latest guidelines for treatment of refractory septic shock.

1. VITAMIN COCKTAIL IN SEPSIS
A JOURNAL CLUB PRESENTATION
Dr. kiran07.02.2018

3. Introduction
 Global burden of sepsis : 15 – 19 million cases / year
 Mostly low income countries
 28 day mortality :
 Short & Log term complications
  Quality of life
  Risk of Death upto 5years
High Income Countries Low income countries
Sepsis : 25%
Septic Shock : 50%
60%

4. Sepsis
 Systemic inflammatory response by the body to infection.
 Spectrum of disease : Systemic inflammation - Multi-organ dysfunction
- Shock.
 Over 100 phase II and phase III clinical trials investigating novel drugs
and interventions
 No new agents have been successful in directly targeting the
pathophysiologic effects of sepsis
 Complete mechanism - not fully elucidated
 Widespread distribution of pro-inflammatory mediators

5. Sepsis
 Pro-inflammatory mediators
 permeability in endothelial layers
 Act locally
 Mitigating hemorrhage from disrupted blood vessels
 delivery of immune cells and antimicrobial mediators
 Distributed throughout the body
 Hypotension
 Hemodynamic instability
 Marked impairment of tissue perfusion

6. Sepsis
 Hypoxia within tissues
 Large quantities of reactive
oxygen species (ROS) and
reactive nitrogen species
(RNS)
 Oxidative stress within
cells
 Tissue and Organ damage
 ROS and RNS
 Post-translational modifications
to cellular proteins
 Impairing the function of cells
 Endothelial dysfunction
  Endothelial permeability
 Impairment of microcirculatory
flow

7. Sepsis
These effects eventually lead to cell death, shock, organ
failure
and if not reversed
Death

8. Mainstay of sepsis treatment – Surviving Sepsis
Campaign
 Early identification & treatment of infection
 Antibiotic administration
 Source control when applicable
 Reversing hemodynamic instability
 Fluid resuscitation
 Vasopressors
 Even when shock is prevented, patients still die of multi-system
organ failure despite adequate perfusion and cardiac output
 Deaths in septic patients - microvascular dysfunction due to
inflammation

9. Mainstay of sepsis treatment – Surviving Sepsis
Campaign
 Current sepsis care bundles do not target the inflammatory and
oxidative stress caused by sepsis
 Current standard therapies can potentially increase inflammation
and cause further damage through the bactericidal effects of
antibiotic administration
 Clearly, there is a need for new, targeted adjuvant therapies that
reverse the inflammatory and oxidative stress present in septic
patients
 However search for an effective targeted therapy has proven
difficult.

10. Several investigations - targeted
adjuvant

11. Vitamin Cocktail
 Vitamin C – cost-effective novel adjuvant therapy
 Ameliorate the effects of inflammation and oxidative stress in
sepsis
 New evidence - reduce mortality
 Deficiency established in sepsis
 Hydrocortisone
 Previously used in Septic Shock
 Mortality benefit – controversial
 Theoritical Synergistic benefit with Vitamin C
 Thiamine
 Thiamine deficiency is common in septic
 patients and is associated with an increased risk of death

13. Methodology

14. Methodology
 Study type: Retrospective before-after clinical study
 Study Setting: Sentara Norfolk General Hospital, Norfolk, USA
 Study Duration: 14 months (June 2015 - July 2016)
 Study Groups:
 Treatment group (n=47)
 Control group (n=47)
 Source of data:
 Electronic Health Record (EHR)

15. Inclusion/Exclusion Criteria
Patient Group (n=47) Control Group (n=47)
 Enlisted from Jan 16 – July 16
 Severe sepsis and Septic shock
 Consecutive ICU admissions
 Procalcitonin level ≥ 2ng/ml
 Treated with IV Hydrocortisone,
Vitamin C and Thiamine (First 24
hrs)
 Enlisted from June 15 – Dec 15
 Severe sepsis and Septic shock
 Consecutive ICU admissions
 PCT level ≥ 2ng/ml
 Not received Vit C and
Thiamine
 Exclusion Criteria: <18 yrs, Pregnancy, Patients with limitation
of care

16. Methodology cont...
 Data collected from Electronic Health Records (EHRs)
• Demography – Age, Sex etc
• Admitting diagnosis
• Comorbidities
• Requirement of mechanical ventilation
• Use of vasopressors (hourly dosage): as norepinephrine
equivalent
• Daily urine output: first 4 days
• Fluid balance: after 24 and 72 hrs
• Length of ICU stay (LOS)
• Lab data

17. Case Definitions
 Immunocompromised:
 Steroid therapy - Prednisolone-equivalent 10mg/day for at
least 2 weeks
 Cytotoxic drug therapy
 AIDS patinets
 Acute Kidney Injury:
 KDIGO (Kidney Disease: Improving Global Outcomes) criteria
 Creatinine increase > 0.3 mg/dl or > 1.5 the baseline
 > 1.5 mg/dl when baseline is unknown

18. ICU Treatment Protocol
Therapy Patient Group Control Group
Hydrocortisone
50 mg IV 6th hourly x 7 days
or until ICU discharge
50 mg IV 6th hourly as
per physician’s
discretion
Vitamin C
1.5 g IV 6th hourly x 7 days
or until ICU discharge _
Thiamine
200 mg IV BD x 4 days or
until ICU discharge _

19. ICU Treatment Protocol
 Empirical Broad spectrum antibiotics De-escalation as per
microbiological and clinical progress
 Fluid therapy
 Vasopressors: Nor-epinephrine Vasopressin
Phenylephrine or Epinephrine (Target MAP - > 65 mmHg)
 Mechanical Ventilation: As per lung protective strategy
 Sedation: Limited used, Preferred agent – Dexmeditomedine
 Enteral nutrition
 DVT prophylaxis: Enoxaparin and Sequential compression
 Permissive hyperglycemia

20. Monitoring
 Clinical Variables
 Severity Scoring:
 APACHE II & IV
 SOFA – First 4 days of
admission
 Lab Data:
 Serum creatinine
 WBC count
 Total bilirubin
 PCT
 Lactate
 Baseline Vit C level (by
HPLC)
APACHE: Acute Physiology and Chronic Health Evaluation
SOFA: Sepsis-Related Organ Failure Assessment
HPLC: High-Pressure Liquid Chromatography

21. Outcome Measurement
 Primary Outcome: SURVIVAL
 Secondary Outcomes:
 Duration of vasopressor therapy
 Requirement of RRT in AKI
 ICU length of stay
 SOFA score: change at 72 hrs
 PCT level: PCT clearance in % at 72 hrs

22. Data Analysis
 Software:
 SPSS statistics version 24 (IBM)
 Propensity score:
 Generated in SPSS based on the clinical variables, Lab data and
Severity scores
SPSS: Statistical Package for the Social Sciences
Odds Ratio for mortality assessed by propensity score adjustment

23. RESULTS

25. E.Coli = 4
GPC = 6
E.Coli = 6
GPC = 3

26. Results
 3 independent pedictors of Mortality
 Treatment with Vitamin C Protocol (F value, 17.33; P < .001)
 APACHE IV score (F value, 13.29; P < .001)
 Mechanical ventilation (F value, 3.75; P = .05)
 None of the patients in the treatment group died of complications
related to sepsis.
 All these patients survived their ICU stay, received “comfort care” on
the hospital floor, and died of complications of their underlying
disease (advanced dementia, severe heart failure, advanced
sarcoidosis, and severe COPD).

27. Results

28.  The dose of
pressors was
predictably
reduced between
2 and 4 h after
the first infusion
of vitamin C
 9 patients in the
control group
received
escalating doses
of vasopressors
and died of
refractory septic
shock
Results

29. None of
the patients in
the treatment
group
developed
new organ
failure (as
reflected by
an increase in
their SOFA
score)
Results

30. Results

31. Results

32. Discussion

33. Discussion
 Marked effect on natural history of patients with severe sepsis and
septic shock
 All eligible patients with sepsis were studied. This is important as
less than 20% of eligible patients with severe sepsis and septic
shock are commonly included in many of the sepsis trials, limiting
the applicability and generalizability of the results
 Combination of three inexpensive and readily available agents with
a long safety record and in clinical use since 1949

34. Discussion
 The findings are supported by extensive experimental and clinical
studies – safety and potential benefit of moderate-dose
hydrocortisone, intravenous vitamin C, and thiamine in critically ill
patients.
 First study to evaluate the combination - synergistically reverses the
pathophysiologic changes of sepsis
 The outcome data are supported by
 Time course of the PCT levels
 SOFA score
 Rapid decline in vasopressor requirements

35. Discussion
 Vitamin C and corticosteroids act synergistically
 Critically ill patients have either low or undetectable vitamin C levels
 Because of the saturable intestinal transporter (sodium-vitamin C
transporter-1) oral administration of doses as high as 1,500 mg
cannot restore normal serum
 Daily dose of more than 3 g is required
 On the basis of pharmacokinetic data and preliminary dose-
response data a daily dose of 6 g combined with hydrocortisone is
optimal

36. Discussion
 vitamin C IV  metabolic
conversion to oxalate 
 Patients with renal impairment
receiving megadose vitamin C,
supersaturation of serum with
oxalate  tissue deposition as
well as crystallization in the
kidney Worsening renal
function
 Glyoxylate, a byproduct of
intermediary metabolism, is
either reduced to oxalate or
oxidized to carbon dioxide by
the enzyme glyoxylate
aminotransferase
 Thiamine pyrophosphate is a
coenzyme required for this reaction
 Thiamine deficiency  the
conversion of glyoxylate to oxalate
 Thiamine deficiency is common in
septic patients and is associated
with an increased risk of death
For these reasons, thiamine was included in vitamin C protocol.

37. Limitations

38. Limitations
 Small sample size
 Single-center design
 Participation of nonconcurrent control subjects
 Treatment and control periods occurred during different seasons
 Propensity score adjustment was used in an attempt to control for
some of these factors
 Lack of clinical equipoise and the ethics of withholding a potentially
lifesaving intervention, randomized controlled trial could not be
initiated
 This observational study suggests that a 4-day course of vitamin C
is optimal, additional studies are required to determine the ideal
dosing strategy
 Contributing role of thiamine requires further exploration.

39. Critical Appraisal of Article
Issue Impression
Relevance of research Relevant
Relevance in our Institution Highly Relevant
Technical Issues
(Limitations)
Additional studies required
Interpretations consistent
with the results
Yes
Conflict of Interest None declared