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Running head: TREATMENT STRATEGIES 1

Treatment Strategies for ARDS

Ashley Williams

Baptist College of Health Sciences


TREATMENT STRATEGIES 2

Abstract

ARDS is a lung condition that causes fluid to leak into the lungs and prevents oxygen

from being delivered to the vital organs in the body. It affects over 190,000 people in the United

States alone each year which results in > 40% morbidity and mortality rates (Grawe, Bennett, &

Hurford, 2016) The syndrome was first described by Ashbaugh in 1967, when there was

mortality rate of approximately 65% (Natt, et al., 2016) Since that time, there have been a variety

of successful treatment strategies used for patients with ARDS. Among those treatments are: (1)

prone positioning; (2) lung protective strategies; (3) early paralysis; (4) extracorporeal membrane

oxygenation (ECMO). Prone positioning has been studied extensively, and data shows that prone

positioning improves oxygenation and lung recruitment when acute lung injuries are present

(Kallet, 2015). Lung protective strategies such as low tidal volume ventilation reduce the risk of

harming lung tissue and alveoli (Mechanical Ventilation, 2016). Another lung protective

strategy is positive end expiratory pressure (PEEP). Studies show a significant decline in

mortality in people who receive higher PEEP levels versus lower PEEP levels (Hess, 2015). The

outcomes of Neuromuscular Blocking Agents (NMBAs) are that they can decrease

inflammation, improve oxygenation, and improve patient ventilator asynchrony in patients with

ARDS (Grawe, Bennett, & Hurford, 2016). ECMO is a rescue strategy for patients with severe

ARDS. After controlled studies, it has become a very common therapeutic strategy for ARDS.

Also, due to technological improvements making it safer and easier to use, physicians are very

favorable to its treatment. The mortality rate of 40% is still considered to be high which requires

more research and studies to be conducted in the treatment of ARDS (Natt, et al., 2016).
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There are a variety of successful treatment strategies for patients with Acute Respiratory

Distress Syndrome (ARDS). ARDS is a lung condition that causes fluid to leak into the lungs

and prevents oxygen from being delivered to the vital organs in the body. ARDS affects over

190,000 people in the United States each year which results in > 40% morbidity and mortality

rates (Grawe, Bennett, & Hurford, 2016). The syndrome was first described by Ashbaugh and his

associates in 1967, when mortality rates were approximately 65% (Natt, et al., 2016). Research

and studies since that time have shown a continued decrease in mortality from ARDS to the

current 40% estimate (Natt, et al., 2016). A 40% mortality rate is still considered very high,

therefore, there has been and will continue to be a great deal of research on the strategies used in

the treatment of severe ARDS. The more severe forms of ARDS have a higher rate of mortality

verses more moderate forms of ARDS (Natt, et al., 2016). Therefore, emphasis of these

therapeutic strategies will be placed on patients with severe ARDS. The major causes of death

in patients with ARDS are severe hypoxemia and multi-system organ failure, secondary to

infection, sepsis, hemodynamic instability, and ventilator induced lung injury (Grawe, Bennett,

& Hurford, 2016, p. 831). The treatment of patients with severe ARDS using the following

strategies: (1) prone positioning; (2) lung protective strategies; (3) early paralysis; (4)

extracorporeal membrane oxygenation (ECMO) has shown favorable outcomes.

More explanation is necessary regarding the history and definitions of ARDS. Prior to

Ashbaughs research in 1967, von Neergaard in 1929 intimated that, surface tension plays a role

in lung elasticity (Haitsma & Lachmann, p. 117). Then his work showed, the pressure

necessary to fill the lung with liquid was less than half the pressure needed to fill the lung with

air (Haitsma & Lachmann, p. 117). In other words, when the surfactant production is reduced or

impaired, it allows for an increase in surface tension which can further lead to: atelectasis
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formation, impaired gas exchange, pulmonary edema, or hypoxemia (Haitsma & Lachmann).

Prior to 1992, the definition of ARDS pertained mainly to adults. It is interesting to note that in

1994, the American-European Consensus Committee on ARDS expanded the definition to all

ages and renamed it Acute Respiratory Distress Syndrome (Toujier, 2003).

Prone positioning (PP) has been in effect since the 1970s when it was observed that

children with cystic fibrosis would position themselves on their hands and knees to improve

ventilation (Kallet, 2015). Concurrently, a study showed that passive mechanical ventilation in

the supine position (SP) resulted in ventilation distributed primarily to nondependent lung

regions where profusion was reduced (Kallet, 2015, p. 1661). Based on further findings, it was

suggested that PP could recruit dependent lung areas. In the recent PROSEVA study and

numerous other meta-analyses randomized control trials, the outcomes showed a reduction in

mortality rates when PP was used as an early and prolonged intervention in patients with severe

ARDS (Kallet, 2015). Experimental studies with moderate PEEP levels (10 cmH2O) have been

conducted on patients with ARDS. The results of these studies showed significant recruitment of

the alveoli in both SP and PP. However, when the patient was placed in SP, recruitment was

limited to the dorsal lung. Whereas, when a patient was placed in PP recruitment was distributed

evenly down the dorsal ventral of the lungs (Kallet, 2015).

Since 1974, the use of PP in ARDS has been studied extensively, both clinically and at

the bedside (Marini, Josephs, Mechlin, & Hurford, 2016). In over 40 observational studies, data

shows that PP improves oxygen and lung recruitment when there are acute lung injuries (Kallet,

2015). One clinical study of PP effects on gas exchange in ARDS reported a decrease in V/Q

mismatching when patients were placed in the PP. Although V/Q mismatch decreased from 44%

to 34% in PP, when the patient was placed back into SP, all improvements that had been made
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were reversed (Kallet, 2015). Initiation of PP in early stages of ARDS shows to be most effective

in improving oxygenation, but numerous studies have also resulted in significant improvement in

oxygenation levels when PP was initiated > 5 days after the onset of ARDS. The following graph

was derived from 31 observational studies conducted in order to determine prevalence of

positive oxygenation response when placed in PP (Kallet, 2015). The studies conducted used

criteria of a minimum of 10-20 mmHg increase in PaO2 or PaO2/FiO2 ratio in order to show

improvement in oxygenation (Kallet, 2015).

Positive Oxygenation Response in 31 Obervational


Studies
100
90
80
70
60
50 Precentage of oxygenation
40 improvement
30
20
10
0
20% of Studies 37% of Studies 47% of Studies

The magnitude of oxygenation response from the studies mentioned above reads as follows: the

increase in ranges is greater than that of the average ranges for the minimum cut off values

(Kallet, 2015). From the studies that showed results of an increase in PaO2, the average

improvement was between 23 to 78 mmHg. The observational studies that reported results of

PaO2/FiO2 showed an improvement between 21 to 161 mmHg (Kallet, 2015). The intensity and

time course using PP in patients with ARDS may vary in improving oxygenation. Therefore,

patients may respond differently. The following chart is derived from studies conducted by

Papazlan and Lim on the percentage of improvement shown in PaO2/FiO2 levels over prolong
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periods of time in prone positioning (Kallet, 2015).

Percentage of Oxygenation Improvement Over


Prolonged Periods of Prone Positioning

6 hours

2 hours
Lim

1 hour Papazlan

30 mins

0 10 20 30 40 50 60 70 80

Based on all of these positive results of using prone positioning, it could be recommended as

standard care for patients with severe ARDS.

Nearly all people with severe ARDS are in need of invasive mechanical ventilation. Lung

protective strategies are needed when this intervention is used. It has been shown that lung

protective mechanical ventilation is a well-established therapy for ARDS (Grawe, Bennett, &

Hurford, 2016). There are a couple different lung protective strategies used during mechanical

ventilation in order to protect the lungs of ARDS patients. The first is low tidal volume

ventilation. This reduces the risk of harming lung tissue and alveoli (Mechanical Ventilation,

2016). It is also standard procedure for people requiring mechanical ventilation. After ten

randomized trials, physicians were convinced that this strategy reduced the mortality rate. The

following chart is derived from the ARDSNet protocol and serves as guideline to initial

ventilator setup (NHLBI ARDS Network).


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Guide to Initial Ventilator Setup


Initial Tidal Volumes: 8mL/kg of Ideal Body Weight
IBW:
MALE: (height in inches-60)*6+106
FEMALE: (height in inches-60)*5+105
Tidal Volume: (IBW in kg * 8mL/kg)
Respiratory Rate < 35 breaths per minute
(RR set to deliver VE between 7-9L/min)
PEEP level > 5cm H2O
FiO2 set to maintain
SaO2: 88%-95%
PaO2: 55-80 mmHg

The second lung protective strategy is high positive end expiratory pressure (PEEP)

versus low PEEP. PEEP is the amount of pressure maintained in the lungs after exhalation that

allows for improvement in gas exchange. It has been stated that a PEEP level should be selected

that balances alveolar recruitment against overdistention (Hess, 2015, p. 1688). During ARDS,

only a fraction of the alveoli are relatively normal: some are collapsed, fluid-filled, or

consolidated (Hess, 2015). When a patient is being mechanically ventilated, the alveoli that are

not affected by ARDS are at risk for overdistention. PEEP coupled with recruitment maneuvers

may benefit alveolar recruitment. A recruitment maneuver is a sustained increase in airway

pressure with the goal to open collapsed alveoli after which sufficient PEEP is applied to keep

the lungs open (Hess, 2015, p.1690). The goal of a recruitment maneuver is to improve

oxygenation. Gattinoni tested the possibility for recruitment in 68 subjects with ARDS. A

computed tomography (CT) was used to take images of the lungs while performing breath holds

at airway pressures of 5, 15, and 45 cmH20 (Hess, 2015). The results of the study showed that

patients at a PEEP of 5 cm H20 with a PaO2/FiO2 of <150, a decrease in dead space, and an

increase in compliance had an increased chance for recruitment, and therefore could benefit from
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the use of recruitment maneuvers or increased levels of PEEP (Hess, 2015). There are various

recruitment maneuvers that can be used, however, for a recruitment maneuver to be effective

there must be sufficient PEEP in order to maintain the recruitment. Patients with severe ARDS

are better candidates for recruitment than patients with mild ARDS (Hess, 2015).

Setting PEEP appropriately is important to lung protective ventilation strategies. Early

clinical studies of ARDS done by Ashbaugh and Downs reported that the use of PEEP was a

therapeutic of apparent value (Hess, 2015, p. 1693). A later study by Kirby suggested the use

of high levels of PEEP resulted in a great reduction in shunt fraction (Hess, 2015). Gas exchange

is a method for setting optimal PEEP that targets oxygenation. Goligher conducted a study

showing that when an increase in PEEP levels is applied and an improvement in oxygenation

results then the risk of death is decreased (Hess, 2015). The following chart is derived from the

ARDSnet protocol which shows the combinations associated with levels of FiO2 and PEEP that

may be used in order to achieve oxygenation goals (NHLBI ARDS Network).

LOWER PEEP associated with HIGHER HIGHER PEEP associated with LOWER
FiO2 FiO2
5 0.3/0.4 5 0.3
8 0.4/0.5 8 0.3
10 0.5/0.6/0.7 10 0.3
12 0.7 12 0.3
14 0.7/0.8/0.9 14 0.3/0.4
16 0.9 16 0.4/0.5
18 0.9 18 0.5
20 0.5/0.6/0.7/0.8
22 0.8/0.9/1.0
24 1.0

Patients with a PaO2/FiO2 <150 that showed an increase of 25 when PEEP levels were

increased were associated with a decrease in the risk of mortality (Hess, 2015).
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Another method for setting optimal PEEP is compliance. Compliance is based on

incremental or decremental PEEP titration and selecting the level of PEEP with the highest

compliance (Hess, 2015, p.1695). This setting was first studied by Suter in 1975. The outcome

showed that PEEP corresponding to maximum oxygen delivery corresponded to the lowest

VD/VT and highest compliance (Hess, 2015, p.1695). Recent data from 9 randomized controlled

trials indicates that if there is an increase in PEEP that results in recruitment and improved

compliance, the driving pressure will decrease and lower mortality. The driving pressure is the

dominator of the compliance equation: compliance = VT/(Pplat-PEEP) (Hess, 2015, p. 1695).

There are other approaches to setting PEEP levels, but current evidence is not conclusive as to

which setting leads to better outcomes (Hess, 2015).

There have been clinical trials providing evidence regarding higher versus lower PEEP

levels. In 2 studies, there was a significant decline in mortality in the group who received higher

PEEP levels (Hess, 2015). In a meta-analysis studied by Briel patients with severe ARDS who

received higher levels of PEEP showed a mortality of 34.1%. Those patients who received a

lower PEEP level had a mortality rate of 39.1% (Hess, 2015). A PEEP level of <5 cmH2O is

considered to be harmful to patients with mild ARDS. A balance between alveolar recruitment

and overdistenion should be taken into consideration when determining the appropriate levels of

PEEP (Hess, 2015).

The use of early paralysis is a therapeutic strategy in treatment of ARDS. Neuromuscular

Blocking Agents (NMBA) are used to aid in comfort and safety in mechanically ventilated

patients (Grawe, Bennett, & Hurford, 2016). Sedatives and opioids are some of the more

common neuromuscular blocking agents that can increase oxygenation and possibly decrease

mortality. NMBAs allow for improvement in patient-ventilator synchrony. When a patient


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becomes asynchronies with the mechanical ventilator, it can cause an increase in patient

discomfort, dyspnea, work of breathing, increase respiratory fatigue, and produce measurement

errors in the assessment of breathing frequency and readiness to wean (Grawe, Bennett, &

Hurford, 2016, p. 830). If a NMBA is administered to patients who have become asynchronous

with the mechanical ventilator; it alleviates the patients effort and allows the mechanical

ventilator to control the triggering and cycling of breaths. Along with controlling the patients

breaths, NMBA allows for tidal volumes to be closely regulated. This may result in the decrease

in risk for volutrauma or barotrauma that is caused by high levels of tidal volumes or pressure

causing overdistension to the alveoli (Grawe, Bennett, & Hurford, 2016). Blanch conducted an

observational study on 50 subjects who were mechanically ventilated in various types of

mechanical ventilation modes. The subjects asynchrony index was measured based on the

number of asynchronous events that occurred within a one hour time period. The results showed

that an index of <10% was related to a decreased time in ICU, mortality, and less time spent on

mechanical ventilation (Grawe, Bennett, & Hurford, 2016).

NMBAs contribute to improving oxygenation in patients with ARDS. In other words,

they can contribute to lowering the mortality rate for people with severe hypoxemia (Grawe,

Bennett, & Hurford, 2016). Gainnier conducted a randomized control trail using 56 subjects with

ARDS. The purpose of the study was to examine the effects of NMBAs on oxygenation

parameters. The results showed that the NMBA group showed significant improvement over

subjects who received a placebo. After a 48 hour time period, the patients who received NMBAs

demonstrated a significant increase in PaO2/FiO2 ratio. The study continued into a 5 day trail,

and the results further indicated the NMBA group having improved lung compliance and quicker

weaning times with PEEP levels. Another randomized trial by Ford also reported improvements
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in oxygenation when NMBAs were administered to patients with ARDS (Grawe, Bennett, &

Hurford, 2016).

Another positive result of using NMBAs on patients with ARDS would be to limit

inflammation (Grawe, Bennett, & Hurford, 2016). Patients who have ARDS and are

mechanically ventilated are at risk for overinflating and overstretching of the lungs. When this

occurs, it produces a systemic inflammatory response that can contribute to multi-system organ

failure. In a trial conducted by Forel, he evaluated inflammatory cytokine levels in the serum

and bronchoalveolar lavage samples of subjects randomized to NMBA versus placebo (Grawe,

Bennett, & Hurford, 2016, p.832). The outcome illustrated a decrease in interleukin and serum

levels for patients who received the NMBA within 48 hours after randomization. The outcomes

of NMBAs are that they can decrease inflammation, improve oxygenation, and improve patient

ventilator asynchrony in patients with ARDS (Garwe, Bennett, & Hurford, 2016).

Extracorporeal Membrane Oxygenation (ECMO) is a rescue strategy for patients with

severe ARDS. ECMO is a machine that allows the lungs of a patient to relax by taking over the

workload of the lungs. ECMO takes the blood supply coming to the lungs out of the body and

provides oxygen to the blood before returning it to the body. ECMO was first used in 1972 in a

trauma patient with shock lung who was supported with venoarterial ECMO for 75 hours and

survived (ECMO as a Rescue Strategy). Since then its use has steadily increased. In addition

to many studies, there have been improvements in technology mostly in pumps and oxygenators

(Natt, et al., 2016). Then between 1997 and 2009 there was improvement in survival of ECMO

for respiratory failure to 50% (ECMO as a Rescue Strategy). In 2009, a randomized trial called

CESAR studied ECMO therapy vs. conventional mechanical ventilation in patients with ARDS.

The results of this trial showed a 63% survival rate for patients in the ECMO group compared to
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a 47% survival rate for patients who used conventional mechanical ventilation (ECMO as a

Rescue Strategy). The following information is proof of the increase in the use of ECMO for

patients with ARDS from 2008-2012: (1) in 2008, 1 in 1,000 patients underwent ECMO; (2)

from 2008 to 2012, there was a 19% absolute increase and a 70% relative increase (Natt, et al.,

2016). The mortality rates are as follows: (1) in 2008, in patients with ARDS when ECMO was

used the mortality rate was 78%; (2) from 2008 to 2012, a 14% absolute reduction in mortality

and a 19% relative reduction (Natt, et al., 2016). In a case-controlled study presented by Tasi, it

was reported that over a 6 year time frame patients with ARDS who were in ECMO treatment

groups showed a decrease in six-month mortality and an increase in hospital survival (ECMO as

a Rescue Strategy). Extracorporeal Life-support (ECLS) centers worldwide reported that as of

January 2017, cumulative adult respiratory ECLS cases numbered 12,346, with 57% of patients

surviving to hospital discharge (ECMO as a Rescue Strategy). The use of ECMO in a patient

with severe ARDS continues to grow. It has become a very common therapeutic strategy for

ARDS due to technological improvements making it safer and easier to use. Also, physicians are

very favorable to its use in the treatment of severe ARDS.

In conclusion, the treatment strategies: (1) prone positioning; (2) lung protective

strategies; (3) early paralysis; (4) extracorporeal membrane oxygenation have been successful in

treating patient with ARDS. ARDS is a lung condition that has affected over 190,000 people just

in the United States each year (Grawe, Bennett, & Hurford, 2016). When ARDS was identified

by Ashbaugh in 1967, the mortality rates were approximately 65% (Natt, et al., 2016). Through

research and studies using the four above mentioned therapeutic treatments, there has been a

continued decrease in mortality from ARDS to the current estimated 40%. The more severe

forms of ARDS have higher mortality rates than moderate forms of ARDS. Because that
TREATMENT STRATEGIES 13

mortality rate is still considered high, there still needs to be a great deal of research regarding the

therapeutic strategies used in treating severe ARDS (Natt, et al., 2016).


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