Analgesia and sedation

Cite this article as:
Anders, M. Analgesia and sedation, Don't Forget the Bubbles, 2013. Available at:
http://doi.org/10.31440/DFTB.3867

Intravenous anaesthetic agents (see table):

  • classified as barbiturates (thiopentone) and non-barbiturates (propofol and ketamine)
  • thiopentone use is largely limited to induction in status epilepticus and for treatment of raised ICP; it has no analgesic properties and is in fact anti-analgesic at sedative doses
  • propofol is suitable for induction (bolus) and maintenance of sedation/anaesthesia (infusion); it is suitable for discrete painful procedures but has only minimal analgesic properties at sedative doses and so must be combined with a suitable analgesic
  • propofol is a direct myocardial depressant and so should be used in caution in patients in (or at risk of) low cardiac-output syndrome (LCOS). It obtunds the normal baroreceptor reflex and so causes a decrease in blood pressure and heart rate
  • ketamine is a dissociative anaesthetic that is also a potent analgesic; it is suitable for discrete painful procedures but increases respiratory secretions and is complicated by psychadelic phenomena (midazolam is suitable to treat or obviate ketamine’s emergence phenomena but will prolong recovery time)
  • combined ketamine and propofol in a ratio ranging from 1:1 to 1:4 (ketofol) is becoming a popular awake-sedative to facilitate medical procedures

Narcotics (see table):

  • morphine, fentanyl and methadone are effective analgesics and sedatives; oxycodone is also a popular analgesic but is less sedating
  • levels of sedation, analgesia and respiratory depression do not correlate (patients may be well sedated and have respiratory depression but not have adequate analgesia)
  • morphine is not a suitable narcotic for discrete painful procedures due to its long and unpredictable effect site equilibration time (fentanyl is more appropriate)
  • fentanyl is often used epidurally and results in significant systemic absorption of drug and resulting side effects
  • sufentanil, alfentanil and remifentanil are phenylpiperidine narcotics used to provide the analgesic component of general anaesthesia. They are very infrequently used in PICU
  • all have predictable effects which include respiratory depression, cough suppression, sedation, meiosis, biliary spasm, constipation, nausea and vomiting, urinary retention and cutaneous flushing (especially about the face)

Benzodiazepines (see table):

  • midazolam and diazepam are effective sedative agents commonly used in PICU
  • they are direct myocardial depressants via blockade of voltage-gated calcium channels (use carefully in patients with LCOS)
  • midazolam is also used to acutely treat seizures in bolus doses and in infusions (up to 1 mg/kg/hour)
  • they are less likely to produce withdrawal syndromes than barbiturates and narcotics (but no analgesic effect)

Alpha2 agonists (see table):

  • clonidine and dexmedetomidine are sedative/anaesthetic agents employed as sedatives in PICU; they also treat symptoms of drug withdrawal
  • their main advantage is lack of respiratory depression which allows quicker weaning of mechanical ventilation
  • they obtund central (brain and spinal cord) sympathetic outflow resulting in negative inotropy and chronotropy and so should not be combined with direct myocardial depressants (benzodiazepines, propofol etc.) in patients at risk of (or in established) LCOS.
  • they cannot be bloused as this can lead to transient alpha1-agonism and severe hypertension

Local anaesthetics:

  • local anaesthetics block voltage gated sodium channels and so prevent conduction along central and peripheral nerve pathways
  • lignocaine is commonly locally infiltrated for short painful procedures (e.g. suturing, insertion of chest drains etc)
  • bupivacaine and ropivacaine are generally used for regional blocks and neuraxial infusions
  • levobupivacaine (S-bupivacaine) and ropivacaine are enantiopure preparations. Cardiotoxicity is less
  • 0.5% solutions contain 5 mg/mL; 1% solutions contain 10 mg/mL; 2% solutions contain 20 mg/mL etc. (1% = 10 mg/ml)
  • onset of effect is related to the pKa of the drug; potency is related to lipid solubility; and duration of action is related to protein binding
  • systemic absorption of local anaesthetics depends on site of infiltration: intercostal > subarachnoid > epidural > brachial plexus > femoral > subcutaneous
  • vasoconstrictors (adrenaline) slow systemic absorption and increase the maximum safe dose
  • EMLA is a mixture of 2.5% lignocaine and 2.5% prilocaine used for topical anaesthesia prior to cannulation/incision; prilocaine can inducemMethaemoglobinaemia and application to mucous membranes will result in rapid systemic absorption of drug
  • CNS toxicity manifests first as excitatory phenomena (circumoral tingling, tinnitus, dizziness and tremors/seizures) followed by CNS depression (unconsciousness, apnoea and coma)
  • CVS toxicity manifests as systemic hypotension, myocardial depression, ventricular arrhythmias and cardiovascular collapse
  • treatment of local anaesthetic toxicity is by supportive therapy (airway management, treatment of seizures with benzodiazepines, fluids +/- inotropes/vascoconstrictors) and administration of 20% lipid emulsion (Intralipid) if in cardiac arrest: 1.5 mL/kg over 1 minute followed by an infusion of 0.25-0.5 ml/kg/min; repeat bolus doses every 5 minutes during CPR

Non-steroidal anti-inflammatory drugs (NSAIDs):

  • classified as specific (COX-2 e.g. parecoxib) or non-specific (COX-1 and COX-2 e.g. ibuprofen)
  • adverse GI effects are due to decreased mucosal blood flow and decreased secretion of mucus and bicarbonate
  • platelet thromboxane A2 is produced from prostaglandins and so NSAIDs impair platelet aggregation
  • prostaglandins are vasodilators involved in physiologic control of vasomotor tone (especially in the kidneys) and their inhibition leads to unopposed vasoconstriction
  • inhibition of prostaglandin synthesis leads to shunting of arachnidonic acid to lypoxygenase which is a bronchoconstrictor
  • specific COX-2 inhibitors are considered to lack effects on platelets and the GIT but will still affect vasomotor tone
  • their use in PICU needs careful consideration due to their wide range of potential side effects
  • paracetamol is generally considered a (central) COX-3 inhibitor; it also acts peripherally by inhibiting bradykinin-chemoreceptor associated pain impulse generation

Other (see table):

  • chloral hydrate is a prodrug that produces the halogenated alcohol chloroethanol; its mechanism is poorly understood but probably acts in a similar way to the volatile halogenated gases via central GABA-A receptors
  • first-generation antihistamines (e.g. promethazine, cyclizine etc.) are also effective sedatives by virtue of their anticholinergic properties; they are generally only used when specific antihistaminergic and/or anticholinergic properties are desired (e.g. antisialogogue for secretions, antitussive)Table: intravenous anesthetic agents
    Thiopentone Propofol Ketamine
    Type/class Barbiturate Isopropylphenol Phencyclidine
    Mechanism GABAA & glycine agonist GABAA & glycine direct agonist and central nicotinic antagonist(Possible 5HT3 blockade) NMDA non-competitive antagonist & blocks central catecholamine reuptake
    Oral bioavailability 25%
    Oral dose n/a n/a 5mg/kg
    IV Bolus 2-7mg/kg 1.5-2.5mg/kg 0.25-0.5mg/kg (analgesia)1-5mg/kg (GA)
    IV Infusion 1-5mg/kg/hour 1-4mg/kg/hour (sedation)5-15mg/kg/hour (GA) 10-40mcg/kg/hour
    Onset time IV < 30seconds < 30seconds 30-60seconds
    ESET 30 seconds < 30 seconds 60seconds
    pKa 7.6 11 7.5
    UNionised fraction 60% > 99% 45%
    Protein binding 80% 99% 25%
    Vd 2.5L/kg 4L/kg 3L/kg
    Clearance 3mL/min/kg 50mL/min/kg 15mL/min/kg
    t ½-dist 8minutes 4 minutes 12minutes
    t ½-elim 12hours 30-60minutes 2-3hours
    Metabolism Hepatic (may become zero-order with prolonged infusion)Some active metabolites Hepatic (CYP2C9 & 2B6) & extrahepatic (site/s unknown)Inactive metabolites HepaticActive metabolites
    Excretion Urine Urine Urine
    Hepatic failure No effect No effect Decreased clearance
    Renal failure Active metabolites will accumulate No effect No effect
    Pros Rapid onsetAnticonvulsantCan produce isoelectric EEG (maximal decreased cerebral metabolic O2 demand)

    Rapid onset & titratabilityBronchodilatorWill obtund airway reflexesAnticonvulsant

    Antiemetic & antipruritic properties at low doses

    Can produce isoelectric EEG

    Mild analgesic properties

    Stable CSHT (<40mins even after >8 hrs infusion)

    Intense analgesia at low doseFavourable haemodynamic profile due to increased central sympathetic outflowBronchodilatorPrevents & treats opioid tolerance

    No respiratory depression/apnoea

    Cons

    Resp depression/apnoeaAntanalgesicCan produce paradoxical excitementWill accumulate with prolonged infusion (long CSHT)

    Tolerance & withdrawal are a problem

    Resp depression/apnoeaMyocardial depressantCan cause a refractory bradycardia (need β-agonist)Rarely causes propofol-infusion syndrome

    Formulation contains soybean oil & egg lecithin

    Myocardial depressantEmergence delirium (especially in older patients – consider midazolam)Increased secretions (consider glycopyrrolate)BrainZ/BIS inaccurate
    Other points ↓BP (↓SVR)↑HR (reflex)Won’t obtund airway reflexesRacaemic formulation ↓BP(↓SVR & ↓CO)↓HR (obtunded baroreceptor reflex) EEG dissociation between thalamus & cortexWon’t obtund airway reflexesTypical induction agent in asthma & sepsis

    Table: benzodiazepines

    Midazolam Diazepam Flumazenil
    Type/class BDZ BDZ BDZ
    Mechanism GABAA receptor indirect-agonist GABAA receptor indirect-agonist BDZ receptor competitive antagonist
    Oral bioavail 40% 95% 25%
    Oral dose 0.5mg/kg up to 20mg 0.05-0.2mg/kg n/a
    IV Bolus 0.05-0.2mg/kgup to 5mg/dose 0.05-0.4mg/kgup to 10mg/dose 8-15mcg/kgup to 200mcg/dose
    IV Infusion 10-100mcg/kg/hour n/a 2-10mcg/kg/hour
    Onset time IV 1-2mins 1-2mins 1-2mins
    ESET 5mins 5mins 5-10mins
    pKa 6.2 3.3 1.8
    % UNionised 90% >99% >99%
    Protein binding 95% 95% 50%
    Vd 1.5L/kg 1.5L/kg 0.5L/kg
    Clearance 10mL/min/kg 1mL/min/kg 20mL/min/kg
    t ½-dist 5mins 5mins 5mins
    t ½-elim 1-4 hours 24-36 hours 60mins
    Metabolism Hepatic (CYP3A4)Active metabolites Hepatic (CYP3A4/5)Active metabolites HepaticNo active metabolites
    Excretion Urine Urine 90% urine
    10% bile
    Hepatic failure Decreased clearance Decreased clearance Decreased clearance
    Renal failure Active metabolite may accumulate Active metabolites will accumulate No effect
    Pros Sedation, amnesia & anxiolysisAnticonvulsantDecreases cerebral metabolic O2 demand Effective orallySedation, amnesia & anxiolysisAnticonvulsantDecreases cerebral metabolic O2 demand Allows specific reversal of BDZ component of resp depression and / or polypharmacy overdoseRarely causes acute anxiety &/or agitation
    Cons Myocardial depressantResp depressionCan cause paradoxical excitement Myocardial depressantResp depressionCan cause paradoxical excitementPainful on injection Can precipitate seizures in epileptics on maintenance BDZs
    Other points ↓BP(↓SVR & ↓CO)[↑HR (reflex)] ↓BP(↓SVR & ↓CO)[HR (reflex)] Is probably a partial agonist

    Table: narcotics

    Morphine Fentanyl Methadone Naloxone
    Type/class Phenanthrene opiate Phenylpiperidine opioid Diphenyl-propylamine opioid Phenanthrene opioid
    Mechanism Non-specific OR agonist MOR agonist with some mild activity at KORs MOR agonist (L-isomer) & NMDA antagonist (D-isomer) Non-specific OR competitive antagonist
    Oral Bioavail. 30% n/a 75% <1%
    Oral dose 0.2-0.5mg/kg q4-6h n/a 0.1-0.2mg/kg q6-24h n/a
    IV bolus dose 0.05-0.2mg/kg 1-10mcg/kg 0.1mg/kg 10mcg/kg
    IV infusion 5-100 mcg/kg/hr 1-10 mcg/kg/hr n/a 10 mcg/kg/hr
    Onset time IV 15-30mins 1-2mins 10-20mins 1-2mins
    ESET 30-90mins 3-6mins 10-20mins 5-10mins
    pKa 8.0 8.4 9.2 7.9
    % UNionised 25% 10% 1% 30%
    Protein binding 35% 85% 90% 50%
    Vd 3L/kg 4L/kg 3.5L/kg 0.2L/kg
    Clearance 25
    mL/min/kg
    10-20 mL/min/kg 1-3 mL/min/kg 30 mL/min/kg
    t ½-dist 2-3mins 1-2mins 1-2 mins
    t ½-elim 2-4hours 2-4hours 18-36 hours 45-60mins
    Metabolism Hepatic & renal10% to active M6G Hepatic (CYP3A4)No active metabolites Hepatic (CYP3A4)No active metabolites HepaticNo active metabolite
    Excretion 90% urine
    10% bile
    90% bile
    10% urine
    50% urine
    50% bile
    Urine
    Hepatic failure May precipitate encephalopathy No effect reduced clearance reduced clearance
    Renal failure Morphine & M6G will accumulate No effect No effect No effect
    Pros No myocardial depressionSedation & euphoriaAntitussive No myocardial depressionSedation & euphoriaAntitussiveNo histamine release Effective enterallyHelpful in withdrawal syndromesSuitable for chronic pain (NMDA actions) Acts rapidly & is titratableAntiinflammatory properties
    Cons

    Respiratory depressionHistamine releaseNausea & vomitingPruritis

    Urinary retention

    Constipation

    Respiratory depressionNausea & vomitingPruritisUrinary retention

    Constipation

    Prolonged CSHT

    Respiratory depressionNausea & vomitingConstipationHistamine release possible but rare

    Prolongs QT interval

    Can precipitate acute withdrawalRarely may cause pulmonary oedema & arrhythmiaUsually needs repeat dosing
    Other points Meiosis↓ HR & BP (↓SVR) Meiosis↓ HR & BP (↓SVR) Meiosis↓ HR & BP (↓SVR) 1mcg/kg effective for narcotic pruritisBP may rise or fall

    Table: alpha2 agonists

    Clonidine Dexmedetomidine
    Type/class Synthetic imidazoline Synthetic imidazoline
    Mechanism α2 adrenoceptor partial agonist α2 adrenoceptor agonist
    Oral bioavail >99% 15%
    Oral dose 1-5mcg/kg up to 300mcg n/a
    IV bolus dose 1-5mcg/kg 1-2mcg/kg
    IV infusion dose 0.5-2mcg/kg/hour 0.2-0.7mcg/kg/hour (sedation)5-10mcg/kg/hour (GA)
    Onset time IV 10-30minutes 10minutes
    ESET 20-30minutes 10-20minutes
    pKa 8.0 7.1
    UNionised % 20% 50%
    Protein binding 20% 95%
    Vd 2L/kg 1.5L/kg
    Clearance 5mL/min/kg 10mL/min/kg
    t ½-dist 30minutes 10 minutes
    t ½-elim 12-18hours 2-3hours
    Metabolism 50% hepatic50% excreted unchanged HepaticNo active metabolites
    Excretion Urine (50% unchanged) Urine
    Hepatic failure No effect Decreased clearance
    Renal failure Active drug will accumulate No effect
    Pros

    Effective sedativeNo respiratory depressionSpinal-mediated analgesia (very effective neuraxially)Known to be useful in opioid & alcohol withdrawal syndromes

    Raises the shivering threshold

    Prolongs regional block by local anaesthetics

    Effective sedativeNo respiratory depressionSpinal-mediated analgesiaUseful for symptoms of opioid withdrawal

    Raises shivering threshold

    Prolongs regional block by local anaesthetics

    Short(er) half time

    Cons

    Rapid IV administration will agonise α1 receptors (↑BP)Negative inotropy & chronotropyDry mouthRebound hypertension can occur (worse if patient is on a TCA or β-blocker)

    Long half time

    Rapid IV administration will agonise α1 receptors (↑BP)Negative inotropy & chronotropyDry mouthCannot be used neuraxially due to glycine in preparation
    Other points ↓HR & ↓BP↓CODry mouth may be used therapeutically if secretions are an issue ↓HR & ↓BP↓CODry mouth may be used therapeutically if secretions are an issue

    Table: others

    Chloral hydrate Promethazine
    Type/class Halogenated alcohol Phenothiazine
    Mechanism Prodrug – below data is for trichloroethanol (active drug)Probably a GABAA agonist H1 receptor antagonist & anticholinergic (antimuscurinic)
    Oral bioavail >99% 25%
    Oral dose 10-100mg/kg 0.25-1.5mg/kg
    IV bolus dose n/a 0.25-1.5mg/kg
    IV infusion dose n/a n/a
    Onset time IV 15minutes (oral) 30-60minutes
    ESET 30-60minutes (oral) 1-3hours
    pKa 12.7 9.1
    UNionised % >99% <1%
    Protein binding 50% 80%
    Vd 1L/kg 7L/kg
    Clearance not known 15mL/min/kg
    t ½-dist n/a 1-2hours
    t ½-elim 4-8hours 12hours
    Metabolism HepaticMetabolites of trichloro-ethanol are inactive Hepatic (CYP2D6)Inactive metabolites
    Excretion Urine Urine
    Hepatic failure Decreased clearance Decreased clearance
    Renal failure No effect No effect
    Pros

    Effective sedative & anxiolyticRapid onset following enteral administrationMild anticonvulsantRelatively wide therapeutic index

    Minimal interference with REM-sleep

    Effective antihistamine & antiemetic at low dosesEffective sedative/hypnotic at high dosesAntitussiveEffective in motion sickness

    Useful in allergic pruritis but not opioid induced pruritis

    Respiratory depression is rare

    Cons

    Respiratory depression in high dosesIrritant to GI mucosaArrhythmias in high dosesTrigger for porphyria

    Patients can develop tolerance & withdrawal

    Anticholinergic effects (dry mouth, blurred vision, urinary retention etc)Central anticholinergic syndrome in overdoseProlonged QT-interval & AV-blockParadoxical excitement may occur
    Other points ↓BP (↓SVR)↑HR (reflex)Actual half time of chloral hydrate is minutes (metabolised by esterases) [↑HR & ↑BP]Antidopaminergic propertiesLocal anaesthetic properties

    All Marc’s PICU cardiology FOAM can be found on PICU Doctor and can be downloaded as a handy app for free on iPhone or AndroidA list of contributors can be seen here.

Author: Marc Anders Marc Anders is a paediatric intensivist.

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