1.Topics to be covered.1. When the ARDS first dIscovered2. Patho physiology of ards and role of CS3. When was the first use of steroid started.4. Current prospective .5.doubble edege sword.

2. Introduction in 1821, in what was probably the first published scientific description,Laennec described the gross pathology of the heart and lungs anddescribed idiopathic anasarca of the lungs; pulmonary edema withoutheart failure in A Treatise on Diseases of the Chest By the 1950s, pulmonary edema had become a medical subjectheading by the National Library of Medicine; however, no distinctionwas made at that time between cardiac and noncardiac causes. But what clearly moved ARDS from a nearly universally fatal form ofdouble pneumonia was the development of methods of establishingsecure airway access using tubes that could be attached to mechanicalventilators to deliver adequate pulmonary distending pressures These techniques extended the lives of these patients from a few hoursto many days or even weekslong enough to recover in some cases. Am. J. Respir. Crit. Care Med. October 1, 2005 vol. 172 no. 7 798-806 3. For a period of time ARDS went by the name of inciting injuries (e.g., DaNang lung,shock lung, post-traumatic lung, etc.).It wasnt until 1967, in a landmark article published in Lancet, that Ashbaugh,Bigelow, Petty, and Levine first described the clinical entity that they called acuterespiratory distress in adults .This article recognized for the first time that ARDS was a constellation ofpathophysiologic abnormalities common to a relatively large number of patients butthat were initiated by a wide variety of unrelated insultS However, in 1971 Petty and Ashbaugh used the term adult respiratory distresssyndrome in another publication, probably to address the perception of ARDS as anadult version of the previously described infant respiratory distress syndrome(IRDS). 4. In 1992 the American European Consensus Conference(AECC) was charged with developing a standardizeddefinition for ARDS to assist with clinical and epidemiologicresearch. In 1994, the American-European Consensus Conference(2) defined two pathogenetic pathways leading to ARDS asa direct ("primary" or "pulmonary") insult, that directlyaffects lung parenchyma, and an indirect ("secondary" or"extrapulmonary") insult, that results from an acutesystemic inflammatory response Braz J Med Biol Res, February 2005, Volume 38(2) 147-159 (Review) 5. Berlin defination of ards jama -2012TimingWithin 1 week of known clinical insult or new or worseningof respiratory symptomsChest imaging b/l opacities not fully explained by effusion;lobar/lung collapse ornoduleOrigin of Respiratory failure not fully explained by cardiac failure or fluidedema overload.need objective assement to exclude the hydrostaticedema if no risk factor present.oxygenationmild200mmhg 5cmh20severepao2/fio2,5cmh20 6. Pathophysiology of ARDS Although the cellular and molecular basis of acute lung injury and ARDS remains an areaof active investigation,it appears that in ARDS, lung injury is caused by an imbalance of pro-inflammatoryand anti-inflammatory mediators.[4] The most proximate signals leading to uncontrolled activation of the acute inflammatoryresponse are not yet understood. However, nuclear factor B (NF-B), a transcription factor whose activation itself istightly regulated under normal conditions, has emerged as a likely candidate shifting thebalance in favor of a pro-inflammatory state. As early as 30 minutes after an acute insult, there is increased synthesis of interleukin-8(IL-8), a potent neutrophil chemotactic and activating agent, by pulmonary macrophages.Release of this and similar compounds, such as IL-1 and tumor necrosis factor (TNF),leads to endothelial activation, and pulmonary microvascular sequestration andactivation of neutrophils. Neutrophils are thought to have an important role in the pathogenesis of ARDS. 7. PATHOGENESIS OF ARDS 8. Role of NFKB GENE.. NF-B (nuclear factor kappa-light-chain-enhancer of activated Bcells) is a protein complex that controls the transcription of DNA. NF-B is found in almost all animal cell types and is involved in cellularresponses to stimuli such as stress cytokines,,Free radicals, oxidizedLDL and bacterial or viral antigens. NF-B plays a key role in regulating the immune response to infection(kappa light chains are critical components of immunoglobulins). Incorrect regulation of NF-B has been linked to cancer, inflammatoryand autoimmune diseases, septic shock, viral infection, and improperimmune development.Gilmore TD (2006). "Introduction to NF-B: players, pathways,perspectives". Oncogene 25 . PMIDHayden MS, West AP, Ghosh S (October 2006). "NF-B and the immune response". PMID. 9. Role of NFKB conti. 10. 3- Histopathological stages of ARDSit has been repeatedly shown that high levels of procollagen peptidesdetected in early stages of ARDS and the degree of fibrosis per se can beregarded as a key predictor of poor clinical outcome. 11. Activation and Regulation of SystemicInflammation in ARDS: Experimental and clinical evidence has demonstrated the cellularmechanisms involved in activating and regulating inflammationare contrasted between patients with resolving and unresolvingARDS. In ARDS, down-regulation of systemic inflammation is essential torestoring homeostasis, decreasing morbidity, and improvingsurvival. At the cellular level, patients with unresolving ARDS havedeficient glucocorticoid (GC)-mediated down-regulation ofinflammatory cytokine and chemokine transcription despiteelevated levels of circulating cortisol, a condition defined assystemic inflammation-associated acquired GC RESISTANCE. Controll sydies shows; Prolonged low-to-moderate dose GCtherapy promotes the down-regulation of inflammatory cytokinetranscription at the cellular level. And consistently reported asignificant reduction in markers of systemic inflammation,pulmonary and extrapulmonary organ dysfunction scores,duration of mechanical ventilation, and ICU length of stay 12. Progression of ARDS: Resolving vs Unresolving The lung injury score (LIS) quantifies the impaired respiratory physiology inARDS patients through the use of a 4-point score that is based on the level1) positive end-expiratory pressure (PEEP),2) the PaO2/FIO2 ratio,3) the quasistatic lung compliance, and4) the degree of infiltration seen on a chest radiograph (1 point per quadrant of chest radiograph involved). Based on simple physiologic criteria, the evolution of ARDS can be dividedinto resolving and unresolving based on achieving a 1-point reduction in LISby day 7. Daily measurement of LIS, MODS score, and CRP levels allow earlyidentification of non improvers. 13. Progression of ARDS conti.VariablesResolving UnresolvingOnset of ARDSSystemic inflammation* Moderate ExaggeratedHPA axis responseAdequate InadequateOver timeSystemic inflammationRegulatedDysregulatedCellularactivation/regulation of GR-driven NF-B-driveninflammationInflammation, markersDecreasing Persistent elevationACM permeability,mark. Decreasing Persistent elevationFibrogenesis, markersDecreasing IncreasingLung repair (histology)Adaptive MaladaptiveReduction in LIS 1 point by day 7 < 1 point by day 7ICU mortalityLowHighG. Umberto Meduri, MD, FCCP; Djillali Annane, MD, PhD; George P. Chrousos, MD;Paul E. Marik, MD, FCCP; Scott E. Sinclair, MD, FCCP,chest-2009 14. PATHWAY OF INHIBITION OF INFLAMATION BYCORTICOSTEROIDS 15. Interaction Between Activated NF-B and GR inARDSLongitudinal relation on natural logarithmic scales between mean levels ofnuclear NF-B and nuclear GR: resolving vs unresolving ARDS (left) and afterrandomization to methylprednisolone vs placebo (right). Activation and Regulation of Systemic Inflammation in ARDS: Rationale for ProlongedGlucocorticoid TherapyFree .G. Umberto Meduri, MD, FCCP; Djillali Annane, MD, PhD; George P. Chrousos, MD; Paul E. Marik, MD,FCCP; Scott E. Sinclair, MD, FCCP,chest-2009 16. Corticosteroids for prevention ofards ARDS develops after a variety of insults, including sepsis,multiple trauma, pneumonia, aspiration of gastriccontents, and severe burns. Its pathogenesis includes immune-mediated injuryleading to loss of the alveolar-capillary barrier, injury tothe alveolar epithelium, an influx of neutrophils andmacrophages, and fibrin. These changes develop overhours to a few days after the initiating event. Therefore, timely modulation of inflammation usingcorticosteroids in these high-risk patients would be arational approach for prevention of ARDS and itsconsequences. There are only a few trials on the role of corticosteroids asimmunomodulators to prevent development of ARDS inhigh-risk patients, such as patients with severesepsis.However, results were not encouraging. 17. weigielt et al;1985; performed a randomized double-blind trial to determine the usefulness of earlymethylprednisolone therapy for patients with pulmonary failure. selected 81 acutely ill, mechanically ventilated patients at high risk for adult respiratorydistress syndrome (ARDS). Thirty-nine patients received methylprednisolone, 30 mg/kg, every six hours for 48hours; 42 patients received mannitol placebo. All patients were given a positive end-expiratory pressure of 5 cm H2O, monitored withpulmonary artery catheters, and treated for their primary disease processes. Twenty-five steroid-treated patients (64%) and 14 placebo-treated patients (33%)developed ARDS. Early infectious complications occurred in 30 steroid-treated patients (77%) and 18placebo-treated patients (43%). There were no significant differences in factorspredisposing to ARDS, ventilatory requirements, or days of intensive care. These results do not support the use of methylprednisolone for ARDS. Steroids failedto improve pulmonary function and were associated with an increased infection rate.Intensive pulmonary and general supportive care remain the preferred therapy forARDS. 18. Bone et al;1987; In this study, 382 patients with sepsis were randomizedto receive either MP (30 mg/kg every 6 hours for 4doses) or placebo. This study showed that there was a trend towardincreased incidence of ARDS in MP group (32%) ascompared with placebo (25%), though results were notstatistically significant. However, mortality at day-14 was significantly higher(52% vs 22%; P = 0.005) in patients having received MPas compared with placebo. Other studies also showed that prophylactic shortcourse high-dose corticosteroids were associated withincreased chances of developing ARDS and/or mortality 19. Trials of corticosteroids for prevention of ARDSAuthour Drug dosage No of pt ORP-yeardeveloping (95%Ci) valueards/total no pts%Corticos Placeboteroid groupgroup 2.36Weigelt et Methylprednisolone 30 mg/kg 25/39 14/42(1.14- 0.008al. 1985 6 hourly for 48 hours (64.1)(33.3) 6.28)Methylprednisolone 30 mg/kg1.48 NotSchein et 7/292/13or Dexamethasone 6 mg/kg(0.48- mential. 1987 (24.1)(15.3)single dose4.44) oned 1.48Bone et Methylprednisolone 30 mg/kg 50/152 38/152(0.93- 0.10al. 19876 hourly for 24 hours (32.9)(25) 2.34) 1.55 NotLuce et Methylprednisolone 30 mg/kg13/38 14/37(0.44- signifial. 19886 hourly for 24 hours(34.2)(37.8)2.32) cant 20. Prevention It is important to note that in all thesestudies, MP was used for a maximumduration of 48 hours and its circulating halflife in ARDS patients varies from 3.8 to 7.2hours; therefore, the effect of this drug willdiminish after 24 to 36 hours at the most. Above study shows, it leads to higher ratesof ARDS, increased infectiouscomplications, and mortality. 21. Prevention conti.Therefore, we strongly argue againstprophylactic use of corticosteroids inseriously ill patients who are prone todevelop ARDS.It is evident from these clinical trials thatcorticosteroids have no role in preventionof ARDS in high-risk patients 22. Animal studies have shown that in acutelung injury, prolonged corticosteroidswere shown to be effective in reducingedema and collagen deposition in lung,while premature withdrawal rapidlynegated these positive effects. 23. Hetsberg et al; In a rat model of butylated-hydroxytoluene-induced ARDS, the timing of corticosteroid administration hadstrikingly different effects. Early administration of steroids resulted in increasedcollagen deposition, increased lung damage, and inhibition oftype II pneumocyte proliferation. Late administration, on theother hand, prevented excessive collagen deposition. Systemic methylprednisolone or dexamethasone at doses of 20or 4 mg kg-/day. respectively, improved pulmonary inflammationand mechanics in animals with acute lung injury. Volpe et al; On this basis, dexamethasone (a single dose of 2.5mg/kg) significantly reduced inflammatory cell protein content inbronchoalveolar lavage fluid (BALF), and improved lungcompliance 24 h after injury induced by oleic acid . 24. Kuwabara and co-workers (39),showed that prophylactic treatment with methylprednisolone (60 mg /kg 30 min before oleic acid infusion, followed by continuous infusion until the end of the experiments) did not attenuate oleic acid-induced acute lung injury or the increased level of phospholipase A2 activity, leukotriene B4 and thromboxane B2 in the BALF, but greatly reduced IL-8Corticosteroid at a dose of 10 mg/kg, starting on day 5 after the infection with reovirus 1/L, and given daily until the end of the time course of the disease, also did not attenuate the infiltration of inflammatory leukocytes, did not suppress key cytokine/chemokine expression, and did not inhibit the development of fibrotic changes in the lungsTherefore, one may argue that in addition to short duration, high doses might have been responsible for the negative results. 25. Hesterberg TW, Last JA. Ozone-induced acute pulmonary fibrosis inrats.Prevention of increased rates of collagen synthesis bymethylprednisolone. Am Rev Respir Dis. 1981;123:4752. Kuwabara K, Furue S, Tomita Y et al. (2001). Effect of methylprednisoloneon phospholipase A2 activity and lung surfactant degradation in acute lunginjury in rats. European Journal of Pharmacology, 433: 209-216. London L, Majeski E, Altman-Hamamdzic S, Enockson C, Paintlia MK,Harley RA & London SD (2002). Respiratory Reovirus 1/L induction ofdiffuse alveolar damage: pulmonary fibrosis is not modulated bycorticosteroids in acute respiratory distress syndrome in rats. ClinicalImmunology, 103: 284-295. Volpe BT, Lin W & Thrall RS (1994). Effect of intratracheal dexamethasoneon oleic acid-induced lung injury in the rat. Chest, 106: 583-587 26. This seems a plausible explanation for thenegative results observed in earlier studies withshort course of high-dose MP. Furthermore, it may be noticed that all thesestudies have used high doses of MP for preventionof ARDS.However, we have seen that the low-dosecorticosteroids are useful in other critical illnessessuch as septic shock. 27. CORTICOSTEROIDS FOR THE TREATMENT OF ARDS Based on above results, researchers triedprolonged course of corticosteroids in patients withestablished ARDS at various stages, that is, early(14 days).Conceptually, corticosteroids administration should be moreeffective during exudative phase (early phase).Unfortunately, clinically, it is difficult to identify different phases of ARDS without lung biopsy; however, its role in clinical practice is yet to be defined. 36. There are many clinical parameters which are important contributors to themorbidity associated with ARDS, such asorgan dysfunction score, lung injury score, oxygenation, duration ofmechanical ventilation, and ICU stay, as these have significant effect on thecost of treatment.Therefore, the effect of corticosteroids on these parameters would beimportant consideration for its use in ARDS.ARDSnet trial showed thatMP increased the number of ventilator-free days (14.1 days vs 23.6 days, P =0.006)Meduri et al. showed that corticosteroids use leads to significant reduction innumber days of ICU stay (7 vs 14.5 days; P = 0.007).Similar findings has been reported by various other studies.Length of ICU stay is an important factor which uses lots of resources.The corticosteroids have been shown to reduce disease severity scores,namely, the multiple organ dysfunction syndrome score and lunginjury score. These agents also improve oxygenation (PaO2/FIO2ratios). 37. Corticosteroids in late ARDS Persistent ARDS at later stages is characterized bymore of fibrosis than cellular inflammation; therefore,corticosteroid effect is expected to be different. It has been observed that there is significantassociation between late initiation corticosteroids andfailure to improve, with 50% failure rate (P = 0.04). In ARDSnet trial in patients with late ARDS (LATESTEROID RESCUE STUDY LASRS enrolled 13 daysafter onset of ARDS), corticosteroids use wasassociated with increased mortality (35% vs 8%; P =0.02) and neuromuscular weakness.These results suggest that corticosteroid use in late stageof ARDS probably have negative effect on finaloutcome. 38. Adverse effect ofcorticosteroids ARDSnet trial showed that rate of newinfections was lower in patients receiving MP(22.4%) as compared with placebo (32.9%),though results were not statistically significant(P = 0.14). Meduri et al. reported similar infection rate inboth the groups and no GI bleed. Annane et al. showed that rates ofsuperinfection (13% vs 12%), GI bleed (2% vs6%), and psychiatric disorders were similar inboth placebo and corticosteroids group 39. Hyperglycemia was observed in ARDSnet trial withMP group having significantly higher glucose. Meduri et al. have shown that patients requiringinsulin to treat hyperglycemia were similar (71.4%vs 64.3%) with MP and placebo. ARDSnet trial reported similar incidence ofneuromuscular weakness in both placebo andtreatment arm (24% vs 29%). However, seriousneuromuscular weakness was observed in 9patients, all were in MP group (P = 0.001) Meduri et al. showed similar incidence ofneuromuscular weakness (6.4% vs 3.6%) inpatients treated with MP as compared withplacebo. 40. A recent meta-analysis has shown that therewas no difference in the incidence ofinfection, neuromyopathy, GI bleeding, andlife-threatening complications, such as majororgan failure (heart, kidney, and liver),between corticosteroid and placebo group. Tang BM, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of corticosteroidsin acute lung injury and acute respiratory distress syndrome: A systematic .review and meta-analysis. Crit Care Med 2009;37:1594603.[PubMed] 41. Corticosteroid use current view. Methylprednisolone-induced down-regulation of systemicinflammation was associated with significant improvement inpulmonary and extrapulmonary organ dysfunction andreduction in duration of mechanical ventilation and ICUlength of stay.Methylprednisolone infusion in early severe ARDS: results of arandomized controlled trial.Meduri GU, Golden E Freire AX, Taylor E,, Zaman M, Carson SJGibsonM, Umberger R,chest-2009 42. Admistration of glucocorticoidsI.C.U PROTOCOL,ISCCM. Wigh the risk and benefits of individualpatients. It should be avoided in patients withactive infection. It is used in 2weeks of onset. Dose should be 1mg/kg bolus followedby 1mg/kg/day infusion. Use only when paralytic agents arediscontinued. 43. Response is seen in 5 days ,if there isno response it may discontinued. If favorabel response continue for 14days or until extubation..there after halfthe dose for 7 days and then stop. The safety profile proven including noadded risk of infection. 44. Exclusion criteria for steroidstreatment. Clinical evidence of active untreated infection. A known undrained abcess or a knownintravascular nidus of infection. A bacterialinfection being treated with std antibiotic regimenwith exception of above. Disseminated fungal infection even if beingtreated. Age