16.6 Other medical issues on the ICU
Procedures (1) Acute respiratory distress syndrome (ARDS)—paralysis allows the
Surgery Inflammation patient to tolerate unusual ventilatory modes, e.g. reverse ratio venti-
(2) raised intracranial pressure—paralysis prevents coughing and strain-
Analgesia Amnesia Catecholamines
(3) status asthmaticus—paralysis can reduce risks of barotrauma to
Anxiety PATIENT DISCOMFORT Personality lungs.
The intravenous route is used almost exclusively for the administration
of analgesia and sedation in the critically ill, as it is faster and more reliable
Discomfort Sleep Mechanical Culture than other routes. Drugs can be given either as repeated bolus doses, or as a
ventilation continuous infusion. Although a continuous infusion has the advantage of
avoiding peaks and troughs associated with bolus doses, there is also an
Mode of Tracheal tube increased risk of inadvertent overdose or accumulation.
ventilation The analgesic needs of most patients can best be met with regular bolus
doses of analgesic titrated against repeated assessment of the pain. A
Fig. 1 Factors contributing to patient discomfort. patient- or nurse-controlled syringe pump driver will deliver a bolus of a
predetermined amount of drug when triggered to do so. There is usually a
predetermined ‘lockout’ safety period during which further requests for
16.6.1 Sedation and analgesia bolus doses will be ignored. Morphine is the drug most commonly given in
this manner, but diamorphine, pethidine, and fentanyl can also be used. A
in the critically ill loading dose may be needed before starting.
G. R. Park and B. Ward
Hazards of sedation and analgesia
Sedation and analgesia are used to increase patient comfort by minimizing The use of drugs for sedation and analgesia involves risks to the patient.
the pain and anxiety produced by illness and its treatment. Factors contrib- These include:
uting to patient discomfort are shown in Fig. 1. (1) over-sedation or a prolonged sedative effect caused by poor elimin-
The relief of pain is an obvious part of being comfortable, but the role of ation in the critically ill;
sedation is more complex. The term sedation covers a broad range of con- (2) hypotension/myocardial depression;
scious states, from almost wide awake to deeply unresponsive. The ‘ideal’
level of sedation for most patients is at ease, without signs of anxiety or (3) antitussive effects leading to failure to clear pulmonary secretions;
agitation and easily rousable from light sleep. Sedation is needed for a var- (4) hypoventilation, delaying weaning;
iety of reasons, including: (5) toxic effects due to accumulation of sedative/analgesic agents or their
(1) reduction of anxiety caused by fear, inability to communicate, loss of metabolites; and
control, or unfamiliar environment; (6) expense, both of the drugs and their adverse effects.
(2) allowing patients to tolerate treatment—e.g. stops them pulling out the There are many reasons why the behaviour of drugs administered to the
tracheal tube; critically ill patient may be abnormal. These include:
(3) allowing patterns of ventilation to be imposed which do not synchron- (1) hepatic failure leading to poor metabolism or biliary excretion of the
ize with a normal breathing pattern; drug;
(4) prevention of awareness when neuromuscular paralysis is used; (2) renal failure leading to decreased excretion of the drug or its metabol-
(5) minimizing distress during uncomfortable procedures; ites;
(6) allowing sleep; and (3) haemoﬁltration/dialysis may have unpredictable effects on clearance of
(7) control of ﬁts. the drug or its metabolites;
Patients will usually tolerate a tracheal tube without the need for par- (4) reduced plasma protein levels (e.g. albumin) may lead to increased free
alysis if the ventilator is properly set and they are properly sedated. The (active) drug levels;
indications for neuromuscular relaxation in the critically ill are listed (5) volume of distribution may be affected by oedema, ascites, or hyper/
below: the use of muscle relaxants is otherwise avoided. hypovolaemia;
2 16 cr itical care medicine
Agitated combination with morphine in order to achieve both analgesia and sed-
Awake X ation. Midazolam is primarily metabolized by the liver, and accumulation
occurs in liver failure. The (phase I) metabolic product,
Roused by voice X X X
l-hydroxymidazolam has around 10 per cent of the activity of the parent
Roused by tracheal suction X drug. In renal failure, accumulation of l-hydroxymidazolam glucuronide
Unrousable (the phase II metabolic product) can cause prolonged sedation or coma.
This has been used as an alternative to midazolam. It undergoes metabol-
Pain YES/NO N Y N N N ism only by glucuronidation to render it water soluble. This makes it less
Comfortable on ventilator YES/NO Y Y Y Y Y likely for the parent drug to accumulate. It is dissolved in propylene gly-
Fig. 2 The Addenbrooke’s Sedation Score.
(6) interactions between drugs; and Diazepam is rarely used in the critically ill, having been replaced by mid-
azolam. It has a much longer duration of action and has many metabolites
(7) solvent toxicity. with signiﬁcant activity of their own. This increases the risk of accumu-
The risks of using drugs can me minimized by a knowledge of their lation.
routes of breakdown and excretion. Agents that are unlikely to accumulate
should be chosen when possible. Drugs with more than one site of metab- Propofol
olism, or those which can undergo non-organ-based breakdown are pre- Propofol (2,6-di-isopropylphenol) was introduced as an anaesthetic agent
ferred. The risk of accumulation of a sedative drug can be reduced by but is widely used for sedation in the critically ill as a continuous infusion.
stopping it every 24 h whenever possible and letting the patient recover Emergence from sedation is rapid and without hangover effect. Propofol is
from its effects. If the patient wakes or becomes restless, the drug can be a respiratory depressant, and prolonged apnoea can occur after bolus doses.
restarted knowing that accumulation has not occurred. Hypotension associated with propofol use is common in the critically ill
To avoid under- or over-sedation, drugs need some assessment of their and is dose related. Although metabolized primarily in the liver, extrahe-
effects. Because of the many components which are involved in sedation, patic breakdown does occur. There are no active metabolites and propofol
no simple method exists. Although work is progressing on physical does not accumulate in hepatic or renal failure to a signiﬁcant extent. How-
methods of assessing the level of sedation (e.g. spectral analysis of electro- ever, because it is formulated in soya bean extract, prolonged infusion
encephalogram waveforms), the most commonly used methods rely on (more than 48 h) can lead to hyperlipidaemia. Propofol is expensive, and
bedside observations. We use a scoring system comprising several different its use is often limited to those patients who require short-term sedation
elements (Fig. 2) (see below). The key to avoiding under- or over-sedation only.
is regular assessment of the patient and adjustment of the sedation regimen
Dexmedetomidine is a potent, highly selective, α2-adrenoceptor agonist. It
has sedative, anxiolytic, amnesic, and sympatholytic effects. In addition,
Psychological disturbances dexmedetomidine appears to reduce requirements for opioid analgesia.
Severe illness, the intensive care environment, and drugs usually prevent These effects are mediated centrally at post-synaptic α2-receptors. In con-
patients from sleeping normally. Deprivation of sleep, especially if pro- trast to the agents already discussed, dexmedetomidine does not seem to
longed, combined with the fear of dying may make some patients psych- cause respiratory depression, and exhibits remarkable cardiovascular sta-
otic. Close attention to environment (e.g. normal day/night light levels, bility. Because of these features, there is currently great interest in the use of
noise etc.) may help. Drugs may be of some beneﬁt, but can cause pro- this agent.
longed sedation. If the patient has a prolonged recovery phase then depres-
sion is common. Antidepressants are rarely of value and can have toxic
effects. The intravenous anaesthetic agent thiopentone retains certain specialized
indications, for example use in status epilepticus or to reduce raised intra-
cerebral pressure. Thiopentone has a half-life of 11 h, and prolonged infu-
sion (i.e. > 24 h) is usually associated with extremely prolonged action.
Before using drugs, causes of pain and agitation such as a full bladder or Combinations of agents
rectum should be excluded. Sedative drugs often act via differing mechanisms and so have slightly dif-
ferent actions. This difference can be used to advantage. For example pro-
Sedative drugs pofol is mostly an hypnotic, whilst midazolam is a good anxiolytic and
amnesic agent as well as producing hypnosis. In combination they are
There are two main types of drugs, those principally sedative and those
mostly analgesic. The agents most commonly used for sedation are the
benzodiazepine midazolam and the anaesthetic agent propofol. These, and
other agents commonly used for sedation in the intensive care unit, are Analgesic drugs
described below. Opioid drugs remain the mainstay of analgesic treatment in the critically ill,
and morphine is the most common choice. Some properties of the opioid
Midazolam drugs used in the critically ill are listed in Table 1.
Midazolam is a water-soluble benzodiazepine, which can be given periph-
erally without causing thrombophlebitis or pain. Like all benzodiazepines it Morphine
has sedative, amnesic, anxiolytic, and anticonvulsive properties. It has a Morphine is a cheap and effective analgesic agent and is the opioid against
rapid onset, short half-life (approximately 2 h), and is commonly used in which others are judged. It has both analgesic and sedative effects, although
16.6.1 sedation and analgesia in the cr itically ill 3
Table: 1 Properties of opioid drugs
Opioid Onset of Suitable* Liable to Liable to
action for PCAS/ accumulate in accumulate in
NCAS hepatic failure renal failure
Morphine Slow Yes Yes Yes
Diamorphine Moderate Yes Yes Yes
Pethidine Moderate Yes Yes Yes
Fentanyl Fast Yes Yes Yes
Alfentanil Very fast No Yes No
Remifentanil Very fast No No No
PCAS, patient-controlled analgesia system; NCAS, Nurse-controlled analgesia system.
*Except with special supervision.
an excessive dose would be required to produce adequate sedation by its use small delays, such as the time taken to make up a new syringe, can leave the
alone. It is often given with a benzodiazepine, such as midazolam, to patient without analgesia.
achieve analgesia and sedation. It is the standard agent for use in patient-
and nurse-controlled syringe pumps. Morphine is metabolized in the liver,
forming two major metabolites—morphine 3-glucuronide (M3G) and Sedative and analgesic antagonists
morphine 6-glucuronide (M6G), both of which are active. M6G is a potent
analgesic, whilst M3G is thought to be antianalgesic. When accumulation of a drug or its metabolite is suspected as the cause of
prolonged sedation, the diagnosis can be conﬁrmed with the use of ant-
agonists. Naloxone will quickly (but temporarily) reverse the effects of opi-
ates, whilst ﬂumazenil is a benzodiazepine antagonist. Their use is not
Pethidine is a synthetic compound and was originally developed as an recommended in patients suffering from head injury. Large doses of either
anticholinergic agent. It does tend to cause anticholinergic effects, such as antagonist given quickly can produce sudden arousal, causing agitation.
dry mouth, blurred vision, and tachycardia. It is claimed that pethidine When using naloxone, the sudden reversal of analgesia can cause a massive
induces less constriction of the biliary sphincter than morphine, and per- outpouring of catecholamines and precipitate arrhythmias.
haps the only indication for its use is in patients with biliary pathology. It is
metabolized in the liver to form norpethidine, pethidinic acid, and pethid-
ine-N-oxide. These metabolites are excreted by the kidneys, and in renal
failure signiﬁcant amounts of norpethidine may accumulate, leading to Regional and epidural anaesthesia
grand mal convulsions. For analgesia after certain surgical procedures or trauma, regional and epi-
dural techniques can be extremely effective. Lumbar or thoracic epidurals
Fentanyl can prevent hypoventilation and diaphragmatic splinting caused by pain
Fentanyl is approximately 100 times as potent as morphine, and has a rapid after abdominal or thoracic procedures and fractured ribs, whilst avoiding
onset of action (3 min). In low doses the analgesic effect of fentanyl ends the side-effects of high-dose opioids. The problem of correct placement of
after about 20 min by its rapid redistribution around the body. With larger regional blocks in critically ill patients is a considerable one, and compli-
doses, tissues may become saturated and drug action is prolonged, termin- cations (such as pneumothorax following intercostal block) must be care-
ation depending on the slow process of N-demethylation in the liver. The fully considered. Epidural analgesia, although desirable, may be
major metabolite, norfentanyl, is excreted by the kidneys, and its accumu- contraindicated in the critically ill patient because of coagulopathy or
lation may cause toxic delirium in patients with renal failure. Accumulation sepsis.
of fentanyl itself may occur in hepatic failure, causing prolonged effect.
Fentanyl has a potent apnoeic effect, and in large doses, fentanyl can pro-
duce muscle rigidity, particularly of the chest wall. Further reading
Bion JF, Oh TE (1997). Sedation in intensive care. In: Oh TE, ed. Intensive care
Alfentanil manual, pp 672–8. Butterworth Heineman, Oxford. [An overview of the
Alfentanil is approximately 10 to 20 times as potent as morphine, and has a principles and practice of sedation in intensive care.]
very fast onset time (1 min). The effects of alfentanil are short lived Burns AM, Shelly MP, Park GR (1992). The use of sedative agents in critically
(approximately 10 to 15 min), ending by redistribution to tissues. Because ill patients. Drugs 43, 507–15. [A full review of the drugs used to sedate
of this, alfentanil is unsuitable for use in patient-controlled syringe pumps, critically ill patients.]
and it is administered by continuous infusion. Elimination takes place Carrupt PA et al. (1991). Morphine 6-glucuronide and morphine
almost exclusively in the liver, and alfentanil is the current drug of choice in 3-glucuronide as molecular chameleons with unexpected lipophilicity.
severe renal impairment. It can accumulate in hepatic failure, cirrhosis, or Journal of Medical Chemistry 34, 1272–5. [An important paper that
describes how metabolites that should be inactive change their
when hepatic enzyme inhibitors such as cimetidine are used.
conﬁguration to become active.]
Park GR (1996). Molecular mechanisms of drug metabolism in the critically ill.
Remifentanil British Journal of Anaesthesia 77, 32–49. [Describes the problems of drug
Remifentanil is a relatively new agent which may prove to have pharmaco- elimination, solvent toxicity, and makes brief mention of protein binding
logical properties useful in critically ill patients. It has a fast onset of action in the critically ill.]
and a very short half-life (10 to 21 min). Remifentanil has an ester linkage Park GR, Sladen RN, eds (1995). Sedation and analgesia in the critically ill, pp
within its structure, which is broken down by a non-speciﬁc, non-saturable 18–50. Blackwell Science, Oxford. [A multinational book that describes
enzyme system present in plasma. This breakdown pathway means that sedation in various diseases, rather than looking at the use of individual
accumulation does not occur, and the drug wears off rapidly even after drugs.]
prolonged infusions and in renal or hepatic failure. Remifentanil must be Shapiro BA et al. (1995). Practice parameters for intravenous analgesia and
given by constant infusion, indeed the effects wear off so rapidly that even sedation for adult patients in the intensive care unit: an executive
4 16 cr itical care medicine
summary. Critical Care Medicine 23, 1596–600. [An American consensus achnoid space), or communicating (where there is a defect in CSF
document on how to provide sedation and analgesia in the critically ill.] reabsorption).
Shelly MP, Pomfrett CJD (1999). Assessment of sedation and analgesia and
4. Space-occupying lesions (SOLs), which may be chronic (for example,
muscle relaxation in the intensive care unit. Current Opinion in Critical
intracranial tumours) or acute (for example, intracranial haematomas
Care 5, 269–73. [A paper reviewing clinical as well as experimental
methods of assessing sedation and analgesia.]
associated with trauma).
Tryba M, Kulka PJ (1993). Critical care pharmacotherapy. Drugs 45, 338–52.
[Interesting review looking at propofol, isoﬂurane, clonidine, and Temporal patterns of ICP change
sufentanil for sedation. Also reviews H2- receptor antagonists and
sucralfate against gastrointestinal bleeding.] Initial increases in intracranial volume are buffered by the displacement or
Venn R et al. (1999). Monitoring the depth of sedation. Clinical Intensive Care reduction in volume of other contents. Thus, cerebral oedema may result in
10, 81–9. [A review on how to measure sedation and analgesia in the compression of the ventricles, with translocation of CSF to the spinal sub-
critically ill.] arachnoid space, and compression of cerebral vasculature. Over longer
periods, normal brain may be compressed and CSF production dimin-
ished. The relationship between intracranial volume (ICV) and ICP is
commonly depicted as a hyperbolic curve, with an initial ﬂat part during
which compensatory mechanisms are effective, moving after their progres-
sive exhaustion to a steep phase when even small increases in intracranial
16.6.2 Management of raised volume produce large increases in ICP. However, the extent and efﬁciency
with which these mechanisms buffer increases in volume depend on the
intracranial pressure speed of disease progression, and given these considerations it is more
David K. Menon
Introduction CSF ICP
The normal intracranial pressure (ICP), measured at the level of the fora- CP
men of Monro, is between 5 and 15 mmHg in supine subjects. Intracranial
hypertension (ICP >20 mmHg) is a common accompaniment of many Arterial Venous
central nervous system (CNS) diseases, when it is often the most important
cause of symptoms and modulator of outcome, and—in fatal cases—
frequently the immediate cause of death. Brain
The cranial cavity contains brain (80 per cent), blood (10 per cent), and
cerebrospinal ﬂuid (10 per cent). These incompressible contents are con- (a) SSAS
tained in a rigid skull with a ﬁxed capacity, hence an increase in volume of
any of these contents, or the presence of any space-occupying pathology, Pressure
results in an increase in ICP unless one of the other constituents can be ICP 100
displaced or its volume decreased (Fig. 1). This principle is referred to as CSF
the Monroe–Kelley doctrine. Increases in intracranial volume may be CP
1. Brain oedema, which may have different pathogenic mechanisms: Arterial Venous
u cytotoxic oedema occurs as a result of cell swelling, most com-
monly due to ischaemic energy depletion and rises in intracellular
sodium and water; Brain
u vasogenic oedema results from an increased permeability of the
blood–brain barrier with an expansion of the extracellular ﬂuid
u interstitial oedema occurs in the context of hydrocephalus, where
increased intraventricular cerebrospinal ﬂuid (CSF) pressures (b) SSAS
result in permeation of CSF into adjacent brain, typically in the
frontal periventricular regions. Fig. 1 Schematic diagram showing intracranial contents in the normal brain (A)
2. Vascular engorgement, which results from an increased cerebral blood and with elevated intracranial pressure (B). Note that cerebrospinal ﬂuid (CSF)
volume. This may be due to the vasodilatation that accompanies nor- produced by the choroids plexus (CP), circulates freely, passing through the
mal or abnormal (for example, epileptiform) neuronal activity. In foramen magnum (FM) into the spinal subarachnoid space (SSAS), before
other situations vasodilatation may be due to the loss of vasoregula- absorption by arachnoid villi (AV) in the cerebral venous sinuses. Increases in ICP
may be due to brain oedema, vascular engorgement, space-occupying lesions
tion, either due to disease (vasoparalysis), or to the effect of potent
(SOL), or impaired CSF circulation or absorption. Compensatory mechanisms
physiological (carbon dioxide) or pharmacological (nitrates and other
include translocation of CSF to the SSAS, and compression of cerebral vascular
nitric oxide donors) cerebral vasodilators.
beds. The ICP trace shows a higher mean value, and the inability of the non-
3. Hydrocephalus, which may be non-communicating (where an obstruc- compliant brain to cope with increased blood during each systole results in an
tion prevents the ventricular system communicating with the subar- increased pulsatility of the ICP waveform.