Serotonin syndrome following septal myectomy in association with fentanyl and methylene blue: A case report

Abstract

The present case report describes a case of serotonin syndrome which developed post-septal myectomy in a patient with hypertrophic cardiomyopathy. This case contributes to an emerging awareness of serotonin syndrome in the context of prescribed serotonergic agents, such as SSRIs, and triggered by the addition of fentanyl and methylene blue, particularly in conjunction cardiological procedures. Clinicians should be aware of such interactions which increase the emergence of the serotonin syndrome and the appropriate management of comorbid delirium post-serotonin syndrome.

Serotonin syndrome results from excessive serotonergic agonistic activity and stimulation of the 5-HT1A and 5-HT2A receptors, leading to neuromuscular hyperactivity, autonomic hyperactivity, and altered mental status.^[1],[2] It is pharmacologically mediated, resulting from a single or combination of agents enhancing serotonergic transmission. We report a case of serotonin syndrome post septal myectomy in a patient with hypertrophic obstructive cardiomyopathy (HOCM). We attribute the emergence of the syndrome to the combined use of a SSRI, fentanyl, methylene blue, bupropion, and possibly herbal supplements. This case contributes to a growing body of literature addressing the development of serotonin syndrome in the setting of cardiovascular procedures.^[3],[4] We also discuss the management of delirium in conjunction with the management of serotonin syndrome.

Case report:

A 42-year-old Caucasian male with a past medical history of ADHD, anxiety, depression, and hypertrophic obstructive cardiomyopathy (HOCM) was admitted from an outside hospital for further workup for worsening left ventricular outflow obstruction. The patient had previously presented to his primary care provider with progressive fatigue over the last 10–12 months that can become worse in the last month before presentation. His primary care provider noted a worsening of a known heart murmur on exam and thus referred the patient to an OSH for electrocardiogram and transthoracic echocardiogram. Initial ECG showed left ventricular hypertrophy and the transthoracic echocardiogram showed ejection fraction of 89% with septal hypertrophy and left ventricular outflow tract obliteration with a peak gradient of 181 mmHg. For reference, LVOT obstruction is defined as having a LVOT gradient greater than 30 mmHg and severe obstruction being greater than 50 mmHg. Given these findings, the patient was transferred to Loyola University Medical Center (LUMC) for further workup. Cardiothoracic surgery was consulted and concluded that given the findings of LVOT gradient with severe left ventricular hypertrophy, the patient would benefit from septal myectomy with possible replacement of the mitral valve. The risks, benefits, and post-operative course were discussed with the patient and surgery was scheduled for five days later. Prior to the operation, home medications for the patient included: lisdexamfetamine 20 mg daily for ADHD, paroxetine 40 mg po daily for depression and anxiety, and, as later discovered, herbal supplements including fenugreek, holy basil, Charlotte’s web, and Korean ginseng. Per cardiology, there was concern that continuation of lisdexamphetamine could contribute to increased myocardial contractility or decreased peripheral resistance, or both, potentially further worsening the patient’s left ventricular outflow obstruction. Therefore, lisdexamphetamine was held and during this process, the patient requested alternative medication for his ADHD symptoms. These symptoms were not of concern to the psychiatry team at this time, but given the request, bupropion was chosen for a better safety profile in regards to his cardiac condition. Lisdexamphatemine was replaced with bupropion XL 75 mg daily for ADHD. The patient was also started on metoprolol 12.5 mg PO BID and enoxaparin 40 mg injectable daily. Paroxetine 40 mg PO daily was continued. The patient was discharged following the medication adjustments and told to return for his scheduled myectomy in five days.

The patient returned to the hospital five days later for the scheduled septal myectomy. After the first myectomy, the left outflow gradient decreased from 150 mm Hg to 20 mm Hg, and after the second myectomy to 5 mm Hg. During the procedure, the patient was put under general anesthesia, which included 1000 mcg of fentanyl. The patient was initially extubated and did well postoperatively. On postoperative day one, the patient began experiencing vasodilation with blood pressure as low as 54/29 mmHg, requiring increasing doses of vasoconstrictors vasopressin and norepinephrine. He had multiple arrhythmias with a heart rate ranging from 58 to 112. These included seven beats of nonsustained ventricular tachycardia, followed by bradycardia, which led him to become pacemaker dependent. He experienced 1–2 minutes of unstable atrial fibrillation with rapid ventricular response and was given metoprolol. He became severely hypotensive refractory to crystalloid, phenylephrine, and vasopressin. He was given methylene blue 70 mg, which inhibits nitric oxide and thus acts as a vasopressor. Respiratory rate was around 31, and maximum temperature was 102.9°F. Within two hours, the patient was diaphoretic and tremulous with increased motor tone and sustained bilateral lower extremity clonus. His fever and tachycardia were ongoing. Serotonin syndrome was suspected, and serotonergic agents were discontinued. A computed tomography scan and EEG were performed to rule out alternative causes of the patient’s symptoms. EEG revealed diffuse slowing and burst attenuation pattern, considered a nonspecific finding. The patient was given 2 mg lorazepam IV incremental doses to a total of 16 mg and then started on a lorazepam infusion to treat Hunter Criteria consistent serotonin syndrome. The patient was re-intubated for airway protection. A 12 mg loading dose of cyproheptadine, a nonspecific 5HT1A and 5HT2A antagonist, was given, followed by 2 mg every 2 hours to also treat serotonin syndrome. In addition, the patient was given a cooling blanket to lower his body temperature.

On the second postoperative day, the central venous pressure rose to 20 mm Hg. An ECHO showed significant right ventricular dysfunction and an empty left ventricle. The patient was placed on venoarterial extracorporeal membrane oxygenation (VA ECMO) due to right ventricular failure. On the seventh postoperative day, the decision to discontinue ECMO was based on the patient’s large diuresis which allowed the right ventricle to recover, as assessed by a bedside transesophageal echocardiogram with lowering of ECMO support.

On the ninth postoperative day, the patient developed mental status changes. He was unable to identify family members and stated he was at home rather than at the hospital. He was disorientated to time, date and all questions were met with a musical theme, such as pop artist Justin Bieber. Later that same day, Toxicology consult with the patient described the patient as being “groggy, slow.” Due to decreased neuromuscular symptoms, a taper of cyproheptadine to 6 mg pNG every 8 hours then further decrease to 4 mg every 8 hours was recommended. Next day, the patient was noted to have mild confusion during his physical therapy session. He was unable to ambulate without assistance. The patient was suspicious of family members and noted to be hot and anxious. Toxicology noted multifactorial delirium and confusion, and recommended discontinuing cyproheptadine due to its potentially contributory effect. Psychiatry was consulted for management of delirium and anxiety, and the patient was noted to have fluctuating consciousness and reportedly believed he had “slept with nurses.” The patient and his family were interested in restarting paroxetine for anxiolytic effects. The decision to delay restarting paroxetine was made as the patient was just recovering from serotonin syndrome. Olanzapine was selected to address his delirium and re-emerging anxiety in the context of recovering from serotonin syndrome. On the eleventh postoperative day, the patient reported recurrent nightmares and that “crimes had been committed” in the hospital, prompting psychiatry to recommend olanzapine 1.25 mg PO BID PRN for anxiety and delirium, while continuing olanzapine 2.5 mg PO QHS. On the next day, psychiatry noted that the patient demonstrated no fluctuations in mental status and was able to remain focused on what was being said with no disorganized thinking. On postoperative day thirteen, the patient was discharged with delirium seemingly improved. He was discharged home on the following medications: olanzapine 2.5 mg once per day, acetaminophen 325 mg 2 tablets every 4 hours PRN, aspirin 81 mg daily, ibuprofen 600 mg 1 tablet 3 times per day, metoprolol tartrate 75 mg 4 times per day, polyethylene glycol as needed for constipation, thiamine 100 mg 3 times per day, vitamin D 1000 units 2 times per day, and atorvastatin 20 mg daily. He was advised to follow up with his outside psychiatrist for ongoing management of anxiety, depression, and ADHD.

Discussion:

This article presents a case of serotonin syndrome post septal myectomy, contributing to an increasing awareness and prevalence of serotonin syndrome in the setting of cardiological procedures.^[5] Onset of the syndrome after fentanyl and/or methylene blue administration is a common observation among reported cases. In the cardiac setting, fentanyl is used for perioperative pain control. Fentanyl belongs to the group of phenylpiperidine opioids, which are known to be especially serotonergic as they have 5-HT1A agonist properties and can augment serotonin release as well as weakly inhibit serotonin reuptake.^[6] Therefore, fentanyl has the potential to contribute to the development of the serotonin syndrome. Methylene blue may be used in the cardiovascular setting in cases of severe refractory hypotension, with low systemic vascular resistance and baseline or increased cardiac output. Methylene blue acts as a vasopressor via nitric oxide inhibition, leading to vasoconstriction and restoration of vascular resistance.^[7] Due to high potential for adverse effects with methylene blue, it is not used as a first line agent. Methylene blue crosses the blood brain barrier and inhibits monoamine oxidase A, thereby inhibiting degradation of serotonin and contributing to serotonin syndrome in the setting of other serotonergic agents.^{[8] [9]}

This patient’s prior use of antidepressants is also commonly seen among cases of serotonin syndrome in combination with fentanyl and methylene blue.^[10] Common antidepressants include serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), all of which have a serotonergic profile. The increasing incidence of prescribing SSRIs and SNRIs highlights the increased risk for development of serotonin syndrome.^[11] In this case, the patient was taking paroxetine, a SSRI, before his scheduled septal myectomy. Adding fentanyl and/or methylene blue to the treatment regimen of a patient on a preexisting serotonergic antidepressant increases the risk of serotonin syndrome. Additionally, the patient was recommended to start bupropion to manage his ADHD symptoms in lieu of lisdexamphetamine due to concerns of worsening cardiac function. Bupropion is a CYP2D6 inhibitor, and paroxetine is a CYP2D6 substrate. This interaction may have been contributory to the development of serotonin syndrome as well.

Since there is no confirmatory laboratory test, various diagnostic criteria, such as the Hunter Criteria, have been developed to assist clinicians in identifying serotonin syndrome.^[12] First line management includes the withdrawal of serotonergic agent(s) and supportive care, including hydration and correction of vital signs. Mild cases will generally resolve in 24 to 72 hours. Benzodiazepines are used for control of agitation and motor tone. Moderate to severe cases can include hyperthermia, autonomic instability, and progressive cognitive changes. Patients with a temperature of above 106.5°F should be sedated, intubated and receive neuromuscular paralysis.^[13] Cyproheptadine, a serotonin 2A antagonist, is the most commonly used antidote in severe cases of serotonin syndrome.^[14]

It is also prudent for clinicians to be aware of the dietary and herbal supplements their patients may be taking. Dietary and herbal supplements, including St. John’s wort, tryptophan, and Panax ginseng, have been associated with the serotonin syndrome.^[13] Tryptophan is known to contribute to serotonin syndrome via 5HT formation. St. John’s wort impairs 5HT reuptake, increasing the amount in the synaptic cleft of the presynaptic neuron. In this case, the patient was taking Panax ginseng. It is important to note that one of its components, Ginsenoside Rd, weakly inhibits CYP3A4 enzyme activity. CYP3A4 is secondarily involved in the metabolism of antidepressants including fluoxetine, sertraline, and bupropion.^[15] The patient was also taking fenugreek, holy basil, and Charlotte’s web. Fenugreek, with the active ingredient 4-hydroxyisoleucine, has antidepressant and antianxiety effects and works to reduce pain through a serotonergic system. Holy basil contains water soluble flavonoids orientin and vicenin, which provide protection against radiation-induced damage, by acting as free radical scavengers, inhibitors of lipid peroxidation, and with immunomodulatory and antimutagenic properties. Charlotte’s web is a high cannabidiol, low tetrahydrocannabinol; it is not known to be associated with serotonin syndrome. While seemingly not serotonergic in nature, discussion of all herbal supplements becomes important because accurate ingredients and doses in herbal supplements are typically not known. Herbal supplements’ ability to interact with other medications highlights the need to obtain a thorough list of all active agents the patient is taking, something which may only be achieved with a targeted history.

This case also raised the issue of diagnosing and managing delirium in the context of the presence of serotonin syndrome. The cause of delirium in this patient was multifactorial. Serotonin syndrome can cause altered mental status. In addition, the patient was in the ICU, post-anesthesia, and critically ill, all of which are risk factors for delirium. Lorazepam, given for serotonin syndrome, is a risk factor for delirium. Lastly, cyproheptadine given as an antidote for severe serotonin syndrome, is anticholinergic and a risk factor for delirium. Among cardiac patients, there is a nearly fourfold increase in risk of delirium in patients with depression. Negative affect, cognitive distress, and behavioral inactivity are predictive of postoperative delirium. Preoperative evaluation could therefore be critical in assessing mood disorders which may increase postoperative delirium risk.^[16]

Olanzapine was not chosen as a treatment for serotonin syndrome, but rather to manage the patient’s delirium and re-emerging anxiety as he recovered from serotonin syndrome. Olanzapine was chosen to treat the patient’s delirium because it has been shown to be as efficacious as low doses of haloperidol in treating delirium.^[17] Olanzapine was chosen as an atypical antipsychotic, particularly one with anxiolytic antidepressant and calming effects. However, efficacy is unproven for olanzapine’s role in serotonin syndrome. Two case studies have shown olanzapine can be implicated in the serotonin syndrome when used in conjunction with either a TCA or SSRI.^[18] It has been proposed that olanzapine antagonizes the 5-HT₂ receptor, a negative feedback receptor. This then could lead to an increased release of serotonin into the synaptic cleft, ultimately resulting in increased serotonin activity at the 5-HT₁ receptor.^[19] However, there has been documented use of sublingual olanzapine in the treatment of serotonin syndrome.^[20] Conflicting evidence suggesting olanzapine as a contributor to the development of serotonin syndrome versus possible adjuvant treatment option highlights the difficulties in choosing appropriate medication to effectively manage delirium in the context of resolving serotonin syndrome.

Conclusion:

Serotonin syndrome is a dangerous medication complication. It is very important to recognize and manage it in a timely manner, in order to avoid life threatening complications including hyperthermia, cardiovascular instability, and hypoventilation from rigidity. Obtaining an accurate record of prescribed as well as over-the-counter consumed serotonergic agents which can lead to serotonin syndrome is essential to minimizing risk.