Transcript The 90-day mortality

Neuromuscular Blockers in
Early ARDS
ARDS
ARDS management
In most studies, ARDS has been fatal in 40 to 60% of patients
Despite intense research, there are no specific pharmacologic
therapies proven to decrease this mortality
The only confirmed therapy is a lung-protective strategy
involving the use of relatively small tidal volumes with
limitation of the end-inspiratory lung stretch
The ARDS Network. N Engl J Med 2000;342:1301-8
• Low VT
• PEEP-FiO2
ACMV
PCV
• Constant
Ppeak
• Sedatives
• NMBAs
PVD
Advantages
Disadvantages
Murray MJ, Cowen J, DeBlock H, et al.
Crit Care Med 2002;30: 142-56
Benefits of NMBAs during mechanical
ventilation
Improved patient–ventilator
synchrony
Improve gas exchange
Minimize ventilator induced lung
injury (VILI) – barotrauma,
atelectrauma & biotrauma
Decrease the O2 consumption of
respiratory and other muscles
Decrease in lung or systemic
inflammation
Forel JM, Roch A, Marin V, et a l. Crit Care Med 2006;34:2749-57
Why we are analyzing this study today?
 Use of NMBAs is well
established in ARDS when
sedation fails to prevent
PVD
 The following study
challenges this existing
concept, providing evidence
in favour of routine use of
NMBAs in early ARDS
Neuromuscular blocking agents
(NMBAs)
Depolarizing
Succinylcholine
Non-depolarizing
Amino-steroidal
Pancuronium
Vecuronium
Benzyl-isoquinoline
Dtubocurarine
Cisatracurium
The ARDS et Curarisation Systematique
(ACURASYS) study
Papazian L, Forel JM, Gacouin A et al
N Engl J Med 2010;363:1107-16
Speaker – Dr. Kirti Damor
Preceptor – Dr. Anurag Vyas
Provence-Alpes-Côte d'Azur (PACA)
(One of the 22 regions of France)
Methodology
Double blind, placebo controlled
March 2006 through March 2008
Multicentre (20 ICUs in 4 hospitals)
Randomisation in blocks of 4 (Age & MV duration)
Centralized telephone system
Ethical clearance
Study protocol and statistical analysis plan was approved for
all centres by the ethics committee of the Marseille University
Hospital according to French law
Written informed consent was obtained from the patients or
their proxies
Funding & assistance
Funded by

Assistance Publique–Hôpitaux de Marseille (AP-HM) – A
public health instituition, involving four hospitals in the
PACA region

Hospital Clinical Research Program by the French ministry
of health
GlaxoSmithKline France provided the study drugs
Inclusion Criteria
Endotracheal mechanical ventilation for acute hypoxemic
respiratory failure for ≤ 48 hours with:
 PaO2/FiO2 < 150 with PEEP ≥ 5 cm H2O & VT 6-8 ml/kg of
predicted body weight (PBW)
 Bilateral pulmonary infiltrates consistent with edema
Additional eligibility criterion: absence of clinical evidence of
left atrial hypertension
 PCWP, if available, of < 18 mm Hg
 If not, echocardiography done if the patient had a history
of, or risk factors for, ischemic heart disease or had
crackles on auscultation
Study drug and regimen
Cisatracurium besylate (NIMBEX, 150-mg formulation) & placebo
prepared in identical separate 30-mL vials (5mg/mL) for IV infusion
3 mL (15 mg) rapid IV infusion followed by continuous infusion of
7.5 mL (37.5 mg) per hour for 48 hours
Peripheral-nerve stimulators were not permitted
Open label cisatracurium
Pplat > 32 cm of water for ≥ 10 minutes
Rapid intravenous injection of 20 mg of cisatracurium
Decrease of the Pplat by > 2 cm of water
Second injection of 20 mg of cisatracurium
Ventilation protocol
Mode
Volume assist–control
Initial VT
6–8 ml/kg of predicted body weight
Pplat
≤32 cm of water
Oxygenation
goal
PaO2 55–80 mm Hg or SpO2 88–95%
pH goal
7.20–7.45
Permitted combinations of
FiO2 and PEEP to maintain
oxygenation
The ARMA Study. N Engl J Med 2000;342:1301-8
Achieving goals
Poor oxygenation
• Inhaled nitric oxide
• Almitrine mesylate
• Prone positioning
• Combination of the
above
Pplat >32 cm for
>10 min
Hypercapnia with
pH <7.20
• Increase sedation
• Reduce VT to 4 ml/kg
• Decrease PEEP by 2
cm of water
• Open label
cisatracurium
• Connect Y-piece
directly to ET tube
• Increase RR to
35/min (max)
• Increase VT to 8
ml/kg (max)
Weaning
Initiation
Goals
• On day 3 (if FiO2 ≤0.6)
• SpO2 ≥88%
• RR 26–35/min
Procedure
• Decrease PEEP over 20–30 min to 5 cm of water
• PSV levels 20, 15, 10, and 5 cm of water
Extubation
• ≥ 2 hr of successful PSV at a level of 5 cm of water
Failure
• Not tolerating PSV 20 cm of water, switch to ACMV
Success
• Spontaneous breathing for a period of ≥ 48 hours
Organ failure
SBP ≤ 90
mm Hg or
need for
vasopressor
Platelet
count ≤
80,000/cu.
mL
S. bilirubin
≥2 mg/dL
S. creatinine
≥ 2 mg/dL
Pneumothorax
Pneumomediastinum
Barotrauma
Subcutaneous
emphysema
Pneumatocele >2 cm
MRC Scale for Muscle Strength
MRC score < 48 = ICU-acquired paresis
Schweickert WD, Hall J. Chest 2007;131;1541-1549
The Ramsay Sedation Scale
Level 1
• Awake and anxious, agitated, or restless
Level 2
• Awake, cooperative, accepting ventilation, oriented, tranquil
Level 3
• Awake; responds only to commands
Level 4
• Asleep; brisk response to light glabellar tap or loud noise
Level 5
• Asleep; sluggish response to light glabellar tap or loud noise
stimulus but does not respond to painful stimulus
Level 6
• Asleep; no response to light glabellar tap or loud noise
Modified from Ramsay M, Savege T, Simpson BRJ, et al. BMJ 1974;2:656–569
Simplified Acute Physiology Score (SAPS) II
Includes 17 variables
 12 physiological variables measured during 24 hours
 Age
 Type of admission (scheduled surgical, unscheduled
surgical, or medical)
 3 underlying disease variables (AIDS, metastatic cancer,
and hematologic malignancy)
Score 0 to 163 (higher scores indicating more severe disease)
Prognostic score for medical conditions
McCabe–Jackson score
1
(nonfatal)
2
(ultimately
fatal)
3
(fatal)
Primary Outcome
Proportion of patients who
died before hospital
discharge and within 90
days after study enrolment
(The 90-day mortality)
Secondary Outcomes
Day-28 mortality
Numbers of days outside the ICU between day 1-28 and
between day 1-90
Number of days without organ or system failure between day
1-28
Rate of barotrauma
Rate of ICU-acquired paresis
MRC scores on day 28 and at the time of ICU discharge
Numbers of ventilator-free days (days since successful
weaning from mechanical ventilation) between day 1-28 and
between day 1-90
Sample size
Assumptions for the sample-size calculation were based on
previous studies
Assuming a 50% mortality at 90 days in the placebo group,
340 patients were need to detect a 15% absolute reduction in
the 90-day mortality in the study group (with 80% statistical
power and a two-sided alpha value of 0.05)
However, the observed mortality in the placebo group in this
study (40.7%) was lower than that in the control groups in the
earlier studies (Hence this study was underpowered)
Statistics
Differences between the groups were assessed using
Student’s t-test, the Wilcoxon test, the chi-square test, or
Fisher’s exact test, as appropriate
All reported P values were two-sided
Kaplan–Meier curves were plotted to assess the time from
enrolment to death and the time to disconnection from the
ventilator for a period of at least 48 hours
Results
Reasons for exclusion
Age < 18 years (19 patients, 1.9%)
Lack of consent (185 patients, 18.8%)
Continuous infusion of a NM blocking agent at enrolment (42 patients, 4.3%)
Pregnancy (19 patients, 1.9%)
Enrolment in another trial within the previous 30 days (57 patients, 5.8%)
Increased intracranial pressure (18 patients, 1.8%)
Severe chronic respiratory disease requiring long-term oxygen therapy or
mechanical ventilation at home (95 patients, 9.6%)
Actual body weight exceeding 1 kg/cm of height (20 patients, 2.0%)
Severe chronic liver disease (Child–Pugh class C) (82 patients, 8.3%)
BM transplantation or chemotherapy-induced neutropenia (97 patients, 9.8%)
Pneumothorax (18 patients, 1.8%)
Expected duration of mechanical ventilation of < 48 hours (15 patients, 1.5%)
Decision to withhold life-sustaining treatment (168 patients, 17.0%)
Other reason (103 patients, 10.4%)
Time window missed (48 patients, 4.9%)
Base-line characteristics
Base-line characteristics
Time to inclusion
NMBA
Placebo
P-value
Median time from the diagnosis of
ARDS to study inclusion in hrs (IQR)
18 (6-31)
15 (7-27)
0.45
Median time from initiation of
mechanical ventilation to study
inclusion in hrs (IQR)
22 (9-41)
21 (10-42)
0.91
Probability of Survival through Day 90
Hazard ratio for death at 90 days
 In the cisatracurium group, as
compared with the placebo
group, was 0.68 (95% CI, 0.48 to
0.98; P = 0.04), after
adjustment for the baseline
PaO2:FiO2, SAPS II, and plateau
pressure
Crude 90-day mortality (P = 0.08)
 Cisatracurium group 31.6%
(95% CI, 25.2 to 38.8)
 Placebo group 40.7% (95%
CI, 33.5 to 48.4)
Outcomes
Probability of survival from the Day 0-90
Beneficial effect of cisatracurium on 90-day survival rate was confined to the 2/3rd of
patients presenting with a PaO2:FiO2 ratio < 120
[90-day mortality was 30.8% in cisatracurium group & 44.6% in control group (P = 0.04)]
Probability of breathing without assistance
from Day 0-90
Adjusted hazard ratio for weaning from MV by day 90, in the cisatracurium group as
compared with the placebo group was 1.41 (95% CI, 1.08 to 1.83; P = 0.01)
Time from inclusion to diagnosis of
pneumothorax
 Pneumothorax occurred
in a larger proportion of
patients in placebo group
(11.7%, vs. 4.0% in
cisatracurium group; P =
0.01)
 Pneumothorax tended
to develop earlier in the
placebo group
Respiratory variables during
the first 7 study days
Pplat and minute ventilation in patients with
pneumothorax during first 48 hours
ABG parameters during the first 7 days
Co-interventions during the study period
Sedation and analgesia during the first
week after inclusion
Safety
Bradycardia developed during the cisatracurium infusion in
one patient
No other side effects were reported
Discussion
Strengths
Large study
Minimal bias (blinded randomization assignments, a welldefined study protocol, complete follow-up, and intention-to-
treat analyses)
Limitations
Underpowered due to less than the expected mortality
Absence of data on conditions known to antagonize or
potentiate neuromuscular blockade
Unanswered questions
Why did the study group require more open label
cisatracurium after the first 48 hours?
Optimal duration of NM blockade in ARDS?
Can NMBAs be used late in the course of ARDS?
Can NMBAs be used on the basis of Pplat or transpulmonary
pressure measurements
Whether the observed benefit is specific to cisatracurium or
shared within the drug class?
Conclusion
Administration of a NMBAs early in the course of severe ARDS
managed with low-tidal-volume ventilation may improve
outcomes
Future studies are needed to confirm and elaborate these
findings before they can be widely adopted in clinical practice
Thank You!
Predefined analyses
The 90-day mortality was adjustment by means of a Cox
multivariate proportional-hazards model that included two
predefined covariates:
 Baseline SAPS II score
 Baseline plateau pressure
The only imbalanced variable between the 2 groups was the
PaO2:FiO2 ratio (2/3rd of patients with a ratio below 120
were compared with the 1/3rd with a higher ratio)
Atracurium
An intermediate-acting nondepolarizing muscle relaxant
(benzylisoquinolinium compound)
Inactivated by ester hydrolysis in plasma and Hofmann elimination
(spontaneous degradation in plasma and tissue at normal body pH
and temperature) , so the duration of blockade should not be
affected by renal or hepatic dysfunction
The main breakdown products are laudanosine and a related
quaternary acid, neither of which possesses neuromuscular
blocking properties
Laudanosine is slowly metabolized by the liver and has a long
elimination half-life (i.e.150 minutes). It readily crosses the bloodbrain barrier, and high blood concentrations may cause seizures
Cis-atracurium
An intermediate-acting nondepolarizing muscle relaxant
(benzylisoquinolinium compound)
Isomer of atracurium
Lesser tendency to cause mast cell degranulation
Less cardiovascular effects
Bolus doses of 0.1–0.2 mg/kg result in paralysis in an average
of 2.5 minutes, and recovery begins at approximately 25
minutes; maintenance infusions should be started at 2.5–3
mcg/kg/min
Metabolized by ester hydrolysis and Hofmann elimination
Train of Four (TOF)
Used to measure the degree of neuromuscular blockade
A peripheral nerve stimulator is used
Do a baseline measurement before paralytic agent is started
to determine current necessary to obtain twitch (Usually 20
mA)
Muscle twitches in response to the TOF stimulus is measured
TOF Procedure
Attach 2 electrodes along the course of the ulnar nerve
(Temporal may be used)
Connect the lead to the peripheral nerve stimulator &
connect the other end to the patient electrodes
Turn the stimulator on. Select the current necessary (usually
20) for that patient to twitch when the stimuli is applied
Press TOF once. It will deliver a train of four pulses where
each is 0.5 seconds apart
Count the number of twitches the patient had out of four
(0/4, 1/4, 2/4, 3/4, 4/4) {Goal is 1/4 to 2/4 twitches}
Almitrine dimesylate
An agonist of peripheral chemoreceptors (located on the
carotid bodies)
Used as a peripheral respiratory stimulant (respiratory
analeptic) effective both on long and short term treatment of
COPD
Individual therapeutic response very variable and
approximately 25% of patients might not respond
Recommended dose 50-100 mg/day during two months,
followed by a resting month
Higher doses or longer treatments could provoke high serum
levels which in turn would increase the risk of pulmonary
hypertension and peripheral neuropathies
1. Rubio Terrés C, López Alvarez M, Vargas Castrillón E. Rev Clin Esp. 1990 Feb;186(2):84-7
2. Smith PD, Gotz VP, Ryerson GG. Drug Intelligence & Clinical Pharmacy. 1987 May;21(5):417-21
Nitric oxide + Almitrine for ARDS
Inhaled nitric oxide, a selective pulmonary vasodilator and
intravenously administered almitrine, a selective pulmonary
vasoconstrictor, have been shown to increase PaO2 in
patients with ARDS
Redistribution of pulmonary blood flow towards aerated lung
areas through selective vasoconstriction of pulmonary vessels
perfusing non-aerated lung areas or selective vasodilation of
pulmonary vessels perfusing aerated lung areas
Gallart L et al. Am J Respir Crit Care Med. 1998 Dec;158(6):1770-7
Extra Slides
Barotrauma
Barotrauma was defined as newly developed pneumothorax,
pneumomediastinum, subcutaneous emphysema, or
pneumatocele >2 cm in diameter
Study drug and regimen
Cisatracurium besylate (NIMBEX, 150-mg formulation,
GlaxoSmithKline) and placebo were prepared in identical
separate 30-ml vials (5mg/ml) for IV infusion
3-ml (15 mg) rapid intravenous infusion followed by a
continuous infusion of 7.5 ml (37.5 mg) per hour for 48 hours
Methodology
Double blind, placebo controlled
March 2006 through March 2008
Multicentre - 20 ICUs in 4 hospitals
Block randomisation in blocks of 4
Centralized telephone system
4 groups per centre, stratified according to:
 Age (≤60 years or >60 years)
 Duration of mechanical ventilation at base-line (≤48 hours
or >48 hours)
Open label cisatracurium
An open-label, rapid, intravenous injection of 20 mg of
cisatracurium was allowed in both groups if Pplat > 32 cm of
water for ≥ 10 minutes despite the administration of
increasing doses of sedatives and decreasing tidal volume and
PEEP (if tolerated)
If this rapid, intravenous injection resulted in a decrease of
the Pplat by > 2 cm of water, a second injection of 20 mg of
cisatracurium was allowed. If after the injection, the Pplat did
not decrease or decreased by < 2 cm of water, cisatracurium
was not administered again during the following 24-hour
period
Organ failure
Patients were monitored daily for 28 days for signs of failure
of nonpulmonary organs or systems
 Circulatory failure was defined as SBP of 90 mm Hg or less
or the need for vasopressor therapy
 Coagulation failure was defined as a platelet count of
80,000 or less per cubic mL
 Hepatic failure was defined as a serum bilirubin level of 2
mg/dL or higher
 Renal failure was defined as a serum creatinine level of 2
mg/dL or higher
Weaning
Weaning attempt: starting on day 3, if FiO2 ≤0.6
Goals during weaning procedure: SpO2 ≥88% and respiratory rate
26–35 cycles per min
Weaning procedure: decrease PEEP over 20–30 min to 5 cm of
water
PSV levels used during weaning procedure: 20, 15, 10, and 5 cm of
water
If weaning procedure fails at a PSV level of 20 cm of water, switch to
volume assist–control mode of ventilation
After at least 2 hr of successful PSV at a level of 5 cm of water,
disconnect patient from the ventilator
Weaning success: Spontaneous breathing without the aid of a
ventilator, for a period of at least 48 hours
Achieving goals
Procedure when oxygenation goal not achieved despite
adjustments to FiO2 and PEEP: use inhaled nitric oxide,
almitrine mesylate, prone positioning, or any combination
thereof
Procedure when Pplat is >32 cm of water for at least 10 min
(in the following order, as needed): increase sedation, reduce
tidal volume to 4 ml/kg, decrease PEEP by decrements of 2 cm
of water, open label cisatracurium
Procedure to correct hypercapnia when pH is <7.20 (in the
following order, as needed): connect Y-piece directly to
endotracheal tube, increase respiratory rate to a maximum of
35 cycles per min, and increase tidal volume to a maximum of
8 ml/kg
AP-HM
Assistance Publique–Hôpitaux de Marseille (meaning, public
hospitals of France) - A public health, involving 4 hospitals and
nearly 3,500 beds and a team of 17,000 people, including
1,800 physicians, the AP-HM is the first hospital in the PACA
region (Provence-Alpes-Côte-d'Azur)
Programme Hospitalier de Recherche Clinique Régional
(meaning, Hospital Clinical Research Program) - By the French
ministry of health
PACA & Marseillees
Marseille (in English traditionally spelled Marseilles) is the
second most populous city in France, after Paris
Located on the south east coast of France on the
Mediterranean Sea, it is France's largest commercial port
Marseille is the administrative capital of the Provence-AlpesCôte d'Azur region
90-day mortality in each treatment group
(According to corticosteroid use)
 Corticosteroids were used during the ICU stay in 189 patients
 No significant effect of cisatracurium use on the 90-day mortality in the
subgroup of patients given corticosteroids
Respiratory
variables
during the
first 7
study days
Plateau
pressure
and minute
ventilation
in patients
with a
pneumotho
rax during
the first 48
hours
following
inclusion
Secondary Pre-specified Outcomes
The beneficial effect of cisatracurium on the 90-day survival
rate was confined to the two thirds of patients presenting
with a PaO2:FiO2 ratio of less than 120. Among these
patients, the 90-day mortality was 30.8% in the cisatracurium
group and 44.6% in the control group (P = 0.04)
The Cox regression model yielded an adjusted hazard ratio for
weaning from mechanical ventilation by day 90, in the
cisatracurium group as compared with the placebo group, of
1.41 (95% CI, 1.08 to 1.83; P = 0.01).
Primary Outcome
The Cox regression model yielded a hazard ratio for death at
90 days in the cisatracurium group, as compared with the
placebo group, of 0.68 (95% confidence interval [CI], 0.48 to
0.98; P = 0.04), after adjustment for the baseline PaO2:FiO2,
SAPS II, and plateau pressure
The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8)
in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in
the placebo group (P = 0.08)
Probability of Survival through Day 90,
According to Study Group
Time to inclusion
The median time from the diagnosis of ARDS to study
inclusion was 16 hours (interquartile range, 6 to 29) in the
study population and did not differ significantly between the
cisatracurium group (median, 18 hours; interquartile range, 6
to 31) and the placebo group (median, 15 hours; interquartile
range, 7 to 27; P = 0.45).
The median time from initiation of mechanical ventilation to
study inclusion did not differ significantly between the
cisatracurium group (22 hours; interquartile range, 9 to 41)
and the placebo group (21 hours; interquartile range, 10 to
42; P = 0.91).
Ventilation protocol
Ventilator mode: volume assist–control
Initial tidal volume: 6–8 ml/kg of predicted body weight
Plateau pressure: ≤32 cm of water
Oxygenation goal: PaO2 of 55–80 mm Hg or SpO2 of 88–95%
Permitted combinations of FiO2 and PEEP, respectively (cm of
water): 0.3 and 5, 0.4 and 5, 0.4 and 8, 0.5 and 8, 0.5 and 10,
0.6 and 10, 0.7 and 10, 0.7 and 12, 0.7 and 14, 0.8 and 14, 0.9
and 14, 0.9 and 16, 0.9 and 18, 1.0 and 18, 1.0 and 20, 1.0 and
22, and 1.0 and 24
pH goal: 7.20–7.45
Case Vignette
C2 ICU
50 year old lady, high grade fever with nasal discharge, sore
throat and dry cough for 2 days
Rapidly progressive dyspnoea over 24 hours
ABG type 1 respiratory failure
CXR
Mechanical ventilation initiated
The association of neuromuscular weakness with prolonged
use of neuromuscular blocking agents has long been
recognized
 Prolonged neuromuscular blockade arising from persistent
drug effect, due to accumulation of drug/metabolites in
the setting of renal/hepatic dysfunction
 Critical illness neuropathy
Hypoxemia
VILI
Prolonged MV
Critical illness
neuropathy
What is the role of NM blockers in ARDS?
Is there any mortality benefit