http://www.rcsed.ac.uk/eselect/cc4.htm
Analgesia and sedation in the critically-ill
Graeme A McLeod
1 Introduction
Pain, anxiety and distress are common sequelae in the critically ill and injured patient. Postoperative pain,
prolonged immobilisation, thirst and repeated stimuli such as tracheal suction are perceived by patients as
amongst their most distressing experiences. In addition, lack of sleep, the effects of the underlying disease
process and sedative medication may contribute to confusion, disorientation and, in some instances, the
development of a psychotic state.
Sedation and analgesia can therefore be regarded as ‘caring for the physical and psychological comfort of
critically ill patients receiving end organ support’.
A variety of management options is available with which the surgeon needs to become familiar. In
considering pharmacological regimens, it should always be remembered that all have unwanted side effects.
The balance of advantages and disadvantages should always be in the patient’s favour. Finally, in recent
years cost-benefit issues have become increasingly important.
2 Aims
After working through this module and applying it to your clinical practice you should be able to:





describe the inter-related psychological and physiological changes contributing to pain, anxiety and
distress in the critically ill
assess pain and the need for analgesia and sedation in the critically ill
give an account of the treatment modalities available and their effects on ill patients
manage patients requiring routine pain relief and sedation
recognise when to refer for specialist pain advice.
3 Examples in practice
We have presented you with seven case studies which you may commonly come across in clinical practice.
We suggest you read each of the individual examples and accompanying key issues. Try relating each to the
other.
Case 1 - Fractured ribs
A previously fit 22-year-old male is admitted to the
Accident and Emergency department following a 30 foot
fall while climbing. He has fractures of ribs 6-11 on his left
side and a fractured pelvis. He is in severe pain and has
difficulty coughing. Arterial oxygen saturation is 86%.










Key Issues
Pre-hospital pain relief.
Mode of injury as a guide to severity of
injury.
Indications for referral to High Dependency
Unit (HDU)/Intensive Care Unit (ICU).
Consideration of analgesia in relation to
other treatment modalities.
Indications for referral to pain team for
analgesia.
Role of pain relief in affecting duration and
outcome from illness.
Planning analgesia/sedation strategy.
Choice of analgesia/sedation agents/
regimens.
Cost-benefit issues.
Case 2 - Epidural analgesia in the postoperative period
An 82-year-old lady with a history of chronic obstructive
airways disease is in the High Dependency Unit (HDU)
following a gastrectomy for gastric cancer. Pain relief is
excellent but during the night sedation scores rise in
successive hours. Her respiratory rate falls to 6
breaths/min.





Respiratory depression in the critically ill.
Risk factors for postoperative respiratory
depression.
Advantages/disadvantages of epidural
analgesia.
Monitoring in HDU/ICU.
Scoring systems for assessing analgesia
and sedation.
Case 3 - Extradural haematoma
A 59-year-old man had an elective and uneventful grafting
of an aortic aneurysm. He remained pain free on coughing
and movement with epidural analgesia for 50 hours in the
HDU. Another emergency admission to HDU necessitated
his transfer to the ward and the epidural catheter was
removed. He had received heparin thromboprophylaxis
one hour previously. On transfer he mentioned that his
legs felt heavy.





Complications of epidural catheterisation.
Indications for neurosurgical opinion and
radiology.
Timing of surgical intervention.

Indications for sedation.
Assessment of analgesic and sedative
requirements.
Approach to analgesia and sedation
influenced by oxygenation and ventilatory
strategy.
Communication with patients, relatives and
staff.
Ethics of analgesia/sedation in the
terminally ill.
Outcome in sepsis Complications of long
term administration of parenteral sedation.
Indications for re-laparotomy.



Reversible causes of confusion.
The environment of ICU.
Organic brain disorders.
Case 6 - Weaning from ventilator


A 63-year-old female with chronic respiratory disease and
pancreatic abscess has been ventilated for two weeks.
She has made a good recovery from surgery but is not
waking up despite stopping sedation.




Weaning protocols.
Pharmokinetics and pharmodynamics in
critically ill patients.
Sedation policies.
Side effects of prolonged sedation.
Case 7 - Road traffic accident






Case 4 - Life threatening sepsis
A 68-year-old non insulin dependent diabetic with
hypertension and ischaemic heart disease is in the
Intensive Care Unit (ICU) following laparotomy for
perforation of sigmoid diverticular disease and faecal
peritonitis. She has severe sepsis and requires increasing
oxygen concentration to maintain P02.




Case 5 -ICU psychosis
A 72-year-old alcoholic with postoperative pneumonia
becomes confused, anxious, restless and hallucinates two
days after discharge from ICU.
A 30-year-old man is admitted to the A&E department
following a car accident. He has fracture of ribs 9-11 on his
left side, lung contusions and pneumothorax requiring a
chest drain. After resuscitation he required a splenectomy
and repair of liver tear and now requires transfer to the
regional Intensive Care Unit for postoperative care.
Role of nurse and physiotherapist.
Pre-hospital analgesia.
Non-pharmacological methods of analgesia.
Preparation for transfer.
Communication with transfer team and ICU.
Guidelines for transfer of the critically ill.
Indications for ventilation
4 What you should think about
4.1 Pathophysiology
Pain, anxiety and distress in the surgical patient can be described under two broad headings:


psychological
physiological
o pain pathways
o stress response to pain
o vital organ function
o outcome from surgery.
Both the psychological and physiological aspects of pain, anxiety and distress are closely inter-related.
However, assessment of analgesic requirements requires knowledge of an individual patient’s psyche,
including past experiences of pain and distress, and thus the psychological aspects of analgesia and
sedation in the critically ill will be discussed first.
4.1.1 Psychological
The environment of the hospital has a profound effect on patients’ wellbeing. Critically ill patients suffer major
sleep disturbance and survivors of critical illness state that sleep disturbance is one of the most unpleasant
features of their stay in hospital. The psychological effects of lack of sleep are confusion, disorientation,
depression and hallucinations.
Sleep disturbance
Sleep has a metabolic role. It is required for tissue growth by stimulating the release of anabolic hormones
for protein synthesis. Sleep deprivation promotes the secretion of catabolic hormones such as cortisol,
glucagon and catecholamines and increases loss of body nitrogen. Sleep deprivation causes:
Critically ill patients are looked after in an artificial and isolated environment and may suffer anxiety, pain and
distress. They feel immobilised by tubes, cables and catheters and are disturbed by machinery alarms and
bleeps. Overheard staff conversations can create confusion and observing the fate of other patients, such as
cardiac arrest or death, may cause great distress. Difficulty in communication is often a major concern.
Patients are subject to artificial light and may be sedated, ventilated or fed continuously. They may be reliant
on infusions of inotropes and may require dialysis for acute renal failure. Critically ill patients lose track of
time. In those treated in the ICU, 25% of survivors cannot even remember any events, yet 25%
retrospectively describe symptoms of ICU psychosis.
Wallace et al in 1988 found that 3% of survivors described being terrified and 8% found ICU an
unpleasant experience, although 45% thought being a patient in ICU was tolerable.
ICU psychosis
In a small number of patients the cumulative effects of sleep disorder, the disease process and the use of
sedative and analgesic drugs may present typically on days 3 to 7 as ICU psychosis (see Case 5). This is
characterised by disordered thinking and speech, hallucinations and a fear of death. The symptoms are
characteristically worse at night and only slowly disappear following discharge.
4.1.2 Physiological
Pain pathways
Pain is transmitted from peripheral subcutaneous mechanoreceptors and nociceptors and by Ad and C
afferent neurones. The Ad fibres are myelinated and responsible for rapid transmission of sharp, localised
pain.
The unmyelinated C fibres are slower and transmit dull, aching, poorly localised pain. These fibres enter the
dorsal horn of the spinal cord where they synapse in laminae II and III (substantia gelatinosa). The dorsal
horn is a complex area, regulated by a multitude of neurotransmitters, the most prominent of which is
Substance P. An intermediary neurone crosses the midline to the lateral spinothalamic tracts which ascend
to the lateral side of the thalamus before being projected to the cerebral cortex. The spinal cord has its own
inbuilt mechanism for combating pain. It is called the descending inhibitory fibre which descends to the
dorsal horn and releases the transmitters noradrenaline and acetylcholine. These attenuate the passage of
painful impulses through the dorsal horn.
Pain fibres also ascend in the spinoreticular tracts to the pons and medulla and are responsible for the state
of arousal and sympathetic drive due to pain. This reflex activity via efferent sympathetic fibres results in
profound effects on vital organs such as the heart, lungs and gut.
The diagram below illustrates the changes in dorsal horn function during surgery. Painful stimuli during
surgery activate dorsal horn neurones which subsequently activate the sympathetic nervous system. The
increased activity of dorsal horn neurones is depicted by the shaded area in the diagram. Cutting a
peripheral nerve during surgery leads to a pronounced and protracted increase in spinal cord activity,
resulting in further activation of neuronal activity, muscle spasm and even greater increase in painful stimuli.
S - painful stimulus
H - area of hyperalgesia
IML- intermediolateral cells
SG - symphatic ganglion
This sustained stimulation from surgery increases the size of the receptive field and alters neurotransmitter
function in the dorsal horn which is associated with the development of chronic pain syndromes. An increase
in activity in the dorsal horn is called ‘wind-up’, such that spinal neurones have an exaggerated response to
a normally painful stimulus (hyperalgesia) and even react to non-noxious stimuli (allodynia). N-methyl Daspartate (NMDA) receptors in the spinal cord seem to be involved in this process.
The stress response in critically ill patients
Patients develop a stress response during and after surgery which is characterised by pain, a neuroendocrine response, hypercatabolism, hypercoagulation and immunomodulation. This can last several days.
Postoperative pain results in lethargy, immobility and muscle spasm. In addition, ASA (American Society of
Anesthesiologists) grade III and IV patients may suffer myocardial infarction, thromboembolism and impaired
respiration and gastrointestinal ileus.
How can we assess patients’ pre-operative condition?
American Society of Anesthesiologists Score (ASA)





I normal healthy individual
II mild systemic disease
III severe incapacitating disease
IV incapacitating disease affecting life
V moribund patient not expected to survive with or without operation
Anaesthesia & Analgesia 1970, 49:564
Initiation of the stress response is primarily due to afferent nerve impulses combined with release of humoral
substances (such as prostaglandins, kinins, leukotrienes, interleukin-1, and tumor necrosis factor), while
amplification factors include semistarvation, infection, and haemorrhage. In particular, the proinflammatory
cytokines TNF and IL-6 play a significant role in the response to major surgery.
The neuroendocrine and cytokine response to major surgery in critically ill patients.
The endocrine response in critically ill patients is profound and catecholamine secretion can promote
arrhythmogenesis, tachycardia and hypertension. Cortisol is released from the anterior pituitary in response
to stimulation by adrenocorticotrophic hormone (ACTH). Plasma levels of both these hormones are elevated
in response to surgery. The magnitude of the cortisol response correlates with poor outcome. Plasma cortisol
levels >1800 nmol/l have been associated with an increased risk of death in ICU. Conversely, an inadequate
cortisol response to surgical stress, as determined by a Synacthen (ACTH) test, is associated with a poor
outcome.
The chart below illustrates the relationship between cortisol and ACTH in a 62-year-old female in the first two
days of intensive care following a road traffic accident. A general guide to outcome from intensive care for
the overall ICU population is the Acute Physiological and Chronic Health Evaluation Score (APACHE),
although this gives no guide to the need for sedation. This patient’s score is 20, indicating that she is
severely ill. The diagram indicates a close correlation between cortisol and ACTH.
The diagram below demonstrates a marked rise in plasma cortisol level in a 75-year-old male to almost 1500
nmol/l on the second day of admission to the ICU. In contrast, cortisol levels in unstressed individuals range
from 150-600 nmol/l. His APACHE score was 29. He subsequently died in ICU from multi-organ failure.
Effect of pain and analgesia on vital organ function
Cardiac disease
Pain has a detrimental effect on myocardial function. The resultant tachycardia and hypertension both
increase myocardial oxygen consumption in the critically ill and tilt the oxygen supply/demand balance in the
direction of myocardial ischaemia. In turn, this stimulates a sympathetic response leading to further
ischaemia and myocardial dysfunction. Epidural anaesthesia has been shown to improve ventricular
emptying and wall function in surgical patients including those undergoing cardiac bypass surgery. Neural
blockade of cardiac sympathetic fibres is associated with dilatation of post-stenotic coronary arteries and a
reduction in the incidence of postoperative silent myocardial ischaemia which is the predominant risk factor
for postoperative myocardial events in non cardiac surgery.
Patients undergoing surgery for arterial disease are at increased risk of both venous and arterial thrombosis
following surgery due to an increase in coagulation factors and inhibition of fibrinolysis.
Respiratory disease
Pain leads to diaphragmatic dysfunction which is associated with reduction in functional lung volumes of up
to 50% and a diminished ability to cough (see the diagram opposite). Inability to clear secretions can often
lead to postoperative atelectasis and pneumonia, especially in those with chronic lung disease and limited
respiratory physiological reserve. Opioids and anaesthetic agents both depress central respiratory drive and
are associated with episodes of profound postoperative hypoxaemia and apnoea for at least 72 hours
postoperatively.
Extradural analgesia has been shown to improve postoperative respiratory function, facilitate physiotherapy
and has led to fewer pulmonary complications compared to systemic analgesia.
Effects of incision - chest and diaphragm
Gastrointestinal function
Gastrointestinal function is impaired after abdominal surgery. The gut is innervated by both the sympathetic
and parasympathetic nervous systems. The latter promotes gut activity, whereas the former inhibits gut
propulsion. Opioids by any route delay gastric emptying and prolong orocaecal transit time. Continuous
epidural anaesthesia and sympathetic block with local anaesthetics may potentially reduce the duration of
ileus and improve colonic blood flow and anastomotic healing. This may allow earlier feeding and prevention
of small bowel mucosal damage.
Effects of incision - sympathetic chain and gut
Effect of pain relief on outcome from surgery
The modifying effect of pain relief on the surgical stress response is dependent upon the technique of
analgesia. Systemic opiate administration, as well as non-steroidal anti-inflammatory drugs, exerts only a
minimal dampening of the response. Afferent neural blockade with local anaesthetics is the most effective
technique for reducing the endocrine-metabolic response, but is more striking in operations on the lower part
of the abdomen. Thoracic epidural analgesia for upper abdominal or thoracic surgical procedures only
partially attenuates the stress response, probably because of an inability to block the phrenic and vagal
nerves.
The benefits of analgesia on outcome from surgery were recognised many years ago. “Interrupting the
neural input from an injured area will neutralise the ancient defence mechanisms to violent injury and restore
appropriate movement and metabolic activities that will permit sufferers to recover more safely, speedily and
effectively from the therapeutic cocoon in which they find themselves.” GW Crile, 1915
Low-dose combined analgesic regimens may provide total pain relief and attenuate the stress response.
Unfortunately, the benefits of epidural analgesia with synergistic mixtures of local anaesthetic and opioid are
often not taken advantage of.
Analgesia should allow coughing, mobilisation and early feeding and this has the potential to improve
postoperative outcome.
Two studies have demonstrated that postoperative pain control in the critically ill is not only a humanitarian
act but also a therapeutic intervention which itself can have a marked effect on outcome (their results are
displayed in the table below).
In both studies, epidural analgesia for at least 36 hours was associated with a significant reduction in cardiac
and respiratory morbidity, intensive care stay and hospital costs. Urinary cortisol excretion, a marker of the
stress response, was significantly diminished in those receiving epidural analgesia in Yeager’s study.
“Acute pain relief should be part of an ‘acute rehabilitation service’ improving physical and mental function
after major surgery. The aim ultimately is for a ‘return to normal function’.” Kehlet, British Journal of
Anaesthesia 1997
Yeager et al 1987
CCF
MI
Death
Infection
Tuman et al 1991
CCF
MI
Death
Infection
Total complications
General
anaesthetic/epidural
General anaesthetic/systemic
opioid
1
0
0
2
10
3
4
10
2
0
0
2
13
4
3
0
8
52
4.2 Differential diagnosis
This section outlines important considerations when reaching a diagnosis and planning treatment.
4.2.1 Causes of delirium









Airway
o hypoxaemia, hypercarbia
Breathing
o carbon monoxide poisoning
Circulation
o anaemia, cardiac failure
Drugs
o steroids, lead, manganese
Endocrine
o hypoglycaemia, adrenal insufficiency
Infection
o encephalitis, meningitis
Metabolic
o acidaemia, alkalaemia, electrolytes, hepatic failure, renal failure, hypothyroidism, vitamin
deficiency
Neurological
o haemorrhage, abscess, seizures, tumour
Withdrawal
o alcohol, opioids
4.2.2 Undersedation
Sudden changes in conscious level allow patients to wake up suddenly, increasing agitation and distress.
Coughing and intolerance of ventilation dislodges tubes and lines, with haemodynamic upset.
4.3.3 Oversedation
Patients are less likely to become disconnected from the ventilator if over-sedated but this is at the expense
of pressure sores, deep venous thrombosis, muscle wasting and nerve injury. Persistent deep sedation due
to drug accumulation may prolong ventilation, increase psychological disturbance, immunological depression
and the risk of infection. Gastric stasis and ileus delay enteral feeding. Thus inappropriate heavy sedation
prolongs ICU stay.
5 What you should do
In the acute situation, initial focus should be on management of the airway, breathing and circulation. Relief
of pain, anxiety and distress is dependent on simple measures such as reassurance, immobilisation of limb
fractures, inhaled entonox or, if feasible and appropriate, local anaesthetic blocks, e.g. femoral nerve block
for fractured neck of femur.
Any subsequent analgesia should be given intravenously by slow, titrated boluses of opioid such as
morphine. Supplementation of analgesia should be given only after assessment of the patient’s response to
the initial bolus. Subsequent boluses of morphine should be given 2-3 minutes apart to allow assessment of
analgesia, level of sedation and vital signs.
Intramuscular opioids may not be adequately absorbed from the site of injection due to peripheral
vasoconstriction in the ill patient. Improvement in the patient’s condition, and subsequent vasodilatation, may
result in rapid absorption of opioid into the circulation, with the risk of respiratory depression.
5.2 Subsequent management
Although the focus of this section will be on pharmacological agents, a number of non-pharmacological
approaches are initially important in reducing the impact of illness and injury in the critically ill patient.
Maintaining patient communication is a prime consideration. Patients may still be able to hear, even when
sedated to apparently deep levels, and require explanation and reassurance. Relatives make a substantial
contribution to care. Set times during the day should be allocated for ward rounds, examination,
physiotherapy and rest. Patients should have light sedation in daylight hours to promote communication,
allowing assessment of their psychological and physiological wellbeing.
5.2.1 Managing pain and sedation
Analgesia and sedation are inter-related. Pain control is an integral part of any sedation regimen and a
successful sedation regimen should reduce the emotional components of pain. Other advantages include
better patient care, comfort and safety.
“A background narcotic... infusion must be the first step in all sedation protocols.” Peruzzi, Editorial Critical
Care Medicine 1997
However, pain is subjective and is difficult to assess if patients are sedated and ventilated. Critically ill
patients are often confused and disorientated as a result of the environment of the ICU, sedative drugs and
the severity of their disease. They therefore may have a poor ability to interpret and express feelings of pain.
It is therefore difficult to judge pain in critically ill patients. The usual visual signs such as facial grimacing,
and vital signs such as sweating, tachycardia and hypertension, may be misleading.
Practice has now changed. No longer are patients kept in ICU at deep levels of sedation and paralysed. A
lighter level of sedation is preferred; either awake and comfortable or asleep and easily rousable. There is
also greater awareness that sedation requirements vary with stage of illness. Patients may occasionally
require deep sedation, analgesia and even paralysis after admission for postoperative analgesia, placement
of lines and procedures such as percutaneous tracheostomy, but sedation can be tailored to the patient’s
requirements as their condition improves.
Assessment of requirements
The dose of sedatives and analgesics should be titrated against patient response. This will improve
analgesia and anxiolysis, minimise overdosage and reduce untoward side effects. The requirement for
analgesia and sedation should be monitored daily as the illness evolves.
Monitoring of sedation requirement in a ventilated critically ill patient is essential. Unfortunately, there is no
universally accepted sedation regimen in ICU. Sedation is difficult to quantify and no routine, clinical monitor
of sedation is available. Despite lack of agreement on the ‘best’ sedation score it is more important that one
is used to monitor sedation trends in individual patients.
“Optimal sedation results in a patient who is free of pain and anxiety, tolerates medical procedures and can
be aroused from light sleep, thus enabling effective neurological assessment.” Ledingham & Bion 1987
For further details of the Glasgow Coma Scale, see the SELECT module ‘Altered consciousness/confusion’.
Severity of illness in intensive care is measured by the APACHE score, and assessment of neurological
function by eliciting verbal and motor responses to voice and pain (Glasgow Coma Scale). Neither makes an
assessment of comfort and cannot be used as a sedation score.
Examples of commonly used sedation scores in intensive care are given below:
Ramsay score 1974
Awake levels
1
anxious, agitated or both
2
co-operative, orientated, tranquil
3
Asleep
levels
4
responds to commands only
5
6
brisk response to loud auditory stimulus
sluggish response to loud auditory
stimulus
no response to loud auditory stimulus
The Ramsay score is widely used by many intensive care units.
Addenbrooke score 1991
0
agitated
1
awake
2
roused by voice
3
roused by tracheal suction
4
unrousable
5
paralyses
6
asleep
The Addenbrookes score includes awareness of sleep and use of neuromuscular blocking agents. Levels 1
and 2 represent the ideal level of sedation. Voice and tracheal suction have been utilised as stimuli because
they are reproducible and do not inflict any painful stimulus.
Pain assessment
Formal testing of pain relief using patient verbal rating scores (VRS) or visual analogue scores (VAS) is only
possible if patients are awake and therefore applies to the HDU environment or in the weaning stages of
ICU. Several national UK reports have stressed the importance of routine systematic assessment of pain in
all patients. The following verbal rating score for assessment of pain is widely used in many countries and
emphasises the importance of dynamic pain relief - the analgesia of coughing and movement.
Pain score
0
no pain at rest or on movement
1
no pain at rest, slight on movement
intermittent pain at rest, moderate on
2
movement
continuous pain at rest, severe on
3
movement
Assessment of sedation level is important in critically ill patients. The use of analgesics and sedatives, and
the disease state can all result in excessive sedation. Regular assiduous assessment of sedation can
identify those patients at risk of respiratory depression.
5.3 Investigations
Investigations should include a history of concomitant medication and any other illnesses, such as cardiac
failure, elevated intracranial pressure, hepatic disease and renal failure, which may render patients more
prone to the side-effects of pharmacological agents.
5.4 Treatment
Critically ill patients vary in their response to analgesic and sedative drugs. Pharmokinetic changes, such as
increased volume of distribution, reduced clearance, acid-base changes and multiorgan dysfunction, all alter
drug requirements. Nevertheless, pharmacological agents can assist the patient in coping with his illness,
particularly during periods of increased stress, discomfort and pain such as tracheal suction, physiotherapy
and transport.
5.4.1 Pharmacological agents
The ideal drug for sedation should have a simple, rapid onset of action, short duration and be easily titrated
to a desired sedation level. Degradation should be independent of hepatic or renal function, with no local or
systemic side effects. The ideal drug should not accumulate or have any active metabolites.
Use of single drugs for sedation is often associated with excessive side effects. Combinations of drugs can
be used to obtain optimal therapeutic effect while minimising adverse effects, e.g. morphine and midazolam.
Analgesic and sedative drugs
The following section will discuss drugs used for analgesia and sedation including:






benzodiazepines
propofol
inhalational agents
non-steroidal anti-inflammatory drugs
opioids
adjuvant drugs.
Benzodiazepines
Passage of sensory information, such as pain, through the CNS is filtered by the gamma amino butyric acid
(GABA) neurotransmitter system. Occupation of relevant receptors by benzodiazepines enhances the effect
of GABA. This sieve-like effect on neural transmission further reduces the number of stimuli reaching the
higher centres and produces sedation, anxiolysis, amnesia, muscle relaxation and anticonvulsant effects.
Diazepam has been used for the sedation of critically ill patients. However, its half life of 36 hours and active
metabolites results in prolonged sedation. It is now rarely used in surgical practice and has been replaced by
newer drugs such as midazolam.
Midazolam is an unusual drug. It exhibits a pH dependent phenomenon in which its constituent imidazole
ring remains open at pH values below 4. Once in the blood stream, the change in pH alters its ring structure,
allowing the molecule to change from being water to fat-soluble. This lets it cross lipid membranes and exert
its effect in the CNS.
Similar to most benzodiazepines, midazolam is bound extensively to plasma proteins. Low plasma albumin
levels in the critically ill increase its volume of distribution and prolong its half life of 1.9 ± 0.9 hr.
Midazolam is metabolised in the liver and excreted in the urine. Its principle metabolite is 1hydroxymidazolam, which retains 10% of activity. Delayed metabolism and prolonged recovery has been
reported in the critically ill, particularly with hypovolaemia and in the elderly.
Think about Case 6. How would you manage sedation for a long stay patient in ICU?
Consult your Intensive Care colleagues for the benefit of their experience in the management of such
patients.
Pharmokinetics of sedative agents
Vdss (1kg)
Clearance mlkg/min)
Propofol
2.8
59.4
Term
(hr)
0.9
Midazolam
1.1
7.5
2.7
Etomidate
2.5
17.9
2.9
Ketamine
3.1
19.1
3.1
3.4
12.0
Thiopentone 2.3
Vdss - volume of distribution: T1/2 - half life
T1/2
Propofol
Propofol (2,6, di-isopropylphenol) is formulated as a 10mg/ml or 20mg/ml oil in water emulsion. It is used for
sedation of critically ill adult patients in ICUs because it is easily titratable, has a rapid redistribution, high
clearance and is associated with rapid recovery, even after prolonged infusion. Its rapid action makes it an
alternative agent for use in specific circumstances, such as insertion of intravascular lines and chest drains,
percutaneous tracheostomy, bronchoscopy etc.
Patterns of sedation
Patients sedated in ICU following surgery exhibit different responses to analgesic and sedative drugs
because of their underlying disease state. The following two examples highlight the variation in sedation
requirement and response to changes in sedation and analgesia in critically ill surgical patients.
Example 1
This was a patient with Guillain-Barré syndrome who was ventilated for respiratory failure. He had no other
medical problems and this allowed a more natural sleep pattern at night.
Note that the patient required a higher initial dosage of sedative drug to achieve adequate sedation.
Thereafter, a constant infusion of sedative drug was given. The graph indicates an increase in sedation
score between 32 and 38 hours. This can be attributed to sleep.
Example 2
This is an example of a patient with persistently deep sedation. The Ramsay scores were 4 to 6 at all times
within the first two days following admission to ICU. Note from the graph that attempts to reduce the dose of
sedative drug were not followed by any fall in sedation score. This patient had an APACHE II score of 24 and
was severely ill due to the Systemic Inflammatory Response Syndrome (SIRS), secondary to peritonitis. The
disease in this instance altered conscious level and it was not possible to manipulate sedation scores.
Inhalational agents
Volatile agents such as isoflurane or desflurane resemble the ideal sedative. They have a low blood
solubility, and sedation is easy to control. Their metabolism (<1%), and therefore elimination, is independent
of renal or hepatic function. However, they are expensive and scavenging of gas can be difficult in the ICU.
NSAIDs
These are particularly good for bony or pleural pain. They may be used in combination with opioids to
optimise analgesia.
NSAIDs often minimise opioid use postoperatively and hence limit the potential opioid side effects of nausea
and vomiting, excessive sedation and ileus.
NSAIDs may be administered intramuscularly but care must be taken not to inject into subcutaneous fat as
fat necrosis may ensue. Intravenous preparations of NSAIDs are available which are of benefit in the postsurgical patient.
However, their use is limited in the critically ill by a potential for gastric mucosal ulceration, bronchospasm
and acute tubular necrosis, especially in the face of hypoxaemia and hypotension.
Opioids
Opioids form the basis of analgesia and sedation regimens for the critically ill. They are valuable even for the
non-surgical patient because they provide analgesia from general aches and pains to insertion of
intravenous lines. A lack of appropriate analgesia may result in excessive sedation and, hence, side effects
from one drug, or severe agitation from poor pain relief. Once analgesia is achieved, specific sedative drugs
can be used as required for anxiolysis, distress and invasive procedures.
Opioids commonly used in the critically ill include:




morphine
fentanyl
alfentanil
remifentanil
Morphine will be discussed later in the text.
Fentanyl, alfentanil and remifentanil are synthetic opioids. Fentanyl and alfentanil are potent opioids with a
rapid onset and short duration of action as a bolus injection. Neither drug releases histamine and thus they
are less likely to produce hypotension compared with morphine.
Alfentanil is metabolised in the liver with no active metabolites and is suitable for continuous infusion. Its use
is restricted to ventilated patients. It is useful for managing analgesia during the weaning period.
Remifentanil is a very potent opioid and can only be given as an infusion. It has an ultra-short half life of only
a few minutes and is associated with bradycardia and hypotension.
The three opioids highlighted above are potent respiratory depressants and should only be administered in
specialised areas such as anaesthesia and intensive care.
Adjuvant drugs
This group includes the neuromuscular blocking agents (NMBAs).
There have been marked changes in attitude towards sedation since the early 1980s. In 1981, 90% of units
used deep sedation and paralysis, compared to 15% in 1991. The change coincided with the introduction of
SIMV ventilation, enabling patients’ breathing pattern to synchronise with the ventilator and achieve the goal
of being asleep but easily rousable.
In some patients, however, it is necessary to use NMBAs when oxygenation is critical, or in those with raised
intracranial pressure who may suffer prolonged elevation of CSF pressure with coughing, tracheal suction,
physiotherapy etc.
It should always be remembered that NMBAs are not analgesic or sedative agents. They should be used
sparingly, and only after ensuring adequate sedation. Use of NMBAs without appropriate analgesia or
sedation may result in patient awareness, anxiety, fear and long term distress. If NMBAs are used,
neuromuscular function must be monitored routinely with a peripheral nerve stimulator.
Indications for NMBAs




intubation
initial control of ventilation following admission to ICU
increased O2 consumption
specific disease states, e.g. tetanus, head injury.
Side effects of NMBAs







patients are dependent on full ventilation
patients require constant nursing attention
neurological assessment is hindered
deep venous thrombosis
bed sores
the cough reflex is suppressed
prolonged muscle weakness.
If NMBAs are used, they should be given in as small a dose and for as short a time as possible, and the
patient carefully monitored.
5.4.2 Route of administration
This section will discuss the route of administration of analgesic and sedative drugs. This can be divided into:




intramuscular
intravenous
patient controlled analgesia
regional analgesia.
Intramuscular
This is the traditional method of analgesia but is not particularly efficacious as pain can still be severe on
mobilisation. There is variable absorption from the site of injection especially in ill, vasoconstricted patients.
This is potentially dangerous as any subsequent vasodilation may result in a large bolus in the circulation. Of
particular relevance is the critically ill child or elderly person. Issues still exist regarding the misconception of
overdosage and addiction and this often prevents optimal analgesia.
Intravenous
Morphine provides the best compromise between ease of use and cost in UK practice and, as an infusion,
forms the basis of most sedation regimens. It is a m agonist given as a slow incremental bolus of 0.05-0.1
mg/kg or at a rate of 15-50 mcg/kg/hr, and is metabolised in the liver to the potent morphine-6-glucoronide.
Morphine clearance depends on renal function as 5-15% is unchanged in the urine.
Like all narcotics, it impairs gastrointestinal function and is associated with pruritus, nausea and vomiting.
Patient controlled analgesia
Patient controlled analgesia (PCA) is a means of titrating morphine intravenously by the patient to a desired
level of analgesia via a dedicated intravenous line or one way valve.
Analgesic requirements vary considerably between patients and this technique improves patient satisfaction
and offers patients a degree of self control. A standard regimen is a solution of 1mg/ml morphine with a 1mg
bolus. The minimum time between boluses is described as the lockout time and is usually five minutes.
“Up to a 30-fold variation in morphine requirements may occur in the first 24 hours after open
cholecystectomy.” A professor of anaesthesia
PCA provides pain relief at rest but not on coughing or mobilisation. It has no influence on surgical outcome
because many patients are prevented from achieving optimal analgesia by the side effects of opioids such
as drowsiness or nausea and vomiting. A lower dose of opioid gives inadequate analgesia, and a higher
dose increases the risk of respiratory depression, nausea and vomiting. Similarly, a background infusion
increases the risk of side effects and is not associated with any improvement in patient satisfaction
compared to PCA. Unfortunately, PCA is a method only available to those who are neurologically and
physically able to co-operate.
These methods of pain relief involve use of infusion pumps. All patients given drugs by machine require
hourly assessment of dose administered and remaining volume to identify early electromechanical
dysfunction.
Above is an example of analgesia in 360 patients using PCA following major surgery and supervised by the
acute pain service. Excellent analgesia can be defined as pain relief on movement and coughing. This was
obtained in only 19% of patients, and pain at rest and severe pain existed in 25% of patients. Therefore,
patients with analgesia from PCA and those with epidural infusions are two cohorts with quite different pain
experiences.
Regional analgesia
Synergistic mixtures of local anaesthetic and opioid represent the ideal solution for analgesia. Patients
develop tolerance to infusions of local anaesthetic alone and the larger dose of drug thus required increases
the incidence of motor block and hypotension.
Infusions or boluses of opioid alone give satisfactory analgesia but at the expense of opioid related side
effects, particularly late onset respiratory depression and delayed return of gut function. Experience of five
years of use of synergistic mixtures in a teaching hospital is summarised below.
Patients are nursed in HDU or ICU and monitored at the same two hourly intervals, e.g. 0200, 0400, 0600
hrs etc., for pain relief at rest and on movement by a verbal rating score (awake and cooperative patients),
sedation score, motor block and vomiting, blood pressure and infusion volume.
The diagram below is a schematic representation of the management of pain using epidurals. It
demonstrates how trained nursing staff, monitoring patients at regular two-hourly intervals, can optimise
analgesia, aiming always for pain relief allowing breathing, coughing and movement. It also indicates when a
doctor should be appropriately called.
Always check first:



Is the pump working?
Is the epidural catheter kinked or leaking?
Is the epidural catheter in place?
Analgesia with epidurals
Excellent perioperative analgesia is achieved with epidurals. The diagram below demonstrates that, over a
five-year period, patients spent 75% of a mean duration of 52 hours with epidural analgesia, free from pain
on movement and coughing. Regimens containing diamorphine appear to offer better analgesia. Only 5% of
time was spent in severe pain with a diamorphine based regimen, compared to 8-9% with fentanyl based
regimens. A contrast can be made between this graph and that previous illustrating the analgesia obtained
from PCA.(see above)
The existence of a dedicated Acute Pain Team has reduced morbidity over the five-year period. There has
been a reduction in anaesthetist top-ups, nausea and vomiting and motor block. The incidence of
hypotension is low; only 1.8% of time is spent with a systolic blood pressure <90 mmHg. A common
misconception is that epidural analgesia is associated with hypotension. The surgical trainee, when
encountering a critically ill patient with hypotension, should exclude all causes of low blood pressure,
particularly hypovolaemia, and be prepared to seek appropriate advice.
Side effects of epidurals
Epidural analgesia offers many benefits but this must be balanced against the risk of potential side effects.
Repetitive assessment and rigorous attention to detail can help optimise analgesia and recognise the side
effects listed below. As with all technical procedures, epidurals are associated with a technical failure rate
which can be minimised in experienced hands. Early referral of any problems to the acute pain team can
prevent morbidity.
Potential problems are summarised in the following table:
Technical
wrong interspace
leakage
Opioids
nausea and vomiting
pruritis
migration
respiratory depression
catheter displacement
sedation
infection
urinary retention
Local anaesthetic
motor block
hypotension
haematoma
neurological injury
The health economic environment dictates that the cost/benefit ratio of any medical intervention be
examined. Attaining excellent analgesia may appear expensive. Epidurals require a higher level of nursing
dependency, expensive monitoring equipment and more drugs. However, a potentially shorter stay in ICU or
HDU, earlier readiness for discharge from hospital and the prospect of possibly reducing the incidence of
chronic pain can make epidural analgesia cost effective.
5.5 Monitoring
The following must all be monitored at two hourly intervals (e.g. 0200, 0400, 0600 hr etc):



respiratory
rate
sedation score
motor block



nausea and
vomiting
infusion volume
blood pressure
6 Outcome
The following considerations influence patient outcome:









Critically ill surgical patients may suffer pain, anxiety, distress and depression.
Lack of sleep and difficulty with communication can often compound these factors.
Assessment of analgesia and sedation in the critically ill should take account of both psychological
and physiological variables.
Scoring systems for analgesia and sedation can help the surgeon administer appropriate treatment.
This varies from simple reassurance and immobilisation to pharmacological manipulation of pain
relief and sedation.
The underlying disease state often dictates the response to analgesic and sedative agents.
Excellent analgesia requires routine and assiduous assessment of physiological parameters and
pain scores, and trained staff who can titrate to optimal analgesia.
Control of incident pain – the pain associated with movement and coughing.
The provision of dynamic pain relief allows mobilisation, physiotherapy and early feeding and a
‘return to normal function’.
Use continuous effective analgesia to promote function throughout the perioperative period to
improve surgical outcome.
7 Summary
Pain control in the critically ill goes beyond analgesia as a humanitarian act but is a therapeutic intervention
which itself can have a marked effect on outcome.
8 References
Adam K, Oswald I (1986). Sleep helps healing. British Medical Journal 289: 1400-1.
Carpenter R, Liu S (1995). Epidural Anaesthesia and Analgesia: Their role in post-operative outcome.
Anesthesiology 182: 1474- 1506.
Cousins and Bridenbaugh (Eds) (1998). 3rd edition. Neural Blockade in Clinical Anesthesia and
Management of Pain. Philadelphia, Lippincott-Raven.
Kehlet H (1997). Multimodal approach to control postoperative pathophysiology and rehabilitation. British
Journal of Anaesthesia 78: 606-17.
Kehlet H (1994). Postoperative pain relief - what is the issue. British Journal of Anaethesia 72:375-7.
Kehlet H, Dahl JB (1993). The value of multi-modal or balanced analgesia in postoperative pain relief.
Anesthesia and Analgesia 77:1048-56.
Liu SS, Carpenter RL, Mackey DC et al (1995). Effects of perioperative analgesia technique on rate of
recovery after colon surgery. Anesthesiology 83:757-65.
Mangano DT, Siliciano D, Hollenberg M, Leung JM, Browner WS, Goehner P, Merrick S, Verrier E (1992).
The Study of Perioperative Ischemia Research Group: Postoperative myocardial ischemia: Therapeutic trials
using intensive analgesia following surgery. Anesthesiology 76:342-53.
McLeod G, Dick J, Wallis C et al (1997). Critical Care Medicine 25: 1976-81.
McLeod G, Wallis C, Cox C et al (1997). Use of 2% propofol to produce diurnal sedation in critically ill
patients. Intensive Care Medicine 23: 428-34.
Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD (1991). Effects of epidural
anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesthesia and
Analgesia 73:696-704.
Yeager M, Glass DD, Neff RK et al (1987). Epidural anesthesia and analgesia in high risk surgical patients.
Anesthesiology 66(6): 729-36.