Psychotropic Drugs and the Perioperative Period: A Proposal
FRITS J. HUYSE, M.D., PH.D., DAAN J. TOUW, PHARM.D., PH.D.
ROB STRACK VAN SCHIJNDEL, M.D., JAAP J. DE LANGE, M.D., PH.D. Evidence-based guidelines for the perioperative management of psychotropic drugs are lacking. The level of evidence is low and is based on case reports, open trials, and non-systematic re-views. However, the interactions and effects mentioned indicate that patients who use psychotrop-ics and require surgery have an enhanced perioperative risk. A group of clinicians from severalclinical disciplines determined which risks should be considered in an integrated preoperativeassessment, as well as how psychotropics might interfere with these risks. The risks that shouldbe considered in the perioperative period are the extent of the surgery, the patient’s physicalstate, anesthesia, the direct and indirect (Phase I and II) effects of psychotropics, risk of with-drawal symptoms, and risk of psychiatric recurrence or relapse. Because of new drug develop-ments, the risk of interactions increases. The literature has not provided articles that systemati-cally address these risks. On the basis of a systematic analysis of the available literature guidedby the formulated perioperative risks, a proposal for the perioperative management of psycho-tropics was formulated. Patients who use lithium, monoamine oxidase inhibitors, tricyclics, andclozepine have serious drug–drug interactions, with increased physical risks, including with-drawal, and therefore qualify for American Society of Anesthesiologists (ASA) Classification 3. From the perspective of the physical risk, they require discontinuation. However, from the per-spective of the risk of withdrawal and psychiatric relapse and recurrence, these patients deserveintensive, integrated anesthetic/psychiatric management. For patients on selective serotonin reup-take inhibitors (SSRIs) who are mentally and physical stable (ASA Classification 2), the risk ofwithdrawal seems to justify their continuation. Yet, patients on SSRIs with higher physical or psy-chiatric risks should be seen in consultation. Both the physical and psychiatric risks of patientswho use antipsychotics and other antidepressants should be regarded as enhanced. From a physi-cal perspective, they qualify for ASA Classification 2. From the perspective of withdrawal andpsychiatric recurrence or relapse, they should be seen by (their) psychiatrists. Preoperative as-sessment clinics offer the opportunity to assess and evaluate these risks in order to deliver pa-tient-tailored integrated care. Authors propose a model for quality management.
Received December 23, 2003; revised April 16, 2004; January 5, 2005;accepted February 4, 2005. From the Dept. of General Internal Medicine,
In1988,acallwasmadeforamorepreventiveandstruc-
tured approach to the preoperative assessment and pre-
University Medical Center, Groningen, the Netherlands; the Depts. of
and postoperative medical evaluation of surgical patients.1
Intensive Care and Anesthesiology, University Medical Center, VrijeUniversiteit, Amsterdam; and Apotheek Haagse Ziekenhuizen, The
The clinical objective for preoperative assessment was a
Hague, The Netherlands. Send correspondence and reprint requests to Dr.
move toward evidence-based guidelines. This should lead
Huyse, Dept. of Internal Medicine, Hanzeplein 1, PO Box 30.001,
to reduction of morbidity and mortality and enhancement
9700RB Groningen, the Netherlands; e-mail: [email protected]
Copyright ᭧ 2006 The Academy of Psychosomatic Medicine
of quality of care. Also, it should result in a reduction of
Psychosomatics 47:1, January-February 2006
costs by avoiding unnecessary procedures. It has guided
of available information.5 Because the risks involved come
the development of pre-assessment clinics, where surgical
from intensivistic, anesthesiological, pharmacological, ge-
patients are procedurally evaluated before elective surgery.
riatric, and psychiatric perspectives, in this article, medical
This offers an opportunity to change from ad-hoc psychi-
specialists who represent these perspectives will combine
atric consultations in inpatients admitted for surgery, where
available evidence and clinical reasoning to formulate a pro-
the anesthesiologist or surgeon perceives a specific surgical
posal for perioperative psychotropic drug-management in
problem related to psychotropic drug use, to a more inte-
elective surgery. For the above-mentioned reasons, the evi-
grated approach in a pre-assessment clinic; this would
dence might be thin; however, the primary objective is to
include guidelines for psychotropic drug-management in
provide a framework for integrating clinical reasoning and
the perioperative period. Their focus should be on risk-
a model for integrated risk-management that can be part of
management to prevent perioperative mortality, physical
morbidity, withdrawal problems, and acute or long-termrelapse of psychiatric morbidity, thereby preventing last-
Such guidelines should include indications for inter-
Through clinical reasoning, the authors formulated a series
disciplinary consultations. The need for a systematic ap-
of risks to be considered in patients who use psychotropics
proach toward perioperative psychotropic drug-manage-
and apply for elective surgery. These risks are described
ment was first addressed in a study assessing the use of
under Decisions to Be Made, in the Results section. The
psychotropic drugs in a preoperative-assessment clinic
literature is reviewed to evaluate the empirical evidence
population. Three hundred surveys were distributed, with
available against these formulated risks. This is described
a response rate of 53%. Of those who responded, 43% used
under Available Evidence, also in the Results section. A
psychotropic drugs. Of these patients, 35% used antide-
MEDLINE search combining “anesthesia” or “preopera-
pressants; 34%, benzodiazepines; 19%, combinations of
tive care” or “perioperative care” and “mental disorders”
these and other psychotropics, such as antipsychotics, lith-
or “psychotropic drugs,” “antipsychotic agents,” “antide-
pressant agents,” or “serotonin reuptake inhibitors,”
A survey (response rate: 75%) among 150 United States
“monoamine oxidase inhibitors,” or “lithium” did reveal
anesthesiology programs, assessing the current practice of
that evidence on the level of metaanalysis, randomized
their perioperative handling of chronic medications, re-
clinical trials, or practice guidelines was not available, ex-
vealed a large inter-practice variation.3 The average rates for
cept for the guideline suggested by Drugs and Therapeu-
discontinuation of the most prevalent types of medication
tics Bulletin.4 The main evidence was on the level of non-
were the following: aspirin: 82%, ibuprofen: 77%, mono-
systematic reviews, open trials, and case reports assessing
amine-oxidase inhibitors (MAOIs): 51%, diuretics: 38%, tri-
selective aspects of the earlier-formulated physical and
cyclics: 9%, and oral contraceptives, 4%. In a recent series
psychiatric risks. As a result of clinical reasoning and avail-
of articles in Drugs and Therapeutics Bulletin, which is a
able evidence, we make a proposal for drug-management
U.K. independent review for doctors and pharmacists from
for psychotropics. The following drugs have been evalu-
the consumers’ association, it is stated that there are few
ated: lithium, MAOIs, tricyclic antidepressants (TCAs), se-
published data to formulate a guideline for chronic drug-
lective serotonin reuptake inhibitors (SSRIs), other anti-
management in the perioperative period.4 Therefore, they
depressants, classic antipsychotics, second-generation
conclude that physicians generally rely on their own expe-
antipsychotics, and clozapine. The risks of benzodiazepine
rience, which explains the large inter-practice variation.3
use for excess sedation or withdrawal related to perioper-
The best evidence for the development of clinical guidelines
ative use are not discussed because this is part of day-to-
is from randomized, controlled trials. Yet, the area of drug–
day anesthetic practice,6 nor are specific perioperative risks
drug interactions is not an area for such studies because the
discussed in patients with substance abuse.
number of combinations of drugs is too high, and studies
could easily become unethical. This is an area where thepatient is the “guinea pig,” and the clinician gains knowl-
edge by being a good observer of clinical evidence of theseinteractions. On the other hand, possible hazards may be
As seen in Table 1, there are two main risks to be dealt
assessed by clinical reasoning, combining different pieces
with in patients selected for elective surgery, who use psy-
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
chotropic drugs. The primary risk of psychotropic use to
of surgery is operationalized as follows: 1) moderate (e.g.,
be considered is excess morbidity and mortality through
appendectomy, mastectomy, TUR); 2) large (e.g., laparot-
physical interferences. The physical risks of surgery in-
omy, bowel-resection, cholecystectomy with choledocho-
clude the extent of the surgery, the specific disease/handi-
tomy, peripheral-vascular surgery, or major amputation);
cap that requires surgery, physical comorbidity, and type
and 3) very large (e.g., aorta surgery, abdomino-perineal
of anesthesia. Psychotropic drug use should be seen as a
resection, pancreatic- or liver resections, esophago-gas-
physical comorbidity with risks of interaction and physical
trectomy).7 In the Practice Advisory for Pre-anesthesia
withdrawal. Thereby, it leads to excess physical morbidity
Evaluation by the American Society of Anesthesiologists,
and mortality. The second risk concerns the impact of dis-
a comparable classification of surgical invasiveness is pro-
continuation of psychotropic drugs on the psychological
posed (low, moderate, or high) without further specifica-
functioning of patients with existing psychiatric morbidity.
tion.8 Another measure for the impact of surgery is the
This includes the risks of psychological withdrawal and
direct operative mortality. However, in elective surgery, the
direct operative mortality is very low and therefore is nota discriminative factor.
is the type and extent of surgery, its stress-inducing effects,
The risk of the patient’s physical status
and its related impact on the metabolism of, for instance,
for the outcome of surgery comprises two components:
cortisol, cathecholamines, and cytokines.7 A classification
1) the status related to the disease/handicap indicated for
for the level of stress-induction by the different surgical
surgery; and 2) the status related to the patient’s comorbid-
procedures has been proposed. Procedures associated with
ity. The impact of the disease/handicap is reflected in the
moderate-to-severe stress, such as open abdominal surgery,
direct operative mortality. The risk of the comorbidity is
increase heart rate and plasma levels of cortisol, as well as
classified in the generally accepted classification of the
epinephrine and norepinephrine. Other procedures, which
American Society of Anesthesiologists; the ASA classifi-
do not induce such changes, are considered as minimally
cation.9 Its main purpose is to differentiate among patients
stress-inducing.7 The level of stress-induction for the size
without comorbidity, those with light-to-moderate system
Risks to be Considered in Patients Receiving Psychotropics in the Perioperative Period Extent and Type of Surgery Local Infiltration for Excisions Versus Larger Surgery
Effects on pharmacokineticsStress-inductionOral or abdominal surgeryNeed for post-operative ventilation
Physical status, including substance use disorders ASA classification9
I. Healthy patientII. Mild systemic diseaseIII. Severe systemic disease with functional limitationsIV. Severe systemic disease, constant threat to lifeV. Moribund, unlikely to survive 24 hours
Anesthesia See Table 2
BeneficialPossibleOf noteHazardousResults in the need to discontinue
Oral, suppository, intramuscular, intravenous
Yes/No/IrrelevantMost evidence available with benzodiazepines and haloperidol
Psychiatric
Results in the need for psychiatric consultation
Risk of psychiatric relapse or recurrence
Results in the need for psychiatric consultation
Psychosomatics 47:1, January-February 2006
problems with no functional impairment, and those with
to cause severe disturbances. Interactions of note are those
more serious system problems, with functional restrictions.
where disturbances have been reported and where caution
Among the patients with physical comorbidity, there are
is necessary when the combinations are used; and 4) haz-
two specific groups who are of interest from the perspective
ardous interactions, when the drug combination should be
of psychotropic drug use: First, there are those patients who
avoided. These concern well-documented interactions
have, because of their physical morbidity, diminished func-
that have caused life-threatening incidents. The authors
tional capacity of organs that are crucial for the metabolism
reviewed the available literature along these criteria but
of drugs and their excretion; the kidney and the liver.10–12
did not specify the criteria of their literature search. Other
The same is true for frail elderly patients, because of re-
available ratings for the severity of drug–drug interac-
duced compensational capacity of several organ systems.13
tions, which broaden the scope beyond surgery, use com-
These are patients at risk for delirium. Such risks should
parable classifications.16 Overviews of relevant interac-
have been taken into account at prescription. The second
tions in comorbid patients seen in consultation–liaison
group comprises addicted patients. These patients might
practice have recently become available.17,18 Given that
underreport their physical state or might not report their
drug–drug interactions result from individual profiles of
addiction and, as a consequence, suffer withdrawal, in-
drugs, and as drug development is an ongoing process,
cluding delirium, and may have complex behavioral prob-
and new relevant complications of drugs or interactions
lems that interferes with medical care. In this group, effects
are reported on a daily basis, the risk of individual drug–
of anesthetics might be influenced by enzyme-induc-
drug interactions should be assessed through available
tion.12,14 Furthermore, these patients are at risk for organ-
The third factor influencing perioperative
Discontinuation: Preoperative Fasting and Route of Ad-
morbidity and mortality is related to anesthesia, itself, and
the increase in this risk due to the combination of anesthetic
routes of administration of drugs because of the anesthe-
drugs with other drugs, such as psychotropics. Modern an-
siological procedures. It influences the decisions concern-
esthesia is flexible. This flexibility offers an opportunity to
ing the (dis)continuation of drugs and the change to par-
reduce or avoid drug–drug interactions. Before the decision
enteral administration. Before surgery, the process of
on type of anesthesia, direct and indirect effects through
gastric-emptying is important for the timing of discontin-
drug–drug interactions should be considered. Therefore,
uation of oral drugs. According to current knowledge, pa-
we recommend a critical evaluation of use and duration, as
tients can use drugs with oral sips until 2 hours before the
well as monitoring of psychotropic drug prescriptions at
operation.4,19,20 This is also in line with more recent rec-
pre-assessment; we need to determine the possible inter-
ommendations of preoperative oral carbohydrate nutrition
actions with drugs for coexisting physical morbidity, as
to prevent postoperative insulin-resistance in elective sur-
well as drug–drug interactions with the proposed anesthet-
gery.21,22 Oral- and abdominal surgery might be an indi-
ics—effects such as hemodynamic instability, including
cation for an additional period of fasting. Oral surgery, such
cardiac conduction changes, and the effects on CNS func-
as in ear-nose-and-throat surgery, might be followed by the
tioning in case of postoperative metabolic instability. A
introduction of gastric tubes, which facilitates the appli-
severity grading for drug–drug interactions pertinent to the
cation of nonparenteral drugs. Also, knowledge of intra-
anesthesiologist was presented in a recent overview.13 It
venous and intramuscular replacement drugs is needed.23
proposes the following classification: 1) beneficial inter-actions, where the combination is used to produce a usefuland advantageous result for the patient; 2) possible inter-Withdrawal and Psychiatric Recurrence or Relapseactions, where an interaction can be expected on a theo-
risk of discontinuation of psychotropics for the induction
retical basis or because of pharmacological profiles of the
of withdrawal syndromes, psychiatric recurrence, or re-
drugs. Such interactions are known to cause minor-to-
lapse should be assessed. The first risk of discontinuation
moderate changes in physiological functioning, and clini-
is the immediate effect of discontinuation in terms of physi-
cians should be aware that an interaction of any severity is
cal and psychological withdrawal. The second risk of dis-
possible should these drugs be used again; 3) interactions
continuation is the risk of recurrence or relapse and its time
of note, where the drug combination can have the potential
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
succinylcholine, are worthy of note.15 The last affect both
the latency and the reversal of neuromuscular blockade.40
A summary of the drug management characteristics for sur-
Withdrawal and Psychiatric Recurrence or Relapse
gery patients is presented in Table 2.
available clinical evidence suggests that there is no with-drawal effect after abrupt discontinuation of lithium.41,42
Abrupt discontinuation of lithium in a patient with bipolardisorder increases the risk of recurrence of the illness, es-pecially mania, within the next few months. (No direct ef-
Pharmacodynamic and Pharmacokinetic Aspects
fects have been found.) This increased risk exceeds the risk
ium gives relief of bipolar disorder by an unknown mech-
of recurrence in the natural course of the illness.43–45
anism. Lithium is only available as tablets. After oral ad-ministration, lithium is well absorbed and distributed over
IV-IM Change and Alternative Drugs
total body water. Lithium is eliminated exclusively by renal
practice, there are no intramuscular (IM) or intravenous
excretion, with a half-life of 20–27 hours after a single
(IV) preparations of lithium available. Antipsychotics used
dose. This might increase to 36 hours in case of chronic
in the acute phase of manic episodes are an option, specif-
use. Lithium is glomerular-filtrated, and 80% is reabsorbed
ically, haloperidol, as there is extensive experience with
in the proximal tubulus. The reabsorption is related to so-
this drug in physically ill patients.46 (See “First-Generation
Antipsychotics” for listing of effects on cardiac conduc-tion, such as QTc47,48 [www.qtdrugs.org]).
Lithium has a narrow therapeutic window.
Toxicity is expressed by gastrointestinal symptoms, ECG
The greater the extent of the surgery and
changes, and CNS symptoms.24 Lithium is well tolerated
the higher the ASA classification, the higher the risk for
by the cardiovascular system. Its use is not absolutely con-
complications due to dysequilibrium of electrolytes
traindicated in patients with coexisting cardiovascular dis-
through gastrointestinal, cardiovascular, and renal dysre-
ease;25 however, cases of changes of the smoothing of the
gulations, and, therefore, the risk of further dysregulation,
T-wave,26,27 ventricular arrhythmia,28,29 and myocardi-
resulting in neurological complications.
tis29,30 have been reported. Sinus dysfunction can lead toextreme atropine-resistant sinus bradycardia, which might
Irreversible and Reversible Monoamine Oxidase
happen with normal as well as toxic blood levels,31–36 and
might only become manifest during anesthesia.37 Toxicityis related to plasma levels of more than 1.5 mmol/liter, but
Pharmacodynamic and Pharmacokinetic Aspects
might occur at lower levels. When the plasma sodium con-
reversible MAOIs tranylcypromine and phenelzine and the
centration is low or when the patient is dehydrated, lithium
selective and reversible MAOI moclobemide act by inhi-
clearance falls, and blood lithium levels rise. Lithium-
bition of the metabolic breakdown of norepinephrine and
related polydipsia, specifically when not compensated, and
serotonin by the MAO enzyme. Thereby, they increase the
a complicated postoperative course are serious additional
level of norepinephrine and serotonin at the receptor site.
Tranylcypromine and phenelzine irreversibly inhibit MAO,and, after cessation, it takes 1–4 weeks for the enzyme to
The interaction with NSAIDs (nonsteroidal
regain its activity. Moclobemide is a reversible inhibitor,
anti-inflammatory drugs) is reported as hazardous.15,38 The
with an elimination half-life of 1–3 hours. All MAOIs are
toxicity of lithium can be increased by drugs that reduce
lithium excretion or increase reabsorption in the kidney;these are drugs such as NSAIDs, ACE-inhibitors, thiazide
There are no direct effects relevant for sur-
diuretics, and metronidazole.24,39 The effect of the loop di-
uretics on lithium excretion is far less than the effect of thethiazides. Furthermore, lithium clearance can be increased
Hazardous interactions in both reversible
by CO2-anhydrase inhibitors. The interactions with neu-
and irreversible MAOIs and anesthesia have been re-
romuscular-blocking agents, specifically pancuronium and
ported.15 They include opioid analgesics (specifically peth-
Psychosomatics 47:1, January-February 2006
Clozapine Antipsychotics First-Generation Tricyclics Elective Patients Management Psychotropic Proposal A
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
idine), nefopam (a non-opioid analgesic), and sympathi-
been case reports of acute exacerbations.64,65 From the sur-
comimetics. These interactions are twofold—effects on the
gical perspective, a period of discontinuation of 2 weeks
blood pressure and on the CNS. Serious, including lethal,
of the irreversible blockade of MAO is needed for its res-
pressor effects have been reported because of interactions
toration. It is suggested that patients on irreversible MAOIs
with indirectly-acting sympathicomimetic agents (amphet-
could change some weeks before the surgery to reversible
amine, ephedrine, metaraminol). These release intracellular
MAOIs, to reduce the period of discontinuation.66 Because
stores of norepinephrine, and produce epinephrine-related
the effects of moclobemide discontinuation are reversed
hypertensive crises.49,50 Directly-acting sympathicomi-
within 16 hours, and no (or only rare) withdrawal has been
metic agents (norepinephrine, epinephrine, isoprenaline)
described, the period of discontinuation starts on the day
are regarded as safer. However, in animal studies, a three-
fold potentiation of the pressor effect of epinephrine bymoclobemide has been reported.51 Epidural or intrathecal
IV-IM Change and Alternative Drugs
anesthesia results in a blockade of the sympathetic system.
ing, there is no IV replacement available.
Consequently, on theoretical grounds, a combination ofMAOI and such type of anesthesia is contraindicated. The
few case reports in the literature are contradictory, how-
pressure and its need for adjustment, the higher the chance
ever.52,53 The reaction on the CNS has two mechanisms:54
of interactions between MAOIs and (indirect-acting) sym-
a Type I reaction is an excitatory form that is attributable
pathicomimetics. The higher the chance of cardiovascular
to a central serotonergic overactivity; the serotonergic syn-
instability, the higher the chance of interactions.15,67
drome.55,56 Pethidine, pentazocine, and dextromethorphanblock presynaptic reuptake of serotonin. Therefore these
drugs potentiate the development of a serotonin syndrome. In such patients, “MAOI-safe” surgery, which excludes
Pharmacodynamic and Pharmacokinetic Aspects
pethidine (meperidine) and dextromethorphan and includes
clic antidepressants act by presynaptic inhibition of the up-
the use of morphine and fentanyl, is recommended.57–59
take of norepinephrine and serotonin. They also block post-
The Type II reaction is a depressive form, and is supposed
synaptic cholinergic, histaminergic, and alpha1-adrenergic
to be related to the inhibition of hepatic microsomal en-
receptors. Tricyclic antidepressants are well absorbed in
zymes, leading to the accumulation of free narcotics and,
the gastrointestinal tract, but there is a large first-pass effect
as a result, CNS depression. Irreversible MAOIs need to
in the liver. Elimination is metabolic by Cytochrome P450
be stopped for 2 weeks for the regeneration of MAO and
isoenzymes (Phase I metabolism), followed by conjugation
normal monoamine metabolism. Even in such patients, car-
of hydroxide metabolites (Phase II mechanism). In addition
diovascular collapse during anesthesia has been reported.60
to the variation between the individual drugs of this class,
With morphine, a Type II (depressive) reaction has been
there is also a large inter-individual variation; elimination
reported.54 Therefore, all reviews recommend discontinu-
half-life varies from 12 to 24 hours for extensive metabol-
ation of the drug. As far as concerns about the discontin-
uation of the reversible MAOIs, the literature is contradic-tory.51,61,62
All tricyclics lower the seizure threshold.
The effects on the cardiac conduction system, such as QTc,
Withdrawal and Psychiatric Recurrence or Relapse
and their relation to arrhythmias, have been amply de-
Treatment with irreversible MAOIs is a clear indicator of
scribed. The main effects are on rate, rhythm, and contrac-
psychiatric treatment of a disorder with a complicated
tility through four mechanisms: 1) anticholinergic action;
course. Abrupt discontinuation of classical MAOIs can re-
2) interference with reuptake of adrenergic amines; 3) direct
sult in severe withdrawal syndromes presenting as medical
myocardial depression; and 4) alterations in membrane per-
emergencies such as serious depression, suicidality, hallu-
meability.48,69 The anticholinergic properties might induce
cinations, and paranoid delusions. The withdrawal syn-
an a-dynamic ileus, glaucoma, and postoperative delirium.
dromes and, consequently, the prevention of an MAOIwithdrawal-precipitated syndrome is a high priority.63,64 It
Hazardous interactions of tricyclics have
is not absolutely clear whether these are pure withdrawal
been reported on blood pressure in combination with sym-
symptoms or they reflect recurrence or relapse; there have
pathicomimetics,15 and induction of seizures has been re-
Psychosomatics 47:1, January-February 2006
ported with enflurane.15,70 Reported interactions of note are
line, fluoxetine, and paroxetine. They act by presynaptic
longer-lasting effects of antimuscarinics.15 In patients us-
inhibition of serotonin reuptake. All drugs are orally well-
ing tricyclic and tetracyclic antidepressant agents, the cir-
absorbed and eliminated by hepatic metabolism. The elim-
culatory effects of adrenaline and noradrenaline are poten-
ination half-life of fluvoxamine is 17–23 hours and cital-
tiated, respectively, 2 and 9 times.71 The mechanism of
opram, 36 hours. Paroxetine has an elimination half-life of
action of the resulting hypertensive crisis is related to the
24 hours, sertraline of 26 hours, and fluoxetine of 2–3 days.
amine reuptake-blocking properties of the tricyclics.72 Car-
Sertraline and fluoxetine, however, are converted to active
diac effects of atropine in patients treated with tri- and
metabolites with an elimination half-life of 3–5 days and
tetracyclic antidepressant medication were assessed in a
7–9 days, respectively. The elimination half-life of fluox-
prospective, controlled design. There was no evidence that
etine and its active metabolite, norfluoxetine, are prolonged
these drugs rendered the heart more susceptible to the car-
diac effects of atropine.72 Recently, Malan et al.73 reportedsevere, refractory hypotension during anesthesia in a pa-
The direct effects of serotonergic reuptake
tient on chronic clomipramine therapy. Hypotensive crises
inhibitors (SSRIs) are related to serotonergic potentiation
can be avoided by using indirect-acting sympathetic pres-
and are therefore gastrointestinal symptoms, headache, an-
sor amines.67 The effects of norepinephrine might be re-
orexia, agitation, sleeplessness, and bleeding.55,56,59,77 Ex-
cept for the gastrointestinal effects (5% to 10%), the inci-dence of these phenomena is low. The increased risk of
Withdrawal and Psychiatric Recurrence or Relapse
gastrointestional bleeding is about three times that of pa-
large variation of withdrawal symptoms has been reported.
tients not using these drugs. The absolute risk is small and
The main group of symptoms is related to cholinergic with-
comparable to the risk in aspirin and NSAID use. This risk
drawal: gastrointestinal symptoms; symptoms of general
is increased when a combination of an SSRI and aspirin or
malaise; and sleep disturbances, including vivid dreams
an NSAID is used. In a recent cohort study in the Neth-
and (hypo)mania. Also, there might be movement disorder-
erlands, the increased risk appeared to be related to the
related symptoms, such as parkinsonism and akathisia and
degree of serotonin-reuptake inhibition, being most ele-
cardiac arrhythmia.64 These symptoms appear during the
vated in fluoxetine, sertraline, clomipramine, and paroxe-
first 2 days after discontinuation and last for about 2 weeks
tine use.78 Also, SSRIs are among the psychotropics those
smoothed by gradual discontinuation.64 In patients on
with the highest risk of the development of the syndrome
maintenance therapy for depressive disorder who discon-
of inappropriate secretion of ADH (SIADH), sustained re-
tinue their medication, the relapse rate is estimated to be 2
lease of ADH resulting in hyponatremia, serum hypo-
to 4 times higher in the year after discontinuation, com-
osmolality, and less than maximally-diluted urine. Al-
though its mechanism is unknown, and SIADH is relatedto pulmonary and neurological diseases, as well as drugs,
IV-IM Change and Alternative Drugs
SIADH should primarily be seen as a direct effect of
international variability in the availability of intravenous
tricyclics. An exception might be clomipramine and ami-triptyline.23
The interactions occur through the effects
of the SSRIs on the Cytochrome P450 system (Phase I).
Most important are inhibition of the metabolism through
higher chance of instability of circulatory volume and re-
competition and the related increased serotonergic activ-
lated blood pressure. In patients using these tricyclics, the
ity, which might result in a serotonergic syndrome. The
circulatory effects of adrenaline and noradrenaline are po-
most hazardous combinations are combinations of SSRIs
tentiated because of their amine reuptake-blocking prop-
or a combination of SSRIs with MAOIs or serotonergic
TCAs such as clomipramine. Although no hazardous in-teractions in anesthesia are mentioned, the combination
Selective Serotonergic Reuptake Inhibitors (SSRIs)
with pethidine, pentazocine, and tramadol can result in aserotonergic syndrome comparable with the combination
Pharmacodynamic and Pharmacokinetic Aspects
of MAOIs.15,56,58,59 In the anesthesia literature, avoidance
SSRIs at present comprise fluvoxamine, citalopram, sertra-
of these opioid analgesics is recommended.59 The literature
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
describes another mechanism for the development of a se-
tions). It mainly inhibits norepinephrine reuptake. No ex-
rotonin syndrome. The supposed mechanism is that com-
plicit complications are mentioned in the literature in com-
petition with other highly protein-bound drugs—in this
bination with surgery. Mianserine is an alpha2 antagonist
case, lidocaine, midazolam, and fentanyl—results in an in-
with alpha1-, serotonin-, and histamine-antagonistic prop-
creased free-drug fraction.81 Because of the inhibition of
erties. Mianserine is regarded as cardiac-safe.87 A special
one or more cytochrome P450 enzymes, a combination of
risk for mianserine is the higher incidence of neutropenia
enzyme-inhibiting psychotropic and type IC antiar-
in elderly patients.88 There is one case report in the Japa-
rhythmic drugs with a narrow therapeutic window should
nese literature of severe hypotension during anesthesia in
only be given after consulting with a clinical pharmacol-
a patient who used amantadine and mianserine.89 Mirta-
ogist experienced with drug–drug interactions. Because of
zapine is an alpha2-antagonist and also blocks serotonin
inhibition of the cytochrome P450 3A4 by a metabolite of
and histamine receptors. No explicit complications are
midazolam, combinations of SSRIs with midazolam
mentioned in the literature in relation to cardiac conduction
should be monitored with caution, specifically when com-
or surgery. Venlafaxine is a serotonin-norepinephrine reup-
bined with fluoxetine. The same is true for the combination
take inhibitor. At high doses, it also inhibits dopamine
with warfarin, because of interactions with the CYP2C iso-
reuptake, but its clinical relevance is unclear. Because of
enzymes. An interaction relevant for the postoperative pe-
its serotonergic characteristics, it might contribute, in com-
riod is the inhibition of the metabolism of tramadol by
binations with other serotonergic drugs, to a serotonergic
paroxetine, resulting in excess sedation and an impairment
syndrome.55,57 Venlafaxine has a low incidence of clini-
of the analgesic action.82 Because of genetic polymor-
cally significant increases in blood pressure.90 No signifi-
phism, clinical implications vary in patients. Specific at-
cant conduction abnormalities nor arrhythmias have been
tention should be paid to possible interactions with drugs
reported.90 However, no studies with venlafaxine have
been performed in cardiovascular-compromised patients.90Venlafaxine is, in-vitro, a weak inhibitor of CYP2D6, but
Withdrawal and Psychiatric Recurrence or Relapse
it has less propensity for important metabolic interac-
Withdrawal is a recognized clinical problem in SSRI
tions.91 Except for fentanyl-induced rigidity during emer-
use.83–86 It is recognized in the anesthesiological literature
gence from general anesthesia, until now, no serious com-
as a reason for the continuation of these drugs during sur-
plications during surgery have been reported.92
gery.66 The withdrawal symptoms are dizziness, lethargy,palpitations, gastrointestinal complaints, a flu-like syn-
drome, sensory phenomena, sleep disturbances, and psy-chic phenomena, such as anxiety, agitation, and tearfulness. Pharmacodynamic and Pharmacokinetic Aspects
There is a wide variety in the incidence of the withdrawal
psychotics block dopamine2, histamine, ␣1-adrenergic, and
phenomena. The symptoms seem to be the most intensive
cholinergic receptors. The antipsychotic effect is probably
in the SSRIs with a short half-life, specifically, paroxetine.
based on their antidopaminergic action. Pharmacokineticsare highly variable, with half-life ranging from 2 hours, for
IV-IM Change and Alternative Drugs
droperidol, to 2 weeks, for the intramuscularly-adminis-
of SSRIs are presently not readily available.
trated esterified depot preparations.
The main side effects of the first generation
drugs through the P450 mechanism, it is not so much the
of antipsychotics are extrapyramidal symptoms. A seldom,
extent of the surgery but the comorbidity that increases the
but serious, complication of antipsychotic drugs is sudden
risk of (avoidable) complications. Therefore, patients with
death related to a prolongation of the QTc interval and
a higher ASA classification potentially have an increased
torsades des pointes. The problem is most evident in the
phenothiazines, specifically thioridazine. These drugs arenowadays replaced by high-potency antipsychotics, inwhich sudden death is less a problem. Therefore, there is
a need for careful preoperative evaluation and periopera-
The risks of maprotiline can be compared with the
tive cardiac monitoring for electrocardiographic changes
tricyclics (see Tricyclic Antidepressant Agents: Interac-
in patients using antipsychotic agents.47,48,93
Psychosomatics 47:1, January-February 2006
No hazardous interactions are mentioned for
lated to other existing physical comorbidity, such as cardiac
phenothiazines.15 Hypotension is reported as a hazardous
pathology, influencing the conduction system, or infectious
interaction in combinations of haloperidol or droperidol
or cerebral pathology, which is a risk of the induction of a
with ketanserin, a serotonergic 5HT2 antagonist with weak
selective alpha1-receptor blocking properties. Seizures arereported with desflurane, a volatile anesthesia.15,94 Inter-
actions of note are reported for the phenothiazines with
The empirical evidence of possible interactions with
antimuscarines. Clinically-relevant interactions with other
anesthetics is almost lacking. However, it is evident that
classes of first-generation antipsychotics are not mentioned
the use of these drugs, which have an advantage in the
in most reviews. Potentiation of the effects of narcotic an-
treatment of patients with schizophrenia because of their
algesics is reported. Chlorpromazine and thioridazine,
lack of extrapyramidal effects, can result in medical com-
which can selectively block ␣-adrenergic receptors, might
plications, such as weight gain, diabetes, and an increase
lead to interactions with drugs with sympathicomimetic ac-
in lipids, as well as sudden death due to torsades de
tion, such as epinephrine, resulting in vasodilatation and
hypotension.67 With halogenated inhalation anesthetics,hypotension has been reported for several antipsychotic
agents. Excess central and peripheral anticholinergic ef-fects have been reported in elderly patients in combinations
The main clinical complications reported are agranu-
of chlorpromazine or thioridazine with atropine or scopol-
locytosis and hyperthermia. It affects cardiac conduction.99
During anesthesia, hypotension has been reported.100 Incase of discontinuation of clozapine, dystonias, dyskine-
Withdrawal and Psychiatric Recurrence or Relapse
sias, delirium, and rapid onset of psychosis have been re-
There are withdrawal symptoms comparable to the cholin-
ported, which require emergency psychiatric-specialist in-
ergic rebound effect described for the tricyclic antidepres-
sant agents. These symptoms appear 1 to 4 days after dis-continuation and abate over 7 to 14 days.64,95 There is an
argument that early relapse is related to dopaminergic hy-persensitivity of the brain due to pharmacological with-
The available empirical evidence is—except for the risk of
drawal, whereas the delayed relapse might reflect the nat-
withdrawal and relapse of psychiatric illness—on the level
ural course of the illness.96 In a metaanalysis including 66
of nonsystematic reviews and case reports. Despite the fact
articles and 4,365 patients with schizophrenia, it is reported
that a systematic review of this multidimensional topic
that patients who continue antipsychotics, in contrast to
would be preferred, we decided that it would be too com-
those who stop, the relapse rate is 16%, versus 53% for
plicated and would be based on a low level of evidence.
those who stopped over a mean period of 9.7 months. The
We came to the conclusion that it would not result in a
relapse rate is much higher in patients who stop suddenly.
level of empirical evidence superior to expert opinion.
In those who stop abruptly, within 10 weeks, 25% had
Consequently, the proposal is based on available literature,
symptoms, and, after 30 weeks, 50% had symptoms.95
expert opinions, and integrated thinking. Therefore, theproposal serves to support clinical reasoning. Specifically,
IV-IM Change and Alternative Agents
in cases with complex psychiatric illness, patient-oriented
best known intravenous preparation, especially in medi-
perioperative management needs to be prepared by the in-
cally ill persons, as it is the drug of choice in delirium
volved physical specialist, the anesthetist, the psychiatric
patients.48,97 Still, haloperidol carries the risk of torsades
consultant, and the outpatient psychiatrist. The literature
de pointes, arrhythmias, and neuroleptic malignant syn-
suggests that the risk of psychotropics in surgery is pri-
marily related to the type of psychiatric disorder, the psy-chotropic drug, physical comorbidity, and related drugs.
The extent of surgery seems less relevant. Therefore, in
influence the interactions between anesthesia and antipsy-
every patient who uses psychotropics and is in need of
chotics. Combinations of certain antipsychotics and anes-
surgery, psychotropic drug management should be consid-
thetics should be avoided. The main risks seem to be re-
ered. The perioperative risk related to psychotropics in-
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
creases in combination with physical illness. In terms of
once because no withdrawal symptoms occur. Patients’
ASA classification, patients who use psychotropics qualify
fluid intake should be thoroughly assessed to adjust peri-
at least for an ASA Classification 2: Physical complications
operative intravenous hydration in case of polydipsia as
from mild systemic disease contribute to postoperative
clinical manifestation of a partial diabetes insipidus. Also,
morbidity and mortality.9 We suggest following Dawson’s
thyroid hormones, sodium, potassium, and creatinine
classification for quantification of the seriousness of drug–
should be assessed. Taking a half-life of 24 to 36 hours
drug interactions as well as for the direct effects of the
into account, we propose that lithium be discontinued 72
drugs; these are then linked to the ASA classification sys-
hours before surgery. When postoperative, and the patient
tem.15 Possible interactions are suggested to be rated as
has normal ranges of potassium, sodium, and creatinine, is
ASA 2, whereas interactions of note and hazardous inter-
hemodynamically stable, and is able and allowed to drink,
actions should be rated as ASA 3. The issue of preoperative
lithium should be restarted, with control of blood levels,
fasting relevant to patients who can continue drugs, seems
within 1 week. This is most important because the psychi-
to offer more flexibility nowadays. Intravenous adminis-
atric risk of recurrence or relapse is hazardous. The same
tration of psychotropics only seems indicated in patients
drug regimen should be provided as in the preoperative
with unstable psychiatric disease, such as psychosis or bi-
period unless kidney function has declined (in case of a
caesarean section, the dosage needs adjustment because ofshifts in fluid distribution).103 Patients should always be
seen by a consulting psychiatrist. An integrated anesthetic/intensivistic/psychiatric management should be decided
The only reason not to stop lithium treatment is minor
The physical perioperative risk of patients who use
surgery, with local anesthesia, meaning infiltration anes-
psychotropics is such that, from a preventive perspective,
thesia, for an atherome cyst, but not using larger nerve- or
they require systematic evaluation integrated into preop-
erative assessment. Patients who use lithium, MAOIs, tri-cyclics, and clozapine have hazardous drug interactions,with serious physical risks, including withdrawal, which
cannot be avoided. Therefore, such patients qualify for
There are two hazardous risks of drug–drug interac-
ASA Classification 3. From the perspective on the man-
tions. The serotonergic risk (Phase I) can be prevented by
agement of the physical risk, they require drug discontin-
avoiding drugs that prevent presynaptic uptake of seroto-
uation. Because the risk of acute withdrawal is high and
nin, such as pethidine, pentazocine, and dextromethorphan.
there is a risk of psychiatric relapse or recurrence, these
The risk of hemodynamic instability is less controllable.
patients require intensive individualized integrated anes-
Therefore, we recommend that irreversible MAOIs be dis-
thetic/intensivistic/psychiatric management. In patients on
continued. When discontinued, they can be restarted when
SSRIs who are mentally and physical stable (ASA Clas-
the patient is hemodynamically stable, is able and allowed
sification 1), the risk of withdrawal seems to justify their
to drink, and is not on new, potentially interacting drugs.
continuation. Patients who use other psychotropics should
One strategy to discontinue irreversible MAOIs is to
be regarded as qualifying for ASA Classification 2 and
change, in the weeks before surgery, to a reversible MAOI.
require individualized evaluation of their perioperative
The reversible MAOI moclobemide only needs to be dis-
continued for 24 hours to restore the depleted neurotrans-mitters. It can be restarted as soon as the patient is hemo-
dynamic stable and is able and allowed to drink. However,
Lithium’s direct effects cause hazardous risks in sur-
patients have a serious risk of withdrawal, psychiatric re-
gery. This is specifically true when hemodynamic instabil-
lapse, or recurrence. These patients should always be seen
ities occur, and renal excretion becomes impeded through
by (their) psychiatrists. An integrated anesthetic/intensivis-
interference with sodium and potassium metabolism. The
tic/psychiatric strategy should be decided upon.
physical risk of intoxication, with its detrimental and fatal
The only reason not to stop MAOIs is minor surgery,
risks for the CNS, is unacceptable. Therefore, lithium dis-
with local anesthesia, meaning infiltration anesthesia for an
continuation is recommended. Lithium can be stopped at
atherome cyst, but no larger nerve- and central blockades.
Psychosomatics 47:1, January-February 2006
serine, mirtazapine, and venlafaxine is thin. No seriouscomplications are described in the literature. There is a risk
There are two hazardous drug interaction risks to be
of withdrawal symptoms, however. When the patient is
avoided: the direct effects on the cardiac system and the
mentally stable, there is no need for a psychiatric consul-
interactions with anesthetic drugs regulating the cardiovas-
tation. Specifically, in patients with more complex physical
cular system. However the literature is controversial.
comorbidity (ASA Classification 2) and with unstable psy-
Therefore, we suggest discontinuation of TCAs in all pa-
chiatric illness, they should be both seen by their psychi-
tients with ASA Classification of 2 and higher, even in
atrist and anesthesiologist. They should balance the risks
minor surgery with local anesthesia. Because abrupt dis-
and decide on individualized management.
continuation can cause serious withdrawal symptoms, thedrugs should be gradually discontinued over 2 weeks be-fore surgery. We recommend a preoperative ECG after dis-
continuation to have a baseline assessment before surgery.
The potentiation of sedation is an interaction of note
When, postoperatively, the patient is hemodynamically sta-
and a controllable phenomenon. The anesthesia literature
ble, is able and allowed to drink, and is not on new, poten-
is quite conclusive about the continuation of the drug in
tially interfering drugs, the medication should be restarted.
the perioperative period. As ECG abnormalities occur in
Specifically, in elderly patients, this start should be gradual
these patients, a preoperative ECG should be done and
because of possible orthostatic effects. When the patient is
evaluated for a prolonged QTc interval in patients with
mentally stable, there is no need for a psychiatric consul-
comorbid physical illness (ASA 2).43 Patients should be
tation. Specifically, patients with more complex physical
seen by their psychiatrist in the perioperative period.
comorbidity and unstable psychiatric illness should be seenby their psychiatrist.
There is not enough evidence for a specific proposal.
It is proposed that patients should be seen by their psychi-
The risks of drug interactions with SSRIs are impor-
atrist and an integrated anesthetic/psychiatric regimen
tant. They are related to serotonergic effects of pethidine,
pentazocine, and dextromethorphan, which prevent pre-synaptic uptake of serotonin and might induce a seroto-
nergic syndrome. The interactions can be avoided by se-rotonin-free anesthesia and analgesia. Interactions with
Clozapine has hazardous risks of drug interactions re-
existing physical illness and the related drug regimens
sulting in effects on circulation. This risk requires drug
should have been taken into account at initiation of therapy.
discontinuation. Discontinuation of clozapine can cause
Discontinuation can cause withdrawal symptoms, specifi-
hazardous withdrawal phenomena. Moreover, patients
cally in the short-acting SSRIs. Therefore, we propose that
treated with clozapine have a high risk of psychiatric re-
SSRI not be discontinued in order to prevent anesthetic
currence or relapse. Therefore, we recommend psychiatric
interactions. The exception to this rule should be when the
consultation well in advance of surgery to come to an in-
SSRI is used in combination with aspirin or an NSAID and
tegrated anesthetic/intensivistic/psychiatric management
when the SSRI is used in patients over 80 years of age. In
these patients, the balance of risks of withdrawal and bleed-ing should at least be discussed. As long as the patient is
preoperatively assessed and recorded as mentally stable,there is no need for a psychiatric consultation.
The intention of the proposal is to stimulate the develop-ment of a preventive, integrated risk assessment in psy-chiatrically vulnerable patients using psychotropic drugs
and who are in need of elective surgery. The presented
Compared with the other drugs—except for the pres-
model allows indicator-based integration in pre-assessment
sure-effects of maprotiline—the available evidence of the
clinics through use of the ASA classification system. In-
risks of perioperative complications of maprotiline, mian-
dications for perioperative psychotropic risk management,
Psychosomatics 47:1, January-February 2006
Handling of Psychotropics in Elective Surgery
including psychiatric referral, have been operationalized. We acknowledge W.A. Nolen for his critical review of
This could be combined with a more generic assessment
the manuscript and for related suggestions.
of integrated health risk and needs, such as is possible withthe INTERMED method.104,105 Such a model would allow
APPENDIX 1. Websites for Information on Drug–Drug
for the prediction of outcomes of surgery, practice audit,
Interactions
and research. Regarding the size of the problem, the vul-
http://www.drugdigest.org/dd/Interaction/ChooseDrugs/1,4109,00.
nerability of the patients and the often-lacking reimburse-
ment as part of health plans, this is an area that deserves a
http://medicine.iupui.edu/flockhart/http://www.dal.ca/ϳpharmwww/druginfo/drugprobleminteraction.
more proactive approach in order to enhance the quality of
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Understanding the Diabetes Medicine Maze Michael Ikeler, M.D. Internal Medicine & Pediatrics Background HbA1c is a test used to measure long-term blood sugar control in people with . Normal HbA1c levels are usually less than 6 percent in people without diabetes; people with diabetes usually have higher HbA1c results. Studies have shown that the higher the HbA1c, the greater the chanc
squall2sparql: a Translator from ControlledCampus de Beaulieu, 35042 Rennes cedex, FranceAbstract. This paper reports on the participation of the systemsquall2sparql in the QALD-3 question answering challenge for DBpe-dia. squall2sparql is a translator from SQUALL, a controlled naturallanguage for English, to SPARQL 1.1, a standard expressive query andupdate language for linked open data. It co