Pharm - Sedation Flashcards
What is remifentanil?
Remifentanil is a synthetic phenylpiperidine derivative of fentanyl. It is a pure μ
agonist. It is presented as a white powder consisting of 1, 2 or 5 mg remifentanil
hydrochloride with glycine. It is reconstituted most commonly with normal
saline and administered as an infusion (0.05–2 mcg/kg/min). It has similar
potency to fentanyl and a bolus of up to 1 mcg/kg may be given over 30–60
seconds as co-induction.
Remifentanil is metabolised by non-specific plasma and tissue esterases; its
duration of action is determined by elimination rather than distribution, unlike
fentanyl. It differs from suxamethonium in that its metabolism is unaffected by
cholinesterase deficiency as it is a poor substrate for that enzyme.
Remifentanil may be associated with profound respiratory depression, chest
wall rigidity, bradycardia and hypotension. Its effects may be completely
reversed with naloxone.
Why might Remifentanyl be used on the ICU?
Remifentanil has a relatively constant context-sensitive half-time (CSHT) of 3–8
minutes, meaning that it has rapid, predictable offset even following prolonged infusions (i.e. is essentially context-insensitive). This pharmacokinetic property lends remifentanil to use in neuro-critical care when frequent partial sedation holds are often required to assess neurology. It may also be useful in patients who are difficult to wean, patients who are expected to be extubated quickly, those with renal or liver impairment, and as analgesia for short procedures.
The analgesic effects wear off rapidly: pain may be a significant problem if
inadequate alternative analgesia is not administered before discontinuing the
remifentanil infusion. Intra-operative use may be associated with hyperalgesia
post-operatively that may necessitate high doses of opioids with their inherent
side effects.
What is context-sensitive half-time and why is it relevant?
The CSHT is the time taken for the plasma concentration to halve, after an infusion designed to maintain constant blood levels is stopped. The context is the duration of the infusion. The higher the ratio of clearance due to redistribution to clearance due to elimination, the greater the possible range of CSHT. It is important because it helps to predict how long a patient will take to wake up from a steady-state infusion of a given sedative drug.
For example, fentanyl redistributes very rapidly and its clearance due to elimination is about 20% of that for distribution. Therefore, the CSHT for fentanyl increases rapidly with increasing duration of infusion. The maximum CSHT for fentanyl is approximately 300 minutes.
In contrast, the clearance due to elimination for propofol is similar to that for redistribution. This rapid elimination means that plasma concentration falls quickly after a propofol infusion is stopped. As a result, the maximum possible CSHT for propofol is approximately 20 minutes.
The distribution clearance of remifentanil is lower than the elimination clearance (i.e. the opposite of fentanyl). Therefore, elimination dictates the clearance of remifentanil from the plasma resulting in very little variation in CSHT.
Tell me about propofol
Propofol is 2,6-di-isopropyl-phenol (Figure 76.1). It is presented as a 1% or 2% lipid-water emulsion containing soya bean oil and purified egg phosphatide. It is highly lipid soluble and poorly water soluble. It is a weak organic acid with a pKa of 11, and is almost entirely unionised at physiological pH.
Propofol is used for induction (1–2 mg/kg) and maintenance (up to 4 mg/kg/ hour, plasma concentration 4–8 mcg/ml) of anaesthesia, and for sedation.
It is 98% protein-bound to albumin with a Vd of 4 l/kg. A bolus dose has a short duration of action due to rapid redistribution. It undergoes mainly hepatic metabolism to inactive compounds that are excreted in the urine (40% glucuronidation, 60% metabolised to a quinol (excreted as a sulphate and a glucuronide)). During prolonged infusion CSHT increases and waking may be protracted due to the slow release of propofol from fat (careful titration may avoid this).
What are the adverse effects of using propofol as a sedative on the ICU?
Respiratory
– Respiratory depression (can lead to apnoea)
Cardiovascular
– Reduction in SVR leading to hypotension
– Can be associated with a bradycardia (i.e. obtunds baroreceptor reflex)
– Reduced sympathetic activity and myocardial contractility
Metabolic
– Propofol infusion syndrome (PRIS) may follow prolonged infusion in high risk patients
Other
– Green discoloration of urine and hair (no correlation with PRIS)
What is propofol infusion syndrome?
PRIS was first described in the paediatric population, and is characterised by acute refractory bradycardia leading to asystole in the presence of one or more of the following:
1 Unexplained metabolic acidosis (base excess >–10 mmol/l)
2 Rhabdomyolysis (high CK, hyperkalaemia, AKI) or myoglobinuria
3 Lipaemic plasma (hypertriglyceridaemia)
4 Fatty liver or hepatomegaly
What is the pathophysiology of PRIS?
The mechanism is thought to be related to impaired mitochondrial fatty acid metabolism and direct inhibition of mitochondrial function leading to impaired oxygen utilisation, anaerobic respiration and lactate production. Additionally, propofol is a direct myocardial depressant. There is cardiac and skeletal myocyte ischaemia and necrosis, with accumulation of unutilised fatty acids. This is associated with arrhythmias.
What are the risk factors for PRIS?
1 High dose propofol infusion (>4 mg/kg/hour)
2 Young age
– Low glycogen stores, high dependence on lipid metabolism
– The Committee on Safety of Medicines has advised that propofol should be contraindicated for sedation in ICU of children ≤16 years-old
3 Brain injury
4 Low carbohydrate intake, high lipid loads, e.g. PN
– There is increased lipolysis in periods of starvation precipitated by high energy demands
5 High endogenous or exogenous catecholamine levels
– Increased propofol clearance, meaning higher infusion rates required
6 High endogenous or exogenous glucocorticoid levels
7 Inborn errors of fatty acid metabolism
How might PRIS present?
PRIS most commonly presents with ECG changes:
1 Bradycardia
2 Brugada-like pattern (coved-type ST elevation in V1-V3)
3 Varying degrees of heart block
4 RBBB
5 Unexplained arrhythmias
There may be unexplained cardiovascular instability and escalating inotrope/ vasopressor requirements.
A high index of suspicion should be maintained, particularly in patients on highdose propofol or with other risk factors. There should be a low threshold for measuring triglyceride levels.
What is the treatment for PRIS?
The management of PRIS is entirely supportive and should follow an ABCDE approach, treating abnormalities as they are found. Specific management involves:
1 Stop the propofol infusion and maintain sedation with an alternative agent,
e.g. midazolam
2 Supportive management
i Titration of vasoactive infusions
ii Rhabdomyolysis treatment (target urine output 2–3 ml/kg/hour, urinary
alkalinisation, diuretics, treatment of hyperkalaemia)
iii RRT for AKI
iv Ensure adequate carbohydrate intake (glucose infusion)
2 Consider temporary pacing
3 VA ECMO has been used successfully
How is level of sedation assessed on the ICU?
The most commonly used methods are the Richmond Agitation-Sedation Scale
0 - Alert and calm
+4 combative
-5 Unrousable
What level of sedation should be targeted?
Patients’ sedation should be titrated according to clinical need and the sedation score target should be set as part of the daily round. In most situations one should follow the 3 C rule (aim to have the patient calm, cooperative and comfortable), i.e. a target RASS of 0 to –1 is used.
However, there are times when a patient may require deeper sedation, i.e. RASS –3 to –5, such as:
1 Brain injury and raised ICP
2 Use of NMBAs
3 Severe respiratory failure/ARDS
4 Ventilator-patient dysynchrony
5 Strict immobilisation, e.g. unstable spinal fractures
6 Status epilepticus
