Dr. Sher Mohammad and others focus on Serotonin Syndrome in the Niche of Acute Medical Care and Peri-Anaesthetic Care
(Serotonin received its name from its apparent property of being a vasoconstriction-inducing constituent of serum).
The discovery of serotonin is attributed to Vittorio Erspmarer [1] during his attempt to purify extracts from enterochromaffin cells in 1935. Serotonin, also called 5-hydroxytryptamine(5HT) is a monoamine neurotransmitter which plays role in several biologic functions [2]. Serotonin forms from hydroxylation and decarboxylation of amino acid tryptophan. It is found in hypothalamus, limbic system, cerebellum, spinal cord, retina and in highest concentration in enterochromaffin cells of the gut. The liver metabolises excess serotonin into 5-hydroxy-indol acetic acid(5HIAA). The metabolism begins with the oxidation of the compound to an aldehyde by monoamine oxidase enzyme. The aldehyde is further oxidated by aldehyde dehydrogenase into 5HIAA (excreted in urine). Urinary 5-HIAA is increased with an increase in serotonin levels.
Richest sources of serotonin are salmon fish, eggs, milk, chicken and turkey. Plants and vegetables rich in serotonin include spinach, tomatoes, soy products, seeds and nuts. Fruit sources are plantains, pineapple, bananas, kiwi fruit and plums. Formula of serotonin (5-hydroxytryptamine):C10 H12N2O
Serotonin has a role in many body processes, including the regulation of mood and other emotional behaviours as well as pain perception, aggression, vomiting, the sleep cycle, appetite, sexual function and body temperature control. It acts indirectly via G protein coupled receptors and second messenger.
Inadequate serotonin production can have widespread effects on a person’s attention and emotional states and may be responsible for many cases of severe chronic depression. Fluoxetine, paroxetine, sertraline and related drugs inhibit the reuptake of serotonin by axonal terminals (hence the name selective serotonin reuptake inhibitors or SSRIs). This inhibition leads to increased serotonin concentration at synapses, and over time, the increase may relieve the symptoms of depression.
Predominantly used in the treatment of depression, SSRIs are also used to treat seemingly diverse conditions such as eating disorders, neuropathic pain, sexual behaviour, sleep, aggression and anxiety disorders. An interplay of over-and underactivity of various 5-HT receptor subtypes, including 5-HT1A,5-HT2A and 5-HT2C, as well as other neurotransmitter systems, notably noradrenergic and glutamatergic, are thought to be involved.
The therapy with SSRIs can result in excessive serotonergic activity in the central and peripheral nervous systems which can lead to serotonin toxicity. Classical features include a combination of mental status changes, autonomic instability, and neuromuscular hyperactivity. The intensity of clinical findings reflects the degree of serotonin toxicity-the term serotonin syndrome usually refers to the severe end of toxicity spectrum.
Herbal products which can cause clinically significant inhibition of CYP 450
Grapefruit juice contains bergamottin which inhibits CYP3A49 (70% of this enzyme is present in small gut epithelial cells and 30% in the liver) [3]. A 200 ml of grapefruit juice reduces the activity to a half within 4 hours. This inhibitory effect continues into next day and possibly 2nd day.
Caffeine can inhibit CYP1A2,theoretically it may increase available levels of other serotonergic drugs metabolised by CYP1A2, notably tricyclic antidepressants.
Other important CYP enzyme interactions with serotonergic medications include St. John Wort which inhibits CYP3A4 and it also contains constituents inhibiting several other enzymes (CYP 12A,2C9,2C19,2D6), cigarette smoke (CYP1A2) and alcohol, especially red wine (CYP2E1) [4].
Drugs Triggering Serotonin syndrome:
There are various serotonin-mimetic products which include
Herbs: St. John Wort, Syrian rue, panax, ginseng, nutmeg, yohimbine
Obesity drug: Diethylpropion
Psychedelics :5 Methoxy-di-isopropyltryptamine, Lysergic acid diethylamide (LSD)
Extra: Tryptophan, L-dopa, valproate, Buspirone
The rest of the serotonin-mimetic drugs are briefly mentioned in table-1
Table-1: SEROTONIN mimetic drugs
Drugs used in the niche of Peri-operative care which have serotonin-mimetic effects
Several antidepressants exert their effect by modulating intrasynaptic serotonin concentrations and some anaesthetic related drugs may affect the metabolism of serotonin, implicating to induce serotonin syndrome in patients taking those antidepressants.
Serotonin Syndrome is relatively rare but a potentially life-threatening spectrum of drug induced toxicity [5].It results from therapeutic drug use, deliberate poisoning, or inadvertent interactions between drugs, and hyperstimulation of 5HT receptors in the CNS. Albeit serotonergic agents such as SSRIs have been regarded as major cause of this syndrome, opioid analgesics commonly used during anaesthesia are also associated with serotonin toxicity [6]
Any increase in serotonergic neurotransmission can lead to serotonin syndrome. The majority of cases are iatrogenic from synergistic medications, although cases of intentional self-poisoning with serotonergic agents also occur [7,8]
Another mechanism for the development of serotonin syndrome is the addition of drugs (that inhibit cytochrome P450 2D6 and/or cytochrome P450 3A4 isoenzymes) to therapeutic regimens of SSRIs. In one case report serotonin syndrome was precipitated in a 12-year-old patient taking a stable dose of sertraline when erythromycin, a CYP3A4 inhibitor, was co-ingested [9]. Another case was reported in which the patient had taken venlafaxine, mirtazapine and tramadol [10].
Presentation of Serotonin Syndrome
Serotonin toxicity is a group of symptoms that may occur with the use of certain serotonergic medications [11]. The symptoms may range from mild to severe, and are potentially fatal [12,13]. Symptoms in mild cases include high BP, fast heart rate and usually without fever[14]. Symptoms in moderate cases include high temperature(>38.00C), agitation, increased reflexes, tremors, sweating, dilated pupils and diarrhoea. In severe cases, body temperature can be greater than 40.00C. Complications may include seizures, rhabdomyolysis and death. See table-2 for the features to remember serotonin toxicity.
Some symptoms of serotonin toxicity overlap with features of other presentations in psychiatry and thus may be mis-attributed to mental illness (‘diagnostic overshadowing’). Further, there may be diagnostic dilemmas in patients on combinations of drugs, those receiving drugs with previously unknown serotonergic properties or where there are drug interactions. Prescriber vigilance and holistic review of the patient, including pharmacotherapy, may be helpful in avoiding progression of serotonin syndrome to more serious outcomes.
Table-2: Clinical features of SEROTONIN syndrome
Symptoms of Serotonin syndrome tend to show up quickly within 24 hours of taking a medication that causes the condition. Within one hour of taking a medication,30% of patients and within 6 hours,60% of patients with the condition will develop symptoms.
Complications of Serotonin Toxicity
Rhabdomyolysis and Myoglobinuria
Renal failure
Respiratory failure
Metabolic acidosis
Seizures
Death
SSRIs and Anaesthetic Implications:
A thorough drug history is important i.e. monotherapy or combination therapy. There are a few implications for the anaesthetists and peri-operative practitioners. Citalopram is more cardiotoxic and associated with QTc prolongation [15,16]. In addition to the features normally seen in SSRIs, QT prolongation and convulsions are potential dose related toxic effects of citalopram overdose (MHRA,2011).
Consequences of discontinuing SSRIs peri-operatively
When the drugs are discontinued pre-operatively and not taken post-operatively due to surgical reasons i.e.SSRIs discontinuation syndrome will be an issue, see table-3 and is remembered as ‘BEE – STING’.
Table-3: SSRIs Discontinuation syndrome, remember BEE-STING
Consequences of continuing SSRIs peri-operatively
On the other hand, if SSRIs are continued, then problem of serotonin toxicity is a possibility. There are a number of interactions with implications for the anaesthetist; probably the most important is the risk of precipitating serotonin syndrome when tramadol or meperidine is given in conjunction with SSRIs. These drugs may interfere with the metabolism of codeine to morphine (CYP2D6). This means patients given codeine may not receive adequate analgesia. There is a risk of bleeding when NSAIDs and/or warfarin and citalopram are co-ingested.
Only one case has been reported in which propofol was implicated in triggering Serotonin syndrome, other anaesthetic agents are regarded as safe.
Case report of 43 years male who was on lisinopril, rosuvastatin and bupropion underwent colonoscopy. He was given propofol for sedation. During the procedure, the patient exhibited bradycardia, respiratory distress and hypotension. Patient was intubated, epinephrine 2 doses given and was admitted to A/E. Temperature 100.90F, HR 160, BP 180/100.Patient was diaphoretic with muscle rigidity, clonus, bilateral Babinski signs and hyperreflexia. Patient was treated with BDZ and cyproheptadine, extubated 48 hour later [17]
Table-4: Strategies to minimise Serotonin-mimetic effects (A,B,C approach)
Hunter Criteria for diagnosing Serotonin Toxicity
Serotonin syndrome was first described in humans by Sternbach in a review of 38 reports [18]. Sternbach had his own criteria of assessing patients with serotonin syndrome. Currently, the diagnosis should be based on the Hunter Toxicity criteria because these criteria are more sensitive (84 vs 75%) and more specific (97 vs 96%) than Sternbach’s assessment [19].
Hunter Serotonin Toxicity Criteria, which require the presence of one of the following classical features i.e. spontaneous clonus, inducible clonus, ocular clonus, tremor/hyper-reflexia, autonomic dysfunction and pyrexia and (evidence that serotonergic agent/s have been used).
Clonus is the most important sign in the Hunter’s criteria. This neuromuscular feature was strongly associated with serotonin toxicity.
Diagnosis is made by ruling out other possibilities as serotonin syndrome is a diagnosis of exclusion. No single diagnostic test (serum serotonin levels do not correlate with toxicity) can confirm this syndrome.
Lancashire Hospital NHS Trust has come up with the flowchart while Managing Serotonin Toxicity (see the flowchart).
NB: This Flow chart is being taken from Lancashire Hospitals NHS Trust Guidelines
(Re-drawn by Dr. Tausif Ahmad)
Supportive Management and Drug Treatment
First line of management involves withdrawal of the offending serotonergic drugs and provision of supportive care. The intensity of treatment depends on the severity of toxicity.
Mild cases generally resolve within 24-72 hours with conservative therapy and removal of causative drugs and most of these cases do not need hospitalisation. Patients with moderate to severe symptoms such as hypertonicity, hyperthermia, autonomic instability or progressive cognitive changes require hospital admission [20,21].
BDZ are used to control agitation and tremor.
Cyproheptadine, a 5HT2A antagonist, is usually recommended and is the most widely used antidote [22,23] An initial dose of 12 mg should be considered, followed by 2 mg every 2 hours if symptoms continue. Once the patient is stabilised, a maintenance dose of 8 mg every 6 hours may be administered. Although cyproheptadine is widely used, definitive evidence is lacking on its effectiveness in this type of toxicity. The mainstay of therapy is managing hyperthermia and increased muscle rigidity in severely ill patients i.e. sedation, neuromuscular paralysis and possible intubation/ventilation.
1.Identify and stop serotonergic medications
2.Avoid opioids with intrinsic serotonin-mimetic potential.
3.Supportive: Normalise vital signs
Supplemental O2
Cooled IV fluids for volume depletion+ Ice packs***
BDZ may be used to treat agitation and tremor
Set Bair Hugger to ambient temperature***
Correct K+ and hypoglycaemia
Consider NaHCO3 if rhabdomyolysis happens
4.Cyproheptadine (IV formulation not available) as mentioned above.
***Paracetamol is of no benefit as the pyrexia is not of hypothalamic origin. It can still be used for pain relief though.
Conclusion
Serotonin toxicity is a drug induced syndrome resulting from increased serotonin activity. The syndrome can evolve from standard treatment, overdose, intoxication or any combination of serotonergic drugs-including pharmacodynamic and pharmacokinetic interactions-that increases serotonergic neurotransmission. The central symptoms are neuromuscular excitation, autonomic dysfunction and altered mental status, which occur in a patient undergoing new, altered or enhanced serotonergic therapy. The Hunter Serotonin Toxicity Criteria are widely accepted diagnostic criteria.
Due to widespread use of serotonergic drugs, clinicians must maintain a high level of clinical suspicion for serotonin syndrome, as early recognition and treatment are crucial to prevent significant morbidity and mortality i.e. seizures, rhabdomyolysis and death.
Conflict of interest: None declared
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Authors and contributors:
Dr.Sher Mohammad, Consultant Anaesthetist(retired),STH NHS FT Sheffield
Dr.Hayat Khan, MRCPsych, Acting Consultant Child and Adolescent Psychiatrist, South West Yorkshire
Dr. Parhaizgar Khan, Professor of Anaesthesia, Pak International Medical College, Peshawar
Dr. Gul Rukh, Year-2 Trainee Anaesthetics, Khyber Teaching Hospital, Peshawar
Dr.Ajmal Khan, Consultant Rheumatologist and Physician, Ambulatory Health Services, Al Ain,UAE
Dr. Tausif Ahmad, Specialist Registrar Dermatology, Royal Hallamshire Hospital, Sheffield
Dr.Asif Zia, Medical Officer Pulmonology, Northwest General Hospital,Peshawar
Dr.Ijaz Hussain, Trainee Medical Officer General Medicine, Lady Reading Hospital, Peshawar
Correspondence Address: smyousafzai@doctors.org.uk
