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In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.
Antipsychotic medications, including risperidone, are widely used in the treatment of psychiatric disorders, including schizophrenia. While hyperthermia is an establish adverse effect of these medications, less is known about the rare occurrence of hypothermia. We present two patients who developed hypothermia, bradycardia and cardiac arrest in association with risperidone. We briefly review previously similarly reported cases.
Hypothermia, defined by a drop in core body temperature below 35°C, is a rare but potentially fatal condition. Primary hypothermia occurs when the body’s thermoregulation mechanism is overwhelmed by exposure to extreme cold, while secondary hypothermia can occur from several causes such as sepsis, hypoglycaemic, hypothyroidism and medication overdose. Antipsychotic drugs (APDs) in particular can impair the body’s thermoregulation, and while hyperthermia is an established adverse effect of APD, less is known about the manifestation of hypothermia with APD use. Our cases are unique for the rare presentation of hypothermia in a patient on APD, and for the consequent occurrence of cardiac arrest.
Case presentation: case 1
An 82-year-old woman with a medical history of dementia, schizophrenia and atrial fibrillation presented with 1 day of worsening confusion. Her family reported episodic involuntary spasmodic movements involving the upper and lower extremities during the 4 days prior to presentation. A review of systems was limited, but notable for hypothermia; her family reported that she had a temperature of 34.4°C at her primary care visit a week before. Her home medications included metoprolol, warfarin and risperidone (which she had been on for over 4 years). Physical examination demonstrated hypotension (91/49 mm Hg), bradycardia (43 beats per minute) and hypothermia with a core body temperature of 28.7 °C; and impaired mentation with Glasgow Coma Score (GCS) of 10 (E3V3M4). She had increased muscle tone in her upper and lower extremities along with occasional non-rhythmic contractions.
Investigations: case 1
Laboratory testing including a complete blood count (haemoglobin: 106 g/L; white cells: 5.48×109/L; platelets: 190×109/L), serum chemistries (sodium: 139 mmol/L; potassium: 3.8 mmol/L; chloride: 105 mmol/L; bicarbonate: 27 mmol/L; BUN: 14 mg/dL; creatinine: 0.6 mg/dL; glucose: 116 mg/dL), lactate (1.3 mmol/L), troponin (high sensitivity troponin T: 26 ng/L), urinalysis and urine toxicology was unremarkable.
Her ECG demonstrated sinus bradycardia and J waves. CT scan of the head was unremarkable, and a chest X-ray (CXR) did not reveal any acute cardiopulmonary process.
Treatment: case 1
Rapid intravenous crystalloid resuscitation along with broad-spectrum antibiotic therapy and stress dose steroids were administered. Active external rewarming was initiated and she was admitted to the intensive care unit (ICU) for vasopressor support and close monitoring. Approximately 12 hours following initial presentation, she developed cardiac arrest with pulseless electrical activity (PEA). Her last recorded temperature prior to cardiac arrest was 35.5 °C. She attained spontaneous circulation following the prompt initiation of the Advanced Cardiac Life Support (ACLS) protocol, following which she was intubated and started on mechanical ventilation. A repeat CT scan of her head and MRI of her brain did not reveal any acute insults. Further investigations, including lumbar puncture, cerebrospinal fluid (CSF) analysis, blood and urine cultures, thyroid stimulating hormone (TSH) (4.03 µIU/mL), ammonia (12 µmol/L), morning cortisol (15.7 µg/dL) and adrenocorticotropic hormone (ACTH) levels (5.3 pg/mL) were unremarkable. Follow-up cortisol and ACTH levels obtained a week after resolution of her acute illness were also within normal limits. Electroencephalography displayed diffuse slowing, periods of attenuation and generalised periodic epileptiform discharges, consistent with non-specific encephalopathy. Given that an extensive multisystem workup ruled out other causes of hypothermia, it was ascertained by exclusion that her presentation was likely related to her risperidone use. Following the cessation of risperidone, she was liberated from the ventilator, and vasopressor support was discontinued.
Outcome and follow-up: case 1
The patient successfully reached her baseline status. A discussion regarding the risks of antipsychotics followed, and a process of shared decision making lead to the permanent discontinuation of risperidone on discharge.
Case presentation: case 2
A 69-year-old man with medical history of diabetes mellitus, chronic obstructive pulmonary disease, hypertension, peripheral vascular disease and schizophrenia to the emergency department (ED) from his personal care home with increasing confusion and weakness for 1 week. His home medications were risperidone, terazosin, finasteride, lisinopril, insulin and metformin. At presentation, he was noted to be bradycardic (39 beats per minute) and hypothermic (30.7 °C). He was normotensive. He was drowsy and lethargic with a GCS of 13 (E3V4M6).
Investigations: case 2
Laboratory testing revealed thrombocytopenia on complete blood count (haemoglobin: 127 g/L; white cells: 3.4 ×109/L; platelets: 160 ×109/L) and fairly unremarkable serum chemistries (sodium: 134 mEq/L; potassium: 5.5 mEq/L; chloride: 96 mEq/L; bicarbonate: 29 mEq/L; BUN: 14 mg/dL; creatinine: 0.8 mg/dL; glucose: 135 mg/dL). Other laboratory tests included an unremarkable TSH (2.536 µIU/mL), ammonia (12 µmol/L) and ethanol levels (undetectable). CXR and CT scan of the head did not reveal any abnormalities. ECG was significant for sinus bradycardia with no ischaemic changes.
Treatment: case 2
Active external rewarming was promptly initiated. He was admitted to the ICU; intravenous hydration and broad-spectrum antibiotics were administered. He subsequently developed severe hypotension, followed by cardiac arrest with PEA 4 hours following initial presentation. His last recorded temperature just prior to the arrest was 33°C. During the ensuing resuscitation, his rhythm changed to ventricular fibrillation, and the patient was defibrillated twice. Return of systemic circulation was achieved after 9 min, following which an amiodarone infusion was started. He was also intubated and initiated on mechanical ventilation at this time. Follow-up ECG did not reveal any ST elevation, and echocardiogram revealed normal ejection fraction and no overt abnormalities. Further subsequent investigations, including blood and urine cultures, morning cortisol (23.6 pg/mL) and ACTH stimulation study were unremarkable. With supportive measures and cessation of antipsychotics, the patient stabilised, and was liberated from the ventilator.
Outcome and follow-up: case 2
Cardiac catheterisation revealed non-obstructive multivessel coronary artery disease (CAD). His antipsychotics were discontinued at discharge after a discussion regarding their risks, and close psychiatry follow-up was encouraged.
Hypothermia is defined as a drop in core body temperature to below 35°C. Every year, about 1500 patients in the USA have hypothermia recorded on their death certificate.1 Hypothermia can occur from exposure to a cold environment, or can be a consequence of conditions such as hypoadrenalism, hypothyroidism, sepsis, cerebrovascular accident, burns, hypoglycaemic, drug intoxication or medication adverse effect. In our two patients, exposure to cold environment was ruled out through careful questioning and examination. A full workup for infectious aetiology yielded no proof of infection. Imaging of the central nervous system ruled out stroke, drug screen was negative, and a biochemical workup that included routine electrolyte and glucose measurement, TSH, ACTH, cortisol, ammonia ruled out associated conditions. Considering this, their presentation can be reasonably attributed to adverse drug reaction; antipsychotic use in particular. Application of the Naranjo probability scale of adverse drug reactions yields a ‘probable’ likelihood of this diagnosis in both these cases.
It is interesting to note that both of these patients had been on risperidone for several years prior to their presentation, with no recent dose changes, suggesting that hypothermia can occur irrespective of the length of exposure to the medication. We postulate that the presence of multivessel CAD in our second patient predisposed him to the cardiac manifestation of this adverse reaction, including severe bradycardia and cardiac arrest. No predisposing factors were found in our first patient. Both patients developed cardiac arrest shortly after presentation; prompt initiation of appropriate resuscitative and supportive measures, along with discontinuation of the offending medication lead to clinical improvement.
The effects of antipsychotic medications on thermal regulation have been noted going as far back as the clinical trials for the first antipsychotic, chlorpromazine.2 3 Hypothermia with antipsychotics is a rare adverse event that can lead to significant morbidity and mortality. The precise mechanism by which atypical antipsychotics, including risperidone, cause thermodysregulation is not known, but a few different mechanisms have been proposed,4 which will be summarised as follows:
Dopamine and serotonin antagonism: The additional action on serotonin is one reason that atypical antipsychotics may produce more hypothermia than typical agents. Serotonin is a known modulator of thermoregulation in the central nervous system; most atypical antipsychotics have a higher affinity for the 5-HT2a receptor than the D2 receptor and are also associated with hypothermia.
Predisposition due to structural disease: There have been studies in rats which demonstrate the potentiation of the hypothermic effects of antipsychotics in the presence of a lesion in the preoptic anterior hypothalamus, which is a centre of thermoregulation.5 Patients with pre-existing structural abnormalities in this region might be more susceptible to alterations in thermoregulation.
Neurotensin (NT) levels: NT is an important endogenous peptide that has been shown to have the ability to induce hypothermia; it also plays a role in the antipsychotic actions of APDs. There is a subset of schizophrenic patients who have a lowered concentration of NT in the CSF; reduced NT concentration appears to correspond with a higher severity of pathology. in this subset of patients, the administration of antipsychotics, when clinically effective, normalises NT levels in the CSF.6 7 The increase in CSF NT concentration, in fact, corresponds to improvement in negative symptoms. It is plausible that our patients belonged to this subgroup with low CSF NT concentration, which, on satisfactory treatment with antipsychotics, subsequently increased, causing thermodysregulation. CSF NT levels were not measured in our patients, because it is not the standard of care.
Environmental factor: Rat studies have shown that there is an environmental component to the hypothermic effect of APDs; their administration at a lower ambient temperature was more likely to cause hypothermia.8
There have been other reports of hypothermia associated with risperidone4 9; Brevik and Farver and Prerera and Yogaratnam describe cases of mild hypothermia in patients on risperidone.10 11 Chekakie at al report a similar effect in a patient taking risperidone and paroxetine.12 Paroxetine, a cytochrome P450 CYP2D6 inhibitor, has been shown to raise the level of plasma risperidone, and they hypothesise that this might have played a role in the development of hypothermia. Bookstaver and Miller report a case of mild hypothermia, bradycardia and seizure activity in a patient who had been switched from oral risperidone to its long acting depot form 10 weeks prior to presentation13 Kamp et al describe hypothermia following the initiation of pipamperone in a patient who was taking risperidone; they propose that the coadministration of two medications with strong 5-HT2 antagonism as the cause.14 This adverse effect was also reported to occur in an 11 years old.15 In these cases, withholding risperidone and supportive measures lead to the resolution of hypothermia. On the other hand, Jordan et al report a case of hypothermia which did not resolve despite the discontinuation of risperidone, and ultimately led to cardiac arrest and the patient’s demise.16 Another case of cardiac arrest as a consequence of risperidone induced hypothermia reported by Nagamine was successfully resuscitated.17
Death in patients with secondary hypothermia is often caused by the underlying condition rather than by hypothermia. In all types of hypothermia, consciousness, breathing and circulation are initially intact but are impaired as the body cools. There exists a high risk of cardiac arrest in the setting of hypothermia. Rapid initiation of external or internal rewarming, depending on the severity of hypothermia, and supportive measures including intravenous fluids and oxygenation as warranted, is crucial to the successful treatment of hypothermia and prevention of cardiac arrest. Mild hypothermia may be treated by passive external rewarming, while more severe presentations require the application of active external rewarming, such as in our patients, or even warm intravenous fluids. Inotropic support may be provided, if deemed necessary. The question of whether to interrupt, or altogether cease, the administration of antipsychotic is an open one. As Zonnenberg et al point out, of their case series of 57 patients with antipsychotic-related hypothermia, only 14 experienced more than one hypothermic episode, and only 3 of these did so following a switch to another antipsychotic.18 While they recommend temporarily withholding the offending antipsychotic in most cases, their findings suggest that resumption of the previous antipsychotic, or switching to another one are both reasonable options. Clinical judgement in this regard is paramount, in order to weigh the benefits and risks of doing so, taking into consideration the presence of additional risk factors for hypothermia. Given the severity of presentation in our patients, with cardiac arrest, we chose to discontinue antipsychotics at the time of discharge.
Hypothermia and cardiac arrest are rare adverse reactions that can occur in association with risperidone, which is a rare adverse reaction.
These adverse reactions can be seen regardless of the dose or length of exposure to risperidone.
Interruption of the medication, in combination with supportive measures, can result in positive outcomes.
Contributors NS contributed to the writing of the clinical presentation of case 1, as well as the literature review, discussion and review of similar cases. SB contributed to the writing of the clinical course of case 2. DR contributed to the literature review, discussion, including commentary on various mechanisms of action. PO was the principal investigator, and assisted in literature review and provided general supervision of the process, and made several changes which are reflected in the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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