1. Medications for procedural sedationBy
Dr. Haitham Osman,MD
Lecturer of Anesthesia and Intensive Care

2. Introduction
Sedation is the depression of a patient's awareness to the environment and reduction of his/her responsiveness to external stimulation. This is accomplished along a continuum of sedation levels:

3. General principles:
Identify the level of sedation required for the procedure and suitable drug or drugs.
Prepare the necessary equipment that one should have readily available prior to starting the procedure.
Clinicians must be prepared for this and should have emergency apparatus available in case problems arise.
The medications used during sedation typically have additional beneficial effects, as important as sedation.
These actions include the following:
Anxiolysis - Relief of trepidation or agitation with minimal alteration of sensorium
Amnesia - Lapse in memory for a period of time
Analgesia - Relief of pain without an altered sensorium
Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet Mar (9512):

4.  Description
Minimal sedation (anxiolysis)
Moderate sedation/analgesia
Deep sedation/analgesia
General Anesthesia
Consciousness
Response to verbal stimulation is normal.
Depression of consciousness is drug- induced.
Loss of consciousness is drug- induced, where the patient is not able to be aroused, even by painful stimulation.
Response to noxious stimuli
Cognitive function and coordination may be impaired.
Patient responds purposefully to verbal commands.
- Patient is not easily aroused, responds purposefully following repeated or painful stimulation.
- Independent maintenance of Ventilatory function may be impaired.
Patient's ability to maintain Ventilatory function independently is impaired.
Ventilatory control
Ventilatory functions are unaffected.
Airway is patent, and spontaneous ventilation is adequate.
Patient may require assistance in maintaining a patent airway.
Spontaneous ventilation may be inadequate.
Patient requires assistance to maintain patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function.
Cardio vascular functions
cardiovascular functions are unaffected
Cardiovascular function is usually unaffected.
Cardiovascular function is usually maintained
Cardiovascular function may be impaired.

5. Goals of Safe Sedation
1. Maintenance of adequate ventilation, homeostasis and circulation
– A-B-C
– Intravenous line is essential
– Supplemental oxygen is appropriate for most cases
2. Maintenance of appropriate level of consciousness
–Alteration of mood
–Still able to cooperate
–Some degree of amnesia is desirable
–Minimize autonomic nervous system response
3.Promotion of comfort by elevation of pain threshold
4.Ensuring patient safety
- Using the essential components required to conduct safe sedation
- Understanding the importance of a systematic approach to sedation that promotes safety and efficacy

6. Patient assessment based on ASA Classifications
ASA I : Normal healthy adult
ASA II : Mild systemic disease
ASA III: Severe systemic disease with functional limitation that is not incapacitating
ASA IV: Severe systemic disease that is a life threating
ASA V: A patient not expected to survive more than 24 hours without surgical intervention.
ASA VI: Declared brain-dead patient whose organs are being removed for donor purposes
(N EnglJ Med 2000;342:913)

7. Agents Used For Sedation
Benzodiazepines
Opioids
Anesthetics
- Barbiturates.
- Non-Barbiturates
Alpha-2Receptors Agonists
Reversal Agents

8. I- Benzodiazepines:
They act by stimulating GABA-A receptors in the CNS that potentiates the inhibitory effects of
gamma-aminobutyric acid (GABA).
This results in chloride influx, hyperpolarization, and decreased ability of the neuron to reach an
action potential, producing sedation and anxiolysis. In addition, this class of drugs produces amnesia and
has anticonvulsant actions.
They have no analgesic properties.
The most significant adverse effect is :
1-respiratory depression and subsequent hypoxemia. Therefore, it is not suitable for to patients with
underlying chronic obstructive pulmonary disease (COPD).
2-Mild Cardiovascular depression, resulting in hypotension with reflex tachycardia, It is not significant
at typical doses unless hypovolemia is present or unless it is coadministered with centrally acting
analgesics.
Charney DA, Mihic SJ, Harris RA. Hardman JG, Limbird LE, eds. Goodman and Gilman's The Pharmacologic Basis of Therapeutics. 10th ed. New York: McGraw-Hill;

9. Midazolam
 Is a benzodiazepine with a unique imidazole ring that allows for both lipophilic and hydrophilic properties.
Depending on the pH when the pH is less than 4, it is water soluble. Unlike other benzodiazepines, midazolam becomes lipophilic at a pH greater than 4.
Midazolam crosses the blood-brain barrier with ease as a lipophilic molecule, producing sedation in less than 5 minutes.
Most commonly used sedative used for conscious sedation
3-5 times more potent than diazepam
Rarely precipitates or causes pain on injection (as valium will)
Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA Mar (11):

10. Midazolam cont.
Doses:
The total dose in adults is mg/kg. The initial pediatric dose is mg/kg
IV or IM.
The effect starts within 1-3 minutes and the duration of action is about 30 minutes,
although sedation may be prolonged in elderly patients.
Midazolam is metabolized by the hepatic microsomal system and is not affected by renal
failure (caution with cirrhosis).
Advantages:
Midazolam is the fastest acting of its class because of its lipophilic abilities, and it is
superior to lorazepam and diazepam in its amnestic effects, making it the ideal
benzodiazepine for use in short procedures.

11. Diazepam
A longer-acting benzodiazepine, was the first benzodiazepine developed for
intravenous use.
It is insoluble in water and is commercially prepared in propylene glycol.
The intravenous dose range for adults is 2-10 mg. The onset of action is
relatively rapid, but the duration of action is 2-4 hours.
It is metabolized almost exclusively in the liver; therefore, this drug should not be
used in patients with cirrhosis.
It has active metabolites with very long half-lives (ie, h), So The drug profile
of diazepam is not very conducive to procedural sedation.
Painful on injection
Peak effect in less than 10 minutes

12. II- Anesthetics: 1- Barbiturates:
Barbiturates are most potent sedatives/hypnotics. So they are commonly used as
induction agent for endotracheal intubation. They possess primarily sedative
properties and some amnestic effects but no analgesic properties.
They are often used as adjuncts to analgesics for painful procedures.
Barbiturates should be given with caution to persons with COPD, as they have been
shown in early studies to increase the potential for respiratory depressive effects
Thiopental sodium and Methohexital

13. Sodium thiopental
Is an ultra-short-acting barbiturate and has been used commonly in the induction phase
of general anesthesia. Its use has been largely replaced with that of propofol.
Following intravenous injection, Onset of action within 30–45 seconds. At one minute,
the drug attains a peak concentration of about 60% of the total dose in the brain.
Duration of action about 5–10 minutes. Usual dose of sodium thiopental (4–6 mg/kg) .
Sodium thiopental is not used to maintain anesthesia in surgical procedures because, in
infusion, it has cumulative effect leading to a long period before consciousness is
regained.

14. Methohexital
Is the shortest acting of the barbiturate sedatives, with a rapid onset of action (< 1
min) and a short duration of action (5-10 min).
The adult dose for induction is mg/kg.
It also can be used as a sedative for brief procedures, in which case, it is titrated to
effect.
Adverse effects include hypotension (due to vasodilatation and myocardial depression
with reflex tachycardia), which can be more evident in hypovolemia so It should be used
with caution in hemodynamically unstable patients.

15. Nonbarbiturate sedatives
Nonbarbiturate sedatives have all of the sedative properties of barbiturates. They have gained significant popularity in procedural sedation.
The most commonly used (and studied) are Propofol Etomidate and Ketamine

16. Propofol
Is an alkyl phenol derivative compound prepared in a 10% lipid emulsion. Originally promoted as an anesthetic induction agent, propofol is also used as a short-acting sedative for bolus administration or continuous infusion.
It has a rapid onset of action (< 1 min) and short duration of action (approximately 10 min but is dose-dependent).
Clearance of the drug is not affected by renal or hepatic dysfunction, as it has no active metabolites.
Propofol is a respiratory and cardiovascular depressant; so it is suitable for deep procedural sedation and used by privileged physicians with enough experience in managing airways and cardiovascular emergencies.
For moderate sedation in patients with ASA score class 1 or 2; Propofol can be used in the ED as a sedative for short-term procedures, starting with 1 mg/kg and titrating to effect in increments of 0.5 mg/kg in adults.

17. Propofol cont.
It has direct cardio depressant effects, leading to decreased blood pressure and heart rate.
As propofol is a pure sedative/amnestic, an analgesic should be given prior to its administration; giving them simultaneously increases risk for adverse effects.
Blood pressure should be frequently monitored during titration. Patients who have underlying disease (American Society of Anesthesiologists [ASA] Class 3 or 4) are at increased risk for developing hypotension.
The suppression of hypoxic respiratory drive is dose-dependent Patients who need ventilator support are generally older.
Propofol is contraindicated in patients with allergies to soybean or eggs.

18. Etomidate
Is an imidazole derivative compound with sedative properties.
IV etomidate has rapid onset of action (< 1 min) but dose-dependent duration of action (5-8 min).
A major feature of this agent is that cardiovascular effects are negligible during deep sedation.
Side effects: It may cause transient neuromuscular twitching that is sometimes confused with seizure activity. One study showed that pretreatment with magnesium sulfate may prevent etomidate-induced myoclonus.
Its major application is induction for endotracheal intubation, especially for patients at risk for hemodynamic compromise.
It can be also be used in procedures as a one-time dose.

19. Ketamine
Is a dissociative anesthetic and analgesic with a short duration of action.
It is unique in that it produces a state in which respiration and airway reflexes are maintained while patients are unaware of their surroundings. At lower doses, patients can respond to simple commands, but they seem to be unaware of painful stimuli.
It rarely produces hemodynamic depression.
Ketamine is water soluble and lipophilic. Given intravenously, the onset of action is rapid (1-3 minutes), and the duration of action is about minutes. The dose recommended is 1-2 mg/kg IV, which typically produces a full dissociative state, though some data suggest that adequate sedation is possible with smaller doses.
The most annoying side effect is emergence reaction (ie, hallucinations developing during recovery from the dissociative state).
It is more severe in adults and can be attenuated with the administration of a benzodiazepine (eg, midazolam) before recovery.

20. Ketamine cont.
Ketamine also inhibits catecholamine reuptake at the neuromuscular junction, which leads to slight increases in the heart rate, blood pressure, and cardiac output.
In children, ketamine can cause increased salivary and respiratory tract secretions; it can be given with atropine to mitigate this effect (0.01 mg/kg; not to exceed 0.5 mg/dose).
Unique advantages of Ketamine:
1- Bronchial smooth muscle relaxation, making it the preferred drug for sedation/analgesia in patients with asthma.
2- Minimal cardiovascular effects and indirect sympathetic stimulation so it is suitable in hemodynamically unstable patients (eg, induction for intubation).
3- Moreover, it shows promise as a preferred drug in patients with traumatic brain injury, countering former claims of increased intracranial pressure with ketamine usage.

21. III- Opioids
Opioids are agents that induce systemic analgesia, some anxiolysis, and mild sedation. They do not induce amnesia of any significance. Opioids are typically coadministered with benzodiazepines for added sedation, anxiolysis, and amnesia.
They act by binding to specific opioid receptors( mu, delta, kappa and nociceptors) in the CNS.
They are the class of drugs most commonly used for pain management.
Commonly used Opioids include morphine, fentanyl and meperidine.

22. Morphine Is the oldest and most established agent for pain management.
In its intravenous form, it has a rapid onset of action 5-10 minutes. Its duration of action, however, can be as long as 3-4 hours.
The dose is mg/kg (5-10 mg initially for adults), with additional doses as needed.
The primary adverse effect is hypotension, explained partially by histamine release. Administering the medication slowly can minimize this effect. Respiratory depression can also occur, and its risk increases with coadministration of sedative agents.

23. Fentanyl
Is a very potent synthetic opioid and one of the commonly used analgesic adjuncts.
Because its lipid solubility it rapidly crosses the blood-brain barrier and thus has a rapid onset of analgesia (< 90 s).
Because of tissue redistribution, the duration of action about minutes.
It has minimal cardiovascular effects such as hypotension.
Respiratory depression is uncommon, but it is potentiated when used in combination with benzodiazepines.
The intravenous dose is 2-3 mcg/kg ( mcg in adults), titrated in 50 to 100-mcg increments.
It is the preferred drug for analgesia in short procedures and in cases of trauma with potential hemodynamic compromise

24. Meperidine It is a synthetic opioid and its duration of action (2-3 h)
Is intermediate when compared with fentanyl and morphine. Intravenous dosing is mg/kg initially ( mg for adults).
It has an active metabolite, normeperidine
e it has epileptogenic effect in known cases of epilepsy, and it is not recommended in renal failure.
It offers no advantage over fentanyl or morphine. It is rarely used in procedural sedation.

25. Nonopioid analgesic Dexmedetomidine (Precedex)
Is a highly selective alpha2-adrenergic agonist that provides sedation, anxiolysis, hypnosis, analgesia, and sympatholysis.
It is indicated for ICU sedation in patients who are mechanically ventilated.
It is also indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.
ICU sedation
Dexmedetomidine is indicated for sedation of initially intubated and mechanically ventilated patients.
In the randomized, double-blind, multicenter MIDEX and PRODEX trials that studied ICU patients receiving prolonged mechanical ventilation, Dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation.
Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol.
Patients receiving Dexmedetomidine had a higher incidence of hypotension and bradycardia compared with midazolam (20.6% vs 11.6% and 14.2% vs 5.2% respectively).

26. Dexmedetomidine (Precedex)
Procedural sedation
Dexmedetomidine is also indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.
The drug has several characteristics that make its use for procedural sedation very appealing.
1- It provides little to no respiratory depression. Also, patients are able to follow commands and respond to verbal and tactile stimulus but fall quickly asleep when not stimulated.
2- It does provide some pain relief, like ketamine, but not to the same degree. This makes the use of other analgesics necessary for the more painful procedures.
3- Minimal cardiovascular effects are seen and include mild bradycardia and a decrease in systemic vascular resistance.
Onset of action is rapid and the drug’s half-life is approximately 4 minutes after a 10-minute infusion.]
Dexmedetomidine is 1600 times more selective for alpha2 than alpha1 receptors and provides predictable results.

27. Reversal for Benzodiazepines (Flumazenil):
Initial Dose: 0.2 mg
– Phase One: Initially 0.2 mg IV over 15 seconds. If patient does not reach desired level of consciousness after 45 seconds.
– Phase Two: Repeat dose at one minute intervals until a cumulative dose of 1mg has been administered (this includes initial dose in phase one).
Peak effect:
6 to 10 minutes, 80% of the maximum response is seen within 3 minutes.
Potential Adverse Reactions:
–nausea, vomiting, sweating, hot flashes, agitation, headache, injection site pain
May precipitate:
–tremors
–profuse sweating
–hypotension
–seizure activity specially in chronic users of benzodiazepines.

28. Reversal of opioid over dose Naloxone (Narcan):
mcg/kg
All opioid effects, including of analgesia, are reversed
Titrate to effect
Avoid rapid reversal -can lead to untoward sympathetic discharge, extreme pain, anxiety, pulmonary edema