Perioperative dexmedetomidine-induced delirium in a patient with schizophrenia: a case report

Abstract

Background

Dexmedetomidine is a selective α2 receptor agonist with sedative, analgesic, anxiolytic, and anti-sympathetic effects. Dexmedetomidine is widely used for various surgical procedures performed under general anaesthesia and sedation in the intensive care unit. Dexmedetomidine was known to relieve or improve the symptoms of delirium. Schizophrenia is a common psychiatric disease, and the number of surgical patients with schizophrenia is increasing gradually. Dexmedetomidine-induced delirium in patients with schizophrenia is a particular case.

Case presentation

This patient was a 75-year-old woman (height: 156 cm; weight: 60 kg) with a 5-year history of schizophrenia. Her schizophrenia was well controlled with medications. She was scheduled for open reduction and internal fixation for a patellar fracture. Spinal anaesthesia was administered for surgery, and dexmedetomidine was administered intravenously to maintain sedation. The patient became delirious half an hour after the surgery began. The intravenous infusion of dexmedetomidine was discontinued immediately, intravenous propofol was subsequently administered, and the patient stopped experiencing dysphoria and fell asleep. After surgery, the patient stopped using propofol and recovered smoothly. She was transferred back to the general ward and was discharged from the hospital without any abnormal conditions on the 9th day after surgery.

Conclusions

To the best of our knowledge, this is the first report of a patient with schizophrenia who developed delirium during the infusion of a normal dose of dexmedetomidine without an intravenous injection of any other sedative. The exact mechanism causing dexmedetomidine-induced delirium remains unclear, and this adverse reaction is rare and easy to ignore. Clinicians and pharmacists should be vigilant in identifying this condition.

Background

Dexmedetomidine is a highly selective α2 receptor agonist with sedative, analgesic, anxiolytic, and anti-sympathetic effects that has been widely used for sedating patients undergoing surgery and sedated in the intensive care unit [1, 2]. Bradycardia and hypotension are among its most common side effects [1]. The incidence of delirium after the administration of dexmedetomidine is very low. Dexmedetomidine has been used to treat delirium, with good results [3, 4]. Although delirium is a rare complication associated with the intravenous infusion of dexmedetomidine, it is clinically relevant.

Case presentation

The patient was a 75-year-old woman (height: 156 cm; weight: 60 kg) with a 5-year history of schizophrenia who experienced persecutory delusions and displayed violent behaviour. Three hours earlier, she experienced pain and limited movement in her right knee, which was diagnosed as a fracture of the right patella. She was scheduled for open reduction and internal fixation of the patellar fracture. On admission, the patient’s chronic medications included oral sodium valproate (600 mg/d) and risperidone (3 mg/d). The patient had not experienced any episodes of mental illness in the previous year. She had had hypertension for decades, which was successfully controlled with lacidipine (4 mg/d). The patient’s medical history, physical examination results, and blood chemistry findings were unremarkable, and her case of schizophrenia was stable.

The patient took her regular medications in the morning before surgery. No premedication was administered. She was conscious, could answer questions clearly and was able to cooperate with the doctors and nurses, and then venous access was established in the preoperating room. The patients were monitored according to American Society of Anaesthesiologists standards in the operating room. Before anaesthesia, her blood pressure (BP), heart rate (HR) and SPO2 were 140/70 mmHg (1 mmHg = 0.133 kPa), 62 beats per minute and 98%, respectively. Spinal anaesthesia was administered (L3/L4). We prepared some vasoactive medicines to maintain haemodynamic stability, such as atropine for bradycardia, intravenous esmolol hydrochloride for tachycardia, fluid and noradrenaline for hypotension, and urapidil hydrochloride for hypertension. Using a face mask, oxygen was inhaled at 3 L/min. The patient was placed in the lateral position. After disinfecting and covering the area intended for operation, local infiltration anaesthesia was administered with 2 mL of 2% lidocaine hydrochloride (40 mg), followed by subarachnoid puncture via the midline. After confirming that the cerebrospinal fluid could flow freely, 1.4 mL of 0.75% ropivacaine (10 mg) was injected intrathecally. A cold swab was used for sensory examination every 1–2 min. The plane of anesthesia was blocked was up to T10 , and the patient’s vital signs were stable (BP 126/66 mmHg, HR 68 beats per min, SPO2 100%). Afte the plane of anesthesia block was fixed, dexmedetomidine was administered intravenously for intraoperative sedation. The loading dose was 0.3 µg/kg for more than 10 min, followed by continuous administration of 0.4 µg/kg per hour.

The patient was emotionally stable at the beginning of the surgery, and the vital signs were as follows: BP 122/62 mmHg, HR 60 beats per min, and SPO2 100%. Half an hour after the operation began, the patient became dysphoric, confused, was unable to communicate, and even removed the intravenous fluids. At this point, the patient’s vital signs were as follows: BP 130/70 mmHg, HR 70 beats per min, and SPO2 100%. After the speed of the dexmedetomidine infusion was increased, the patient became increasingly dysphoric. The patient’s vital signs were as follows: BP 145/72 mmHg, HR 88 beats per min and SPO2 100%. The patient underwent the confusion assessment method, which was positive for delirium [5]. The intravenous dexmedetomidine infusion was discontinued immediately, intravenous propofol (40 mg) was administered, and the patient subsequently stopped experiencing dysphoria and fell asleep. At this point, the patient’s vital signs were as follows: BP 125/63 mmHg, HR 61 beats per min and SPO2 100%. Anaesthesia was maintained with a continuous infusion of propofol (100 mg·h^− 1).

The surgery lasted for 1 h and 30 min. The total blood loss volume and the volume of intravenously administered crystalloids were 50 mL and 1000 mL, respectively. The anaesthetic (propofol) was discontinued after surgery, but the patient still developed dysphoria. Propofol was pumped continuously for half an hour and then discontinued, and the patient woke up peacefully. The patient had no recollections of what had happened. The patient’s haemodynamic status, as indicated by the vital signs, remained unremarkable during this period. The patient responded well to anaesthesia without pain or other discomfort. We continued to observe the patient for an hour and found no significant changes in her haemodynamic status or neurological vital signs. Because the patient’s condition remained unremarkable, she was transferred to the general ward. No dysphoria or communication disturbance was observed after the patient returned to the general ward. The patient did not receive benzodiazepines or vasoactive agents throughout the perioperative period. The subsequent postoperative course was uneventful, and the patient was discharged on postoperative day 9.

Discussion and conclusions

We present the case of a patient with schizophrenia who developed delirium during a dexmedetomidine infusion. The patient was an elderly woman who regularly took medications to control her schizophrenia. She has experienced persecutory delusions and displayed violent behaviour. Because the patient had no history of delirium, endocrine abnormalities, or stable intraoperative vital signs and the newly developed neurological abnormalities occurred only once, drug-induced delirium was suspected. The patient recovered from delirium 1.5 h after dexmedetomidine was discontinued. Owing to the half-life of dexmedetomidine in elderly patients, delirium can resolve upon discontinuation of dexmedetomidine infusion. The patient did not develop any psychiatric symptoms, including delirium, during the remainder of the hospital stay, further supporting the diagnosis of dexmedetomidine-induced delirium. Schizophrenia is a chronic and severe brain disorder that afflicts approximately 1% of the population worldwide [6–8]. Despite its relatively low prevalence, schizophrenia usually presents early in life, resulting in severe lifelong disability for patients and increasing financial and nursing burdens on their families [7]. Between 20% and 40% of patients with schizophrenia attempt suicide during the course of their illness [9, 10], and the lifetime risk of suicide is estimated to be 3.23% [11]. The main causes of this disease are an abnormal brain structure, genetic factors, pregnancy, childbirth factors, and environmental influences [7]. Schizophrenia is one of the most severe yet common psychiatric diseases, and the number of surgical patients with schizophrenia is increasing gradually.

Delirium is an acute and fluctuating cognitive impairment that manifests as a decreased ability to maintain attention, disorientation to time and place, memory impairment, and disturbance of the sleep and wake cycle [12]. Postoperative delirium is an acute, short-lived syndrome that usually occurs within seven days after surgery and is characterized by fluctuating disturbances in attention, awareness and cognition [12, 13]. Delirium usually presents with emotional abnormalities, confusion, gibberish, restlessness, confusion and other symptoms and can lead to long-term cognitive impairment and affect patient prognosis [14].

Dexmedetomidine is a selective α2 receptor agonist with sedative, analgesic, anxiolytic and anti-sympathetic effects that is widely used in various surgical procedures performed under general anaesthesia and sedation, and for sedation in the intensive care unit [1, 2]. The sedative and analgesic effects of dexmedetomidine are mediated by α2 adrenergic receptors in the brain (plaque coeruleus) and spinal cord, making sedation in patients similar to the natural sleep and wake cycle [2]. Some studies [15, 16] have shown that dexmedetomidine can reduce the occurrence of postoperative delirium in nonpsychiatric patients. It can also reduce the incidence of delirium and its duration in intensive care unit patients receiving mechanical ventilation and after surgery [17]. Nevertheless, a study has shown that patients with schizophrenia are more likely to develop delirium [18]. Another study [19] revealed that the postoperative sleep quality of patients with schizophrenia improved and that postoperative delirium in patients with schizophrenia was effectively prevented after the application of dexmedetomidine at a load dose of 1.0 µg/kg and a maintenance dose of 0.4 µg·kg^− 1·h^− 1. Dexmedetomidine is now available as an orally dissolving film administered sublingually or buccally for the treatment of acute agitation associated with schizophrenia or bipolar I or II disorders in adults [20, 21]. The mechanism of action and pharmacodynamics of dexmedetomidine differ significantly from those of the drugs currently used to treat acute agitation in psychiatric settings. Dexmedetomidine is a selective and potent agonist of the α2-adrenergic receptor with high potency for all three enzymatic isoforms (A, B, C), with a Ki (inhibitor constant) of 4–6 nM [20, 22, 23]. Agonism of α2-adrenergic receptors within the brainstem, specifically α2a-adrenoreceptors, affects two pathways that contribute to a reduction in the stress response. Modulation of norepinephrine release from the locus coeruleus reduces sympathetic hyperarousal, and modulation of the bed nucleus of the stria terminalis decreases corticotrophin-releasing factors. Through the activation of presynaptic α2a-adrenoreceptors, it is believed that dexmedetomidine exerts its effect in the treatment of acute agitation associated with schizophrenia and bipolar disorders [20]. The locus coeruleus plays an important role in brain circuits. The locus coeruleus can affect brain function in a way that ranges from normal arousal to anxiety/fear, a subjective experience to agitation, which advances from subjective to behavioural manifestations depending on how rapidly the locus coeruleus neurons are firing. The locus coeruleus plays a role in regulating and coordinating the cardiovascular and respiratory systems, as does the intensity of afferent inputs to the brain. Activation of the locus coeruleus enhances the sympathetic tone and increases the ratio of sympathetic to parasympathetic activity. The locus coeruleus influences numerous parameters of the cardiovascular system, including cardiac output and peripheral resistance, which are essential in fight or flight reactions [23].

However, some studies have revealed psychiatric complications caused by dexmedetomidine [24–26] (Table 1). Straw et al. [24] reported the case of a 41-year-old female patient who required mechanical ventilation for acute respiratory distress syndrome. Her analgosedation was stopped to facilitate weaning from mechanical ventilation, and dexmedetomidine was used to manage agitation after extubation, and she subsequently developed delirium and fever. The symptoms of delirium disappeared, and the body temperature returned to normal after discontinuation of dexmedetomidine. Nishizaki et al. [25]. reported a case of Lewy body dementia in a patient who was sedated with dexmedetomidine and experienced hallucinations during the recovery of consciousness. Qiu et al. [26] reported that an 81-year-old male with severe pain in the left toe due to bipedal blue toe syndrome developed irritability and delirium after intravenous injection of dexmedetomidine for 6 h. During hospitalization, the drug was discontinued several times, and delirium improved; however, delirium was observed after the use of dexmedetomidine. On the sixth day after discontinuation, the patient regained consciousness and did not develop delirium. Furthermore, acute agitation, hallucinations and delirium have been reportedly associated with clonidine, a similar alpha-2 selective adrenergic agonist [27–29]. In each of these previously reported cases, changes in mental status occurred shortly after the initiation of clonidine or an increase in dose and resolved upon discontinuation of the agent. With the previously increased use of dexmedetomidine, uncommon and undiscovered adverse drug reactions are emerging.

Table 1.

Published reports of cases of Dexmedetomidine-Induced Delirium

	Straw et al [24]	Nishizaki et al. [25]	Qiu et al [26]
Age/Sex	41/F	87/F	81/M
Diagnosis	ARDS	Lewy Body Dementia	Bipedal blue toe Syndrome
Operation	Extubation	Dental treatment	None
Major Medical History	Depression, Anxiety	Hypertension, Stroke	Hypertension Coronary heart disease
Other Sedative Related to delirium	Benzodiazepines, Fentanyl, Propofol	None	None
Dose of DEX	0.3–1.7 µg·kg − 1·h − 1	initial load 3 µg·kg − 1·h − 1 for 10 min, maintain 0.24 µg·kg − 1·h − 1,	16 µg·h − 1
Complications	Fever, Delirium	Visual Hallucinations	Delirium, Dysphoria
Management	Discontinuation of dexmedetomidine	Discontinuation of dexmedetomidine	Discontinuation of dexmedetomidine

Abbreviations: ARDS, acute respiratory distress syndrome; DEX, dexmedetomidine;

Propofol is a classic sedative drug that is widely used in operating rooms and intensive care units [30]. Propofol produces hypnotic/sedative effects by activating γ-aminobutyric acid (GABA-A) receptors directly and inhibiting N-methyl-D-aspartate (NMDA) receptors [31]. Several studies have revealed a higher incidence of delirium after the administration of propofol than after the administration of dexmedetomidine [32, 33]. However, patients who developed intraoperative delirium were also excluded from the study by Zhu et al., and the authors did not compare the incidence of delirium after the administration of dexmedetomidine to that of lighter sedation with propofol, which was not significantly different [32]. Zhu et al. reported that heavier sedation with dexmedetomidine was prone to cause haemodynamic instability in older patients, so they used a lower dose. Moore AD et al. [34]. reported that the use of propofol as a monotherapy anaesthetic can reduce the risk of emergence delirium in paediatric patients anesthesia. Therefore, the effects of propofol on cognition are currently inconclusive. Dexmedetomidine was compared with modulators of GABA receptors [35], which are well known to increase the incidence of delirium [36]. Therefore, it is unclear whether dexmedetomidine induces delirium, unlike other sedatives, or whether it even prevents delirium. However, the mechanisms underlying the development of delirium are not clear for either drug. The symptoms of delirium improved after the administration of propofol, which may be related to the different mechanisms of action of the drugs used in this case.

Benzodiazepines are frequently used for patients undergoing surgery and anaesthesia, because of their anxiolytic and amnestic properties and are used as a premedication or intraoperatively as part of anaesthesia [37]. Nevertheless, many studies have shown that benzodiazepines are associated with an increased risk of delirium [38, 39]. Ketamine is an anaesthetic with both analgesic and sedative properties that is used in both surgical and medical critically ill adults for analgosedation [40, 41]. Ketamine is an NMDA receptor antagonist that results in a dissociative state that clinically manifests as catatonia and amnesia and is associated with hallucinations and psychosis in a dose-dependent manner [42]. There are similarities between the clinical effects of ketamine and the symptoms of delirium [43]. Ketamine use increases the risk of postoperative delirium and cognitive impairment in surgical patients [44, 45].

A search of the pharmacovigilance database of the World Health Organization (http://www.vigiaccess. org) (as of December 26, 2023) revealed 5483 cases of adverse reactions related to dexmedetomidine, of which 488 (6%) were nervous system adverse reactions.

Prior to our case, there have been reports [24, 26] of similar occurrences of delirium caused by dexmedetomidine, although none have involved the occurrence of delirium in a patient with schizophrenia. To the best of our knowledge, this is the first report of a patient with schizophrenia who developed delirium during the infusion of a normal dose of dexmedetomidine without an intravenous injection of any other sedatives. The exact mechanism causing dexmedetomidine-induced delirium remains unclear, and this adverse reaction is rare and easy to ignore. Clinicians and pharmacists should be vigilant in this regard. Vital signs and psychiatric symptoms should be closely monitored during an intravenous infusion of dexmedetomidine. Additional research is needed to better quantify the incidence of adverse events and confirm our novel finding that dexmedetomidine can induce delirium in patients with schizophrenia.

Abbreviations

cm

centimetre

Kg

kilogram

Mg/d

milligram per day

µg/kg

microgram per kilogram

Mg/h

milligram per hour

L/min

litre per minute

BP

blood pressure

HR

heart rate

GABA

γ-aminobutyric acid

NMDA

N-methyl-D-aspartate

Author contributions

Lingling, Sun MD; Jing, Mu MD; Yajie, Wang UD; Huanzhong, He MD; Department of Anesthesiology, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China.L.S. contributed to the data collection and manuscript preparation. J.M. AND Y.W. assisted with literature review. H.H. contributed to the manuscript modification.The authors declare no conflict of interest.

Funding

Not applicable.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this report.

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors have no conflicts of interest to declare.