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It Was a GraveyARD Smash:

Early Paralysis in Acute Respiratory Distress Syndrome (ARDS)

Clay Small, PharmD

PGY2 Critical Care Resident

University Health System

The University of Texas at Austin College of Pharmacy

UT Health San Antonio

November 1st, 2019

Learning Objectives

1. Define the pathophysiology and epidemiology of ARDS

2. List the pharmacologic and non-pharmacologic management of ARDS

3. Compare pharmacokinetic and pharmacodynamics properties of neuromuscular blocking

agents (NMBA)

4. Evaluate literature surrounding the use of NMBA in ARDS patients

5. Determine when early paralysis in ARDS patients is indicated

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It Was a GraveyARD Smash: Early Paralysis in Acute Respiratory Distress Syndrome

Clay Small, PharmD

November 1st

, 2019 at 3:00 PM

UT Pharmacotherapy Rounds Presentation

Learning Objectives:

At the completion of this activity, the participant will be able to:

1. Define the pathophysiology and epidemiology of ARDS

2. List the pharmacologic and non-pharmacologic management of ARDS

3. Compare pharmacokinetic and pharmacodynamics properties of neuromuscular blocking agents (NMBA)

4. Evaluate literature surrounding the use of NMBA in ARDS patients

5. Determine when early paralysis in ARDS patients is indicated

Assessment Questions:

1. Which of the following stages is NOT a pathologic stage of ARDS?a. Fibrotic Stageb. Exudative Stagec. Regenerative Staged. Fibroproliferative Stage

2. According to the Berlin Criteria, which answer represents a patient with severe ARDS?a. Patient has a history heart failure with reduced ejection fraction who complained of progressive

dyspnea at rest; PaO2/FiO2 = 74, PEEP = 8b. Patient was found on the side of the road after a motor vehicle collision; PaO2/FiO2 = 163, PEEP =

5c. Patient presented to the hospital with concern for sepsis secondary to pneumonia; PaO2/FiO2 =

81, PEEP = 10

3. Which of the follow neuromuscular blocking agents is associated with an increase in histamine releasethat can lead to flushing, tachycardia, and hypotension?

a. Atracuriumb. Cisatracuriumc. Vecuroniumd. Rocuronium

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic

CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an

email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Clay Small has indicated he has no relevant financial relationships to disclose relative to the content of his

presentation.

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Acute Respiratory Distress Syndrome

a. Previously referred to as “congestive atelectasis” or “shock lung”

b. Life-threatening respiratory condition characterized by hypoxemia and lung stiffness1,2

i. Consequence of alveolar injury producing diffuse alveolar damage

ii. Typical clinical development occurs within 7 days after recognition of a known risk

factor

c. Pathologic Stages of ARDS3-5

i. Early exudative stage

1. Time frame: begins within 24 hours and continues for 7-10 days

2. Innate immune cell-mediated damage

a. Accumulation of protein-rich edema fluid within interstitium and

alveoli

b. Alveolar marcophages secrete pro-inflammatory cytokines leading to

neutrophil, monocyte, and macrophage recruitment

3. Characterized by diffuse alveolar damage

ii. Fibroproliferative stage

1. Time frame: after first 7-10 days (unknown duration)

2. Essential for host survival

3. Alveolar epithelial regeneration

4. Release of matrix metalloproteinases further degrades chemotactic gradient

and prevents further inflammatory cell migration

5. Resorption of provisional matrix by MMPs is critical final event for restoring

alveolar architecture and function

6. Resolution of pulmonary edema

7. Proliferation of type II alveolar cells

8. Early deposition of collagen

iii. Fibrotic stage

1. Not all patients progress to fibrotic stage

2. Associated with prolonged mechanical ventilation and increased mortality

3. Underlying mechanism is poorly understood, but obliteration of normal lung

architecture occurs leading to fibrosis and cyst formation

Epidemiology5,6

a. Population-based estimates of ARDS range from 10 to 86 cases per 100,000

b. Higher incidence rates of ARDS in United States and Australia than in other countries

c. Approximately 75% of ARDS cases are categorized as moderate or severe

d. Approximately one-third of patients with initially mild ARDS progress to moderate or severe

disease

e. Largely under-recognized disease state

a. According to 2016 study, 60.2% of all ARDS patients were recognized5

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Factors Associated with Higher Rates of Clinician Recognition of ARDS

Lower nurse-to-patient ratios

Lower physician-to-patient ratios

Younger patient age

Lower PaO2/FiO2 ratio

Presence of pneumonia or pancreatitis

Mortality7-15

a. Meta-analysis of 9 randomized controlled trials including 5,159 patients

b. Patient factors associated increased mortality

i. Males: higher age-adjusted mortality rate per 100,000 patient years (4.00 patients vs.

3.03 patients, p < 0.001)

ii. African-Americans: higher mortality rate per 100,000 patient years compared to

Caucasians (4.07 patients vs. 3.33 patients, p < 0.001)

iii. Older age

iv. Pneumonia is underlying pathology of ARDS associated with highest mortality (35-

50%)

v. Lower associated mortality if due to non-pulmonary sepsis (30%), aspiration (10%), or

trauma (10%)

vi. Crude mortality rate decreased from 35.4% in 1996 to 28.3% in 2013

vii. Estimated mortality based on severity

a. Mild: 34.9%

b. Moderate: 40.3%

c. Severe: 46.1%

c. Factors associated with decreased mortality15

a. Conservative fluid management strategy

b. Lower tidal volume and plateau pressure

c. Higher PEEP

Clinical Diagnosis16-17

a. Berlin Criteria

Berlin Definition of ARDS

Respiratory symptoms must have begun within one week of a known clinical insult, or the patient must

have new or worsening symptoms during the past week

Bilateral opacities must be present on a Chest X-ray or CT scan

Patient’s respiratory failure must not be fully explained by cardiac failure or fluid overload

Severity PF Ratio Criteria

Mild ARDS PaO2/FiO2 > 200 mmHg, but < 300 mmHg*

Moderate ARDS PaO2/FiO2 > 100 mmHg, but < 200 mmHg*

Severe ARDS PaO2/FiO2 < 100 mmHg*

*PEEP > 5 cm H2O

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Risk Factors18-24

Risk Factor Pathophysiology

Sepsis Upregulation of pro-inflammatory adhesion molecules, release of pro-inflammatory cytokines and lipid products

Disruption of capillary blood flow and enhanced microvascular permeability Aspiration Acidic contents, gastric enzymes, and food particles cause direct lung injury and loss

of pulmonary barrier function Pneumonia Alveolar macrophages produce cytokines that generate an inflammatory response

Severe Trauma Tear develops in lung tissue where positive pressure causes for alveoli to collapse

Shearing force created by trauma damages alveoli tissue

Sudden increases in airway pressure cause shock waves that compress gas within tissues

Massive Transfusion

Neutrophils and complement in blood products intensify the host response

Lipids, cytokines, and microparticles accumulate and cause endothelial injury

Medications/Toxins25-31

Agent Pathogenesis of Injury

Chemotherapeutic Agents (basiliximab, carmustine, cyclophosphamide, etc.)

Direct injury to epithelial cells in alveolar capillaries and these agents impair repair mechanisms

Opioids, Heroin Opioids cause endothelial dysfunction at high doses which lead to fluid leaking from capillaries

Opioids have also been found to increase production of nitric oxide and free radicals which disrupt cellular membranes and lead to edema

Radiation Therapy Causes localized release of energy that breaks strong chemical bonds and generates highly reactive free radical species

Ionizing radiation interacts with tissue water and interferes with cellular molecules such as peptides, lipids, and DNA

Oxygen Toxicity Increased production of reactive oxygen intermediates that impair function of intracellular macromolecules

Increases inflammatory response and cytotoxicity

Cocaine Deposition of cocaine within alveoli causes a dark, tarry residue to restrict appropriate oxygenation

A decrease in capillary permeability due to chronic sodium channel destruction leads to poor oxygen exchange

Alcohol Impairs surfactant production and increases oxidant-mediated necrosis

Increases protein leak across alveolar barrier and decreases alveolar liquid clearance

Mechanical Ventilation of the ARDS Patient32-55

a. Mechanical ventilation is mainstay of ARDS management

i. Indications for Mechanical Ventilation

1. Hypoxia

2. Hypercapnia

b. Mechanical Ventilator Adjustments

i. Tidal volume (TV)

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1. Tidal volume is the volume of air that is transported into and out of the lungs

with each respiratory cycle

2. Low tidal volumes mitigate alveolar over distention induced by mechanical

ventilation

3. In combination with higher PEEP strategies, tidal volumes of 12-15 mL/kg used

in ARDS patients are associated with higher rates of mortality and more

incidence of barotrauma

4. Recommended to administer 4-8 mL/kg IBW and maintain plateau pressure <

30 mmHg in ARDS patients

5. Clinicians underutilize low tidal volume ventilation due to concerns with

retention of carbon dioxide and under-recognition of ARDS

ii. Positive Expiratory End Pressure (PEEP)

1. PEEP is positive pressure in airways at the end of expiration that is greater

than atmospheric pressure

2. PEEP is used keep alveoli from collapsing so that a sufficient amount of oxygen

can be transferred into the bloodstream

3. PEEP can open already collapsed alveoli in pressure-dependent lung; can also

cause hyperinflation in a non-pressure-dependent lung

4. Recruitment maneuvers (RM) can be applied prior to initiating a higher PEEP

strategy to open up more alveoli

5. Early literature found that PEEP > 5 cm H2O improved oxygenation, however, it

did not improve mortality in undifferentiated ARDS35-37

6. Recent meta-analysis showed higher PEEP was associated with potentially

lower all-cause mortality at 28 days and more ventilator-free days in moderate

ARDS patients who have a positive oxygenation response (PaO2/FiO2 < 200)38

7. In a randomized, controlled trial, a higher PEEP strategy of PEEP > 10 cm H2O

was associated with higher 6-month mortality compared to low PEEP strategy40

8. A systematic review and meta-analysis of six RCTs including 2,580 patients

found improvement in oxygenation with high PEEP but no difference in

mortality

c. ARDS-Net Protocol

i. Prior to the ARDS-Net Protocol study in 2000, patients typically received higher tidal

volumes to avoid hypercapnia (12-15 mL/kg vs. 7-8 mL/kg)

1. In animal models, high tidal volume ventilations caused disruption of

pulmonary epithelium and endothelium, lung inflammation, atelectasis,

hypoxemia, and release of inflammatory mediators

ii. The ARDS-Net study was conducted to investigate if lower tidal volume ventilation

would decrease inflammatory response and improve clinical outcomes

iii. Lower tidal volume (4-6 mL/kg) was compared to standard treatment

1. Tidal volume was started at 4 mL/kg in intervention group and increased by 1

mL/kg if plateau pressure (pressure at the end of inspiration) was < 45 cm H2O

iv. Mortality was found to be significantly lower in low tidal volume group and the trial was

stopped early due to futility (31% vs. 39.8%, P = 0.007)

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Sedation of the Mechanically Ventilated Patient

a. According to the 2018 Prevention and Management of Pain, Agitation/Sedation, Delirium,

Immobility, and Sleep Disruption (PADIS) Guidelines, lighter sedation preferred to deep

sedation56

i. Richmond Agitation-Sedation Scale (RASS)57

1. Validated scale that assesses a patient’s depth of sedation

2. Scale ranges from -5 to +4; lighter sedation is -1 to +1

3. Scale relies on individual assessment which can lead to variability

ii. Ramsay Sedation Scale (RAS)57

1. First subjective tool to evaluate the level of consciousness or arousal

2. Non-validated

3. Weak inter-rater agreement compared to RASS58

iii. Lighter sedation has been shown to improve patient-centered outcomes

1. Decreased time to extubation59,60

2. Decreased rates of delirium59

3. Increased ventilator-free days60,61

4. Decreased length of hospital stay60,61

5. Decreased rates of post-traumatic stress disorder (PTSD)61

b. Length of continuous infusion should be limited through implementation of spontaneous

awakening trials (SATs) 26

i. Decreased length of hospital stay62

ii. Decreased number of days on mechanical ventilation62,63

iii. Increased survival rate at 1 year after discharge62,63

c. Agent selection

i. PADIS guidelines recommend limiting benzodiazepine use as it is associated with

negative outcomes58,69-71

a. Longer duration of delirium

b. Longer time to ventilator synchrony

c. Longer recovery time

d. Longer mechanical ventilation time

e. Higher analgesia requirements

ii. Propofol and dexmedetomidine are recommended over benzodiazepines, if sedation is

required

Sedation of the ARDS Patient65-68

a. Sedation is frequently instituted in ARDS patients and can improve ventilator compliance

i. Better adaptation

ii. Reduces patient-ventilator asynchronies

iii. Reduces oxygen consumption by reducing spontaneous muscle activity during

hypoxemia

b. In landmark sedation literature, a small percentage of patients with ARDS were included

i. SEDCOM = 0%69

ii. MENDS = 5%70

iii. PRODEX, MIDEX = excluded patients if indication for deeper sedation71

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c. Deep sedation (RASS -4 to -5) is often instituted in ARDS patients due to the implementation of

therapeutic techniques such as prone positioning, extra-corporeal membrane oxygenation

(ECMO), and neuromuscular blockade

i. Lack of literature investigating lighter sedation targets and unknown tolerability of

lighter sedation in patients who are proned

d. For ethical reasons, neuromuscular blocking agents cannot be implemented without deep

sedation

e. Agent selection

i. Sedation goal is often achieved with opioids and benzodiazepines

ii. Lack of comparative literature in patients with ARDS who received propofol or

dexmedetomidine compared to benzodiazepines and opioids due to concern of under-

sedating patients

Treatment

a. Prone positioning72

i. Improves ventilation-perfusion matching and lung and chest wall mechanics

ii. Provides more uniform distribution of lung stress and strain

iii. Intrapleural pressure becomes closer to homeostatic levels and allows for pressure

dependent apex of lungs to reestablish a more beneficial pressure gradient

iv. PROSEVA trial73

1. Severe ARDS patients with PaO2/FiO2 < 150 were proned for at least 16

consecutive hours after 12-24 hours from study inclusion

2. Low-tidal volume ventilation (6 mL/kg IBW) was initiated with a standardized

FiO2-PEEP protocol

3. Patients were proned up to 28 days and patients were re-proned after up to 4

hours in supine position

4. Lower mortality in the prone group compared to the supine group (16% vs.

32.8%, P < 0.001)

b. Extracorporeal Membrane Oxygenation (ECMO)74

i. Veno-venous ECMO removes venous blood and reinfuses oxygenated blood into vein

ii. Effectively function as a lung outside of body in patients with refractory ARDS

iii. Veno-arterial ECMO can be instituted in ARDS if patients have pulmonary hypertension,

cardiac dysfunction associated with sepsis, or arrhythmias

iv. Requires specialized training and frequent monitoring for clotting or bleeding

complications

v. CESAR Trial75

1. Severe ARDS patients with PaO2/FiO2 < 150 and Murray score > 3 were

randomized in a 1:1 ratio to ECMO or conventional ventilator management

a. Murray score is a composite of number of lung quadrants with

consolidation, PaO2/FiO2, PEEP, and compliance to evaluate eligibility

for ECMO

2. ECMO decreased mortality compared to conventional therapy (63% vs. 47%, P

= 0.03)

3. Referral to treatment by ECMO led to a gain of 0.03 quality-adjusted life-years

at 6-month follow-up

vi. ECMO for Severe ARDS, 201876

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1. Compared ECMO vs. conventional therapy in patients with severe ARDS

(PaO2/FiO2 < 50 for > 3 hours or PaO2/FiO2 < 80 for > 6 hours)

2. Crossover to ECMO allowed for patients in conventional group if refractory

hypoxemia

3. No significant difference in 60-day mortality between groups (P = 0.09)

4. Significantly higher number of bleeding and thrombotic events in ECMO group

c. Intravenous Fluids77

i. Initially, ARDS patients have a septic-like state characterized by decreased intravascular

volume

ii. Due to pulmonary edema that is typical in ARDS, fluid restriction strategies were

implemented that initially lead to hemodynamic aggravation and dysfunction of

multiple organs

iii. Conservative vs. Liberal Fluids Trial, 200678

a. No significant differences in in-hospital between groups

b. Conservative fluid management group aimed for net zero fluid balance

with up to 3 fluid boluses each day if patients did not have severe

hypoxemia (FiO2 > 0.7) or cardiac index > 4.5 L/min/m2

c. Conservative fluid management associated with more ventilator-free days,

days free of CNS failure, and ICU-free days during first 28 days

d. Targeting a CVP > 8 mmHg found to increase pulmonary edema

d. Corticosteroids79

i. In the 1980s, investigators found that the inflammatory exudate from patients with

ARDS could be reduced with high doses of systemic corticosteroids

ii. If underlying cause of ARDS is receptive to glucocorticoid therapy (ex. septic shock or

acute eosinophilic pneumonia), there is a larger benefit with addition of glucocorticoids

compared to other disease states

iii. Corticosteroids for Persistent ARDS, 200680

1. Randomized, controlled trial of methylprednisolone vs. placebo in patients

with ARDS (PaO2/FiO2 < 200)

2. Methylprednisolone dosing:

a. 2 mg/kg predicted body weight x1, then 0.5 mg/kg Q6H for 14 days,

then 0.5 mg/kg Q12H for 7 days; study drug tapered over a period of 4

days if 21 days of treatment had been completed

3. Methylprednisolone increased number of ventilator-free and shock-free days,

improved oxygenation, and decreased number of vasopressor-days during first

28 days of therapy

4. Methylprednisolone was associated with significantly increased 60- and 180-

day mortality rates among patient enrolled at least 14 days after onset of ARDS

5. Corticosteroids may be initiated in early ARDS, particularly if underlying cause

is steroid-responsive

iv. Exploratory Reanalysis of 2006 Study81

1. Similar results from previous study, however, this study supported rapid

corticosteroid discontinuation post extubation as likely cause of disease relapse

2. Gradual tapering might be necessary to preserve improvement achieved by

methylprednisolone administration

e. Neuromuscular blocking agents (NMBA)82

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i. Mechanism of Benefit

1. Prohibits respiratory muscle contraction

a. Decreases lung and systemic inflammation, oxygen consumption, and

cardiac output

b. Increases alveolar recruitment and mixed venous O2 and partial

pressure of oxygen (PaO2)

c. Associated with improvement in oxygenation, decrease in plateau

pressure, and decreased PEEP

d. Decreases serum concentrations of proinflammatory cytokines TNF-α,

IL-1β, IL-683

ii. NMBA Selection

Atracurium Cisatracurium Vecuronium Rocuronium

Dosing

LD: 0.4-0.5 mg/kg (can

repeat 0.08-0.1 mg/kg

boluses)

MD: 9-10 mcg/kg/min

(15 mcg/kg/min max

dose)

LD: 0.15-0.2 mg/kg

bolus (max dose 0.4

mg/kg)

MD: 3 mcg/kg/min

(titrated by 1-2

mcg/kg/min)

LD: 0.08-0.1 mg/kg

MD: 0.8-1.7

mcg/kg/min

LD: 0.6-1 mg/kg

MD: 8-12

mcg/kg/min

Metabolism Hoffman elimination

(produces laudanosine)

Hoffman elimination

(produces laudanosine)

Spontaneous

deacetylation by

hepatic metabolism (3

active metabolites)

Minimally hepatic

metabolism to 17-

desacetylrocuronium

Elimination < 5% urine 95% by urine 15% renal, 50% bile 31% feces, 26%

urine

Monitoring

Peripheral nerve stimulator with train of four monitoring

Vital signs and prolonged paralysis

Adverse Effects

Increased histamine

release (flushing,

tachycardia,

hypotension),

decreased rate of ICU-

acquired weakness

Decreased rate of ICU-

acquired weakness,

lack of histamine

release, typically

transient

Prolonged paralysis and ICU-acquired weakness

are more prevalent

1. Hoffman elimination

a. Quaternary ammonium reacts to create a tertiary amine that is eliminated

via urine or bile

b. Laudanosine is the other byproduct that does not have any neuromuscular

blocking activity, but may lead to hypotension or CNS excitation and

seizures

2. Comparative efficacy

a. Cisatracurium vs. atracurium88

i. 2017 retrospective study in patients with severe ARDS patients

(PF ratio < 150; n = 18 on atracurium, n = 58 on cisatracurium)

ii. No significant differences in PaO2/FiO2 ratio at baseline or at 72

hours after NMBA between groups (P = 0.65)

iii. No difference in ventilator-free days (13 days in atracurium group

vs. 15 days in cisatracurium group, P = 0.72) or mortality between

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groups (50% in atracurium group vs. 62% in cisatracurium group,

P = 0.42)

3. Cisatracurium vs. vecuronium89

a. 2017 database study of propensity-matched cohort (n = 3,802) on

cisatracurium or vecuronium with a diagnosis of ARDS or with a known

ARDS risk factor

b. No significant differences in mortality (P = 0.40) or hospital days (P = 0.411)

c. Fewer ventilator days (-1.01 days, P = 0.005) and ICU days (-0.98, P =

0.028) in cisatracurium group

Neuromuscular Blocking Agents Literature

Gainnier et al. (2004)90

Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome

Objective To evaluate effects of a 48-hr NMBA infusion on gas exchange over a 120-hr time period in patients with ARDS

Methods

Design Prospective, controlled, and randomized trial in four medical or medical-surgical ICUs over 15-month period

Population 56 patients with acute respiratory distress syndrome defined as a PaO2/FiO2 ratio <150 at a PEEP of >5 cm H2O (Excluded patients: chronic respiratory, neuromuscular disease, left heart failure, cerebral edema, bone marrow or lung transplantation)

Groups - NMBA group o Paralysis with cisatracurium 50 mg bolus and then a continuous infusion of 5

mcg/kg/min o If patients had 1 reflex on train of four monitor, rate was increased by 20% by a non-

blinded nurse; TOF assessed 1 hour (goal was TOF = 0) after drug initiation and every 8 hours thereafter

- Conventional therapy group o Sedation obtained with midazolam and sufentanil to target a Ramsay Sedation Score

of 6 o Nitric oxide and almitrine besylate allowed o Prone positioning was not allowed in study period unless PaO2/FiO2 ratio < 60 o Tidal volume for all patients was 6-8 mL/kg and ventilator settings were adjusted to

target a PaO2 between 70 and 90 and a SaO2 between 92 and 97% o Titration per ARDS-Net protocol

Outcomes Primary Endpoint - Mean PaO2/FIO2 ratio evaluated at 48 hrs after inclusion Secondary Endpoints - Ventilator-free days (up to 28 days) and number of ventilator-free days up to 60 days - Duration of mechanical ventilation - ICU death - Incidence of barotrauma - Duration of critical illness neuromyopathy - Duration of sedation

Statistics - 56 patients were selected to detect a difference of 30 in mean PaO2/FiO2 ratio at 48 hours - Intention-to-treat analysis - Student t-test for unpaired data, Mann-Whitney U test for nonparametric data, two-way

repeated-measures analysis of variance, and chi-square analysis

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Results

Baseline Characteristics

NMBA Group

(n = 28) Control Group

(n = 28)

Age (yrs) 59.8 + 17.5 61.5 + 14.6

Simplified Acute Physiology Score (SAPS) II 41.8 + 10.4 45.4 + 10.5

Onset of ARDS, days 0.96 + 0.79 1.14 + 1.72

Pulmonary Origin (n, %) 23 (82) 22 (79)

Length of Mechanical Ventilation

Days 2.7 + 2.6 3.4 + 3.5

Median 2 (1–3.5) 2 (1–5.5

Norepinephrine, n (%) 18 (64) 22 (79)

Dobutamine, n (%) 8 (28.6) 5 (17.9)

Central Venous Pressure (CVP), mmHg 9.6 + 4.2 9.6 + 5.5

Primary Endpoint

- No modification of the PaO2/FIO2 ratio found at 1 hr after randomization in the NMBA group

(142 + 46 vs. 130 + 34 at baseline, p = .29) nor in the control group (126 + 38 vs. 119 + 31, p =

.48)

NMBA Group Control Group Group P-

value

Time P-

value

Baseline 48 hrs 72 hrs Baseline 48 hrs 72 hrs

PaO2/FiO2 130 + 34 183 + 88 196 + 78 119 + 31 139 + 42 170 + 65 0.21 0.001

PEEP (cm H2O)

12.3 + 3.0

11.0 + 2.4

10.3 + 3.4

11.4 + 2.5

10.8 + 2.5

11.2 + 2.6

NS 0.001

Vt (mL/kg)

7.1 + 1.1 7.0 + 1.0 7.2 + 1.0 7.5 + 1.9 7.6 + 1.5 7.4 + 1.6 NS NS

PPlat (mmHg)

27.1 + 6.2

25.7 + 7.2

25.1 + 6.4

26.0 + 4.0

24.4 + 4.8

24.8 + 5.0

NS 0.012

Secondary Endpoints

- Duration of sufentanil and midazolam was longer in the control group, however, this was not

statistically significant (6 days in NMBA group vs. 13 days in control group, p = NS) - Dosage of sufentanil and midazolam was not significantly different between groups - No difference in ventilator-associated pneumonia or critical illness neuromyopathy - 7 more patients died in the control group than in the NMBA group

NMBA Group Control Group P-Value

Duration of MV 20.9 + 15.0 21.2 + 17.4 0.94

Duration of MV at day 28 27.4 + 14.2 34.1 + 20.3 0.30

Duration of MV in ICU survivors 24.5 + 13.1 26.4 + 13.9 0.76

Vent Free Days at Day 28

Days 3.7 + 7.2 1.7 + 5.3 0.24

Median 0 0 0.24

Vent Free Days at Day 50

Days 19.0 + 20.3 9.8 + 16.9 0.071

Median 14 0 0.11

Mortality at day 28 10 (35.7) 17 (60.7) 0.061

Mortality at day 60 13 (46.4) 18 (64.3) 0.18

ICU mortality 13 (46.4) 20 (71.4) 0.057

Author’s Conclusions - Early NMBA use over a 48-hr period provides sustained improvement in oxygenation up to 120

hours - No difference in oxygenation within 1 hour of NMBA administration

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Reviewer’s Critique

Strengths Limitations

- NMBA were administered for 48 hours due to previous literature suggesting that the first 48 hours are associated with the most severe hypoxemia

- Patient groups comparable in baseline characteristics

- Small patient population - Targeted a train-of-four monitor of 0, which is a higher level

of paralysis than currently recommended - Strict prone positioning criteria which limited the number of

patients who were proned - CVP = 9.6 on average in both groups, no protocolized

approach to fluid management - Longer sedation in the control group could lead to higher

rates of mortality and longer mechanical ventilation

Overall Conclusions - PaO2/FiO2 ratio improved in patients who received NMBA more than in control group - Although not statistically significant, overall ventilator requirement clinically improved over

time and showed an overall benefit for ARDS patients within 7 days of therapy - The small patient population limits external validity of this study, but it provides positive

results for potential decreases in mortality in patients with ARDS that should be explored further

Papazian et al. (2010)91

Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome (ACURASYS)

Objective - To determine whether a short period of treatment with the NMBA cisatracurium besylate early in the course of severe ARDS improves clinical outcomes

Methods

Design - Multicenter, randomized, placebo-controlled, double-blind trial

Population - 340 patients enrolled from March 2006 through March 2008 at 20 ICUs in France - All of the following criteria present for < 48 hours: - PaO2/FiO2 ratio < 150 and PEEP > 5 cm H2O, Vt 6-8 mL/kg IBW, bilateral pulmonary

infiltrates without evidence of volume overload

Groups - NMBA vs. Placebo o 15 mg bolus of cisatracurium, followed by 37.5 mg/hr for 48 hours, started once

Ramsay sedation score at 6 o Rapid bolus of 20 mg of cisatracurium allowed in both groups if end-inspiratory

plateau pressure elevated > 32 mmHg for at least 10 minutes o Peripheral-nerve stimulators were not permitted o Sedation was titrated to Ramsay Sedation Scale 6 in both groups

- Ventilation and Weaning o Goal SpO2: 88-95% or PaO2: 55-80 mmHg o Weaning per ARDS-Net Protocol o Vt 6-8 mL/kg IBW

Outcomes Primary Outcome: proportion of patients who died before hospital discharge and within 90 days after study enrollment Secondary Outcomes: - Day-28 mortality - ICU free days from day 1 to day 28 and from day 1 to day 90 - Ventilator-free days - Rate of barotrauma and ICU-acquired paresis

Statistics - Assuming a 50% mortality at 90 days in the placebo group, estimated 340 patients needed to detect a 15% absolute reduction in 90-day mortality in cisatracurium group

- Baseline demographics analyzed using student’s t-test, Wilcoxon, chi-square, or Fisher’s exact test; no adjustment for multiple comparisons

- Primary analysis with Cox multivariate proportional-hazards model, adjusted for baseline SAPS II and plateau pressure

- Secondary analysis conducted based on baseline PaO2/FiO2 ratio (> 120 vs < 120)

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Results

Baseline Characteristics

Characteristic Cisatracurium

(N = 177) Placebo

(N = 162) P-value

Age (yr) 58 + 16 58 + 15 0.70

SAPS II 50 + 16 47 + 14 0.15

PaO2:FiO2 106 + 36 115 + 41 0.03

Tidal volume (ml/kg)

6.55 + 1.12 6.48 + 0.92 0.52

PEEP (cm H2O) 9.2 + 3.2 9.2 + 3.5 0.87

FiO2 0.79 + 0.19 0.77 + 0.20 0.33

Prone positioning or inhaled vasodilator

n, (%) 50 (28) 47 (29) 0.88

Corticosteroids for septic shock n,(%)

70 (39.5) 73 (45.1) 0.30

- Median time from diagnosis of ARDS to enrollment = 16 hours - 70% of patients were admitted to the medical ICU

Primary Endpoint - Cox regression model for 90 day mortality adjusted for baseline SAPS II, plateau pressure, and PaO2/FiO2 ratio

o Hazard ratio = 0.68 (95% CI 0.48-0.98; p = 0.04) o 30.8% in cisatracurium group vs. 44.6% in placebo group in patients with

PaO2/FiO2 < 120 - Crude 90-day mortality

o 31.6% in cisatracurium group vs. 40.7% in placebo group (95% CI 33.5-48.4; p = 0.08))

- Absolute difference in 28-day mortality in patients with PaO2/FiO2 < 120 = -9.6 percentage points

- Survival benefit of NMBA confined to the two thirds of patients with a PaO2/FiO2 < 120

Secondary Endpoints

Outcome Cisatracurium

(N = 177) Placebo (N = 162

P-value

Death, n

At 28 days 42 54 0.05

ICU 52 63 0.06

Hospital 57 67 0.08

Ventilator-free days, n

Day 1-28 10.6 + 9.7 8.5 + 9.4 0.04

Day 1-90 53.1 + 35.8 44.6 + 37.5 0.03

Days outside ICU, n

Day 1-28 6.9 + 8.2 5.7 + 7.8 0.16

Day 1-90 47.7 + 33.5 39.5 + 35.6 0.03

Barotrauma, n 9 19 0.03

Pneumothorax, n 7 19 0.01

Patients without ICU-

acquired weakness, n(%)

Day 28 68/96 (70.8) 52/77 (67.5) 0.64

ICU discharge 72/122 (64.3) 61/89 (68.5) 0.51

- No significant benefit of NMBA in subgroup of patients given corticosteroids (189 patients) - No significant differences in sedation requirements

Author’s Conclusions - Treatment with cisatracurium for 48 hours early in severe ARDS improved the adjusted 90-

day survival rate, increased the numbers of ventilator-free days, increased days outside the ICU, and decreased incidence of barotrauma during the first 90 days

15 | S m a l l

Reviewer’s Critique

Strengths Limitations

- Blinded, randomized study design - Wide variety of patients from 20 different ICUs - Trial was monitored by an independent data and safety

monitoring board - Larger patient population than in previous trials - Cox proportional-hazards model conducted to identify

impact in severe ARDS patients and control for severity of illness and baseline PF ratio

- Under-powered: 339 patients studied vs. 340 patients to reach power

- Efficacy of paralysis was not studied with a train-of-four stimulation and, therefore, effective paralysis cannot be confirmed

- Unclear if paralysis or another effect (i.e. anti-inflammatory) accounts for mortality benefit

- Use of Ramsay sedation score - No protocol for fluid administration - Higher doses of paralytics administered than in current

practice

Overall Conclusions - Paralysis increased ventilator-free days and decreased 90 day mortality in patients with a PaO2/FiO2 ratio < 120

- NMBA associated with a decrease in rate of barotrauma and pneumothorax - Benefit for NMBA may be more pronounced in severe ARDS patients; more judicious

NMBA use in patients with higher PaO2/FiO2 ratios > 120

Moss et al. (2019)92

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome (ROSE Trial)

Objective - To determine efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets

Methods

Design - Prospective, multicenter, randomized, placebo-controlled, unblended trial

Population - 1006 patients enrolled from January 2016 to April 2018 with a PaO2/FiO2 < 150 mm Hg, PEEP > 8 cm H2O, and meeting Berlin criteria for diagnosis of ARDS

Groups - NMBA and deep sedation vs. no NMBA and lighter sedation o Designed to be consistent with medication titration in ACURASYS trial o Deep sedation defined as Ramsay sedation score of 6 o Lighter sedation defined as:

RASS 0 to -1 Riker Sedation-Agitation Scale 3 to 4 Ramsay Sedation Scale 2 to 3

o Low tidal volume ventilation and higher PEEP strategy utilized o Prone positioning usage left to the discretion of the provider

Outcomes Primary Outcome: - In-hospital death from any cause at 90 days Secondary Outcomes: - Organ dysfunction (assessed by Sequential Organ Function Assessment [SOFA] score) - In-hospital death at day 28 - Days free of organ dysfunction, free of mechanical ventilation, not in the ICU, and not in the hospital at

day 28 Safety: - Recall of paralysis assessed by modified Brice questionnaire - ICU-acquired weakness (assessed with MRC scale) up to day 28 - Limitations on physical activity (assessed with ICU mobility scale) - New-onset atrial fibrillation (AF) or supraventricular tachycardia (SVT) - Barotrauma - Investigator-reported adverse events

16 | S m a l l

Statistics - Assuming 27% in NMBA group and 35% in the control group would die, 1408 patients would be needed to provide 90% power with a two-sided alpha level of 0.05

- Wald test for primary outcome - Pre-specified subgroup analyses according to severity of ARDS (PaO2/FiO2 < 120 vs. > 120 mmHg) and by

duration of ARDS - Adverse events: weighted Poisson regression (non-serious events = 1; serious events = 2) - Mortality at 90 days and 1 year by Z-test - Intention-to-treat analysis without adjustment for multiple comparisons

Results

Baseline Characteristics

Characteristic NMBA Group

(N = 501) Control Group

(N = 505) P-value

Age (yr) 56.6 + 14.7 55.1 + 15.9 NS

Median time to randomization, hr 8.2 6.8 0.047

Shock at baseline (n, %) 276 (55.1) 309 (61.2) 0.05

APACHE III Score 103.9 + 30.1 104.9 + 30.1 NS

Total SOFA score 8.7 + 3.6 8.8 + 3.6 NS

Tidal volume (mL/kg) 6.3 + 0.9 6.3 + 0.9 NS

FiO2 0.8 + 0.2 0.8 + 0.2 NS

PEEP (cm H2O) 12.6 + 3.6 12.5 + 3.6 NS

PaO2/FiO2 98.7 + 27.9 99.5 + 27.9 NS

Primary Endpoint

Outcome NMBA Group

(N = 501) Control Group

(N = 505)

Between-Group

Difference P-value

In-hospital death by day

90 n, (%)

213 (42.5 + 2.2) 216 (42.8 + 2.2) -0.3 (-6.4 to 5.9) 0.93

Secondary Endpoints

Outcome NMBA Group

N = 501 Control Group

N = 505 Between-Group

Difference (95% CI)

In-hospital death at day 28, n (%)

184 (36.7) 187 (37.0%) -0.3 (-6.3 to 5.7)

Days free of ventilation, n

9.6 + 10.4 9.9 + 10.9 -0.3 (-1.7 to 1.0)

Days not in ICU, n 9.0 + 9.4 9.4 + 9.8 -0.4 (-1.6 to 0.8)

Days not in hospital, n 5.7 + 7.8 5.9 + 8.1 -0.2 (-1.1 to 0.8)

Change in PEEP in 7 days (cm H2O)

-3.7 -2.9 NS

Outcome NMBA Group

N = 501 Control Group

N = 505 P-Value

Serious adverse events, n

35 22 0.09

Serious CV events, n 14 4 0.02

Afib or SVT, n 101 99 0.88

Barotrauma, n 20 32 0.12

Pneumothorax (Day 0-2), n

8 10 0.81

Pneumothorax (Day 0-7), n

14 25 0.10

ICU-acquired weakness through day 28, n (%)

107/226 (47.3) 89/228 (39.0) NS

- No differences in PaO2/FiO2 ratios between the intervention and control groups - Prone positioning used in 15.8% of patients (84 patients in placebo group vs. 75 in NMBA group)

17 | S m a l l

- 74 patients (14.8%) in the NMBA group stopped treatment early because of clinical improvement - No significant difference in mortality rate for patients with PaO2/FiO2 < 120 - Significant reduction in mortality found in Hispanic patients who received NMBA (p = 0.015) - Fluid administration was not protocolized, but there were no significant differences in fluid balance

between groups

Author’s Conclusions

- Among patients with moderate-to-severe ARDS treated with a higher PEEP strategy, administration of an early and continuous infusion of cisatracurium did not result in significantly lower mortality at 90 days than usual care with lighter sedation

Reviewer’s Critique

Strengths Limitations

- Same protocol for paralysis as in ACURASYS trial to appropriately compare

- Outcomes were assessed by a non-biased third party

- Similar groups by baseline characteristics for comparison

- Provided rationale for each exclusion criteria in supplementary material

- No measurement of ventilator dyssynchrony - Unknown sedation agents and doses used - Non-blinded treatment groups - Low percentage of proning - Paralytics use in control group - No train-of-four monitoring for paralyzed patients - Higher CV SOFA scores and unknown history of cardiovascular

events - Higher doses of paralytics administered than in current practice - Protocol adherence ranged from 79.9% to 64% as trial progressed

Overall Conclusions

- Raises question about benefit of NMBA in moderate-to-severe ARDS - Low rate of proning potentially impacts mortality rates in comparison to optimal therapy - Patients still saw significantly improved ventilator settings within first 48 hours of NMBA - Potentially exemplifies benefit of lighter sedation outweighs benefit of paralysis with NMBA - Further research with higher implementation of proning and higher adherence could increase the

external validity of this study’s results

Comparison of ACURASYS vs. ROSE

Outcomes ACURASYS ROSE

PEEP (cm H2O) 9.2 + 3.2 12.6 + 3.6

Time to enrollment, hr 16 8

Proning, n (%) 152 (44.8) 159 (15.8)

Location France United States

PaO2/FiO2 < 120 mortality, p-value

0.05 0.76

Level of sedation in control group, Ramsay sedation score

6 2 – 3

Recommendations in all ARDS patients

1) Ventilator management per the ARDS-Net protocol

2) Light sedation in ARDS patients NOT receiving NMBA (RASS -2 to +1)

3) Conservative Fluid Therapy

ARDS Patients with Refractory Hypoxemia

- Consider cisatracurium infusion if PaO2/FiO2 < 120 with deep sedation (RASS -4 to -5)

- Consider prone positioning

- Consider ECMO

18 | S m a l l

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