Treatment of benzodiazepine withdrawal syndrome in a severe traumatic brain injury patient

Abstract

Prolonged exposure to benzodiazepines (BDZ) may contribute towards physical dependence, which is manifested by iatrogenic Benzodiazepine Withdrawal Syndrome (BWS), a condition often underdiagnosed. Current evidence recommends precluding BDZ infusion as sedation in the intensive care unit to avoid possible withdrawal and delirium issues. Administration of dexmedetomidine should be considered to facilitate weaning in patients with BWS.

Background

Although modern medical practice has proposed for a shift towards non-benzodiazepine (BDZ) based sedation, BDZ are still preferentially used in both resource-limited and high-income areas.^1–3 Current guidelines emphasise minimal or avoidance of BDZ use in the effort to prevent iatrogenic complications but certain clinical scenarios may preclude this practice, which effectively puts patients at risk of benzodiazepine withdrawal syndrome (BWS). The considerable overlap with other conditions in addition to lack of understanding of the pathophysiology of BWS render this a challenging diagnosis.⁴ Our report documents the case of a patient with severe traumatic brain injury (TBI) who developed BWS and our subsequent successful management of his condition. The focus of this article is on the titration of various sedative agents used, which eventually led to the ultimate successful weaning of patient from the ventilator.

Case presentation

A healthy 18-year-old man weighing 50 kg, sustained severe TBI in a motor vehicle accident. On admission into the intensive care unit (ICU), he was immediately intubated and sedated with midazolam (2.7 mcg/kg/min) and fentanyl (0.027 mcg/kg/min) infusions for cerebral resuscitation (CR). A repeated CT of the brain showed an expanding right basal ganglia haemorrhage, which necessitated him undergoing urgent decompressive craniectomy. Postoperatively, he was mechanically ventilated and sedated.

On day 3 postcraniectomy, he was still being maintained on high sedation infusions as attempts to wean him from mechanical ventilation resulted in excessive agitation that required multiple boluses of midazolam.

On day 17 post-trauma, a tracheostomy was performed due to the patient exhibiting weaning difficulty with poor Glasgow Coma Scale (GCS) recovery. Post-tracheostomy, he again demonstrated persistent agitation, tachycardia, tachypnoea and hypertension despite being on minimal infusion of sedatives. No evidence of worsening sepsis or hepatorenal impairment was ascertained.

Investigations

• Preoperative CT of the brain indicated expanding right basal ganglia bleeding.

• Arterial blood gases and other haematological parameters were within normal values.

Differential diagnosis

Our initial differential diagnosis was paroxysmal sympathetic hyperactivity (PSH), which is associated with severe TBI. However, the patient did not respond to bromocriptine and propranolol as his agitation and restlessness persisted, requiring infusions of midazolam. Although he developed sepsis secondary to ventilator associated pneumonia, he responded well to antibiotics as evidenced by his improving condition and blood gas measurements. Opioid withdrawal syndrome and serotonin syndrome were excluded as fentanyl infusion was minimal at a range of 0.014–0.027 mcg/kg/min. Delirium in ICU, a common diagnosis, could not be assessed in our patient due to his restlessness and underlying TBI.

Treatment

Two days after the patient’s tracheostomy, we decided to initiate an infusion of dexmedetomidine at an initial dose of 0.2 mcg/kg/hour. This dose was titrated up to 0.5 mcg/kg/hour on the second day and maintained at that level for the next 3 days. Midazolam infusion was simultaneously tapered down from 2.0 mcg/kg/min by approximately 0.33 mcg/kg/min daily until its complete discontinuation on day 5 of dexmedetomidine (figure 1). Fentanyl infusion was also reduced by 50% daily from 0.014 mcg/kg/min and discontinued the next day. During this period, he was supported on synchronised intermittent mandatory ventilation mode and tolerated spontaneous breathing trial from the fourth day onwards.

Figure 1.

Trend of drugs used during patient’s mechanical ventilation and weaning in ICU. ICU, intensive care unit; SBT, spontaneous breathing trial; SIMV, synchronised intermittent mandatory ventilation.

The patient was free from midazolam infusion on the fifth day of dexmedetomidine. He tolerated tracheostomy mask with 50% oxygen. Dexmedetomidine was reduced by 50% daily and discontinued 2 days later. He did not develop any agitation, restlessness or anxiety during this period with a GCS of E₃V_TM₅.

In total, the patient received 25 days of midazolam infusion overlapped with dexmedetomidine coverage in the final 4 days to facilitate its progressive withdrawal.

Outcome and follow-up

The patient was discharged 3 days later and recuperated well with regular physiotherapy. He returned to the clinic for review after 2 weeks and did not demonstrate any agitation and restless with a GCS of E₄V_TM₆.

Discussion

Short-acting BDZ such as midazolam demonstrate acceptable pharmacokinetics and pharmacodynamics⁵ and are commonly used for their anxiolytic, anticonvulsive and hypnotic properties in the ICU. However, repeated boluses or prolonged infusion in high doses may lead to substantial lipid accumulation of its active metabolites, prolong its sedative effects and contribute to withdrawal symptoms on abrupt discontinuation.⁶ This is particularly true in patients who are obese, or with hepatic impairment and renal dysfunction.

BWS, common among critically ill patients in ICU, is demonstrated as central nervous system irritability, gastrointestinal dysfunction and autonomic nervous system dysregulation.⁷ This condition occurs when there is a sudden drug dosage reduction that leads to reduced plasma concentration. Risk factors attributed to BWS include prolonged infusion of opioids or BDZ, abrupt discontinuation, obesity, young age, history of drug abuse and heavy alcoholism. BWS may lead to prolonged ICU stay and mechanical ventilation. No articles have reported the range of midazolam dosage that precipitate BWS in adults, although Hughes et al have noted the occurrence of BWS in infusion of >0.3 mg/kg/hour in paediatrics.⁸ In a mixed study of opioid and BDZ administration in children, a cumulative BDZ dose of >60 mg/kg was significantly associated with BWS.⁹

The massive overlap of clinical features between BWS and other important disorders poses a diagnostic challenge for clinicians. This in addition to severe TBI could lead to cerebral dysfunction, which was observed in our patient. The BWS diagnosis was confirmed by the appearance of agitation, tachycardia, tachypnoea, hypertension and fever shortly after the reduction of the infusion. In addition, the symptoms could only be controlled effectively by either intermittent boluses of midazolam or restarting the infusion.

Dexmedetomidine is a centrally acting alpha-2-agonist with sedative, anxiolytic and analgesic properties. Its coverage has been proven to facilitate withdrawal from BDZ with no cardiorespiratory depression and rebound effects, which were indicated in our patient.¹⁰ This is possible because dexmedetomidine counteracts the increase sympathetic outflow and noradrenergic activity state seen in withdrawal, rather than acting as a substitute to BDZ. In addition to having minimal delirious effects, dexmedetomidine also reduces the number of days of mechanical ventilation and improves patient outcomes.^{2 11–14}

Our decision to initiate dexmedetomidine was timely and judicious. This was in addition to progressively reducing midazolam and fentanyl infusions to overcome BWS from day 19 onwards, which resulted in the patient becoming calmer and less anxious, subsequently leading to successful weaning on day 27 of his hospitalisation.

This achievement is ultimately the backbone of this article. From our vast reading, there were no published articles, which carefully depict the stepwise approaches in managing BWS.

Patient’s perspective.

I cannot remember much about what happened after the accident apart from being brought to the hospital for medical attention. My family told me that I was kept sedated for a long period to allow my brain to rest. At the same time, the very medications that were used to sedate me had unexpectedly slowed my recovery. It was only after they found out the actual cause that treatment could be promptly started. I woke up soon after that and started breathing on my own. I feel much better now and am looking forward to my rehabilitation process.

Learning points.

• Benzodiazepine (BDZ) withdrawal syndrome is not uncommon but requires a high index of suspicion especially in patients with severe TBI requiring prolonged infusion of BDZ.

• Current evidences favour excluding BDZ infusions and opioids to prevent delirium and withdrawal syndromes.

• Dexmedetomidine infusion should be considered to facilitate progressive weaning in patients with prolonged BDZ usage and prevent withdrawal syndromes.