Conference Lectures

ICU SEDATION:
Principles of sedation
Sedation allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It plays a pivotal role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Modern day sedation involves more than endotracheal tube tolerance and is now focused on the multifactorial individual needs of the patient.Pain is a common problem and may be worsened by invasive and unpleasant procedures. Agitation is thought to occur at least once in 71% of patients in a medical-surgical ICU.
Monitoring sedation - Why is it important?

How much sedation is given, and for how long, is important in determining patient outcome as both over and under-sedation can have potentially deleterious consequences. Over-sedation can increase time on ventilatory support and prolong ICU duration of stay. Under-sedation can cause hyper-catabolism, immunosupression, hypercoagulability, and increased sympathetic activity. 
Scoring systems
Clinical scoring systems
There are many clinical scoring systems in use such as the Ramsay, Addenbrookes, and the Bloomsbury scales. Each of these gives a quantitative score to a clinical finding in the awake or asleep state.
Instrumental measures of sedation
Instrumental tools provide another approach to monitoring sedation and avoid the interpreter variability of clinical scoring systems. There are two main techniques:

  1. Electroencephalograms (EEG): This requires specifically trained personnel and equipment and is thus not practical in the intensive care environment.
  2. Bispectral index (BIS): This technique is mostly used to monitor depth of surgical anaesthesia in the operating theatre; it provides a quantitative value between 0 and 99. A BIS value of 0 equals EEG silence, near 100 is the expected value in a fully awake adult, and between 40 and 60 indicates a level recommended for general anaesthesia. BIS has also been investigated in critical care, and several studies have shown a good correlation between BIS and Ramsay scoring for a Ramsay Score of 1–5. However, at the deeper levels of sedation (Ramsay Score 6), the BIS value showed greater variability.

Non-pharmacological methods of aiding sedation
Ensuring patient comfort requires a multidisciplinary approach in addition to pharmacotherapy. This includes frequent communication and explanation to the patient by all staff directly involved in their care, both nursing and medical, and relatives. Physiotherapy plays an important role as prolonged immobility may be painful and this can be reduced by daily assessment and treatment. Basic needs such as feeding and hydration require addressing regularly to prevent the symptoms of hunger and thirst.
Pharmacological management
The correct way to initiate sedation is to administer a loading dose which is titrated to effect and then to start an infusion. Increases in sedative infusion rate should follow the same principle, i.e. a bolus, titrated to effect, should be administered and the infusion rate increased by a small increment.
I.V. anaesthetic agents
Propofol
Propofol is extensively used in the intensive care setting as a sedative. It has been shown to be more effective compared with midazolam with respect to quality of sedation, and shortening of time between termination of sedation and extubation. In some studies, this has equated to a shorter ICU stay; however, in others, the duration of stay was the same.
Propofol has a high clearance, and metabolism is mainly dependent on hepatic degradation to glucuronide metabolites, which are subsequently excreted into the urine. Significant accumulation of propofol does not occur after bolus doses or a continuous infusion. Infusion should be titrated to response (range 0.5–6 mg kg−1 h−1). Problems with propofol sedation include bradycardia, myocardial depression, reduced systemic vascular resistance, and green coloured urine. Propofol infusion syndrome may follow prolonged use because of its high calorie content (900 cal litre−1). This consists of severe metabolic acidosis and muscle necrosis, probably due to impairment of oxidation of fatty acid chains and inhibition of oxidative phosphorylation in the mitochondria. Because of this, propofol is not licensed for children <3 yr old.
Standard Dose:
Induction of anaesthesia by intravenous bolus injection:
1.5-2.5 mg/kg (less in the elderly) at a rate of 20-40 mg every 10 seconds
Sedation in critical care by continuous intravenous infusion 0.3- 4mg/kg/hour. Monitor blood-lipid concentration if at risk of fat overload or if sedation used for longer than 3 days. If lipid levels high change to alternative sedation and consider starting lipid lowering agent
Thiopental
Thiopental is now only administered by continuous infusion in the management of refractory status epilepticus. It has a low clearance and, when given as an infusion, its metabolism may become linear (zero order) due to saturation of hepatic enzymes; thus accumulation is a serious concern, and may lead to myocardial depression and immunosupression.
Etomidate
Although possessing the best haemodynamic profile of all the induction agents, etomidate is not administered by infusion due to potential suppression of adrenocorticol function via inhibition of 11β-hydroxylase. Its use as a sedative in ICU has been shown to increase mortality.
Ketamine
Ketamine is a phencyclidine derivative that antagonizes the excitatory neurotransmitter glutamate at NMDA receptors. It produces a state of dissociative anaesthesia, profound analgesia, and amnesia. It is also a potent bronchodilator. Ketamine is not commonly used as a sedative infusion due to sympathetic nervous system stimulation resulting in increased cardiac work and a rise in cerebral metabolic oxygen consumption. Hallucinations, delirium, nausea and vomiting frequently follow its use, but it still has a role in the management of status asthmaticus.
Neuroleptic agents
Haloperidol
Haloperidol is an anti-psychotic that produces a state of neurolepsis via central dopaminergic D2 blockade. Haloperidol is useful in the management of postoperative psychosis and delirium as it produces profound sedation with minimal respiratory depression. It is commonly administered by i.v. bolus doses of 1–2.5 mg. It is metabolized in the liver to products with minimal activity; only 1% is excreted unchanged in the urine.
Chlorpromazine
Chlorpromazine has similar indications and mechanism of action as haloperidol. Chlorpromazine has a much wider profile of possible adverse effects. It is less sedative than haloperidol with a greater incidence of respiratory depression, and is rarely administered in ICU.
Benzodiazepines
Benzodiazepines provide anxiolytic, anticonvulsant, amnesic, hypnotic and provide some muscle relaxation. Their effects are mediated by depressing the excitability of the limbic system via reversible binding at GABA-benzodiazepine receptor complex. They have minimal cardiorespiratory depressant effect. The common drugs in this class are diazepam, midazolam, and lorazepam

Midazolam
Midazolam is a benzodiazepine sedative used in critical care. When given as bolus doses it has a short elimination half-life (1-4 hours), rapid onset, and short duration of action. Its active metabolite, alpha-hydroxy-midazolam can accumulate leading to prolonged sedation in patients following infusion, and especially in patients with a reduced GFR.

Standard dose:
As an adjunct to induction of anaesthesia by slow intravenous bolus injection 30-300 mcg/kg in steps of 1-2.5 mg every two minutes
Sedation in critical care by continuous intravenous infusion - 200 mcg/kg/hour or 1-10 mg/hr If patient has been exposed to midazolam for more than 7 days, do not stop abruptly, unless there is a good clinical indication. Decrease dose, or start equivalent doses of alternative benzodiazepine and wean appropriately.
Diazepam:
Elimination half-life of diazepam is 21 to 37 hours. Its major active metabolite, desmethyldiazepam, has a half-life of 48 to 96 hours. In terms of cost, diazepam has a clear advantage, being one-tenth the price of midazolam. Minimal dose: 5 to 10mg bolus. Infusions are not recommended generally.
Lorazepam:
Lorazepam has lower lipid-solubility than midazolam. It produces less hypotension. It is metabolised by liver to inactive metabolites. It has lower cost. Loading dose: 0.02-0.06 mg/kg. Infusion dose: 0.01-0.1 mg/kg/hr

α-2 agonists:
Dexmedetomedine:
Unlike most sedatives used in the ICU, dexmedetomidine is an α-2 agonist and does not work on the gamma-amino butyric acid (GABA)-mimetic system. Therefore, dexmedetomidine causes sedation and analgesia without depressing the respiratory drive. The sedative properties of dexmedetomidine are produced by the stimulation of α-2 receptors on presynaptic neurons. Dexmedetomidine has been reported to have an eight times higher affinity for the α-2 receptor than clonidine. The sedation produced by dexmedetomidine has been termed “cooperative sedation”, as it allows the patient to interact with healthcare professionals. Cooperative sedation allows patients to be easily transitioned from sleep to wakefulness, which may aid in evaluation of neurological status and allow the patient to perform tasks. Typical doses (target plasma levels 0.3-1.2 ng/ml): 0.5 ug/kg load, 0.5 ug/kg/hr infusion. 1.0 ug/kg load, 0.7 ug/kg/hr infusion. Increase dose by bolus/infusion. Load only - short procedures. Patients with high sympathetic activity may need very high doses
Clonidine
Clonidine, a centrally acting alpha 2 receptor agonist, is often used to aid weaning from prolonged opioid sedation, when withdrawal features such as hypertension and tachycardia may be problematic.
Opioids
Choice of Analgesia  
Opioid analgesics are generally used to provide analgesia for intubated and ventilated patients as they also provide a degree of sedation. However, some patients in critical care may not require opioid analgesia. Examples include some medical patients, and post- operative patients with other forms of analgesia such as an epidural infusion. Morphine, Fentanyl, Alfentanil and Remifentanil are the most commonly used opioid analgesics within critical care.  As with sedative drugs initial loading of the opioid is needed until patient is comfortable and then followed by low dose infusion of said opioid.
Morphine
Morphine is a widely used opioid analgesic utilised in critical care. It is metabolised in the liver to water-soluble renally excreted compounds including morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). In patients with renal failure accumulation of M6G will lead to prolonged narcosis. Following bolus dosing the peak effect of morphine is achieved after 15 minutes and its duration of action is 2-3 hours. Prolonged infusion leads to accumulation with prolonged narcosis.
Standard Dose:
Intravenous bolus injection - 2.5-5 mg every 15 minutes
Continuous Intravenous Infusion - 1-12 mg/ hr
If patient has been exposed to morphine for more than 7 days, do not stop abruptly, unless there is a good clinical indication. Decrease dose, or start equivalent doses of alternative opioids and wean appropriately.

Alfentanil
Alfentanil has a short duration of action and a rapid, predictable recovery even following infusion. It is hepatically metabolised to inactive substances and has a small volume of distribution. It is useful in patients with renal failure, but may accumulate in patients with liver failure. It is comparatively expensive.
Standard Dose
Induction of anaesthesia by intravenous bolus injection - 50 - 100mcg/kg bolus
Maintenance of anaesthesia by continuous intravenous infusion - 0.5-10 mg/hr (up to 1mcg/kg/min)

Fentanyl
Following IV bolus injection, Fentanyl has rapid onset of action, with short/medium duration of approximately 10-20 minutes. But following a prolonged infusion it becomes a long-acting drug, with a greater half-life than that of morphine. It is the most cardio-stable opioid. In critical care settings it is usually given as a bolus - at induction of anaesthesia, or as analgesia for short surgical procedures. It is comparatively expensive.
Remifentanil
This is an ultra-short acting opioid with a half-life of only three minutes even after prolonged infusion. It is metabolised by non-specific blood/tissue esterases and does not accumulate even in severe renal or liver failure. It has potent analgesic and respiratory depressant properties. Remifentanil should only be prescribed by a Consultant Intensivist. Expensive.

Neuromuscular blocking agents
Neuromuscular blocking agents do not provide sedation, and are only occasionally used in critical care due to concerns about chronic muscle weakness and the risk of paralysis without adequate sedation. Development of myopathy is directly related to duration of infusion. Indications include:

  1. invasive ventilation modes (e.g. inverse ratios, high pressures);
  2. control of ventilation in those with a high respiratory drive;
  3. reduction of oxygen consumption in critically hypoxaemic patients;
  4. control of raised intracranial pressure.

Delivery of sedation
Sedative agents can be administered as boluses when required or by continuous infusion. The latter is most common, providing a constant level of sedation with less chance of intermittent agitation. However, a continuous infusion of sedation has been identified as an independent predictor of a longer duration of mechanical ventilation and a longer stay in the intensive care unit and in the hospital.
Target sedation scores should be set and re-evaluated on a regular basis. This allows therapy to be titrated appropriately, to achieve the desired response, and should therefore prevent over and under-sedation as the clinical needs of the patient change.

Sedation holidays
A sedation holiday involves stopping the sedative infusions and allowing the patient to wake. The infusion should only be restarted once the patient is fully awake and obeying commands or until they became uncomfortable or agitated and deemed to require the resumption of sedation. Ideally, this should be performed on a daily basis. This strategy has been shown to decrease the duration of mechanical ventilation and the length of stay in ICU, without increasing adverse events such as self-extubation.

Accumulation of sedatives
Accumulation of the sedative drug or its active metabolites is common, especially when hepatic and renal dysfunction occurs. This leads to over-sedation, greater haemodynamic instability, and prolonged duration of intubation and ICU stay. The action of anaesthetic induction agents is usually terminated by redistribution rather than clearance. Hence drugs with a low clearance given as a continuous infusion may accumulate leading to over-sedation. Accumulation and over-sedation may be reduced or even avoided by the use of sedation scoring and sedation holidays.

Sedation protocols
Sedation protocols should be standard in every critical care, and followed by nursing and medical staff. Such protocols should be regularly updated. Titration of individual patients’ sedation throughout their ICU admission should reduce over-sedation and side-effects, and contribute to reduced duration of mechanical ventilation and length of stay.