Polypharmacy induced serotonin syndrome in a cancer patient: Case study

Introduction

Polypharmacy in older adults is a well-described phenomenon. One third of patients aged 65 and older are prescribed or taking five or more medications daily, elevating their risk of drug interaction and adverse events. (Kim & Parish, 2017) This issue is particularly concerning for young and middle-aged cancer patients, who are at high risk for polypharmacy due to chemotherapy and adjunctive prescriptions to manage side effects. Clinicians may underestimate the association between a cancer diagnosis and increased pharmacotherapy, erroneously assuming younger age confers lower vulnerability. (Murphy et al., 2018) Acute care providers facing urgent medical issues are challenged to undergo a swift and comprehensive medication reconciliation. Therefore, it is crucial to be knowledgeable of a vast drug adverse reactions and interactions, to consider a wide range of differential diagnoses in emergencies involving cancer patients and to be mindful of how additional medications might interact with their current regimen.

Background

Hypoxemic respiratory failure often requires intensive care unit (ICU) intervention, with etiologies spanning infectious, inflammatory, and extra-pulmonary origins. Methemoglobinemia, although infrequent, is acknowledged in critical care as a life threatening but at times under-detected cause of hypoxemia.

Methemoglobinemia manifests as a form of functional anemia where the oxygen-carrying capacity of hemoglobin is compromised due to the oxidation of its iron ion from the reduced [Fe2+] to the oxidized [Fe3+] state. (Curry, 1982; Wright et al., 1999) The condition’s severity escalates with methemoglobin levels: cyanosis appears at levels above 10%, and dyspnea, cardiac and neurologic symptoms emerge when levels exceed 20% (Vallurupalli, 2010) and can lead to death in levels >70%. (Iolascon et al., 2021) The threshold to treat, however, is less dependent on the methemoglobin percentage and more on the severity of symptoms, as patients with pre-existing conditions may have symptoms out of proportion to the methemoglobin percentage. Both congenital and acquired factors, including medications such as dapsone and local anesthetics, are known triggers.

Treatment typically involves tetra methylthionine chloride (methylene blue [MB]) or ascorbic acid (vitamin C), with MB often preferred for its rapid effectiveness and established role as treatment. (Curry, 1982; Dotsch et al., 1998; Dunne et al., 2006; Rino et al., 2014)

A notable side effect of MB is its inhibition of monoamine oxidase A (MAO-A), posing a risk of serotonin syndrome (SS), characterized by altered mental status, neuromuscular hyperactivity (e.g., tremor, hyperreflexia), and autonomic hyperactivity (e.g., fever, tachycardia). (Ramsay, Dunford & Gillman, 2007) This risk is amplified in patients taking selective serotonin reuptake inhibitors (SSRIs) or other serotonergic medications.

This case report details a cancer patient administered two serotonin-active medications and treated with MB for dapsone-induced methemoglobinemia, leading to serotonin syndrome (SS).

Case Presentation

A 54-year-old female, with a history of hypothyroidism on levothyroxine (88 mcg daily), anxiety disorder treated with lorazepam (1mg once daily as needed), major depressive disorder on treatment with paroxetine (20 mg daily) and bupropion (150mg daily) and recurrent diffuse large B-cell lymphoma managed with rituximab, dexamethasone, cytarabine, oxaliplatin (RDHAX), last dose being 2 weeks prior to admission. While she’s receiving high-dose dexamethasone as part of her chemotherapy regimen, she is at risk for opportunistic fungal infection such as Pneumocystis jirovecii pneumonia (PJP), for which she was receiving dapsone 100mg daily, as a PJP prophylaxis. She presented to our Urgent Care Center for three days of shortness of breath and worsening fatigue. On presentation, she was afebrile, hypoxic to 88% on room air, mildly tachypneic, and tachycardic. Physical exam was unremarkable with no adventitious pulmonary findings. Labs were within normal limits except for thrombocytopenia (White blood cell 6.8 cells/mm³, hemoglobin 10g/dL and platelets 66,000/mm³). Chest CT imaging identified ground-glass opacity in the right lower lobe, suggesting an infectious or inflammatory origin. Supplemental O2 (3L/min nasal cannula was administered for hypoxia. Empiric ceftriaxone 1gm daily and azithromycin 250mg daily was initiated for presumed community-acquired pneumonia, along with her home antidepressant and dapsone were continued. Despite two days of antibiotic therapy, her clinical picture worsened, with progressively worsened hypoxemia requiring supplemental oxygen via high-flow nasal cannula (HFNC). This prompted a consultation with the Critical Care Medicine (CCM) team. On initial evaluation, she was tachypneic with respiratory rate of 34 per minute, and hypoxemic on a non-rebreather mask at 15L/min. Despite near 100% fraction of inhaled oxygen (FiO2), her oxygen saturation was between 85-90%, measured by pulse oximetry (SpO2). An arterial blood gas (ABG) was obtained which showed a disparity between PaO2 and SpO2 levels (pH 7.45, partial pressure CO2 35 mmHg, partial pressure of oxygen 188mm Hg, SpO2 85-90%). The discordant oxygen values between oxygen value measured by pulse oximetry, and ABG, coupled with her current dapsone use, prompted a suspicion for diagnosis of acquired methemoglobinemia. A co-oximetry test was ordered, and results confirmed the diagnosis (methemoglobin level of 11.1%). The CCM team administered MB 100mg IV under emergent conditions due to ongoing hypoxemia, associated dyspnea, and headache. Her glucose 6 phosphate dehydrogenase (G6PD) level was verified to be within normal limits. Shortly after MB treatment, the patient’s clinical status started to improve, with increase of oxygen saturation measured by pulse oximetry to 98% and amelioration of symptomatology. Oxygen supplementation was downgraded to nasal canula 2L/minute and dapsone was discontinued.

Within an hour of MB treatment, the patient displayed signs of acute encephalopathy despite improving SpO2. A repeat ABG ruled out rebound methemoglobinemia, hypercarbia or hypoxemia as culprit of the neurological change. Neurological evaluation by Neurology team revealed inattention, confusion, repetitive speech, and perseveration on the word “ok”, accompanied by sinus tachycardia and a fever of 39.3°C (102.7 F) unresponsive to antipyretics. She was moving all 4 extremities spontaneously, at least 4/5 strength, localized to noxious stimuli to all 4 extremities, with intact upper and lower extremity deep tendon reflexes. Even though there was an absence of classic neuromuscular hyperactivity symptoms, such as rigidity or clonus, the symptoms onset’s temporal association with MB administration nevertheless led the Neurology team as well as the CCM team to suspect early serotonin syndrome (SS), likely triggered by MB and her concurrent SSRI use. Subsequent diagnostic testing, including CT of the head, ABG analysis, and thyroid stimulating hormone (TSH) levels were unremarkable. Her antidepressants were discontinued, Lorazepam (0.5mg IV) and antipyretic (Acetaminophen) was given, along with IV crystalloids to facilitate MB clearance. A Foley catheter was placed with the expected blue colored urine after MB administration. With these interventions, her mental status returned to normal over several hours. Repeat neurological exam displayed normal attention span and concentration, fluent speech with normal naming, repetition and comprehension, and normal foundation of knowledge, awareness of current events and ability to provide full history. The patient was discharged home two days following the resolution of symptoms, on reduced doses of home antidepressants and monthly pentamidine for PJP prophylaxis.

Discussion

Patients with persistent hypoxemia, that is refractory to high dose supplemental oxygen, cyanosis, chocolate colored arterial blood, and a concurrent discrepancy between PaO2 and SpO2 on ABG, should prompt providers to suspect methemoglobinemia. This is especially important in those with a history or exposure to causative agents like dapsone, local anesthetics (e.g., benzocaine and prilocaine), rasburicase, nitrates and certain nitrate-containing drugs including nitroglycerin, sulfamethoxazole, and Pyridium among others. (Wright et al., 1999; Alyahya et al., 2021) Diagnosis can be made by detecting a discrepancy between SpO2 and PaO2, blood co-oximetry measurement of methemoglobin percentage, or pulse co-oximetry (non-invasive measurement of methemoglobin percentage [SpMet]). (Feiner & Bickler, 2010) It is notable to mention that MB alone at high doses can cause methemoglobinemia, so patients receiving it as treatment for other conditions (e.g. Ifosfamide toxicity) should be monitored for development of methemoglobinemia. If MB is administered, the dosage for severe cases is 1-2mg/kg intravenously, and providers should be cautious to not exceed 7mg/kg, to avoid hemolysis. (Prchal, 2024) For mild cases of asymptomatic methemoglobinemia with level less than 20%, observation and supportive care alone are advised, with a readiness to escalate treatment if symptoms worsen. MB is contraindicated in patients with severe kidney injury, G6PD deficiency, or those on serotonergic medications due to risk of hemolysis or SS. (Curry, 1982)

The human body typically corrects methemoglobinemia through enzymatic reduction of methemoglobin to hemoglobin, primarily via nicotine adenine dinucleotide-dependent methemoglobin (NADH-MetHb) reductase and nicotinamide adenine dinucleotide phosphate hydrogen methemoglobin (NADPH-MetHb) reductase, with NADPH-MetHb reductase usually playing a secondary role. (Curry, 1982) Acquired methemoglobinemia occurs when a patient is exposed to exogenous oxidizing agents, such as medications. These drugs potentiate higher rates of iron oxidation, leading to increased levels of methemoglobin, outpacing the endogenous enzymatic reduction process and cause methemoglobin accumulation, leading to oxygen binding defect and hypoxemia. (Singh et al., 2014) MB on the other hand, exerts therapeutic effect by acting as a cofactor, significantly enhancing the enzymatic reduction process and promotes rapid reduction of methemoglobin.

In cases where acquired methemoglobinemia is refractory to MB, such as with G6PD deficiency, or when MB administration is contraindicated, like in pregnancy, treatment options are limited to stopping the offending agent and providing supportive care. Alternative treatments include ascorbic acid, riboflavin, hyperbaric oxygen therapy, exchange transfusion, and plasmapheresis. (Curry, 1982) High doses of ascorbic acid can reduce methemoglobinemia levels up to 10%, though the effective doses may exceed recommended oral dose, risking precipitation of calcium oxalate crystals in the kidneys, thereby leading to acute kidney injury. (Dotsch et al., 1998; Dunne et al., 2006; Rino et al., 2014) Ascorbic acid, acting more slowly than MB, has limited utility in acute hypoxemia due to methemoglobinemia. (Prchal, 2024) Riboflavin, through the nicotinamide adenine dinucleotide-flavin reductase system, can reduce methemoglobin level, but its effectiveness as an antidote requires further study. (Iolascon et al., 2021) Hyperbaric oxygen therapy, used in some refractory cases, can reduce methemoglobin levels by approximately 8% per hour, though availability of this therapy and consistency of treatment outcomes is lacking. Exchange transfusion has been successful in replacing methemoglobin with normal hemoglobin in cases refractory to MB. (Khetarpal & Kotwal, 2018) Finally, plasmapheresis, though less commonly utilized, may disrupt oxidative stress-induced hemolysis caused by methemoglobinemia, and has been used effectively in methemoglobinemia refractory to other therapies. (Shatila et al., 2017) Considering the limitations of MB in certain scenarios, further investigation into the efficacy of these alternative treatments is worthwhile.

MB inhibits MAO-A, which is an important enzyme for serotonin breakdown through metabolization to 5-hydroxyindoleacetic acid (5-HIAA), leading to elevated serotonin levels. (Ramsay et al., 2007) Therefore, when administered in conjunction with other serotonergic agents such as SSRI, commonly prescribed to treat anxiety and depressive disorders, MB may lead to SS. Notably, bupropion, a common norepinephrine and dopamine reuptake inhibitor (NDRI) used to treat depression, can indirectly elevate serotonin levels despite not affecting its reuptake, thereby increasing the risk for SS particularly when used concurrently with SSRIs. (Munhoz, 2004; Dong & Blier, 2001; Piacentini et al., 1985) The prevalence of antidepressant use in the United States has risen from 6% to 10.4% from 1999 to 2010, paralleling an increase in SS incidents. Notably, SSRI antidepressants emerged as the ninth leading cause of drug overdose fatality in 2016. (Scotton et al., 2019) In 2018, antidepressant use among adults 18 years and older in the past month was reported at 13.2%, with higher usage among women (17.7%) and peaking at 24.3% in women over 60. (Brody & Gu, 2018) Nearly 25 million adults in the U.S. have been on antidepressants for two or more years, marking a 60% rise since 2010. Given its prevalence in use, interactions or overdose involving antidepressants that inhibit MAO-A (e.g. selegiline, isocarboxazid, phenelzine, and tranylcypromine), over-the-counter dietary supplements (St John’s wort, ginseng, tryptophan), illicit drugs (ecstasy, amphetamines, or cocaine), and MB can increase serotonin activity, precipitating SS. (Pratt et al., 2017)

SS is a toxidrome characterized by heightened serotonergic activity due to free serotonin (5-hydroxytryptamine [5-HT]) accumulation or 5-HT receptor activation, often linked to serotonergic antidepressant use. 5-HT, a crucial monoamine neurotransmitter, plays diverse roles in the central nervous system (CNS), including attention regulation and thermoregulation, and in the peripheral nervous system (PNS), such as vasoconstriction and bronchoconstriction. (Scotton et al., 2019)

SS classically manifest as a triad of acute encephalopathy (anxiety, agitation, and confusion), autonomic dysfunctions (diaphoresis, diarrhea, arrhythmia, blood pressure and temperature dysregulation), and neuromuscular hyperactivity (tremor and clonus), with varied grades of severity. Severe SS cases may present with hyperthermia above 41.1C, hemodynamic instability, and muscle rigidity. These symptoms are similar to neuroleptic malignant syndrome triggered by dopaminergic antagonists such as haloperidol, and malignant hyperthermia due to inhaled anesthetics. SS is diagnoses of exclusion, therefore, providers should take care to consider life-threatening differentials including acute cerebrovascular accident, tonic-clonic seizures, encephalitis, and meningitis. A physical sign that is specific to SS but not always present is spontaneous or inducible clonus of lower limbs. Possible complications from SS include seizures, shock, renal failure, metabolic acidosis, rhabdomyolysis, and acute respiratory distress syndrome (ARDS). (Scotton et al., 2019) The consequence of overlooking SS, especially in the context of drug-drug interaction (DDI) between multiple serotonergic agents is severe, as SS has the potential for rapid progression to fatality within 24 hours. (Ramsay et al., 2007) Treatments for SS center on discontinuing the offending agents, administration of Cyproheptadine, a histamine-1 receptor and nonspecific 5-HT antagonist, and providing supportive measures, such as supplemental oxygen for hypoxemia, sedation with benzodiazepine for autonomic hyperactivity, paralytic agents for profound muscle hypertonicity, and admission to ICU for close monitoring. Prognosis of SS is generally favorable if diagnosed and treated promptly. (Scotton et al., 2019)

Admitted patients undergo medication reconciliation by a clinical pharmacist. It’s unclear if this patient’s regimen was undergoing adjustment and that’s why certain medications were not discontinued at the time of decompensation. In any case, pharmacists play a crucial role in reducing polypharmacy among cancer patients by conducting comprehensive medication reviews, identifying potentially inappropriate medications, and collaborating with the healthcare team to optimize pharmacotherapy.

Conclusion

In the oncology populations, polypharmacy contributes to DDI’s, increased medication errors, and elevated chemotherapy toxicity, regardless of age. Notably, serotonin-active drugs can reduce the effectiveness of certain antineoplastics, such as tamoxifen, by disrupting their metabolism. Cancer patients receiving multiple serotonin-active medications and dapsone for PJP prophylaxis are at heightened risk for SS and methemoglobinemia, especially following MB treatment. This case highlights the complex challenges of managing polypharmacy in cancer patients, particularly when involving time-sensitive conditions needing rapid intervention. It also demonstrates the critical need for meticulous medication reconciliation in these at-risk groups. Prompt recognition of methemoglobinemia and serotonin syndrome symptoms is essential for effective intervention and requires a comprehensive, interdisciplinary approach to medication management.