ards - venti strategies

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Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

CHEST

CHEST / 137 / 5 / MAY, 2010 1203www.chestpubs.org

The American-European Consensus Conferenceon ARDS1 standardized the definition of acute

lung injury (ALI) and ARDS on the basis of the fol-lowing clinical parameters: acute onset of severerespiratory distress; bilateral infiltrates on frontal chestradiograph; absence of left atrial hypertension, a pul-

monary capillary wedge pressure 18 mm Hg, or noclinical signs of left heart failure; and severe hypox-emia (ALI, PaO

2FIO

2 ratio 300 mm Hg; ARDS,

PaO2FIO

2ratio 200 mm Hg). The definition does

not take into consideration, however, the etiology(pulmonary or extrapulmonary) or the level of positiveend-expiratory pressure (PEEP) required. More than80% of patients with ARDS require intubation andmechanical ventilation.2 A lung-protective ventilationstrategy should be used with a tidal volume of 4 to8 mLkg ideal body weight (IBW), a plateau pressure(Pplat) of 30 cm H

2O, and modest levels of PEEP.

Such an approach affords a survival benefit and isstandard care.3

Patients with ARDS who are placed on lung-protective mechanical ventilation may have animprovement in oxygenation and disease severity

within 24 h; their mortality is 13% to 23%4,5; and

they should be continued on lung-protective venti-lator settings. In patients with little improvement inPaO

2 FIO

2 ratio in the first 24 h after instituting

mechanical ventilation, the observed mortality is sig-nificantly higher and varies from 53% to 68%.4,5 Inone study, setting PEEP at 10 cm H

2O allowed better

differentiation of ARDS and ALI. After the PEEPtrial, about one-third of patients initially classified ashaving ARDS were reclassified as having ALI, and9% had a PaO

2FIO

2 ratio of .300 mm Hg. The

mortality rates for reclassified categories were 45%for ARDS, 20% for ALI, and 6% for others.6

Severe Hypoxemic Respiratory Failure

Part 1Ventilatory Strategies

Adebayo Esan, MD; Dean R. Hess, PhD, RRT, FCCP; Suhail Raoof, MD, FCCP;Liziamma George, MD, FCCP; and Curtis N. Sessler, MD, FCCP

Approximately 16% of deaths in patients with ARDS results from refractory hypoxemia, whichis the inability to achieve adequate arterial oxygenation despite high levels of inspired oxygenor the development of barotrauma. A number of ventilator-focused rescue therapies that canbe used when conventional mechanical ventilation does not achieve a specific target level ofoxygenation are discussed. A literature search was conducted and narrative review written tosummarize the use of high levels of positive end-expiratory pressure, recruitment maneuvers,airway pressure-release ventilation, and high-frequency ventilation. Each therapy reviewedhas been reported to improve oxygenation in patients with ARDS. However, none of themhave been shown to improve survival when studied in heterogeneous populations of patients

with ARDS. Moreover, none of the therapies has been reported to be superior to another forthe goal of improving oxygenation. The goal of improving oxygenation must always be bal-anced against the risk of further lung injury. The optimal time to initiate rescue therapies, ifneeded, is within 96 h of the onset of ARDS, a time when alveolar recruitment potential is thegreatest. A variety of ventilatory approaches are available to improve oxygenation in the setting ofrefractory hypoxemia and ARDS. Which, if any, of these approaches should be used is oftendetermined by the availability of equipment and clinician bias. CHEST 2010; 137(5):12031216

Abbreviations: ALI5acute lung injury; APRV5airway pressure-release ventilation; CPAP5continuous positiveairway pressure; HFOV5high-frequency oscillatory ventilation; HFPV5high-frequency percussive ventilation;

IBW5 ideal body weight; mPaw5mean airway pressure; OI5oxygenation index;DP5pressure amplitude of oscillation;PCIRV5pressure-controlled inverse-ratio ventilation; PCV5pressure-controlled ventilation; PEEP5positive end-expiratory pressure; Pplat5plateau pressure; RCT5 randomized controlled trial; VCV5volume-controlled

ventilation


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1204 Postgraduate Education Corner

Another parameter that may identify patients withsevere ARDS is a PEEP requirement of 15 cm H

2O.

to maintain adequate oxygenation. Indirect evidencefor this parameter comes from Kallet and Branson,7

who reviewed data for 197 patients from 16 studies.They determined that 84% of patients with ARDShad a lower inflection point of 15 cm H

2O on

the pressure-volume curve, suggesting that a PEEP

of 15 cm H2O may identify severe ARDS. In aseries of 47 patients with ARDS, refractory hypox-emia was associated with a 16% mortality rateamong ARDS deaths.8 In the same vein, Luhr et al2

reported that patients with a PaO2FIO

2 ratio of

,100 mm Hg required more aggressive therapyfor oxygenation.

The oxygenation index (OI) incorporates theseverity of oxygenation impairment (PaO

2FIO

2 ratio)

and mean airway pressure into a single variable:

OI5(FIO23mPaw3100)/PaO

2

(where mPaw5mean airway pressure). The OI is usedmore commonly in neonatal and pediatric patients butalso has been used in adults with ARDS and may be abetter predictor of poor outcome than the PaO

2FIO

2

ratio.9-12 A high OI 12 to 24 h after the onset of ARDSand rising values of OI from persistent ARDS havebeen shown to be independent risk factors formortality.10-12 An OI of .30 is reported to representfailure of conventional ventilation and may be con-sidered an indication for nonconventional modes of

ventilation.9,13-16

For the purpose of this article, we have used the fol-lowing definition of refractory hypoxemia: PaO

2FIO

2

ratio of ,100 mm Hg or inability to maintain Pplat,30 cm H

2O despite a tidal volume of 4 mLkg IBW

or the development of barotrauma. An OI of.30 alsocategorizes a patient as having refractory hypoxemicrespiratory failure. We define high ventilator require-ment as an FIO

2 of 0.7 mm Hg and a PEEP of

.15 cm H2O or Pplat.30 cm H

2O with a tidal volume

of ,6 mLkg IBW. This requirement should be rec-

Manuscript received October 9, 2009; revision accepted January14, 2010.Affiliations:From the New York Methodist Hospital (Drs Esan,Raoof, and George), Division of Pulmonary and Critical CareMedicine, Brooklyn, NY; Respiratory Care Services (Dr Hess),Massachusetts General Hospital, Boston, MA; and Pulmonaryand Critical Care Medicine (Dr Sessler), Virginia CommonwealthUniversity, Richmond, VA.Correspondence to:Suhail Raoof, MD, FCCP, Division of Pul-monary and Critical Care Medicine, New York Methodist Hospi-tal, 506 Sixth St, Brooklyn, NY 11215; e-mail: [email protected] 2010 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians (www.chestpubs.orgsitemiscreprints.xhtml).DOI: 10.1378/chest.09-2415

ognized early in the course of ARDS (,96 h) whenthe potential for alveolar recruitment is greatest.17-20

Consideration also should be given to transferringpatients with refractory hypoxemia to a center withestablished expertise in caring for such patients.21-23

What is the physiologic basis for rescue therapiesin severe ARDS? In the lungs of patients with ARDS,there are alveoli that are relatively normal, that

are collapsed but recruitable, and that are nonre-cruitable.24 Rescue methods are used to recruit thecollapsed, but potentially recruitable alveoli. Alveolarrecruitment reduces the shunt fraction, reduces deadspace, and improves compliance. Another importantphysiologic concept is optimally matching ventilationand perfusion.

The primary focus should be on prevention ofrefractory hypoxemia rather than on reversing it afterit develops. If small tidal volumes and adequate levelsof PEEP are used and careful attention given to fluidstatus and patient-ventilator synchrony, the need for

rescue therapy may be obviated in many cases.25 Res-cue therapies can be categorized arbitrarily as ventila-tory and nonventilatory strategies. Nonventilatoryinterventions, such as neuromuscular blockade, inhaled

vasodilator therapy, prone positioning, and extracor-poreal life support, are discussed in a companionarticle forthcoming in the June 2010 issue of CHEST,26

whereas ventilatory approaches are addressed here.Use of rescue therapies is controversial, as, to ourknowledge, none to date has been shown to reducemortality when studied in large heterogeneous popu-lations of patients with ARDS. However, some rescue

therapies have been shown to improve oxygenation,which may be important as a short-term goal in the16% of patients deteriorating with hypoxemic respi-ratory failure.8When instituting rescue strategies, anattempt should be made to assess for alveolar recruit-ment. If alveolar recruitment is demonstrated, higherlevels of PEEP should be considered.27-30 Other res-cue therapies include airway pressure release ventila-tion (APRV),31 high-frequency oscillatory ventilation(HFOV),32 and high-frequency percussive ventilation(HFPV).33,34 In patients demonstrating very severehypoxemic respiratory failure, defined as a PaO

2

FIO2ratio of ,60 mm Hg,27 consideration of extra-corporeal life support,35 HFOV, or HFPV may beappropriate.

Because there are no data establishing the superi-ority of one rescue mode over another,36 the choice ofrescue therapy is based on equipment availability andclinician expertise. Some clinicians may choose not touse a rescue therapy, which is legitimate on the basisof the level of available evidence. If a rescue therapydoes not result in improved oxygenation or if compli-cations from the therapy occur, that rescue therapyshould be abandoned.


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Thus, a reasonable evidence-based approach mightbe one in which lung-protective ventilation is used(volume and pressure limitation with modest PEEP).This approach may require permissive hypercapnia(ie, a higher-than-normal PaCO

2)37 and permissive

hypoxemia (ie, a lower-than-normal PaO2).38 If a clin-

ical decision is made to implement rescue therapy forthe patient with ARDS and refractory hypoxemia,

one or more of the strategies described in this articlecan be used.

In this narrative review, we discuss ventilatorytechniques that have been used in the setting ofrefractory hypoxemia in patients with ARDS. APubMed search was conducted, with each strategyused as a key term. We narrowed the search to arti-cles published in English and those that studiedhuman subjects. We broadened the search to includeadditional articles, as appropriate, from the referencelists of those identified from our primary search.

Positive End-Expiratory Pressure

Increasing the level of PEEP often is the first con-sideration when the clinician is faced with a patient

with refractory hypoxemia. If PEEP results in alve-olar recruitment, the shunt is reduced, and PaO

2

increases. Three randomized controlled trials (RCTs)have evaluated modest vs high levels of PEEP inpatients with ALI and ARDS (Table 1).27,28,39 Althoughnone of these studies reported a survival advan-tage for use of higher PEEP, each reported a higherPaO

2FIO

2 ratio in the higher PEEP group. More-

over, two of the studies reported lower rates of refrac-tory hypoxemia, death with refractory hypoxemia,and use of rescue therapies.27,28 Gattinoni andCaironi40 argued for the use of higher PEEP on thebasis of fewer pulmonary deaths and absence ofreported complications with this strategy.

The National Heart, Lung, and Blood Institute ARDSClinical Trials Network39 and Meade et al27 set individ-ualized PEEP using a table of FIO

2-PEEP combina-

tions based on oxygenation. Mercat et al28 individual-ized PEEP to a level set to reach a plateau pressure of28 to 30 cm H

2O. Post hocanalysis of data from their

study suggested that compared with ARDS, mild lunginjury may be associated with less benefit and moreadverse effects from higher levels of PEEP. Thus, astrategy of a higher PEEP and lower tidal volume witha plateau pressure target of 28 to 30 cm H

2O should

not be used in patients with ALI. Moreover, criticshave argued that the low PEEP (5-9 cm H

2O) used in

the control group in Mercat et al may have been exces-sively conservative and a suboptimal control.

The benefit of PEEP in patients with refractory hyp-oxemia might depend on the potential for alveolarrecruitment.24 If the recruitment potential is low, then

an increase in PEEP will have a marginal effect onshunt and PaO

2, and it may contribute to overdistension

of already-open alveoli,41which could lead to increasedrisk for ventilator-induced lung injury and increaseddead space and might potentially result in redistribu-tion of pulmonary blood flow to nonventilated regionsof the lungs. If an increase in PEEP results in alveolarrecruitment, then the strain (distribution of pressure) in

the lungs is reduced. On the other hand, if an increasein PEEP increases transpulmonary pressure, then thestress (change in size of the lungs during inflation) onthe lungs is increased. PEEP may adversely affect PaO

2

in the presence of unilateral lung disease.42

The potential for recruitment can be identified inan individual patient by use of a short (30-min) trialof increased PEEP. If an increase in PEEP results inminimal improvement (or worsening) of PaO

2, an

increase in dead space (increased PaCO2) with stable

minute ventilation, and worsening compliance, thenalveolar recruitment is minimal.43 Conversely, if an

increase in PEEP results in a large increase in PaO2,a decrease in PaCO

2, and improved compliance, it sug-

gests significant recruitment. Some have suggested adecremental rather than an incremental PEEP trial.44,45

With this approach, PEEP is set to 20 cm H2O and

then decreased to identify the level that produces thebest PaO

2and compliance.

The stress index was recently proposed to assessthe level of PEEP to avoid overdistension. 29 Thisapproach uses the shape of the pressure-time curveduring tidal volume delivery. Worsening complianceas the lungs are inflated (upward concavity; stress index,

.1) suggests overdistension, and the recommenda-tion is to decrease PEEP (Fig 1). Improving compli-ance as the lungs are inflated (downward concavity;stress index,,1) suggests tidal recruitment and poten-tial for additional recruitment, thus a recommenda-tion to increase PEEP.

The use of an esophageal balloon to assess intra-pleural pressure has been advocated to allow moreprecise setting of PEEP.30,46 If pleural pressure is highrelative to alveolar pressure (ie, PEEP), there may bepotential for alveolar derecruitment, which is mostlikely seen with a decrease in chest wall compliance,

such as occurs with abdominal compartment syndrome,pleural effusion, or obesity. In this case, it is desirableto keep PEEP greater than pleural pressure. Unfor-tunately, artifacts in esophageal pressure, especiallyin supine patients who are critically ill, make it verydifficult to measure absolute pleural pressureaccurately.47-50 Although it is important to considerpleural pressure when setting PEEP, the use of anesophageal balloon may not be required. In patients

with abdominal compartment syndrome, bladderpressure may be useful to assess intraabdominal pres-sure, the potential collapsing effect on the lungs, and


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the amount of PEEP necessary to counterbalancethis effect.48

The available evidence does not clearly indicatethe best method to select PEEP in patients withARDS. Various options are listed in Table 2. A PEEPsetting of 0 cm H

2O generally is accepted to be

harmful in the patient with ARDS. A PEEP setting of8 to 15 cm H

2O is appropriate in most patients with

ARDS. Higher levels of PEEP should be used inpatients for whom a greater potential for recruitmentcan be demonstrated. Care must be taken to avoidoverdistension when PEEP is set. Higher PEEP set-tings may be required in patients with refractory hyp-oxemia; however, a PEEP of .24 cm H

2O seldom is

required. In the decision-making for each patient,the potential benefit of high levels of PEEP shouldbe balanced against the risk of harm (ventilator-induced lung injury, barotrauma, hypotension).

Lung Recruitment Maneuvers

A recruitment maneuver is a transient increasein transpulmonary pressure intended to promotereopening of collapsed alveoli 52-54 and has beenshown to open collapsed alveoli, thereby improvinggas exchange.17,18,55-58 However, to our knowledge,there have been no RCTs demonstrating a mortalitybenefit from this improvement in gas exchange.

A variety of techniques have been described asrecruitment maneuvers (Table 3).52,54 One approach

Figure 1. Graphic representation of the stress index. Flow andairway pressure vs time are displayed for three examples of stressindex categories. The ventilator is set for constant-flow inflation.The stress index is derived from the airway pressure waveformbetween the dashed lines. For stress index values,1, the airwaypressure curve presents a downward concavity, suggesting a con-tinuous decrease in elastance (or increase in compliance) duringconstant-flow inflation, and further recruitment of alveoli is likely.For stress index values .1, the curve presents an upward con-

cavity, suggesting a continuous increase in elastance (decreasein compliance), and excessive positive end-expiratory pressuremay be present. Finally, for a stress index value51, the curve isstraight, suggesting the absence of tidal variations in elastance.Pao5airway pressure. (Reprinted with permission from theAmerican Thoracic Society.29)

involves a sustained high-pressure inflation usingpressures of 30 to 50 cm H

2O for 20 to 40 s.51,56 A sus-

tained inflation usually is achieved by changing to acontinuous positive airway pressure (CPAP) modeand setting the pressure to the desired level. Pressure-controlled breaths can be applied in addition to thesustained high pressure.18,57 Another approach is touse intermittent sighs, using three consecutive sighs

set at a pressure of 45 cm H2O.59 An extended sighalso has been used in which there is a stepwise increasein PEEP and a decrease in tidal volume over 2 min toa CPAP level of 30 cm H

2O for 30 s.60 Another method

applies an intermittent increase in PEEP for 2 breathsmin.55 Pressure-controlled ventilation (PCV) of 10 to15 cm H

2O with PEEP of 25 to 30 cm H

2O to reach a

peak inspiratory pressure of 40 to 45 cm H2O for 2 min

also has been used as a recruitment maneuver.57 Pronepositioning61 and HFOV62 also have been used toimprove alveolar recruitment.

Just as it is unclear which, if any, recruitment

maneuver is superior to another, the optimal pressure,duration, and frequency of recruitment maneuvers hasnot been established. Many patients require increasedsedation, paralysis, or both during the application of arecruitment maneuver. Studies using a decrementalPEEP trial after a recruitment maneuver have reportedsignificant oxygenation benefits for at least 4 to 6 h. 18,44

However, it is unclear whether this finding was due tothe recruitment maneuver, the PEEP titration strategy,or both. An improvement in oxygenation with arecruitment maneuver may indicate that the level ofPEEP is too low. A recruitment maneuver may be of

limited benefit when higher levels of PEEP are used.63A recent systematic review reported the acute

physiologic effects of a recruitment maneuver inapproximately 1,200 patients.52 Oxygenation was sig-nificantly increased after a recruitment maneuver(Fig 2). Hypotension (12%) and desaturation (8%)

were the most common complications of recruitmentmaneuvers. Serious adverse events, such as barotrauma(1%) and arrhythmia (1%), were infrequent. The overallmortality was similar to observational studies ofpatients with ALI (38%). The finding of improvedoxygenation was more common in the following sub-

groups: difference between pre- and post-recruitmentmaneuver PEEP (5 cm H

2O vs.5 cm H

2O), baseline

PaO2FIO

2ratio (,150 mm Hg vs 150 mm Hg), and

baseline respiratory system compliance (,30 mLcmH

2O vs 30 mLcm H

2O).

Many of the studies of recruitment maneuversreported a rapid decline in oxygenation gains, some

within 15 to 20 min of the maneuver.52 The applica-tion of higher levels of PEEP after a recruitmentmaneuver may affect the sustainability of the effect.

Whether improvements in oxygenation associated withrecruitment maneuvers result in reduced lung injury


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and improved outcomes remains to be determined.Some studies have shown a survival advantage with alung-protective ventilation strategy incorporatingrecruitment maneuvers,51,64 whereas others havenot.27 The potential for lung recruitment likely variesconsiderably among patients,24 which likely affectsthe response to a recruitment maneuver.

The routine use of recruitment maneuvers is not

recommended at this time. Given that they pose littlerisk of harm if the patient is carefully monitoredduring their application and that some patients mayhave a dramatic improvement in oxygenation withtheir application,57 recruitment maneuvers may playa role in patients who develop life-threatening refrac-tory hypoxemia. It is prudent to avoid the use ofrecruitment maneuvers in patients with hemody-namic compromise and those at risk for barotrauma.65

If the application of a recruitment maneuver resultsin an important improvement in oxygenation, higherlevels of PEEP should be used to maintain recruit-

ment. However, caution must be exercised to avoidoverdistension with excessive levels of PEEP.

Pressure-Controlled Ventilation

In patients with severe ARDS, some clinicianschoose PCV as an alternative to volume-controlled

ventilation (VCV) based on several lines of rea-

soning. First, the peak inspiratory pressure is loweron PCV, but this is related to the flow patternduring pressure control and, for the same tidal vol-ume delivery, there is no difference in plateau pres-sure for PCV and VCV. Second, patient-ventilatorsynchrony is believed to be better with PCV.However, Kallet et al66 reported that the work ofbreathing is not better with PCV than with VCVduring lung-protective ventilation in patients whoare actively breathing. Moreover, the active inspi-ratory effort resulted in an increase in tidal vol-ume such that lung-protective ventilation may have

Table 1Summary of Results of Three Randomized Controlled Trials of Lower vs Higher Levels of PEEP

Study Control Group Experimental Group Major Findings

ALVEOLI39 Volume assist-control. Vt56 mLkgIBW; Pplat 30 cm H

2O. Combinations

of PEEP and Fio2to maintain Pao

2

(55-80 mm Hg) or SpO2(88%-95%).

PEEP on days 1-4 was 8.363.2 cmH

2O. n5273

Volume assist-control. Vt56 mLkgIBW; Pplat30 cm H

2O.

Combinations of PEEP and Fio2

to maintain Pao2(55-80 mm Hg) or

Spo2(88%-95%). PEEP on days 1-4

was 13.263.5 cm H2O. In the first

80 patients, recruitment maneuversof 35-40 cm H

2O for 30 s. n5276

Higher Pao2Fio

2ratio in high PEEP group

(220689 vs 168666) on day 1. Highercompliance in the higher-PEEP group(39634 vs 31615 mLcm H

2O) on day 1.

Mortality before hospital discharge (lowPEEP, 24.9%; high PEEP, 27.5%; P5.48).

Ventilator-free days (low PEEP, 14.5610.4 d;high PEEP, 13.8610.6 d; P5.50). Incidenceof barotrauma (low PEEP, 10%; highPEEP, 11%; P5.51).

LOV27 Volume assist-control. Vt56 mLkgIBW; Pplat30 cm H

2O. Combinations

of PEEP and Fio2to maintain Pao

2

(55-80 mm Hg) or Spo2(88%-93%).

PEEP on days 1-3 was 9.862.7 cmH

2O. n5508

Pressure control. Vt56 mLkgIBW; Pplat40 cm H

2O.

Combinations of PEEP and Fio2

to maintain Pao2(55-80 mm Hg) or

Spo2(88%-93%). PEEP on days 1-4

was 14.663.4 cm H2O. Recruitment

maneuvers after each disconnectfrom the ventilator of 40 cm H

2O

for 40 s. n5475

Higher Pao2Fio

2ratio in higher-PEEP group

(187669 vs 149661) on day 1. HigherPplat in the high-PEEP group (30.266.3

vs 24.965.1). The higher-PEEP group hadlower rates of refractory hypoxemia (4.6%

vs 10.2%; P5.01), death with refractoryhypoxemia (4.2% vs 8.9%; P5.03), andpreviously defined eligible use of rescuetherapies (5.1% vs 9.3%; P5.045). Twenty-eight day mortality (high PEEP, 28.4%;low PEEP, 32.3%; P5.2). Incidence ofbarotrauma (high PEEP, 11.2%; low PEEP,9.1%; P5.33).

EXPRESS28 Volume assist-control. Vt56 mLkgIBW. Moderate PEEP (5-9 cm H

2O).

n5382

Volume assist-control. Vt56 mLkgIBW. PEEP set to reach Pplat of28-30 cm H

2O (14.663.2 cm H

2O)

on day 1. n5385

Higher Pao2Fio

2ratio in higher-PEEP group

(218697 vs 150669) on day 1. Highercompliance in the high-PEEP group(37.2622.7 mLcm H

2O vs 33.7614.3

mLcm H2O) on day 1. The increased

PEEP group had higher median numberof ventilator-free days (7 d vs 3 d; P5.04),organ failure-free days (6 d vs 2 d; P5.04),and use of adjunctive therapies. Incidenceof barotraumas (high PEEP, 6.8%; lowPEEP, 5.8%; P5.57).

ALVEOLI5Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury Trial; EXPRESS5ExpiratoryPressure Trial; IBW5ideal body weight; LOV5Lung Open Ventilation Trial; PEEP5positive end-expiratory pressure; Pplat5plateau pressure;SpO

25oxygenation by pulse oximetry; Vt5tidal volume.


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been violated in many patients.66 Third, some clini-cians expect an improvement in gas exchange withPCV. With PCV, the pressure waveform approxi-mates a rectangle, and flow decreases during theinspiratory phase. The resulting increased mean

airway pressure and lower end-inspiratory flowtheoretically should improve gas exchange. However,on many current-generation ventilators, a descend-ing ramp of flow can be used with VCV, and this mayresult in similar findings with PCV and VCV with adescending ramp waveform.67-70 With careful atten-tion to tidal volume, plateau pressure, PEEP, andinspiratory time, the differences between PCV and

VCV are minor, and neither is clearly superior to theother. It is also worth pointing out that the ARDSNettrial was conducted with VCV.3

Pressure-Controlled Inverse-Ratio

Ventilation

Following reports71-75 of improved oxygenationwith pressure-controlled inverse-ratio ventilation(PCIRV) published 20 years ago, considerable enthu-siasm for this method was generated. The approachto PCIRV is to use an inspiratory time greater than theexpiratory time to increase mean airway pressureand, thus, improve arterial oxygenation. PCIRV mostoften is used with PCV, although VCV with inverseratio also has been described.76 Following the initial

enthusiasm for this ventilatory approach, a numberof subsequent controlled studies reported no ben-efit or marginal benefit of PCIRV over more conven-tional approaches to ventilatory support in patients

with ARDS.68,77-80 The elevated mean airway pres-

sure and auto-PEEP that occur with PCIRV alsomay adversely affect hemodynamics. Because thisapproach can be very uncomfortable for the patient,sedation and paralysis often are required. On thebasis of the available evidence, there is no clear ben-efit for PCIRV in the management of patients withARDS. The likelihood of an improvement in oxygen-ation with PCIRV is small, and the risk of auto-PEEPand hemodynamic compromise is great.81-83

Airway Pressure Release Ventilation

APRV is a mode of ventilation designed to allowpatients to breathe spontaneously while receivinghigh airway pressure with an intermittent pressurerelease (Fig 3). The high airway pressure maintainsadequate alveolar recruitment. Oxygenation is deter-mined by high airway pressure and FIO

2. The timing

and duration of the pressure release (low airway pres-sure) as well as the patients spontaneous breathingdetermine alveolar ventilation (PaCO

2). The ventilator-

determined tidal volume depends on lung compli-ance, airway resistance, and the duration and timingof the pressure-release maneuver.

Table 2Methods for Selecting PEEP

Method Description

Incremental PEEP3,27,39 This approach uses combinations of PEEP and Fio2to achieve the

desired level of oxygenation or the highest compliance.Decremental PEEP44,45 This approach begins with a high level of PEEP (eg, 20 cm H

2O), after

which PEEP is decreased in a stepwise fashion until derecruitmentoccurs, typically with a decrease in Pao

2and decrease in compliance.

Stress index measurement29 The pressure-time curve is observed during constant-flow inhalation

for signs of tidal recruitment and overdistension.Esophageal pressure measurement30,46 This method estimates the intrapleural pressure by using an esophageal

balloon to measure the esophageal pressure and subsequentlydetermine the optimal level of PEEP required.

Pressure-volume curve guidance51 PEEP is set slightly greater than the lower inflection point.

See Table 1 for expansion of the abbreviation.

Table 3Different Lung Recruitment Maneuvers

Recruitment Maneuver Method

Sustained high-pressure inflation51,56 Sustained inflation delivered by increasing PEEP to 30-50 cm H2O for 20-40 s

Intermittent sigh59 Three consecutive sighsmin with the tidal volume reaching a Pplat of 45 cm H2O

Extended sigh60 Stepwise increase in PEEP by 5 cm H2O above baseline with a simultaneous stepwise decrease

in tidal volume over 2 min leading to implementing a CPAP level of 30 cm H2O for 30 s

Intermittent PEEP increase55 Intermittent increase in PEEP from baseline to set level for 2 consecutive breathsminPressure control1PEEP57 Pressure control ventilation of 10-15 cm H

2O with PEEP of 25-30 cm H

2O to reach a peak

inspiratory pressure of 40-45 cm H2O for 2 min

CPAP5continuous positive air pressure. See Table 1 legend for expansion of other abbreviation.


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An active exhalation valve allows the patient tobreathe spontaneously throughout the ventilator-imposed pressures, although spontaneous breathingtypically occurs only during high airway pressuredue to the short time at low airway pressure. Dia-phragmatic contraction associated with spontaneousbreaths during APRV may recruit dependent (dorsal)

juxtadiaphragmatic alveoli, thus reducing shunt andimproving oxygenation. Because high airway pres-sure usually is much longer than low airway pres-sure, APRV is functionally the same as PCIRV inthe absence of spontaneous breathing. Because the

patients ability to breathe spontaneously is pre-served, APRV allows for a prolonged inspiratoryphase without the need for heavy sedation andparalysis.

Various time ratios for high-to-low airway pres-sure have been used with APRV, ranging from 1:1 to9:1 in different studies.84-88 In order to sustain opti-mal recruitment, the greater part of the total timecycle (80%-95%) occurs at high airway pressure. Inorder to minimize derecruitment, the time spent atlow airway pressure is brief (0.2-0.8 s in adults).89

Neumann et al88 demonstrated that spontaneous

inspiratory and expiratory time intervals are indepen-dent of the time at high to low airway pressure cyclebecause patients who are breathing spontaneouslycan maintain their innate respiratory drive duringhigh and low airway pressure; thus, the release phasedoes not reflect the only expiratory time. If the timeat low airway pressure is too short, expiration maybe incomplete, and intrinsic PEEP may result.88

However, creating intrinsic PEEP is, by design,required with some approaches to APRV in whichlow airway pressure is set to 0 cm H

2O.89With this

approach, the time at low airway pressure is set such

that the expiratory flow reaches 50% to 75% of thepeak expiratory flow.

Crossover studies have reported improvementsin physiologic end points with APRV.31,85,86,90-92 Thesestudies reported that APRV required lower inflationpressure and less sedation and often producedbetter oxygenation than other forms of mechanical

ventilation. Putensen et al87 randomized 30 trauma

patients to APRV or PCV. With APRV, the inotropicsupport was lower, and the duration of ventilatorysupport and length of ICU stay were shorter. How-ever, these findings are debatable because patientsrandomized to the conventional ventilation group

were paralyzed for the initial 72 h of support. Thelargest RCT of APRV84 was terminated early forfutility after recruiting 58 out of a targeted 80 sub-

jects. At 28 days, there were no statistical differencesin the number of ventilator-free days. In addition,mortality at 28 days and at 1 year was similar. How-ever, the authors used prone positioning in both

arms, which is known to improve the oxygenation in60% to 70% of patients; thus, prone position mayhave eclipsed any oxygenation differences betweenthe two groups. Additionally, the ventilator used toprovide APRV in the test group is not designedto provide APRV and required modification to theexpiratory limb.

Spontaneous breathing during high airway pres-sure has the potential to generate negative pleuralpressures that may add to the stretch applied fromthe ventilator. This situation must be considered

when evaluating the maximal stretch to which the

lungs are exposed. Neumann et al88 reported tidalvolumes of approximately 1 L and large pleural pres-sure swings with APRV. There is concern that theserelatively large tidal volumes and transpulmonarypressures could contribute to the risk of ventilator-induced lung injury. The potential benefits ofimproved oxygenation and reduced need for sedationmake APRV an attractive ventilator mode.89 However,

without RCTs demonstrating improved patient out-comes, routine use of this mode cannot be recom-mended. If APRV is used, auto-PEEP and tidal vol-ume must be closely monitored.

High-Frequency Oscillatory Ventilation

High-frequency ventilation is any application ofmechanical ventilation with a respiratory rate of .100breathsmin. This can be achieved with a small tidal

volume and rapid respiratory rate with conven-tional mechanical ventilation, various forms of exter-nal chest wall oscillation, HFPV, high-frequency jet

ventilation, or HFOV, which currently is the form ofhigh-frequency ventilation most widely used in adultcritical care.62,93-95 It delivers a small tidal volume by

Figure 2. The relationship between oxygenation (Pao2Fio

2ratio)

after the application of a recruitment maneuver (post-RM) withbaseline (pre-RM) oxygenation in each individual study presented.Oxygenation was significantly increased post-RM (Pao

2Fio

2ratio,

139 mm Hg vs 251 mm Hg; P,.001). PF5Pao2Fio

2. (Reprinted

with permission from the American Thoracic Society.52)


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oscillating a bias gas flow in the airway. The oscillatorhas an active inspiratory and expiratory phase. Afrequency of 3 to 15 Hz can be used, although lowerrates (3-6 Hz) are used in adults. Nevertheless, higherrates are feasible and may result in smaller tidal

volumes and decreased risk for lung injury.96

HFOV oscillates the gas delivered to pressuresabove and below the mean airway pressure(mPaw).

The mPaw and FIO2 are the primary determinantsof oxygenation, whereas the pressure amplitude ofoscillation (DP) and the respiratory frequency are thedeterminants of CO

2elimination. The tidal volume

varies directly with DP and inversely with frequency.95

The mPaw is initially set to a level approximately5 cm H

2O above that with conventional ventilation,

and DP is set to induce wiggle, which is visible tothe patients mid-thigh.96,97 Much of the pressureapplied to the airway is attenuated by proximalairways and does not reach the alveoli, resulting in asmall tidal volume that may be less than dead

space.98,99 The delivery of a small tidal volume and a

Figure 3. Display of airway pressure and flow vs time during airway pressure-release ventilation.Spontaneous breaths occur at a high pressure level, leading to a pressure release to a lower pressurelevel, as seen in this figure. During this mode, ventilation occurs by intermittent switching betweenthe two pressure levels while allowing spontaneous breathing to occur in either phase of the ventilatorcycle. Because time at low airway pressure is brief, in practice, spontaneous breathing occurs primarilyduring the time of high airway pressure. Maintaining an adequate level of time during a high airwaypressure enhances alveolar recruitment, whereas keeping time short prevents alveolar collapse duringthe release to low airway pressure. CPAP5continuous positive air pressure; P

aw5airway pressure;

T High5time at high airway pressure; T Low5time at low airway pressure; V5flow. (Reprinted with per-mission from the Intensive Care On-line Network.89)

high mPaw may result in improved alveolar recruit-ment with less risk of overdistension, thus providingimproved gas exchange and lung protection. HFOValso has been combined with other strategies, such asrecruitment maneuvers,100 inhaled nitric oxide,101 andprone positioning.102

Most of the evidence for HFOV has been fromsmall observational studies,9,19,103,104 often in the set-

ting of refractory hypoxemia. These studies haveshown that HFOV is safe and effective, resulting inimprovements in oxygenation and providing ample

ventilation in adult patients with severe ARDS.There have been only two RCTs of HFOV in adultpatients with ARDS.32,105 Derdak et al32 random-ized 148 patients to receive either HFOV or conven-tional ventilation. The HFOV group showed an earlyimprovement in the PaO

2FIO

2 ratio, but this was

not sustained beyond 24 h. There was a nonsignifi-cant trend toward a lower 30-day mortality in theHFOV group (37% vs 52%; P5.102). A criticism of

this trial is that patients in the conventional ventilation


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group were ventilated with relatively large tidal vol-umes, which may have contributed to the high mor-tality in the control group.93 Bollen et al105 reportedno significant difference in mortality betweenpatients randomized to HFOV and those to conven-tional ventilation. A post hocanalysis, however, sug-gested that HFOV might improve mortality inpatients with a higher oxygenation index. Complica-

tions reported with HFOV are relatively infrequentand include barotrauma,19,32,100,104 hemodynamiccompromise,9,104 mucus inspissations resulting in endo-tracheal tube occlusion or refractory hypercapnia,31

and increased use of sedation or neuromuscularblocking agents.9,19,32,102,106 In the two RCTs comparingHFOV with conventional ventilation, Derdak et alreported no significant effect of HFOV on hemody-namics, barotrauma, or mucus plugging, and Bollenet al did not report any increased risk of complica-tions with HFOV.

The use of HFOV may improve oxygenation inpatients with refractory hypoxemia. However, thereis not sufficient evidence to conclude that HFOVreduces mortality or long-term morbidity in patients

with ALI or ARDS.107

High-Frequency Percussive Ventilation

HFPV was introduced in the early 1980s as theVolumetric Diffusive Respirator (PercussionaireCorporation; Sandpoint, ID). Compared with HFOV,only a few studies have investigated the use of HFPVin adult patients with ARDS.33,108-112 HFPV is a flow-regulated, pressure-limited, and time-cycled venti-lator that delivers a series of high-frequency (200-900 cyclesmin) small volumes in a successivestepwise stacking pattern, resulting in the formationof low-frequency (upper limit, 40-60 cyclesmin) con-

vective pressure-limited breathing cycles (Fig 4).34,110,113

Figure 4. High-frequency percussive ventilation. An interplay of the percussive frequency, peak inspiratory pressure (indirectlymodulated by altering the pulsatile flow rate), inspiratory and expiratory times (of both percussive and convective breaths), and theoscillatory and demand continuous positive air pressure (CPAP) levels either singly or in combination is involved in determining meanairway pressure as well as the degree of gas exchange. The percussions are of lower amplitude at oscillatory CPAP (baseline oscillations)during exhalation and are of higher amplitude during inspiration as a result of the selected pulsatile flow rate (see pressure-time dis-play). During inspiration, the lung volumes progressively increase in a cumulative, stepwise manner by continually diminishing subtidaldeliveries that result in stacking of breaths. The peak pressure is reached as a result of modulations in the flow rate of the percussivebreaths. Once an oscillatory pressure peak is reached and sustained, periodic programmed interruptions occur at specific times forpredetermined intervals to allow for the return of airway pressures to baseline oscillatory pressure levels (ie, oscillatory CPAP), therebypassively emptying the lungs. A5pulsatile flow during inspiration at a percussive rate of 655 cyclesmin; B5convective pressure-limited breath with low-frequency cycle (14 cyclesmin); C5demand CPAP (provides static baseline pressure); D5oscillatory CPAP(provides high-frequency baseline pressure as a mean of the peak and nadir of the oscillations during exhalation); E 5single percussivebreath; F5periodic programmed interruptions signifying the end of inspiration and subsequent onset of exhalation.


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An interplay of the Volume Diffusive Respirator con-trol variables, either singly or in combination, con-tribute to the determination of mean airway pressureand gas exhange.34,109,112,114 At high percussion fre-

quencies (300-600 cyclesmin), oxygenation isenhanced, whereas at low percussion frequen-cies (180-240 cyclesmin), CO

2 elimination is

enhanced.34,109,113

Figure 5. Ventilatory strategies for the management of refractory hypoxemic respiratory failure,showing the alternative ventilator strategies that can be used in patients with acute lung injury or ARDS

with refractory hypoxemia following evaluation of the recruitment potential of the lungs. In patients withrecruitable lungs, higher levels of positive end-expiratory pressure (PEEP) or other methods of settingappropriate levels of PEEP may be used initially.However, failure of the aforementioned techniquescan result in the use of the alternative ventilatory strategies in centers familiar with their use. 5othermethods of setting appropriate levels of PEEP include setting PEEP to reach a plateau pressure of28 to 30 cm H

2O using esophageal pressure monitoring or the stress index. ALI5acute lung injury;

APRV5airway pressure-release ventilation; ECLS5extracorporeal life support; ETCO25end-tidal

carbon dioxide; HFOV5high-frequency oscillatory ventilation; HFPV5high-frequency percussiveventilation. See Table 1 legend for expansion of other abbreviations.

ARDS/ALI

Conventional Management

P O /FIO < 1 00

gof ARDS/ALI

ARDSnet Guidelines

PaO2 2 < 100Or

Pplat > 30 cm H2O on VT 4 mL/kg IBWOr

OI > 30 ?

noyesNon-ventilatory strategies

to improve PaO2(Part 2)

yes

Increase PEEP by 5 - 10 cm H2O to a maximum of 20 cm H2O

and/orRecruitment maneuver (eg, 30 - 40 cm H2O for 30 - 40 s)

yesHigh recruitment potential

SpO2 increase > 5%

OrPaCO2 decreaseLow recruitment potential

no

Higher Levels of PEEP (ALVEOLI TRIAL)*

High recruitment potentialPaCO2 decrease

OrCompliance increase

Low recruitment potential

ECLS (PaO2/FIO2 < 60)

FIO 0 3 0 3 0 3 0 3 0 3 0 4 0 4 0 5 0 5 0 5 0 8 0 9 1 0 1 0

Reassess in 6 24 hours

FIO2 0.3 0.3 0.3 0.3 0.3 0.4 0.4 0.5 0.5 0.5-

0.8

0.8 0.9 1.0 1.0

PEEP

cm H2O

5 8 10 12 14 14 16 16 18 20 22 22 22 24

PaO2/FIO2 60 - 100PaO2/FIO2 < 60

Consider:HFOV/HFPVECLS

Consider:APRV

HFOV/HFPV


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HFPV has been reported to improve oxygenationand ventilation in patients with ARDS refractory toconventional ventilation, although these studies aresmall in size, few in number, and nonrandomized. Ina prospective trial of seven patients with ARDSrequiring increased ventilator support on conventional

ventilation, Gallagher et al112 found that when thepatients were switched to HFPV at the same level of

airway pressure and FIO2, the patients had a signifi-cant increase in PaO

2, a slight reduction in PaCO

2,

and no change in cardiac output. In another prospec-tive study comparing HFPV and conventional venti-lation in 100 adult patients with acute respiratory failure,no difference was found between the two groups inthe time to reach the study end points of PaO

2FIO

2

ratio .225 or shunt ,20%.114 In the subgroup ofpatients with ARDS, HFPV provided equal oxygena-tion and ventilation at significantly lower airway pres-sures, although there was no difference in the inci-dence of barotrauma, ICU days, hospital days, or

mortality.114 In a retrospective series of 32 adultmedical and surgical patients with ARDS unresponsiveto at least 48 h of conventional ventilation, Velmahoset al33 demonstrated improved oxygenation within 1 hof being switched to HFPV. Peak inspiratory pressuredecreased with HFPV, but mPaw increased. Althoughthe peak inspiratory pressure decreased, peak alveolarpressure was not reported. In 12 patients with ARDSfollowing blunt trauma who were switched to HFPVafter failure of conventional ventilation, there was animprovement in oxygenation within 12 to 24 h.108

However, these improvements were not due to a rise

in mPaw because there was no significant change fol-lowing the switch to HFPV. The mechanisms thatcontribute to gas exchange in HFPV and other high-frequency ventilatory techniques have been describedin a review by Krishnan and Brower.98

An additional reported benefit of HFPV is theenhanced mobilization and drainage of secretionsfrom the lung periphery to the larger airways, poten-tially decreasing pulmonary infections.33,109,115 None-theless, HFPV has not demonstrated improved out-comes. Unlike other ventilatory strategies that mightbe applied in the patient with refractory hypoxemia,

both HFOV and HFPV require a ventilator that isnot available in all hospitals as well as respiratorytherapists and physicians skilled in its use.

Summary

Figure 5 summarizes a proposed algorithmicapproach to ventilator management of refractoryhypoxemia. We recommend that lung-protective ven-tilation (volume and pressure limitation with mod-erate levels of PEEP) be instituted in patients with

ALI and ARDS requiring mechanical ventilation.Rescue therapies may be considered in patients whodevelop refractory hypoxemia, with the use of thesetherapies based on a variety of factors, such as theseverity of hypoxemia, likelihood of alveolar recruit-ment, response to the intervention, and patient char-acteristics. Rescue strategies are aimed at improvingalveolar recruitment (high PEEP, recruitment maneu-

vers, APRV, HFOV) and, thereby, oxygenation; how-ever, none of these modalities have been consistentlyshown to improve outcome in a critically ill patientpopulation. Before a trial of rescue therapy is initi-ated, the target outcome should be established. If therescue strategy does not achieve this end point, itshould be abandoned. Nonventilatory rescue strat-egies, such as inhaled vasodilators, prone positioning,and extracorporeal life support, may be considered inconjunction with the ventilatory strategies outlined inthis article. They are discussed in detail in part 2 ofthis series, which will appear in the June 2010 issue of

CHEST.26 Further research is needed to elucidatehow these rescue strategies may be better used toprovide an outcome benefit.

Acknowledgments

Financialnonfinancial disclosures:The authors have reportedto the CHEST the following conflicts of interest: Dr Hesshas received royalties from Impact. He was a consultant forRespironics and Pari. He also discloses relationships with Cardinal(CaseFusion) and Ikaria. Dr George was a consultant to Eubien,Boehringer Ingelheim, from 2006 to 2007. She has received moneyfrom AstraZeneca, Pfizer, Penexel, and Talceda. Drs Esan, Raoof,and Sessler report that no potential conflicts of interest exist withany companiesorganizations whose products or services may bediscussed in this article.

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