Anaesthetic

General anesthetics

CNS drugs must be lipid soluble (cross the BBB) or be actively transported.

Drugs with decreased solubility in blood (eg, nitrous oxide [N₂O]) = rapid induction and recovery times.

Drugs with increased solubility in lipids (eg, isoflurane) = increased potency.

MAC = Minimum Alveolar Concentration (of inhaled anesthetic) required to prevent 50% of subjects from moving in response to noxious stimulus (eg, skin incision). Potency = 1/MAC.

Drug	CMRO₂	CBF	ICP	Anticonvulsant effect	Mechanism	Adverse effects / notes
Inhaled anesthetics	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ
Sevoflurane	Decrease	Increase at MAC 1.0	Increase at MAC 1.0	No	Mechanism unknown	Respiratory depression, decreased cough reflex; myocardial depression, decreased BP; increased cerebral blood flow (increased ICP), decreased metabolic rate; decreased skeletal and smooth muscle tone; postoperative nausea and vomiting; malignant hyperthermia
Desflurane	Decrease	Increase at MAC 1.0	Increase at MAC 1.0	No	Mechanism unknown	Same as above
Isoflurane	Decrease	Increase at MAC 1.0	Increase at MAC 1.0	No	Mechanism unknown	Same as above
N₂O	Increase	Increase	Increase	No	Mechanism unknown	Diffusion into and expansion of gas‑filled cavities (eg, pneumothorax); very low potency; muscle rigidity
Intravenous anesthetics	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ
Propofol	Decrease	Decrease	Decrease	Yes	Potentiates GABAA receptor; inhibits NMDA receptor	Respiratory depression, decreased BP; most commonly used IV agent for induction of anesthesia; may reduce CPP
Etomidate	Decrease	No effect	No effect	No	Potentiates GABAA receptor	Acute adrenal insufficiency; postoperative nausea and vomiting; hemodynamically neutral
Ketamine	Increase	Increase	Increase	No	Inhibits NMDA receptor	Sympathomimetic: increased BP, increased HR, bronchodilation; psychotomimetic: hallucinations, vivid dreams
Midazolam	No effect	No effect	No effect	Yes	ㅤ	ㅤ
Thiopental	Decrease	Decrease	Decrease	Yes	ㅤ	ㅤ
Other	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ	ㅤ
Succinylcholine	Increase (non-significant)	Increase (non-significant)	Increase	No	ㅤ	Secondary to increased muscle
Vercuronium	No effect	No effect	No effect	No	ㅤ	ㅤ
Optiates	Minimal decrease	Minimal decrease	Variable	No	ㅤ	ㅤ

Fentanyl decreases cerebral blood flow

Types of general anaesthetic agents

General

Anesthetic considerations in IOM

TIVA Propofol

Gaseous agents

Volatile anaesthetics

All volatile agents

Uncouple CMRO₂ and CBF.

Reduce cerebral metabolism and oxygen demand.
Dose-dependent cerebral vasodilatation and therefore ⬆️CBF and ⬆️ICP.

If want to use in the context of raised ICP do perform Hyperventilation to cause vasoconstriction
Halothane » enflurane > isoflurane > sevoflurane
Desflurane > isoflurane > sevoflurane

Response to CO2 is maintained

Sevoflurane

Volatile of choice

Enables faster recovery than isoflurane and causes less cerebral vasodilatation.
Does not increase CBF
Minimal effects on autoregulation

Nitrous oxide (N₂O)

Traditionally not used in Neurosurgery because

⬆️CMRO₂ ⬆️CBF and ⬆️ICP.
Absolutely contraindicated in pneumocephaly and procedures with high risk of air embolism.

Approximately 25% of patients have evidence of intracranial air 3 weeks after craniotomy
Tension pneumocephalus can occur if nitrous oxide anaesthesia is not discontinued prior to closure of the dura during surgery

N₂O is not recommended for at least 6 weeks after a procedure involving dural opening.

Intravenous anaesthetics

All IV induction agents (except ketamine)

Reduce ICP.
CMRO₂ and CBF change in parallel.

Options

Barbiturates

Mechanism

Inc. GABAA action → inc. duration of Cl− channel opening

Thiopental causes

Dose dependent ⬇️CMRO₂ and CBF until EEG becomes isoelectric (at high doses of 10 to 55 mg/kg).
CO2 reactivity and autoregulation are maintained,

MAP can decrease.

Prolonged infusions can result in electrolyte abnormalities and awakening can be slow.

Pentobarbital

Dosage

A loading dose of 10 mg/kg is administered over 30 minutes then 5 mg/kg per hour is administered over 3 hours. If systolic blood pressure drops by more than 10 mm Hg or the perfusion pressure falls below 60 mm Hg, the loading dose infusion should be slowed. A maintenance infusion of 1 to 3 mg/kg per hour is begun after loading is completed.
The infusion is titrated to burst suppression on the electroencephalogram and a serum level of 3 to 4 mg/dL. When checking for brain death, remember that the level of pentobarbital must be less than 10 μg/mL.

Methohexitone cause

Not use in neuro

Epileptiform changes on EEG

Propofol

Mechanism

Potentiates GABAa Receptor (Main)

Propofol acts by binding to the GABA receptors and increasing the duration of their action. This leads to prolonged opening of the central chloride channels that causes hyperpolarization of post-synaptic neurons, thereby making it difficult for an action potential to fire.

Inhibits NMDA receptor

Similar effects to thiopental.

Less liable to cause CNS depression and awakening is more rapid.

Pros

Does not impair autoregulation
Has anti-convulsant effects.
Less likely to cause Post op NV than volatiles
Can be used throughout the case.

Useful if the case involves transfer to other areas (e.g. stereotactic biopsy).

Cons

As propofol reduces CBF, hyperventilation should be avoided as this can result in very low CBF.
Propofol infusion syndrome (PIS)

A rare
Potentially fatal condition
Due to high doses and long-term use of propofol.
Mechanism

Propofol hinders the uptake and usage of FFAs and mitochondrial activity at molecular and cellular levels
Propofol impairs the electron transport chain or the respiratory chain function (mitochondria dysfunction), which in turn leads to the collapse of the body's metabolic activities

Dose

More than 4mg/kg/hr

Causes

Present like worsening sepsis

Metabolic acidosis
Hypotension

Cardiac failure: Refractory bradycardia
Rhabdomyolysis
Death

Should not be administered for more than 4 to 5 days.
Extreme caution must be taken when using doses greater than 5 mg/kg/h or when usage of any dose exceeds 48 hours in critically ill adults
Paediatric more at risk

Singh 2022: <3 yrs of age experienced severe neurodevelopmental damage, leading to behavioural changes and abnormalities as they grew up.

Inc. risk in

Critically ill patients receiving high-dose propofol (> 5 mg/kg/h), steroids, and elevated catecholamine levels (endogenous or exogenous).

Etomidate

Mechanism

Potentiates GABAa Receptor

Pros

Reduces CMRO₂ with a coupled reduction in CBF.
BP is well maintained.
CO2 reactivity and autoregulation maintained.

Cons

It has a high incidence of excitatory phenomena but without EEG changes.

Benzodiazepines

Mechanism

Potentiates GABAa Receptor

Pros

Dose dependent ⬇️CMRO₂ coupled with ⬇️CBF (less than with thiopental and it shows a ceiling effect).
CO2 reactivity and autoregulation are maintained.

Ketamine

Mechanism

Inhibits NMDA receptor
NMDA receptor signalling is involved in neuronal death,

NMDA antagonists could be neuroprotective.

Traditionally ketamine is not used in neuro as it was thought to ⬆️CMRO₂ ⬆️CBF and ⬆️ICP

Data has been reassessed recently. The original studies are flawed and recent evidence suggests

ICP and CBF are unchanged during ketamine anaesthesia.

Ketamine results in a better CPP with a reduced need for vasopressors.

Compared with opiates

Dexmedetomidine

Mechanism

α2-adrenoreceptor agonist

Pros

Dose-dependent

Sedation
Anxiolysis
Analgesia

Minimal effects on ventilation.

Dexmedetomidine is finding a useful role in awake craniotomy where it can be used as the sole agent and is associated with excellent operating conditions.

Potent vasoconstrictors (venous > arteriolar).

As the venous compartment comprises most of cerebral blood volume theoretically α2-agonists could ⬇️ ICP without marked ⬆️ in arteriolar cerebrovascular resistance.
The response to CO2 is maintained.

Anti-convulsant

Cons

Response to hypoxia is blunted but present.
At awakening/extubation there are often episodes of hypertension.

Can be blunted by opiates but this carries the risk of respiratory depression.

⬇️ CBF without ⬇️ CMRO₂.

Limits adequate oxygenation of brain tissue already at risk for ischaemic injury.

A healthy volunteer study suggests CBF and CMRO₂ ⬇️ together so further work is required.
The effect on autoregulation has also not been established.

Adjunctions

Opioids

Minimal direct effect on CMRO₂ and CBF.

May cause ⬆️pCO2 which will cause ⬆️CBF.

No effect on ICP if MAP is maintained.

This is unlikely to be clinically significant if detrimental haemodynamic changes and blood gas changes avoided.

Remifentanil

Drug of choice in NSx
Pros

Rapid changes in response to changing surgical stimulation while still allowing rapid wake-up.
Suppress stress response and hyperglycaemia.

A recent retrospective study

In craniotomy patients (for tumour and aneurysm clipping) remifentanil vs fentanyl.
Suggested

Shorter hospital stay
Lower in-hospital mortality

Neuromuscular blockade

Pros

Most non-depolarizing muscle relaxants have little effect on CBF or CMRO₂.

Cons

Marked histamine release (e.g. tubocurarine) can cause ⬆️CBV / ICP due to vasodilatation.
Modern relaxants are all clean although rocuronium has some vagolytic activity, and atracurium can cause histamine release especially with high doses.

Vecuronium

Agent of choice.

Suxamethonium

Causes ⬆️ICP (transient effect) but this is not a reason to avoid suxamethonium if it is required.
However, it can cause ⬆️K+. This is relevant in spinal cord injury or prolonged bed rest.

Lidocaine

This can be used to obtund rise in ICP at intubation (1 - 1.5 mg/kg). It causes depression of CMRO₂ and stabilises cell membranes. It is used less frequently since the introduction of remifentanil.

Sedatives and analgesic

Name	Category	Onset	Duration	Dose	Comments
Propofol	GABA agonist, NMDA antagonist	1 min	15 min	1–3 mg/kg/hr (max 5 mg/kg/hr)	Sedation; mild analgesia; respiratory depression; hypotension; propofol infusion syndrome; hypertriglyceridemia
Midazolam	Benzodiazepine binding site on GABA‑A receptor	5 min	4 h	0.02–0.1 mg/kg/h	Drug of choice for short‑term sedation; lacks analgesic effect; anterograde amnesia
Flumazenil	Benzodiazepine antagonist	1–2 min	50 min	0.2 mg × 1–5 doses (max 3 mg/hr)	Half‑life shorter than many benzodiazepines
Morphine	Hydrophilic opioid	3 min	1–2 h	0.1 mg/kg IV q 1–2 h; PCA: basal 0.5–1.0 mg/hr, bolus 0.5–1.0 mg q 10 min	Hydrophilic opioid
Fentanyl	Opioid	1 min	30 min	0.1 mcg/kg/min (max 300 mcg/h); PCA: basal 25–50 mcg/h, bolus 10–50 mcg q 10 min	100 × potency of morphine
Sufentanyl	Opioid	Immediate	10 min	0.01 mcg/kg/min	1000 × potency of morphine
Remifentanil	Opioid	Immediate	10 min	0.1 mcg/kg/min	Selective mu‑receptor agonist; potency like fentanyl
Thiopental	Barbiturate	20–30 sec	20 min	1.5–3.5 mg/kg IV bolus; 0.3 mg/kg/min continuous	Respiratory depression; myocardial depression; hypotension; lowers ICP
Pentobarbital	Barbiturate	15 min	Variable (3–4 h); half‑life often 48 h	1) Loading: 10 mg/kg IV over 30 min; 2) Then 5 mg/kg/hr × 3 h; 3) Then 1 mg/kg/hr	Indication: barbiturate coma; side effects: respiratory depression, hypotension; burst suppression around serum 50 mcg/ml; level for brain death: <10 mcg/ml
Dexmedetomidine	α₂ agonist	5 min	2–6 h	1) Loading: 0.1 mcg/kg IV for 10 min; 2) Then 0.2–0.7 mcg/kg/h	Sedative and analgesic; no amnesia; no respiratory depression; hypotension and bradycardia
Haloperidol	Neuroleptic butyrophenone	10 min	12 h	1–5 mg increments IV q h until sedation; then 25% of effective dose IV q 6 h (max 300 mg/24 h)	Contraindications: Parkinson’s disease, pregnancy, seizures; does not cause respiratory depression; caution: extrapyramidal symptoms even after single use, QT prolongation
Ketamine	NMDA antagonist	10 min	1 h	1) 0.5–2.0 mg/kg IV bolus; 2) Then 0.1–0.5 mg/min IV continuous	Anesthetic, hypnotic, analgesic, amnestic; caution: ICP increase, seizure risk
Etomidate	GABA‑A modulator and agonist	30 sec	5 min	0.3 mg/kg IV bolus	Sedative; reduces ICP; caution: prolonged use suppresses corticosteroid synthesis and may increase mortality
Diphenhydramine	H1 receptor antagonist	1–5 min	6–8 h	25–50 mg IV q 6–8 h	Sedation; used to treat extrapyramidal symptoms of neuroleptics, pruritus, and as antitussive

Remifentanyl: Ondine's curse

Loss of autonomic breath control, while voluntary respiration remains intact

The nymph Ondine was an immortal water spirit who became human after falling in love for a man, marrying him, and having a baby. In one of the versions of the tale, when she caught her husband sleeping with another woman, she cursed him to remain awake in order to control his own breathing.