Paul Wade, BPharm (Hons), MSc (Clin Pharm), MRPharmS.
Principal Pharmacist for Clinical Services
Professional Nurse 2003 Jan;18(5):285-6
Anaesthetic agents can be administered by inhalation, injection (either as a bolus or as a continuous infusion), or in tablet form. Inhalational agents are most commonly used for general anaesthesia in the operating theatre and may require scavenging systems to prevent inhalation by health-care workers.
Sedation is used to promote patient comfort and the tolerance of mechanical ventilation, endotracheal tubes, and various treatments and procedures (Saggs, 1998). It is administered as a bolus, leading to possibly alternating levels of under- or over-sedation (Shelly, 1998), or a continuous infusion, which provides a more constant level of sedation, although this can still lead to over-sedation (Shelly, 1998). The aim is to achieve a lightly sedated co-operative patient, who is comfortable and free from anxiety (Murdoch and Cohen, 2000).
The dose of drug necessary to achieve the required level of sedation will vary from patient to patient, and over the period of time the patient is sedated (Table 1). This is due to a variety of factors, such as age, weight, renal and hepatic function, and the possible development of tolerance to the drug.
Over- or under-sedating a patient can be harmful, so there is a need to assess levels and titrate doses of sedation, using a sedation scoring tool (Saggs, 1998). The use of a tool, such as the New Sheffield Sedation Scale (Box 1), enables nurses to increase levels of awareness of sedation, and to attempt to achieve the desired level for an individual patient (Olleveant, 1998).
Sedatives commonly used in the intensive care unit (ICU) include benzodiazepines, opioids and propofol. Benzodiazepines act selectively on gamma-aminobutyric acid (GABA) receptors in the brain. This leads to an enhanced response to GABA by increasing the affinity of the receptors for the molecule.
Benzodiazepines used for sedation in the ICU include midazolam, lorazepam, and diazepam.
Midazolam is by far the most commonly used benzodiazepine sedative in ICU. It is short-acting with a relatively rapid onset of action. Accumulation of midazolam may be a problem with prolonged use but in ‘normal’ circumstances it has a relatively rapid offset of action. It is commonly administered as a continuous infusion although repeat bolus administration may be appropriate in some patients.
Midazolam is metabolised to an active metabolite, which is renally excreted. So both renal and hepatic impairment can also lead to accumulation and an increase in the duration of action, with subsequent difficulty in waking the patient. Prolonged effects may also be seen in elderly patients and in patients who may be slow metabolisers of midazolam.
Adverse effects seen during therapeutic use of midazolam include respiratory depression, hypotension (particularly in hypovolaemic patients) and paradoxical excitation when used in high doses (>10mg per hour).
Lorazepam has a longer duration of action (around 12-18 hours) than midazolam and so may lend itself more to repeat bolus administration, although lorazepam infusions have been used for sedation.
Diazepam has an even longer duration of action (24-48 hours) and so it is not suitable for long-term use. However, it may be beneficial in weaning anxious patients. Adverse effects of the other benzodiazepines are similar to those seen with midazolam.
Opioids are commonly used agents in ICUs, mainly for their analgesic action. However, their sedative effect is useful as well. The euphoria, well-being and sedation that opioids promote seems mainly to be due to their action on m-receptors, and so different opioids will give rise to different levels of response. The drugs most commonly used are morphine, diamorphine and fentanyl.
Morphine is the standard against which other opioids are measured. It is well established in ICU practice for several reasons:
- Ease of use
- Known and predictable clinical and adverse effects
- Low cost.
It can be used either by repeat bolus dosing or by continuous infusion. It is metabolised in the liver, giving rise to metabolites that are both active (morphine-6-glucuronide, M6G) and inactive (morphine-3-glucuronide, M3G).
M6G is a more potent analgesic than morphine, and as the metabolites are excreted in the urine doses of morphine need to be adjusted in both renal and hepatic dysfunction.
Adverse effects of opioids are well known, and include:
- Respiratory depression
- Depression of cough reflex (diamorphine, codeine)
- Nausea and vomiting
- Contraction of the gall bladder and constriction of the biliary sphincter
It is also known that opioids have immunomodulatory effects in both therapeutic and chronic use.
Other opioids that have been used on ICU include diamorphine and fentanyl. Diamorphine has few advantages over morphine as it is converted to morphine in the body. It is more water-soluble and so may be useful in situations where fluid restriction is necessary.
Fentanyl has similar actions to morphine but it is a much more potent analgesic with some sedative properties. It has a quick onset and short duration of action, and it is suited to patient-controlled analgesia or epidural use.
Accumulation can occur with prolonged use and in hepatic dysfunction. Chest wall rigidity can be an important adverse effect.
Propofol is an intravenous anaesthetic agent that is commonly used in the ICU setting. It has a very rapid onset of action and leads to very fast recovery due to its rapid metabolism. It does not give rise to a hangover effect, making it ideal for short-term sedation. Situations where it may be useful are:
- Postoperatively, in cases where regular assessment of neurological status is required (it also lowers intracranial pressure)
- In cases where rapid weaning from the ventilator may be necessary.
It can be given either by repeat boluses or, more usually, by continuous infusion. However, prolonged use can lead to development of tolerance and a need for increasing doses. As propofol is an expensive agent (compared to midazolam) this can place a high burden on budgets.
Adverse effects seen with propofol use include profound hypotension, bradycardia, convulsions (may be delayed) and pain on intravenous injection. There is also a risk that fat overload may develop as the drug is formulated in a 10% lipid emulsion.
Blood lipid concentrations may require monitoring if the patient is at risk of fat overload or if propofol is infused for longer than three days (BMA/RPSGB, 2002). It is contraindicated for use in children under 17 years of age due to several fatalities associated with its use in this age group (BMA/RPSGB, 2002).
British Medical Association and Royal Pharmaceutical Society of Great Britain. (2002) British National Formulary (No 43). London: BMA/RPSGB.
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Murdoch, S., Cohen, A. (2000)Intensive care sedation: a review of current British practice. Intensive Care Medicine 26: 922-928.
Olleveant, N., Humphris, G., Roe, B. (1998)A reliability study of the modified New Sheffield Sedation Scale. Nursing in Critical Care 3: 2, 83-88.
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