Substance misuse remains a major health problem in the United States. In a study of the economic costs to society of alcohol and drug misuse, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health estimate the cost to be $246 billion in 1992, the most recent year for which sufficient data were available. Alcohol misuse and alcoholism generated about 60% of the estimated costs ($148 billion), while drug misuse and dependence accounted for the remaining 40% ($98 billion).¹ Among the drugs, heroin and cocaine were the largest contributors.

Several pharmacological approaches for managing withdrawal have been suggested based on the substance used. Benzodiazepines remain the gold standard for alcohol withdrawal delirium and methadone is often used to prevent opioid withdrawal syndrome.² Propofol, an intravenous anaesthetic agent, used for sedation in the intensive care unit is easily titrated to the effect and consciousness returns rapidly after withdrawal of the drug with minimal residual central system effects.³ The use of multiple agents acting on different neurotransmitter systems reduces the required dose and side effects of one drug while blocking the symptoms of withdrawal effectively. In this paper, we describe our experience of combination therapy with propofol and lorazepam in three patients presented to the intensive care unit with poly substance misuse and severe withdrawal symptoms, which were not controlled by large doses of lorazepam alone.

CASE REPORTS

Case 1

A 42 year old man was admitted to the intensive care unit (ICU) because he was found unresponsive after an attack of tonic clonic seizures. He had a history of chronic alcoholism and his last alcohol intake was two days before admission. Physical examination was significant for asterixis and an enlarged liver. The alcohol concentration on admission was less than 1 g/l. Other significant laboratory findings were a low magnesium, phosphorus and moderate increase of transaminase activities. He was given lorazepam (Ativan, Wyeth-Ayerst Laboratories, USA) 2 mg boluses for agitation as needed. After about an hour of presentation he woke up but was restless, agitated, and extremely tremulous. He was tachycardic, tachypnoeic, and hypertensive. He continued to deteriorate and he developed delirium tremens (DTs). He needed deep sedation with lorazepam and was electively intubated for airway protection. The rate of infusion was titrated using a 5 point sedation score (4—completely awake and open eyes, 3—drowsy, closed eyes; 2—asleep but responds to verbal commands; 1—asleep but responds to touch or pain; 0—does not respond). He required progressively escalating doses of lorazepam and the DTs remain uncontrolled despite lorazepam given at the rate of 15 mg/h. After 24 hours, lorazepam infusion was reduced to 2 mg/h and propofol (Diprivan, AstraZeneca Pharmaceuticals, USA) infusion was given at a rate of 10 μg/kg/min. Propofol was titrated up to achieve the symptom control and he required a maximum dose of up to 50 μg/kg/min. With this regimen, we could maintain tranquility and stable haemodynamics for 24 hours. In the morning every day, the propofol infusion was stopped for half hour and the patient was assessed for agitation, tremors, sweating, hallucinations, and orientation/clouding of consciousness. On the third day of propofol infusion, the patient remained calm, opened his eyes, oriented, and was properly responding to verbal commands. It took only 15 minutes for the patient to wake up after stopping propofol infusion. He remained haemodynamically stable and was successfully weaned off from the mechanical ventilation and extubated. The patient’s ICU stay was complicated because he developed pneumonia, which was treated with empirical antibiotics. Once the patient started taking orally lorazepam infusion was stopped and oral chlordiazepoxide 25 mg every eight hours was started and the patient was transferred to the general medical floor.

Case 2

A 36 year old man with history of psychotic illness attributed to longstanding alcoholic and intravenous drug misuse came to the emergency room with right leg cellulitis. His alcohol concentration on admission was 265 mg% and his urine for opioid was positive. He was admitted to the general medical floor and treated with antibiotics and haloperidol 10 mg twice daily. He also received methadone 50 mg every day and was given chlordiazepoxide 24 hours after admission at 75 mg every six hours (alcohol concentrations less than 10 mg%) to prevent alcohol withdrawal symptoms. He became increasingly agitated requiring 100 mg chlordiazepoxide every hour and was transferred to the ICU. In the unit, he was given a lorazepam infusion and the patient was symptomatic with doses more than 10 mg/h. He was intubated for airway protection. Propofol infusion was started immediately after intubation (first ICU day and 72 hours after admission). Lorazepam was reduced to 2 mg/h and propofol infusion was titrated up to control agitation and achieve the appropriate level of sedation. Propofol was continued for four days at the maximum dose of 100 μg/kg/min. On the fifth day, the patient started responding appropriately to verbal commands without agitation or tremors after stopping propofol infusion. He was extubated and observed in the ICU for an additional eight hours. Lorazepam was stopped and he was then transferred to the general medical floor where he was given chlordiazepoxide, haloperidol, and methadone. He was referred to substance misuse rehabilitation programme. He had transient increase in hepatic transaminases during his ICU stay. Hepatitis profile and abdominal ultrasound were negative. The enzymes returned to normal baseline values upon discharge from intensive care unit.

Case 3

A 39 year old woman with a history of moderate persistent asthma came to the emergency room with acute onset of respiratory distress and received inhaled bronchodilators and corticosteroids. However, she did not respond very well and her arterial blood gas pressure showed uncompensated respiratory acidosis. She was persistently tachypnoeic, tachycardic, and in severe distress with minimal air entry to the chest. She was intubated and mechanically ventilated. She received lorazepam 2 mg bolus and given an infusion titrated to sedation. Her bronchospasm subsided but she continued to be diaphoretic, tachycardic, agitated, and restless. Urine toxicology was positive for cocaine, opioids, and methadone. We suspected drug withdrawal syndrome. She required increasing doses of lorazepam up to 13 mg/h. We gave the patient clonidine 0.1 mg three times a day and methadone 30 mg/day. This regimen did not affect the patient’s agitation. We decided to give propofol in low doses 10 μg/kg/min. We continued lorazepam at 2 mg/h and propofol was required up to 60 μg/kg/min for 36 hours. The patient was weaned off from the ventilator and sedation and extubated at this time. After extubation she was observed for 24 hours before being discharged with bronchodilators She was referred to a substance misuse programme.

DISCUSSION

Symptoms of alcohol withdrawal typically begin within 4 to 12 hours after cessation or reduction of alcohol use, peak in intensity during the second day of abstinence, and generally resolve within four to five days. Symptoms of alcohol withdrawal include tremors, autonomic dysfunction (tachycardia, tachypnoea, fever, and sweating), insomnia, restlessness, agitation, anxiety, panic attacks, and gastrointestinal upset. Fewer than 5% of patients withdrawing from alcohol progress to delirium tremens; a condition that has significant morbidity and mortality.⁴ Delirium tremens is a state of confusion accompanied by visual, tactile, and auditory hallucinations. Cocaine withdrawal symptoms are mild and no specific pharmacological treatment is indicated on a regular basis. Although the untreated opioid addict experiences significant anxiety and discomfort, the process itself presents no serious risks.² The classic symptomatology and the typical onset and duration of symptoms of alcohol withdrawal may be modified by the concurrent misuse of other substances such as heroin and cocaine.

Benzodiazepines are the mainstay of treatment for alcohol withdrawal states. Alcohol withdrawal delirium may require large doses of benzodiazepines (such as 1000 mg diazepam).^5,6 There are reports in which massive doses of benzodiazepines failed to prevent or shorten the duration of DTs.^7,8 Benzodiazepines bind at the GABA benzodiazepine receptor in the central nervous system and when these receptors are saturated additional drug cannot bind. These patients may tolerate these exceedingly higher doses but not necessarily benefit from them.⁶ Residual sedation and prolonged rehabilitation may increase the hospital stay in these patients because benzodiazepines are sequestrated in fat stores after high dose therapy.⁹ Propylene glycol toxicity marked by acidosis, tubular necrosis leading to acute renal failure has been reported with higher doses of lorazepam or prolonged infusion of the drug.^10,11 Considering these disadvantages, there is a need for an alternate and additive drug in the treatment of these patients.

Coomes et al first reported the successful use of propofol in DT in a patient refractory to massive doses of benzodiazepines.¹² McGowan et al concluded in their case series that propofol should be considered as a therapeutic option in patients with refractory DT.⁸ All of their patients had improved symptom control with propofol. Benzodiazepines act only through GABA receptors. Propofol is synergistic with lorazepam at GABA receptors. In addition, propofol inhibits NMDA subtype of glutamate receptors, which explains its superiority over benzodiazepines.¹³ NMDA-receptors seem to play a central part in alcohol and other substance dependence, withdrawal states, and alcohol induced neurological disorders.^14,15 The mechanism of action of propofol in opioid withdrawal states may also be related to NMDA receptors or this could just be a general anaesthetic effect. Propofol has been successfully used for sedation during rapid opioid detoxification.^16,17 There is no pharmacological evidence for propofol acting at opioid receptors.

In our case series, we added propofol and reduced the dose of lorazepam once we realised the resistance of symptoms to high dose lorazepam. Lorazepam and chlordiazepoxide were preferred to midazolam because of their intermediate half life and benefit in the prevention of seizures and a much more smoother withdrawal course in these patient populations with less breakthrough symptoms after short acting propofol has been stopped.¹⁸ Carrasco et al have shown the synergistic effects of co-administration of midazolam and propofol for sedation after coronary artery bypass surgery. Combination therapy provided safe and effective sedation with advantages over conventional regimen with propofol or midazolam administered as sole agents, such as absence of haemodynamic impairment, >68% reduction in maintenance dose, and lower pharmaceutical cost.¹⁹ Reduction in dose and duration of propofol infusion with combined sedation will avoid problems of long term high dose propofol sedation such as higher cost, hypertriglyceridaemia,²⁰ pancreatitis,²¹ severe protracted metabolic acidosis,²² haemodynamic impairment and delayed seizures.²³ Currier et al described a patient who developed alcohol withdrawal syndrome in the postoperative period after internal fixation of ankle fracture.²⁴ The patient’s symptoms were not controlled by midazolam or propofol and required muscle relaxation and mechanical ventilation. The authors explained the refractoriness of withdrawal symptoms by the acute tachyphylaxis to propofol because the patient initially responded to small doses of propofol and failed to respond later on even with 1000 μg/kg/h of propofol infusion. We did not encounter propofol related complications in any of the three patients.

Various scales have been described to evaluate the severity of withdrawal symptoms such as the objective opiate withdrawal scale, the subjective opiate withdrawal scale,²⁵ and the revised clinical institute withdrawal assessment for alcohol scale.²⁶ These scales may be useful in patients with mild withdrawal symptoms in the general medical floor but were very difficult to use in ICU patients with severe symptoms requiring very deep sedation, endotracheal intubation, and mechanical ventilation. These scales also will not be useful in patients with psychotic disorders such as case 2. However, we used sedation scoring, which is simple to use by our nursing staff to titrate the drugs to control the symptoms such as agitation, restlessness, hallucinations, sweating, and tremors. It was aimed to achieve symptom control with a sedation score of 2 in all the patients. None of the patients responded and sedation was deepened to score 1.

All patients became awake and responding after 15–20 minutes of stopping propofol infusion. This is an advantage over the other drugs studied in the treatment of alcohol withdrawal syndrome such as flunitrazepam, chlormethiazole, haloperidol, and clonidine.²⁷ Haloperidol can aggravate delirium and lower seizure threshold in these patients.^28,29 In combination with benzodiazepines, the duration of mechanical ventilation may be prolonged and a small percentage of patients may develop neuroleptic malignant syndrome.²⁷ Clonidine is less effective in suppressing hallucinations and may increase the cardiovascular complications.²⁷ We used haloperidol in case 2 because of his psychiatric history and clonidine was used in case 3 to suppress autonomic signs.

In conclusion, propofol added to lorazepam is safe and effective in controlling the symptoms of acute withdrawal syndrome associated with poly substance misuse. Multimodal therapy using benzodiazepines, propofol, haloperidol, clonidine, and methadone should be tried in these patients to reduce the required dose and side effects of any individual drug. Further well controlled clinical studies are recommended with various combinations of drugs to find out an ideal cost effective regimen to treat these patients requiring ICU admission.