when midazolam fails

© U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$–see front matterPublished by Elsevier, New York, New York PIIS0885-3924(01)00412-2

256 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 GABA

A

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 ex-perience symptoms that are refractory despiteall efforts to identify a tolerable therapy thatdoes not compromise consciousness.

1

After re-medial causes have been excluded, sedation isconsidered to be ethically justifiable in thesecases.

2

It is emphasized that palliative sedationwith midazolam should follow attempts at con-trolling the symptoms with first-line medica-

tions such as haloperidol, methotrimeprazine,or chlorpromazine in the case of agitation andthe optimization of analgesic regimens in thecase of pain.

1,3

Sedation may also be appro-priate for some patients who experience cata-strophic, distressing events such as sudden as-phyxia or massive hemorrhaging.

4,5

In initiatingsedation, it is recognized that the level of seda-tion can vary from mild sedation, where thegoal is to have a patient somnolent but com-municative, to deep sedation, where the pa-tient is not conscious. Where the goal is deepsedation, midazolam by continuous subcutane-ous infusion is often the drug of choice.

3,5–9

Midazolam is a water-soluble benzodiaze-pine with a rapid onset. On initial administra-tion, it has a short duration of action in most

Address reprint requests to:

Jose Pereira, MD, Director,Palliative Care Unit, Unit 47, Foothills Hospital, 140329 St. NW, Calgary, AB T2N 2T9, Canada.

Accepted for publication: June 25, 2001.

Vol. 23 No. 3 March 2002 When Midazolam Fails 257

subjects.

10

It has a short elimination half-life oninitial administration, a relatively large volumeof distribution, and a high plasma clearance.These properties facilitate rapid induction ofsedation and titration to clinical effect.

6,7,11

Itsmajor metabolic pathway is hydroxylation andsubsequent conjugation with glucuronic acidbefore elimination in the urine. It undergoesbiotransformation by the P450 system, mainlyin the liver. The metabolites 1-hydroxymidazo-lam, 4-hydroxymidazolam and 1,4-dihydroxy-midazolam are conjugated quickly, contribut-ing little to the pharmacological effect. Lessthan 1% of the drug appears unchanged in theurine. Midazolam binds extensively to serumalbumin, leaving only 2–5% as free drug. Themetabolites have a shorter elimination half-lifethan midazolam itself.

Midazolam, like other benzodiazepines, isan agonist at the gamma aminobutyric acid(GABA)-benzodiazepine-chloride receptor com-plex and exerts its effect by potentiating the ac-tion of the inhibitory neurotransmitter GABAat the GABA

A

receptors, thereby modulating in-hibitory transmission at these sites. Two majortypes of GABA receptor complexes exist, GABA

A

and GABA

B

. GABA

A

is the most prevalent of thetwo and has specific binding sites for the GABAneurotransmitter. Unlike GABA

B,

it also hasbinding sites for benzodiazepine agonists andantagonists, as well as for barbiturates and cor-ticosteroids, among other compounds.

Midazolam is generally effective at doses of 1mg/hr to 10 mg/hr.

3

While prolonged seda-tion has been reported in some individuals,

12–14

failure to respond adequately poses a clinicalchallenge, particularly where rapid sedationis required to control very distressing situa-tions.

3,7–9

Two patients are described who de-veloped intractable stridor and did not re-spond promptly and adequately to midazolaminfusions. These cases serve to explore the pos-sible causes for the lack of response to mida-zolam and to illustrate some of the optionsavailable when midazolam appears to be inef-fective.

Case Reports

Patient A

A 48-year-old man with squamous cell carci-noma of the head and neck was admitted toour tertiary palliative care unit (TPCU) for

control of neuropathic pain in his right side,which emanated from invasion of the tumorinto his brachial plexus. He was also myoclonicand delirious. He had been diagnosed ninemonths previously and had undergone surgeryand extensive radiation treatment. His rightneck and supraclavicular region was includedin the radiation field. Unfortunately the cancerhad progressed aggressively despite the treat-ment, resulting in the placement of gastros-tomy and tracheostomy tubes because of diffi-culties swallowing and breathing five monthslater. He had abused alcohol and smoked formany years (his CAGE scoring for screening ofalcohol abuse was 4/4) but had stopped thesefollowing the placement of the tubes. Upon ad-mission to the TPCU, his liver function para-meters were within normal limits. His albuminlevel was low at 28 g/L.

Following admission to the TPCU, he wasswitched to methadone. A concomitant hyper-calcemia was treated by a clodronate infusion.His delirium resolved but his pain worsened,requiring further titration of his methadonedose. By day 17 of his admission, he was receiv-ing 60 mg of methadone per day in three di-vided doses via his gastrostomy tube. On day18, dexamethasone was added as an adjuvantanalgesic, with a good response. Unfortunately,on day 23 he developed methadone-related tox-icity (delirium and myoclonus) and was switchedto hydromorphone. The toxicity cleared. Onday 25, he started experiencing some stridor.Further palliative radiation treatment was notpossible. On the evening of day 26, he experi-enced an episode of acute stridor. A bolus in-jection of midazolam 5 mg subcutaneously(SC) settled his anxiety and the stridor im-proved after his dexamethasone dose was in-creased to 10 mg SC 4 times a day. It was feltthat the edema surrounding the advancing tu-mor had contributed to the episode.

On the morning of day 28, the stridor re-curred, causing significant distress. He had dif-ficulties speaking but was able to request seda-tion. The possibility of sedation as a treatmentoption had been discussed with him previously.A continuous SC infusion of midazolam at 1–6mg per hour was started and he was switched tooxycodone at a dose of 20 mg SC every 4 hrsbecause myoclonus was noted. On our unit,the nursing staff is comfortable and skilled intitrating the dose to adequate effect; they typi-

258 Cheng et al. Vol. 23 No. 3 March 2002

cally begin at the lowest dose range and in-crease the dose every 30 to 60 minutes asneeded. Unfortunately, his respiratory distressintensified and his midazolam dose was in-creased. Six hours after starting the infusion,his dose was 20 mg per hour. At that dose, heappeared sedated and comfortable. During thenight, the nursing staff was able to titrate themidazolam dose down to 14 mg per hour, with-out compromising his comfort. The followingevening (day 29), he became agitated againand the dose was titrated up to 30 mg perhour. Once again this proved successful and heexperienced a quiet, comfortable night. Thefollowing morning, restlessness recurred and adecision was made to add methotrimeprazineat a dose of 25 mg SC every 4 hours. He settledafter this. No myoclonus was evident at thispoint. On day 31, he became agitated againand appeared to be breathing with difficulty.The midazolam dose was titrated up once again.He remained agitated, even when the dose ofmidazolam was increased to 50 mg per hour. Adecision was made to add phenobarbital at adose of 100 mg SC 3 times a day. He settled ap-proximately an hour after the first phenobar-bital dose was administered. The methotrime-prazine was decreased and discontinued twodays later. On day 32, it was felt that the dex-amethasone was of no further benefit and a ta-pering regimen was started. By day 40, the dosewas down to 4 mg SC once a day. The mida-zolam dose was successfully tapered over thecourse of 2 days to 8 mg per hour after thephenobarbital dose had been increased to 150mg 3 times a day on day 33. He died peacefullyon day 41.

Patient B

A 48-year-old man with advanced non-smallcell cancer of the lung was admitted to ourTPCU for the management of delirium. Hehad been diagnosed 11 months previously whenhe had presented with superior vena cava ob-struction. Extensive mediastinal lymphadenop-athy had been noted and he underwent radia-tion treatment at the time. Four months priorto his admission, he had received further pal-liative radiation treatment to his right rib cagefor painful bone metastases. Upon admissionto the unit, he was receiving hydromorphoneat a dose of approximately 300 mg per day by acontinuous SC infusion. A variety of adjuvant

analgesics, including amitriptyline, paroxetine,gabapentin, and carbamazepine had been addedto his analgesic regimen during the two tothree weeks prior to admission to control neu-ropathic pain in his right arm related to tumorinvasion of his brachial plexus. He had no his-tory of alcohol abuse and had never smoked.On physical examination, he was found to haveptosis of the right eye and a mass was palpablein his right supraclavicular region. He appearedin no acute distress and denied shortness ofbreath. However, a plain radiograph of his chestrevealed marked deviation of the distal tracheasecondary to mediastinal lymphadenopathy. Thedelirium was thought to be drug-related. Hewas switched to methadone and by the thirdday was on a dose of 25 mg of methadone every8 hours. The amitriptyline was discontinuedand the gabapentin and carbamazepine weretapered and discontinued 4 days later.

On the second day of his admission, it wasnoted that he was experiencing some difficul-ties with inspiration, but he denied any short-ness of breath. Dexamethasone at a dose of 10mg SC twice a day was started (as an adjuvantanalgesic and in an attempt to decrease the air-way obstruction). On day 3, the dexametha-sone dose was increased to 10 mg four times aday. Despite this treatment, his respiratory sta-tus deteriorated. The right main bronchus ob-structed completely. He became very short ofbreath and, following a discussion with himand his wife, a decision was made to sedate himwith a continuous SC infusion of midazolam. Astarting dose at a range of 1 to 6 mg per hourproved unsuccessful and by the evening thedose had been increased to 10 mg per hour.He settled with this increased dose. On day 4,he became agitated and stridorous again, andrequired further increases in the midazolamdose. By the evening, the dose was up to 20 mgan hour. The addition of methotrimeprazineat a dose of 25 mg every 8 hours proved unsuc-cessful (three doses were given). Adequate se-dation was finally achieved after phenobarbitalat a dose of 100 mg SC twice a day was addedthat evening. On the morning of day 5, thedexamethasone was discontinued since it ap-peared that it had had no significant clinicalimpact. In the afternoon of day 5 he becamevery agitated again. The phenobarbital and mi-dazolam doses were increased to 200 mg threetimes a day and 50 mg per hour respectively,


the latter in aliquots of 5 mg every 30 to 60minutes. Adequate sedation, without any respi-ratory depression, was achieved in the earlymorning of day 6. He died later that evening.

Discussion

The failure of the two patients under discus-sion to respond promptly and adequately led todelays in achieving control of distressing events.They initially both displayed poor responses tomidazolam at doses that would ordinarily havebeen effective. With significant dose titration,there were some periods of adequate response.However, these periods were short-lived andrapid dose escalation, as well as the addition ofother sedating medications, was required. Thepoor responses in these individuals are con-sistent with several reports indicating consider-able inter-individual variation in response to mi-dazolam and other sedatives.

3,7–9,11,12,15–22

Various patterns of “poor response” to mida-

zolam are noted. Some individuals appear toexhibit a limited response, even at high doses.In one report, paradoxical agitation was ob-served.

18

Others exhibit an initial favorable re-sponse followed by a need to escalate the doseto achieve the same level of sedation. The esca-lation in dose may be gradual or, as demon-strated in these cases, very rapid. In the clinicalsetting, the term “tolerance” is often used todescribe the phenomenon of diminution ofdrug action in association with continued drugexposure. When “tolerance” occurs rapidly, asillustrated in these cases, the term “tachyphy-laxis” is sometimes used.

Tolerance to the pharmacodynamic effectsof benzodiazepines, both after single doses andduring continuous administration, has beennoted.

22,23

The acute sedative effects of benzo-diazepines following single doses may diminishor disappear far more rapidly than the plasmaand/or brain concentrations fall to zero.

21

Shelley and colleagues, in their study of 50 in-tensive care patients, noted that to maintainthe same degree of sedation it was necessary toincrease the daily dose of midazolam in somepatients.

11

Animal studies indicate that devel-opment of tolerance to benzodiazepines mayoccur rapidly.

23

In humans, several cases havebeen reported of patients awakening prema-turely from midazolam-induced sedation.

12,24

Rapid tolerance has been reported in patientsoverdosing on benzodiazepines.

25

Despite theabove observations, the phenomenon of toler-ance development, as demonstrated by the needfor increased doses over time, has been chal-lenged.

13

The mechanisms underlying the develop-ment of tolerance to benzodiazepines and mi-dazolam are unclear, as are the mechanisms re-sponsible for the wide variations in responsesthat are occasionally observed. The mechanismsappear to be complex

19

and include numerouspharmacodynamic and pharmacokinetic fac-tors.

21,26–28

To explore variation in drug respon-siveness one can use the theoretical frameworkproposed by Bourne and Roberts.

29

They de-scribe four general mechanisms but emphasizethat their categorization is rather artificial inthat variation in clinical responsiveness is causedby more than one mechanism. The four mech-anisms are: 1) variations and alterations in thestructure, number, or function of receptors; 2)alterations in concentration of drug that reachesthe receptors; 3) variations in concentration ofan endogenous receptor ligand; and 4) changesin components of response distal to receptor.We will focus on the first two general mecha-nisms.

Variations and Alterations in Structure, Function, or Number of GABA Receptors

The lack of response to midazolam may beattributed to genetically determined variationsin the GABA-receptors making some individu-als relatively less sensitive.

21,26,27,30

The GABA

A

receptor complex is believed to be a glycopro-tein composed of five polypeptide subunits.

31

Five distinct classes of polypeptide subunits (al-pha, beta, gamma, delta, and rho) have beenidentified, and multiple isoforms of each havebeen shown to exist so that the total number ofidentified subunits now stands at 15 (alpha

1–6

,beta

1–4

, gamma

1–3

, delta, and rho). A family ofat least 15 genes genetically encodes these sub-units. The binding site for the benzodiazepinesis located in the alpha subunit of the GABA

A

receptor whereas the GABA binding site re-sides on the beta-subunit.

31,32

The expressionof the gamma-subunits is essential for confer-ring the modulatory action of benzodiazepineson GABA

A

receptors.

32

In addition, co-expres-sion of individual gamma subunits with alpha-and beta-subunits results in varying degrees of


modulation by benzodiazepine receptor ligands(agonists, antagonists, inverse agonists). Theheterogeneity of alpha- and gamma-subunitexpression seems to determine the diversityof the physiological and pharmacological re-sponses characteristic of the GABA

A

receptorcomplex.

The heterogeneity of the GABA

A

receptorcomplex may also provide diversity in the way itadapts or alters to various stimuli and condi-tions. This could explain, to some degree, therelative “down-regulation” of the receptor com-plex to the influence of midazolam over time.It appears that the GABA

A

receptor complexcan be functionally altered by a variety of stim-uli and compounds that bind to its differentsites, resulting in “down-regulation” of the recep-tors. These compounds include alcohol, barbi-turates and corticosteroids. Alcohol may affectthe functioning of GABA receptors.

33

It is pos-sible that chronic alcohol use may “down-regu-late” the GABA receptors, thereby renderingthe receptors relatively insensitive to the effectsof midazolam. However, this theory has beenchallenged by Bauer and colleagues, who sug-gest that within 2–3 weeks of withdrawal fromalcohol, the GABA receptor may revert to itsusual configuration.

33

Other animal modelssuggest that cross-tolerance between alcoholand benzodiazepines is a short-lived phenome-non.

34

Although alcohol administration hasbeen shown to potentiate benzodiazepine–GABA receptor function in some in vitro stud-ies, many cells that respond to GABA agonistsdo not respond to alcohol.

34

Thus it is likelythat tolerance to alcohol’s central nervous sys-tem effects is mediated by a small subpopula-tion of GABA receptors and/or by other mech-anisms. The role that chronic alcohol useplayed in Patient A is unclear. Corticosteroidsalso may change the structure and the functionof the GABA

A

receptor complex, and phospho-rylation of the GABA

A

receptor channels, by asyet unclear mechanisms, may be important forboth short-term and long-term regulation ofGABA

A

receptor function and expression.

31

Alterations in Concentration of Midazolam Reaching the Receptors

Midazalom is metabolized primarily by theCYP 3A4 iso-enzyme group of the P450 en-zyme-complex.

35

Other enzymes, including theCYP 2D6 isoenzyme, may also be involved, but

to a lesser degree.

35

Enzyme activity and ex-pression may be influenced genetically.

30,36,37

Distinct subpopulations with different rates ofmetabolism and elimination of some drugshave been identified.

38

A pharmacogenetic ab-normality is thought to occur in 6–10% of thenormal population resulting in a decreasedmetabolism of midazolam.

39

This would confera relative increase in responsiveness. On theother hand, the existence of “increased metab-olizers” may confer a relatively lack of respon-siveness. However, this hypothesis has beenchallenged.

39

Enzyme activity may also be regulated byother factors, including age,

40–42

concurrentdisease, overall health status,

11,12,41,43

alcoholuse,

44

smoking,

45

and hormonal status. AlthoughBottomley and Hanks found no relationshipbetween age and response to midazolam,

19

el-derly patients appear to respond more readilyto the actions of midazolam.

40–42

This increasedresponsiveness may relate to the aging liverhaving fewer enzymes and metabolism beingslower.

40

Another theory is that increased re-ceptor sensitivity may occur with age. In termi-nally ill patients, it may be difficult to separatethe effects of age from the effects of organ dys-function related to advanced disease.

The impact of chronic alcohol abuse onP450 enzyme action is unclear. It has beennoted that chronic ethanol consumption in-duces enzyme activity.

44

On the other hand,chronic alcohol liver damage may impair metab-olism, resulting in drug accumulation. Smokingmay increase the metabolism of some drugs byinducing enzyme activity.

45

Both of the patientsdescribed had not smoked for several weeksprior to the sedation.

The possibility of significant drug interac-tions resulting in increased metabolism of mi-dazolam also must be considered. The induc-tion, or inhibition, of hepatic drug metabolismby various drugs is a major source of variabilityin drug response.

35,46,47

Both patients were re-ceiving high doses of dexamethasone concur-rent with the midazolam and one was on car-bamazepine. Both these drugs are known toinduce the CYP 3A4 isoenzyme.

46,47

They maytherefore have enhanced the breakdown of themidazolam. Unlike drugs such as phenobar-bital, benzodiazepines have little effect on liverenzyme activity and do not induce their ownmetabolism.

21


Another possible, yet unlikely, factor respon-sible for altering the concentration of mida-zolam reaching the receptors in these two pa-tients relates to the pH of the drug. Midazolamhydrochloride is very acidic, with a pH of 3.When it is prepared for injection in a dextrosesolution, its pH increases to 4. After adminis-tration, at physiological pH (7.4), the drug be-comes lipophylic, allowing it to cross the bloodbrain barrier.

48

Both patients were in respira-tory distress and may have had a respiratoryacidosis. It is also possible that large volumes ofmidazolam over long periods of time may haveexacerbated this relative acidotic state.

Anticipating a Poor Response

It would be useful to predict the responsive-ness of an individual patient to midazolam. Al-though wide interindividual variation in re-sponse may make prediction difficult, a searchfor predictors is warranted. Based on the abovediscussions, predictive factors that may requireconsideration include concurrent medications,age, overall disease status, functional status, con-current liver and/or renal disease, and blood al-bumin levels.

Some commonly used drugs in palliativecare may interfere with the metabolism of mi-

dazolam (Table 1). More comprehensive listsmay be found elsewhere.

35,47

Elderly patients,those with extensive disease, and those withvery poor functional status appear to be moreresponsive to midazolam.

11

Whether or not liver disease affects mida-zolam action is unclear. Although prolongedsedation has been observed in patients withliver disease,

11,49

others have reported reducedclearance of midazolam in patients with cir-rhosis.

50,51

Park and colleagues found a widerange in the metabolism of midazolam in pa-tients with end-stage liver disease

52

and liver tis-sue affected by cirrhotic disease showed greaterpreservation of enzyme function than that af-fected by hepatocellular disease. Because mi-dazolam has a high hepatic extraction, the rateof its metabolism is dependent on hepatic bloodflow and any reduction in liver perfusion couldreduce the rate of its metabolism.

It is uncertain whether renal impairment re-duces clearance or not.

11,43

Shelley and col-leagues found that the time to awaken follow-ing cessation of a midazolam infusion wasprolonged in patients who had renal impair-ment. However, this may have been the resultof opioid accumulation. Extremely ill patientsdo appear to be more responsive to mida-zolam.

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 cannibinoids carbamzepinecarbamazepine fluconazole dexamethasonealfentanyl ketoconazole phenobarbitalfentanyl itraconazole phenytoindexamethasone metronidazole rifampicinnefazodone norfloxacin erythromycinsertraline fluoxetine omeprazolewarfarin fluvoxamine cyclophosphamide

setralineerythromycinclarithromycin

CYP 2D6 midazolam cimetidine carbamazepinecodeine desipramine phenobarbitaloxycodone fluoxetine phenytoinmethadone haloperidolmorphine paroxetinetramadol sertralinedesipraminefluoxetineparoxetinevenlafaxinerisperidonehaloperidol

This is not a comprehensive list and readers are referred to other references—see text.


liative, were relatively young and did not havemulti-organ involvement. Whether or not low al-bumin levels play a role is unclear. Decreases inthe plasma protein concentration and reduc-tions in the strength and extent of bindingcould increase the fraction of free drug, therebyincreasing its availability at the GABA receptors.In contrast to other benzodiazepines, hepaticclearance of midazolam is of the non-restrictivetype, indicating that both bound and unbounddrug can be degraded by the liver enzymes.

53

Managing Non-Response

When faced with an apparent failure toachieve a satisfactory response to midazolam,one needs to review the diagnosis, the indica-tions for sedation, and the treatment. In hind-sight, Patient B may have benefited from theinsertion of a tracheal/bronchial stent

54

or race-mic epinephrine inhalations. Once the appro-priateness of palliative sedation is established,

concurrent medications should be reviewed andjudgments are needed concerning further esca-lation of the midazolam dose, administration ofan additional sedative, or substitution of the mi-dazolam with an alternative drug. Unfortunately,evidence-based guidelines and protocols arelacking and the overall effectiveness of variousapproaches for palliative sedation have not beensystematically evaluated. Although the ethical con-siderations surrounding palliative sedation havereceived extensive, deserved attention,

3

the tech-nicalities related to administering the sedationhave not.

Alternative options when midazolam fails in-clude adding methotrimeprazine

55

or pheno-barbital

56–58

to the midazolam or substitutingthe midazolam with phenobarbital or propo-fol.

15–18

The relative advantages, disadvantages,and dosing regimens suggested in the litera-ture are listed in Table 2. Phenobarbital can beadministered 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 action

16

Short half of life:easily titratable

Subcutaneousadministration

Minimal cardiovasculareffects

Lack of efficacy in some individuals

Relatively costly, particularly at high doses

18

See textStarting 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.

Propofol

15–18

Rapid onset of actionUltra-short duration of

action: easily titrable, fast recovery

60

Antiemetic effectDecreases pruritus due

to cholestasis

61

Requires anesthetist supervision in most institutions/programs

No subcutaneous administration

Painful intravenous injection

16

May increase risk of infection

59

Development of tachyphylaxis

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

Phenobarbitone

56–58

Rapid onset of actionSubcutaneous

administrationAnticonvulsant actionDissociative effects

Long half-lifeLoading dose requiredPotent inducer of hepatic

enzymes (high potential for drug interactions)

No analgesic or antiemetic properties

Considerable interindividual variability in pharmacokinetics

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 hours

3

(subcutaneous infusion). Can also be administered intermittently in 3 daily divided doses (cases described here).


which must be administered intravenously. Someinstitutions require that propofol be adminis-tered under anesthetic supervision, as is thecase with our institution. This requirement lim-its the use of this potentially beneficial drug inthese circumstances and is, given the circum-stances, somewhat redundant. Propofol, whichhas a lipid medium, favors yeast and bacterialgrowth and also appears to impair the immunesystem by diminishing the chemotactic motionof human leucocytes.

59

However, the increasedrisk for infection is moot given the circum-stances for which it is being used. The idealdrug for sedation in palliative care settingsshould provide for a consistently fast, smoothonset of action and easily titratable level of se-dation.

Following these cases, our threshold for in-troducing an alternative drug has been low-ered. It appears that there is a point at which afurther increase in midazolam dose is beyondmaximal enhancement of the GABA-nergic in-hibitory system and so has little or no addedbenefit. This point is unclear but we suggest adose of 15–20 mg per hour as the threshold.This dose has been arbitrarily chosen.

Conclusions

Although the mechanisms underlying thespectrum of response to midazolam warrant re-search, other areas related to the technicalitiesof providing palliative sedation deserve furtherattention. Three key areas include clarifyingthe frequency of midazolam failure, identify-ing factors predicting poor or adequate re-sponse, and developing evidence-based guide-lines on alternative treatment options shouldmidazolam fail. In the interim, to limit the dis-tress caused by intractable symptoms that arenot responsive to midazolam, a lower thresh-old for adding an alternative drug such as phe-nobarbital or substituting midazolam with pro-pofol should be considered.

Acknowledgments

The authors are grateful to La Ligue deLutte Centre le Cancer des Vosges (France), laFondation de France, and Bristol-Myers Squibbfor the financial support of Dr. C. Roemer’sFellowship. The authors also wish to thank Pro-fessors William Drysden and Peter Smith fortheir insightful comments.

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when midazolam fails

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