Sedation and analgesia in ICU

Dr. B. Uma

University College of Medical Sciences & GTB Hospital, Delhi

Sedation
Sedation comes from the Latin word sedare.
Sedare = to calm or to allay fear Conscious sedation: A minimally depressed level of

consciousness induced by the administration of pharmacologic agents in which a patient retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands

Why is sedation necessary?

To improve patient comfort Facilitate interventions To allay fear, anxiety and agitation Adequate sleep Avoid pain Facilitation of mechanical ventilation/airway management/ weaning Protection against myocardial ischemia Amnesia during neuromuscular blockade

Goals for sedation and analgesia

To minimize physical discomfort or pain during procedures

To minimize psychological disturbance

To maximize the potential for amnesia To guard patient safety

To control behavior

Complications from pain and anxiety

Stimulation of the autonomic nervous system and release of humoral factors increased heart rate,

blood pressure, and myocardial oxygen consumption myocardial ischemia or infarction

Altered humoral response can lead to hypercoagulability as a result of increased level of factor VIII, fibrinogen, platelet activity, and inhibition of fibrinolysis

Complications (contd.)
Stress hormones also produce insulin resistance, increased metabolic rate, and protein catabolism Immunosuppression with reduction in number and function of lymphocytes and granulocytes Psychological disturbances - memories of vivid nightmares, hallucinations, and paranoid delusions

Assessment of pain and anxiety

Any scoring system should be simple, easily performed, noninvasive, and reproducible. Six levels of sedation are used: 1. Anxious and agitated 2. Cooperative, orientated, and tranquil 3. Responds to verbal commands only 4. Asleep but brisk response to loud auditory stimulus/light glabellar tap 5. Asleep but sluggish response to loud auditory stimulus/light glabellar tap 6. Asleep, no response

Commonly used sedation tools

Glasgow coma scale (GCS) assessment of level of consciousness 6 point Ramsay scale most commonly used sedation scale Sedation Agitation Scale (SAS) Motor Activity Assessment scale (MAAS) Richmond AgitationSedation Scale

Glasgow coma scale

GCS modified by Cook and Palma

Richmond agitation sedation scale

Score +4 +3 +2 +1 0 -1 -2 -3 -4 -5 Term Combative Very agitated Agitated Restless Alert and calm Drowsy Light sedation Moderate sedation Deep sedation Unarousable Not fully alert but awakens for >10s, with eye contact, to voice Briefly awakens (<10s), with eye contact, to voice Any movement to voice but no eye contact No response to voice but movement to physical stimulation No response to voice or physical stimulation Description Violent; immediate danger to staff Pulls/ removes tubes, catheters; aggressive Frequent non purposeful movement; patient ventilator asynchrony Anxious or apprehensive

Ramsay sedation scale

Awake 1 2 3 Asleep 4 5

Anxious and/or agitated Cooperative, oriented, and tranquil Responds to commands

Quiescent with brisk response to light glabellar tap or loud auditory stimulus Sluggish response to light glabellar tap or loud auditory stimulus No response

Sedation agitation scale

1: Unarousable 2: Very sedated 3: Sedated 4: Calm and cooperative 5: Agitated 6: Very agitated 7: Dangerous agitation

Bispectral index
A practical, processed EEG parameter that measures the direct effects of sedatives on the brain
Provides objective information about a patients response to sedation Optimizes sedation assessment and titration

Numerical scale correlates to sedation endpoints

BIS monitor

BIS sensor

BIS range guidelines

Value of BIS in ICU

Minimize consequences of over- and under-sedation

Objective sedation assessment

Optimize clinical and economic outcomes

Improve quality of sedation management

Recommendation for Assessment of Sedation

The use of a validated sedation assessment scale (SAS, MAAS, or Vancouver Interaction and Calmness Scale

[VICS]) is recommended. (Grade of recommendation = B) The SCCM guidelines state: Objective measures of sedation, such as Bispectral Index, have not been completely evaluated and are not yet proven useful in the ICU. (Grade of recommendation = C)

Sedation therapy
NON PHARMACOLOGICAL THERAPY: Good communication with regular reassurance from nursing staff Environmental control such as humidity, lighting, temperature, and noise Explanation prior to procedures Management of thirst, hunger, constipation, and full bladder Variety for the patient e.g. radio

Pharmacologic therapy

The sedative agent should possess the following qualities: Both sedative and analgesic properties Minimal cardiovascular side effects Controllable respiratory side effects Rapid onset/offset of action No accumulation in renal/hepatic dysfunction Inactive metabolites Inexpensive No interactions with other ICU drugs

Pharmacologic therapy
Benzodiazepines
Propofol Etomidate

Ketamine

Barbiturate

Short acting opioids

Alpha 2 agonists

Inhalational agents

Benzodiazepines
Anxiolytic, anticonvulsant, amnesic, hypnotic and provide some muscle relaxation
Effects are mediated by depressing the excitability of the limbic system via reversible binding at GABAbenzodiazepine receptor complex Minimal cardiorespiratory depressant effect The common drugs in this class are diazepam, midazolam, and lorazepam

Benzodiazepines: Midazolam
Water-soluble
Short elimination half life (1-4 hrs) No long acting metabolites

In ICU patients, midazolam's elimination half-life may be greatly prolonged and clinically important accumulation may occur Minimal dose: 1 to 2 mg bolus
Infusions@ 0.5 to 10 mg/hr

Benzodiazepines: Diazepam
Elimination half-life of 21 to 37 hours 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 not recommended

Benzodiazepines : Lorazepam

Lower lipid-solubility than midazolam Less hypotesnion Metabolised by liver to inactive metabolites Lower cost Loading dose: 0.02-0.06 mg/kg Infusion dose: 0.01-0.1 mg/kg/hr

MIDAZOLM LOADING DOSE MAINTANENCE DOSE ONSET DURATION CARDIAC EFFECTS 0.02-0.1 mg/kg 0.04-0.2 mg/kg/hr 1-5 min 1-2 hrs Minimal

LORAZEPAM 0.02-0.06 mg/kg 0.01-0.1 mg/kg/hr 5-20 min 2-6 hrs Minimal

DIAZEPAM 0.05-0.2 mg/kg Rarely used 2-5 min 2-4 hrs Present

RESPIRATORY EFFECTS
ANALGESIA

Important depressant effect

None

Important depressant effect

None

Important depressant effect

None

AMNESIA
ACTIVE METABOLITES

Potent
Yes

None
No

None
Yes

COST/24HRS

4 mg/hr: $37

2 mg/hr: $52

8 mg q 4h: $24

Flumazenil
Benzodiazepine antagonist
Given in incremental doses of 0.2 to 0.5 mg upto 3 mg Onset 2 min Duration- 30 to 60 min

Propofol

The mode of action of propofol is via the GABA receptor Rapid onset of action; metabolized rapidly hepatically and extrahepatically

Recovery within 10 minutes of discontinuation, can accumulate with prolonged use Ideally infused via a large or central vein Prolonged infusions increase triglyceride and cholesterol levels

A theoretical maximum recommended dose is 4 mg/kg/hour.

Propofol (contd.)
Bolus dose not recommended
Infusions @25 to 100g/kg/hr Theoretical maximum dose- 4mg/kg/hr

Cautious about propofol infusion syndrome

Propofol: adverse effects

Hypotension
Reliable, dose-related
Decreased SVR and contractility (CO)

Respiratory depression
Apnea with bolus dosing

Synergistic CV and respiratory depression with opioids Vehicle (soybean emulsion):

Hypertriglyceridemia Venoirritation Infection

Propofol infusion syndrome

Propofol infusion syndrome is an adverse drug event

associated with high doses (>4 mg/kg per hour or >67 g/kg per minute) and long-term (>48 hours) use of propofol. Clinical features: - Cardiomyopathy with acute cardiac failure. - Myopathy. - Metabolic acidosis, K+ - Hepatomegaly. Inhibition of FFA entry into mitochondria failure of its metabolism.

Management

Supportive treatments addressing the clinical

manifestations The propofol infusion should be discontinued immediately Alternative sedative should be started Intravenous crystalloid and colloid replacement and vasopressor and/or inotropic support Cardiac pacing may be used for symptomatic bradycardia Hemodialysis or continuous renal replacement therapy to treat the acute renal failure

Ketamine
Ketamine acts at the N-methyl-D-aspartate (NMDA) receptor
In subanesthetic doses, sedative and analgesic Generally not used because of the increase in blood pressure, intracranial pressure (ICP), and pulse rate Bronchodilatory properties, sometimes has a role in severe asthma In the ICU conjunction with a narcotic Dose : 5 to 30 g/kg/min

Others

ETOMIDATE :For maintenance of hypnosis, target

concentration of 300 to 500 ng/mL may be achieved by administration of a two- or three-stage infusion

BARBITURATES: Barbiturates such as Pentothal have been used in the ICU, especially in the management of patients with head injuries and seizure disorders. They cause significant cardiovascular depression and accumulate during infusions, leading to prolonged recovery times.

Others (contd.)

BUTYROPHENONES AND PHENOTHIAZINES An aggressive dosing regimen of haloperidol may be useful in a patient with delirium to promote calm, 2 to 10 mg IV every 10 to 15 minutes until the desired response is achieved VOLATILE AGENTS Isoflurane has been used in concentrations of up to 0.6% for longterm sedation, with minimal cardiorespiratory side effects and rapid awakening. Desflurane has been shown to be effective in sedation, with rapid offset of effects.

Others (contd.)
Shorter acting opioids
Fentanyl, alfentanyl, remifentanyl

Muscle relaxants
2 agonists Clonidine

dexmedetomidine

Alpha-2 Agonists
H Cl N N

Clonidine

Cl

CH3 N

Dexmedetomidine

CH3 CH3

2 Agonists
Clonidine
Selectivity: 2:1 250:1
Imidazole derivate 16:1 t1/2 10 hrs Antihypertensive

Dexmedetomidine
Selectivity: 2:1 1620:1
Imidazole derivate 31:1 t1/2 2 hrs 94% protein bound Sedative

Eliminated by liver/kidney Only available in IV form

Dexmedetomidine
Pharmacology of dexmedetomidine
Molecular targets + neural substrates
locus ceruleus
natural sleep pathways alpha 2 agonist

Clinical paradigms for use of dextomed in anesthesia

sedation + analgesia w/o respiratory depression
attenuation of tachycardia

smooth emergence + weaning from mechanical

ventilation

Pharmacokinetics
Rapid redistribution: 6 min
Elimination half-life: 2 h Vd steady state: 118 L

Clearance: 39 L/h

Protein binding: 94%

Metabolism: biotransformation in liver to inactive

metabolites + excreted in urine No accumulation after infusions 12-24 h Pharmacokinetics similar in young adults + elderly

Sedation
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 is synergistic with opioids and acts at the spinal cord to inhibit nociceptive inputs, thus imparting analgesia
It is contraindicated in hypovolemia and can cause hypotension, bradycardia, and dry mouth

The Art of Sedation

Under sedation: Fighting the ventilator. V/Q mismatch. Accidental extubation. Catheter displacement. CV stress ischemia. Anxiety, awareness. Post-traumatic stress disorder.

Over sedation: Tolerance, tachyphylaxis. Withdrawal syndrome. Delirium. Prolonged ventilation. CV depression. neuro testing. Sleep disturbance.

Unwanted side-effects
Benzodiazepines Hypotension Respiratory depression Agitation/Confusion

General Over sedation Delayed awakening/extubation

2-agonists
Hypotension Bradycardia

Propofol Hypertriglyceridemia CVS depression Hypotension

Ketamine Hypertension

Secretions
Dysphoria

Analgesia in ICU

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Thus,
perception of sensory events is a requirement, but actual tissue damage is not.

Although a majority of ICU patients receive parenteral analgesics routinely , 50% of patients discharged from the ICU remember pain as their worst experience while in the ICU. This emphasizes the need for effective pain control in the ICU.

Indices of pain severity applicable in the critically ill

Subjective Visual analogue scale Numeric rating scale Verbal descriptor scale
Objective Vital signs measurements Behavioural responses

Verbal rating scale

None mild moderate severe

Visual analog scale

No pain Worst pain

Recommendation for assessment of pain

Use of the numeric rating scale(NRS) is recommended to assess pain. (Grade of recommendation = B) Patients who cannot communicate should be assessed through subjective observation of pain and physiological indicators and the change in these

parameters following analgesic therapy. (Grade of recommendation =B)

Analgesics used in ICU

Pain in the critically ill is best treated with a pure opioid agonist In a recent clinical guideline, the recommended choices have been narrowed to morphine, fentanyl, and hydromorphone. Other drugs with analgesic properties and variable use in critically ill patients are :

meperidine (pethidine) tramadol nonsteroidal anti-inflammatory drugs (NSAIDs) mixed opioid agonist-antagonist agents ketamine, a sedative drug with analgesic qualities 2 agonists.

Opioids :Morphine

Plasma levels do not correlate with clinical effect. Low lipid solubility causes slow equilibration across BBB. Metabolized in the liver by conjugation. Morphine6-glucuronide active metabolite with sedative action. The analgesic dose is highly variable, and may be delivered as an intermittent boluses or as a continuous infusion. Minimal cardiovascular side effects Relatively contraindicated in asthma and renal failure

Morphine
CNS effects mediated via 1 and 2 receptors Analgesia: pain components
Affective- greater effect Sensory

Euphoria Sedation Mood change

Mental cloudiness

Fentanyl
Fentanyl : synthetic opioid derived from meperidine (pethidine)
Short-acting opioid with rapid onset After prolonged infusion the duration of action approaches that of morphine Does not accumulate in renal failure It does not cause histamine release and is suitable for analgesia in the hemodynamically unstable patient

Alfentanyl
Alfentanil is a synthetic opioid
Onset of action about five times faster than fentanyl, due to the small volume of distribution Less lipid soluble The duration of action is about one-third that of fentanyl Alfentanil has minimal cardiovascular effects

Remifentanil

Remifentanil, an ultra-short-acting opioid

metabolized by nonspecific tissue esterases Rapid onset of action Does not accumulate after infusions even in organ dysfunction. Selective mu-receptor agonist. Potency similar to fentanyl. Terminal half-life < 10 min. Rapid blood-brain equilibrium. Can cause significant bradycardia

Morphine Loading dose Onset Duration Infusion rate Active metabolites Histamine release Cost / 24hrs 5-10 mg 10-20 min 2-3.5 hrs 1-5 mg/hr Yes Yes 5mg/hr: $ 16

Hydromorphone 1-1.5 mg 5-15 min 2-3 hrs 0.2-0.5 mg/hr Yes No 0.75 mg/hr: $ 10

Fentanyl 50-100g 1-2 min 30-60 min 50-350g/hr No No 100g/hr: $ 5.50

Epidural analgesia
Opioids
Morphine Fentanyl

Concentration
20- 100 g/ml 2- 5 g/ml

Adverse effects of epidural analgesia are more common with morphine than fentanyl. Epidural morphine can produce respiratory depression, and the onset can be delayed up to 12 hours . The incidence of respiratory depression is equivalent with epidural and intravenous morphine. More frequent side effects of epidural analgesia include pruritis, nausea, and urinary retention.

Unwanted side-effects of opioids

Opioids
Vasodilation Confusion Gut motility depression

Respiratory depression

Other opioid agonists

Tramadol Synthetic 4-phenyl-piperidine analog of codeine Stimulates the -receptor 1/5th to 1/10th as potent as morphine Analgesic doses of tramadol may produce less respiratory depression and have minimal effects on gastrointestinal motor function

Naloxone
Opioid antagonist
Used to restore spontaneous ventilation in patients who breathe inadequately after opioid overdose Onset of action is 1 -2 min Dosage 0.4 to 0.8mg Duration of effect is 30 -60 min

Side effects: tachycardia, hypertension, pulmonary edema

Non steroidal anti inflammatory drugs

There is only one NSAID approved for use in the United States: ketorolac.
Nonspecific inhibitor of cyclooxygenase with strong analgesic activity and moderate anti inflammatory activity

Metabolized in the liver and excreted by the kidneys

Dose: 30 mg IV or 60 mg IM, f/b 30 mg IM or IV every 6 hours (maximum of 120 mg/day) for up to 5 days

iv paracetamol
The time course of action is quick with iv paracetamol as it reaches peak concentration as soon as infusion is complete (about 15 minutes).
According to the product information, the analgesic effect starts within 5 minutes, peaks at 1 hour and lasts 4 to 6 hours.

Clinical practice guidelines for sedation and analgesia from the Society of Critical Care Medicine and American College of Critical Care Medicine Pain

Pain

An assessment of pain and the response to therapy should be regularly assessed using an appropriate

pain scale. Therapeutic plans and goals should be developed for all patients. Recommended intravenous opioids are fentanyl for acute distress, fentanyl or hydromorphone for patients with hemodynamic instability or renal insufficiency, and morphine and hydromorphone for longer-term therapy. Scheduled doses or continuous infusions are preferred over intermittent boluses. Nonsteroidal anti-inflammatory drugs and acetaminophen can be useful adjuncts, but beware of renal insufficiency or gastrointestinal bleeding.

Sedation

Treatment of pain and other reversible causes should be conducted before sedating an agitated patient. A treatment plan/goal should be established for each patient; therapy should be assessed with a sedation scale. Midazolam or diazepam is useful for the acutely agitated patient. Propofol is preferred when rapid awakening is crucial; triglyceride levels should be monitored for >2 d of continuous infusions. Lorazepam is recommended for longer infusions. Doses should be tapered daily to assess underlying mental status, and sedation protocols can be helpful

and beneficial.

Guidelines for sedation and analgesia in ICU

References
Gabrielli A, Layon A, Joseph, et al. Anesthesia in the ICU.

Civetta, Taylor, & Kirby's: Critical Care, 4th Edition; Lippincott Williams & Wilkins:2009
Marino, PL. Analgesia and Sedation. ICU Book, 3rd

Edition; Lippincott Williams & Wilkins:2007

Miller RD. Critical care protocols. Millers Anaesthesia.

7th edition:2010

Thank you