Butorphanol-midazolam combination therapy for the treatment of intracranial hypertension in a patient with tuberculous meningitis: a case study

Tuberculosis is one of the most devastating infectious diseases worldwide. The global incidence of tuberculosis peaked around 2004 and has decreased at a rate of less than 1% per year (Lawn and Zumla 2011). However, the incidence and prevalence of tuberculosis is high in most developing countries, including those in Asia (Lawn and Zumla 2011). At present, the incidence of tuberculosis in Japan is lower than that in developing countries in Asia (Lawn and Zumla 2011), but is higher among older people as compared with Europe and North American (Global Tuberculosis Control 2008 2013). Central nervous system involvement, while rare, is the most severe form of tuberculosis. Reportedly, about 10 percent of patients with tuberculosis have central nervous system involvement (Murthy 2005). Tuberculous meningitis (TBM) is primarily a disease of the meninges, which can cause edema, infarction, or hydrocephalus, and multiple pathological changes lead to elevated intracranial pressure (Murthy 2005). Intracranial hypertension (ICH), which often occurs in patients with TBM, is associated with high morbidity and mortality (Murthy 2005). ICH can be managed by osmotic treatment with mannitol or hypertonic saline or by anti-inflammatory and immunomodulatory treatment with steroids. ICH must be treated with these options in addition to antituberculosis therapy to avoid complications; however, surgical intervention including ventriculo-peritoneal shunt is a second option reserved for patients who do not respond to pharmacological therapy (Murthy 2005). We describe a patient with TBM who had ICH-induced fulminant headache that responded to intravenous butorphanol-midazolam combination therapy. This case suggests that this combination therapy can be an alternative treatment for the management of ICH in patients who do not respond to osmotic therapy or steroids, which have been recommended for the medical management of ICH associated with tuberculous meningitis.

This report describes a patient with intolerable, refractory, fulminant headache caused by ICH without hydrocephalus. The headache finally responded to intravenous butorphanol-midazolam combination therapy. To our knowledge, this is the first time to document the use of this combination therapy in a patient with severe headache.

ICH is well known to frequently cause headache (Murthy 2005). TBM is primarily a disease of the meninges associated with multiple potential causes of ICH, such as cerebral edema, hydrocephalus, infarction, adhesion formation of the basal subarachnoid cisterns, or tuberculoma (Murthy 2005). These changes were not found on CT or MRI studies in our patient, except for enhancement of the colloid plexus. We speculate that an imbalance between CSF production and absorption caused by the colloid plexus lesions may have contributed to ICH, leading to the fulminant headache.

Osmotic therapy or steroids have been recommended for the medical management of ICH associated with TBM (Murthy 2005), but these treatments failed to resolve the intolerable, refractory, fulminant headache caused by ICH without hydrocephalus in our patient. We tried high-dose intravenous propofol, but adequate sedation could not be induced because of the intense headache. Intravenous butorphanol-midazolam combination therapy was finally able to control the headache. Midazolam or butorphanol is widely used as a sedative or analgesic, and the combination of these two medications is also useful for sedation (Dershwitz et al. 1991). Midazolam is a benzodiazepine derivative that stimulates γ-aminobutyric acid-A (GABA-A) receptors by enhancing channel opening (Bai et al. 1999), and its agonist activity leads to generalized inhibition of neuronal firing (Enna and Mohler 1987). Similar to midazolam, propofol is effective for the management of refractory headache (Mendes et al. 2002). Butorphanol is believed to act as a partial agonist at kappa opioid receptors (Wood et al. 1983), and the resulting kappa-type opioid produces sedation (Abboud et al. 1987). The mechanism by which butorphanol-midazolam combination therapy alleviated headache remains uncertain, but may have involved a reduction in intracranial pressure or down-regulation of headache. The consciousness of our patient was clear after the withdrawal of the combination therapy. Sedation induced by such combination of drugs was not accompanied by amnesia or impaired psychomotor function (Dershwitz et al. 1991), and the combination therapy may have no neurophysiological effect when used as a supplement to propofol-induced anesthesia.

Butorphanol-midazolam combination therapy may be useful for ICH-induced fulminant headache in patients who do not respond to recommended osmotic or steroids treatments for ICH. The efficacy of low-dose butorphanol-midazolam combination therapy without the need for mechanical ventilation is unknown, but the treatment might be an option for the management of ICH or ICH-induced headache because of potent analgesic and anxiolytic efficacy in patients with central nervous system infections.

Written informed consent was obtained from the patient for publication of this case and any accompanying images.

HK was responsible for the overall study design, and wrote the manuscript. HK contributed to analysis and interpretation of data. HK and SU contributed to drafting and critical revision of part of the submitted materials. HK and SU involved in the treatment of the patient shown in the manuscript and read and approved the final manuscript.