risk factors for having an uncomplicated CAP turn in to sepsis? Mr. Worst Case Scenario Age, gender, ethnicity, comorbidities, immune suppression, pneumonia as admission diagnosis.

69 EXAMPLE CASE L.S. quickly deteriorates on the medical ward. He becomes anuric, hypotensive, and needs to be intubated for extreme SOB and falling O2 sats. L.S. is taken to the ICU with an updated diagnosis of septic shock. In ICU his blood pressure is stabilized after several fluid bolus and a low dose of norepinephrine infusion. The ICU physician asks your opinion on starting this patient on stress dose steroids for sepsis. How do you respond? Steroids not appropriate at this time as patient is hemodynamically stable with use of fluid bolus and vasopressors.

70 EXAMPLE CASE L.S. course in the ICU takes a dramatic turn for the worse. Despite maximal doses of multiple vasopressors, L.S. s blood pressure continues to plummet. The topic of steroids is raised again. How do you respond? Steroids would not be unreasonable, based on hypotension refractory to vasopressors. (Weak evidence) The ICU physician also recently read an article about using high dose Vitamin C in sepsis. Would it be appropriate to start L.S. on the Marik protocol? Evidence based answer: no, not enough quality evidence to support its use Anecdotal answer:..

71 THE END THANK YOU!