New Therapies for Sepsis - UP 2017… · New Therapies for Sepsis Fathima Paruk MBChB, FCOG, Crit...
Transcript of New Therapies for Sepsis - UP 2017… · New Therapies for Sepsis Fathima Paruk MBChB, FCOG, Crit...
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