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Serotonin Syndrome Signs & Symptoms


You respond to a 24-year-old male patient complaining of shaking extremities, nausea and feeling “cold.” En route, you contemplate potential causes that could create this array of symptoms. You think that perhaps the patient has an infection, toxin, traumatic injury, epilepsy or a metabolic imbalance. When you arrive on scene, you and your partner roll the stretcher into the home, loaded with the cardiac monitor, ALS bag and oxygen tank. The frantic mother explains that her son hasn’t been feeling well for a few days. You begin assessing your patient while your ALS partner begins performing interventions. While your partner applies oxygen, obtains an ECG strip and O2 saturation level, assesses vital signs and establishes an IV, you begin your SAMPLE and OPQRST.

Patient Assessment
During your assessment, you find that the patient has tremors in all extremities, nausea, brown emesis without traces of blood, and he’s hot to the touch. He has no known drug allergies and takes Lithium, Zoloft, Trazadone and Xanax for bipolar disorder, anxiety and depression. He reports he had a light breakfast of toast. The patient also says he’s nauseous, but has no pain. You note that tremors are present in all extremities. Although the patient says some of his symptoms began two days ago, you note that the tremors started 15 minutes ago. His vitals are as follows: airway= patent; breathing=mildly labored; skin=hot and dry; heart rate=112 and regular; BP=168/104; RR=16; blood glucose level=118. An ECG notes a sinus tachycardia.

After your initial assessment, you’re able to rule out trauma, and epilepsy seems to be unlikely because the tremors aren’t accompanied by loss of consciousness. An infection is still possible, as are toxins and metabolic or endocrine disorders. You package the patient and load him into the ambulance. You begin to do a head-to-toe assessment during this time.

You also note his skin is hot to touch, and his cheeks are flushed.His pupils are round and reactive to light. His neck shows no tracheal deviation; flat neck veins. You note that his lung sounds are clear and equal bilaterally, but you do note mildly labored respiratory effort.His abdomen is soft and tremors are noted in his extremities.

After you have completed this assessment, the patient stops responding to you and loses control of his bladder. The tremors in the extremities increase in intensity, and it becomes apparent that the patient is having a seizure. You prepare and administer 5 mg of diazepam via IV. You should be at the hospital in two minutes, and your partner is calling in a report to the emergency department (ED). You administer another 5 mg of diazepam, and again, there’s no change in the patient’s status. The seizures continue.

Arrival at the ED
After you arrive at the ED and transfer the patient to the hospital bed, the staff immediately administers another 5 mg of diazepam without any effect. They decide to electively intubate the patient with fentanyl, etomidate and Succinylcholine. After successful intubation, they administer midazolam and vecuronium. Blood is drawn, and the laboratory performs an ABG, CBC, electrolyte panel and blood glucose test.

The ED physician also contacts the patient’s pharmacist and primary care physician. The pharmacist makes a note that one potential side effect of the combination of Zoloft & Trazadone is serotonin syndrome, and he mentions that the patient has only been prescribed Trazadone for the past 16 days.

The patient is admitted to the intensive care unit (ICU) on a ventilator. After 24 hours, medications are excreted, and the patient’s symptoms resolve. The physician responsible for the patient’s care in the ICU makes temporary changes to the patient’s home medication regimen, and the patient is referred to his primary care physician for long-term adjustments to his prescriptions.

Serotonin Syndrome
In 2006, the FDA released an alert pertaining to the potential risk of developing serotonin syndrome during administration of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), and 5-hydroxytryptamine receptor agonists (triptans). Serotonin syndrome is a potentially lethal condition in which an increase of serotonin stimulation occurs because of the utilization of a common set of drug combinations.

The combination of antidepressants such as SSRIs and SNRIs in conjunction with triptans is common in the U.S., with approximately Although reported cases of severe serotonin syndrome are limited, the condition may be barely noticeable to some, considering the wide variety of symptoms with varying degrees of severity.

Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter synthesized from the amino acid tryptophan. Eighty percent of the serotonin found in the body is located in the gastrointestinal (GI) tract, where it aids in the regulation of intestinal movement. Serotonin from the GI tract enters the plasma of the bloodstream and eventually reaches the platelets, where it’s stored. It plays a role in wound healing by acting as a growth factor for platelets and stimulating vasoconstriction within the blood vessels.

The remaining 20% of the body’s serotonin is synthesized in the sertonergic neurons in the central nervous system. Here it’s responsible for a variety of functions, including mood, appetite, sleep, muscle contraction, pain perception, thermoregulation and various cognitive functions, such as memory and learning. With the broad effects of serotonin on mood and behavior, diminished levels of serotonin have been correlated with depression, anxiety, bulimia, anorexia and seasonal affective disorder (SAD).

Excess serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which is then secreted by the kidneys. It is measured during urinalysis to determine serotonin levels within the body. However, it can be inaccurate because of renal disorders, tumors or small bowel resections. Serotonin syndrome is also known as serotonin storm, serotonin toxicity, serotonin toxidrome, hyperserotonemia, or sertonergic syndrome. This condition can be caused by a several precipitating events including SSRI or SNRI overdose, recreational drug usage, or therapeutic dosages of a combination of SSRIs or SNRIs with triptans. This complication can range in severity from mild irritation to potentially life threatening.

Signs & Symptoms
Signs and symptoms of serotonin syndrome can range in severity and can affect cognitive, autonomic and somatic functions. Symptom manifestation can occur within minutes or hours of ingestion of the triggering substance. The clinical presentation of patients with serotonin syndrome will vary, and is not all-encompassing. Patients may experience some or all of the potential symptoms throughout the duration of the incident.

Cognitive deficits may present initially as a headache. This may be difficult to differentiate from the normal or non-critical headache because patients may be prescribed triptans for migraine therapy. The condition may later progress to include agitation, nervousness and insomnia. Severe cases may present with confusion, agitation, incoherent speech and delirium. Untreated cases will ultimately lead to a semi-coma or coma state.

Patients may also display autonomic symptoms, including hemodynamic changes, such as tachycardia, severe hypertension or hypotension, tachycardia, tachypnea and dyspnea. EMS providers may also note dilated pupils, diaphoresis, fever as high as 40 °C (104° F) and shivering. The patient may also complain of nausea, vomiting and diarrhea.

Somatic idiosyncrasies include akathisia, mydriasis and impaired coordination. Untreated symptoms will progress to myoclonic twitching, tremors, ataxia, rigidity, hyperreflexia and clonus around the eyes. The neuromuscular abnormalities that present in the limbs are more likely to affect the lower limbs then the upper limbs. Later stages may include seizures refractory to benzodiazipines.

Although this clinical triad of abnormalities is the primary indicator of serotonin syndrome, other symptoms may also present. Some irregularities may include metabolic acidosis, rhabdomyolysis, renal failure and disseminated intravascular coagulation (DIC). Patients may also experience distributive shock second to the autonomic effects.

Although a survey of signs and symptoms, along with a detailed medical history are the primary means of diagnosis for serotonin syndrome, it’s imperative that EMS provider consider various differential diagnoses and rule out other potential causes. In hospital health-care providers should consider arterial blood gas analysis (ABG) to rule out metabolic abnormalities, blood cultures to rule out infections, complete blood count (CBC), blood chemistry analysis, electrocardiogram, kidney function tests, liver function tests, thyroid function tests and toxicology screens. However, in the field, EMS providers will have to rely on signs and symptoms observed during the patient assessment because serotonin syndrome can mimic various conditions, including drug withdraw, cocaine overdose, lithium toxicity, monoamine oxidase inhibitor (MAOI) toxicity and neuroleptic malignant syndrome.

Treatment of serotonin syndrome begins with removal of the agent causing the response. If SSRI or SNRI medications have been ingested, a nasogastric tube may be placed and the stomach may be cleared by lavage. Benzodiazepines are often used to manage seizures and other neurological symptoms, such as agitation that could endanger the patient or EMS provider. Neuromuscular paralytics may also be necessary to restrain the patient, control seizures and involuntary muscle spasms that cannot be managed by benzodiazipines, and manage airway compromise. Paralytics may also help to reduce the severity of hyperthermia, which is exacerbated by the heat generated from these involuntary movements.

To specifically treat serotonin syndrome, cyproheptadine, or Periactin, is often used. This medication is a serotonin antagonist, which blocks the effects of serotonin. It’s unlikely, however, that cyproheptadine is beneficial in patients experiencing advanced or profound symptoms. Since this medication is administered orally, its usefulness is also limited in patients who have received activated charcoal orally or by gastric tube. Intravenous fluids are sometimes used to dilute the concentration of serotonin within the bloodstream, as well.

When serotonin syndrome is recognized early and treated effectively, the chances of recovery are very high. Most cases, with proper treatment, resolve within 24 hours. If left untreated, however, neurological symptoms advance, and the lack of neuromuscular control will result in death, generally from prolonged seizures. A few patients report muscle pain for as long as several months after resolution of all other symptoms, but this pain may also be due, in part, to the discontinuation of SSRI or other antidepressant medications.

Serotonin syndrome is an important disorder of which EMS providers should be aware because many of the causative medications are among the most commonly prescribed in the country. Furthermore, with rapid recognition and appropriate treatment, the prognosis for recovery is often excellent. Early diagnosis is imperative to a positive outcome, and an understanding of the chemical foundations of this disorder improve the EMS provider’s ability to recognize and treat this life-threatening condition.

1. Ailawadhi S., Sung W., Carlson, L. A., et al. Serotonin syndrome
caused by interaction between citalopram and fentanyl. Journal of Clinical Pharmacy and Therapeutics. 2007:32;199–202.

2. Bush E, Miller C, Friedman I. A case of serotonin syndrome and mutisim associated with methadone. Journal of Palliative Medicine, 9:6, 1257–1259.

3. Federal Drug Administration.“Selective Serotonin Reuptake Inhibitors.” 2006. Washington, DC; U. S. Government Printing Office.

4. Phan H., Casavanti MJ, Crockett S., et al. (2008). “Serotonin syndrome following a single 50 mg dose of sertraline in a child.” Clin Toxicol. 2008: 46;845–849.

5. Silins E, Copeland J, Dillon P. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: Hierarchy of risk. Austr NZ Jour Psychiatry. 2007:1;649–655.

6. Steinburg M, Morin A. Mild serotonin syndrome associated with concurrent linezolid and fluoxetine. Am J of Health-Syst Pharm. 2007: 64(1);59–62.


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