P seudocholinesterase Deficiency

Pseudocholinesterase Deficiency

Etiology and considerations

Angela HeplerRN, BS Biology, SRNA

Allegheny Valley Hospital School of Anesthesia

Objectives

• 1. Review physiology, diagnosis, prevalence, and effects of pseudocholinesterase deficiency

• 2. Address the management implications and contraindications which result

• 3. Discuss alternative therapy choices

Case Study

• 64 year old male undergoing craniotomy listing Succinylcholine as an “allergy”

• The patient has a diagnosis of pseudocholinesterase deficiency, secondary to a muscle biopsy

• H&P reveals hypertension, CAD, and hyperlipidemia

Concerns

Craniotomies often involve:• Remifentanil, Propofol, and 0.5 MAC of volatile agent• Succinylcholine for induction, no long term paralytics• Antihypertensives on emergence, sometimes including

Esmolol

Succinylcholine is contraindicated, but can we still use Remifentanil and Esmolol?

A&P Review• The Motor Neuron Body resides within the Grey Matter of

the spinal chord

• Axon terminates within the target muscle Myofibrils• Endplate• Neuromuscular Synapse

• Propagation of the impulse:• Releases Acetylcholine (Ach) into the synaptic cleft• Engages Nicotinicm receptors on the distal neuron• Depolarizes and contracts the innervated muscle

Motor end plate

Tb

Motor neuron

Succinylcholine• First used in 1951

• Chemically similar to 2 Acetylcholine (Ach) molecules

• Depolarizing neuromuscular blockade

• A competitive antagonist of Ach

• Short term paralysis, limited by pseudocholinesterase metabolism

Acetylcholine and Succinylcholine

Acetylcholine Succinylcholine

Indications for Succinylcholine

• Rapid Sequence Induction (RSI)

• Electroshock Therapy (ECT)

• Motor evoked potential (MEP) monitoring

• Any situation where brief paralysis is desirable

Pseudocholinesterase

• Also known as: Acetylcholine Acyl Hydrolase Butyrylcholinesterase (BChE)

• Primary metabolic pathway for Succinylcholine

• Located on Chromosome 3

H

,

Pseudocholinesterase• Present in all tissues except RBCs

• Represents 0.01% of total body protein

• Results in Ester hydrolysis of:Succinylcholine, Mivacurium, Ester LA, Heroin, and Cocaine

• Unknown physiological use

Pseudocholinesterase• Normal levels range from 3,000- 6,600 IU/L

• Lab testing is available for direct quantification

• Reportedly ≥ 80% of patients presenting with symptoms will have atypical pseudocholinesterase present

Pseudocholinesterase inhibitors

• Onset of symptoms usually occurs when 75% suppression of the wild type is present

• Can occur with as little as 50% depression, depending on comorbidities and coexisting conditions

Pseudocholinesterase inhibitors• Each can decrease the effectiveness of normal BChE:

• Advancing Age

• Renal failure

• Malnutrition

• Hepatic failure

• Pregnancy

HELLP -Induced Deficiency• Case study:

• Primigravida at 29 wk gestation, presented with abdominal pain

• Day 1-2: medically managed, tocolytics administered

• Day 3: Rapid elevation in LFT’s and deterioration, decision made C-Section

Departure from “the norm”…..

HELLP-Induced Deficiency• Case study (cont.):

• Plt count 125,000/µL- Spinal and Epidural deferred

• GETA, intraoperatively stable, no long term paralysis• End of surgery: No response to TOF stimulus

• ICU, extubated 3 hours post section• Pseudocholinesterase levels ~ 2,200 IU/L

• Spontaneous return to normal levels as LFT’s returned to baseline on POD 16

Other Cholinesterase inhibitors• Organophosphates- permanent

• Carbamates – temporary (our reversal agents)

• Various medications: some antidepressants, antibiotics, and chemotherapeutics echothiophate, LAs, cocaine and heroin

• Malignancies

• Burns

• Cardiopulmonary Bypass

Comorbidities with multifaceted deficiency

• Case Study:

• 54 year old female

• 5’4”, 156 kg

• OSA

• Recent prolonged exposure to pesticides

Presenting with Cellulitis of the Abdomen; for I&D

Comorbidities with multifaceted deficiency• Case Study:

• No TOF response post Succinylcholine

• Remained intubated x 12 hours

• Post op Pseudocholinesterase level: 552 IU/L

• 6 months post: ~ 700 IU/L: Undiagnosed homozygous deficiency

Atypical Pseudocholinesterase• Results from a mutation of the BCHE gene All atypical varieties are autosomal recessive:

• Heterozygous patients: minimal prolongation of paralysis• Homozygous: variable paralysis, from 1-4 hours or more

• More prevalent among:• Inuit / Native Alaskans• Persian descendants/Jewish communities• Specific Hindu populations

N

d

N- normal genetic coding (wild type allele)d- heterozygous, atypical BCHE (carrier) - homozygous, atypical BCHE

N d

NN Nd

Nd

N N

NN NN

Nd Nddd

The Genetics Of It All

Pseudocholinesterase Variants

• Up to 98% of individuals are homozygous for normal pseudocholinesterase

• 4 major varieties, with 65 variants known

Pseudocholinesterase Deficiency types

1. K variant

• Minimal effects alone, but often present in conjunction with other variants

• Slight prolongation of apnea

• Most prevalent variant (1.5% population)

Pseudocholinesterase Deficiency types

2. Dibucaine resistant/ Atypical

• First subtype identified

• Paralysis can last up to 2 hours

• Affects 0.01-0.03%

Pseudocholinesterase Deficiency types• Dibucaine Number

• A qualitative test of enzyme activity

• Dibucaine (Nupercaine) attenuates normal enzyme action, but the atypical type is unaffected

• Normal: 80 (80% attenuation of BChE)

• Heterozygous: 40-60 (reduced attenuation)

• Homozygous: 20 or less (only slight attenuation noted)

Pseudocholinesterase Deficiency types (cont.)

• 3. Silent variant

oHomozygous results in complete lack of pseudocholinesterase

oAll metabolism by alternative methods

oRelatively rare (0.008-0.01%)

oParalysis can last 3-4 hours

Pseudocholinesterase Deficiency types (cont.)

• 4. Fluoride resistant

• Very rare (0.0007%)

• Effects similar to Dibucaine resistant variant

• Fluoride number

• Quantitative test, similar to Dibucaine number test

• Normal Fluoride number: 55-65

Treatment…….

Treatment• Supportive measures for unanticipated prolonged paralysis

• Known Congenital deficiency:• Avoid Succinylcholine with known congenital deficiency • Avoid Tetracaine, Chloroprocaine, and Procaine (OB patients)

• Consider NDMR in patients with potential for attenuated pseudocholinesterase activity

• ALWAYS assess for return of muscle function (TOF) prior to NDMR following Succinylcholine administration

Alternative Therapies• RSI and ECT- Consider low dose Rocuronium,

Vecuronium or Cisatracurium

• MEP testing- consider Remifentanil for depressed respiratory effort (cough) and/or higher volatile agent concentrations

• Plant-derived recombinant pseudocholinesterase?

What about our Case Study?

What about our Case Study?

• Remifentanil- metabolized by nonspecific plasma esterases

• Esmolol- metabolized by RBC esterases

Both are unaffected by BChE deficiency

What about our Case Study?• Our plan of care:

• Intubated with minimal Rocuronium dosage, with spontaneous recovery during positioning

• Baseline MEP’s then obtained

• Remifentanil, Propofol, and 0.5 MAC

• Nitroglycerin, Hydralazine, and Labetalol used on emergence

• Patient awake within 5-7 minutes of Remifentanil termination, fully responsive with no respiratory depression

Summary• Pseudocholinesterase (BChE) deficiency can be:

• 1. Drug, environment, or comorbidity induced (affecting quality)• 2. Congenital (affecting quantity of true BChE)

• Heterozygous carriers -slightly prolonged paralysis

• Homozygous silent type -most prolonged paralysis

• Alternative therapies include intermediate acting paralytics, volatile gases, and opioids

Questions?

References• Soliday, Conley, Henker. “Pseudocholinesterase deficiency: A Comprehensive

Review of Genetic, Acquired, and Drug Influences.” AANA Journal 2010: Vol. 78, No. 4, p313-320.

• http://stevegallik.org/sites/histologyolm.stevegallik.org/htm/HOLM_Chapter07_Page06.html

• Manullang, J., and T. D. Egan. "Remifentanil's effect is not prolonged in a patient with pseudocholinesterase deficiency." Anesthesia and analgesia 89.2 (1999): 529.

• Niazi, Ahtsham, Irene E. Leonard, and Breda O'Kelly. "Prolonged neuromuscular blockade as a result of malnutrition-induced pseudocholinesterase deficiency." Journal of clinical anesthesia 16.1 (2004): 40-42.

• Williams, Joseph, et al. "Pseudocholinesterase deficiency and electroconvulsive therapy." The journal of ECT 23.3 (2007): 198-200.

• Lang, John B., Susan A. Kunsman, and Michael T. Hartman. "Acquired pseudocholinesterase deficiency." Current Anaesthesia & Critical Care 21.5 (2010): 297-298.

References• Lurati, A. R. "Organophosphate exposure with pseudocholinesterase

deficiency." Workplace health & safety 61.6 (2013): 243-245• Geyer, Brian C., et al. "Reversal of Succinylcholine Induced Apnea with an

Organophosphate Scavenging Recombinant Butyrylcholinesterase." Plos one 8.3 (2013): e59159.

• Bryson, E. O., et al. "Prolonged succinylcholine action during electroconvulsive therapy (ECT) after cytarabine, vincristine, and rituximab chemotherapy." The journal of ECT 27.1 (2011): e42.

• Sivak, Erica L., and Peter J. Davis. "Review of the efficacy and safety of remifentanil for the prevention and treatment of pain during and after procedures and surgery." Local and regional anesthesia 3 (2010): 35.

• Cerf, C., Mesguish, M. et al. “Screening patients with prolonged neuromuscular blockade after Succinylcholine and Mivacurium.” Anesthesia & Analgesia 2002; 94:461-66.

• Lurie, Samuel, Sadan, Oscar, et al. “Pseudocholinesterase deficiency asociated with HELLP syndrome”. American Journal of Perinatology, 2004; 21:315-17.