This document discusses serotonine syndrome, which is caused by increased serotonergic activity in the central nervous system. It defines serotonine syndrome and notes that the incidence is increasing due to more widespread use of serotonergic drugs. It describes the synthesis and receptors of serotonin. It lists drugs that can cause serotonine syndrome and discusses diagnostic criteria. Potential complications are outlined. Treatment involves discontinuing causative drugs, supportive care, sedation with benzodiazepines, and treating autonomic instability and hyperthermia.
2. Serotonin (5-hydroxytryptamine)
• Widely distributed amine (animals + plants)
In humans, present in :
• GI enterochromaffin cells (90%)
• Platelets (8 %)
• Brain (2%).
• Synthesized from tryptophan (in diet).
• Platelets do not synthesize but take up from blood
(active uptake process in platelets and nerve terminals).
• Cell storage in granules similar to catecholamines.
3. N
COOH COOH
C
N
C NH2
NH2
OH
Tryptophan 5-Hydroxytryptophan
OH H
N
C NH2
5-Hydroxytryptamine
N
C COOH
5-OH Indole
Acetaldehyde
Hydroxy Indole
Acetic Acid
Tryptophan
hydroxylase
5-OH Tryptophan
decarboxylase
(Rate limiting)
In diet. Active
CNS transport
4. Serotonin Receptors
• At least 15 types and subtypes
• Multiple transduction mechanisms
• 5HT-1A: role in anxiety/depression
• 5HT-1D: role in migraine
• 5HT-2 : role in CNS various behaviours,
and in cardiovascular system
• 5-HT3 : role in nausea and vomiting
esp. due to Chemotherapy.
5. Serotonine syndrome
DEFINITION — Serotonin syndrome is a potentially life-threatening
condition associated with increased serotonergic
activity in the central nervous system (CNS).
It is seen with : @ therapeutic medication use
@ Interactions between drugs
@ Intentional self-poisoning
6. EPIDEMIOLOGY— SEROTONIN SYNDROME HAS BEEN
OBSERVED IN ALL AGE GROUPS, INCLUDING NEWBORNS AND
THE ELDERLY.
THE INCREASING INCIDENCE OF THIS CONDITION IS
THOUGHT TO PARALLEL THE INCREASING USE OF
SEROTONERGIC AGENTS IN MEDICAL PRACTICE .
THE MAJORITY OF CASES OF SEROTONIN SYNDROME
PRESENT WITHIN 24 HOURS, AND MOST WITHIN SIX HOURS,
OF A CHANGE OR INITIATION OF A DRUG
7. Drugs associated with serotonin toxicity
Serotonin reuptake inhibitors
Selective SSRIs: Fluoxetine, Paroxetine, Citalopram, Sertraline, Escitalopram
Other antidepressants:SNRIs : Effexor(Venlafaxine), Clomipramine, Imipramine,
St John's Wort (plant)
Opioid analgesics: Pethidine, Tramadol, Fentanyl, Dextromethorphan
Monoamine oxidase inhibitors
Irreversible MAOIs: Phenelzine, Tranylcypromine
Reversible MAOIs: Moclobemide
Others: Linezolid, Methylene blue
Serotonin-releasing agents
Fenflouramine, Amphetamines, MDMA (ecstasy)
Miscellaneous
Lithium, Tryptophan
Medications prescribed for nausea, such as primperan (metoclopramide), and
Zofran (ondansetron)
Dextromethorphan,( a cough suppressant)
Migraine treatments such as Axert (almotriptan), Amerge (aratriptan), Imitrex
(sumatriptan), and Zomig (zolmitriptan)
8. Serotonin syndrome
is a clinical diagnosis;
serum serotonin
concentrations do not
correlate with clinical
findings, and no
laboratory test confirms
the diagnosis
9. CAN you diagnosis serotonin syndrome?
C COGNITIVE CHANGES:
Agitation, confusion, euphoria, insomnia,
hypomania, hallucinations
A AUTONOMIC CHANGES:
Tachycardia, HTN, fever, diaphoresis,
mydriasis, arrythmias, tachypnea
N NEUROMUSCULAR CHANGES:
Tremor, hyperreflexia, clonus, ataxia,
incoordination, seizures
12. Sternbach’s Criteria
• Addition or increased dose of a known
serotonergic agent
• At least three of the clinical manifestations.
• Other etiologies excluded
• Withdrawl, sympathomimetics, anticholinergics, CNS
infections, neuroleptic malignant syndrome
14. Laboratory Findings
No specific laboratory abnormalities have been identified in association
with the serotonin syndrome. Those that have been reported have been
either nonspecific (e.g., leukocytosis) or secondary to complications of the
syndrome (e.g., azotemia, thrombocytopenia). However, a thorough
laboratory evaluation is often needed to rule out other causes of the clinical
features associated with serotonin syndrome, especially in moderate to severe
cases.. Rhabdomyolysis with associated elevations in creatine
phosphokinasc (CPK) levels was reported led to myoglobinuria-induced
acute renal failure and death. Findings indicative of disseminated
intravascular coagulation (DIC). Similarly, clinically significant hepatic
transaminase elevations were reported Hyponatremia, hypomagnesemia
and hypercalcemia also have been reported in isolated cases. These
abnormalities are likely to be secondary to fluid and electrolyte
disturbances resulting from the syndrome
16. Serotonin Syndrome vs. NMS
Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998;49:1163-1172.
17. Anticholinergic toxicity classically presents with hyperthermia, agitation,
altered mental status, mydriasis, dry mucous membranes, urinary retention, and
decreased bowel sounds after the use of an anticholinergic agent. In contrast with
serotonin syndrome, muscular tone and reflexes are normal in anticholinergic
poisoning
Malignant hyperthermia occurs in susceptible individuals exposed to
halogenated volatile anesthetics and depolarizing muscle relaxants (eg,
succinylcholine). It classically presents with increased concentrations of end-tidal
carbon dioxide, rigor -like muscle rigidity, tachycardia, hyperthermia, and acidosis
Serotonin syndrome may be distinguished from other causes of Agitated delirium
on the basis of neuromuscular findings. Whereas patients with serotonin syndrome show
signs of neuromuscular activation (eg, tremor, hyperreflexia and clonus that are
greater in the lower extremities, ocular clonus, and increased muscle tone),
patients with sympathomimetic toxicity or infections of the central
nervous system lack these findings.
19. Treatment of serotonine
Discontinuastyionnd roof malle serotonergic
agents
Supportive care is the mainstay of
therapy. For all patients who fulfill the
Hunter Criteria, we suggest the
following standard treatments :
•Oxygen to maintain SpO2 ≥94 %
•Intravenous fluids for volume depletion
•Continuous cardiac monitoring
•Correction of vital signs
20. Sedation with benzodiazepines
is important for controlling agitation.
Lorazepam 2 – 4 mg IV
or Diazepam 5 - 10 mg IV
These doses can be repeated every 8- 10
minutes based upon patient response.
Haloperidol should be avoided; as drug has
anticholinergic properties that inhibit sweating
and dissipation of body heat.
21. Autonomic instability — patients
with severe hypertension and tachycardia
should be treated with short-acting
agents, such as esmolol or nitroprusside .
Dosing of these short-acting
cardiovascular agents should be titrated to
maintain autonomic stability; longer-acting
agents, such as propranolol, should be
avoided
22. Hypotension from MAOIs in patients with
serotonin syndrome should be treated with
low doses of direct-acting sympathomimetic
amines, such as phenylephrine,
epinephrine, or norepinephrine
. Indirect agents (eg, dopamine) should be
avoided because they are metabolized to
epinephrine and norepinephrine; when
monoamine oxidase is inhibited, epinephrine
and norepinephrine production at the cellular
level is not controlled, possibly leading to an
exaggerated hemodynamic response.
23. Hyperthermia —Patients whose temperature is
above 41.1ºC require immediate sedation, paralysis, and
tracheal intubation . Standard rapid sequence intubation
(RSI) using an induction and paralytic agent should be
performed.
Etomidate (0.3 mg/kg IV)
succinylcholine (1.5 to 2 mg/kg IV )
Succinylcholine is not recommended for muscular paralysis as it
may increase the risk of cardiac dysrhythmia from hyperkalemia
associated with rhabdomyolysis
Antipyretic agents(paracetamol) are not recommended as the
increase in body temperature is due to muscular activity , not a
hypothalamic temperature set point abnormality.
Clinicians must provide adequate sedation, typically with
a benzodiazepine, while the patient is paralyzed
24. Hunter Area Toxicology Service
Therapy
Application of these principles varies with the severity
of illness.
• In mild cases : discontinuation of inciting
medications
,supportive care and sedation with benzodiazepines
is generally sufficient.
• Moderate cases :
• when oral therapy suitable
• Cyproheptadine 8 mg stat then 4 mg q4–6h
• when oral therapy unsuitable or cyproheptadine fails
• chlorpromazin 50 mg IM/IV stat then up to 50 mg orally or IM/IV
q6h
25. Therapy
Hunter Area Toxicology Service
Severe cases :
when symptoms are not progressive and fever <
39oC
• chlorpromazine 50–100 mg IM/IV stat then 50–100 mg orally or IM/IV q6h
when symptoms are progressive and fever < 39oC
• chlorpromazine 100–400 mg IM/IV over first two hours
when symptoms are progressive and fever > 39oC
• barbiturate anaesthesia, muscle relaxation ±
active cooling
• chlorpromazine 100–400 mg IM/IV over first two hours
