Phenobarbital for weaning continuous sedative agents in critically ill patients: a report of two cases

Introduction

Background

Phenobarbital, a long-acting barbiturate, exerts its effects by enhancing the activity of gamma-aminobutyric acid (GABA) receptors in the central nervous system. This mechanism leads to inhibitory neurotransmission and reduced neuronal excitability (1). Beyond its established role as an anticonvulsant, phenobarbital has been utilized as a sedative agent and as a potential treatment option for alcohol withdrawal in critically ill patients (2).

Rationale and knowledge gap

While clinical practice guidelines provide recommendations for sedation depth and choice of sedative agents, they often overlook the specific challenge of weaning continuous sedative and analgesic medications (3). This can pose difficulties in critically ill patients due to underlying disease complexities, development of tolerance, and the presence of agitation, anxiety, or delirium. Moreover, titratable continuous medications are typically limited to intensive care units (ICUs) within healthcare systems. As a result, the inability to successfully wean these infusions in patients who no longer require ICU-level care can lead to prolonged stays in the ICU and hospital (4).

Objective

Efficiently addressing the weaning of continuous sedative and analgesic infusions is crucial for optimizing patient outcomes and resource utilization. The potential of phenobarbital as a solution in this context warrants further investigation and consideration as part of comprehensive sedation management strategies in critically ill patients. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-127/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report was waived from patient consent according to the UCLA Institutional Review Board.

Case 1

A 42-year-old male with a history of polysubstance use disorders was transferred to our institution directly from another hospital’s emergency department for higher level of care and ongoing treatment of presumed wound botulism. The patient reported using black tar heroin on three separate occasions (2 weeks, 4 days, and 2 days) prior to admission. He had wounds on bilateral upper extremities for 2 weeks. Developed double vision followed by difficulty swallowing 2 days prior to arrival. At the outside hospital emergency department, the patient was given heptavalent botulism antitoxin and intubated due to negative inspiratory force (NIF) of negative 18 and concern for acute neuromuscular respiratory failure. Upon admission to our medical/surgical critical care unit, multiple disciplines including infectious disease, neurology, orthopedics, and surgery were consulted. On hospital-day 2, the patient underwent surgical incision, drainage, and debridement of wounds. Broad-spectrum antibiotics were continued. Patient remained on mechanical ventilation postoperatively and required fentanyl infusion at 100 mcg/h, propofol at 20 mcg/kg/min, dexmedetomidine at 0.5 mcg/kg/h, and ketamine at 1.5 mg/kg/h to maintain Richmond Agitation Sedation Scale (RASS) 0 to −2 and Critical Care Pain Observation Tool (CPOT) of less than 3. From hospital-day 3 through day 5, the continuous analgesia and sedative medications were titrated to obtain the minimum required doses to maintain light sedation and adequate analgesia. This was accompanied by daily trials of spontaneous awakening and breathing trials based on our institutional guidelines. On day 5, there was an attempt to extubate the patient, however the critical care team did not appreciate posterior oropharyngeal tone and the patient was re-intubated for persistent neuromuscular weakness and inability to protect airway. The patient continued to remain on mechanical ventilation and required continuous analgesia and sedation. On hospital-day 10, the patient was intubated for the third time following self-extubation causing respiratory distress and oxygen desaturation. On hospital-day 12, the patient underwent a successful tracheostomy procedure. However, even 24 hours post-tracheostomy procedure, the patient remained on infusions of propofol 20–30 mcg/kg/min, dexmedetomidine 1.5 mcg/kg/h, and fentanyl 200 mcg/h. Despite multidisciplinary efforts to wean continuous analgesia and sedation, the patient experienced acute episodes of discomfort and agitation marked by CPOT scores of 4 to 5 and RASS scores of +2 to +3. At this time, the addiction medicine team was consulted due to difficulties in tapering the continuous infusion medications. The primary recommendation of the addiction medicine team was starting a phenobarbital taper as follows:

Day 1 (hospital-day 14): phenobarbital intravenous (IV) 150 mg five times daily for five doses;

Day 2 (hospital-day 15): phenobarbital IV 150 mg every 6 hours for four doses;

Day 3 (hospital-day 16): phenobarbital IV 150 mg every 8 hours for three doses;

Day 4 (hospital-day 17): phenobarbital IV 150 mg every 12 hours for two doses.

Significant improvement in RASS and CPOT scores were observed upon initiation and throughout the phenobarbital taper with maximum scores of +1 and 3, respectively. Propofol was weaned off and discontinued on day 2 of phenobarbital taper (hospital-day 15). Fentanyl and dexmedetomidine infusions were weaned gradually and turned off on days 3 and 4 of the phenobarbital taper, respectively. There was no further need for other continuous sedatives or analgesic agents. Patient’s alertness started to improve on day 2 of phenobarbital taper. He was able to follow commands and answer yes/no questions appropriately. Phenobarbital taper was completed in the critical care unit and the patient was transferred out of ICU to the hospital ward on day nineteen of admission.

Case 2

A 30-year-old female with cystic fibrosis status post bilateral orthotopic lung transplant in 2018 complicated by recurrent admissions for pneumonia was admitted to the hospital for hypoxic respiratory failure with oxygen saturations in the 70s. Of note, the patient had been known to the addiction medicine consult service and maintained on buprenorphine and hydromorphone for chronic pain as well as diazepam for panic disorder prior to admission. Multidrug-resistant organisms were isolated from respiratory cultures for which the patient was receiving appropriate antibiotics. On the fourth day of hospital admission, her respiratory status decompensated, and she was promptly intubated and transferred to the ICU. Due to her high tolerance from chronic use of benzodiazepines and opioids, she required high doses of hydromorphone (up to 1 mg/h, midazolam (up to 4 mg/h), and propofol (up to 20 mcg/kg/min) infusions to maintain CPOT score less than 3 and RASS score between 0 and −2. Patient’s oxygen requirements improved over the next few days however, any attempt at weaning continuous sedation and analgesia resulted in acute agitation and anxiety associated with significant oxygen desaturation episodes. Throughout hospital-days 10 to 14, patient was receiving dexmedetomidine at 1.5 mcg/kg/h, hydromorphone at 4–5 mg/h, midazolam at 4–10 mg/h, and propofol at 30–40 mcg/kg/min. Despite high doses of these medications, the patient was arousable with an RASS score of −1 to −2 and a CPOT score of 0. Although from oxygenation standpoint, patient was determined to be a candidate for extubation, due to high requirements for continuous analgesia and sedation, the addiction medicine team was consulted to assist with weaning of these infusions and eventually transitioning to an oral regimen of opiates and benzodiazepines. Addiction medicine team recommended starting a phenobarbital taper regimen as follows:

Day 1 (hospital-day 14): phenobarbital IV 30 mg every 4 hours for six doses;

Day 2 (hospital-day 15): phenobarbital IV 30 mg every 6 hours for four doses;

Day 3 (hospital-day 16): phenobarbital IV 30 mg every 8 hours for three doses;

Day 4 (hospital-day 17): phenobarbital IV 30 mg every 12 hours for two doses.

The patient was successfully extubated on hospital-day 14 and remained on hydromorphone at 4 mg/h and dexmedetomidine at 1 mcg/kg/h after extubation. By hospital-day 16, hydromorphone and dexmedetomidine infusions were discontinued and the patient was downgraded from ICU to the medicine unit. Addiction medicine team continued to follow the patient to ensure appropriate transition to oral analgesics and anxiolytics. Four-day phenobarbital taper assisted with mitigating the need for otherwise difficult to wean continuous analgesia and sedative infusions.

Discussion

Key findings

Length of stay in the ICU is a critical factor in healthcare resource utilization. Weaning continuous sedative and analgesic infusions can pose challenges, leading to prolonged ICU stays for patients who are otherwise eligible for lower levels of care. The cases described above demonstrate the potential of a short course of IV phenobarbital in facilitating the weaning of continuous sedative medications ultimately reducing ICU and hospital lengths of stay.

Strengths and limitations

Intermittent dosing of phenobarbital allows for easier administration compared to continuous medications and could eliminate the need for ICU stays due to such medications. Additionally, its prolonged half-life aids in weaning patients off continuous sedative medications. In both cases described here, the phenobarbital taper facilitated less invasive respiratory support strategies and was not associated with any adverse hemodynamic effects. Nevertheless, it is important to recognize the limitations of using phenobarbital for weaning continuous sedation. Phenobarbital does not bind opioid receptors, and thus it does not address opiate withdrawal or pain. Inappropriate dosing of phenobarbital can cause over-sedation and has been associated with hypotension and respiratory depression. Phenobarbital is also considered a strong inducer of cytochrome P450 (CYP) enzymes, which may lead to drug-drug interactions and pose potential barriers to its use.

Comparisons with similar research

Various strategies using enterally administered opiates, benzodiazepines, or barbiturates have been reported to facilitate weaning continuous sedative and analgesic agents (5-9). However, there is a lack of high-quality randomized controlled trials and guidelines outlining optimal practices for this process. This case series builds upon these existing approaches by demonstrating the potential benefits of using phenobarbital, adding to the body of evidence supporting alternative weaning strategies for continuous sedative medications (5).

Explanation of findings

The presented cases involve patients with high tolerance for opiates and benzodiazepines, highlighting the difficulty of weaning such patients off continuous sedative and analgesic infusions due to withdrawal. Phenobarbital, through modulation of GABA receptors, can overcome medication tolerance and achieve the desired sedative effect. Its long half-life minimizes withdrawal risks since it can slowly self-taper.

Implications and actions needed

Individualization of phenobarbital dosing, considering factors such as age, weight, comorbidities, and concurrent medications, is crucial to optimize outcomes and strike a balance between the benefits of sedative weaning and the risks of over-sedation, hypotension, respiratory depression, and drug-drug interactions.

In case 1, the patient was noticeably agitated, with a RASS score of +2 to +3 indicating restlessness, anxiety, combativeness, and ventilator non-compliance, necessitating continuous sedative infusions. The addiction medicine team, in collaboration with critical care, initiated a phenobarbital taper starting with a dose of approximately 10 mg/kg on the first day, similar to loading doses studied for alcohol withdrawal (10).

In case 2, the patient, although similar in needing continuous analgesics and sedatives, was not agitated but experienced desaturation episodes likely due to anxiety and medication withdrawal. The patient was arousable with a RASS score of −1 to −2. A lower phenobarbital dose was chosen to replace benzodiazepines without causing over-sedation. A study has used a conversion of phenobarbital 60 mg to clonazepam 1 mg (equivalent to ~1–4 mg midazolam), consistent with the dosing selection in this case based on benzodiazepine requirements (11). In the cases described here, the loading dose was omitted in favor of intermittent bolus administration in a tapered fashion to avoid over-sedation and to successfully wean continuous sedative agents while maintaining patients in an alert and arousable state (RASS of 0 to −1). Intermittent smaller doses provide the flexibility to assess dose-response and make necessary adjustments. Smaller doses of phenobarbital can be administered via IV push and are easily accessible via automated medication dispensing machines in intensive and intermediate care units. In contrast, larger loading doses require compounding in the hospital pharmacy’s clean IV admixture facility and must be administered over longer periods.

Conclusions

This case series suggests that phenobarbital taper may be a promising strategy for weaning off continuous sedative infusions in critically ill patients with high tolerances and withdrawal risks. Its potential to reduce ICU length of stay highlights its value in optimizing patient care. However, individualized dosing and close monitoring are essential to maximize benefits and minimize risks. Further research is needed to establish optimal protocols, compare different sedation weaning strategies, and explore long-term outcomes associated with phenobarbital taper in critically ill patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-127/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-127/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-127/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report was waived from patient consent according to the UCLA Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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