PERSPECT IVE

Continuous infusions of midazolam and interruptedhydration – like insulin infusions without glucose?

Continuous subcutaneous (SC) infusions of midazo-

lam for the treatment of agitation or restlessness

were used in approximately a third of dying patients

on the LCP (1) and it is likely that future attempts

to translate elements of palliative care to the hospital

setting, as replacements for the LCP will continue

this trend. Provision of artificial hydration at the end

of life is debated; however, rendering a patient

unconscious and unable to drink through the use of

sedatives or where artificial hydration has been

stopped, can initiate a potentially lethal pharmaco-

logical cascade in the context of continuous infusions

of midazolam. This could be considered analogous

to the administration of parenteral insulin without

glucose in a nil-by-mouth patient. The pharmacolog-

ical basis of this will be discussed.

Midazolam is a benzodiazepine derivative com-

monly used in its parenteral form in anaesthetic

practice and licensed for premedication, induction of

anaesthesia, a sedative component in combined

anaesthetic, and conscious sedation for diagnostic

and therapeutic procedures. It is also licensed for use

for monitored continuous sedation in adults and

children in intensive care.

Midazolam is used off-label in palliative care, but

is considered by consensus as one of the three or

four most essential drugs in this clinical practice (2).

It has therefore played a central role in the transla-

tion of palliative care practices from hospice to hos-

pital in pathways such as the Liverpool care pathway.

The favoured route for parenteral midazolam in this

setting is SC administration, which has comparable

bioavailability compared with the intravenous (IV)

route in healthy volunteers (3).

In human liver microsomes, midazolam is exten-

sively metabolized to two primary metabolites, 1′-hy-

droxymidazolam (1′-OH MDZ) and

4-hydroxymidazolam (4-OH MDZ)

(4,5). However, the hydroxylated

metabolites can be further metabo-

lised and are excreted from the body

as glucuronic acid conjugates.

Urinary analysis has revealed that

60–80% of the administered dose is

eliminated as 1′-hydroxymidazolam

glucuronide (1′OH MDZ glucuro-

nide) (6,7). The biotransformation

products of midazolam contribute to

the net pharmacological effect of mi-

dazolam by activity at the benzodiazepine receptor:

1′-OH MDZ has 63% of the potency of midazolam

(8); however, the effect of 1′OH MDZ glucuronide is

usually neglected because of its lower potency (6%)

and normally rapid excretion.

Version 12 of the LCP provides generic medica-

tion recommendations for local providers to imple-

ment in accordance with their governance

frameworks (9). Typically, patients who have had

two or three ‘as required’ (10,11) doses of 2.5–5 mg

of midazolam SC for restlessness or agitation are

escalated to midazolam by continuous infusion by

syringe driver. The National Care of the Dying Audit

– Hospitals indicates that 29% (1110/3893) of

patients were prescribed and received midazolam ‘as

required’ doses in the last 24 h, median dose 5 mg

(range 0.5–60 mg). The audit details that 31%

(1208/3893) were prescribed and received midazolam

by continuous infusion, median 10 mg/24 h (range

0.1–100 mg/24 h) (1). Other drugs used alone or in

combination with midazolam for this indication

included levomepromazine and haloperidol.

The pharmacology of midazolam at the end of life

is complex. The half-life of midazolam may be pro-

longed by four times in patients over the age of 60, six

times in those with critical illness and doubled in

patients with cardiac impairment (12). The dying

patient is likely to fit some or all of these categories.

Dosing, which does not take into account such vari-

ability, is likely to lead to increased steady state serum

levels (if reached) with mounting pharmacological

effects. Dying or critically ill patients may also have

significant hypoalbuminaemia, an important factor

predisposing to greater sensitivity to midazolam (13).

In dying patients, the interruption of oral hydration

(resulting from iatrogenic sedation) or through the

The Liverpool Care Pathway (LCP) for the dying patient

is a UK care pathway covering palliative care options for

patients in the final days or hours of life; it has recently

been recommended for decommission in the UK following

an independent review. The pathway was widely imple-

mented in UK hospitals in part because of governmental

financial incentives. One of the criticisms of the LCP

included reports of the rapid escalation to continuous

infusions of sedatives in patients who then became quickly

unconscious and unable to communicate.Risks of

midazolam

infusions and

interrupted

hydration

410ª 2014 John Wiley & Sons Ltd

Int J Clin Pract, April 2014, 68, 4, 410–412. doi: 10.1111/ijcp.12330

cessation of artificial hydration (IV/SC fluids) is com-

mon (latter, 83% of patients, LCP goal 3.3) (1). Oligu-

ria/anuria may be perceived as beneficial at the end of

life, because patients will not micturate or require uri-

nary catheters. However, oliguric/anuric patients are

at increased risk of midazolam toxicity as a result of its

predominant renal excretion. Several case series have

reported prolonged sedation amongst patients with

acute or deteriorating renal function (8,14–16).Although the half-life of midazolam is indeed pro-

longed in such cases (1.7 times), the renal clearance of

the 1′OH MDZ glucuronide metabolite has been

found to be markedly prolonged by approximately 34

times (4 ml/min vs. 139 ml/min) (16). The serum

level of 1′OH MDZ glucuronide has been reported to

rise 10–30 times the level of midazolam (8,14,15),

thereby contributing a significant or occasionally greater

proportion of pharmacological effect, despite having

less affinity for the benzodiazepine receptor. Plasma lev-

els of midazolam and its metabolites are therefore likely

to rise in the dying and dehydrated patient coinciding

with the onset of oliguria and anuria.

The ‘More Care, Less Pathway’ independent review

of the LCP states (section 1.74), ‘Dehydration can

sometimes cause a patient to become agitated and

confused. If this happens, this can usually be

improved by giving the patient fluids. If this agitation

from dehydration is not recognised for what it is, and

is then treated with sedatives, it makes the confused

and agitated person even less able to accept any fluids

offered to them, starting a vicious cycle.’ The report

also highlights with some anxiety cases of patients

being rapidly escalated to continuous infusions of

sedatives, who then became quickly unconscious and

unable to communicate (sections 1.66, 1.67, 1.69).

Elderly patients appear particularly sensitive to mi-

dazolam-induced respiratory depression and arrest,

especially in combination with opioids, which are

commonly employed in this context (17). The

MHRA product guidance for administration for its

licensed indications recommends, ‘Midazolam should

be administered only by experienced physicians in a

setting fully equipped for the monitoring and sup-

port of respiratory and cardiovascular function and

by persons specifically trained in the recognition and

management of expected adverse events including

respiratory and cardiac resuscitation.’ (18) This is

unsurprising, as hypoxic events are common after a

single IV or SC dose of 5 mg Midazolam, occurring

in 20% of healthy male volunteers aged 18–31 years:

one episode lasting 8 min (3). However, patients on

the LCP are typically unmonitored and receive

reduced clinical observations, which may not include

respiratory rate or intermittent pulse oximetry.

The purpose of this discussion is to highlight that

the dying patient is particularly vulnerable to the

sedative and toxic effects of continuous SC infusions

of midazolam because of pharmacokinetics that may

significantly diverge from normal. The administra-

tion of excessive or unmonitored midazolam to the

dying patient may render them rapidly unconscious,

and therefore unable to voluntarily drink; the onset

of oliguria will lead to the accumulation of 1′OH

MDZ glucuronide and therefore increased net phar-

macological effect – the risk of respiratory arrest is

significantly augmented. If the diagnosis of imminent

death is incorrect, then the result could be cata-

strophic, yet self-fulfilling.

Seemingly moderate doses of sedative drugs, deliv-

ered by continuous infusion combined with interrup-

tion of hydration, could produce unnecessary and

unanticipated over-sedation and death. It could be

argued that parenteral midazolam should routinely

be co-administered with judicious fluid sufficient to

maintain urine output in sedated or unconscious

patients. This approach would be analogous to insu-

lin infusions when nil-by-mouth, which are co-

administered with glucose to prevent hypoglycaemia.

In situations where even judicious fluid cannot be

administered, clinicians should be mindful of the

dangers of prescribing continuous infusions of par-

enteral midazolam and could resort to intermittent

therapy with increased interval and reduced dose,

guided by the level of sedation (knowing that accu-

mulation is likely). Furthermore, just as blood glu-

cose is checked with insulin therapy, it would seem

prudent to perform intermittent pulse oximetry and

respiratory rate assessment in those patients receiving

continuous parenteral midazolam.

M. A. QuailInstitute of Cardiovascular Science, Great Ormond Street

Hospital for Children, University College London,London, UK

Email: m.quail@ucl.ac.uk

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Acknowledgements

Dr Quail is supported by a British Heart

Foundation Clinical Research Training

Fellowship. The funding source had no

role in the content development of the

manuscript.

Disclosures

MAQ has no conflicts of interest to

declare in relation to this article.

Paper received August 2013, accepted September 2013

ª 2014 John Wiley & Sons LtdInt J Clin Pract, April 2014, 68, 4, 410–412

412 Perspective