BJA Education, 20(1): 10e17 (2020)
doi: 10.1016/j.bjae.2019.10.003
Matrix codes: 1A02,
2A06, 3I00
Serotonin syndrome in the perioperative period
A. Bartakke1, C. Corredor1,* and A. van Rensburg2,3
1
St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK, 2Toronto General Hospital, Toronto, ON,
Canada and 3University of Toronto, Toronto, ON, Canada
*Corresponding author: Carlos.corredorrosero@nhs.net
Learning objectives
By reading this article, you should be able to:

Explain the Sternbach and Hunter criteria for
diagnosing serotonin syndrome.

Describe the wide variety of signs and symptoms
of serotonin syndrome.

Distinguish the pathophysiology of serotonin
syndrome.

Summarise the principles of management of a
patient with serotonin syndrome.
The serotonin syndrome (SS) is a potentially life-threatening
drug interaction caused by excessive serotoninergic activity
in the CNS. It can arise from therapeutic drug use, drug in-
teractions, or intentional overdose of medications that affect
the serotonergic system. The clinical features of SS have been
described as a triad of changes in mental status, neuromus-
cular abnormalities, and autonomic hyperactivity.1 Clinical
Ashish Bartakke FRCA EDAIC is a senior clinical fellow in cardio-
thoracic anaesthesia and critical care who has special interests in
cardiothoracic anaesthesia, cardiopulmonary exercise testing, and
pain management.
Carlos Corredor FRCA FFICM is a consultant in cardiothoracic
anaesthesia and intensive care whose interests include anaesthesia
for major aortovascular surgery, mechanical circulatory support,
and perioperative echocardiography.
Adriaan van Rensburg FCA (SA) MMED (ANES) MD FRCPC is an
associate professor in anaesthesiology at the University of Toronto.
Dr van Rensburg has clinical and research interests in cardiovas-
cular and transplant anaesthesia and perioperative ultrasound. He is
the Chair for the annual meeting of the Canadian Anaesthesiologists’
Society.
Accepted: 14 October 2019
© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com
Advance Access Publication Date: 4 December 2019
Key points

Serotonin syndrome has been described as a triad
of changes in mental status, neuromuscular ab-
normalities, and autonomic hyperactivity.

It is difficult to diagnose serotonin syndrome in a
patient under general anaesthesia because the
signs and symptoms are similar to other periop-
erative conditions.

Concurrent use of antidepressants has been
strongly associated with the occurrence of sero-
tonin syndrome.

The Hunter criteria for predicting serotonin
toxicity are both more sensitive and more specific
than the Sternbach criteria.

Early diagnosis and aggressive supportive care
are the mainstays of management.
presentation is highly variable, and ranges from mild symp-
toms to a severe life-threatening condition.
The first human case reports of serotonin-related adverse
effects of psychotropic drugs were published in the 1950s. The
term serotonin syndrome was first used in the early 1980s to
describe the presence of hyperthermia and behavioural
changes in patients receiving medications that have seroto-
ninergic activity.2 Diagnosis during the perioperative period is
particularly challenging because many confounding factors
can obscure the clinical picture. In addition, other conditions,
such as malignant hyperthermia and neuroleptic malignant
syndrome, have similar features to SS, and are part of the
differential diagnosis of delirium and neuromuscular abnor-
malities during the perioperative period. Many agents with
potential serotoninergic activity are given during relatively
short periods of time in the perioperative period. This in-
creases the likelihood for drug interactions and their conse-
quences, such as the SS.
In this article, we review the epidemiology, diagnostic
challenges, and management of perioperative SS. In addition,
10

Paent on serotonergic agent + potenal perioperave trigger interacon
Yes
Spontaneous Clonus
No
Inducible OR ocular
clonus
No
Tremor AND
hyper-reflexia
Fig 1 Algorithm using the Hunter criteria for the diagnosis of SS in the perioperative period.
we summarise the characteristics of the cases of perioperative
SS that have been reported in the literature.
Epidemiology
Prescriptions for antidepressant drugs in England have
doubled in the past decade. This has been linked to the
increasing awareness of mental health illness, improvement
in diagnosis of mental health conditions, and a greater will-
ingness of patients to seek help.3 The annual report of the
American Association of Poison Control Centers lists antide-
pressants as the third most common cause of reported toxic
substance poisoning, accounting for 9% of the total exposures
in adults. Many of these reports are of selective serotonin re-
uptake inhibitors (SSRIs) and associated SS.4
Significant numbers of patients presenting for surgery are
taking SSRIs. A study using data from a large database of
530,416 patients undergoing major surgery found that 72,540
(13.7%) of patients received an SSRI during the perioperative
period.5 The variability in clinical presentation of SS makes
the true incidence of this condition difficult to ascertain, with
many cases probably going underdiagnosed.
Diagnosis
The diagnosis of SS is based on the presence of the triad of
change in mental status, neuromuscular irritation signs, and
autonomic hyperactivity in a patient with current or previous
exposure to a medication with serotoninergic activity. The
onset of SS typically occurs all of a sudden within 24e48 h of
exposure to the triggering agents, and usually resolves quickly
after the triggering agent is discontinued. However, the
‘washout’ period after discontinuation of psychotropic drugs
is highly variable because of wide variations in their elimi-
nation half-lives, which range from 15 h for paroxetine and
sertraline to 7 days with fluoxetine.6 Therefore, SS can occur
even when serotonergic drugs have been discontinued several
days before exposure to a trigger.
The perioperative period
Yes
Agitaon
Yes
OR Meets
+ Diaphoresis
OR
Yes
Hunter’s
Criteria for
serotonin
Hypertonia and syndrome
temperature >38ºC Yes
Yes
Sternbach described the most commonly encountered
signs and symptoms in 12 case reports, including 37 patients
suffering from SS.7 Mental status changes were the most
frequently reported symptoms, followed by restlessness,
myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and
diarrhoea in decreasing order of frequency. Based on these
clinical features, Sternbach suggested that the presence of
three or more of these clinical manifestations combined with
previous or new exposure to a serotoninergic agent was sug-
gestive of SS.7
The analysis of a large toxicology database (Hunter Area
Toxicology Service) containing data from 2222 patients after
an overdose of serotoninergic drugs was used to derive a
model that was predictive of serotonin toxicity based on
clinical features. This Hunter model contains seven clinical
features and decision rules that, when applied to the data-
base, were highly predictive of serotonin toxicity. The Hunter
criteria were found to be more sensitive (84% vs 75%) and more
specific (97% vs 96%) than Sternbach’s criteria.8 Application of
Sternbach’s criteria alone may rule out mild or subacute
presentations of SS. However, the Hunter criteria should be
used to improve diagnostic accuracy (Fig. 1).
Serotonin syndrome can present in a clinical spectrum
ranging from mild symptoms to severe life-threatening
toxicity. There are no laboratory or imaging tests specific to
SS, and it remains a diagnosis made on the bases of clinical
presentation. Laboratory abnormalities, such as metabolic
acidosis, increased liver enzymes, increased serum creati-
nine, and leucocytosis are frequent and likely reflect severity
of associated organ dysfunction. Increased serum creatinine
phosphokinase can occur in cases where rhabdomyolysis is
present. There is no correlation between serum serotonin
concentrations and the severity of SS.1
The reliance on clinical signs for the detection of SS makes
its diagnosis particularly challenging in the perioperative
period. The detection of all three elements of the diagnostic
triad can be obscured by common circumstances or condi-
tions encountered in the perioperative period. Observation of
abnormal movements, pupillary changes, and abnormal
BJA Education - Volume 20, Number 1, 2020 11
The perioperative period

Table 1 Differential diagnosis of SS in the perioperative period.

History Clinical

Malignant Family history adverse reactions associated with anaesthesia; exposure (i) Hyperthermia >41 C
hyperthermia to halogenated anaesthetics or depolarising NMBAs (ii) Rigidity
(iii) Hyporeflexia
(iv) No myoclonus
Anticholinergic History of exposure to an anticholinergic agent (e.g. neostigmine and (i) Miosis
syndrome pyridostigmine) (ii) Bradycardia
(iii) Bronchoconstriction
(iv) Salivation
(v) Diarrhoea
(vi) Cramps
Opioid toxicity Exposure to opioids (i) Miosis
(ii) Hypothermia
(iii) Respiratory depression
(iv) Hyporeflexia
Neuroleptic Associated with the use of an antipsychotic (neuroleptic agents) (i) Gradual onset
malignant (ii) Lead-pipe rigidity, fever, and
syndrome dysautonomia
(iii) No gastrointestinal symptoms
Perioperative Acute onset and fluctuating course; multifactorial origin (i) Inattention, disorganised thinking,
delirium and altered level of arousal
(ii) No neuromuscular activation signs
(e.g. tremor, clonus, or hyperreflexia)
Sedativeehypnotic History of chronic intake and abrupt cessation of sedativesehypnotics (i) Confusion and agitation
withdrawal (e.g. benzodiazepines, baclofen, ethanol, and barbiturates) (ii) Autonomic dysfunction may be
present
(iii) No inducible clonus

muscle tone can be very difficult in a patient who is anaes- Pathophysiology

thetised and receiving neuromuscular blocking agents
Hyperstimulation of postsynaptic serotonin receptors is the
(NMBAs), and who is covered by surgical drapes. Confusion
main mechanism postulated to be responsible for SS. There-
and agitation after surgery and anaesthesia are not uncom-
fore, an understanding for serotonin physiology is necessary
mon and have a number of causes. Alterations in body tem-
to explain the effects of excess serotonin in the body. Sero-
perature can be related to an underlying pathology or to the
tonin or 5-hydroxytryptamine (5-HT), first isolated by Rapport
inflammatory response that accompanies surgery.
in 1948, is a neurotransmitter produced by the hydroxylation
Perioperative manifestations of SS can overlap with other
and decarboxylation of the essential amino acid L-tryptophan.
conditions, such as malignant hyperthermia, neuroleptic
Serotonin is synthesised in the CNS in the brainstem raphe
malignant syndrome, anticholinergic syndrome and opioid
nuclei and concentrated in the serotonergic pathways in the
toxicity (Table 1). However, it is very important to remember
hypothalamus, thalamus, limbic system, cerebellum, spinal
that a combination of some of the aforementioned signs and
cord, and retina. Serotonin can also be found peripherally in
symptoms (e.g. hyperthermia, severe haemodynamic fluctu-
the enterochromaffin cells of the enteral nervous system,
ations, rhabdomyolysis, acute kidney injury, disseminated
platelets, and mast cells.9 The role of serotonin centrally is
intravascular coagulation, severe agitation and seizures)
regulation of mood, wakefulness, appetite, and sexual
could point towards life-threatening SS, and the clinician
behaviour. Serotonin is also involved in the pathways that
should be vigilant for these.
control emesis, core body temperature, and pain signals.9

Table 2 Mechanisms and pharmacological agents associated with perioperative SS. MAO,monoamineoxidase; MDMA,3,4methylenediox-
ymethamphetamine; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Serotonin synthesis L-tryptophan

Serotonin metabolism
Enhanced release
Reuptake inhibition
Direct serotonin agonist
MAO inhibitor antidepressants (phenelzine, moclobemide, and selegiline); drugs with MAO inhibition
activity (methylene blue, hydralazine, and linezolid)
MDMA (Ecstasy), cocaine, fenfluramine, phenylpiperidine opioids (fentanyl and meperidine),
oxycodone, and tramadol
SSRIs (paroxetine, sertraline, citalopram, and fluoxetine); SNRIs (venlafaxine and duloxetine); tricyclic
antidepressants (amitriptyline, imipramine, clomipramine, and desipramine); phenylpiperidine
opioids and tramadol; other antidepressants (trazodone); ondansetron and granisetron
Triptans (sumatriptan, rizatriptan, and zolmitriptan); ergot alkaloids

12 BJA Education - Volume 20, Number 1, 2020

BJA Education - Volume 20, Number 1, 2020

Fig 2 Tree map graph illustrating the frequency of reporting of signs and symptoms of perioperative SS in case reports.

The perioperative period

13
The perioperative period
Mild
(Shivering, sweang, mydriasis, tachycardia)
Disconnuaon of potenal trigger
Supporve care including maintaining adequate hydraon and oxygenaon, and monitoring
Cyproheptadine (12 mg stat then 2 mg 2 hourly; maximum 32 mg in 24 h).
Benzodiazepines (e.g. lorazepam 2 to 4 mg i.v. or diazepam 5–10 mg i.v.)
Fig 3 Suggested treatment algorithm for perioperative SS.
Enteral motility, secretions, and vasomotor tone are influ-
enced by serotoninergic activity with the gastrointestinal tract
being the largest producer of serotonin in the body. Serotonin
also plays an important role in platelet function and coagu-
lation homeostasis.
Serotonin is stored in presynaptic vesicles, and upon
release, its effects are mediated by 5-HT receptors. 5-HT re-
ceptors are a family of G-protein-coupled receptors, with the
exception of 5-HT3, a ligand-gated Naþ and Kþ channel, that
exert excitatory or inhibitory postsynaptic responses through
activation of intracellular second messenger cascade. There
are seven classes of 5-HT receptors (5HT1e7) with further
subdivisions in each class of receptor (e.g. 5-HT1a to 5-HT1f).
The classification was based upon their pharmacological and
molecular biology properties.10 Multiple receptors are
responsible for the clinical manifestations of SS. The 5-HT2a
receptors have been found to be of particular relevance in
animal models or serotonin toxicity. Animal studies have also
found high concentrations of noradrenaline (norepinephrine)
in the hypothalamus of rats with drug-induced serotonin
toxicity, suggesting that noradrenaline also plays an impor-
tant role in the clinical manifestations of SS.11
Multiple pharmacological agents have been associated
with SS. In essence, any drug that alters the synthesis, release,
metabolism, or reuptake of serotonin has the potential to
cause toxicity (Table 2). Selective serotonin reuptake in-
hibitors are also of subtypes of cytochrome P450 enzymes,
which can lead to the accumulation of pro-serotoninergic
drugs (e.g. tramadol, venlafaxine, oxycodone, risperidone,
and dextromethorphan). Therefore, the pro-serotoninergic
effect can be potentiated when combinations of these medi-
cations occur.
Individual variability and genetic differences may explain
why some patients develop SS with particular doses and
combinations of serotoninergic drugs, whereas others do not.
Knock-out mice with disruption in the serotonin transporter
(SERT) exhibit a marked susceptibility to developing SS when
14 BJA Education - Volume 20, Number 1, 2020
Severe
Moderate
(Agitaon, clonus, hyperreflexia, tachycardia, fever) (Coma, severe autonomic instability, hyperthermia
>40ºC, rigidity, seizures)
Oral or nasogastric if paent’s trachea was intubated
Dexmedetomidine (infusion of 0.7 to 1.4 µg kg –1 h–1 i.v.; no bolus dose)
Esmolol (500 mcg kg –1 bolus i.v. over 30 s then 50–300 µg kg –1 min–1) for
treatment of severe hypertension
Glyceryl trinitrate (GTN) (1–15 mg h –1 ) for treatment of severe
hypertension
Noradrenaline if hypotension requiring vasopressor (avoid
indirectly-acng agents e.g. dopamine)
Tracheal Intubaon, sedaon and neuromuscular
block (avoid suxamethonium)
exposed to serotoninergic agents.12 Polymorphism in cyto-
chrome isoforms CYP2D6 and CYP3A4 may also explain in-
dividual susceptibility to develop SS.13
Our literature search found that methylene blue and phe-
nylpiperidine opioid derivatives (e.g. fentanyl and meperidine)
were reported in numerous case reports as being associated
with the development of SS in the perioperative period.
Methylene blue is a phenothiazine derivative, which can be
administered for both therapeutic and diagnostic purposes.
Methylene blue has been used for the treatment of severe
vasodilatation and methaemoglobinaemia. It is also a medical
dye used to enhance the surgical visualisation of anatomical
structures, such as the parathyroid glands. Methylene blue is a
reversible inhibitor of both isoforms of the monoamine oxi-
dase (MAO) enzyme with high selectivity for MAO-A, which is
the isoform responsible for the metabolism of serotonin.
Doses as low as 1 mg kg1 are sufficient to produce inhibition
of the MAO-A, and have been reported to be associated with
severe serotonin toxicity.14
Severe serotonin toxicity occurring with overdose of SSRIs
or reversible MAO inhibitors, such as methylene blue, as sin-
gle agents has not been reported in the literature. Neverthe-
less, the additive effect of an increase in serotonin release and
a reduction in extracellular clearance that occurs with the co-
administration of SSRIs and reversible MAO inhibitors has
resulted in severe life-threatening toxicity.14 Multiple mech-
anisms have been postulated to explain the serotonergic ef-
fects of opioids and their relationship with SS. Mechanisms
include weak serotonin uptake inhibition and increased
release of serotonin through stimulation of the 5HT-1a re-
ceptor (e.g. fentanyl and meperidine) and increase of intra-
synaptic concentrations of serotonin (morphine, oxycodone,
and tramadol). Similar to methylene blue, opioids alone have
not been described in cases of SS, but in combination with
other serotonergic drugs, such as SSRIs.15
Ondansetron is a known trigger of SS, as it antagonises the
5HT3 receptor with a resulting increase in serotonin
 The perioperative period

availability at the 5HT1 and 5HT2 receptors, and needs to be dependency care environment (Level 2 or 3). Discontinuation
considered as a contributor, despite not being commonly of serotonergic agents; supportive treatment; and manage-
implicated in the development of SS by itself. ment of agitation, hyperthermia, and autonomic instability
are the mainstays of treatment for all presentations of SS.
Supportive care should aim to restore normal physiology in all
Characteristics of reported cases of cases. Aggressive hydration is particularly important in the
perioperative SS presence of rhabdomyolysis to avoid acute kidney injury.
Agitation and anxiety are usually managed with benzodi-
We conducted a review of case reports that recorded occur-
azepines. The use of different agents, including lorazepam,
rences of SS in the postoperative period to further character-
midazolam, and diazepam, have been described. In an animal
ise the clinical presentation of perioperative SS (see
model of SS, diazepam attenuated the development of hy-
Supplementary Table 1). The reports covered a period of time
perthermia.20 However, there is no clinical evidence that fa-
spanning from 1994 to 2018. We reviewed 29 case reports that
vours the administration of any particular benzodiazepine
included 31 patients reported to have suffered SS in the peri-
over the others.
operative period.
Autonomic instability can be severe, and can present with
The median age of patients was 58 with 61% (19 cases) of
rapid swings in arterial BP and HR. Hypotension should be
the cases reported in female and 39% (12 cases) in male pa-
treated with i.v. fluids, and in more severe cases, directly
tients. Agitation was the most commonly reported clinical
acting sympathomimetic amines (noradrenaline, adrenaline
presentation, followed by delayed awakening from anaes-
[epinephrine], or phenylephrine) may be required. Indirectly
thesia and confusion. Nystagmus, clonus, and myoclonic
acting catecholamines, such as dopamine and ephedrine,
jerks were the most commonly reported neuromuscular
should be avoided especially when agents that inhibit the
manifestations. Hyperthermia, tachycardia, and diaphoresis
activity of MAO are involved. In the presence of MAO inhibi-
were frequently reported as signs of autonomic instability.
tion, the effects of indirect amines can be unpredictable.1
The tree map in Figure 2 graphically displays the reported
Hypertension and tachycardia appear to be far more
symptoms and signs with reported frequency.
prevalent than hypotension in reported cases of perioperative
Cardiac surgery was the surgical specialty with the most
SS. Because of the unpredictable nature of changes in arterial
reported cases of SS, followed by orthopaedic and general
BP and HR in SS, only short-acting agents, such as esmolol and
surgery, each with the same number of cases. This could be
glyceryl trinitrate, are recommended for the treatment of
attributable to the high dose of fentanyl used during cardiac
hypertension and tachycardia. Hydralazine should be avoi-
surgery. Head and neck surgery followed in fourth place with
ded, as it has significant inhibitory effects on MAO and may
parathyroidectomy as the only procedure reported from this
exacerbate serotonin toxicity.21
group. We reviewed the preoperative medication with sero-
Hyperthermia in SS is mostly mediated by muscle hyper-
toninergic activity that patients were receiving, and also the
activity, which renders paracetamol ineffective as a treat-
likely triggers of SS reported by the authors of the case reports.
ment. Mild hyperthermia can be treated with topical cooling
The great majority of patients (65%) were reported as tak-
and benzodiazepine sedation to decrease muscle activity.
ing an SSRI before their procedure and the development of SS.
Severe uncontrolled hyperthermia (temperature >41.1 C) can
Other medications in order of frequency were atypical anti-
lead to severe complications, such as rhabdomyolysis, meta-
psychotics (7%); tricyclic antidepressants (7%); gamma-
bolic acidosis, and disseminated intravascular coagulation.
aminobutyric acid analogues (pregabalin) (5%); amphet-
Aggressive treatment with sedation, ventilation, and neuro-
amines (5%); and with smaller percentages for MAO in-
muscular block with non-depolarising agents is necessary to
hibitors, ergot alkaloids, sympathomimetic amines
reduce muscle activity and control body temperature. Depo-
(ephedrine), and tramadol.
larising NMBAs, such as suxamethonium, should be avoided,
The most common potential trigger of serotonin toxicity
as they can result in life-threatening hyperkalaemia brought
identified by the authors of the case reports was methylene
about by rhabdomyolysis and metabolic acidosis.
blue, accounting for 52% of reported triggers. Fentanyl was
Dantrolene, used for the management of malignant hy-
reported as a potential contributor in five cases, accounting
perthermia, has not been proved to be effective for the man-
for 15% of triggers. Other phenylpiperidine derivatives
agement of hyperthermia associated with SS in animal or
(meperidine, remifentanil, and dextromethorphan) were also
clinical studies.22
reported as potential triggers. Ondansetron, cyclobenzaprine,
The literature suggests that specific serotonin antago-
oxycodone, and lidocaine were also associated with cases of
nists should be given when supportive care and sedation fail
perioperative SS.
to control symptoms, and in severe presentations of SS.1
There was only one reported death among the case reports
Cyproheptadine is an H1 receptor antagonist that also has
reviewed.16 The great majority of cases reported full recovery
5-HT1A and 5HT2A receptor antagonist activity. Case reports
with no lasting sequelae, with only two reports disclosing that
have found cyproheptadine to be useful in providing
patients were discharged to a rehabilitation facility.17,18 One
symptomatic relief in cases of serotonin toxicity.23,24 Our
study reported a patient requiring prolonged ICU stay.19 It was
review of the literature also found multiple cases where
unclear whether the occurrence of SS was directly responsible
cyproheptadine was administered for the management of
for the need for a rehabilitation facility or prolonged ICU stay.
SS occurring during the perioperative period. The recom-
mended regimen is an initial dose of 12 mg with further 2
mg h1 doses until clinical improvement is observed.1 A
Management potential limitation for the use of cyproheptadine in the
The type and intensity of management depends on the clin- perioperative period is that it is only available in oral tablet
ical manifestations of SS. Patients manifesting more than form. However, the tablet can be crushed and administered
mild symptoms should be closely monitored in a high- via a nasogastric tube.

BJA Education - Volume 20, Number 1, 2020 15

The perioperative period

Antipsychotic agents with serotonin 5-HT2A receptor MCQs

blockade, such as chlorpromazine and olanzapine, have been
used as alternative therapies for SS, but there are little data
regarding their effectiveness and safety in the perioperative
period.
Dexmedetomidine is an a2-adrenergic receptor agonist
used for sedation in anaesthesia and intensive care. Several of
its pharmacological features make dexmedetomidine attrac-
tive for the treatment of SS. Alpha-2 receptor stimulation in
serotonergic neurones inhibits the release of serotonin, and
animal studies suggest that this mechanism explains the su-
periority of dexmedetomidine over midazolam for the treat-
ment of serotonin toxicity in animal models.25
Dexmedetomidine produces effective sedation and anx-
iolysis without significant respiratory depression. The
autonomic instability that characterises more severe forms
of SS is mediated by excess serotonergic and noradrenergic
activity. Dexmedetomidine decreases central sympathetic
output, and can effectively control hypertension and
tachycardia.
A recent case series described the effective use of dexme-
detomidine for the management of severe SS refractory to
conventional therapies. The use of dexmedetomidine was
associated with effective stabilisation of the autonomic sys-
tem with improvement in tachycardia, hyperthermia, and
myoclonus.26 Figure 3 contains an algorithm of suggested
treatment for perioperative SS.
Prevention
The increasing prevalence of patients receiving serotonergic
medication requires preoperative screening of patients at risk
of serious drug interactions during the perioperative period.
Discontinuation of serotonergic agents before surgery is not
always practical or free from risk. In the case of SSRIs,
serotoninenoradrenaline reuptake inhibitors, and MAO in-
hibitors, abrupt cessation can be associated with unpleasant
withdrawal symptoms and exacerbation of psychiatric con-
ditions.27 Therefore, the risks and benefits of continuing
psychotropic medications during the perioperative period
should be carefully considered. Perioperative SS is a relatively
rare condition; therefore, psychotropic agents should not be
routinely discontinued. Instead, prevention should focus on
avoidance of known triggers and early identification of signs
or symptoms of serotonin toxicity.
There must be a clear plan for managing patients at risk of
adverse drug interactions presenting for surgery, where
exposure to methylene blue is likely for diagnostic or thera-
peutic purposes. A discussion between the patient, surgeon,
anaesthetist, and primary care or psychiatry team should take
place. Planned cessation of psychotropic medication may be
considered. Alternatively, other medical dyes, such as indigo
carmine or indocyanine green, may be used instead.
The risk of end-organ damage from severe vasoplegia
should be weighed against the risk of SS when methylene blue
is administered for vasodilatory shock in patients receiving
serotonergic medications. Finally, the importance of raising
patients’ awareness and education about the risk of periop-
erative drug interactions cannot be overstated.
Declaration of interest
The authors declare that they have no conflicts of interest.
The associated MCQs (to support CME/CPD activity) will be
accessible at www.bjaed.org/cme/home by subscribers to BJA
Education.
Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bjae.2019.10.003.
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