Abstract

Methylphenidate, a central stimulant, is used in the treatment of individuals who have  attention-deficit  hyperactivity  disorder  (ADHD).  ADHD  is  a  notorious  world-wide disorder with a prevalence rate of 8−12% in schoolchildren, which is charac-terized by hyperactivity, impulsivity, and inattention. Currently, there have been few  reports  in  the  anesthetic  literature  examining  ADHD  patients  who  have  had  long-term  use  of  methylphenidate,  especially  the  extended-release  formulation.  Here, we report a case of a 14-year-old boy with ADHD treated chronically with the long-acting  form  of  methylphenidate  (Concerta®),  and  who  was  scheduled  to  receive  orthopedic  surgery  under  general  anesthesia.  No  significant  problems  or  fluctuations  in  hemodynamics  were  encountered  during  anesthesia  induction,  maintenance,  and  emergence.  The  patient  made  an  uncomplicated  recovery  and  was discharged 3 days later without incident.

Keywords

attention deficit disorder with hyperactivity; anesthesia, general; methylphenidate;

1. Introduction

Attention-deficit hyperactivity disorder (ADHD) is a common heritable neurobehavioral disorder charac-terized by inattention, impulsivity, and hyperactiv-ity,  and  has  a  worldwide  prevalence  of  8−12%  in  schoolchildren.¹  Central  neurotransmitter  dysfunc-tion  or  imbalance  has  been  speculated  to  play  a  major  role  in  the  pathophysiology  of  this  disorder.  Methylphenidate, one of the most popular medica-tions, is prescribed for individuals who have ADHD. It is a central nervous system (CNS) stimulant and is generally  thought  to  act  as  a  norepinephrine  and dopamine  reuptake  inhibitor.  However,  there  is  a  scarcity  of  reviews  or  commentaries  in  the  an-esthesiology  literature  concerning  the  anesthetic  experience in handling ADHD patients taking meth-ylphenidate  chronically,  especially  the  extended-release  formulation.  The  potential  interaction  of  methylphenidate with general anesthetics and its influence  on  hemodynamics  are  clinically  impor-tant  and  are  of  interest  to  anesthesiologists  who  have a good chance of managing these patients. We report the case of a 14-year-old boy with ADHD man-aged by chronic use of long-acting methylphenidate (Concerta®; Ortho-McNeil-Janssen Pharmaceuticals Inc.,  Titusville,  NJ,  USA),  who  was  scheduled  to  receive surgery under general anesthesia.

2. Case Report

A 14-year-old boy with ADHD was scheduled to re-ceive orthopedic surgery for a displaced fracture of the right distal radius. Apart from having ADHD and orthopedic  problems,  he  appeared  to  be  in  good  health and had no previous anesthetic experience. However,  the  patient  had  been  taking  Concerta® at a dose of 36 mg once daily for 3 years until the morning of surgery. Complete blood count, electro-lyte profile, chest X-ray, and electrocardiogram ob-tained before the operation were normal. His body height was 156 cm and weight was 52 kg. Atropine (0.01  mg/kg,  intravenously)  was  given  as  premedi-cation. After a standard monitoring system and in-travenous access had been established, induction of anesthesia was carried out with propofol (100 mg) and  fentanyl  (150  μg).  Tracheal  intubation  with  a  7-mm  cuffed  endotracheal  tube  was  facilitated  after administration  of  0.15  mg/kg  cisatracurium.  Anesthesia was maintained with sevoflurane in 50% oxygen. The surgery lasted for about 90 minutes and was uneventful. At the end of anesthesia, spontane-ous  ventilation  was  promptly  reestablished.  After  reversal  of  residual  muscle  paralysis  with  2  mg  of  neostigmine and 1 mg of atropine, the endotracheal tube  was  removed  and  he  was  sent  to  the  pos-tanesthesia care unit in a stable condition. The pa-tient  maintained  hemodynamic  stability  and  did  not require any form of hemodynamic intervention during  induction,  maintenance,  and  extubation.  After surgery, morphine and tenoxicam were used for  pain  control.  The  patient  made  an  uncompli-cated  recovery  and  was  discharged  from  hospital  3 days later.

3. Discussion

ADHD  was  first  described  by  Still  in  1902  and  has  emerged as the most common behavioral disorder in children.²  ADHD  has  been  found  to  be  associated  with genetic defects, prematurity, perinatal hypoxic complications, maternal smoking during pregnancy, parental alcoholism, low birth weight, family con-flict, and low socioeconomic status. Although the pathophysiology  of  ADHD  is  not  well  understood  and there is no single explanation that is universally accepted, genetic and developmental factors have been strongly implicated in the etiology of this dis-ease. The management of ADHD involves a multimo-dal approach including medication, family education, counseling,  school  remediation,  and  behavioral interventions.  The  medications  used  in  the  treat-ment  of  ADHD  are  effective  in  alleviating  symp-toms  and  improving  overall  functioning,  and  can  be  broadly  divided  into  CNS  stimulants  and  non-stimulants. For 40 years, the stimulant drugs, meth-ylphenidate  and  amphetamine,  have  been  the  treatments of choice for ADHD and are thought to enhance neurotransmission of dopamine and nore-pinephrine.³  In  contrast,  the  CNS  non-stimulants  include tricyclic antidepressants, monoamine oxi-dase inhibitors, α2-adrenergic agonists, as well as atomoxetine, modafinil, and bupropion.

Methylphenidate, created in 1955 and used for more than 50 years, is structurally similar to cate-cholamines (Figure 1) and has been the medication most  commonly  prescribed  to  treat  ADHD  around  the  world.  The  proposed  mechanism  of  action  of  methylphenidate  is  by  binding  to  the  dopamine  transporter, which inhibits the reuptake of dopamine into presynaptic neurons, and subsequently increases extracellular   dopamine   in   the   corpus   striatum.   Methylphenidate  is  metabolized  primarily  by  de-esterification to ritalinic acid (α-phenyl-2-piperidine acetic acid), which has little to no pharmacologic ac-tivity and is mainly eliminated in the urine. The use of  methylphenidate  is  contraindicated  in  patients with marked anxiety, tension, agitation, thyrotoxi-cosis, tachyarrhythmias, severe angina pectoris, and glaucoma since the drug may aggravate their symp-toms. Common side effects include anorexia or ap-petite disorder, sleep disturbances, and body weight loss. Brand names of drugs that contain methylphe-nidate include Ritalin® (Novartis, Basel, Switzerland), Attenta®   (Alphapharm   Pty.   Ltd.,   Glebe,   NSW,   Australia),  Concerta®,  and  Metadate®  (UCB  Inc.,  Smyrna, GA, USA). Concerta® is a once-daily, long-acting formulation of methylphenidate and is indi-cated for the treatment of ADHD in children aged 6−12  years  and  in  adolescents.  Compared  with  short-acting formulations such as Ritalin®, Concerta® can  minimize  the  fluctuations  between  peak  and trough concentrations.

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The chemical structure of methylphenidate.

Patients with ADHD may need surgery for a vari-ety  of  reasons.  Anesthesia  concerns  mainly  focus  on  the  potential  interactions  of  the  anesthetics and ADHD drugs, which may lead to cardiovascular disturbances, alterations in minimum alveolar con-centration (MAC) of anesthetic, postoperative nau-sea and vomiting, and a reduced seizure threshold.⁴ However,  many  of  the  above  concerns  are  based  on theoretical concepts supported by a few studies and  case  reports  in  the  literature.  Preoperative  evaluation for patients with ADHD should include a 12-lead electrocardiogram, electrolyte profile and detailed history about medication and other coex-isting diseases, such as epilepsy.

ADHD patients with a history of long-term use of CNS  stimulants  may  have  a  blunted  ability  to  re-spond  to  intraoperative  hypotension  as  a  result  of  depletion  of  catecholamine  stores,  or  receptor  downregulation.⁵ Careful titration of the anesthetic agent  is  important  to  avoid  unexpected  hemody-namic changes during general anesthesia. In the work of  Wilens  et  al,⁶  methylphenidate  was  associated  with a minor but statistically significant increase in heart rate. Methylphenidate has also occasionally been  reported  to  induce  cardiac  arrhythmias.⁷⁻⁹ More  recently,  in  a  series  of  case  reports  of  eight  patients receiving CNS stimulant medications chron-ically, two of whom were prescribed methylpheni-date  for  ADHD  and  attention  deficit  disorder,  all  patients  maintained  hemodynamic  stability  and  had an uneventful course of general anesthesia.¹⁰ In addition, propofol and etomidate were success-fully used as induction agents in the two patients taking  methylphenidate.  In  the  work  of  Attalah  et  al,¹¹  methylphenidate  increased  the  incidence  of vomiting, talkativeness, and limb movements in patients  receiving  anesthesia  with  ketamine  for  transurethral urologic procedures.

Although  several  animal  studies  have  shown  that  dexamphetamine  can  alter  the  MAC  of  vola-tile  agents  and  some  clinicians  suggest  that  CNS  stimulants may increase the MAC of volatile anes-thetics, there are no studies investigating the MAC requirements  in  ADHD  children  treated  with  CNS  stimulants.^4,5 The bispectral index and electroen-cephalograms, if available, should be used to mon-itor the depth of anesthesia and the occurrence of seizures  in  these  patients.  A  case  report  by  Ririe  et al¹² showed that methylphenidate may have re-duced  the  sedative  effects  of  midazolam  and  re-sulted  in  severe  postoperative  nausea,  vomiting,  and dehydration because of a possible adverse in-teraction  with  ketamine.  Compared  with  mida-zolam, clonidine, a drug for the treatment of ADHD, may  be  a  better  choice  of  premedication  in  pa-tients with ADHD because it can blunt the hemody-namic  responses  to  various  perioperative  stimuli,  reduce  the  incidence  of  postoperative  vomiting  and shivering, and offer several benefits, such as an anesthetic-sparing effect.^13,14 Stella and Bailey¹⁵ reported a pediatric patient with ADHD who devel-oped agitation and hallucinations after premedica-tion with midazolam and was successfully managed with intranasal clonidine.

ADHD and other neurological conditions such as epilepsy  can  coexist.  The  prevalence  of  ADHD  in  children with epilepsy is three to five times greater than  in  the  general  population,¹⁶  and  the  treat-ment of children with combined symptoms of ADHD and epilepsy is problematic. Certain ADHD medica-tions,  including  methylphenidate,  are  commonly  believed  to  lower  the  seizure  threshold  with  the  potential to precipitate or exacerbate seizure dis-orders,  especially  when  they  are  given  in  a  high  dose  or  are  used  with  other  drugs  that  can  also  lower the seizure threshold. However, the evidence that   methylphenidate   does   not   lower   seizure   threshold  to  a  clinically  significant  degree  is  not  well  substantiated.¹⁷  Nevertheless,  methylpheni-date does not appear to increase the frequency or severity  of  seizures  in  children  who  are  also  re-ceiving appropriate anticonvulsant medications.^18,19 Thus the anticonvulsant medications should not be discontinued  before  surgery.  The  evidence  exam-ining  the  possibility  of  perioperative  seizure  pre-cipitation  or  aggravation  by  methylphenidate  is  very  limited.  However,  the  risk  should  not  be  completely   ignored   in   children   with   seizure   disorders or in those receiving drugs which may in-duce  seizures,  such  as  ketamine,  tramadol,  and  pethidine.

Up  to  now,  there  has  been  no  commentary  or  discourse in the literature about an unexpected re-sponse  or  reaction  to  regional  anesthesia  in  ADHD  patients. However, as with general anesthesia, peri-operative convulsions and cardiovascular instability are  major  concerns  in  clinical  practice.  Besides,  premedications  are  important  to  promote  better  cooperation  and  reduce  perioperative  anxiety  in  ADHD patients during regional anesthesia

In summary, we report our positive experience in the successful application of general anesthesia for surgery in a 14-year-old boy with ADHD under long-term  medication  with  Concerta®. Anesthesia was induced with propofol, atropine, fentanyl, and cisatracurium, and was maintained with sevoflurane in oxygen, and cisatracurium. Although no episode of seizure, arrhythmia or cardiovascular instability was noted throughout the entire anesthetic course, we would suggest that anticonvulsants, antiarrhyth-mic  agents  and  direct-acting  vasopressors  should  be readily available intraoperatively for any unpre-dictable sequelae, no matter whether the surgery is under general or regional anesthesia. Therefore, it may be unnecessary to discontinue ADHD medica-tions  before  an  operation  to  avoid  perioperative  complications.