SEPSIS 2020: HOW IS OUR VISION · Figure 2 The Kaplan-Meier curves for cumulative survival of the study patients depending on the administration of adjunctive i\൮travenous vitamin

$Page 1: SEPSIS 2020: HOW IS OUR VISION · Figure 2 The Kaplan-Meier curves for cumulative survival of the study patients depending on the administration of adjunctive i\൮travenous vitamin$
SEPSIS 2020: HOW IS OUR VISION

R. Phillip Dellinger MD, MSc, MCCMProfessor of Medicine and Distinguished ScholarCooper Medical School of Rowan UniversityDirector Cooper Research InstituteSenior Critical Care AttendingCamden NJ USA

Objectives

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Fluid Rx Septic Shock

ESRD and CHF

Vitamin C,Thiamineand (Steroids)

Dobutamine inSeptic Shock

( )

No Conflicts of Interest

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ESRD and CHF

30 ml/kg crystalloid first 3 hrs

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Surviving Sepsis Campaign

End Stage Renal Disease on Dialysis

Compensated Congestive Heart failure


Crit Care. 2014 Apr 23;18(2):R79

No Correlation Between Fluid Administration and PaO2/FiO2 Ratio Over First 24 Hours

ControlsR = 0.0019

Pre-existing Left Ventricular Systolic Heart FailureR = 0.001


Liu et al Am J Respir Crit Care Med 2016; 193(11):1264–1270

Liu et al Am J Respir Crit Care Med 2016;193(11):1264–1270

Presenter

Presentation Notes

hemodynamically stable patients with sepsis and intermediate lactate values in the emergency department. 4000 patients with heart failure and more than 6000 patients with renal failure. Mortality drops after implementation of a sepsis bundle that includes fluids.

Chest. 2019 Oct 14. pii: S0012-3692(19)34013-9. doi: 10.1016/j.chest.2019.09.029


Distribution of Patient According to Volume


Probability of Intubation within 72 hours



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Vitamin C, Thiamine and (Steroids)

( )

• Anti-oxidant• Reduced endothelial permeability• Improved microvascular function• Attenuated cellular apoptosis• Reduction of inflammatory mediators• Maintaining vascular vasopressor responsiveness?

Vitamin C

• Essential for generation of glutathione, an important antioxidant• Essential for aerobic respiration• Extreme thiamine deficiency syndrome, beri beri, has many of the

same characteristics of septic shock

Thiamine


Shin TG et al. J Clin Med 2019 8, 102; doi:10.3390/jcm8010102

Comparisons of Primary and Secondary Outcomes



Presenter

Presentation Notes

Random-effects multivariate analysis of 28-day and in-hospital mortality in unmatched subgroups.


Presenter

Presentation Notes

Random-effects multivariate analysis of 28-day and in-hospital mortality in unmatched subgroups.

Mitchell AB et al. The American Journal of Medicine. 2019

Mortality Outcomes

Mitchell AB et al. The American Journal of Medicine. 2019

Ahn JH et al. J Thorac Dis 2019; 11(4):1562-1570.

Ahn JH et al. J Thorac Dis 2019; 11(4):1562-1570.

Survival ICU Days

Presenter

Presentation Notes

Figure 2 The Kaplan-Meier curves for cumulative survival of the study patients depending on the administration of adjunctive intravenous vitamin C therapy. P=0.2 between the vitamin C and control groups. Figure 3 The cumulative incidence function plot of time to shock reversal in the vitamin C and control groups. P=0.81 for comparison between the two groups by treating death as a competing risk.


Outcomes and Treatment Variables

Sadaka F. et al. Journal of Intensive Care Medicine 2019


Forest plot of OR and 95% CI for 28-day mortality from five studies

Wei X. et al. European Journal of Pharmacology 868 (2020) 172889

Favors HAT Favors Control

Presenter

Presentation Notes

Fig. 2. Forest plot of OR and 95% CI for 28-day mortality from five studies including 1347 patients (332 in vitamin C treatment group and 1015 in control group). The incidence of 28-day mortality was 25.8% and 20.2% in the treatment and control groups, respectively. The pooled data based on the random-effects model indicated that the use of vitamin C did not reduce the 28-day mortality (OR = 0.84, 95% CI: 0.43–1.65, P = 0.611, I2 = 56.3%).

Forest plot of OR and 95% CI for ICU mortality from five studies



Presenter

Presentation Notes

Fig. 3. Forest plot of OR and 95% CI for ICU mortality from five studies including 337 patients (167 in vitamin C treatment group and 170 in control group). The incidence of ICU mortality was 32.9% and 37.6% in the treatment and control groups, respectively. The pooled estimate showed that vitamin C administration was not associated with a significant difference in ICU mortality (OR=0.79, 95% CI: 0.51–1.25, P = 0.319, I2 = 46.2%).

Forest plot of OR and 95% CI for in-hospital mortality from seven studies



Presenter

Presentation Notes

Fig. 4. Forest plot of OR and 95% CI for in-hospital mortality from seven studies including 1565 patients (437 in vitamin C treatment group and 1128 in control group). The incidence of in-hospital mortality was 25.2% and 23.0% in the treatment and control groups, respectively. The meta-regression results with the random-effects analysis suggested no difference in the in-hospital mortality in the treatment and control groups (OR = 0.76, 95% CI: 0.47–1.22, P = 0.251, I2 = 51.0%).

Fowler AA. et al. JAMA 2019. 322 (13) :1261-1270. doi: 10.1001/jama.2019.11825.


Primary Endpoint Change in Modified Sequential Organ Failure Assessment Score from Baseline to 96 Hours.

• Vitamin C – 9.8 to 6.8

• Placebo – 10.3 to 6.8

• P = 0.86



Presenter

Presentation Notes

Plasma Ascorbate Concentrations, Modified Sequential Organ Failure Assessment Score, and Plasma Biomarkers Median values are shown by the horizontal line inside the box, interquartile range (IQR) by the top and bottom of the boxes, 95%CI by the whiskers, and values were outside the 5th and 95th percentiles by circles. Box plots have been offset to avoid superimposition. A, Plasma ascorbate levels at enrollment were marginally deficient (dotted line, <28 μM) in both groups. After initiation of treatment, plasma ascorbate levels were significantly greater in vitamin C patients compared with placebo patients (median at baseline, 22 vs 22 μM[IQR, 8-39 vs 11-37], P = .68). At 48 hours, median was 166 μM [IQR, 88-376] for vitamin C vs 23 μMfor placebo [9-37], P < .001). At 96 hours, median was 169 μM [IQR, 87-412] for vitamin C vs 26 μM for placebo [9-41], P < .001). At 168 hours, median was 46 μM[IQR, 19-66] for vitamin C vs 29 μMfor placebo [12-39], P < .002). After cessation of vitamin C infusion, plasma levels in the vitamin C cohort decreased below 100 μM but remained significantly higher than plasma ascorbate levels in placebo patients. B, There was no difference in the initial modified Sequential Organ Failure Assessment (mSOFA) scores of the 2 groups at baseline (vitamin C vs placebo, median, 10 [IQR, 7-12] vs 10 μM [8-12]). During the next 96 hours, mSOFA scores decreased but were not different between the 2 groups. C and D, Plasma levels of C-reactive protein and thrombomodulin were measured at baseline and at 48, 96, and 168 hours. At no time were the levels of these significantly different between the 2 groups.

All-Cause Mortality From Randomization Among Patients With Sepsis-Associated ARDS


Presenter

Presentation Notes

Vitamin C–infused patients exhibited a significant reduction in 28-day all-cause mortality, although the P value was not adjusted for multiple comparisons. The median observation time was 28 days (interquartile range, 15-28 days) for the vitamin C group and 28 days (interquartile range, 5-28 days) for the placebo group.

Fujii T et al. JAMA January 17, 2020. doi: 10.1001/jama.2019.22176


Vasopressor Use during the First 10 day of the Trial


Kaplan-Meier Analysis by Randomization Group

Fujii T et al. JAMA 2020. doi:10.1001/jama.2019.22176

Wald EL. et al. AJRCCM January 9, 2020 https://doi.org/10.1164/rccm.201908-1543LE

Retrospective propensity score matched557 total patients – 333 controls, 181 steroids, 43 HAT therapy

Mortality at 90 days – 30%, 39%, 6%

Matched cohort – 43 and 43 and 43Mortality at 90 days – 35% and 37% and 6% p ≤ 0.03


500 patients

https://www.facebook.com/elephantincloset/


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During Septic Shock

10 Days Post Shock

EndDiastole

EndSystole

EndDiastole

EndSystole

Courtesy of J. Parrillo MD

Presenter

Presentation Notes

This slide demonstrates radionuclide angiography in a patient during septic shock and following recovery. The top left panel shows end-diastole and demonstrates increased diastolic size of the ventricles (increased compliance), which is thought to be an adaptive mechanism. The top right image shows end-systole in this patient demonstrating a very low ejection fraction (little change in chamber size compared to end-diastole). The bottom two frames following recovery demonstrate a decrease in end-diastole volume, smaller ventricle at end systole and therefore significant improvement in ejection fraction.

Pulmonary Artery Catheter

Fluids to maintain PAOP 16

Norepinephrine to maintain MAP 65-70

Dobutamine to maintain cardiac index ≥ 3.0

• We suggest using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and use of vasopressor agents.

(Weak recommendation, low quality of evidence)

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2016


Gattinoni L et al. NEJM 1995. 133(16) 1025-1032

Presenter

Presentation Notes

Survival curves from study entry to the six month follow-up In the three study groups.

Hayes MA et al. NEJM 1994. 33-(24)

In-Hospital Survival

Hayes MA et al. NEJM 1994. 33-(24)

Gordan AC. et al. NEJM 2016. 375(17) 16-38-1648

Gordan AC. et al. NEJM 2016. 375(17) 16-38-1648


Tacon CL et al. Intensive Care Med 2012. 38:359-367


Mortality Odds Ratios in Pair-Wise Treatment Comparisons

Abraham WT. et al. JACC 2005. 46(1); 57-64.

Morelli A et al. JAMA 2013. 310(16) 1683-1691

Esmolol and Norephinephrine Drug Infusions


Changes in Hemodynamic Variables




Sato R. et al. J of Intensive Care Med 2019. Dec 3:885066619892218. doi: 10.1177/0885066619892218.

Sato R. et al. J of Intensive Care Med 2019. Dec 3:885066619892218. doi: 10.1177/0885066619892218.

• We suggest using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and use of vasopressor agents.

(Weak recommendation, low quality of evidence)

69

2016

Summary

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ESRD and CHF

Vitamin C,Thiamineand (Steroids)


( )

Thank you

Documents

SEPSIS 2020: HOW IS OUR VISION · Figure 2 The Kaplan-Meier curves for cumulative survival of the study patients depending on the administration of adjunctive i\൮travenous vitamin