Pseudocholinesterase Deficiency Etiology and considerations Angela Hepler RN, 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 neuron Motor end plate Tb 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 • Located on Chromosome 3 • Also known as: Acetylcholine Acyl Hydrolase Butyrylcholinesterase (BChE) • Primary metabolic pathway for Succinylcholine 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 The Genetics Of It All N d N N NN Nd N NN NN dd Nd d Nd Nd N- normal genetic coding (wild type allele) d- heterozygous, atypical BCHE (carrier) - homozygous, atypical BCHE 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 o Homozygous results in complete lack of pseudocholinesterase o All metabolism by alternative methods o Relatively rare (0.008-0.01%) o Paralysis 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_Page 06.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. 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