Munzur Morshed, Pharm D. candidate 2011Arnold & Marie Schwartz College of Pharmacy and Health Sciences

Kingsbrook Jewish Medical CenterCritical Care -Advance Pharmacy Practice

Neuromuscular Blockers in Early

Acute Respiratory Distress Syndrome

Objectives

Provide the background info of the journal Provide a brief overview of ARDS and its

management Discuss the overview of a previous clinical

trial Explain the methodology of the study Display the assessed endpoints and the

results of the study Discuss author’s strengths and weakness

of the study Provide my critique of the study Assess the appropriateness of use in

clinical practice

Overview of the Journal

New England Journal of Medicine

English language peer reviewed medical journal, published by the Massachusetts Medical Society

Founded in 1812- one of the oldest medical journal in the world

Publishes editorials, primary research article, review articles, and case reports

Acute Respiratory Distress Syndrome

Life threatening condition The lung is damaged to a point

where it can no longer function properly in exchange of airlow level of oxygen in the blood

Fluids starts to accumulate in the air sacs Makes the lung heavy and stiff

decreasing its ability to expand

Acute Respiratory Distress Syndrome

http://emedicine.medscape.com/article/165139-overview

EtiologyAny sort of swelling or injury to the

lung▪ Aspiration▪ Chemical Inhalation▪ Pneumonia▪ Septic Shock▪ Trauma

Symptoms

Shortness of breathLabored, rapid breathingHypotensionCold extremities

Tests and Procedures

Ausculating the chest with a stethoscope Abnormal lung sounds▪ Crackles-accumulation of fluid in the lungs  

In order to help diagnose ARDS, the following tests are usually done▪ CBC-no expected lab abnormalities▪ Sputum Cultures▪ Chest X-Ray▪ ECG or Swan-Ganz catheterization rule out

CHF▪ Arterial blood gas-PaO2/FiO2 ratio of ≤ 200

Progression

PROGNOSIS 1/3 of patient

expires Patients that do

recover usually have memory loss or other problems due to the brain damage

COMPLICATIONS

Lung damage Organ system

failure Ventilator-

associated pneumonia

Treatment Patient’s are

admitted into the ICU

Goal: Treat the underlying

cause ▪ ABX if infection ▪ reduce the inflammation ▪ remove the fluid out of

the lungs   Provide breathing

support Patients are

intubated and put on a ventilator Deliver high dose of oxygen

via CPAP

http://www.aic.cuhk.edu.hk/web8/Hi%20res/Intubation.jpg

Intubation Procedure

Neuromuscular Blocking Agents

Indication Adjunct to general anesthesia Facilitate intubation and procedures,

and mechanical ventilation Manage increased intracranial pressure Treat muscle spasms▪ Hypothermia after cardiac arrest

Decrease oxygen demand

Neuromuscular Blocking Agents

Pharmacology Inhibits the

cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in the blockage of neural transmission

Can be antagonized by Neostigmine (Prostigmin)▪ 0.5mg – 2 mg IV

PRN-slow IV push

http://www.ispub.com/ispub/ijos/volume_7_number_2_7/orthopaedic_surgery_implications_of_a_novel_encapsulation_process_that_improves_neuromuscular_blockade_and_reversal/nmb-fig3.jpg

Types of NMBA’spancuronium vecuronium rocuronium

- An aminosteroid- Duration of paralysis- 90-100 minutes- Recovery-120 to 180 minutes- Elimination - Renal-45-75% - Bile-10 to 15%- Renal failure- increase duration of the drug- Common ADR - elevated heart rate - muscle weakness - elevated BP 

-An aminosteroid- Duration of paralysis-35-45 minutes- Takes about 45-60 minutes to recover- Elimination -Renal- 50% -Bile-35-50% -Renal failure- Increased duration of the drug-The drug has active metabolites- Common ADR - muscle weakness - elevated heart rate - respiratory depression

- An aminosteroid- Duration of paralysis- 30 minutes- Recovery- 20-30 minutes- Elimination-Renal- 33% - Biliary Tract- 75% - The drug has no active metabolites- Renal failure- minimal effect on the duration of the drug. -Common ADR -Transient Hypotension -Muscle weakness 

Cisatracurium

Dosing Adults▪ 150-200 mcg/kg IV x 1

Pediatrics▪ 0.03mg/kg IV

Warnings/precautions May have profound

effects in patients with neuromuscular disease such as myasthenia gravis ▪ Use a dose no more

than 0.02mg/kg http://www.ismp.org/images/PACKAGING/NIMBEX.gif

Cisatracurium cont…

Pharmacokinetics 80% of drug is metabolized by the liver 95% excreted in the urine; 4% excreted

in the feces Elimination half life: 22-29 minutes Renal Failure- No dose adjustment

required

Cisatracurium cont...

Adverse Reactions (<1%) Bradycardia Hypotension Flushing Bronchospasm

Cisatracurium cont…Drug Interactions

Aminoglycosides▪ Combo may potentiate, prolong

neuromuscular blockade▪ avoid combo or monitor closely

Quinidine▪ Potentiate neuromuscular blockade by

synergistic effect ▪ use alternative or avoid quinidine 24h after

neuromuscular blocker use

Inhaled anesthetics ( enflurane, isoflurane, desflurane, sevoflurane)▪ Potentiate and prolong neuromuscular blockade

by providing an additive/synergistic effects

Patient Considerations

Kidney or Liver Disease- Cisatracurium Monitor Clinically- Train of four

Four electrical pulses are transmitted to the ulnar nerve▪ If four pulses- no blockade▪ Goal= 1-2 pulse

Comparative Study Grannier M, Roch A, Forel JM, et al. Effects

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

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

Design: Multicenter, Open label-prospective, controlled, and randomized trial

N=56 pt’s with ARDS Intervention: Conventional Therapy or

Conventional therapy PLUS cisatracurium

Comparative Study cont…

Primary endpoint Improvement in oxygenation within w/in 120

hours after randomization Result: Administering NMBA up to 48 hours

in patients with ARDS, improves oxygenation and a decrease trend toward mortality in the ICU compared to patients who did not receive NMBA’s

Limitation Was not designed or powered to evaluate

mortality. Further study on benefits and risk of NMBA’s in

ARDS patients receiving ventilation is required

Purpose To determine whether treatment with

cisatrocurium for a short period of time would improve clinical outcomes in the course of severe ARDS

Methods-Inclusion

Patients who received endotracheal mechanical ventilation for acute hypoxemic respiratory failure PLUS the presence of the following for up to 48 hours: PaO2:FiO2 less than 150 Bilateral pulmonary infiltrates that were

consistent with edema Absence of clinical evidence of left atrial

hypertension▪ Pulmonary-capillary wedge pressure of less

than 18 mmHg 

Methods-Exclusion Age < 18 years Lack of consent Continuous infusion of

NMBA’s at enrollment Known pregnancy Enrollment in another

trial within the previous 30 days

Increased intracranial pressure

Severe chronic respiratory disease requiring long-term oxygen therapy or mechanical ventilation at home

Actual body weight> 1 kg/cm of height

Severe chronic liver disease

Bone marrow transplantation or chemotherapy-induced neutropenia

Pneumothorax Expected duration of

mechanical ventilation of less than 48 hours

Decision to withhold life-sustaining treatment

Methods cont…

Study Design Multicenter, randomized, placebo-

controlled, double-blind clinical trial Monitored by an independent data and

safety monitoring board Consolidated Standards for the

Reporting of Trials (CONSORT) guidelines ▪ Performed randomization and blinding

regarding of the study group

Population

March 2006 – March 2008; 340 patients in 20 ICU’s in France

1326 patients were assessed for eligibility; and 986 patients met the exclusion criteria.

Written consent were obtained from patients or from the patients proxies

Population cont…

Study Endpoints Primary

Proportion of patients who died before hospital discharge and within 90 days after enrollment

Secondary 28-day mortality Numbers of days outside the ICU between day 1 and 28 and

between day 1 and 90 Numbers of ventilator-free days between day 1 and day 28

and between day 1 and day 90.▪ If the patient died before day 28 or before day 90, then

the number of ventilator free days were considered to be zero

Numbers of days without organ or system failure between day 1 and day 28

Rate of ICU-acquired paresis Medical Research Council (MRC) scores on day 28 to assess

the three muscle groups in each arm and leg, between 0 (paralysis) to 5 (normal strength)

The time of ICU discharge  

Study Procedure cisatracurium besylate vs. placebo via IV

infusion Patients were sedated and then given a

3mL(15mg) rapid intravenous infusion of cisatracurium or placebo were administered, followed by a 37.5 mg per hour for 48 hours

Patients were put on a ventilator that was set to deliver a tidal volume of 6-8 mL/Kg of O2

If the end-inspiratory plateau pressure > 32 cm of water for at least 10 minutes open-label, rapid, intravenous injection of 20 mg of cisatracurium

Study Procedure cont… If end-inspiratory plateau pressure decreased by

less than 2cm of water second injection of 20mg cisatracurium administered

If the end-inspiratory plateau pressure did not decrease or decreased by less than 2 cm of water, then no administration of cisatrocurium were given for the next 24 hours

Patients were monitored every day for up to 28 days for signs of non pulmonary organ failure: Circulatory failure= SBP of 90 mmHg or less,

need for vasopressor Coagulation failure= Platelet count of 80,000 or

less per cubic mL. Hepatic failure= Serum bilirubin of 2 mg/dL or

higher Renal Failure= SCr of 2 mg/dL or higher

Statistical AnalysisSample size were calculated based

on the authors previous study which used the same inclusion criteria and the ALIVE study

Estimated that a 340 patients would needed to be enrolled to detect a 15% absolute reduction in the 90 day mortality in the cisatracurium group compared to the placebo

P= 80% and a 2 sided alpha value of 0.05

Result-Primary Endpoint

90 day mortality in the cisatrocurium group Vs. placebo 31.6% (95% CI,

25.2 to 38.8) vs. 40.7% (95% CI, 33.5-48.4) (p= 0.08)

Result: Secondary Endpoint

Author’s Conclusions

Treating patients with NMBA’s for 48 hours early in the course of therapy with low-tidal-volume ventilation improves the adjusted 90 day survival rate increases the number of days off of the

ventilator Increases days spent outside the ICU decreases the occurrences of any sort of

barotraumas in the first 90 daysDid not improve the overall 90-day

mortality significantly

Author’s Strengths/Weakness

Strength’s Minimized bias by

undergoing randomization, complete follow up, and intent to treat analysis

The data can be generalized in other ICU’s due to performing the study in 20 different ICU’s

Limitations The results were obtained for

cisatrocurium only and not other NMBA’s

Did not asses the use of NMBA’s in the late course of ARDS

Absence of data on the conditions known to antagonize or potentiate neuromuscular blockade.

Felt the study was underpowered Post-hoc analysis ▪ Beneficial effects of NMBA’s

were confined to those patients who had the PaO2:FiO2 ratio below 120 ▪ about 2/3 of the patients in

the study group 

My Critique-Strength A very good study method, rigorous

blinding process to patients and investigators

Treatment groups were appropriately randomized and were very similar in characteristics at baseline

The primary and secondary endpoints that were chosen are in line with other similar clinical trials

The study brings forth a strong opposition to the idea set by many authorities that NMBA’s should be limited in their use in treating patients with ARDS mainly due to the concern of muscle weakness that can develop in long-term

My Critique-Weakness Result obtained from this study may be robust In order to make a strong argument of the beneficial

effect of the NMBA”s in reducing mortality, the result of the study must be reproduced The authors had conducted similar trials using the

same inclusion criteria but found that the mortality rate is much lower in the placebo group of this study compared to the other study

Unknown whether or not the observed benefit seen by cisatracurium is specific to cistracurium or shared within the drug class Further study is needed to be done, especially when

succinylcholine is more preferred to be used due to it’s quick onset of action and duration

The drug should have been compared to other agents in the class to see it’s benefit in pharmacotherapy in the ICU over the other NMBA’s  

Use in Clinical Practice Should be utilized in practice when

performing mechanical ventilation procedure or surgery

Provides beneficial effects in terms of mortality and complications from occurring from intubation

Very good pharmacologic profile compared to the other types of NMBA’s Cardiovascular stability Organ independent elimination Lack of metabolites with neuromuscular blocking

activity Reduced rhabdomyolysis

References Nimbex (Package Insert). Abbott Park, IL: Abbott

Laboratories; 2008 Lexi Comp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-

Comp, Inc.;2007;October 17,2010. Medline Plus, NIH. Acute Respitatory Distress Syndrome.

Available at http://www.nlm.nih.gov/medlineplus/ency/article/000103.htm. Accessed on 10/16/2010 

Food and Drug Administration, FDA-Drugs shortages. Available at http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm

Arnal JM., Constantin JM., Courant P., Forel JM., Gacouin A. Guerin C., , Jaber S., Lefrant JY., Loundou A., Morange S., Papazian L.,Penot-Ragon C., Perez D., Perrin G., Prat G., Roch A.Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. N England J Med 2010;363(12);1107-16

Gainnier M., Roch A., Forel JM., Thirion X., Arnal JM., Donati S., Papazian L.Effect of neuromuscular blocking agents on gas exhange in patients presenting with acute respiratory distress syndrome.Crit Care Med 2004;32(1);113-119.

Thank You!