Serotonine syndrome

BY

Dr. Mostafa shalaby

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.

N

C

N

C NH2

COOH COOH

NH2

OH

N

C NH2

OH H

Tryptophan 5-Hydroxytryptophan

5-Hydroxytryptamine

N

C COOH

5-OH Indole

Acetaldehyde

5-Hydroxy Indole

Acetic Acid

Tryptophan

hydroxylase

5-OH Tryptophan

decarboxylase

(Rate limiting)

In diet. Active

CNS transport

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.

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

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

Drugs associated with serotonin toxicitySerotonin 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)

Serotonin syndrome

is a clinical diagnosis;

serum serotonin

concentrations do not

correlate with clinical

findings, and no

laboratory test confirms

the diagnosis

CAN you diagnosis serotonin syndrome?

CCOGNITIVE CHANGES:

Agitation, confusion, euphoria, insomnia, hypomania, hallucinations

AAUTONOMIC CHANGES:

Tachycardia, HTN, fever, diaphoresis, mydriasis, arrythmias, tachypnea

NNEUROMUSCULAR CHANGES:

Tremor, hyperreflexia, clonus, ataxia, incoordination, seizures

Spectrum of clinical findings

NEJM, 352;11. 2005

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

Diagnostic criteria- the Hunter criteria

validated in >2000 SSRI overdoses

Laboratory FindingsNo 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

DIFFERENTIAL DIAGNOSIS —

Neuroleptic malignant syndrome (NMS)

Malignant hyperthermia

Anticholinergic toxiciy

Sympathomimetic toxicity

Sedative-hypnotic withdrawal

Meningitis

Encephalitis.

Serotonin Syndrome vs. NMS

Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998;49:1163-1172.

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.

Complications OF SEROTONINE

SYNDROME

Disseminated intravascular coagulation (DIC)

Rhabdomyolysis

Metabolic acidosis

Renal failure

Acute respiratory distress syndrome (ARDS)

Generalized seizures

Treatment of serotonine

syndrome Discontinuation of all 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

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.

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

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.

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

TherapyApplication 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

Hunter Area Toxicology Service

Therapy• 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

Hunter Area Toxicology Service

THANK YOU