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When Midazolam Fails
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Journal of Pain and Symptom Management
Vol. 23 No. 3 March 2002
Clinical Note
When Midazolam Fails Christine Cheng, MD, Célia Roemer-Becuwe, MD, and Jose Pereira, MD Palliative Care Program (C.C., C.R.-B.), Grey Nuns Community Hospital, Edmonton; and Division of Palliative Medicine (J.P.), University of Calgary and Tertiary Palliative Care Unit (J.P.), Foothills Hospital, Calgary, Alberta, Canada
Abstract Significant distress is experienced by patients, families, and caregivers when a symptom or disorder, such as an agitated delirium, becomes an intractable, or a catastrophic event, such as irreversible stridor. When palliative sedation is indicated for these patients, midazolam is usually the preferred drug. In some cases, however, midazolam fails to provide adequate sedation. Two cases are presented to illustrate this phenomenon and explore the possible mechanisms underlying this lack of response. These mechanisms appear to be multifaceted. The heterogeneity of the GABAA receptor complex and the alterations that this complex can undergo functionally can explain, to some degree, the diversity of the physiological and pharmacological outcomes. Other factors responsible for the diversity in response may include concomitant medications, age, concurrent disease, overall health status, alcohol use, liver disease, renal disease, smoking and hormonal status. Evidence-based guidelines on alternative treatment options should midazolam fail are required. In the interim, a lower threshold for adding an alternative drug, such as phenobarbital, or substituting midazolam with another drug, such as propofol, should be considered in these circumstances. J Pain Symptom Manage 2002;23:256–265. © U.S. Cancer Pain Relief Committee, 2002. Key Words palliative, sedation, midazolam, propofol, phenobarbital
Introduction A small number of terminally ill patients experience symptoms that are refractory despite all efforts to identify a tolerable therapy that does not compromise consciousness.1 After remedial causes have been excluded, sedation is considered to be ethically justifiable in these cases.2 It is emphasized that palliative sedation with midazolam should follow attempts at controlling the symptoms with first-line medica-
Address reprint requests to: Jose Pereira, MD, Director, Palliative Care Unit, Unit 47, Foothills Hospital, 1403 29 St. NW, Calgary, AB T2N 2T9, Canada. Accepted for publication: June 25, 2001. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York
tions such as haloperidol, methotrimeprazine, or chlorpromazine in the case of agitation and the optimization of analgesic regimens in the case of pain.1,3 Sedation may also be appropriate for some patients who experience catastrophic, distressing events such as sudden asphyxia or massive hemorrhaging.4,5 In initiating sedation, it is recognized that the level of sedation can vary from mild sedation, where the goal is to have a patient somnolent but communicative, to deep sedation, where the patient is not conscious. Where the goal is deep sedation, midazolam by continuous subcutaneous infusion is often the drug of choice.3,5–9 Midazolam is a water-soluble benzodiazepine with a rapid onset. On initial administration, it has a short duration of action in most 0885-3924/02/$–see front matter PIIS0885-3924(01)00412-2
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subjects.10 It has a short elimination half-life on initial administration, a relatively large volume of distribution, and a high plasma clearance. These properties facilitate rapid induction of sedation and titration to clinical effect.6,7,11 Its major metabolic pathway is hydroxylation and subsequent conjugation with glucuronic acid before elimination in the urine. It undergoes biotransformation by the P450 system, mainly in the liver. The metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1,4-dihydroxymidazolam are conjugated quickly, contributing little to the pharmacological effect. Less than 1% of the drug appears unchanged in the urine. Midazolam binds extensively to serum albumin, leaving only 2–5% as free drug. The metabolites have a shorter elimination half-life than midazolam itself. Midazolam, like other benzodiazepines, is an agonist at the gamma aminobutyric acid (GABA)-benzodiazepine-chloride receptor complex and exerts its effect by potentiating the action of the inhibitory neurotransmitter GABA at the GABAA receptors, thereby modulating inhibitory transmission at these sites. Two major types of GABA receptor complexes exist, GABAA and GABAB. GABAA is the most prevalent of the two and has specific binding sites for the GABA neurotransmitter. Unlike GABAB, it also has binding sites for benzodiazepine agonists and antagonists, as well as for barbiturates and corticosteroids, among other compounds. Midazolam is generally effective at doses of 1 mg/hr to 10 mg/hr.3 While prolonged sedation has been reported in some individuals,12–14 failure to respond adequately poses a clinical challenge, particularly where rapid sedation is required to control very distressing situations.3,7–9 Two patients are described who developed intractable stridor and did not respond promptly and adequately to midazolam infusions. These cases serve to explore the possible causes for the lack of response to midazolam and to illustrate some of the options available when midazolam appears to be ineffective.
Case Reports Patient A A 48-year-old man with squamous cell carcinoma of the head and neck was admitted to our tertiary palliative care unit (TPCU) for
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control of neuropathic pain in his right side, which emanated from invasion of the tumor into his brachial plexus. He was also myoclonic and delirious. He had been diagnosed nine months previously and had undergone surgery and extensive radiation treatment. His right neck and supraclavicular region was included in the radiation field. Unfortunately the cancer had progressed aggressively despite the treatment, resulting in the placement of gastrostomy and tracheostomy tubes because of difficulties swallowing and breathing five months later. He had abused alcohol and smoked for many years (his CAGE scoring for screening of alcohol abuse was 4/4) but had stopped these following the placement of the tubes. Upon admission to the TPCU, his liver function parameters were within normal limits. His albumin level was low at 28 g/L. Following admission to the TPCU, he was switched to methadone. A concomitant hypercalcemia was treated by a clodronate infusion. His delirium resolved but his pain worsened, requiring further titration of his methadone dose. By day 17 of his admission, he was receiving 60 mg of methadone per day in three divided doses via his gastrostomy tube. On day 18, dexamethasone was added as an adjuvant analgesic, with a good response. Unfortunately, on day 23 he developed methadone-related toxicity (delirium and myoclonus) and was switched to hydromorphone. The toxicity cleared. On day 25, he started experiencing some stridor. Further palliative radiation treatment was not possible. On the evening of day 26, he experienced an episode of acute stridor. A bolus injection of midazolam 5 mg subcutaneously (SC) settled his anxiety and the stridor improved after his dexamethasone dose was increased to 10 mg SC 4 times a day. It was felt that the edema surrounding the advancing tumor had contributed to the episode. On the morning of day 28, the stridor recurred, causing significant distress. He had difficulties speaking but was able to request sedation. The possibility of sedation as a treatment option had been discussed with him previously. A continuous SC infusion of midazolam at 1–6 mg per hour was started and he was switched to oxycodone at a dose of 20 mg SC every 4 hrs because myoclonus was noted. On our unit, the nursing staff is comfortable and skilled in titrating the dose to adequate effect; they typi-
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cally begin at the lowest dose range and increase the dose every 30 to 60 minutes as needed. Unfortunately, his respiratory distress intensified and his midazolam dose was increased. Six hours after starting the infusion, his dose was 20 mg per hour. At that dose, he appeared sedated and comfortable. During the night, the nursing staff was able to titrate the midazolam dose down to 14 mg per hour, without compromising his comfort. The following evening (day 29), he became agitated again and the dose was titrated up to 30 mg per hour. Once again this proved successful and he experienced a quiet, comfortable night. The following morning, restlessness recurred and a decision was made to add methotrimeprazine at a dose of 25 mg SC every 4 hours. He settled after this. No myoclonus was evident at this point. On day 31, he became agitated again and appeared to be breathing with difficulty. The midazolam dose was titrated up once again. He remained agitated, even when the dose of midazolam was increased to 50 mg per hour. A decision was made to add phenobarbital at a dose of 100 mg SC 3 times a day. He settled approximately an hour after the first phenobarbital dose was administered. The methotrimeprazine was decreased and discontinued two days later. On day 32, it was felt that the dexamethasone was of no further benefit and a tapering regimen was started. By day 40, the dose was down to 4 mg SC once a day. The midazolam dose was successfully tapered over the course of 2 days to 8 mg per hour after the phenobarbital dose had been increased to 150 mg 3 times a day on day 33. He died peacefully on day 41.
Patient B A 48-year-old man with advanced non-small cell cancer of the lung was admitted to our TPCU for the management of delirium. He had been diagnosed 11 months previously when he had presented with superior vena cava obstruction. Extensive mediastinal lymphadenopathy had been noted and he underwent radiation treatment at the time. Four months prior to his admission, he had received further palliative radiation treatment to his right rib cage for painful bone metastases. Upon admission to the unit, he was receiving hydromorphone at a dose of approximately 300 mg per day by a continuous SC infusion. A variety of adjuvant
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analgesics, including amitriptyline, paroxetine, gabapentin, and carbamazepine had been added to his analgesic regimen during the two to three weeks prior to admission to control neuropathic pain in his right arm related to tumor invasion of his brachial plexus. He had no history of alcohol abuse and had never smoked. On physical examination, he was found to have ptosis of the right eye and a mass was palpable in his right supraclavicular region. He appeared in no acute distress and denied shortness of breath. However, a plain radiograph of his chest revealed marked deviation of the distal trachea secondary to mediastinal lymphadenopathy. The delirium was thought to be drug-related. He was switched to methadone and by the third day was on a dose of 25 mg of methadone every 8 hours. The amitriptyline was discontinued and the gabapentin and carbamazepine were tapered and discontinued 4 days later. On the second day of his admission, it was noted that he was experiencing some difficulties with inspiration, but he denied any shortness of breath. Dexamethasone at a dose of 10 mg SC twice a day was started (as an adjuvant analgesic and in an attempt to decrease the airway obstruction). On day 3, the dexamethasone dose was increased to 10 mg four times a day. Despite this treatment, his respiratory status deteriorated. The right main bronchus obstructed completely. He became very short of breath and, following a discussion with him and his wife, a decision was made to sedate him with a continuous SC infusion of midazolam. A starting dose at a range of 1 to 6 mg per hour proved unsuccessful and by the evening the dose had been increased to 10 mg per hour. He settled with this increased dose. On day 4, he became agitated and stridorous again, and required further increases in the midazolam dose. By the evening, the dose was up to 20 mg an hour. The addition of methotrimeprazine at a dose of 25 mg every 8 hours proved unsuccessful (three doses were given). Adequate sedation was finally achieved after phenobarbital at a dose of 100 mg SC twice a day was added that evening. On the morning of day 5, the dexamethasone was discontinued since it appeared that it had had no significant clinical impact. In the afternoon of day 5 he became very agitated again. The phenobarbital and midazolam doses were increased to 200 mg three times a day and 50 mg per hour respectively,
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the latter in aliquots of 5 mg every 30 to 60 minutes. Adequate sedation, without any respiratory depression, was achieved in the early morning of day 6. He died later that evening.
Discussion The failure of the two patients under discussion to respond promptly and adequately led to delays in achieving control of distressing events. They initially both displayed poor responses to midazolam at doses that would ordinarily have been effective. With significant dose titration, there were some periods of adequate response. However, these periods were short-lived and rapid dose escalation, as well as the addition of other sedating medications, was required. The poor responses in these individuals are consistent with several reports indicating considerable inter-individual variation in response to midazolam and other sedatives.3,7–9,11,12,15–22 Various patterns of “poor response” to midazolam are noted. Some individuals appear to exhibit a limited response, even at high doses. In one report, paradoxical agitation was observed.18 Others exhibit an initial favorable response followed by a need to escalate the dose to achieve the same level of sedation. The escalation in dose may be gradual or, as demonstrated in these cases, very rapid. In the clinical setting, the term “tolerance” is often used to describe the phenomenon of diminution of drug action in association with continued drug exposure. When “tolerance” occurs rapidly, as illustrated in these cases, the term “tachyphylaxis” is sometimes used. Tolerance to the pharmacodynamic effects of benzodiazepines, both after single doses and during continuous administration, has been noted.22,23 The acute sedative effects of benzodiazepines following single doses may diminish or disappear far more rapidly than the plasma and/or brain concentrations fall to zero.21 Shelley and colleagues, in their study of 50 intensive care patients, noted that to maintain the same degree of sedation it was necessary to increase the daily dose of midazolam in some patients.11 Animal studies indicate that development of tolerance to benzodiazepines may occur rapidly.23 In humans, several cases have been reported of patients awakening prematurely from midazolam-induced sedation.12,24
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Rapid tolerance has been reported in patients overdosing on benzodiazepines.25 Despite the above observations, the phenomenon of tolerance development, as demonstrated by the need for increased doses over time, has been challenged.13 The mechanisms underlying the development of tolerance to benzodiazepines and midazolam are unclear, as are the mechanisms responsible for the wide variations in responses that are occasionally observed. The mechanisms appear to be complex19 and include numerous pharmacodynamic and pharmacokinetic factors.21,26–28 To explore variation in drug responsiveness one can use the theoretical framework proposed by Bourne and Roberts.29 They describe four general mechanisms but emphasize that their categorization is rather artificial in that variation in clinical responsiveness is caused by more than one mechanism. The four mechanisms are: 1) variations and alterations in the structure, number, or function of receptors; 2) alterations in concentration of drug that reaches the receptors; 3) variations in concentration of an endogenous receptor ligand; and 4) changes in components of response distal to receptor. We will focus on the first two general mechanisms.
Variations and Alterations in Structure, Function, or Number of GABA Receptors The lack of response to midazolam may be attributed to genetically determined variations in the GABA-receptors making some individuals relatively less sensitive.21,26,27,30 The GABAA receptor complex is believed to be a glycoprotein composed of five polypeptide subunits.31 Five distinct classes of polypeptide subunits (alpha, beta, gamma, delta, and rho) have been identified, and multiple isoforms of each have been shown to exist so that the total number of identified subunits now stands at 15 (alpha1–6, beta1–4, gamma1–3, delta, and rho). A family of at least 15 genes genetically encodes these subunits. The binding site for the benzodiazepines is located in the alpha subunit of the GABAA receptor whereas the GABA binding site resides on the beta-subunit.31,32 The expression of the gamma-subunits is essential for conferring the modulatory action of benzodiazepines on GABAA receptors.32 In addition, co-expression of individual gamma subunits with alphaand beta-subunits results in varying degrees of
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modulation by benzodiazepine receptor ligands (agonists, antagonists, inverse agonists). The heterogeneity of alpha- and gamma-subunit expression seems to determine the diversity of the physiological and pharmacological responses characteristic of the GABAA receptor complex. The heterogeneity of the GABAA receptor complex may also provide diversity in the way it adapts or alters to various stimuli and conditions. This could explain, to some degree, the relative “down-regulation” of the receptor complex to the influence of midazolam over time. It appears that the GABAA receptor complex can be functionally altered by a variety of stimuli and compounds that bind to its different sites, resulting in “down-regulation” of the receptors. These compounds include alcohol, barbiturates and corticosteroids. Alcohol may affect the functioning of GABA receptors.33 It is possible that chronic alcohol use may “down-regulate” the GABA receptors, thereby rendering the receptors relatively insensitive to the effects of midazolam. However, this theory has been challenged by Bauer and colleagues, who suggest that within 2–3 weeks of withdrawal from alcohol, the GABA receptor may revert to its usual configuration.33 Other animal models suggest that cross-tolerance between alcohol and benzodiazepines is a short-lived phenomenon.34 Although alcohol administration has been shown to potentiate benzodiazepine– GABA receptor function in some in vitro studies, many cells that respond to GABA agonists do not respond to alcohol.34 Thus it is likely that tolerance to alcohol’s central nervous system effects is mediated by a small subpopulation of GABA receptors and/or by other mechanisms. The role that chronic alcohol use played in Patient A is unclear. Corticosteroids also may change the structure and the function of the GABAA receptor complex, and phosphorylation of the GABAA receptor channels, by as yet unclear mechanisms, may be important for both short-term and long-term regulation of GABAA receptor function and expression.31
Alterations in Concentration of Midazolam Reaching the Receptors Midazalom is metabolized primarily by the CYP 3A4 iso-enzyme group of the P450 enzyme-complex.35 Other enzymes, including the CYP 2D6 isoenzyme, may also be involved, but
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to a lesser degree.35 Enzyme activity and expression may be influenced genetically.30,36,37 Distinct subpopulations with different rates of metabolism and elimination of some drugs have been identified.38 A pharmacogenetic abnormality is thought to occur in 6–10% of the normal population resulting in a decreased metabolism of midazolam.39 This would confer a relative increase in responsiveness. On the other hand, the existence of “increased metabolizers” may confer a relatively lack of responsiveness. However, this hypothesis has been challenged.39 Enzyme activity may also be regulated by other factors, including age,40–42 concurrent disease, overall health status,11,12,41,43 alcohol use,44 smoking,45 and hormonal status. Although Bottomley and Hanks found no relationship between age and response to midazolam,19 elderly patients appear to respond more readily to the actions of midazolam.40–42 This increased responsiveness may relate to the aging liver having fewer enzymes and metabolism being slower.40 Another theory is that increased receptor sensitivity may occur with age. In terminally ill patients, it may be difficult to separate the effects of age from the effects of organ dysfunction related to advanced disease. The impact of chronic alcohol abuse on P450 enzyme action is unclear. It has been noted that chronic ethanol consumption induces enzyme activity.44 On the other hand, chronic alcohol liver damage may impair metabolism, resulting in drug accumulation. Smoking may increase the metabolism of some drugs by inducing enzyme activity.45 Both of the patients described had not smoked for several weeks prior to the sedation. The possibility of significant drug interactions resulting in increased metabolism of midazolam also must be considered. The induction, or inhibition, of hepatic drug metabolism by various drugs is a major source of variability in drug response.35,46,47 Both patients were receiving high doses of dexamethasone concurrent with the midazolam and one was on carbamazepine. Both these drugs are known to induce the CYP 3A4 isoenzyme.46,47 They may therefore have enhanced the breakdown of the midazolam. Unlike drugs such as phenobarbital, benzodiazepines have little effect on liver enzyme activity and do not induce their own metabolism.21
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Another possible, yet unlikely, factor responsible for altering the concentration of midazolam reaching the receptors in these two patients relates to the pH of the drug. Midazolam hydrochloride is very acidic, with a pH of 3. When it is prepared for injection in a dextrose solution, its pH increases to 4. After administration, at physiological pH (7.4), the drug becomes lipophylic, allowing it to cross the blood brain barrier.48 Both patients were in respiratory distress and may have had a respiratory acidosis. It is also possible that large volumes of midazolam over long periods of time may have exacerbated this relative acidotic state.
Anticipating a Poor Response It would be useful to predict the responsiveness of an individual patient to midazolam. Although wide interindividual variation in response may make prediction difficult, a search for predictors is warranted. Based on the above discussions, predictive factors that may require consideration include concurrent medications, age, overall disease status, functional status, concurrent liver and/or renal disease, and blood albumin levels. Some commonly used drugs in palliative care may interfere with the metabolism of mi-
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dazolam (Table 1). More comprehensive lists may be found elsewhere.35,47 Elderly patients, those with extensive disease, and those with very poor functional status appear to be more responsive to midazolam.11 Whether or not liver disease affects midazolam action is unclear. Although prolonged sedation has been observed in patients with liver disease,11,49 others have reported reduced clearance of midazolam in patients with cirrhosis.50,51 Park and colleagues found a wide range in the metabolism of midazolam in patients with end-stage liver disease52 and liver tissue affected by cirrhotic disease showed greater preservation of enzyme function than that affected by hepatocellular disease. Because midazolam has a high hepatic extraction, the rate of its metabolism is dependent on hepatic blood flow and any reduction in liver perfusion could reduce the rate of its metabolism. It is uncertain whether renal impairment reduces clearance or not.11,43 Shelley and colleagues found that the time to awaken following cessation of a midazolam infusion was prolonged in patients who had renal impairment. However, this may have been the result of opioid accumulation. Extremely ill patients do appear to be more responsive to midazolam.19 Patients A and B, although clearly pal-
Table 1 Drugs Used in Palliative Care as Substrates, Inducers and Inhibitors of Cytochrome CYP 3A4 and CYP 2D6 Substrate
Inhibitor
Inducer
CYP 3A4
midazolam carbamazepine alfentanyl fentanyl dexamethasone nefazodone sertraline warfarin
carbamzepine dexamethasone phenobarbital phenytoin rifampicin erythromycin omeprazole cyclophosphamide
CYP 2D6
midazolam codeine oxycodone methadone morphine tramadol desipramine fluoxetine paroxetine venlafaxine risperidone haloperidol
cannibinoids fluconazole ketoconazole itraconazole metronidazole norfloxacin fluoxetine fluvoxamine setraline erythromycin clarithromycin cimetidine desipramine fluoxetine haloperidol paroxetine sertraline
This is not a comprehensive list and readers are referred to other references—see text.
carbamazepine phenobarbital phenytoin
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liative, were relatively young and did not have multi-organ involvement. Whether or not low albumin levels play a role is unclear. Decreases in the plasma protein concentration and reductions in the strength and extent of binding could increase the fraction of free drug, thereby increasing its availability at the GABA receptors. In contrast to other benzodiazepines, hepatic clearance of midazolam is of the non-restrictive type, indicating that both bound and unbound drug can be degraded by the liver enzymes.53
Managing Non-Response When faced with an apparent failure to achieve a satisfactory response to midazolam, one needs to review the diagnosis, the indications for sedation, and the treatment. In hindsight, Patient B may have benefited from the insertion of a tracheal/bronchial stent54 or racemic epinephrine inhalations. Once the appropriateness of palliative sedation is established,
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concurrent medications should be reviewed and judgments are needed concerning further escalation of the midazolam dose, administration of an additional sedative, or substitution of the midazolam with an alternative drug. Unfortunately, evidence-based guidelines and protocols are lacking and the overall effectiveness of various approaches for palliative sedation have not been systematically evaluated. Although the ethical considerations surrounding palliative sedation have received extensive, deserved attention,3 the technicalities related to administering the sedation have not. Alternative options when midazolam fails include adding methotrimeprazine55 or phenobarbital56–58 to the midazolam or substituting the midazolam with phenobarbital or propofol.15–18 The relative advantages, disadvantages, and dosing regimens suggested in the literature are listed in Table 2. Phenobarbital can be administered subcutaneously, unlike propofol,
Table 2 The Pros and Cons of Some Alternative Agents for Sedation When Midazolam Is Ineffective Drug
Pros
Cons
Suggested Dosing Regimens
Midazolam
Rapid onset of action16 Short half of life: easily titratable Subcutaneous administration Minimal cardiovascular effects
Lack of efficacy in some individuals Relatively costly, particularly at high doses18
Propofol15–18
Rapid onset of action Ultra-short duration of action: easily titrable, fast recovery60 Antiemetic effect Decreases pruritus due to cholestasis61
Requires anesthetist supervision in most institutions/programs No subcutaneous administration Painful intravenous injection16 May increase risk of infection59 Development of tachyphylaxis
Phenobarbitone56–58
Rapid onset of action Subcutaneous administration Anticonvulsant action Dissociative effects
Long half-life Loading dose required Potent inducer of hepatic enzymes (high potential for drug interactions) No analgesic or antiemetic properties Considerable interindividual variability in pharmacokinetics
See text Starting dose ranges of 1–6 mg per hour are often quoted. Sometimes a loading dose of 2.5 to 5 mg is suggested. Sometimes a single dose is suggested instead of a range and the dose then titrated accordingly. The decision to order a range or single dose may depend on the comfort level and experience of the staff in titrating the dose to effect. Continuous infusion: When initiating propofol, the infusion rate should be increased from 10 mg/hr by 10 mg/hr increments every 15–20 min until sedation is satisfactory.15 If there is an urgent need to increase the sedation, boluses of between 20 mg and 50 mg may be administered by increasing the rate for 2–5 min.15 Doses of between 5 mg/hr to 70 mg/hr generally suggested. Loading dose of 20 mg followed by an infusion of 50 mg/hr, titrating up to 70 mg/hr as need be.16 Stat 100–200 mg intramuscular or subcutaneously for sedation in a catastrophic event.5 Intramuscular loading dose of 100–200 mg, followed by a subcutaneous infusion of 1200 mg/day (median) (range of 600–1600 mg/day).57 200–2500 mg/24 hours3 (subcutaneous infusion). Can also be administered intermittently in 3 daily divided doses (cases described here).
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which must be administered intravenously. Some institutions require that propofol be administered under anesthetic supervision, as is the case with our institution. This requirement limits the use of this potentially beneficial drug in these circumstances and is, given the circumstances, somewhat redundant. Propofol, which has a lipid medium, favors yeast and bacterial growth and also appears to impair the immune system by diminishing the chemotactic motion of human leucocytes.59 However, the increased risk for infection is moot given the circumstances for which it is being used. The ideal drug for sedation in palliative care settings should provide for a consistently fast, smooth onset of action and easily titratable level of sedation. Following these cases, our threshold for introducing an alternative drug has been lowered. It appears that there is a point at which a further increase in midazolam dose is beyond maximal enhancement of the GABA-nergic inhibitory system and so has little or no added benefit. This point is unclear but we suggest a dose of 15–20 mg per hour as the threshold. This dose has been arbitrarily chosen.
Conclusions Although the mechanisms underlying the spectrum of response to midazolam warrant research, other areas related to the technicalities of providing palliative sedation deserve further attention. Three key areas include clarifying the frequency of midazolam failure, identifying factors predicting poor or adequate response, and developing evidence-based guidelines on alternative treatment options should midazolam fail. In the interim, to limit the distress caused by intractable symptoms that are not responsive to midazolam, a lower threshold for adding an alternative drug such as phenobarbital or substituting midazolam with propofol should be considered.
Acknowledgments The authors are grateful to La Ligue de Lutte Centre le Cancer des Vosges (France), la Fondation de France, and Bristol-Myers Squibb for the financial support of Dr. C. Roemer’s Fellowship. The authors also wish to thank Professors William Drysden and Peter Smith for their insightful comments.
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28. Owen RT, Tyrer P. Benzodiazepine dependence. A review of the evidence. Drugs 1983;25:385–398.
46. Herman RJ. Drug interactions and the statins. CMAJ 1999;161(10):1281–1286.
29. Bourne HR, Roberts JM. Drug receptors and pharmacodynamics. In: Katzung BG, ed. Basic Clinical Pharmacology, 6th ed. East Norwalk, CT: Appleton and Lange, 1995:9–32.
47. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;18(1):84–112.
30. Crabbe JC, Phillips TJ, Busck KJ, et al. Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci 1999;22(4):173–179. 31. Cooper JR, Bloom FE, Roth RH. Amino acid transmitters. In: Cooper JR, Bloom FE, Roth RH, eds. The biochemical basis of neuropharmacology, 7th Ed. New York: Oxford University Press, 1996:126–193. 32. Luddens H, Wisden W. Function and pharmacology of multiple GABAA receptor subunits. Trends Pharmacol Science 1991;12:49–51. 33. Bauer LO, Gross JB, Meyer RE, Greenblatt DJ. Chronic alcohol abuse and the acute sedative and neurophysiologic effects of midazolam. Psychopharmacology 1997;133:293–299. 34. Aguayo LG. Ethanol potentiates the GABA-A activated Cl-current in mouse hippocampal and cortical neurons. Eur J Pharmacol 1990;187:127–130. 35. Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol 2000;18(8):1780–1799.
48. Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinetics 1998; 35(1):37–47. 49. Lloyd-Thomas AR, Booker PD. Infusion of midazolam in paediatric patients after cardic surgery. Br J Anaesth 1986;58:1109–1115. 50. Chauvin M, Haberer JP, Ferrier C, et al. Pharmacokinetics of midazolam in anesthetized cirrhotic patients. Anesthesiology 1987;67:A290. 51. Macgilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986;27:190–195. 52. Park GR, Miller E. What changes drug metabolism in critically ill patients? Effect of pre-existing disease on the metabolism of midazolam. Anaesthesia 1996;51:432–434. 53. Halliday NJ, Dundee JW, Collier PS, et al. Influence of plasma proteins on the onset of hypnotic action of intravenous midazolam. Anesthesia 1985;40:763–766.
36. Dundee SW, Collier PS, Carlisle RJT, Harper KW. Prolonged midazolam elimination half-life. Br J Clin Pharmacol 1986;21:425–429.
54. Cortese DA, Edell ES. Role of phototherapy, laser therapy, brachytherapy, and prosthetic stents in the management of lung cancer. Clin Chest Med 1993;14:149–159.
37. Nelson DR, Kamataki T, Waxman DJ, et al. The
55. Oliver DS. The use of methotrimeprazine in ter-
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minal care. Br J Clin Pract 1985;39:339–340. 56. Greene WR, Davis WH. Titrated intravenous barbiturates in the control of symptoms in patients with terminal cancer. South Med J 1991;84:332–337. 57. Stirling CL, Kurowska A, Tookman A. The use of phenobarbitone in management of agitation and seizures at the end of life. J Pain Symptom Manage 1999;17(5):363–368. 58. Troug D, Berde DB, Mitchell C, Grier HE. Barbiturates in the care of terminally ill. N Engl J Med 1991;327:1678–1681.
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59. Quinn AC, Newman PJ, New LC, Grounds P. Clinical significance of the growth of microorganisms in Propofol. Anesthesia 1993;48:923. 60. Pratila MG, Fisher ME, Alagesan R, et al. Propofol versus midazolam for monitored sedation: a comparison of intraoperative and recovery parameters. J Clin Anaesth 1993;5:268–274. 61. Borgeat A, Saiah M, Wider-Smith OHG, Mentha G. Sub hypnotic doses of propofol relieve pruritus associated with liver disease. Gastroenterology 1993; 104:244–247.
Journal of Pain and Symptom Management
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Clinical Note
When Midazolam Fails Christine Cheng, MD, Célia Roemer-Becuwe, MD, and Jose Pereira, MD Palliative Care Program (C.C., C.R.-B.), Grey Nuns Community Hospital, Edmonton; and Division of Palliative Medicine (J.P.), University of Calgary and Tertiary Palliative Care Unit (J.P.), Foothills Hospital, Calgary, Alberta, Canada
Abstract Significant distress is experienced by patients, families, and caregivers when a symptom or disorder, such as an agitated delirium, becomes an intractable, or a catastrophic event, such as irreversible stridor. When palliative sedation is indicated for these patients, midazolam is usually the preferred drug. In some cases, however, midazolam fails to provide adequate sedation. Two cases are presented to illustrate this phenomenon and explore the possible mechanisms underlying this lack of response. These mechanisms appear to be multifaceted. The heterogeneity of the GABAA receptor complex and the alterations that this complex can undergo functionally can explain, to some degree, the diversity of the physiological and pharmacological outcomes. Other factors responsible for the diversity in response may include concomitant medications, age, concurrent disease, overall health status, alcohol use, liver disease, renal disease, smoking and hormonal status. Evidence-based guidelines on alternative treatment options should midazolam fail are required. In the interim, a lower threshold for adding an alternative drug, such as phenobarbital, or substituting midazolam with another drug, such as propofol, should be considered in these circumstances. J Pain Symptom Manage 2002;23:256–265. © U.S. Cancer Pain Relief Committee, 2002. Key Words palliative, sedation, midazolam, propofol, phenobarbital
Introduction A small number of terminally ill patients experience symptoms that are refractory despite all efforts to identify a tolerable therapy that does not compromise consciousness.1 After remedial causes have been excluded, sedation is considered to be ethically justifiable in these cases.2 It is emphasized that palliative sedation with midazolam should follow attempts at controlling the symptoms with first-line medica-
Address reprint requests to: Jose Pereira, MD, Director, Palliative Care Unit, Unit 47, Foothills Hospital, 1403 29 St. NW, Calgary, AB T2N 2T9, Canada. Accepted for publication: June 25, 2001. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York
tions such as haloperidol, methotrimeprazine, or chlorpromazine in the case of agitation and the optimization of analgesic regimens in the case of pain.1,3 Sedation may also be appropriate for some patients who experience catastrophic, distressing events such as sudden asphyxia or massive hemorrhaging.4,5 In initiating sedation, it is recognized that the level of sedation can vary from mild sedation, where the goal is to have a patient somnolent but communicative, to deep sedation, where the patient is not conscious. Where the goal is deep sedation, midazolam by continuous subcutaneous infusion is often the drug of choice.3,5–9 Midazolam is a water-soluble benzodiazepine with a rapid onset. On initial administration, it has a short duration of action in most 0885-3924/02/$–see front matter PIIS0885-3924(01)00412-2
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subjects.10 It has a short elimination half-life on initial administration, a relatively large volume of distribution, and a high plasma clearance. These properties facilitate rapid induction of sedation and titration to clinical effect.6,7,11 Its major metabolic pathway is hydroxylation and subsequent conjugation with glucuronic acid before elimination in the urine. It undergoes biotransformation by the P450 system, mainly in the liver. The metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1,4-dihydroxymidazolam are conjugated quickly, contributing little to the pharmacological effect. Less than 1% of the drug appears unchanged in the urine. Midazolam binds extensively to serum albumin, leaving only 2–5% as free drug. The metabolites have a shorter elimination half-life than midazolam itself. Midazolam, like other benzodiazepines, is an agonist at the gamma aminobutyric acid (GABA)-benzodiazepine-chloride receptor complex and exerts its effect by potentiating the action of the inhibitory neurotransmitter GABA at the GABAA receptors, thereby modulating inhibitory transmission at these sites. Two major types of GABA receptor complexes exist, GABAA and GABAB. GABAA is the most prevalent of the two and has specific binding sites for the GABA neurotransmitter. Unlike GABAB, it also has binding sites for benzodiazepine agonists and antagonists, as well as for barbiturates and corticosteroids, among other compounds. Midazolam is generally effective at doses of 1 mg/hr to 10 mg/hr.3 While prolonged sedation has been reported in some individuals,12–14 failure to respond adequately poses a clinical challenge, particularly where rapid sedation is required to control very distressing situations.3,7–9 Two patients are described who developed intractable stridor and did not respond promptly and adequately to midazolam infusions. These cases serve to explore the possible causes for the lack of response to midazolam and to illustrate some of the options available when midazolam appears to be ineffective.
Case Reports Patient A A 48-year-old man with squamous cell carcinoma of the head and neck was admitted to our tertiary palliative care unit (TPCU) for
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control of neuropathic pain in his right side, which emanated from invasion of the tumor into his brachial plexus. He was also myoclonic and delirious. He had been diagnosed nine months previously and had undergone surgery and extensive radiation treatment. His right neck and supraclavicular region was included in the radiation field. Unfortunately the cancer had progressed aggressively despite the treatment, resulting in the placement of gastrostomy and tracheostomy tubes because of difficulties swallowing and breathing five months later. He had abused alcohol and smoked for many years (his CAGE scoring for screening of alcohol abuse was 4/4) but had stopped these following the placement of the tubes. Upon admission to the TPCU, his liver function parameters were within normal limits. His albumin level was low at 28 g/L. Following admission to the TPCU, he was switched to methadone. A concomitant hypercalcemia was treated by a clodronate infusion. His delirium resolved but his pain worsened, requiring further titration of his methadone dose. By day 17 of his admission, he was receiving 60 mg of methadone per day in three divided doses via his gastrostomy tube. On day 18, dexamethasone was added as an adjuvant analgesic, with a good response. Unfortunately, on day 23 he developed methadone-related toxicity (delirium and myoclonus) and was switched to hydromorphone. The toxicity cleared. On day 25, he started experiencing some stridor. Further palliative radiation treatment was not possible. On the evening of day 26, he experienced an episode of acute stridor. A bolus injection of midazolam 5 mg subcutaneously (SC) settled his anxiety and the stridor improved after his dexamethasone dose was increased to 10 mg SC 4 times a day. It was felt that the edema surrounding the advancing tumor had contributed to the episode. On the morning of day 28, the stridor recurred, causing significant distress. He had difficulties speaking but was able to request sedation. The possibility of sedation as a treatment option had been discussed with him previously. A continuous SC infusion of midazolam at 1–6 mg per hour was started and he was switched to oxycodone at a dose of 20 mg SC every 4 hrs because myoclonus was noted. On our unit, the nursing staff is comfortable and skilled in titrating the dose to adequate effect; they typi-
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cally begin at the lowest dose range and increase the dose every 30 to 60 minutes as needed. Unfortunately, his respiratory distress intensified and his midazolam dose was increased. Six hours after starting the infusion, his dose was 20 mg per hour. At that dose, he appeared sedated and comfortable. During the night, the nursing staff was able to titrate the midazolam dose down to 14 mg per hour, without compromising his comfort. The following evening (day 29), he became agitated again and the dose was titrated up to 30 mg per hour. Once again this proved successful and he experienced a quiet, comfortable night. The following morning, restlessness recurred and a decision was made to add methotrimeprazine at a dose of 25 mg SC every 4 hours. He settled after this. No myoclonus was evident at this point. On day 31, he became agitated again and appeared to be breathing with difficulty. The midazolam dose was titrated up once again. He remained agitated, even when the dose of midazolam was increased to 50 mg per hour. A decision was made to add phenobarbital at a dose of 100 mg SC 3 times a day. He settled approximately an hour after the first phenobarbital dose was administered. The methotrimeprazine was decreased and discontinued two days later. On day 32, it was felt that the dexamethasone was of no further benefit and a tapering regimen was started. By day 40, the dose was down to 4 mg SC once a day. The midazolam dose was successfully tapered over the course of 2 days to 8 mg per hour after the phenobarbital dose had been increased to 150 mg 3 times a day on day 33. He died peacefully on day 41.
Patient B A 48-year-old man with advanced non-small cell cancer of the lung was admitted to our TPCU for the management of delirium. He had been diagnosed 11 months previously when he had presented with superior vena cava obstruction. Extensive mediastinal lymphadenopathy had been noted and he underwent radiation treatment at the time. Four months prior to his admission, he had received further palliative radiation treatment to his right rib cage for painful bone metastases. Upon admission to the unit, he was receiving hydromorphone at a dose of approximately 300 mg per day by a continuous SC infusion. A variety of adjuvant
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analgesics, including amitriptyline, paroxetine, gabapentin, and carbamazepine had been added to his analgesic regimen during the two to three weeks prior to admission to control neuropathic pain in his right arm related to tumor invasion of his brachial plexus. He had no history of alcohol abuse and had never smoked. On physical examination, he was found to have ptosis of the right eye and a mass was palpable in his right supraclavicular region. He appeared in no acute distress and denied shortness of breath. However, a plain radiograph of his chest revealed marked deviation of the distal trachea secondary to mediastinal lymphadenopathy. The delirium was thought to be drug-related. He was switched to methadone and by the third day was on a dose of 25 mg of methadone every 8 hours. The amitriptyline was discontinued and the gabapentin and carbamazepine were tapered and discontinued 4 days later. On the second day of his admission, it was noted that he was experiencing some difficulties with inspiration, but he denied any shortness of breath. Dexamethasone at a dose of 10 mg SC twice a day was started (as an adjuvant analgesic and in an attempt to decrease the airway obstruction). On day 3, the dexamethasone dose was increased to 10 mg four times a day. Despite this treatment, his respiratory status deteriorated. The right main bronchus obstructed completely. He became very short of breath and, following a discussion with him and his wife, a decision was made to sedate him with a continuous SC infusion of midazolam. A starting dose at a range of 1 to 6 mg per hour proved unsuccessful and by the evening the dose had been increased to 10 mg per hour. He settled with this increased dose. On day 4, he became agitated and stridorous again, and required further increases in the midazolam dose. By the evening, the dose was up to 20 mg an hour. The addition of methotrimeprazine at a dose of 25 mg every 8 hours proved unsuccessful (three doses were given). Adequate sedation was finally achieved after phenobarbital at a dose of 100 mg SC twice a day was added that evening. On the morning of day 5, the dexamethasone was discontinued since it appeared that it had had no significant clinical impact. In the afternoon of day 5 he became very agitated again. The phenobarbital and midazolam doses were increased to 200 mg three times a day and 50 mg per hour respectively,
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the latter in aliquots of 5 mg every 30 to 60 minutes. Adequate sedation, without any respiratory depression, was achieved in the early morning of day 6. He died later that evening.
Discussion The failure of the two patients under discussion to respond promptly and adequately led to delays in achieving control of distressing events. They initially both displayed poor responses to midazolam at doses that would ordinarily have been effective. With significant dose titration, there were some periods of adequate response. However, these periods were short-lived and rapid dose escalation, as well as the addition of other sedating medications, was required. The poor responses in these individuals are consistent with several reports indicating considerable inter-individual variation in response to midazolam and other sedatives.3,7–9,11,12,15–22 Various patterns of “poor response” to midazolam are noted. Some individuals appear to exhibit a limited response, even at high doses. In one report, paradoxical agitation was observed.18 Others exhibit an initial favorable response followed by a need to escalate the dose to achieve the same level of sedation. The escalation in dose may be gradual or, as demonstrated in these cases, very rapid. In the clinical setting, the term “tolerance” is often used to describe the phenomenon of diminution of drug action in association with continued drug exposure. When “tolerance” occurs rapidly, as illustrated in these cases, the term “tachyphylaxis” is sometimes used. Tolerance to the pharmacodynamic effects of benzodiazepines, both after single doses and during continuous administration, has been noted.22,23 The acute sedative effects of benzodiazepines following single doses may diminish or disappear far more rapidly than the plasma and/or brain concentrations fall to zero.21 Shelley and colleagues, in their study of 50 intensive care patients, noted that to maintain the same degree of sedation it was necessary to increase the daily dose of midazolam in some patients.11 Animal studies indicate that development of tolerance to benzodiazepines may occur rapidly.23 In humans, several cases have been reported of patients awakening prematurely from midazolam-induced sedation.12,24
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Rapid tolerance has been reported in patients overdosing on benzodiazepines.25 Despite the above observations, the phenomenon of tolerance development, as demonstrated by the need for increased doses over time, has been challenged.13 The mechanisms underlying the development of tolerance to benzodiazepines and midazolam are unclear, as are the mechanisms responsible for the wide variations in responses that are occasionally observed. The mechanisms appear to be complex19 and include numerous pharmacodynamic and pharmacokinetic factors.21,26–28 To explore variation in drug responsiveness one can use the theoretical framework proposed by Bourne and Roberts.29 They describe four general mechanisms but emphasize that their categorization is rather artificial in that variation in clinical responsiveness is caused by more than one mechanism. The four mechanisms are: 1) variations and alterations in the structure, number, or function of receptors; 2) alterations in concentration of drug that reaches the receptors; 3) variations in concentration of an endogenous receptor ligand; and 4) changes in components of response distal to receptor. We will focus on the first two general mechanisms.
Variations and Alterations in Structure, Function, or Number of GABA Receptors The lack of response to midazolam may be attributed to genetically determined variations in the GABA-receptors making some individuals relatively less sensitive.21,26,27,30 The GABAA receptor complex is believed to be a glycoprotein composed of five polypeptide subunits.31 Five distinct classes of polypeptide subunits (alpha, beta, gamma, delta, and rho) have been identified, and multiple isoforms of each have been shown to exist so that the total number of identified subunits now stands at 15 (alpha1–6, beta1–4, gamma1–3, delta, and rho). A family of at least 15 genes genetically encodes these subunits. The binding site for the benzodiazepines is located in the alpha subunit of the GABAA receptor whereas the GABA binding site resides on the beta-subunit.31,32 The expression of the gamma-subunits is essential for conferring the modulatory action of benzodiazepines on GABAA receptors.32 In addition, co-expression of individual gamma subunits with alphaand beta-subunits results in varying degrees of
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modulation by benzodiazepine receptor ligands (agonists, antagonists, inverse agonists). The heterogeneity of alpha- and gamma-subunit expression seems to determine the diversity of the physiological and pharmacological responses characteristic of the GABAA receptor complex. The heterogeneity of the GABAA receptor complex may also provide diversity in the way it adapts or alters to various stimuli and conditions. This could explain, to some degree, the relative “down-regulation” of the receptor complex to the influence of midazolam over time. It appears that the GABAA receptor complex can be functionally altered by a variety of stimuli and compounds that bind to its different sites, resulting in “down-regulation” of the receptors. These compounds include alcohol, barbiturates and corticosteroids. Alcohol may affect the functioning of GABA receptors.33 It is possible that chronic alcohol use may “down-regulate” the GABA receptors, thereby rendering the receptors relatively insensitive to the effects of midazolam. However, this theory has been challenged by Bauer and colleagues, who suggest that within 2–3 weeks of withdrawal from alcohol, the GABA receptor may revert to its usual configuration.33 Other animal models suggest that cross-tolerance between alcohol and benzodiazepines is a short-lived phenomenon.34 Although alcohol administration has been shown to potentiate benzodiazepine– GABA receptor function in some in vitro studies, many cells that respond to GABA agonists do not respond to alcohol.34 Thus it is likely that tolerance to alcohol’s central nervous system effects is mediated by a small subpopulation of GABA receptors and/or by other mechanisms. The role that chronic alcohol use played in Patient A is unclear. Corticosteroids also may change the structure and the function of the GABAA receptor complex, and phosphorylation of the GABAA receptor channels, by as yet unclear mechanisms, may be important for both short-term and long-term regulation of GABAA receptor function and expression.31
Alterations in Concentration of Midazolam Reaching the Receptors Midazalom is metabolized primarily by the CYP 3A4 iso-enzyme group of the P450 enzyme-complex.35 Other enzymes, including the CYP 2D6 isoenzyme, may also be involved, but
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to a lesser degree.35 Enzyme activity and expression may be influenced genetically.30,36,37 Distinct subpopulations with different rates of metabolism and elimination of some drugs have been identified.38 A pharmacogenetic abnormality is thought to occur in 6–10% of the normal population resulting in a decreased metabolism of midazolam.39 This would confer a relative increase in responsiveness. On the other hand, the existence of “increased metabolizers” may confer a relatively lack of responsiveness. However, this hypothesis has been challenged.39 Enzyme activity may also be regulated by other factors, including age,40–42 concurrent disease, overall health status,11,12,41,43 alcohol use,44 smoking,45 and hormonal status. Although Bottomley and Hanks found no relationship between age and response to midazolam,19 elderly patients appear to respond more readily to the actions of midazolam.40–42 This increased responsiveness may relate to the aging liver having fewer enzymes and metabolism being slower.40 Another theory is that increased receptor sensitivity may occur with age. In terminally ill patients, it may be difficult to separate the effects of age from the effects of organ dysfunction related to advanced disease. The impact of chronic alcohol abuse on P450 enzyme action is unclear. It has been noted that chronic ethanol consumption induces enzyme activity.44 On the other hand, chronic alcohol liver damage may impair metabolism, resulting in drug accumulation. Smoking may increase the metabolism of some drugs by inducing enzyme activity.45 Both of the patients described had not smoked for several weeks prior to the sedation. The possibility of significant drug interactions resulting in increased metabolism of midazolam also must be considered. The induction, or inhibition, of hepatic drug metabolism by various drugs is a major source of variability in drug response.35,46,47 Both patients were receiving high doses of dexamethasone concurrent with the midazolam and one was on carbamazepine. Both these drugs are known to induce the CYP 3A4 isoenzyme.46,47 They may therefore have enhanced the breakdown of the midazolam. Unlike drugs such as phenobarbital, benzodiazepines have little effect on liver enzyme activity and do not induce their own metabolism.21
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Another possible, yet unlikely, factor responsible for altering the concentration of midazolam reaching the receptors in these two patients relates to the pH of the drug. Midazolam hydrochloride is very acidic, with a pH of 3. When it is prepared for injection in a dextrose solution, its pH increases to 4. After administration, at physiological pH (7.4), the drug becomes lipophylic, allowing it to cross the blood brain barrier.48 Both patients were in respiratory distress and may have had a respiratory acidosis. It is also possible that large volumes of midazolam over long periods of time may have exacerbated this relative acidotic state.
Anticipating a Poor Response It would be useful to predict the responsiveness of an individual patient to midazolam. Although wide interindividual variation in response may make prediction difficult, a search for predictors is warranted. Based on the above discussions, predictive factors that may require consideration include concurrent medications, age, overall disease status, functional status, concurrent liver and/or renal disease, and blood albumin levels. Some commonly used drugs in palliative care may interfere with the metabolism of mi-
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dazolam (Table 1). More comprehensive lists may be found elsewhere.35,47 Elderly patients, those with extensive disease, and those with very poor functional status appear to be more responsive to midazolam.11 Whether or not liver disease affects midazolam action is unclear. Although prolonged sedation has been observed in patients with liver disease,11,49 others have reported reduced clearance of midazolam in patients with cirrhosis.50,51 Park and colleagues found a wide range in the metabolism of midazolam in patients with end-stage liver disease52 and liver tissue affected by cirrhotic disease showed greater preservation of enzyme function than that affected by hepatocellular disease. Because midazolam has a high hepatic extraction, the rate of its metabolism is dependent on hepatic blood flow and any reduction in liver perfusion could reduce the rate of its metabolism. It is uncertain whether renal impairment reduces clearance or not.11,43 Shelley and colleagues found that the time to awaken following cessation of a midazolam infusion was prolonged in patients who had renal impairment. However, this may have been the result of opioid accumulation. Extremely ill patients do appear to be more responsive to midazolam.19 Patients A and B, although clearly pal-
Table 1 Drugs Used in Palliative Care as Substrates, Inducers and Inhibitors of Cytochrome CYP 3A4 and CYP 2D6 Substrate
Inhibitor
Inducer
CYP 3A4
midazolam carbamazepine alfentanyl fentanyl dexamethasone nefazodone sertraline warfarin
carbamzepine dexamethasone phenobarbital phenytoin rifampicin erythromycin omeprazole cyclophosphamide
CYP 2D6
midazolam codeine oxycodone methadone morphine tramadol desipramine fluoxetine paroxetine venlafaxine risperidone haloperidol
cannibinoids fluconazole ketoconazole itraconazole metronidazole norfloxacin fluoxetine fluvoxamine setraline erythromycin clarithromycin cimetidine desipramine fluoxetine haloperidol paroxetine sertraline
This is not a comprehensive list and readers are referred to other references—see text.
carbamazepine phenobarbital phenytoin
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liative, were relatively young and did not have multi-organ involvement. Whether or not low albumin levels play a role is unclear. Decreases in the plasma protein concentration and reductions in the strength and extent of binding could increase the fraction of free drug, thereby increasing its availability at the GABA receptors. In contrast to other benzodiazepines, hepatic clearance of midazolam is of the non-restrictive type, indicating that both bound and unbound drug can be degraded by the liver enzymes.53
Managing Non-Response When faced with an apparent failure to achieve a satisfactory response to midazolam, one needs to review the diagnosis, the indications for sedation, and the treatment. In hindsight, Patient B may have benefited from the insertion of a tracheal/bronchial stent54 or racemic epinephrine inhalations. Once the appropriateness of palliative sedation is established,
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concurrent medications should be reviewed and judgments are needed concerning further escalation of the midazolam dose, administration of an additional sedative, or substitution of the midazolam with an alternative drug. Unfortunately, evidence-based guidelines and protocols are lacking and the overall effectiveness of various approaches for palliative sedation have not been systematically evaluated. Although the ethical considerations surrounding palliative sedation have received extensive, deserved attention,3 the technicalities related to administering the sedation have not. Alternative options when midazolam fails include adding methotrimeprazine55 or phenobarbital56–58 to the midazolam or substituting the midazolam with phenobarbital or propofol.15–18 The relative advantages, disadvantages, and dosing regimens suggested in the literature are listed in Table 2. Phenobarbital can be administered subcutaneously, unlike propofol,
Table 2 The Pros and Cons of Some Alternative Agents for Sedation When Midazolam Is Ineffective Drug
Pros
Cons
Suggested Dosing Regimens
Midazolam
Rapid onset of action16 Short half of life: easily titratable Subcutaneous administration Minimal cardiovascular effects
Lack of efficacy in some individuals Relatively costly, particularly at high doses18
Propofol15–18
Rapid onset of action Ultra-short duration of action: easily titrable, fast recovery60 Antiemetic effect Decreases pruritus due to cholestasis61
Requires anesthetist supervision in most institutions/programs No subcutaneous administration Painful intravenous injection16 May increase risk of infection59 Development of tachyphylaxis
Phenobarbitone56–58
Rapid onset of action Subcutaneous administration Anticonvulsant action Dissociative effects
Long half-life Loading dose required Potent inducer of hepatic enzymes (high potential for drug interactions) No analgesic or antiemetic properties Considerable interindividual variability in pharmacokinetics
See text Starting dose ranges of 1–6 mg per hour are often quoted. Sometimes a loading dose of 2.5 to 5 mg is suggested. Sometimes a single dose is suggested instead of a range and the dose then titrated accordingly. The decision to order a range or single dose may depend on the comfort level and experience of the staff in titrating the dose to effect. Continuous infusion: When initiating propofol, the infusion rate should be increased from 10 mg/hr by 10 mg/hr increments every 15–20 min until sedation is satisfactory.15 If there is an urgent need to increase the sedation, boluses of between 20 mg and 50 mg may be administered by increasing the rate for 2–5 min.15 Doses of between 5 mg/hr to 70 mg/hr generally suggested. Loading dose of 20 mg followed by an infusion of 50 mg/hr, titrating up to 70 mg/hr as need be.16 Stat 100–200 mg intramuscular or subcutaneously for sedation in a catastrophic event.5 Intramuscular loading dose of 100–200 mg, followed by a subcutaneous infusion of 1200 mg/day (median) (range of 600–1600 mg/day).57 200–2500 mg/24 hours3 (subcutaneous infusion). Can also be administered intermittently in 3 daily divided doses (cases described here).
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which must be administered intravenously. Some institutions require that propofol be administered under anesthetic supervision, as is the case with our institution. This requirement limits the use of this potentially beneficial drug in these circumstances and is, given the circumstances, somewhat redundant. Propofol, which has a lipid medium, favors yeast and bacterial growth and also appears to impair the immune system by diminishing the chemotactic motion of human leucocytes.59 However, the increased risk for infection is moot given the circumstances for which it is being used. The ideal drug for sedation in palliative care settings should provide for a consistently fast, smooth onset of action and easily titratable level of sedation. Following these cases, our threshold for introducing an alternative drug has been lowered. It appears that there is a point at which a further increase in midazolam dose is beyond maximal enhancement of the GABA-nergic inhibitory system and so has little or no added benefit. This point is unclear but we suggest a dose of 15–20 mg per hour as the threshold. This dose has been arbitrarily chosen.
Conclusions Although the mechanisms underlying the spectrum of response to midazolam warrant research, other areas related to the technicalities of providing palliative sedation deserve further attention. Three key areas include clarifying the frequency of midazolam failure, identifying factors predicting poor or adequate response, and developing evidence-based guidelines on alternative treatment options should midazolam fail. In the interim, to limit the distress caused by intractable symptoms that are not responsive to midazolam, a lower threshold for adding an alternative drug such as phenobarbital or substituting midazolam with propofol should be considered.
Acknowledgments The authors are grateful to La Ligue de Lutte Centre le Cancer des Vosges (France), la Fondation de France, and Bristol-Myers Squibb for the financial support of Dr. C. Roemer’s Fellowship. The authors also wish to thank Professors William Drysden and Peter Smith for their insightful comments.
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