Case Series: Repeated Brief Dexmedetomidine Infusion to Prevent Withdrawal and Worsening in Alcohol Withdrawal Delirium

Alcohol withdrawal delirium (AWD) is the most serious manifestation of alcohol withdrawal. Benzodiazepines (BZDs) are the recommended primary first-line pharmacotherapy for AWD. It has been estimated that around 7% of people with severe AWD may be refractory to BZDs. ¹ High BZDs doses may not only fail to alleviate symptoms but also increase the risk of respiratory depression and ICU delirium. ¹ BZDs alone may be insufficient in controlling autonomic hyperactivity. People with AWD are also likely to have compromised liver function, and therefore, adjunctive medications like antipsychotics, antiepileptics, β-blockers, and α2-agonists have been used to enhance symptom control and reduce BZD dose in AWD. ²

Dexmedetomidine, a highly selective α2 adrenergic receptor agonist, has emerged as a promising adjunct in AWD management, acting as a potent sympatholytic agent that reduces BZD requirements and improves hemodynamic parameters.^3,4 While dexmedetomidine has been increasingly used off-label for AWD, the phenomenon of dexmedetomidine withdrawal exacerbating AWD symptoms has not been described in the literature. The Food and Drug Administration (FDA) still recommends that dexmedetomidine infusions be less than 24 hours. ⁵ Short infusions can limit their clinical utility in scenarios such as AWD, which typically last for a few days. Clinicians have therefore used infusions lasting up to a few days in various conditions, including for AWD. ⁶ In this case series, we describe the clinical course of patients with AWD who experienced worsening following dexmedetomidine withdrawal, and we propose a novel strategy of repeated brief infusions to mitigate this risk while preserving its therapeutic benefits. The cases were all managed in the high dependency unit of the psychiatry ward by psychiatrists. Our method is a practical approach to extending dexmedetomidine use beyond the FDA-recommended window in a controlled manner, potentially informing future protocols for managing refractory AWD.

Case Report 1

A 45-year-old male presented with moderate alcohol withdrawal (Clinical Institute Withdrawal Assessment – Alcohol Revised (CIWA-AR) = 12). ⁷ His withdrawal was controlled (CIWA-Ar < 10) in the first 48 hours with a 24-hour IV lorazepam dose between 20 and 40 mg. On Day 3, he developed AWD (ICD-11 diagnosis: Alcohol induced delirium [6C40.5]) with the same BZD dose. ⁸ Laboratory investigations revealed normal electrolytes except hypomagnesemia (Serum magnesium: 1.33 mg/dl), and hence magnesium supplementation was started. The time of onset from the last drink and clinical features (autonomic hyperactivity, sweating, hyperactive delirium) led the team to conclude a diagnosis of alcohol-related delirium over hypomagnesemia-related delirium. Over the next 24 hours, AWD remained uncontrolled (Richmond Agitation Sedation Scale [RASS] score fluctuating between +3 and +2 and CIWA-AR score >18) despite increasing lorazepam to 60 mg/24 hrs. ⁹ For all cases in this series, the 24-hour dose was determined by administering a bolus of 8 mg lorazepam intravenously (i.v.) and evaluating the patient every 15 minutes. Due to the presence of sustained autonomic dysregulation and to achieve greater sedation, dexmedetomidine infusion was started on Day 5 at a rate of 0.4 μg/kg/hr. This lowered the lorazepam requirement to 40 mg/24 hrs. AWD continued to improve on Day 7, and the lorazepam requirement dropped further with adequate sedation. The patient’s orientation improved on Day 8; therefore, in an attempt to withdraw dexmedetomidine, the infusion rate was decreased to 0.2 μg/kg/hr. After 6 hours, the patient developed tachycardia, hypertension, diaphoresis, hyperthermia, and became delirious again. After thorough evaluation to rule out any other contributory cause, dexmedetomidine infusion was restarted at the previous infusion rate of 0.4 μg/kg/hr. The patient’s symptoms reduced after a few hours, and it was decided to gradually taper dexmedetomidine to reduce the risk of developing withdrawal. Over the next 5 days, the rate of infusion was gradually tapered (by 0.1 μg/kg/hr and then by 0.05 μg/kg/hr on the last day) till Day 12, when dexmedetomidine had been completely withdrawn without further complications. He was eventually transitioned to oral BZDs and subsequently discharged.

Case Report 2

A 42-year-old male presented with moderate alcohol withdrawal (CIWA-AR = 10). He required 16 mg and 32 mg of IV lorazepam on Day 1 and Day 2 (with additional supportive medications), respectively. On Day 3, he developed AWD (ICD-11 diagnosis: Alcohol induced delirium [6C40.5]). The I.V. Lorazepam dose was increased to 48 mg/24 hrs on Day 3 and 60 mg/24 hrs on Day 4. Despite this, the patient remained agitated (requiring haloperidol for symptom control) with symptoms of autonomic instability (for the CIWA-AR and RASS scores, please refer to the supplementary file). Laboratory investigations ruled out an organic cause for delirium. Dexmedetomidine infusion was initiated on Day 5 at a rate of 0.4 μg/kg/hr. This resulted in reduced autonomic instability, a lower lorazepam requirement, and greater sedation. The patient became oriented and showed signs of AWD resolving on Day 7. The infusion rate of dexmedetomidine was decreased to 0.2 μg/kg/hr, and after 4 hours, the patient was again disoriented, with tachycardia, diaphoresis, and hyperthermia. Dexmedetomidine was re-initiated at the original rate (accompanied by an increase in lorazepam dose), followed by a taper over 4 days (at a rate of 0.1 μg/kg/hr) till Day 11, when the AWD finally resolved. He was eventually transitioned to oral BZDs and discharged following relapse prevention therapy.

Case Report 3

A 36-year-old male, with a history of long-term heavy alcohol use, was admitted to the addiction medicine unit with symptoms of AWD (ICD-11 diagnosis: Alcohol induced delirium [6C40.5]) following a road traffic accident 72 hours earlier. Complete blood count, liver and kidney function tests, serum electrolytes, and a CT scan of the head ruled out organic causes of delirium. The patient was administered 40 mg of IV lorazepam in the first 12 hours with partial control of agitation (and continued autonomic instability). On Day 2, the dose of I.V. lorazepam was increased to 96 mg/24 hrs. To reduce the BZD requirement, dexmedetomidine infusion was initiated at a rate of 0.4 μg/kg/hr on the same day. This reduced autonomic instability, resulting in adequate sedation. However, mindful of the withdrawal experience by the previous two patients, we chose to limit dexmedetomidine infusion to a maximum of 12 hours a day. These infusions were administered during the daytime. Dexmedetomidine was infused at a rate of 0.4 μg/kg/hr for 8 hours and then tapered at a rate of 0.1 μg/kg/hr per hour for 4 hours. A 12-hour infusion-free period was observed (BZD was used at the previous rate during this period). This was repeated every day for the next 3 days. The patient’s AWD was well controlled, and there was no observed increase in agitation or worsening of the symptoms in the hours when dexmedetomidine was not infused. By Day 5, AWD had resolved, and the patient had become oriented and cooperative. He was subsequently transferred to the orthopedic ward for continued management.

Discussion

This case series demonstrates an innovative way to prolong the use of dexmedetomidine while mitigating the risk of withdrawal. Comparative tables containing relevant clinical history and daily medications for all three patients are detailed in the supplementary file. For all cases, the lorazepam dose requirement over 4 hours was extrapolated to estimate the 24-hour dose requirement. Dexmedetomidine withdrawal causes sympathetic overactivity. This was consistent with symptoms observed in the first two patients. ⁵ This is the first description of dexmedetomidine withdrawal in AWD. Dexmedetomidine withdrawal in AWD is significant due to overlapping symptoms, neurochemical mechanisms, and complications in management. Dexmedetomidine’s advantage in AWD stems from its targeting of the noradrenergic system—an overlooked secondary mechanism. However, its withdrawal leads to hyperactivity of the same system, complicating management. Despite being effective for AWD (especially among those unresponsive to standard BZD treatment), the scenario, duration, and dose for optimal use of dexmedetomidine remain undetermined. ⁴ Individual patient factors and response to treatment are likely the determinants of these questions. ¹⁰

In AWD, the duration of dexmedetomidine infusion has extended to many days altogether.^11,12 Although not described for AWD, the incidence of dexmedetomidine withdrawal in other critically ill patients has ranged from 1/3rd to 2/3rd of all people who received infusion.^5,13 Peak doses of 0.8 µg/kg/hr and cumulative daily doses greater than 12.9 µg/kg/d were identified as risk factors. ⁵ Both the patients who developed withdrawal in our center had lower peak and cumulative doses. Moreover, the cumulative dose was nearly half in the patient who received repeated short infusions compared to those who received continuous infusions. This is a particular advantage of the repeated short infusions method that we have used.

The peak dose of dexmedetomidine used was within the dose range of 0.39–0.83 µg/kg/hr that has been associated with withdrawal. ¹³ The development withdrawal at the lower limit (and also at lower cumulative doses) might have been because of the concomitant decrease in the lorazepam dose. Concomitant withdrawal of opioids or BZDs has also been identified as a risk factor for developing withdrawal. The purpose of dexmedetomidine infusion is to reduce the 24-hour BZD requirement because of its BZD-sparing effect. Our case series, therefore, demonstrates that rather than using dexmedetomidine to reduce BZD requirements, dexmedetomidine may be better used in AWD as a short-term procedure to manage transient increases in autonomic hyperactivity and agitation—again highlighting that short-term infusions may be a better strategy.

Strategies to prevent dexmedetomidine withdrawal after prolonged infusion include shorter infusions, gradual weaning, transitioning to enteral clonidine, and subcutaneous dexmedetomidine. ¹⁴ We used a combination of short infusions and weaning to minimize the risk of withdrawal. Our third case demonstrates that this strategy of repeated brief dexmedetomidine (rbDex) can minimize the risk of withdrawal while maintaining clinical efficacy. This method has additional advantages. It simplifies dexmedetomidine administration, maintains clinical efficacy, and enhances the utility of dexmedetomidine for prolonged conditions, such as AWD. Animal studies have indicated that desensitization of alpha-2 receptors begins between 24 and 48 hours of dexmedetomidine exposure and can result in a reduction in sedation. ¹⁵ The infusion breaks in the rbDex strategy can potentially prevent such receptor desensitization and may be a reason behind reduced tolerance.

Beyond minimizing the risk of withdrawal, there is one additional benefit to the rbDex strategy in AWD. Alteration of the sleep-awake cycle is a cardinal feature of AWD. ¹⁶ Altered sleep architecture may be pathognomonic for the development of DT, with complete Stage 1 sleep and the absence of Stage 2 and NREM sleep being observed just before the onset of AWD. ¹⁷ Dexmedetomidine acts on the endogenous sleep-promoting pathway, and the sedation produced by dexmedetomidine more closely mirrors natural sleep (specifically Stage 2 non-rapid eye movement sleep [NREM]) compared to BZDs. ¹⁸ Although we infused dexmedetomidine during daytime (to allow for greater clinical monitoring), a short-term infusion of dexmedetomidine (especially during the periods of natural sleep) may be more effective in correcting abnormalities in the sleep-awake cycle and enhancing recovery from AWD.

These cases highlight that although dexmedetomidine may be an effective adjuvant for the management of AWD, careful administration is needed, given withdrawal risks. Dexmedetomidine withdrawal can be indistinguishable from AWD and worsen it. Its clinical utility lies in achieving short-term sedation and controlling autonomic arousal rather than reducing BZD dose. The rbDex strategy is suitable for achieving clinical improvement while minimizing withdrawal risk. This approach adheres to FDA dosing guidelines while remaining effective beyond 24 hours. Such brief infusions have helped control agitation and autonomic hyperactivity in other psychiatric conditions, such as methamphetamine use, bipolar disorder, and illicit drug ingestion.^19,20 Repeated brief infusions are valuable in AWD requiring high-dose BZDs compared to prolonged infusions.

Conclusions

While dexmedetomidine may be helpful in AWD management, clinicians must be aware of withdrawal risk. Its use must be measured and doses carefully determined to minimize the risk of withdrawal. Repeated brief dexmedetomidine may be superior to prolonged infusion and likely maximizes clinical utility in AWD. The drug’s properties, including rapid onset and offset, make it suitable for short infusions and as an AWD adjunct. Larger studies are needed to validate these findings.

Reporting Guideline (Supplementary Online Material): CARE reporting guidelines. ²⁰

Supplemental Material

Supplemental material for this article available online.

Supplemental Material

Supplemental material for this article available online.