New Therapies for Sepsis

Fathima ParukMBChB, FCOG, Crit Care(SA), PhD

Academic and Clinical HODDepartment of Critical Care

University of PretoriaSouth Africa

DisclosuresSpeaker bureaux, advisory boards or research grants

• Astra-Zeneca• Pfizer• Sandoz• Edwards Life sciences• Hexor• MSD - Merck• 3M• GSK• Thermo Fischer Scientific

• Mylan• Fresenius Kabi• Aspen• Abbvie• Abbot • Pharmadynamics• Litha• Takeda• Dr Reddy’s

• I• lllll

1979-2000: mainly G+ 2009-present: mainly G- (62%)

Incidence Mortality 20-40%

South Africa-28% sepsis in ICU-Mortality

USASevere Sepsis

-750 000/year- Cost 14B USD/year-10 of ICU admissions Angus DC et al, NEJM,2013

Paruk F et al,SAMJ;2012Vincent JL JAMA,2009

CDC 2012

• Recognition• Pathophysiology• Individualized/Personalized medicine• One size does not fit all• Select strategies-specific patients

• Appropriate patient selection• Timeous initiation• Correct dose • Appropriate duration

Pathophysiology

• T

Sepsis “A race to… death”MAN versus Microbe, where one of the 2 contenders will “die”

VirulenceAgeSiteComorbiditiesGeneticEfficacy of Rx

Sepsis

MicrocirculationMacrocirculation

MODS

Cellular hypoxia

DO2/ VO2 imbalance

Hypotension & Tissue perfusion ↓

Capillary LeakHypovolemiaVasodilatory shock Vasopressor hyporeactiveness

Endothelial glycocalx~~- MicrothrombiFunctional capillariesBlood flow

Sepsis

MicrocirculationMacrocirculation

MODS

Cellular hypoxia

DO2/ VO2 imbalance

Hypotension & Tissue perfusion ↓

RESTORE-Hypovolemia-Vascular tone-MAP Functional capillaries

Blood flowMicrothrombi

Hemodynamic incoherance

Diagnosis of Sepsis: New Paradigms

10

Sepsis

Septic Shock

with - Hypotension requiring vasopressors to keep MAP > 65mmHg- Lactate >2mmoL/L with adequate volume resuscitation

INFECTION + SOFA Score by ≥ 2 points

INFECTION + SOFA Score by ≥ 2 points

Suspect an infection: Emergency or ward setting

• Quick SOFA: To ID patients who are likely to deteriorate or have a poor outcome

• 2 of the following• Current evidence

ABC+

Aggressive Source Control

+Optimize Perfusion and

DO2+

Monitor

Diagnosis + Microbiology

Fluid Resuscitation

Haemodynamic Targets

• MAP >65 mm Hg

• Adrenaline• Steroids

Ventilation• ARDS net

Source Control +

Antibiotics

Additional• Infection control• Head up• Monitor • Glucose <10 mmol/L• Nutrition• Stress ulcer• Thromboprophylaxis

Surviving Sepsis Guidelines 2016http://www.survivingsepsis.org/Guidelines

Assessment of perfusionMedical/Surgical source controlHypovolemia

-Fluids DO2 (Flow, Pressures)-Hb-Vasopressors

Microcirculation (Flow and DO2)-VasodilatorsAdjunctive strategies

Evidence?

Redox

Metabolic resuscitation Gut microbiome

Immune-modulation

Adjunctive Therapies

To counteractoxidative stress

mediated cell damage

Evidence?

Vitamin C

Vitamin D

Vitamin E Selenium

Zinc

Melatonin

Antioxidant enzymes, Vitamins, trace elements

Topical currently

Vitamin C/ Ascorbic acid

Berger M et al, Curr Opinion Clin Nutr Metab Care,2015

ROS scavengerRestore microcirculatory blood flow

SepsisTrauma Major Burns Deficit

High doses (≥3g/24 hours)[=30XRDA]Restores redox balanceImproves microcirculatory BFClinical benefit

Metabolic resuscitation

• Mitochondrial dysfunction– Early– Drives MODS

• Mitochondrial hibernation• Mitochondrial efficiency

– Pharmacological– Nutrients

M

REDOX balanceImmunityRegulate cell death

Metabolic resuscitation: Mitochondrial target therapy

Mitochondrial efficiency– Nutrients

– Pharmacological

M

REDOX balanceImmunityRegulate cell death

Thiamine(B1), Vit C, Vit E, selenium, zinc

CoQ10(ubiquinol), cytochrome oxidase, melatonin, Lcarnitine

Thiamine

• Deficiency• Lactic acidosis improvement dramatic

Domino et al(Crit Care Med,2016)n=79 septic shock and elevated lactate

- 35% thiamine deficient- thiamine or placebo supplemented

Supplemented group vs Placebo- lactate clearance- survival

Consider• Malnutrition• ROH• Chronic wasting• RRT• Hyperemesis• Gastric bypass• Refeeding

Metabolic resuscitation: Mitochondrial target therapy

• Mitochondrial dysfunction• Mitochondrial hibernation• Mitochondrial efficiency

– Nutrients

– Pharmacological

REDOX balanceImmunityRegulate cell death

Thiamine(B1), Vit C, Vit E, selenium, zinc

CoQ10 (ubiquinol), cytochrome oxidase, melatonin, L-carnitine

Gut microbiota

• Landscape changes in critical illness• Microbes and environment

– Proportion– Distribution– Virulence – (ID alone insufficient, virulence testing)

• Sequencing Gut-barrier functionModulates innate and Adaptive immune system

Gut microbiota

• Manipulation of structure or function– Microbial replacement

• Faecal transplant– SDD– Probiotics– Nutrition (EN within 48 hr)

M

Evidence?Cytokineremoval

Immune inactivation

Cytokine inactivation

Inhihibit innate

immunity

IV immuno-globulin Augment

immuno-modulation

Statins

Anticoag-ulation

Immunomodulation Strategies

Cytokine and endotoxin removal

• T

Hemoperfusion/Hemoadsorption

• Sorbent (absorptive material) attracts and removes cytokines/inflammatory mediators from circulating blood (hydrophobic interaction)

• Blood perfused through– Absorptive membrane column (Polymyxin B

binding Fibre column)– Sorbent containing cartridge (Cytosorb)®

Cruz DN et al, JAMA,2009Iwagcmi M, CCM,2014

Hemoperfusion though an absorptive material

Sorbent containing cartridge (Cytosorb)®• Benefits

– Vasopressor reduction– Mortality below predicted (p<0.05)

• Evidence in sepsis– 14 000– SA

Cruz DN et al, JAMA,2009Iwagcmi M, CCM,2014

• Cartridge filled with divinylbenzene beads

• Surface area >40 000SM• 1000-50 000 Daltons• Biocompatible• > 14000 patients

Anticoagulation • Heparin

– Immunomodulation– Antithrombotic

• Septic shock– Retrospective– Vasopressor discontinuation earlier– Haemorrhage or transfusion risk not increased

• HETRASE (n=319)– 500U/hour not beneficial– ? Higher dose required

• Current trial: Varied dosing regimens Zarychanski R et al,CCM,2008James F et al, CCM,2009

Statins

• Anti-inflammatory properties suppress up regulation of TLR-4 and TLR-2

• Initial trials promising• Recent trials and MA of RCTs• Currently not recommended

Papazian L et al, JAMA,2013Deshpande A et al, A m J Med,2015

Dingles VD et al, thorax,2016

Corticosteroids

• A

Annane D et al. Cochrane Data Systematic Rev, 2015

Anti-inflammatoryImmunomodulatory

33 Trials (9 new added)n=4268

>3 days: <400mg/dayD28 Mortality (RR 0.87, 95% CI 0.78-0.97; p=0.01)Hospital and ICU mortality (p<0.05) Shock reversal by D7 RR1.31 (p=0.0001)No GIT Bleeding, superinfection, NM weaknessHyperglycemia RR1.26 (p<0.05)Hypernatremia RR 1.64 (p<0.05)(Moderate quality evidence)

Polyclonal and monoclonal Immunoglobulins

• Endotoxin neutralisation• Ig M enriched Ig therapy

– RCT: Mortality benefit compared with placebo • Heterogeneity

– 2 MA: No benefit– Cochrane Systematic Review

• Trials with minimal bias -No mortality benefit

• Not recommended

Werdans K et al, Crit Catre Med,2007Pildel J et al, Crit Care Med,2007

Kreymann KG et al, Crit Care Med,2009Alejanandriu MM et al, Cochrane Sys Rev,2013

Inhibition of innate immunity

• T

TLR inhibitors-Eritoran (TLR-4inhibitor)(ACCESS trial): mortality unchanged-TAK(Resativid): D28 mortality(p>0.05)

Cytokine inactivation

• T

Il-1 Antagonism (Anakinra)- Initial trials- Subsets:

- DIC- Renal or hepatic dysfunction

Fischer CT et al,JAMA1994Opal SM et al, CCM,1997

Immunomodulation augmentation/Immune stimulants (anti-inflammatory response) • Macrophage migration inhibition factor Abs

– Restore glucocorticoid actions

Proinflammatory gene expression inhibition• δ Interferon/TNFβ /IL-2

Granulocyte –Macrophage CSF or G-CSF• Reduce infections • LOS• Antibiotic duration reduced• Mortality unchanged

Inhibit programmed cell death• Increase lymphocytes- bacterial clearance

β Blockers

• Ventricle and arterial load is mismatched (ventriculo-arterial uncoupling)– HR increase– Depressed myocardium– Increased AL (vasopressor VC)myocardial failure

• HR – diastolic dysfunction

Morelli A et al, JAMA,2013

HR associated withmortalityHR>95/min+ Nep for >24 hours:mortality

HR Due To• Compensatory

-Vasodilatation-Hypervolemia -Pain/anxiety

• Sympathetic overstimulation

• Chronotropicdysfunction

• Exogenous catecholamine

Toxin mediated

β Blockers • MOA

– Reduce down regulation of β1 receptors and restore vasoreactiveness

– Inflammatory– Coagulation

• 20% Reduction from baseline does not compromise perfusion if HR>110/min

• Ultra short acting Selective β1 selective Blocker (Esmolol)• Associated with lower mortality in septic shock (48vs 80%)• Not recommended yet

Morelli A et al, JAMA,2013

HR associated withmortalityHR>95/min+ Nep for >24 hours:mortality

Vasopressin and its analogues

• Biphasic Vasopressin response (decline at 72 hours)

• First line therapy compared with Nep : p>0.05– RRT– Mortality– LOS

• Adjunctive role with Nep• Serlipressin (selective V1a: better CVS profile)

Miscellaneous: Recent trials

• Naloxone– HD improvement– But: Pulmonary oedema, seizures, hypertension

• Pentoxyfilline– Prevent RBC deformation and neutrophil adhesion– Mortality unchanged

• Stem cell Therapies– Limited by concerns of a deregulated immune

response