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  2. 2. ABJUNCTS IN TREATMENT OF ARDS2. Ventilatory Strategies other than Lung Protective Strategy. - Prone Ventilation - Liquid Ventilation - High Frequency Ventilation - Tracheal Gas Insufflation - Extracorporeal Gas Exchange8. Hemodynamic Management – Fluids, Vasopressors.9. Selective Pulmonary vasodilators.10. Surfactant replacement therapy.11. Anti-inflammatory Strategies. a) Corticosteroids. b) Cycloxygenase & lipoxygenase inhibitors. c) Lisofylline and pentoxifylline.15. Antioxidants – NAC : Procysteine16. Anticoagulants.
  3. 3. PRONE VENTILATION Effect on gas exchange Improves oxygenation – allows decrease Fio2; PEEP - Variable - not predictable response rate – 50-70% Proposed mechanism – how it improves oxygenation 1) Increase in FRC 2) Improved ventilation of previously dependent regions. (a) Difference in diaphragmatic movement - supine : dorsal and ventral portion move symmetrically - prone : dorsal > ventral
  4. 4. PPL PPL -3.0 -1.0 Supine +2.8 prone +1.0PPL at dorsal Higher LessTP pressure Lower MoreResult Atelactasis openingf) Decrease chest wall compliance in p.p Redistribution of tidal volume to atelactatic dorsal region. Weight of heart may affect ventilation.8. Improvement in Cardiac output9. Better clearance of secretions10. Improved lymphatic damage
  5. 5. CONTRAINDICATION- Unresponsive cerebral hypertension- Unstable bone fractures- Left heart failure- Hemodynamic instability- Active intra abdominal pathologyTIMING ARDS > 24 hrs./ 2nd dayFREQUENCY Usually one time per dayDURATION 2 to 20 hrs/day.OUTCOMEImprovement in oxygenationNo improvement in survivalPOSITIONING ACHIEVED BYCirc Olectric, bed (Late 1970s).Manual 2 stepLight weight portable support frame (Vollman pronepositioner)
  6. 6. NO. OF PERSONS 3-5POSITION OF ABDOMENallowed to protude ; partial/complete restrictionPOSITION OF HEADHead down/ Head up position.ADEQUATE SEDATION +/- NMBACOMPLICATIONS- pressure sore- Accident removal of ET; Catheters- Arrhythmia- Reversible dependent odema (Face, anterior chest wall)Gattinoni et al, in a MRCT evaluated the effect of 7 hr / dayprone positioning x 10 dayimprovement in oxygenation, no survival benefitNEJM 2001, Vol 345 No 8 568-573
  7. 7. PARTIAL LIQUID VENTILATIONIn ARDs there is increased surface tension which can beeliminated by filling the lungs with liquid (PFC). Perflurocarbon: Colourless, clear, odourless, inert, high vapour pressure Insoluble in water or lipids MC used – perflubron (Perfluoro octy bromide) (Liquivent) Bromide → radiopaqueANIMAL EXPERIENCEImproved - Compliance - Gas exchange (dose dependent) - lung function - SurvivalAnti-inflam. propertiesDecrease risk of nosocomial pneumonia.Reduces pulm. vascular resistance.Little effect on central hemodynamics.
  8. 8. Mechanism of actionii) Reduces surface tensioniii) Alveolar recruitment – liquid PEEP. Selective distribution to dependent regions.iv) Increases surfactant phospholipid synthesis and secretion.v) Anti Inflam. PropertiesA. Indirect Mitigation of VILIB. Direct a)decrease endotoxin stimulated release of TNF; IL-1; IL-8. b)decrease production of reactive oxygen species. c)Inhibit neutrophil activation and chemostaxis. d)Lavage of cellular debris.
  9. 9. Technique of PFC Ventilation :2. Total liquid ventilation3. Partial liquid ventilation TLV PLV1. Ventilator Liquid Conventional2. Tidal volume delivered of Oxygenated PFC Gas3. Lungs are filled Completely by Filled till FRC by PFC PFC4. Feasibility Expt. Yes5. Disadvantage Loss of gas by evap., cost.
  10. 10. Recommended dose of PFC -20 ml/kg Beyond this dose – decrease co.More clinical trials are req. to demonst. efficacy.Additive effect of PLV has been shown in combination with: - NO - Surfactant - HFOV - prone ventilation2 published adult trials of PLV in ARDS have confirmed its safetybut not efficacy. Hirschl et al JAMA 1996, 275; 383-389 Gauger et al, CCM 1996, 24; 16-24
  11. 11. TRACHEAL GAS INSUFFLATION (TGI)In ARDS/ALI Increase physiological dead space OLS / permissive hypercapniaDURING CONVENTIONAL VENTILATION : Bronchi and trachea are filled with alveolar gas at end exhalation which is forced back into the alveoli during next inspiration.IN TGI Stream of fresh air (4 to 8 L/min) insufflated thr. – small cath. or through small channel in wall of ET into lower trachea flushing Co2 laden gas.
  12. 12. COMPLIC.2) Dissecation of secretions3) Airway mucosal injury4) Nidus for accumulation of secretions5) Auto – PEEP
  13. 13. HIGH FREQUENCY VENTILATIONUtilizes small volume (<VD) and high RR (100 b/min) Avoids over distention (Vili). Alveolar recruitment. Enhances gas mixing, improves V/Q.APPLIC.6. Neonatal RDS.7. ARDS.8. BPF.COMPLIC. Necrotizing trachebronchitis. Shear at interface of lung. Air trapping.Two controlled studies (113 and 309) no benefit. Carlon et al, 1983, Chest 84; 551-559 Hurst et al, 1990, Ann Surg 211; 486-91
  14. 14. Comparison of HFV Vs Conv. Ventil. JET Oscillator ConventionalFreq avail upto 600 b/min 300-3000 b/min 2-60 b/minTidal volume <or> VD < VD >> VDdeliveredExpiration Passive Active PassivePotentiation of 3+ 2+ 1+intrinsic PEEPVT x f product >> Conv >> Convfor effective VAPPK < Conv < ConvP mean <or> conv <or> conv
  15. 15. EXTRACORPOREAL MEMBRANE OXYGENATIONAdaptation of conventional cardiopulmonary bypass technique.Oxygenate blood and remove CO2 extracorporally.TYPES4. High-flow venoarterial bypass system.5. Low-flow venovenous bypass system.Criteria for treatment with extracorporeal gas exchangeFast entry criteriaPaO2 <50 mmHg for >2 h at FiO2 1.0; PEEP > 5 cmH2OSlow entry criteriaPaO2 <50 mmHg for >12 h at FiO2 0.6; PEEP > 5 cmH2Omaximal medical therapy >48 hQs /Qt > 30%; CTstat <30 ml/cmH2O
  16. 16. ComplicationMechanical Patient related Problem3. Oxygenator failure Bleeding4. Circuit disruption Neurological complications5. Pump or heat exchanger Additional organ failure mal functioning.7. Cannula placement/removal Barotrauma, infection, metabolicYear Survival1966 – 1975 10-15%1980 onward 40-50% Critical care 2000, 4; 156-168
  17. 17. HEMODYNAMIC MANAGEMENTControversialRestriction of FluidBenefitObs. Studies Show↓pulm. edema formation↑ compliance, lungs fn.Improved survivalNegative fluid balance is associated with improved survival Humphrey et al., 1990 Chest 97 ; 1176-80.Net positive balance <1 lt. in first 36 hrs. a/w improved survivaldecrease length of ventilation, ICU stay and hospitalization.Shorter duration of mech. venti., stay in ICU in pat. managed by fluidrestriction directed by EVLV c/w PAOP. No mortality benefit. Mitchell JP, Am Rev. Respr. Dis. 1992; 145; 990-998.
  18. 18. DetrimentalIneffective Circulatory Volume (Sepsis). Reduced co & tsperfusion.Goal Correct Volume deficit Guidelines for management of tissue hypoxia International consensus conference (AJRCCM- 1996)8. Promote oxygen delivery Adequate volume CVP – 8-12 mmHg PAOP-14-16 mmHg (Optimal co; less risk of Edema) Crystalloids vs Colloids Transfuse < 10 gm/dl13. Reduce oxygen demand : a) Sedation : Analgesia, NMBA b) Treat Hyperpyrexia c) Early institution of mech. vent. (shock).No role of supraphysiol. oxygen delivery
  19. 19. Vasopressors Following fluid resuscitation Norepinephrine vs Dopamine GOAL to achieve MAP 55 to 65 mmHgInotropesCo. is low
  20. 20. PULMONARY VASCULAR CHANGES IN ARDS/ALI1. Reduced pulmonary vasoconstriction in hypoxic shunt areas, along with vasoconstriction in well ventilated areas.2. PAH (Pulm. Vasoconst. ; Thromboembolism; Interstitial edema) - PAH aggravates edema by increasing inflow pressure. - So role of pulm. vasodilatorsSelective Pulmonary Vasodilators : Inhaled Nitric oxide (iNo)7. iv almitrine with/without iNo.8. Aerosolized prostacyclins.9. Inhibition of cyclic nucleotide phosphodiesterase.10. Inhalation of Endothelin receptor antagonists.
  21. 21. 1. Inhaled Nitric Oxide How it is beneficial in ARDs3. Improves Oxygenation - Selective vasodilatation of vessel a/w better ventilation → (decrease shunt) - Improves v/q mismatch.6. Reduction in pulmonary artery pressure - Improves oxygen - direct smooth muscle relaxation - improved RV Fn. - reduced capillary leak.11. Inhibit platelet aggregation and neutrophil adhesion.Selectivity of iNORapid inactivation on contact with hemoglobin. 60 % of pat respond to iNo by increase in PO2 >20%.
  22. 22.  DOSAGE Effect Dose Increase PaO2 1-2 ppm to <10 ppm decrease PAP 10-40 ppmTime of Response <10 min to several hours. Response to iNo is not static phenomenon.Intra-individual variation in response : - lung recruitment - Coexistent pathology - resolution of inflammationMortality Benefits – None
  23. 23. S/EMinimal Rebound pulm. hypertension & hypoxemia Methemoglobinemia Toxic NO2 ; Nitrous & Nitric Acid Prevent by decrease – contact time & conc. of gas.
  24. 24. Almitrine iv : low dose Potentates hypoxic vasoconstriction Decrease shunt, improved oxygenation Has additive effect with iNo iNo + prone position
  25. 25.  Aerosolized Prostacyclin iv prostacyclin decrease pulm. a. pressure (non selective vasodilatation) can increase shunt; worsen oxygenation. Inhaled prostacyclin selectively vasodilates the well perfused areas Selectivity in dose of 17-50 ng/kg/min. PGI2- Not metabolized in lung so selectively lost at higher doses. PGE1- 70-80% is metabolized in lung.7. Inhibition of cyclic nucleotide phosphodiesterases No → increase CGMP → Protein G-Kinase Calcium gated potassium Channels ↓ Vasodilatation PDE prevent degradation of CGMP (PDE-5)PDE –5 InhibitorsDipyridamole ; Sildenafil
  26. 26. Ziegler et al. 11 paed PAH Augmentation of iNo-1998 induced vasodilate by dipyridamol in 50% pt.Sildenafil Oral or iv Animal Exp. – decrease PPAInhaled PGI2 → CAMPPDE-2, PDE-3 : PDE-4 – Selectively degrade CAMP.Inhalation of Endothelin receptor antagonistIn ARDS – increased Endothelin levels ETA → Vasoconst.ENDOTHELIN ETB → release No; PGI2Non Selective ET antagonist Bosentan (oral)Selective ETA2 antagonist LU-B135252 (Neb) ,
  27. 27. SURFACTANT REPLACEMENT THERAPYIn ARDs there is deficiency and fn abn. of surfactant Decrease production (injury to type-2 pneumocytes) Abn. composition (decrease phosphatidyl choline, phosphotidylglycerol, Sp.A & Sp. B) Inhibitors of surfactant fn (TNF- α, reactive oxygen sp. Peroxynitrite, neutrophil elastases) Conversion of large to small surfactant aggregates Alteration/Destruction caused by substances in alveolar space (plasma, fibrinogen, fibrin, alb; Hb)Impaired surfactant fn → 1) Atelactasis / collapse 2) Increase edema formationIn experimental ALI models surfactant replacement. Improved lungs fn., compliance, oxygenation.
  28. 28. Surfactant of possible therapeutic use : Class Origin Example3. Natural Amniotic Human amniotic fluid surfactant4. Modified - Bovine Infasurf, alveofact Natural BLESS, Survanta - Procine Curosurf Synthetic Exosurf, ALEC, KL4 Surfactant, VenticuteDOSESufficient dose should reach alveolar environmentTIMING• As early as possible [<48 hr]• Little benefit at 3 to 5 days [Fibrosis already set]
  29. 29. Surfactant Delivery TechniquesInstillation •Lavage Aerosolization•Rapid • May remove toxic Continuous•Can deliver large subst. smaller vol. volume •Can deliver large•Homogenous vol. distribution •Homogenous Non uniform•Efficacious in distrib. distribution. clinical trials •Lab studies Lab. Studies suggest efficacy show efficacy• Techn. Not • Vol. recover can Slow, no optimal standardized be poor device, Filters• Short term • Short term may plug. impairment in impairment in ventilation ventil.
  30. 30. GLUCOCORTICOIDS IN ARDSTwo meta analysis of short course (< 48hr) of high dose methylpred. (30mg/kg/d) in early sepsis and ARDS found no evidenceof beneficial effects. - LEFERING et al CCM 1995, CRONIN l et al., CCM 1995In a Recent Randomized control trial prolongedadministration of methyl pred. in patients with unresolvingARDS was a/w improved LIS, MODS, mortality JAMA 1998 Vol. 280 ; 159 –165.Randomized double blind, placebo controlled trial24 pat. with severe ARDS who failed to improve LIS by 7th day ofmech. ventil.16 received methyl pred. while 8 rec. placebo 4 pat. whose LISfailed to improve by at least 1 point after 10 days of treatmentwere blindly crossed over to alternate treatment.
  31. 31. SIGNIFICANT IMPROVEMENT IN :• LIS (1.7 v 3.0)• Pao2/Fio2 (262 v 148)∀↓ MODS score (.7 v 1.8)• Successful Extubation (7 v 0)• ↓ mortality (0 v 62 %)• No signif. differences in nosocomial episodePROTOCOLDay Dose (Methy. Pred.) (mg/kg/d)1-14 2.015-21 1.022-28 0.529-30 0.2531-32 0.125
  32. 32. HOW STEROIDS ARE BENEFICIAL : Inhibit transcriptional activation of various cytokines. Inhibit synthesis of phospholipase A2 : cycloxygenase. Reduced prod. of prostanoids, PAF, No. ↓ fibrinogenesisLISOPHYLLINE AND PENTOXIFYLINEPDE-IInhibit neutrophil chemostaxis and activation.Lisophylline inhibit release of FF from cell memb. underoxidative stress↓ TNF : IL-1 ; IL-6NIH ARDS trial no benefit.
  33. 33. CYCLOOXYGENASE INHIBITORSTxA2 and Prostaglandin produced from AA by Cyclooxygenase pathway.Cause Neutrophil chemostaxis and adhesion Broncho constriction ↑ vascular permeability platelet aggregationAnimal studies shown that C.I• Attenuate lung injury• Improve pulm. hypertension and hypoxia
  34. 34. Bernard et al. 455 No reduction in1997 sepsis mort.,durationRDB PCT of shock; ARDSiv IbuprofenArons et al. Subgroup In hypothermic pt1999 analysis of Ibuprofen - trend above study towards ↑ in no. of days free of MODS. Sig. ↓ in mort.
  35. 35. KETOCONAZOLETxA22) Pulmonary vasoconstriction3) Platelet and neutrophil aggregationBlockade of Tx synthesis or receptor antagonism ameliorates experimental lung injuryKetoconazole Specific inhibitor of thromboxane synthetase Inhibits 5 – Lipoxygenase [LTB4 & procoag activity]
  36. 36. Summary of trials of Ketoconazole in ALI/ARDSStudy, yr No. of Pat. OutcomeSlotmann, 1988 71 high risk • Reduced Incidence of ARDS, ICU surgical stay, cost • No improve in mortalityYu & Tomasa, 54 sepsis • Reduced incidence of ARDS1993 • Significant lower mortalityNIH ARDS 234 No – Mortality benefitNetwork, 1997 ALI/ARDS No effect on lung function, duration ofTrial Ventilat.
  37. 37. ANTIOXIDANTSReactive oxygen metabolites derived from neutrophils, macrophagesand endothelial cellsOXIDANTS INCLUDE• Super oxide ion (02-), hydrogen peroxide (H2O2)• hypochlorous acid (Hocl), hydroxyl radical (OH..)Interact with proteins, lipid and DNAENDOGENOUS ANTIOXIDANTS• Superoxide dismutase, Glutathione, Catalase•Vit E & Vit C•SulfhydrylsIN EXPERIMENT (ANIMALS)A : ENZYMESSOD – Variable responseCATALASE – some benefit
  38. 38. REPLENISH GLUTATHIONE2) Glutathione itself3) Glutathione ethyl esters4) Cysteine derivatives a) NAC b) Procysteine
  39. 39. SUMMARY OF TRIALS OF NAC IN ALI/ARDSStudy, yr No. of Therapy Outcome PatientsJepsen, 1992 66 Placebo, No effect – Pao2/Fio2 NAC time to improve LIS. Improve – compl.*NS. Mortality – No diff.Suter 1994 61 Placebo, Improve – Pao2/Fio2; NAC Lis; need for M.V. Mortality – No diff.Bernard 1997 48 Placebo, Improve – ALI free NAC OTZ days & cardiac index ↓ new organ failure. Mortality – No diff.Domenighetti, 42 Placebo, Improved – LIS1997 NAC No effect – Pao2/Fio2, mortality.
  40. 40. ANTICOAGULANT THERAPY IN ALI/ARDS• In ARDS – Fibrin deposition intra-alveolar and interstitial.• Local procoagulant activity and reduced fibrinolysis.↑ Procoagulant ↓ Fibrinolysis↑ TF (VIIa) Fibrinolytic inhibitors ↑ PAI–1 ; PAI-2, α2 antiplasmin ↓ urokinase and tPA↑ Fibrin• Inhibit surfactant → atelactasis• + Fibrinonectin → Matrix on which fibroblast aggregate• +N Fibroblast proliferation• Potent chemotactic (Neutrophil recruitment)•
  41. 41. TF PATHWAY INHIBITORS AND FACTOR Vll aiIn Expt studies∀↓ Cytokine [IL-6, IL-10, IL-13]∀↓ Fibrin clot∀↓ Sepsis related organ damage∀↓ LIS•Improved survival20 % RR reduction in 28 days all cause mortality and improvement inorgan dysfn. in patient with severe sepsis. ABRAHAM E, ; CCM 2001 29 2081HEPARINEffectiveness in blocking fibrin deposition debatable.In Expt. animals large doses of UFH reduced fibrin deposition; prevent ↑EVLV; improved Pao2/Fio2Human data lacking.
  42. 42. ANTITHROMBINBroad spectrum serine protease Inhibitor.Action of Antithrombin3. Inhibits a) Thrombin b) Inactivates TF – VIIa complex(6) Stimulate prostacylin release(- plat. aggreg. neut. activation, cytokine rel.)In animal studies↓vascular injury; leukocyte accumulation ; vascular permeability.
  43. 43. Kybersept trial, 2314 pat. with severe sepsisNo reduction in 28 days all cause mortality but excess rate of bleeding events in pat. receiving concomitant heparin prophylaxis.Expl.v) AT levels below expected Heparin prophylaxis must have influenced efficacy.Improvement in 90 days survival rate in pat. receivingantithrombin without heparin. Warren BL et al ; Jama 2001; 286; 1869-1878
  44. 44. PROTEIN- C Inactivates Va & VIIa – limit thrombin generation. Inhibit PAI-1 activity - ↑ fibrinolysis. Anti-inflam. - ↓ cytokines, inhibit apoptosis.In the PROWESS study APC administ. Improved survival.28 days absolute risk reduction in mortality – 6.1%. 19.4%reduction in relative risk.↑ Risk of bleeding (3.5% vs 2.0%) Faster resolution of respiratory dysfun.↑ ventilatory free days (14.3 vs 13.2 days) Bernad GR ; NEJM 2001; 344; 699-709
  45. 45. ENHANCED RESOLUTION OF ALVEOLAR EDEMAAlveolar clearance of edema depends on active sodiumtransport across the alveolar epitheliumβ2 adrenergic stimulation :5. Salmetrol6. Dopamine7. DobutamineENHANCED REPAIR :Mitogen for type-II pneumatocyte : Hepatocyte growth factor Keratinocyte growth factor.