contemporary use of paralytics in the critically ill pgr3 paralysis... · contemporary use of...

©2017 MFMER | slide-1

Contemporary Use of Paralytics in the Critically IllPatrick Wieruszewski, PharmDPGY1 Pharmacy ResidentPharmacy Grand RoundsJune 20, 2017


Objectives• Review the pharmacology of neuromuscular

blocking agents• Discuss applications of neuromuscular

blockade in the critically ill adult• Identify complications of paralytics and

considerations for their use


How comfortable are you with recommending paralytics?• Very comfortable• Somewhat comfortable• Uncomfortable• Get them as far away from me as possible


History of Paralysis• “The decision to treat a patient in the intensive

care unit with neuromuscular blocking agents is a difficult one that is guided more commonly by individual practitioner preference than by standards based on evidence-based medicine.”

Society of Critical Care Medicine, 2002

Murray et al. Crit Care Med 2002;30(1):142-56.


Warr et al. Ann Pharmacother 2011;45:1116-26.Greenberg et al. Crit Care med 2013;41:1332-44.

Ca2+

Ca2+

Ca2+

Ca2+ Ca2+ Ca2+ Ca2+

Ca2+ Ca2+

Ca2+

Na+

Na+

Na+ Na+

Na+

Na+

Na+

Na+

Acetylcholine

Depolarizing

Non-depolarizingNeuromuscular Junction



Ca2+

Ca2+

Ca2+

Ca2+ Ca2+ Ca2+ Ca2+

Ca2+ Ca2+

Ca2+

Na+

Na+

Na+ Na+

Na+

Na+

Na+

Na+

Acetylcholine

Depolarizing

Non-depolarizingDepolarizing Neuromuscular Blocker



Ca2+

Ca2+

Ca2+

Ca2+ Ca2+ Ca2+ Ca2+

Ca2+ Ca2+

Ca2+

Na+

Na+

Na+ Na+

Na+

Na+

Na+

Na+

Acetylcholine

Depolarizing

Non-depolarizingNon-depolarizing Neuromuscular Blocker


Pharmacokinetics/Pharmacodynamics

Succinylcholine Vecuronium Rocuronium Atracurium CisatracuriumMOA Depolarizing Non-depolarizing

Type -- Aminosteroidal Benzylisoquinolinium

DoseBolus*

Infusion†

1

--

0.08 - 0.1

0.8 - 1.7

0.6 - 1

8 - 12

0.4 - 0.5

5 - 20

0.1 - 0.2

1 - 3

Onset (s) 60 180 75 110 150

Duration (m) 10 33 33 43 45

Elimination Plasma cholinesterase

Hepatic, renal excretion

Hepatic, renal excretion

Hofmann elimination

Hofmann elimination

Other Effects

InitialfasciculationsHyperkalemia,Hyperthermia

Vagolytic(high doses)

Vagolytic(high doses)

Histamine release --


*mg/kg†mcg/kg/min


Intensive Care Unit Applications• Respiratory

• Acute respiratory distress syndrome• Status asthmaticus

• Compartmental syndromes• Increase intracranial pressure• Intraabdominal hypertension

• Procedural uses• Therapeutic hypothermia

• Miscellaneous uses


Acute Respiratory Distress Syndrome

↑Tidal volumesActive exhalation

Ventilator asynchrony

AtelectraumaBiotraumaVolutrauma

Lung Injury

ARDS Task Force. JAMA 2012;307:2526-33.Slutsky AS. N Engl J Med 2010;363:1176-80.PEEP = positive end expiratory pressure

• Berlin criteria• Within 1 week of insult• Bilateral pulmonary infiltrates• Non-cardiac related edema• PaO2/FiO2 ≤ 300 with PEEP ≥ 5 mmHg


Paralysis in ARDS

ARDS Task Force. JAMA 2012;307:2526-33.Slutsky AS. N Engl J Med 2010;363:1176-80.

Paralysis

↓spontaneous respiration

↓ work of breathing

↓ pulmonary blood flow

↑arterial oxygenation


ACURASYS• Design

• Multicenter, randomized, placebo-controlled, double blind• N = 340

• Intervention• Protective ventilation strategy PLUS

• Cisatracurium 15 mg bolus then 37.5 mg/hr infusion x 48 hrs• Placebo

• Population• Mechanical ventilation for moderate-severe ARDS

• PaO2/FiO2 < 150

Papazian et al. N Engl J Med 2010;363:1107-16.PEEP = positive end expiratory pressure


ACURASYS• 90-day mortality HR 0.68 (p = 0.04)

• ↓Barotrauma, ↑ventilator- and organ failure-free days

• No differences in ICU-acquired muscle weakness

00

Surv

ival

(pro

babi

lity)

Days

0.2

0.4

0.8

1.0

45 90

0.6

00

Surv

ival

(pro

babi

lity)

Days

0.2

0.4

45 90

0.8

1.0

0.6

p = 0.051

p = 0.74

PF < 120 PF ≥ 120

Paralysis

Placebo

Papazian et al. N Engl J Med 2010;363:1107-16.HR = hazard ratioPF = PaO2/FiO2


Limitations• Under powered• No difference in crude mortality• Lack of true blinding• Depth of paralysis not measured• Lack of long-term paresis follow up• Optimal dosing strategy unknown

Papazian et al. N Engl J Med 2010;363:1107-16.


ROSE• Assess the efficacy and safety of early neuromuscular

blockade in patients with moderate to severe acute respiratory distress syndrome

ACURASYS ROSEHypoxemia inclusion criterion

PF < 150 on PEEP ≥ 5 mmHg

PF < 150 on PEEP ≥ 8 mmHg, or SF

PEEP Lower HigherBlinding Yes NoSedation (control) Deep LightSample size 340 1,408

Long-term outcomes None 3, 6, 12-mo phone interviews

Huang et al. Ann Am Thorac Soc 14(1):124-33.PEEP = positive end expiratory pressurePF = PaO2/FiO2SF = SaO2/FiO2


Agent Selection in ARDS• Studies limited to cisatracurium

• Less laudanosine• Less histamine release, hypotension• High cost

• Retrospective cohort (N = 76)• NBMA within 72 h for moderate-severe ARDS• No differences in clinical outcomes• Atracurium significantly lower cost

• Per patient: $166 vs. $2,256

Moore et al. Respir Care 2017; Epub ahead of print.


Status Asthmaticus

Positive pressure mechanical ventilation

Hyperventilation↑Airway pressure

Barotrauma+/-

Hemodynamic collapse

deBacker et al. CHEST 2017;151:697-706.

ParalysisRelax

overworked muscles

↑ventilator synchrony

Tight control of RR, lung volumes

Improved minute

ventilation


Adnet et al. 2001

Adnet et al. Intensive Care Med 2001;27:1729-36.

• Retrospective cohort (n = 101)• Status asthmaticus requiring mechanical ventilation• NMBA + sedation vs. sedation alone

• Outcomes• ↑ ICU stay and MV time with NMBAs

05

1015202530354045

Multi-organ failure VAP Myopathy Mortality

% P

atie

nts

ParalysisNo paralysis

p = 0.007

p < 0.0001

p = 0.010

p = 0.844

NMBA = neuromuscular blocking agentMV = mechanical ventilationVAP = ventilator-associated pneumonia


Status Asthmaticus

• Case series (n = 3) + literature review (n = 15)• Steroidal NMBAs resulted in severe myopathyGriffin et al. 1992

• Retrospective cohort (n = 107)• Muscle weakness associated with ↑ duration of

paralysis and steroid use• No differences with non-steroidal NMBAs

Leatherman et al. 1996

• Retrospective cohort (n = 86)• ↑2.1-fold odds myopathy every day of paralysis• Dosage and type of NMBA no effect on

myopathy

Behbehani et al. 1999

NMBA = neuromuscular blocking agent

Griffin et al. CHEST 1992;102:510-4.Leatherman et al. Am J Respir Crit Care Med 1996;153:1686-90.Behbehani et al. CHEST 1999;115:1627-31.


Traumatic Brain Injury• Cerebral vasodilation• Cerebral edema• Traumatic masses

SuctioningTests/proceduresIatrogenic stimuli

CoughAgitationPosturing

↑Intracranial Pressure

Rangel-Castillo et al. Neurol Clin 2008;26:521-41.


Paralysis in ↑ ICP

Paralysis

↓shivering

↓cough reflex

↓energy expenditure

↑ventilation

↓positive end-

expiratory pressure

Prohibit neurologic

exam

Mask post-traumatic seizures

Prolong mechanical ventilation

Rangel-Castillo et al. Neurol Clin 2008;26:521-41.Greenberg et al. Crit Care Med 2013;41:1332-44.


Hsiang et al. 1994

Hsiang et al. Crit Care Med 1994;22:1471-6.GCS = Glasgow Coma Score*** = significant, no p-value reported

• Retrospective database review (n = 514)• Severe head injury (GCS ≤ 8)• Paralysis ≥ 12 hours vs. no paralysis

• Outcomes• ↑ ICU stay with NMBAs

05

1015202530354045

Dead Severe disability Vegetative state Pneumonia

% P

atie

nts

ParalysisNo paralysis

p < 0.001

***

p < 0.001

***


Increased Intracranial Pressure

• Prospective, open-label study (n = 8)• Traumatic head injury patients• Bolus doxacurium (0.05 mg/kg) followed by

continuous infusion (0.015 mg/kg)• No changes in blood pressure or ICP• Did not report adverse events or myopathies

Prielipp et al. 1997

• Randomized controlled trial (n = 14)• Neurosurgical patients• Bolus atracurium (0.75 mg/kg) or cisatracurium

(0.15 mg/kg)• Atracurium ↓ICP, CPP, CBF, and MAP• Cisatracurium no changes in ICP, CPP, or CBF

Schramm et al. 1998

Prielipp et al. Crit Care Med 1997;25:1236-41.Schramm et al. Anesth Analg 1998;86:123-7.

CPP = cerebral perfusion pressureCBF = cerebral blood flowMAP = mean arterial pressure


Abdominal Compartment Syndrome

Third spaced fluidsTense abdominal closures

Pain

↓abdominal wall compliance

↑Intra-abdominal Pressure

00

% O

rgan

Fun

ctio

n

IAP (mmHg)

20

40

80

100

20 40

60

3010

Normal IAH ACS

IAP = Intraabdominal pressureIAH = Intraabdominal hypertensionACS = Abdominal compartment syndrome

Luckianow et al. Crit Care Res Pract 2012;2012:908169.Roberts et al. Curr Opin Crit Care 2016;22:174-85.


Paralysis in ↑ IAP

Paralysis

↓abdominal muscle

tone

↑abdominal wall

compliance

Allow time for

intervention

Avoid surgery

Greenberg et al. Crit Care Med 2013;41:1332-44.


De Waele et al. 2003

0

5

10

15

20

25

30

0 2 4 6 8 10 12

IAP

(mm

Hg)

Time (hours)

Cisatracurium 10 mg bolus

De Waele et al. Intensive Care Med 2003;29:332.

• 81 y/o male, GI bleed, surgical management• 12 units packed reds, 4L+ crystalloid• IAP 26 mmHg, ↓ urine output

Cisatracurium 5 mcg/kg/min infusion


IAH/ACS

• Prospective cohort study (n = 10)• Cisatracurium 0.15 mg/kg IV bolus in sustained

IAP ≥ 12 mmHg, organ dysfunction• ↓IAP with NMBA at 15, 30 minutes, with

subsequent recovery, no differences in MAP, APP, CVP, HR

De laet et al. 2007

• Prospective observational study (n = 478)• Surgical/medical management algorithm of

IAH/ACS including NMBAs (unspecified)• ↑survival 50% to 72% (p = 0.015)

Cheatham et al. 2010

De laet et al. Intensive Care Med 2007;33:1811-4.Cheatham et al. Crit Care Med 2010;38:402-7.

MAP = mean arterial pressureAPP = abdominal perfusion pressureCVP = central venous pressureHR = heart rate


Therapeutic Hypothermia


Paralysis ↓shivering

↓peripheral O2

consumption↓time to goal temperature

Mask seizures

↓body temperature Shivering↑heat, metabolic rate

↑ICP↓brain tissue O2


Jurado et al. 2011

Jurado et al. Pharmacotherapy 2011;31:1250-6..TOF = train of fourROSC = return of spontaneous circulationOR = odds ratio

• Retrospective chart review (n = 123)• NMBA 2 hours after cooling or onset of shivering• Vecuronium 0.8 mcg/kg/min vs. 0.05 mg/kg q2h

• Continuous infusion• Quicker recovery from blockade• Quicker time to extubation

• Intermittent boluses• Quicker to goal TOF• Less total NMBA exposure


Post-Arrest Therapeutic Hypothermia

• Prospective observational study (n = 111)• NMBA (unspecified) within 24 hours of ROSC• Cooled to 35-56 oC• ↑survival with NMBA (OR 7.23, CI 1.6-33.4)

Salciccioli et al. 2013

• Retrospective cohort study (n = 144)• Cisatracurium 10 mg bolus then 10 mg/hr

continuous infusion• Cooled to 32 oC• NMBAs ↓ICU mortality, ↑pneumonia

Lascarrou et al. 2014

Salciccioli et al. Resuscitation 2013;84:1728-33.Lascarrou et al. Resuscitation 2014;85:157-62.

TOF = train of fourROSC = return of spontaneous circulationOR = odds ratio


Miscellaneous Uses• Intubation• Tetanus• Neuroleptic malignant syndrome• Serotonin syndrome• Organophoshate poisoning• Opioid-induced chest wall rigidity

Powles et al. Anesthesia 1985;40:879-81.Sangal et al. JAMA 1985;254:2795-6.Wang et al. Cleve Clin J Med 2016;83:810-7.Hulse et al. Am J Respir Crit Care Med 2014;190:1342-54.Coruh et al. CHEST 2013;143:1145-6.


Are Paralytics Worth It?

Annane D. Semin Respir Crit Care Med 2016;37:51-6.

• Optimization of mechanical ventilation• ↓ barotrauma• Transient ↓ IAP• ↓ shivering

• Acquired neuromuscular disorders• Mask neurologic status• Prolonged ICU stay• Potential for under-sedation• High risk medication• Cost


Concomitant Supportive Therapies

Paralysis

Artificial respiration

Analgesia

Sedation

VTE prophylaxis

Corneal lubrication

Secretion suctioning

Re-positioning,

bunny boots

Head of bed

elevation



Monitoring

Ulnar, facial, or posterior tibial nerve

Train-of-Four

Muscle twitch

• Is this necessary?• Titration to TOF• Titration to effect


Reversal• Acetylcholinesterase inhibitors

• ↑Acetylcholine at neuromuscular junction• ↓Residual neuromuscular blockade• Concomitant antimuscarinics• DO NOT give if near full neuromuscular recovery

• Sugammadex• Tight complex with steroidal NMBA• Reversal of rocuronium blockade in ~3 minutes• Not studied in the ICU population



Which agent has the quickest onset and duration of action?• Vecuronium• Succinylcholine• Atracurium• Rocuronium• Cisatracurium


All patients receiving paralytics should routinely be administered pharmacological therapy for reversal of neuromuscular blockade.• True• False


Conclusion• Neuromuscular blocking agents can provide

depolarizing or non-depolarizing paralysis• There are a wide variety potential applications

for neuromuscular blockade in the intensive care unit

• Intensive care unit providers should be vigilant with regards to providing appropriate supportive care while patients are paralyzed


Contemporary Use of Paralytics in the Critically IllPatrick Wieruszewski, PharmDPGY1 Pharmacy [email protected]

Pharmacy Grand RoundsJune 20, 2017


Acute Respiratory Distress Syndrome• Meta-analysis of 48h cisatracurium infusion

• 3 studies, n = 431

28-day

0.2 0.5 1 2 5

Mortality

Favors Paralysis Favors Control

ICUHospital

BarotraumaICU-acquired weakness

Risk ratio

Alhazzani et al. Critical Care 2013;17:R43.


Intubation• Cochrane review 2017

• 34 RCTs, n = 3565• NMBAs ↑ ease of tracheal intubation• NMBAs ↓ upper airway discomfort and injury

• Cochrane review 2015• 50 RCTS, n = 4151• Improved intubation conditions with

succinylcholine compared to rocuronium

Lundstrom et al. Cochrane Database Syst Rev 2017;5:CD009237.Tran et al. Cochrane Database Syst Rev 2015;10:CD002788.RCT = randomized controlled trial


Monitoring

Bispectral Index

I/O →←☼

BIS

44EMG

EEG

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