Nonventilatory strategies for patients with life-threatening 2009H1N1 influenza and severe respiratory failure

Lena M. Napolitano, MD; Pauline K. Park, MD; Krishnan Raghavendran, MD; Robert H. Bartlett, MD

Severe respiratory failure, in-cluding acute lung injury (ALI)and acute respiratory distresssyndrome (ARDS) (1), in pa-tients with 2009 H1N1 influenza pulmo-nary infection has been described world-wide (2–9). A common feature of thesepatients is severe hypoxemia, ARDS, andan inability to achieve adequate oxygen-ation with conventional ventilation mo-dalities commonly used in the treatmentof severe ARDS. In addition, high casefatality rates have been reported, withmultiple organ failure as the leadingcause of death. Our case series of inten-sive care unit (ICU) patients with severe2009 H1N1 influenza virus infection andARDS in Michigan, reported in June2009, documented the use of a number ofrescue therapies for the treatment of se-vere hypoxemia in these patients (2).

MATERIALS AND METHODS

Outcomes of Patients WithARDS Attributable to Influenza

A recent retrospective cohort study exam-ined 111 critically ill patients with confirmedinfluenza virus infection. ARDS complicated

the ICU course in 25 (23%) of the patients,with a mortality rate of 52%. Multivariate lo-gistic regression analysis identified the devel-opment of ARDS (odds ratio [OR], 7.7; 95%confidence interval [CI], 2.3–29) as an inde-pendent risk factor for hospital mortality incritically ill patients with confirmed influenzavirus infection (10).

Similarly, a report of children with ARDSattributable to highly pathogenic avian influ-enza A (H5N1) also documented a significantlyhigher mortality rate (83%) compared to chil-dren with ARDS who were H5N1-negative(48%) (11). The H5N1-positive patients withARDS also had significantly reduced survivaltime compared to H5N1-negative ARDS pa-tients (12.3 � 5.7 days [median, 11 days] vs.21.5 � 13.8 days [median, 22 days]), respec-tively). These observations clearly docu-mented the adverse outcomes associated withinfluenza A (H5N1)-induced fulminant ARDS.

In contrast to the high reported mortalityrates in patients with severe ARDS attributableto influenza infection, over the past decadethere has been a significant improvement insurvival among patients with ALI treated atARDS Network centers (Fig. 1), strongly sug-gesting that advancements in critical care andlung-protective ventilation have accounted forthis improvement in mortality (12).

For patients with 2009 H1N1 influenza se-vere respiratory failure, early initiation of ap-propriate antiviral treatment is of paramountimportance, including oseltamivir or zanami-vir (13, 14). In a recent review (15) of theepidemiology of laboratory-confirmed severeand fatal human influenza infections in Thai-land, treatment with oseltamivir was associ-ated with survival (OR, 0.11; 95% CI, 0.04–0.30) in hospitalized human influenzapneumonia patients. Additional treatment of

ALI and ARDS is supportive care, includingoptimal mechanical ventilation, nutritionalsupport, manipulation of fluid balance, sourcecontrol with treatment of sepsis, and preven-tion of intervening medical complications.Optimal lung-protective ventilatory strategiesin these patients, as in those with severe ARDSattributable to other etiologies, focus on lim-iting end-inspiratory plateau pressure (Pplat)to �30 cm H2O and tidal volumes to �6mL/kg of predicted body weight, with provi-sion of optimal positive end expiratory pres-sures for alveolar recruitment.

Mechanical ventilatory support can be in-jurious and lead to additional lung injurywhen used at the extremes of pulmonary phys-iology, a concept that has been termed venti-lator-induced lung injury (16). A number ofmechanisms can lead to the development ofventilator-induced lung injury, includingbarotrauma, diffuse alveolar injury attribut-able to overdistension (volutrauma), injury at-tributable to repeated cycles of recruitment/derecruitment (atelectrauma), and the mostsubtle form of injury attributable to the re-lease of local mediators in the lung (bio-trauma) (17).

ARDS and ALI are associated with patho-logically complex changes in the lung, mani-fested by an early exudative phase, followed byproliferative and fibrotic phases (18). Theacute inflammatory state leads to increasedcapillary permeability and accumulation ofproteinaceous pulmonary edema, leading tohypoxemia. Hypoxia may further aggravatelung injury; therefore, treatment strategies fo-cus on improvement of oxygenation and cor-rection of the underlying problem (19).

Most patients who die of 2009 H1N1 influ-enza do so as a result of unrelenting hypox-emic respiratory failure. Hypoxemia was iden-

From Department of Surgery; University of Michi-gan Health System, Ann Arbor, MI.

The authors have not disclosed any potential con-flicts of interest.

For information regarding this article, E-mail:lenan@med.umich.edu

Copyright © 2010 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181cc5373

Severe respiratory failure (including acute lung injury andacute respiratory distress syndrome) caused by 2009 H1N1 influ-enza infection has been reported worldwide. Refractory hypox-emia is a common finding in these patients and can be challeng-ing to manage. This review focuses on nonventilatory strategies inthe advanced treatment of severe respiratory failure and refrac-tory hypoxemia such as that seen in patients with severe acuterespiratory distress syndrome attributable to 2009 H1N1 influ-

enza. Specific modalities covered include conservative fluid man-agement, prone positioning, inhaled nitric oxide, and extracorpo-real membrane oxygenation and life support. Pharmacologicstrategies (including steroids) investigated for the treatment ofsevere respiratory failure are also reviewed. (Crit Care Med 2010;38[Suppl.]:S000–S000)

KEY WORDS: ●●●

S1Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

tified as an independent risk factor formortality in the report from Mexico, docu-menting a median PaO2-to-FIO2 ratio of 164(range, 87–250) in patients who survived (n �11) compared to 53 (range, 46–107) in thosewho died (n � 7), with hazard ratio for death0.95 (95% CI, 0.91–0.99; p � .02). Consider-ation of rescue therapies for refractory hypox-emia therefore is fully warranted (20). Thisreview focuses on nonventilatory managementstrategies for the treatment of patients withsevere respiratory failure, hypoxemia, andARDS.

DISCUSSION

Conservative Fluid Management

Diuresis to dry weight is a commonstrategy used in the treatment of patientswith severe hypoxemia attributable to2009 H1N1 influenza bilateral pneumo-nia. We utilize continuous infusion furo-semide or bumetanide therapy to achievenet negative fluid balance in patients withsevere hypoxemia. Evidence supports thissimple clinical strategy.

The National Heart, Lung, and BloodInstitute ARDS Network prospective, ran-domized, clinical trial (Prospective, Ran-domized, Multicentered Trial of FluidConservative vs. Fluid Liberal Manage-ment of ALI and ARDS, FACCT) that eval-uated the use of a liberal vs. conservativefluid strategy (using diuretics to target acentral venous pressure �4 mm Hg orpulmonary artery occlusion pressure �8mm Hg) in patients with ALI docu-mented that a fluid-conservative strategyresulted in a significant increase in ven-tilator-free days and a nonsignificant de-crease in mortality by 3% (Fig. 2) (21).The same clinical trial found no addi-tional benefit to the use of a pulmonaryartery catheter rather than a central ve-nous catheter in fluid management (22).No significant difference in the need forhemodialysis was identified in the con-servative vs. liberal fluid managementstrategies in this clinical trial (14% vs.10%; p � .06), but the indications forinitiation of hemodialysis were not con-trolled, making comparison difficult. A

secondary analysis of the NationalHeart, Lung, and Blood Institute ARDSNetwork tidal volume study cohort doc-umented that cumulative negative fluidbalance on day 4 of the study was asso-ciated with significantly lower hospitalmortality (OR, 0.50; 95% CI, 0.28 – 0.89;p � .001) and more ventilator-free andICU-free days (23). Similarly, a post hocsubgroup analysis of 1000 surgical pa-tients enrolled in the FACTT trial doc-umented that a conservative fluid-administration strategy resulted inmore ventilator-free and ICU-free days,and no difference in mortality or renalfailure (24).

A small (n � 40) double-blind, place-bo-controlled, multicenter trial random-ized patients with ALI/ARDS and hy-poproteinemia (serum total proteinconcentrations �6 g/dL) to receive furo-semide with albumin or furosemide withplacebo for 72 hrs, titrated to fluid lossand normalization of serum total pro-tein concentration. Albumin-treatedpatients had greater increase in oxygen-ation (mean change in PaO2/FIO2, �43vs. �24 mm Hg at 24 hrs and �49 vs.�13 mm Hg at day 3), with greater netnegative fluid balance (�5480 mL vs.�1490 mL at day 3) and better mainte-nance of hemodynamic stability (25).Additional larger definitive clinical tri-als are warranted to confirm these pre-liminary findings.

It should be noted, however, thatmany patients with severe ARDS attrib-utable to 2009 H1N1 influenza pneumo-nia present with acute kidney injury andmultiple organ dysfunction and/or fail-ure. In these patients, early initiation ofcontinuous renal replacement therapymay facilitate optimal management offluid balance with the ability to titratefluid removal and achieve goals for netnegative fluid balance on an hourly basis.In the recent report of 722 patients ad-mitted to ICUs in Australia and New Zea-land with confirmed infection with the2009 H1N1 virus, 506 patients (70.1%)required renal replacement therapy, and498 (69.0%) required vasopressor drugsduring their ICU stay (26).

Prone Positioning

Changes in patient positioning canhave a dramatic effect on oxygenationand ventilation in severe ARDS. Chang-ing the patient position to prone or asteep lateral decubitus position can im-prove the distribution of perfusion to

Figure 1. Crude 60-day mortality among acute respiratory distress syndrome (ARDS) Network patients,1996 to 2005. From: Erickson SE, Martin GS, Davis JL, et al; for the NIH NHLBI ARDS Network: CritCare Med 2009; 37:1574–1579.

Figure 2. Fluid management strategies in the FACTT trial. Left, Fluid-conservative strategy, in whichdiuretics were administered to a target central venous pressure �4 mm Hg or pulmonary arteryocclusion pressure �8 mm Hg. Right, Fluid-liberal strategy in which fluids were administered tomaintain a central venous pressure between 10 and 14 mm Hg. From: Liu KD, Matthay MA: Advancesin critical care for the nephrologists: Acute lung injury/ARDS. Clin J Am Soc Nephrol 2008; 3:578–586.

S2 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

ventilated lung regions, decreasing in-trapulmonary shunt and improving oxy-genation (27).

The use of intermittent prone posi-tioning can significantly improve oxygen-ation in 60% to 70% of patients (28, 29).A multicenter, randomized trial of con-ventional treatment vs. placing patientsin a prone position for �6 hrs daily for 10days was conducted on patients 16 yrs orolder with ALI or ARDS (30). No differ-ences were identified between the groupsin mortality or complications at any timepoint during the study, with up to 6 mosfollow-up. The mean increase in the PaO2-to-FIO2 ratio was greater in the pronethan in the supine group (63 � 67 vs.45 � 68; p � .02). Of note is that themean PaO2 of 85 to 88 mm Hg and meanPaO2-to-FIO2 ratio of 125 to 129 are stillhigh for patients with severe ARDS;therefore, these patients may not havebeen likely to benefit considerably by theprone intervention with regard to mor-tality. A retrospective analysis of patientsin the prone position arm of this studyrevealed that ALI/ARDS patients who re-sponded to prone positioning with a re-duction in their PaCO2 �1 mm Hgshowed an increase in survival at 28 days,with a decrease in the mortality rate from52% to 35% (31).

A multicentered, randomized, con-trolled clinical trial of supine versusprone positioning in 102 pediatric pa-tients failed to demonstrate a significantdifference in the main outcome measure,which was ventilator-free days to day 28.There were also no differences in the sec-ondary end points study conducted, in-cluding proportion alive and ventilator-free on day 28, mortality, time torecovery from lung injury, organ-failure-free days, and functional health (32).

A prospective, randomized study (n �136), with guidelines established for ven-tilator settings and weaning, examinedthe efficacy of the prolonged prone posi-tion (continuous prone position for 20hrs daily) in severe ARDS patients with 48hrs of tracheal intubation. Multivariateanalysis documented that randomizationto the supine position was an indepen-dent risk factor for mortality (OR, 2.53;p � .03). These authors concluded thatprone ventilation is feasible and safe andmay reduce mortality in patients withsevere ARDS when it is initiated early andapplied for most of the day (33).

An open, randomized, controlled trialin 17 medical–surgical ICUs enrolled 40mechanically ventilated patients withearly and refractory ARDS despite protec-tive ventilation in the supine position.

Patients were randomized to remain su-pine or to be moved to early (within 48hrs) and continuous (�20 hrs/day) proneposition until recovery or death. The trialwas prematurely stopped because of a lowpatient recruitment rate. PaO2/FIO2tended to be higher in prone than insupine patients after 6 hrs (202 � 78mm Hg vs. 165 � 70 mm Hg); this dif-ference reached statistical significance onday 3 (234 � 85 vs. 159 � 78). Prone-related side effects were minimal and re-versible. Sixty-day survival reached thetargeted 15% absolute increase in pronepatients (62% vs. 47%) but failed to reachsignificance because of the small sample.This study adds data to reinforce the po-tential beneficial effect of early continu-ous prone positioning on survival inARDS patients (34).

The most recent systematic review ofthe effect of prone mechanical ventilationon clinical outcomes in patients withacute hypoxemic respiratory failure re-ported that it does not reduce mortalityor duration of ventilation, despite im-proved oxygenation and a decreased riskof pneumonia (Figs. 3, 4) (35). However,despite no significant effect on mortalityreduction, these data do confirm a sig-nificant improvement in oxygenationand support the use of prone positionventilation as a rescue strategy in pa-tients with severe hypoxemia. Addi-tional systematic reviews and meta-analyses have confirmed similarfindings. Interestingly, the pooled ORfor ICU mortality in the selected groupof the more severely ill patients favoredprone positioning (OR, 0.29; 95% CI,01.12– 0.70) (36 – 40).

Prone positioning may be labor-intensive with associated risks, includinginadvertent extubation and pressuresores, and requires the use of appropriatecushioning of the dependent portions ofthe body to avoid pressure ulcerations.However, the technique can be per-formed safely by trained and dedicatedcritical care staff aware of its potentialbenefits in critically ill patients with se-vere respiratory failure and hypoxemia.Interestingly, prone positioning was usedin 42% of patients in the conventionalmanagement group (control arm) of theconventional ventilation or extracorpo-real membrane oxygenation (ECMO) forsevere adult respiratory failure (CESAR)trial, compared to only 4% in the ECMOgroup.

Extended prone position ventilation insevere ARDS has been confirmed in a

Figure 3. Effect of ventilation in the prone position on daily ratio of partial pressure of oxygen toinspired fraction of oxygen. A random-effects model was used in the analysis. Values were recorded atthe end of the period of prone positioning (prone group) and simultaneously in the supine group. Ratioof means indicates mean ratio of partial pressure of oxygen to inspired fraction of oxygen in the pronegroup divided by that in the supine group. I2 indicates percentage of total variation across studiesowing to between-study heterogeneity rather than chance. CI, confidence interval. From: Sud S, SudM, Friedrich JO, et al: Effect of mechanical ventilation in the prone position on clinical outcomes inpatients with acute hypoxemic respiratory failure: A systematic review and meta-analysis. CMAJ 2008;178:1153–1161.

S3Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

recent pilot feasibility study. Extendedprone position ventilation was defined asprone position ventilation for 48 hrs oruntil the oxygenation index was �10. Aprospective interventional study in 15 pa-tients confirmed that there was a statis-tically significant improvement in oxy-genation (PaO2/FIO2 92 � 12 vs. 227 � 43;p � .0001) and oxygenation index (22 �5 vs. 8 � 2; p � .0001), reduction ofPaCO2 (54 � 9 vs. 39 � 4; p � .0001) andPplat (32 � 2 vs. 27 � 3; p � .0001), andimproved static compliance (21 � 3 vs.37 � 6; p � .0001) with extended proneposition ventilation. All the parameterscontinued to improve significantly whilethe subjects remained in the prone posi-tion and did not change on returning thepatients to the supine position. The re-sults obtained suggest that extendedprone position ventilation is safe and ef-fective in patients with severe ARDSwhen it is performed by a trained staffand within an established protocol. Ex-tended prone position ventilation isemerging as an effective rescue therapyfor patients with severe ARDS and severehypoxemia (41).

In our experience, prone positioning isa useful tool for treatment of hypoxemia,can sometimes prevent the need for ex-tracorporeal life support (ECLS), and isused for lung recruitment in patients onECLS. One technique involves alternat-ing prone with supine positioning every 6hrs. Patients will often experience an ini-

tial worsening in their respiratory statuswith each change in position, but thispasses quickly in the first 15 to 30 mins,followed by eventual improvement in ox-ygenation and ventilation. Prone posi-tioning, although not associated with asignificant survival advantage, may servea role as rescue therapy for patients withARDS and refractory life-threatening hy-poxemia.

Nitric Oxide

Nitric oxide (NO), a naturally occur-ring product identical to endothelial-derived relaxing factor (42–44), is an im-portant endogenous mediator in severalphysiologic processes in vivo. One of itsmost important cardiovascular actions ispotent vasodilation, which results fromdecreased calcium in smooth muscle cellcytoplasm after NO-dependent increasein cyclic-guanosine monophosphate. Theactivity of NO can be pharmacologic aswell as physiologic. Inhaled NO (INO) hasthe advantage of selective delivery to ven-tilated alveolar units. The impact of INOdepends on the relative contribution ofhypoxic vasoconstriction and ventilation/perfusion mismatch to the hypoxemia.

INO affects gas exchange by increasingblood flow in ventilated areas to improveventilationA/perfusionc matching. Be-cause of its high affinity for hemoglobin,INO is active principally in ventilatedlung regions, with relatively little diffu-

sion into neighboring nonventilated tis-sues. A major established therapeutic useof INO is in pulmonary hypertension ofthe newborn (45–48). INO has also beenshown to reduce pulmonary artery pres-sures and/or pulmonary vascular resis-tance in a number of animal models ofacute pulmonary injury (49–54), makingit relevant for patients with ALI/ARDS.

Two small single-center studies andfour multicenter, randomized, placebo-controlled trials have failed to determinethe therapeutic role of INO in patientswith acute respiratory failure. Low-doseINO in ALI and ARDS has been associatedwith improved short-term oxygenationbut has had no substantial impact on theduration of mechanical ventilatory sup-port or on mortality (55–59).

The Cochrane Database systematic re-view of INO for acute hypoxemic respira-tory failure in children and adults in-cluded five randomized, controlled,clinical trials assessing 535 patients withacute hypoxemic respiratory failure.There was no significant difference inmortality with the use of NO in trialswithout crossover (risk ratio [RR], 0.98;95% CI, 0.66–0.44). Published evidencefrom one study demonstrated that NOtransiently improved oxygenation in thefirst 72 hrs of treatment. Limited datademonstrated no significant difference inventilator-free days between treatmentand placebo groups, and no specific doseof NO was significantly advantageousover another. Other clinical indicators ofeffectiveness, such as duration of stays inthe hospital and ICU, were inconsistentlyreported. No significant complicationswere directly attributable to this treat-ment. NO did not demonstrate any statis-tically significant effect on mortality andtransiently improved oxygenation in pa-tients with hypoxemic respiratory failure(60). The authors conclude that if furthertrials comparing INO with an inhaled pla-cebo are to proceed, then they should bestratified for primary disease, shouldassess the impact of other combinedtreatment modalities for respiratoryfailure, and must specifically evaluateclinically relevant outcomes before anybenefit of INO for respiratory failurecan be excluded.

A more recent systematic review andmeta-analysis of the effect of NO on oxy-genation and mortality in ALI included12 trials randomly assigning 1237 pa-tients. Overall methodologic quality wasgood. On day 1 of treatment, NO in-creased oxygenation as measured by the

Figure 4. Effect of ventilation in the prone position on mortality. A random-effects model was used foranalysis. The duration of prone positioning was up to 24 hrs for 1 to 2 days in the short-term trialsand up to 24 hrs daily for �2 days in the prolonged-duration trials. The trial by Gattinoni et al (24)included data only for patients with acute hypoxemic respiratory failure. Including all patients fromthis trial (7 of 25 deaths in the prone group and 14 of 28 deaths in the supine group) did not changethe result (risk ratio [RR], 0.95; 95% CI, 0.83–1.08; p � .41). I2 indicates percentage of total variationacross studies owing to between-study heterogeneity rather than chance. From: Sud S, Sud M,Friedrich JO, et al. Effect of mechanical ventilation in the prone position on clinical outcomes inpatients with acute hypoxemic respiratory failure: A systematic review and meta-analysis. CMAJ 2008;178:1153–1161.

S4 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

PaO2/FIO2 ratio (13%; range, 4%–23%)and decreased the oxygenation index(14%; range, 2%–25%; Fig. 5). Evidencesuggested that improvements in oxygen-ation persisted until day 4. Using randomeffects models, they found no significanteffect of NO on hospital mortality (RR,

1.10; 95% CI, 0.94–1.30), duration ofventilation, or ventilator-free days (Fig.6). There was no effect on mean pulmo-nary arterial pressure. Interestingly, pa-tients receiving NO had an increased riskof developing renal dysfunction (1.50;range, 1.11–2.02) (61).

The improvement in oxygenation as-sociated with INO in ALI and ARDS hasnot been translated into improved clini-cal outcome. Variable response to INOmay be related to increased blood flow innonventilated areas in the setting of dis-ordered pulmonary vasoregulation inALI/ARDS. INO may improve oxygenationby decreasing intrapulmonary shunt, orit may worsen oxygenation by reversinghypoxemic pulmonary vasoconstriction,thereby increasing ventilation/perfusionmismatch. This may also be related to thefact that ARDS is a heterogeneous condi-tion with multiple causes (pulmonaryand extrapulmonary), and that only asmall minority of patients with ARDS dieof respiratory failure; the majority die ofmultiple organ dysfunction and failure.These data do not support the routine useof INO in the treatment of ALI or ARDS,but it should be considered as a salvage orrescue therapy in patients who continueto have life-threatening hypoxemia de-spite optimization of all other treatmentstrategies.

It can be challenging to wean INO inALI/ARDS patients who are responders toINO. Some have advocated the use ofenteral off-label sildenafil, a selective andpotent inhibitor of phosphodiesterasetype 5, particularly to ameliorate the ef-fect of INO withdrawal (62). Further-more, some data suggest that sildenafilmay augment and prolong the pulmonaryvasodilatory effects of INO, allowing suc-cessful weaning and discontinuation ofINO in patients in whom INO withdrawalhad previously failed (63).

In patients with severe ARDS attribut-able to 2009 H1N1 influenza, INO hasbeen used as a rescue strategy in somepatients. We also use it in a strategy tostabilize ECMO evaluation patients withsevere hypoxemia for transfer to our fa-cility. Variable efficacy has been observed,and no formal recommendation can yetbe made. Organized data collection ef-forts are needed regarding treatmentstrategies used in these critically ill pa-tients with severe ARDS attributable to2009 H1N1 influenza to assess the effi-cacy of these rescue therapies for thetreatment of severe hypoxemia.

Prostacyclin and OtherVasodilatory Prostaglandins

Prostacyclin is a microcirculatory va-sodilator and inhibitor of platelet aggre-gation used for several indications in neo-natal and adult medicine. When

Figure 5. Effect of nitric oxide (NO) on PaO2/FIO2 ratio and oxygenation index at 24 hrs. Weight is therelative contribution of each study to overall estimate of treatment effect (ratio of means, NO relativeto control) on log scale assuming a random effects model. For some trials, number of patients withdata are less than number randomized. From: Adhikari NKJ, Burns KEA, Friedrich JO, et al: Effect ofnitric oxide on oxygenation and mortality in acute lung injury: Systematic review and meta-analysis.BMJ 2007; 334:779.

Figure 6. Effect of NO on mortality. Weight is the relative contribution of each study to the overallestimate of treatment effect on a log scale assuming a random effects model. Two trials with �50%of control patients crossing-over to NO also reported mortality date (w2 w6). Inclusion of these trialsdid not alter summary mortality estimate (RR, 1.09; CI, 0.94–1.27). From: Adhikari NKJ, Burns KEA,Friedrich JO, et al: Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematicreview and meta-analysis. BMJ 2007; 334:779.

S5Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

aerosolized, its vasodilatory action inventilated areas should be similar to thatof INO in improving ventilationA/perfu-sionc matching without promoting sys-temic hypotension. Consistent with this,aerosolized prostacyclin improved acuterespiratory function to the same degreeas INO in several studies in patients withARDS (64 – 66). Observational studieshave documented that prostacyclin is anefficacious selective pulmonary vasodila-tor, with significant dose-related im-provements in oxygenation, no demon-strable effect on systemic arterialpressures over the dose range of 0 to 50ng/kg/min, and no demonstrable plateletfunction defect despite significant sys-temic levels of prostacyclin metabolite(67, 68).

Inhaled iloprost is the stable carbacy-clin analog of prostacyclin. In contrast toprostacyclin, iloprost is stable at roomtemperature, has physiologic pH, and hasnormal light conditions. Whereas prosta-cyclin has a half-life of only 3 mins, ilo-prost has a half-life of 20 to 30 mins andexerts its pulmonary vasodilating effectsfor 30 to 90 mins. Clinical studies haveshown that inhaled iloprost has compa-rable pulmonary hemodynamic effects toINO and inhaled prostacyclin (69). It wasapproved by the U.S. Food and Drug Ad-ministration in 2004 for pulmonary hy-pertension with New York Heart Associ-ation class III or IV symptoms. Wecurrently use INO and inhaled iloprost asrescue therapies for patients with severeARDS and hypoxemia.

Another vasodilatory prostaglandin,alprostadil, has also been shown to allowimprovements similar to those of INOwhen delivered by aerosol to patientswith ARDS (70, 71). These results suggest

that aerosolized prostacyclin or similardrugs could be viable therapeutic alterna-tives to INO. Additionally prostacyclinmay have some advantages over NO be-cause it is easier to administer and hasharmless metabolites; however, it is moreexpensive and has not shown any survivalbenefit in human trials.

Extracorporeal Life Support

In patients with acute and severe re-spiratory failure and ARDS that do notrespond to any advanced modes of me-chanical ventilation, the use of ECLS orECMO is an option. ECLS is a provenmodality for treatment of severe respira-tory failure in the neonate (72, 73) anduse has increased since its inception (74).For infants, children, and adults with se-vere ARDS, ECLS therapy has producedsurvival rates of 85%, 74%, and 52%,respectively (75). The indications forECLS for adult respiratory failure arelisted in Table 1. Referral to an ECLScenter should occur early if need for thistechnology is suspected. This will allowsafe patient transport and avoidance ofthe “crash on,” with all of its inherentcomplications.

The technique of ECLS for patientswith severe respiratory failure involves aveno-venous or veno-arterial life supportcircuit with a membrane oxygenator totemporarily take over the lung functions.Mechanical ventilator settings are ad-justed to minimize ventilator-inducedlung injury and to maximize the recruit-ment to functional residual capacity. Thetreatment program for adults involves analgorithm that aims to normalize bodyphysiology, aggressively recruit func-tional residual capacity, and minimize

barotrauma. This algorithm, used in 141patients with respiratory failure referredfor consideration of ECLS, yielded asurvival rate of 62% in patients withsevere ARDS (median initial PaO2/FIO2ratio, 66) (76).

The primary indication for ECLS inpatients with severe respiratory failure iswhen the risk of dying of ARDS is con-sidered �80% despite optimal ventilatorand medical management. This translatesto an alveolar–arterial oxygen gradient�600 mm Hg or a PaO2-to-FIO2 ratio of�70 on 100% oxygen.

The majority of patients with severeARDS are managed with veno-venousECMO. Adult patients are typically can-nulated percutaneously with 21-F to 23-Fcatheters for drainage and infusion ofblood. Veno-arterial access is used to pro-vide respiratory and hemodynamic sup-port for patients in shock (as may be thecase in some H1N1 patients). Anticoagu-lation is necessary and is titrated by mea-surement of whole blood activated clot-ting time and/or serial partialthromboplastin time. ECLS allows for adecrease in mechanical ventilator set-tings to nondamaging “rest” levels whilemaintaining functional residual capacityrecruitment measures. Once the patient’snative lung function has improved, a trialoff ECLS is attempted at moderate venti-latory settings that allow for potentialincreases in therapy (e.g., FIO2, 0.5–0.6).If the trial of ECLS is successful, thecannulae are removed and the recoverycontinues.

In a series of 255 adult patients whowere placed on ECLS for severe ARDSrefractory to all other treatment strate-gies, 67% were weaned off ECLS, and52% survived to hospital discharge (77).Multivariate analysis identified the fol-lowing pre-ECLS variables as significantindependent predictors of survival: (1)age; (2) gender; (3) arterial blood pH�7.10; (4) PaO2-to-FIO2 ratio; and (5) daysof mechanical ventilation. None of thepatients who survived ECLS required per-manent mechanical ventilation or sup-plemental oxygen therapy. Those whocan be successfully decannulated fromECLS had a 77% chance of being dis-charged from the hospital and of com-plete recovery.

An analysis of 1473 adult ECMO pa-tients with respiratory failure from theExtracorporeal Life Support Organization(ELSO) registry during 1986 to 2006 wasrecently reported (Table 2) (78). MedianPaO2-to-FIO2 ratio pre-ECMO was 57, with

Table 1. Adult respiratory failure ECLS Criteria

Indications Contraindications

Duration of mechanical ventilation� 5–7 days7–10 days only if mechanically

ventilated with high pressures for�7 days

There is no absolute contraindication to ECLS,because each patient is considered individuallywith respect to risks and benefits. There areconditions, however, that are known to beassociated with a poor outcome despite ECLSand can be considered as relativecontraindications.

Pulmonary compliance Mechanical ventilation at high settings (FIO2 �0.9,P-plat �30) for �7 days�0.5 mL/cm H2O/kg

OxygenationPaO2/FIO2 �100 and no response to

standard therapies for severe ARDSShunt �30%

Major pharmacologic immunosuppression (absoluteneutrophil count �400 cells/mm3)

CNS hemorrhage that is recent or expandingContraindication to systemic anticoagulation

ECLS, extracorporeal life support; CNS, central nervous system.

S6 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

interquartile range (IQR) of 46 to 75.Survival among this cohort of adults was50%, and most patients (78%) were sup-ported with veno-venous ECMO. Ad-vanced age, increased duration of me-chanical ventilation before ECMO,diagnosis, and complications while onECMO were associated with increasedmortality. This report identified some in-teresting trends with the use of ECMO inadults with respiratory failure over thepast 20 yrs. These include increased age,reduced hours of ventilation pre-ECMO,increased use of high-frequency venti-lation and INO before ECMO, and in-creased use of veno-venous ECMO. Sur-vival has remained at approximately50% since 1992. Interestingly, ECMOuse has been increasing for broader in-dications, including the use of veno-venous ECMO for respiratory support asa bridge to lung transplantation, docu-mented by some centers with a 1-yrsurvival of 68% (79).

A long-term (�1 yr) follow-up studyreporting on pulmonary morphology,function, and health-related quality of lifein 21 survivors of severe ARDS and ECMOwas recently published (80). Most pa-tients had residual lung parenchymalchanges suggestive of fibrosis on high-resolution computed tomography of thelungs. However, the extension of mor-phologic abnormalities were limited andwithout the typical anterior localization,and were presumed to indicate ventilator-associated lung injury. Pulmonary func-tion tests confirmed low-normal values,with some subclinical obstruction noted.Most patients had reduced quality of life

but had fewer respiratory symptoms com-pared to conventionally treated patientswith ARDS, as reported in previous stud-ies. The majority were integrated backinto normal work and physical and socialfunctioning.

The CESAR Trial

The CESAR trial was a multicentered,prospective, randomized trial performedin the United Kingdom in adults (n �180) with severe, but potentially revers-ible, acute respiratory failure, defined asMurray score �3 or pH �7.20 (81). Ex-clusion criteria were high pressure (�30cm H2O of peak inspiratory pressure) orhigh FIO2 (�0.8) ventilation for �7 days,intracranial bleeding, any other contrain-dication to limited heparinization, or anycontraindication to continuation of activetreatment. The primary outcome mea-sures included death or severe disability 6mos after randomization or before dis-charge from hospital.

The study was planned to enroll 300patients randomly allocated to consider-ation for treatment by an algorithm thatcould include ECMO or conventionalmanagement. The conventional mechan-ical ventilation arm of the trial was man-aged as follows: “Conventional ventila-tory support can include any treatmentmodality thought appropriate by the pa-tient’s intensivist (excluding ECMO). In-tensivists had full discretion to treat pa-tients as they thought appropriate, but itwas recommended that they adopt a lowtidal volume ventilation strategy.” Detailsof compliance with lung protective ven-

tilation in the control cohort were notreported. Patients in the ECMO arm weretransferred to the ECMO center at Leic-ester for protocol management andECMO if needed. Analysis was by inten-tion to treat. The study was stopped bythe Data Safety Monitoring Board for ef-fectiveness after 180 patients. Of the 90conventional treatment patients, 41 sur-vived. Of the 90 ECMO patients, five diedbefore or during transport to the ECMOcenter, 17 improved on the managementalgorithm, and 68 patients requiredECMO. Six-month survival without dis-ability was 63% (57 of 90) in the ECMOgroup compared to 47% (41 of 90) in theconventional management group (RR,0.69; 95% CI, 0.05–0.97; p � .03). Theconclusion of the CESAR trial was thatmanagement of ARDS with a standard-ized algorithm including ECMO in an ex-pert center resulted in better survivalthan the best care in other centers in theUnited Kingdom.

ECMO and 2009 H1N1 InfluenzaSevere ARDS

ECMO support has been used as atreatment for severe respiratory failureattributable to 2009 H1N1 influenza inthe United States (2) and worldwide, butU.S. multicentered data on its efficacy arenot yet available. The Australian and NewZealand Intensive Care (ANZIC) study oncritical care services and 2009 H1N1 in-fluenza in Australia and New Zealand re-ported the clinical characteristics andoutcome of 722 patients with confirmedH1N1 infection who were admitted to anICU. Data on the use of mechanical ven-tilation in the ICU were available for 706patients; of these, 456 (64%) underwentmechanical ventilation for a median of 8days, and 53 (11.6%) of these patientswere subsequently treated with ECMO,representing 2.1 patients per one millioninhabitants (82). Overall mortality ratewas 14.3% (103 of 722 patients), withmedian treatment of 7.0 days (IQR, 2.7–13.4) in the ICU.

The recent case series report of allpatients (n � 68) with 2009 H1N1 influ-enza-associated ARDS treated with ECMOin 15 ICU in Australia and New Zealandbetween June 1 and August 31, 2009 doc-umented a 21% mortality rate (83). Dur-ing the study period, 194 patients witheither confirmed 2009 H1N1 influenza orinfluenza A not subtyped were admittedto the participating ICU requiring me-chanical ventilation, and 61 patients

Table 2. ECMO in adult patients with acute respiratory failure: Clinical features and outcomes overtwo decades

Pre-ECMO Variable 1986–1991 1992–1996 1997–2001 2002–2006 p

n 52 304 517 600 —Survival, n (%) 19 (40) 153 (50) 268 (52) 301 (50) �.001Age (yr), median (IQR) 25 (19–35) 31 (21–43) 36 (22–49) 37 (23–51) .001Weight (kg) 60 (56–77) 61 (50–75) 74 (60–90) 75 (63–90) .001Hours of ventilation,

median (IQR)72 (12–192) 120 (30–192) 55 (18–143) 42 (17–139) .02

Cardiac arrest, n (%) 0 5 (2) 43 (8) 60 (11) �.001SaO2 (%) 87 (52–98) 87 (76–91) 87 (77–92) 86 (77–92) .62FIO2 100 100 100 100 .49INO 0 2 (1) 71 (14) 118 (20) �.001High-frequency ventilation 0 4 (1) 16 (5) 50 (9) .09VV mode, n (%) 4 (44) 29 (69) 301 (72) 419 (72) .32ECMO duration (hr),

median (IQR)192 (84–323) 150 (86–319) 166 (86–301) 144 (67–259) .94

ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; SaO2, arterial oxygensaturation; INO, inhaled nitric oxide; VV, veno-venous.

Modified from Brogan et al (78).

S7Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

(31.4%) were treated with ECMO. BeforeECMO, patients had severe hypoxemiadespite advanced mechanical ventilatorysupport, with a median PaO2-to-FIO2 ratioof 56 (IQR, 48–63), positive end-expira-tory pressure of 18 cm H2O (IQR, 15–20),and an ALI Murray score of 3.8 (IQR,3.5–4.0). All patients fulfilled the ARDSseverity criteria for enrollment in the CE-SAR trial of ECMO treatment. Interest-ingly, approximately 15% of these pa-tients were pregnant or postpartum, thelargest case series of such patients in theliterature. Median (IQR) duration of me-chanical ventilation before initiation ofECMO was 2 (1–5) days. The initial modeof ECMO was veno-venous in 93% andveno-arterial in 7% of patients. Median(IQR) duration of ECMO support was 10(7–15) days. Hemorrhagic complicationsoccurred in 54% of patients, most com-monly at the ECMO cannulation sites. Atthe time of reporting, 48 of the 68 pa-tients (71%; 95% CI, 60%–82%) survivedto ICU discharge, of whom 32 survived tohospital discharge. Fourteen patients(21%; 95% CI, 11%–30%) died and sixremained in the ICU, two of whom werestill receiving ECMO. The patientstreated with ECMO had longer durationof mechanical ventilation (median[IQR], 18 [9 –27] vs. 8 [4 –14] days; p �.001), ICU stay (median [IQR], 22 [13–32] vs. 12 [7–18] days; p � .001), andgreater ICU mortality (14 [23%] vs. 12[9%]; p � .01).

The ELSO has collected data on ECMOpatients from international centers since1986 and thus represents a cross-sectionof ECMO practice. Because of the over-whelming request for information onH1N1 patients who go on to receive ECLSfor severe hypoxemia and ARDS, theELSO has developed a method to trackthese cases (H1N1 ECLS Registry). The formis brief with a minimal data set to capturecritical ECLS information and outcome.The case report form and additional infor-mation can be found at the ELSO website(http://www.elso.med.umich.edu/H1N1.htm).ELSO has initiated an open call for sub-mission of ECMO cases and welcome theparticipation of all participating ELSOcenters and non-ELSO centers in this im-portant effort. We aim to subsequentlyexamine the ELSO data registry for adultpatients with respiratory failure attribut-able to 2009 H1N1 influenza to describethe population and determine factors as-sociated with hospital survival.

ECMO guidelines (general and pa-tient-specific) are available from the

ELSO web site and contain important andcomplete information regarding initiationand maintenance of ECMO support throughdecannulation and discontinuation of ECMO(http://www.elso.med.umich.edu/guide.htm).

Advances in ECMO

There have been a number of signifi-cant advances in ECMO support over thepast few years. Traditional cannulationfor veno-venous ECMO has been a two-cannulae system, with venous drainagefrom the right femoral vein and return tothe right atrium via a right internal jug-ular vein cannula. A single bicaval dual-lumen cannula placed in the internal jug-ular position (Avalon Elite; AvalonLaboratories, Rancho Dominguez, CA) isnow available. This is placed percutane-ously in the right internal jugular veinand allows simultaneous removal ofblood from the superior and inferior venacavae with return of blood into the rightatrium with minimal recirculation.

In most adults, a 27-Fr to 31-Fr Ava-lon catheter is inserted with a Seldingertechnique using an extended lengthguidewire (100 cm or 210 cm length) toensure that the distal port tip of the cath-eter is positioned in the inferior vena cavafor venous drainage to the ECMO circuitwith the oxygenator. The proximal drain-age port drains blood from the superiorvena cava. A uniquely designed medialinfusion port returns blood to the rightatrium for concentrated oxygen deliv-ery. Optimal orientation of this medialinfusion port is critical, and we haveused transesophageal echocardiographyin some cases to ensure adequacy ofsupport.

For decades the standard ECMO cir-cuit was based on a high-resistance,thrombogenic membrane lung that re-quired a servo-regulated roller pump andcontinuous anticoagulation. Continuousattendance by the ICU nurse and anECMO specialist was required to manageanticoagulation and manage emergen-cies. In the past few years, low-resistance,high-flow, hollow fiber membrane lungshave become available (Quadrox PLS Dif-fusion Membrane oxygenator; Maquet;and Novalung; Novalung GmbH). Thesedevices are less thrombogenic and can beused with safer centrifugal pumps (Bio-medicus, Medtronic Inc; Centrimag, Lev-itronix; and Maquet; Medos), leading tolonger life, increased reliability, and re-duction in the incidence of device-relatedadverse events. These features permit safe

automatic perfusion for many days. Thepatient and the circuit can be managed bya trained ICU nurse, thus decreasing theexpense of ECMO.

The development of mobile ECMOprograms in critical care began years ago,and a number of centers in the UnitedStates have provided mobile ECMO, in-cluding the University of Michigan andC. S. Mott Children’s Hospital in AnnArbor, MI; the Arkansas Children’s Hos-pital in Little Rock, AR; the Miami Chil-dren’s Hospital in Miami, FL; and Wil-ford Hall Medical Center in SanAntonio, TX (84).

Selective CO2 removal can be accom-plished with low blood flow rates (10 mL/kg/min) with the device attached witharteriovenous access (arterial cannula in-serted into femoral artery, membrane ox-ygenator with venous cannula return tofemoral vein, driving force is patient’sblood pressure) (85–88). This technologyis effective as an arteriovenous CO2 re-moval device (effective treatment for sta-tus asthmaticus) but has significant lim-itations in providing oxygenationsupport.

In H1N1 severe ARDS cases, nativelung function is usually so compromisedwith resultant severe hypoxemia that fulloxygenation, and therefore high bloodflow (60 mL/kg/min), is required. Addi-tionally, the combination of extracorpo-real carbon dioxide removal and limita-tion of tidal volume to �6 mL/kg wasassociated with improved markers oflung protection and the reduction ofpulmonary cytokines concentration(89). Prospective, randomized trials arewarranted to examine the efficacy ofthis new technology.

Pharmacologic Strategies

Multiple pharmacologic interventions(including prostaglandins, prostacyclin,lisofylline, ketoconazole, N-acetylcyste-ine, corticosteroids, and NO) have beeninvestigated in the treatment of ALI andARDS, but none yet has demonstratedimproved survival (90, 91). Two pharma-cologic strategies (ketoconazole and liso-fylline) were investigated by the ARDSClinical Trials Network, and both studieswere stopped by the Data Safety and Mon-itoring Boards for futility at interim anal-yses (92, 93).

A Cochrane Database Systematic Re-view of pharmacologic therapy for adultswith ALI and ARDS reviewed 33 trialsrandomizing 3272 patients and con-

S8 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

cluded that two interventions were ben-eficial in single small trials: corticoste-roids administered for late-phase ARDSreduced hospital mortality (n � 24) andpentoxifylline reduced 1-month mortality(n � 30). Individual trials of nine addi-tional pharmacologic interventions failedto show a beneficial effect, concludingthat effective pharmacotherapy for ALIand ARDS is extremely limited, with in-sufficient evidence to support any specificintervention (94).

Corticosteroids

Because ARDS is associated with per-sistent inflammation and excessive fibro-proliferation, previous studies have inves-tigated the use of corticosteroids. Fourclinical trials of high-dose, short-coursecorticosteroids for early ARDS failed toshow any improvements in survival(95–98). In contrast, several small caseseries (99 –104) and a single-center ran-domized trial (n � 24) (105) reportedimproved lung function and survivalwith moderate-dose corticosteroids inpatients with persistent (�7 days)ARDS.

The multicenter trial (n � 180) fromthe National Heart, Lung, and Blood In-stitute ARDS Clinical Trials Network(www.ardsnet.org) randomized patientswith ARDS of at least 7 days’ duration toreceive either methylprednisolone or pla-cebo in a double-blind manner (106).Methylprednisolone therapy was not as-sociated with a survival benefit (29.2% vs.28.6% mortality) despite increased venti-lator-free and shock-free days, improvedoxygenation, and improved pulmonarycompliance during the first 28 days.Compared with a placebo, methylpred-nisolone was associated with signifi-cantly increased 60- and 180-day mor-tality rates in patients enrolled at least14 days after the onset of ARDS. Ahigher rate of neuromuscular weaknessand increased blood glucose concentra-tions, with no increase in infectiouscomplications, were also identified.These results do not support the rou-tine use of methylprednisolone for per-sistent ARDS.

A recent post hoc secondary analysisof this trial examined 128 study patientswho survived 60 days to hospital dis-charge. Forty-three patients (34%) hadevidence of ICU-acquired neuromyopathyassociated with prolonged mechanicalventilation and therefore delayed dis-charge after the critical illness. However,

treatment with methylprednisolone wasnot significantly associated with an in-creased risk of neuromyopathy (OR, 1.5;95% CI, 0.7– 0.32). This study docu-mented that ICU-acquired neuromyopa-thy is common in ARDS survivors but isnot associated with steroid treatment(107). Similar results were found withearly, but prolonged, administration oflow-dose methylprednisolone (1 mg/kg/d)in a recent randomized, controlled trialby Meduri et al (108).

A meta-analysis reported in 2008showed that prolonged administration ofsystemic steroids is associated with favor-able outcomes and survival benefit whenadministered before day 14 of ARDS(109). The latter finding stood particu-larly true when subgroups from theARDS were reanalyzed based on the timeof treatment initiation.

The most recent meta-analysis (110)included both cohort studies with signif-icant limitations and randomized, con-trolled trials, and concluded that the useof low-dose corticosteroids was associatedwith improved mortality and morbiditywithout an increase in adverse reactionsor improved oxygenation (Fig. 7). Theauthors concluded that the consistency ofresults in both study designs suggestedthat steroids are an effective treatmentfor ALI or ARDS. An additional meta-analysis of just eight controlled studies(n � 628) confirmed that reduction inmortality was substantial for all patients(RR, 0.75; 95% CI, 0.63–0.89; p � .001;I2, 43%) and for those treated before day14 (RR, 0.71; 95% CI, 0.59–0.85; p �.001; I2, 40%) (111).

The use of steroids in ALI and ARDSclearly remains controversial. The poten-tial mortality benefits of steroids in ARDSwill be confirmed only by an adequatelypowered large randomized trial (112,113). Additional questions regarding theefficacy of steroids arise when ARDS pa-tients also manifest refractory septicshock requiring vasopressor therapy andreceive low-dose corticosteroid therapy(114, 115).

Steroids and 2009 H1N1Influenza ARDS

No clear data are available regardingthe potential efficacy of steroids in thetreatment of severe ARDS attributable to2009 H1N1 influenza at this presenttime. In animal studies, the use of dexa-methasone in a murine ARDS model in-duced by H5N1 viral infection did not

improve mortality. There was no signifi-cant amelioration of the hypoxemia andARDS-associated pathologic changes indexamethasone-treated mice. Further-more, dexamethasone therapy did not in-hibit inflammatory cellular infiltrationand cytokine release (interleukin-6 andtumor necrosis factor-alpha) in bron-choalveolar lavage fluid induced by theH5N1 infection (116). In contrast, low-dose dexamethasone was documented tosignificantly reduce pulmonary inflam-mation and fibrosis after lipopolysaccha-ride-induced ALI in a rat model, and wasassociated with elevation of glucocorti-coid receptor expression in the lung,likely through up-regulation of glucocor-ticoid receptor levels and promotion ofthe nuclear translocation of glucocorti-coid receptor protein (117).

Steroids have been useful as adjunc-tive therapy to suppress inflammatory re-sponses in certain serious infections(118), including Pneumocystis cariniipneumonia (119). In contrast, steroidsmay be detrimental in some infections,particularly acute viral hepatitis (120).Steroid-based immunosuppression hasbeen implicated in the increased severityof recurrent hepatitis C virus infection inliver transplant patients. Evidence sug-gests that steroid boluses used to treatacute rejection are associated with an in-crease in hepatitis C virus viral load andthe severity of recurrence. Two possiblemechanisms for a steroid-mediated effecton hepatitis C virus viral loads are postu-lation: a direct effect of steroids on thevirus by enhancing its replication and anindirect effect attributable to the suppres-sion of the hepatitis C virus immune re-sponse, allowing unrestricted hepatitis Cvirus replication (121).

Steroid use has been reported in somecase reports of H1N1-associated ARDSwithout any adverse outcome (122).Some have advocated that the rationalefor using steroids in the treatment ofsevere cases of H5N1 avian influenza, re-lated to cytokine storm, may also be ap-plicable in cases of severe 2009 H1N1influenza ALI and ARDS (123, 124). Innorthern Vietnam, mortality was 59%among 29 recipients of steroids comparedwith 24% among 38 patients who did notreceive steroids (p � .004) (125).

A retrospective case series studied pa-tients (n � 29) with influenza A (H5N1)admitted to the National Institute of In-fectious and Tropical Diseases in Hanoi,Vietnam, from January 2004 throughJuly 2005, with symptoms of acute respi-

S9Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

ratory tract infection and positive find-ings for A/H5 viral RNA by reverse-transcription polymerase chain reaction.The mean age was 35 yrs and seven pa-tients (24.1%) died. Mortality rates were20% (5 of 25) and 50% (2 of 4) amongpatients treated with or without oselta-mivir (p � .24), respectively. Additionallythe mortality rates were 33.3% (5 of 15)and 14.2% (2 of 14) among patientstreated with and without methylpred-nisolone (p � .39), respectively. After lo-gistic regression analysis was adjusted forvariation in severity, no significant effec-tiveness for survival was observed amongpatients treated with oseltamivir ormethylprednisolone (126).

The World Health Organization, intheir update on avian influenza A (H5N1)virus infection in humans, stated thatcorticosteroids should not be used rou-tinely because they have not been shownto be effective and may result in seriousadverse events. Interestingly, in the re-cent ANZIC publication of 722 patientsadmitted to ICU with confirmed infectionwith the 2009 H1N1 virus, 494 (68.4%)received steroids. The overall mortalityrate was reported as 14.3% in this caseseries (26).

Exogenous Surfactant Therapy

The rationale for exogenous surfactanttherapy in ALI/ARDS is primarily to re-verse surfactant dysfunction (inhibition),although surfactant deficiency is alsotreated by this intervention. Regardless ofthe cause, a common pathophysiologicfeature of patients with ARDS is a dys-function of the endogenous surfactantsystem. Exogenous surfactant therapy isan effective standard of care in neonateswith ARDS (127, 128), but no similareffect is seen for adults. Ongoing andfuture research efforts suggest that thismay eventually be feasible (129, 130).

Abnormalities in surfactant in lung la-vage from patients with ALI/ARDS arewell-documented (131–138). Exogenoussurfactant therapy has a strong scientificrationale based on extensive biophysicalresearch showing that increasing surfac-tant concentration can overcome inhibi-tion by endogenous compounds presentin injured lungs (91). In addition, theability of exogenous surfactants to im-prove pulmonary mechanics and functionhas been established in multiple animalmodels of ALI/ARDS including acid aspi-ration, meconium aspiration, anti-lungserum, bacterial or endotoxin injury, va-

Figure 7. Effect of steroid treatment on mortality and oxygenation in ALI and ARDS. From: Tang BMP,Craig JC, Eslick GD, et al: Use of corticosteroids in acute lung injury and acute respiratory distresssyndrome: A systematic review and meta-analysis. Crit Care Med 2009; 37:1594–1603.

S10 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

gotomy, hyperoxia, in vivo lung lavage,N-nitroso-N-methylurethane injury, andviral pneumonia.

In addition to its essential biophysicalactions in lowering surface tension andstabilizing alveolar inflation– deflation,surfactant is known to play a role in hostdefense against infection through the bi-ological activity of the two hydrophilicsurfactant proteins A and D. These pro-teins have been shown to influence theopsonization, phagocytosis, and aggluti-nation of microorganisms within the re-spiratory tract (139–142). The localiza-tion of surfactant protein A/surfactantprotein D in the alveolar hypophase ide-ally positions these proteins (and othercomponents of the surfactant system)to act as “first responders” to inhaledpathogens. More recent data indicatethat the pulmonary surfactant directlyaffects Mycobacterium tuberculosisgene transcription in ways that suggesta preconditioning of the Mycobacte-rium for interactions with macro-phages, evoking a multitude of tran-scriptional responses (143).

Consistent with these laboratory find-ings, surfactant therapy has been shownto be successful in infants with ARDS-related lung injury associated with meco-nium aspiration or pneumonia (144 –147), as well as in children and youngadults with ALI/ARDS (148–151). Partic-ularly impressive is the recent double-blind, placebo-controlled trial (152) ofcalfactant (a natural lung surfactant con-taining high levels of surfactant-specificprotein B) compared with placebo in 153infants, children, and adolescents (up toage 21 yrs) with respiratory failure fromALI. Improved oxygenation and signifi-cantly decreased mortality were seen af-ter treatment with the bovine-derivedsurfactant Infasurf (calfactant; ForestPharmaceuticals, New York, NY). Inter-estingly, no significant decrease in thecourse of respiratory failure (duration ofventilation, ICU, or hospital stay) was ob-served. Aside from low tidal volume ven-tilation, this is one of the few controlledstudies to show substantive survival im-provement in patients with ALI/ARDS.

Several small pilot studies have alsodocumented improved respiratory func-tion (oxygenation) in adults with ALI/ARDS (153–157). However, larger con-trolled, clinical trials in adults have beenless successful. By far, the largest pro-spective, controlled study of surfactanttherapy in adults with ARDS was defini-tively negative. Anzueto et al (158) ad-

ministered nebulized Exosurf (colfos-ceril; Glaxo Wellcome, New York, NY) vs.placebo to 725 adults with ARDS second-ary to sepsis and found no improvementin any measure of oxygenation and noeffect on morbidity or mortality. How-ever, interpretation of these negative re-sults is confounded because laboratoryand clinical studies have documentedthat Exosurf has low activity compared toanimal-derived surfactants. Furthermore,Exosurf is no longer marketed in the U.S.In addition, aerosolization has not beenshown to be as effective as airway instil-lation in delivering surfactant.

Gregory et al (159) reported onlysmall benefits in oxygenation in a con-trolled trial in adults with ARDS whoreceived four 100-mg/kg doses of Sur-vanta (beractant; Abbott Laboratories,Abbott Park, IL), but with no overall ad-vantage in survival in the 43 surfactant-treated patients studied. However, thisexogenous surfactant contains onlyvery small amounts of surfactant pro-tein B (160), which is known to be themost active apoprotein in native surfac-tant (161).

A more recent study (162) using re-combinant surfactant protein C (Venti-cute; Altana Pharma, Atlanta, GA) inadults with ARDS showed immediate im-provements in oxygenation, but no im-provement in duration of mechanicalventilation, lengths of stay, or mortality.Post hoc analysis did suggest, however,that the response in the subgroup of pa-tients with ARDS attributable to “directlung injury” was positive (163). A fol-low-up prospective phase III study inthis category of patients (Venticute inPatients with Pneumonia or Aspirationof Gastric Contents and Intubation/Ventilation/Oxygenation Impairment;NCT00074906) was recently halted be-cause of futility.

Exogenous surfactant therapy in ALI/ARDS requires the use of the most activeclinical surfactant drugs plus effective de-livery methods. In addition to animal-derived surfactants such as Infasurf,highly active new synthetic lipid/peptidelung surfactants are being developed thathave significant potential advantages inmanufacturing, economy, and puritycompared to biological products (164–166). Such synthetic surfactants includepreparations with novel physicochemicalproperties like phospholipase-resistance,which may be of particular importance inALI/ARDS when these lytic enzymes can

be elaborated in high concentrations inthe interstitium and alveoli (167).

Most recently, an international, mul-ticenter, stratified, randomized, con-trolled, open, parallel group study (n �418 adult patients) examined the efficacyof exogenous natural porcine surfactantHL 10 instilled as a large bolus. No dif-ference in 28-day mortality was identified(24.5% in the usual care group vs. 28.8%in the HL 10 group). The estimated ORfor death at day 28 in the usual caregroup vs. the HL 10 group was 0.75 (95%CI, 0.48–1.18; p � .220. The most com-mon adverse events related to HL 10 ad-ministration were temporary hypoxemiadefined as oxygen saturation �88%(51.9% in HL 10 group vs. 25.2% in usualcare) and hypotension defined as meanarterial blood pressure �60 mm Hg(341% in HL 10 group vs. 17.1% in usualcare). In this study, large bolus of exog-enous natural porcine surfactant HL 10in patients with ALI/ARDS did not im-prove outcome and showed a trend to-ward increased mortality and adverse ef-fects (168).

In summary, because of the results ofthese randomized, clinical trials, exoge-nous surfactant therapy is not a strategythat can be used in adult patients withARDS. In the future, other surfactantswith different compositions may showbeneficial effects and warrant continuedinvestigation.

Future Pharmacologic Strategies

Most recently, alterations in coagula-tion and fibrinolysis in the pathogenesisof ALI and ARDS have been examined,particularly related to alveolar fibrin dep-osition. Increased local tissue factor-mediated thrombin generation and de-pression of local fibrinolysis related toincreased plasminogen activator inhibi-tors have been reported (169). Pulmonarycoagulopathy may be a prominent featureof ARDS and ventilator-induced lung in-jury, just as microvascular thrombosis isa common feature of sepsis. Plasma pro-tein C was found to be decreased in pa-tients with nonseptic ALI and was associ-ated with higher mortality and fewerventilator-free days (170).

Recent studies have documented thatintravenous infusion and inhalation ofaerosolized recombinant human-acti-vated protein C attenuated ovine lipopo-lysaccharide-induced lung injury by pre-venting a decline in the volume of aeratedlung tissue and improving oxygenation

S11Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

(171–173). A recent randomized, placebo-controlled trial failed to show a beneficialeffect (no difference in ventilator-freedays or 60-day mortality) of activated pro-tein C vs. placebo treatment in patientswith ALI without sepsis (174). Additionalstudies in this important area are war-ranted.

Novel pharmacologic therapies specif-ically for the prevention and treatment ofinfluenza infection are also needed. Re-cent reports (175–177) suggest that st-atins (administered either therapeuticallyor prophylactically) might also have ben-eficial effects on influenza outcomes. Arecent study documented that a statin/caffeine combination (50 �g statin/200�g caffeine) effectively ameliorated lungdamage, inhibited viral replication, andwas at least as effective as traditional an-tiviral agents in a murine model of H5N1,H3N2, and H1N1 infection (178).

Developing optimal single-agent andcombination therapies for ALI/ARDSclearly requires integrated basic scienceand clinical research. Detailed testing ofputative agents for their activity aloneand in mechanistically complementarycombinations in cell and animal modelsis essential, because it is not feasible toexamine all relevant agents and combina-tions in human studies. This is particu-larly true for ALI/ARDS, for which clini-cal trials are complicated by theheterogeneity of associated patient popu-lations and the multiple etiologies andbroad pathology of lung injury. A rationalapproach to developmental pharmaco-therapy that integrates findings on mech-anistic activity and agent efficacy in basicresearch to facilitate the design and anal-ysis of focused clinical trials is crucial fordefining optimal therapeutic strategiesfor ALI/ARDS-related lung injury in pa-tients of all ages.

CONCLUSION

Incremental Approach to theManagement of Patients WithSevere ARDS

In patients with severe refractory hy-poxemia and ARDS attributable to 2009H1N1 influenza, there is potential utilityin the incremental approach to ARDSmanagement (Fig. 8). Implementation ofthe specific strategies discussed here mayresult in improved oxygenation, im-proved pulmonary compliance, and, ulti-mately, survival in individual patients.

Figure 8. Treatment algorithm for ARDS. This “admission algorithm” applies to the first 24 hrs oftreatment and uses all advanced treatment options for patients with ARDS discussed in this review.From: Deja M, Hommel M, Weber-Carstens S, et al: Evidence-based therapy of severe acute respiratorydistress syndrome: an algorithm-guided approach. J Int Med Res 2008; 36:211–221.

S12 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

There is also the possibility that some ofthese interventional strategies may haveadditive effects. We also have used thesetreatment strategies in stabilization ofpatients with severe ARDS before trans-port to our institution to enable safertransport (179).

It is important to have full knowl-edge of the results of prospective, ran-domized trials that have carefully as-sessed the impact of these treatmentstrategies on patient outcome in ALIand ARDS. Nevertheless, appropriatebedside implementation of these poten-tial treatment strategies may providelife-saving salvage in individual pa-tients with refractory hypoxemia attrib-utable due to severe ARDS and 2009H1N1 influenza infection.

REFERENCES

1. Bernard GR, Artigas A, Brigham KL, et al:Report of the American-European consen-sus conference on ARDS: definitions, mech-anisms, relevant outcomes and clinical trialcoordination. The Consensus Committee.Intensive Care Med 1994; 20:225–232

2. Napolitano LM, Park PP, Sihler KC, et al:Centers for Disease Control and Prevention(CDC). Intensive care patients with severenovel influenza A (H1N1) virus infection—Michigan, June 2009. MMWR Morb MortalWkly Rep 2009; 58:749–752

3. Rello J, Rodriguez A, Ibanez P, et al; H1N1Semicyuc Working Group T: Intensive careadult patients with severe respiratory fail-ure caused by Influenza A (H1N1) in Spain.Crit Care 2009; 13:R148

4. Perez-Padilla R, de la Rosa-Zamboni D,Ponce de Leon S, et al; INER WorkingGroup on Influenza: Pneumonia and respi-ratory failure from swine-origin influenza A(H1N1) in Mexico. N Engl J Med 2009; 361:680–689

5. Chowell G, Bertozzi SM, Colchero MA, et al:Severe respiratory disease concurrent withthe circulation of H1N1 influenza. N EnglJ Med 2009; 61:674–679

6. Jain S, Kamimoto L, Bramley AM, et al; forthe 2009 Pandemic Influenza A (H1N1) Vi-rus Hospitalizations Investigation Team:Hospitalized patients with 2009 H1N1 In-fluenza in the United States, April–June2009 N Engl J Med 2009; 361:1–10

7. Kumar A, Zarychanski R, Pinto R, et al; forthe Canadian Critical Care Trials GroupH1N1 Collaborative: Critically ill patientswith 2009 Influenza A (H1N1) infection inCanada. JAMA 2009; ●●●

8. Dominguez-Cherti G, Lapinsky SE, MaciasAE, et al: Critically ill patients with 2009Influenza A (H1N1) in Mexico. JAMA 2009;●●●

9. Jain S, Kamimoto L, Bramley AM, et al; the2009 Pandemic Influenza A (H1N1) Virus

Hospitalizations Investigation Team: Hospi-talized patients with 2009 H1N1 Influenzain the United States, April–June 2009.N Engl J Med 2009; ●●●

10. Li G, Yilmaz M, Kojicic M, et al: Outcome ofcritically ill patients with influenza virusinfection. J Clin Virol. 2009; ●●●

11. Kawachi S, Luong ST, Shigematsu M, et al:Risk parameters of fulminant acute respira-tory distress syndrome and avian influenza(H5N1) infection in Vietnamese children.J Infect Dis 2009; 200:510–515

12. Erickson SE, Martin GS, Davis JL, et al; forthe NIH NHLBI ARDS Network: Recenttrends in acute lung injury mortality:1996 –2005. Crit Care Med 2009; 37:1574–1579

13. CDC: Updated interim recommendationsfor the use of antiviral medications in thetreatment and prevention of influenza forthe 2009 –2010 season (September 22,2009). Available at: http://www.cdc.gov/h1n1flu/recommendations.htm

14. Kidd IM, Down J, Nastouli E, et al: H1N1pneumonitis treated with intravenous zana-mivir. Lancet 2009; 374:1035

15. Hanshaoworakul W, Simmerman JM, Na-rueponjirakul U, et al: Severe human influ-enza infections in Thailand: Oseltamivirtreatment and risk factors for fatal out-come. PLoS One 2009; 4:e6051

16. Tremblay LN, Slutsky AS: Ventilator-induced lung injury: From the bench to thebedside. Intensive Care Med 2006; 32:24–33

17. DosSantos CC, Slutsky AS: The contribu-tion of biophysical lung injury to the devel-opment of biotrauma. Annu Rev Physiol2006; 68:585–618

18. Ware LB, Matthay MA: The acute respira-tory distress syndrome. N Engl J Med 2000;342:1334–1349

19. Vuuichard D, Ganter MT, Schimmer RC, etal: Hypoxia aggravates lipopolysaccharide-induced lung injury. Clin Exp Immunol2005; 141:248–260

20. Dernaika TA, Keddissi JI, Kinasewitz GT:Update on ARDS: Beyond the low tidal vol-ume. Am J Med Sci 2009; 337:360–367

21. Wiedemann HP, Wheeler AP, Bernard GR,et al: Comparison of two fluid-managementstrategies in acute lung injury. N EnglJ Med 2006; 354:2564–2575

22. Wheeler AP, Bernard GR, Thompsont BT, etal: Pulmonary artery versus central venouscatheter to guide treatment of acute lunginjury. N Engl J Med 2006; 354:2213–2224

23. Rosenberg AL, Dechert RE, Park PK, et al;NIH NHLBI ARDS Network: Review of alarge clinical series: association of cumula-tive fluid balance on outcome in acute lunginjury: A retrospective review of the ARDS-net tidal volume study cohort. J IntensiveCare Med 2009; 24:35–46

24. Stewart RM, Park PK, Hunt JP, et al; NIH/NHLBI ARDS Clinical Trials Network: Lessis more: Improved outcomes in surgical pa-tients with conservative fluid administra-

tion and central venous catheter monitor-ing. J Am Coll Surg 2009; 208:725–735

25. Martin GS, Moss M, Wheeler AP, et al: Arandomized, controlled trial of furosemidewith or without albumin in hypoproteine-mic patients with acute lung injury. CritCare Med 2005; 33:1681–1687

26. The ANZIC Influenza Investigators: Criticalcare services and 2009 H1N1 Influenza inAustralia and New Zealand. N Engl J Med2009; ●●●

27. Richter T, Bellani G, Scott Harris R, et al:Effect of prone position on regional shunt,aeration, and perfusion in experimentalacute lung injury. Am J Respir Crit CareMed 2005; 172:480–487

28. Piehl MA, Brown RS: Use of extreme posi-tion changes in acute respiratory failure.Crit Care Med 1976; 4:13–14

29. Douglas WW, Rehder K, Beynen FM, et al:Improved oxygenation in patients withacute respiratory failure: The prone posi-tion. Am Rev Respir Dis 1977; 115:559–566

30. Gattinoni L, Tognoni G, Pesenti A, et al:Effect of prone positioning on the survivalof patients with acute respiratory failure.N Engl J Med 2001; 345:568–573

31. Gattinoni L, Vagginelli F, Carlesso E, et al:Decrease in PaCO with prone position ispredictive of improved outcome in acuterespiratory distress syndrome. Crit CareMed 2003; 31:2727–2733

32. Curley MA, Hibberd PL, Fineman LD, et al:Effect of prone positioning on clinical out-comes in children with acute lung injury: Arandomized controlled trial. JAMA 2005;294:229–237

33. Mancebo J, Fernandez R, Blanch L, et al: Amulticenter trial of prolonged pron ventila-tion in severe acute respiratory distress syn-drome. Am J Respir Crit Care Med 2006;173:1233–1239

34. Fernandez R, Trenchs X, Klamburg J, et al:Prone positioning in acute respiratory dis-tress syndrome: A multicenter randomizedclinical trial. Intensive Care Med 2008; 34:1487–1491

35. Sud S, Sud M, Friedrich JO, et al: Effect ofmechanical ventilation in the prone posi-tion on clinical outcomes in patients withacute hypoxemic respiratory failure: A sys-tematic review and meta-analysis. CMAJ2008; 178:1153–1161

36. Kopterides P, Siempos II, Armaganidis A:Prone positioning in hypoxemic respiratoryfailure: Meta-analysis of randomized con-trolled trials. J Crit Care 2009; 24:89–100

37. Abroug F, Ouanes-Besbes L, Elatrous S, etal: The effect of prone positioning in acuterespiratory distress syndrome or acute lunginjury: a meta-analysis. Areas of uncertaintyand recommendations for research. Inten-sive Care Med 2008; 34:1002–1011

38. Alsaghir AH, Martin CM: Effect of pronepositioning in patients with acute respira-tory distress syndrome: A meta-analysis.Crit Care Med 2008; 36:603–609

39. Tiruvoipati R, Bangash M, Manktelow B, et

S13Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

al: Efficacy of prone ventilation in adultpatients with acute respiratory failure: Ameta-analysis. J Crit Care 2008; 23:101–110

40. Wells DA, Gillies D, Fitzgerald DA: Position-ing for acute respiratory distress in hospi-talised infants and children. Cochrane Da-tabase Syst Rev 2005; 2:CD003645

41. Romero CM, Cornejo RA, Galvez LR, et al:Extended prone position ventilation in se-vere acute respiratory distress syndrome: Apilot feasibility study. J Crit Care 2009; 24:81–88

42. Ignarro LJ, Buga GM, Wood KS, et al: En-dothelium-derived relaxing factor producedand released from artery and vein is nitricoxide. Proc Natl Acad Sci U S A 1987; 84:9265–9269

43. Palmer R, Ferrige A, Moncada S: Nitric ox-ide release accounts for the biologic activityof endothelium-derived relaxing factor. Na-ture 1987; 327:524–526

44. Palmer R, Ashton D, Moncada S: Vascularendothelial cells synthesize nitric oxidefrom L-arginine. Nature 1988; 333:664–666

45. Roberts JD, Fineman JR, Morin FC, et al:Inhaled nitric oxide and persistent pulmo-nary hypertension of the newborn. N EnglJ Med 1997; 336:605–610

46. Kinsella JP, Truog WE, Walsh WF, et al:Randomized, multicenter trial of inhalednitric oxide and high frequency oscillatoryventilation in severe persistent pulmonaryhypertension of the newborn. J Pediatr1997; 131:55–62

47. Goldman AP, Tasker RC, Haworth SG, et al:Four patterns of response to inhaled nitricoxide for persistent pulmonary hyperten-sion of the newborn. Pediatrics 1996; 98:706–713

48. Hoffman GM, Ross RA, Day SE, et al: In-haled nitric oxide reduces the utilization ofextracorporeal membrane oxygenation inpersistent pulmonary hypertension of thenewborn. Crit Care Med 1997; 25:352–359

49. Shah NS, Nakayama DK, Jacob TD, et al:Efficacy of inhaled nitric oxide in oleic acid-induced acute lung injury. Crit Care Med1997; 25:153–158

50. Putensen C, Rasanen J, Lopez F, et al: Con-tinuous positive pressure modulates effectof inhaled nitric oxide on the ventilation-perfusion distributions in canine lung in-jury. Chest 1994; 106:1563–1569

51. Fratacci MD, Frostell C, Chen TY, et al:Inhaled nitric oxide: A selective pulmonaryvasocilator of heparin-protamine vasocon-striction in sheep. Anesthesiology 1991; 75:990–999

52. Berger JI, Gibson RL, Redding GJ, et al:Effect of inhaled nitric oxide during groupB streptococcal sepsis in piglets. Am RevRespir Dis 1993; 147:1080–1086

53. Shah NS, Nakayama DK, Jacob TD, et al:Efficacy of inhaled nitric oxide in a porcinemodel of adult respiratory distress syn-drome. Arch Surg 1994; 129:158–164

54. Krause MF, Lienhart H-G, Haberstroh J, et

al: Effect of inhaled nitric oxide on intrapul-monary right-to-left shunting in two rabbitmodels of saline lavage induced surfactantdeficiency and meconium instillation. EurJ Pediatr 1998; 157:410–415

55. Dellinger RP, Zimmerman JL, Taylor RW,et al: Effects of inhaled nitric oxide in pa-tients with acute respiratory distress syn-drome: results of a randomized phase IItrial. Crit Care Med 1998; 26:15–23

56. Lundin S, Mang H, Smithies M, et al: Inha-lation of nitric oxide in acute lung injury:results of a European multicentre study.Intensive Care Med 1999; 25:911–919

57. Taylor RW, Zimmerman JL, Dellinger RP,et al: Low-dose inhaled nitric oxide in pa-tients with acute lung injury: a randomizedcontrolled trial. JAMA 2004; 291:1603–1609

58. Payen D, Vallet B: l’ARDS GdEdNd: resultsof the French prospective multicentric ran-domised double-blind placebo controlledtrial on inhaled nitric oxide (NO) in ARDS.Intensive Care Med 1999; 25:S166

59. Griffiths MJD, Evans TW: Inhaled nitric ox-ide therapy in adults. N Engl J Med 2005;353:2683–2695

60. Sokol J, Jacobs SE, Bohn D: Inhaled nitricoxide for acute hypoxemic respiratory fail-ure in children and adults. Cochrane Data-base Syst Rev 2003; 1:CD002787

61. Adhikari NKJ, Burns KEA, Friedrich JO, etal: Effect of nitric oxide on oxygenation andmortality in acute lung injury: systematicreview and meta-analysis. BMJ 2007; 334:779

62. Atz AM, Wessel DL: Sildenafil ameliorateseffects of inhaled nitric oxide withdrawal.Anesthesiology 1999; 91:307–310

63. Atz AM, Lefler AK, Fairbrother DL, et al:Sildenafil augments the effect of inhalednitric oxide for postoperative pulmonaryhypertensive crises. J Thorac CardiovascSurg 2002; 124:628–629

64. Zwissler B, Gregor K, Habler O, et al: In-haled prostacyclin (PGI2) versus inhaled ni-tric oxide in adult respiratory distress syn-drome. Am J Respir Crit Care Med 1996;154:1671–1677

65. Walmrath D, Schneider T, Schermuly R, etal: Direct comparison of inhaled nitric oxideand aerosolized prostacyclin in acute respi-ratory distress syndrome. Am J Respir CritCare Med 1996; 153:991–996

66. Pappert D, Busch T, Gerlach H, et al: Aero-solized prostacyclin versus inhaled nitricoxide in children with severe acute respira-tory distress syndrome. Anesthesiology1995; 82:1507–1511

67. VanHeerden PV, Barden A, MichalopoulosN, et al: Dose-response to inhaled aerosol-ized prostacyclin for hypoxemia due toARDS. Chest 2000; 117:819–827

68. Siobal M: Aerosolized prostacyclins. RespirCare 2004; 49:640–652

69. Lowson SM: Inhaled alternatives to nitricoxide. Crit Care Med 2005; 33(Suppl):S188–S195

70. Putensen C, Hormann C, Kleinsasser A, et

al: Cardiopulmonary effects of aerosolizedprostaglandin E1 and nitric oxide inhalationin patients with acute respiratory distresssyndrome. Am J Respir Crit Care Med 1998;157:1743–1747

71. Lowson SM: Inhaled alternatives to nitricoxide. Anesthesiology 2002; 96:1504–1513

72. Bartlett RH, Roloff DW, Cornell RG, et al:Extracorporeal circulation in neonatal re-spiratory failure: A prospective randomizedstudy. Pediatrics 1985; 76:479–487

73. UK Collaborative ECMO Trial Group: UKcollaborative randomized trial of neonatalextracorporeal membrane oxygenation.Lancet 1996; 348:75–82

74. Keckler SJ, Laituri CA, Ostlie DJ, et al: Areview of venovenous and venoarterial ex-tracorporeal membrane oxygenation in ne-onates and children. Eur J Pediatr Surg2009; ●●●

75. Extracorporeal Life Support Organization:Annual ECMO Registry Report. July 2003

76. Rich PB, Awad SS, Kolla S, et al: An ap-proach to the treatment of severe adult re-spiratory failure. J Crit Care 1998; 13:26–36

77. Hemmila MR, Rowe SA, Boules TN, et al:Extracorporeal life support for severe acuterespiratory distress syndrome in adults.Ann Surg 2004; 240:595–607

78. Brogan TV, Thiagarajan RR, Rycus PT, et al:Extracorporeal membrane oxygenation inadults with severe respiratory failure: amulticenter database. Intensive Care Med2009; ●●●

79. Santambrogio L, Nosotti M, Palleschi A, etal: Use of venovenous extracorporeal mem-brane oxygenation as a bridge to urgentlung transplantation in a case of acute re-spiratory failure. Transplant Proc 2009; 41:1345–1346

80. Linden VB, Lidegran MK, Frisen G, et al:ECMO in ARDS: A long-term followup studyregarding pulmonary morphology andfunction and health-related quality of life.Acta Anaesthesiol Scand 2009; 53:489–495

81. Peek GJ, Mugford M, Tiruvoipati R, et al; forthe CESAR trial collaboration: Efficacy andeconomic assessment of conventional ven-tilatory support versus extracorporealmembrane oxygenation for severe adult re-spiratory failure (CESAR): a multicentrerandomized controlled trial. Lancet 2009;●●●

82. The ANZIC Influenza Investigators: Criticalcare services and 2009 H1N1 Influenza inAustralia and New Zealand. N Engl J Med2009; 361: 1–10

83. The Australia and New Zealand Extracorpo-real Membrane Oxygenation (ANZ ECMO)Influenza Investigators: Extracorporealmembrane oxygenation for 2009 influenzaA (H1N1) acute respiratory distress syn-drome. JAMA 2009; 302:●●●

84. Heulitt MJ, Taylor BJ, Faulkner SC, et al:Inter-hospital transport of neonatal patientson extracorporeal membrane oxygenation:Mobile ECMO. Pediatrics 1995; 95:562–566

85. Reng M, Philipp A, Kaiser M, et al: Pumpless

S14 Crit Care Med 2010 Vol. 38, No. 3 (Suppl.)

extracorporeal lung assist and adult respi-ratory distress syndrome. Lancet 2000; 356:219–220

86. Ruettimann U, Ummenhofer W, Rueter F,et al: Management of acute respiratory dis-tress syndrome using pumpless extracorpo-real lung assist. Can J Anaesth 2006; 53:101–105

87. Bein T, Scherer MN, Philipp A, et al: Pump-less extracorporeal lung assist (pECLA) inpatients with acute respiratory distress syn-drome and severe brain injury. J Trauma2005; 58:1294–1297

88. Zimmerman M, Bein T, Philipp A, et al:Interhospital transportation of patientswith severe lung failure on pumpless extra-corporeal lung assist. Br J Anaesth 2006;96:63–66

89. Terragni PP, Del Sorbo L, Mascia L, et al:Tidal volume lower than 6ml/kg enhanceslung protection. Anesthesiology 2009; 111:826–835

90. Adhikari N, Burns KE, Meade MO: Pharma-cologic treatments for acute respiratory dis-tress syndrome and acute lung injury: sys-tematic review and meta-analysis. TreatRespir Med 2004; 3:307–328

91. Raghavendran K, Pryhuber GS, Chess PR,et al: Pharmacotherapy of acute lung injuryand acute respiratory distress syndrome.Curr Med Chem 2008; 15:1911–1924

92. ARDS Network: Ketoconazole for the earlytreatment of acute lung injury and acuterespiratory distress syndrome: a random-ized controlled trial. JAMA 2000; 283:1995–2002

93. ARDS Network: Randomized, placebo-controlled trial of lisofylline for the earlytreatment of acute lung injury and acuterespiratory distress syndrome. Crit CareMed 2002; 30:1–6

94. Adhikari N, Burns KE, Meade MO: Phmar-cologic therapies for adults with acute lunginjury and acute respiratory distress syn-drome. Cochrane Database Syst Rev 2004;4:CD004477

95. Bone RC, Fisher CJ Jr, Clemmer TP, et al:Early methylprednisolone treatment forseptic syndrome and the adult respiratorydistress syndrome. Chest 1987; 92:1032–1036

96. Luce JM, Montgomery AB, Marks JD, et al:Ineffectiveness of high-dose methylpred-nisolone in preventing parenchymal lunginjury and improving mortality in patientswith septic shock. Am Rev Respir Dis 1988;138:62–68

97. Bernard GR, Luce JM, Sprung CL, et al:High-dose corticosteroids in patients withthe adult respiratory distress syndrome.N Engl J Med 1987; 317:1565–1570

98. Weigelt JA, Norcross JF, Borman KR, et al:Early steroid therapy for respiratory failure.Arch Surg 1985; 120:536–540

99. Ashbaugh DG, Maier RV: Idiopathic pulmo-nary fibrosis in adult respiratory distresssyndrome: Diagnosis and treatment. ArchSurg 1985; 120:530–535

100. Biffl WL, Moore FA, Moore EE, et al: Arecorticosteroids salvage therapy for refrac-tory acute respiratory distress syndrome?Am J Surg 1995; 170:591–596

101. Hooper RG, Kearl RA: Established ARDStreated with a sustained course of adreno-cortical steroids. Chest 1990; 97:138–143

102. Braude S, Haslam P, Hughes D, et al:Chronic adult respiratory distress syn-drome—a role for corticosteroids? CritCare Med 1992; 20:1187–1189

103. Keel JB, Hauser M, Stocker R, et al: Estab-lished acute respiratory distress syndrome:benefit of corticosteroid rescue therapy.Respiration 1998; 65:258–264

104. Meduri GU, Belenchia JM, Estes RJ, et al:Fibroproliferative phase of ARDS: clinicalfindings and effects of corticosteroids.Chest 1991; 100:943–952

105. Meduri GU, Headley AS, Golden E, et al:Effect of prolonged methylprednisolonetherapy in unresolving acute respiratorydistress syndrome: A randomized controlledtrial. JAMA 1998; 280:159–165

106. Steinberg KP, Hudson LD, Goodman RB;National Heart, Lung, and Blood InstituteAcute Respiratory Distress Syndrome(ARDS) Clinical Trials Network: Efficacyand safety of corticosteroids for persistentacute respiratory distress syndrome. N EnglJ Med 2006; 354:1671–1684

107. Hough CL, Steinberg KP, Taylor ThompsonB, et al: Intensive care unit-acquired neu-romyopathy and corticosteroids in survi-vors of persistent ARDS. Intensive Care Med2009; 35:63–68

108. Meduri GU, Golden E, Freire AX, et al:Methylprednisolone infusion in early severeARDS: results of a randomized controlledtrial. Chest 2007; 131:954–963

109. Meduri GU, Marik PE, Chrousos GP, et al:Steroid treatment in ARDS: a critical ap-praisal of the ARDS network trial and therecent literature. Intensive Care Med 2008;34:61–69

110. Meduri GU, Annane D, Chrousos GP, et al:Activation and regulation of systemic in-flammation in ARDS: Rationale for pro-longed glucocorticoid therapy. Chest 2009;●●●

111. Meduri GU, Annane D, Chrousos GP, et al:Activation and regulation of systemic in-flammation in ARDS: Rationale for pro-longed glucocorticoid therapy. Chest 2009;●●●

112. Tang BMP, Craig JC, Eslick GD, et al: Use ofcorticosteroids in acute lung injury andacute respiratory distress syndrome: A sys-tematic review and meta-analysis. Crit CareMed 2009; 37:1594–1603

113. Ferguson ND: ACP Journal Club. Review:Low-dose corticosteroids improve out-comes in acute lung injury and the acuterespiratory distress syndrome. Ann InternMed 2009; 151:JC3–JC12

114. Dellinger RP, Levy MM, Carlet JM, et al;International Surviving Sepsis CampaignGuidelines Committee. Surviving Sepsis

Campaign: International guidelines formanagement of severe sepsis and septicshock: 2008. Crit Care Med 2008; 36:296–327

115. Marik PE, Pastores SM, Annane D, et al:Recommendations for the diagnosis andmanagement of corticosteroid insufficiencyin critically ill adult patients: Consensusstatements from an international task forceby the American College of Critical CareMedicine. Crit Care Med 2008; 36:1937–1949

116. Xu T, Qiao J, Zhao L, et al: Effect of dexa-methasone on acute respiratory distresssyndrome induced by the H5N1 virus inmice. Eur Respir J 2009; 33:852–860

117. Wang XO, Zhou S, Zhou Y, et al: Low-dosedexamethasone alleviates lipopolysaccha-ride-induced acute lung injury in rats andupregulates pulmonary glucocorticoid re-ceptors. Respirology 2008; 13:772–780

118. Aberdein J, Singer M: Clinical review: Asystematic review of corticosteroid use ininfections. Crit Care 2006; 10:203

119. Gagnon S, Boota AM, Fischl MA, et al: Cor-ticosteroids as adjunctive therapy for severePneumocystis carinii pneumonia in the ac-quired immunodeficiency syndrome. A dou-ble-blind, placebo-controlled trial. N EnglJ Med 1990; 323:1444–1450

120. Gregory PB, Knauer CM, Kempson RL, etal: Steroid therapy in severe viral hepatitis.A double-blind randomized trial of methyl-prednisolone versus placebo. N Engl J Med1976; 294:681–687

121. Henry SD, Metselaar JH, Van Dijck J, et al:Impact of steroids on hepatitis C virus rep-lication in vivo and in vitro. Ann NY AcadSci 2007; 1110:439–447

122. Kidd IM, Down J, Nastouli E, et al: H1N1pneumonitis treated with intravenous zana-mivir. Lancet 2009; 374:1036

123. Carter MJ: A rationale for using steroids inthe treatment of severe cases of H5N1 avianinfluenza. J Med Microbiol 2007; 56(P