Pain and Sedation

Question 1

Differences in Pain Between Children and Adults

Answer 1

• Neonate:
  
  • Descending pain pathway not complete until 30-32 weeks gestation
  • Under 32 weeks have lower pain threshold and hypersensitivity that develops after repeat painful procedures
  • Final stage of neural development complete at 37 weeks gestation
• Infants:
  
  • Decreased accuracy in pain perception, difficulty in distinguishing painful response from non-painful response
• Children may have higher oxygen consumption & smaller lung volumes, more prone to periods of apnea with an opioid or sedative
• Consider ADME differences
  • Neonates/Infants – higher exposure of topically administered medications
• Transdermal fentanyl should be avoided in children younger than 2 years of age due to unpredictability of dosing
• Neonates and infants may have inability to metabolize medications via hepatic system and inability to clear medications via renal system
• Children between 1-9 may have increased metabolic clearance
• Obese children will have a higher Vd for lipophilic medications
  
  • Dosing continuous intravenous fentanyl by actual body weight may lead to higher risk of overdosing and adverse effects
• Compare adult dose to pediatric dose and consider using lowest dose

Question 3

AAP Guidelines for Use of Topical Lidocaine in the ED

Answer 3

• Consider topical anesthetics in any patient with likelihood of non-emergent invasive procedure on intact skin in ED:
• Contraindications:
  
  • Emergent need for IV access
  • Allergy to amide anesthetics
  • Non-intact skin
  • EMLA only: congenital or idiopathic methemoglobinemia

Question 4

AAP Guidelines for Use of Sucrose in ED

Answer 4

Indications:

• Neonates and infants younger than 6 months
• Adjunct for limiting pain associated with procedures such as heel sticks, venipuncture, IV line insertion, arterial puncture, insertion of Foley catheter, and lumbar puncture

Procedure:

• Administer 2 mL of 25% sucrose solution by syringe into infant’s mouth (1 mL in each cheek) or allow infant to suck solution from a nipple (pacifier) no more than 2 min before the start of the painful procedure
• Sucrose seems more effective when given in combination with a pacifier; nonnutritive suck also contributes to calming the infant and decreasing pain-elicited distress
• Contraindications: None

Question 5

Pain Assessment Tools

Answer 5

Question 6

Opioid Receptors

Answer 6

μ (mu)

• Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release

δ (delta)

• Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release

κ (kappa)

• Supraspinal and spinal analgesia; psychotomimetic effects; slowed gastrointestinal transit

Question 7

Calculating a PCA - Hydromorphone

Answer 7

• Children ≥5 years weighing <50 kg & Adolescents weighing <50 kg:
• Usual concentration: 0.2 mg/mL
  
  • Demand dose: Usual initial: 0.003 to 0.004 mg/kg/dose
  • Lockout: Usual initial: 5 doses/hour
  • Lockout interval: Range: 6 to 10 minutes
  • Usual basal rate: 0 to 0.004 mg/kg/hour
• Sammy is a 10 year old patient who weights 20 kg

Question 8

Morphine

Answer 8

• Available as oral elixirs, tablets, SR products, intravenous
• Metabolism
  
  • Metabolized via glucuronidation to active and inactive metabolites
  • Neonates can not metabolize (to active or inactive), less effective
• AE:
  
  • Significant hypotension
  • Histamine release: induced bronchospasm in history of asthma, higher risk of itching

Question 9

Hydromorphone

Answer 9

• 5x more potent opioid – oral and intravenous dosage forms
• Preferred over morphine for intermittent dosing for patients in renal failure due to less metabolites
• Pharmacologically similar to morphine

Question 10

Fentanyl

Answer 10

• Synthetic opioid structurally similar to meperidine
• 70-100x more potent IV opioid – intravenous
  
  • Other formulations – spray, tablets/film/solution for sublingual or
• buccal administration, intranasal solution, transdermal, lozenge
• More lipophilic than morphine and has a quicker onset of action with shorter half-life
• Useful for intubation and procedures (dressing changes, lumbar puncture)
• AE: Chest wall rigidity observed with bolus doses (managed with a dose of naloxone and dose of NMB before fentanyl bolus)

Question 11

Methadone

Answer 11

• Long acting opioid
  
  • Used for chronic pain and treatment of iatrogenic opioid withdrawal in critically ill children; (detoxification programs for heroin substance abuse in adults)
• Has an extended half-life 19 +/- 14 hours (range 4-62 hours) in children
• Same potency as morphine, but longer peak onset of action
• Similar structure to verapamil
  
  • May exert calcium channel blockade
  • Bradycardia, hypotension, cardiac arrhythmias (QRS prolongation)
  • Higher risk of cardiac toxicities with rapid IV administration

Question 12

Meperidine

Answer 12

• Less potent synthetic opioid with shorter duration of action
• Limiting AE due to metabolite accumulation:
  
  • Seizures, agitation, hyperreflexia
• Risk factors for AE
  
  • Higher doses
  • Renal Failure
• Reserved use for
  
  • Prevention of rigors after administration of blood product or amphotericin
  • Treatment of post-anesthetic shivering
  • Limited use for acute pain

Question 13

Hydrocodone and Oxycodone (PO)

Answer 13

Oral administration, similar to morphine and more potent than codeine

• Oxycodone – more potent than hydrocodone, indicated for moderate to severe pain
• Hydrocodone – moderate pain, only available as combination with acetaminophen (combination products have limited acetaminophen content to 325 mg)
  
  • **Counsel on excessive acetaminophen content**

Question 14

Codeine and Tramadol

Answer 14

Codeine

• Metabolized to morphine via CYP2D6
• Poor metabolizers (decreased analgesic effects) versus ultra-fast metabolizers (increased respiratory depression)
• Not routinely utilized

Tramadol

• Centrally acting opioid (binds to mu receptors) plus inhibits reuptake
• of norepinephrine and serotonin
• Decreases seizures threshold
• Avoid with concomitant SSRI – serotonin syndrome
• FDA approved for 17 years and older only

Question 15

Opioid-related AE

Answer 15

[removed many because duh]

Tolerance: Increase opioid dose or switch to a longer-acting agent. Add non-opioid analgesic, or agent that prevents/delays tolerance

Withdrawal: Taper opioid dose slowly or add long-acting opioid agonist; Add alpha2 agonist

Question 16

Gamma-aminobutyric acid (GABA)

Answer 16

GABA binds to 3 types of receptors

• GABA_A Receptor*
  
  • Functions as a gated Chloride ion channel
    
    • Activation of channel causes an inhibitory postsynaptic potential (IPSP) that dampens neuronal excitability
  • Site of neuroactive drugs
    
    • Benzodiazepines, Barbiturates, Ethanol, Anesthetics
  • Contains 3 subunits of α, β, ɣ in various combinations throughout CNS

Question 17

Benzodiazepines

Answer 17

Benzodiazepines

• Enhances GABAergic inhibition (increases effects)
• Increase frequency of GABA-gated channel openings
• Do not activate receptors (need GABA)

Absorption: Most are lipid soluble. Ethanol enhances absorption.

Distribution: High lipid solubility increases rate of CNS penetration

Metabolism*: Major pathway for most agents. Caution with active metabolites.

• Phase I reactions – oxidation reaction to active or inactive metabolites
  
  • Primarily involves CYP-450 system
• Phase II reactions – metabolite conjugated to form glucuronides that are excreted in the urine

Excretion: Dose adjustment not typically needed

• Agonists – facilitate GABA actions
  
  • BZD binds to BZD receptor to facilitate GABA binding to GABA receptor, increases frequency of channel opening
    
    • Benzodiazepines
    • Non-benzodiazepines (selective for α1 subunit)
• Antagonists – blocks BZD & non-BZD actions
  
  • Flumazenil – antidotes for overdose
    
    • Shorter t1⁄2 compared to BZD – requires multiple doses
    • Caution w/inducing abstinence/withdrawal syndrome

Question 19

Versed

Answer 19

Advantages

• Anxiolytic, sedation, motion control
• Retrograde amnesia
• PO, IV, IM, IN, PR dosing routes
• Onset 2-6 min after IV administration, 45-60 min duration
• Available reversal agent

Disadvantages

• No analgesia
• Paradoxical reactions
• More than additive risk of respiratory compromise when added to opiate
  
  • Esp in pts with pulmonary disease
  • Toxic Doses - depression of medullary respiratory center leads to death
• Neonates: hypotension and seizures with rapid injection
  
  • Significant CV effects especially in hypovolemic states, and/or with impaired cardiovascular function
  • Toxic Doses – depressed myocardial contractility & vascular tone leads to circulatory collapse

Question 20

Ketamine the wonder drug

Answer 20

• Produces dissociative anesthesia by direct action on the cortex and limbic system
• Produces NMDA receptor blockade
• Pharmacokinetics
  
  • Quickly crosses the blood brain barrier
  • Elimination half-life 2.2 hours
  • Peak concentrations seen within one minute of IV administration
  • Tolerance develops with repeated doses
  • Hepatically metabolized - use cautiously in patients with hepatic failure
• Less respiratory or cardiovascular depression than narcotic/ benzodiazepine combination

Advantages

• Provides both analgesia and amnesia
• Preserves upper airway tone and reflexes
• Causes bronchodilation

Disadvantages

• Increases intracranial pressure
• Laryngospasm
• Hyper-secretory response
• Emergence phenomenon/agitation

Question 21

Pediatric Physiology Considerations for NMB

Answer 21

Neonates

• Neuromuscular junction continues to develop through 1st year of life
• Increased volume of distribution
• Less efficient metabolism/elimination through liver/kidneys
  
  • Drug may have prolonged duration of action

Children

• Increased volume of distribution
• Higher muscle to fat ratio leading to more acetylcholine receptors
  
  • Require higher doses compared to adults
• Neuromuscular activity recovers quicker than in adults

Question 22

Types of Neuromuscular Blocking Agents (NMBA)

Answer 22

Depolarizing -

Depolarizing bind to Ach receptors and cause prolonged depol of motor end plate, resulting in flaccid paralysis
Succinylcholine

Nondepolarizing -

Nondepolarizing bind to Ach receptors and prevent depol of motor end plate​
Benzylisoquinolines

• Atracurium
• Cisatracurium

Aminosteriods

• Pancuronium
• Rocuronium
• Vecuronium

Question 23

Indications for Neuromuscular Blockade

Answer 23

• Facilitate intubation
• Sustained neuromuscular blockade
  
  • Ventilator dyssynchrony
  • Protection of surgical repair
  • Induced hypothermia
  • Ablate spasms associated with tetanus
  • Elevated ICP

Question 24

Rapid Sequence Intubation

Answer 24

• Means of securing airway of decompensating patient
• Goal of RSI
  
  • Conscious unconscious/intubated without positive-pressure ventilation
• Medications used include induction agents and neuromuscular blocking agents

Question 25

NMBA for Sustained Blockade Intermediate Duration of Action

Answer 25

* Slowest onset: cisatracurium * Fastest onset: roc * Longest duration: pancuronium * Shortest duration: atra * +active metabolites: atra, cisatra, panc * +hepatic metabolism: roc, vec, panc **Complications of Sustained Blockade** * Tachyphylaxis/Tolerance * Prolonged immobility * Muscle atrophy * Joint contractures * Pressure sores * Pulmonary atelectasis, pneumonia * Corneal drying, potential corneal damage 2/2 absence of eye blink * Prolonged muscle weakness 2/2 atrophy, +steroids, +aminoglycosides, +metabolite accumulation, polyneuropathy * Critical Illness Polyneuropathy * Degeneration of skeletal muscles resulting from their denervation * Characterized by generalized weakness, areflexia, delayed weaning from mechanical ventilation * Risk factors may include NMBA and aminoglycoside use; malnutrition * Critical Care Myopathy * Significant muscle weakness in the ICU * Isolated injury to muscle, nerves not involved * Risk factors include • Sepsis • Acute lung injury • Nondepolarizing NMBA • Sedation with propofol • Large doses of corticosteroids

Question 26

NMBA Drug Interactions

Answer 26

**Antagonizing effects** * Phenytoin * Carbamazepine * Theophylline * Sympathomimetic drugs * Chronic exposure to NMBAs **Potentiating effects** * Antibiotics * Beta blockers * Calcium channel blockers * Corticosteroids * Diuretics * Lasix, thiazides * Inhaled anesthetics * Lithium * Magnesium * Cyclosporine

Question 27

Succinylcholine

Answer 27

* Classic depolarizing * Quickest onset, shortest duration of all NMBA * Metabolized by plasma cholinesterase * Many potential adverse effects * Increased airway secretions * Vagal-mediated effects * Sympathetic stimulation * Hyperkalemia * Malignant hyperthermia (rare)

Question 28

Malignant Hyperthermia Treatment

Answer 28

* Administer: * Dantrolene * Cold NS to promote internal cooling * Insulin +/- Dextrose to decrease potassium * Treat arrhythmias (No CCB – can decrease calcium influx and can interact with dantrolene to produce hyperkalemia and myocardial depression ) * Monitor and treat lab abnormalities

Question 29

Succinylcholine & Hyperkalemia

Answer 29

* Succinylcholine induced arrhythmias well documented * Avoid use in patients with * History of renal failure * Paralysis * Significant burn * Prolonged immobilization * Risk with undiagnosed myopathy

Question 30

Pancuronium

Answer 30

* Vagolytic effects * Tachycardia and hypertension * More than 90% of ICU patients will have increase in HR \> 10 bpm. * Limits use in pts who cannot tolerate increased heart rate * Hepatic or renal failure * Prolonged neuromuscular blocking effects

Question 32

Vecuronium

Answer 32

* Pancuronium analog, slightly more potent * Lacks vagolytic effects * Hepatic and/or renal failure * Decreased dose requirements * Accumulation of parent compound and metabolites * Longer duration of action in younger children due to increased Vd * Prolongedblockadeupondiscontinuation more common than with other agents

Question 33

Rocuronium

Answer 33

* Common for intubation when non-depolarizing agent is indicated * Rapid onset, approximately half of vecuronium * Laryngeal adductor paralysis is significantly slower than with succinylcholine * Minimal cardiovascular effects, although high doses may cause vagolysis * Potential accumulation in hepatic or renal failure

Question 34

Atracurium

Answer 34

**Pros** * No prolonged effect with renal or hepatic failure * Minimal cardiovascular adverse effects **Cons** * Histamine release at higher doses * Concern for seizures with metabolite * Hypothermia prolongs duration of action * Reduce dose by 50% * Inhaled anesthetics increase effects * Reduce dose by 33%

Question 35

Cis-atracurium

Answer 35

* R’-cis isomer of atracurium * Slower onset but 3-4 times more potent than atracurium * Increasingly used in place of atracurium * Less or no cardiovascular effects * Lesser tendency of mast cell degranulation * Not affected by renal or hepatic dysfunction * Faster recovery time compared to vecuronium

Question 36

Monitoring Sustained Blockade

Answer 36

* Train-of-four (twitch response) * Monitors degree of neuromuscular blockade * Assessment to find lowest possible dose to use * At least once every 24 hours * Ulnar nerve most common * 2-3 twitches generally adequate * Heart rate and blood pressure * Drug holidays * Intermittent discontinuation of continuous infusion neuromuscular blocking agents * When safe to do so * At least once every 24 hours * Lasting until spontaneous movement returns * Facilitates neurological examination * Allows assessment of analgesia and sedation level * Reduces total dose of agent being administered * Clinical observation * Movement of fingers and toes, breathing, coughing **Problems** * Difficult to perform in small children * Direct stimulation of muscle group * Dose-response curve varies by muscle group * Results may be variable depending on other factors * Peripheral edema * Hemodynamic status * Hydration * Acid-base derangements * Electrolyte disturbances

Question 38

NMBA Add'l Considerations

Answer 38

* Adequate sedation/analgesia prior to starting NMBA * Ocular lubricant to prevent permanent damage * DVT prophylaxis * **Reversal Agents** * Nondepolarizing antagonists (Acetylcholinesterase inhibitors) * Neostigmine * Pyridostigmine * Sugammadex * **No antagonist for succinylcholine**