An amide anaesthetic structurally similar to bupivacaine, with similar potency and duration as bupivacaine but less cardiotoxicity (Fig. 11.2). This may be because it is manufactured in the S (–) form, whereas bupivacaine exists in the racemic (RS) form. The sensory block is similar to that provided by bupivacaine but the motor block is slower in onset, less intense and shorter in duration. It is an effective vasoconstrictor (bupivacaine vasodilates) and has no detrimental effect on placental blood flow. Cardiotoxicity and CNS symptoms occur at higher doses compared with bupivacaine.

Figure 11.2 Ropivacaine and bupivacaine.

Maximum recommended doses

Table 11.2 Maximum recommended doses of some common local anaesthetics

	Plain	With adrenaline
Lidocaine	3 mg/kg	7 mg/kg
Bupivacaine	2 mg/kg	2 mg/kg
Prilocaine	5 mg/kg	8 mg/kg
Cocaine	2 mg/kg
Tetracaine	1.5 mg/kg

Guidelines for the Management of Severe Local Anaesthetic Toxicity

Association of Anaesthetists of Great Britain and Ireland 2007

Signs of severe toxicity:

• Sudden loss of consciousness, with or without tonic-clonic convulsions

• Cardiovascular collapse: sinus bradycardia, conduction blocks, asystole and ventricular tachyarrhythmias may all occur

• Local anaesthetic (LA) toxicity may occur some time after the initial injection.

Immediate management:

• Stop injecting the LA

• Call for help

• Maintain the airway and, if necessary, secure it with a tracheal tube

• Give 100% oxygen and ensure adequate lung ventilation (hyperventilation may help by increasing pH in the presence of metabolic acidosis)

• Confirm or establish intravenous access

• Control seizures: give a benzodiazepine, thiopentone or propofol in small incremental doses

• Assess cardiovascular status throughout.

Management of cardiac arrest associated with LA injection

• Start cardiopulmonary resuscitation (CPR) using standard protocols

• Manage arrhythmias using the same protocols, recognizing that they may be very refractory to treatment

• Prolonged resuscitation may be necessary; it may be appropriate to consider other options, e.g. cardiopulmonary bypass or treatment with lipid emulsion.

Treatment of cardiac arrest with lipid emulsion: (approximate doses for a 70-kg patient)

• Give an intravenous bolus injection of Intralipid 20% 1.5 mL.kg⁻¹ over 1 min (give a bolus of 100 mL)

• Continue CPR

• Start an intravenous infusion of Intralipid 20% at 0.25 mL.kg⁻¹.min⁻¹ (give at a rate of 400 mL over 20 min)

• Repeat the bolus injection twice at 5 min intervals if an adequate circulation has not been restored (give two further boluses of 100 mL at 5 min intervals)

• After another 5 min, increase the rate to 0.5 mL.kg⁻¹.min⁻¹ if an adequate circulation has not been restored (give at a rate of 400 mL over 10 min)

• Continue infusion until a stable and adequate circulation has been restored.

Remember:

• Continue CPR throughout treatment with lipid emulsion.

• Recovery from LA-induced cardiac arrest may take >1 h.

• Propofol is not a suitable substitute for Intralipid.

Follow-up action:

• Report cases from the UK to the National Patient Safety Agency (via www.npsa.nhs.uk). Whether or not lipid emulsion is administered, please also report cases to the LipidRescue site: www.lipidrescue.org

• If possible, take blood samples into a plain tube and a heparinized tube before and after lipid emulsion administration and at 1 h intervals afterwards. Ask your laboratory to measure LA and triglyceride levels (these have not yet been reported in a human case of LA intoxication treated with lipid).

Bibliography

Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe local anaesthetic toxicity. Reproduced with the kind permission of the Association of anaesthetists of Great Britain and Ireland, 2007.

Heavener J.E. Local anesthetics. Curr Opin Anaesth. 2007;20:336-342.

Leskiw U., Weinberg G.L. Lipid resuscitation for local anesthetic toxicity: is it really lifesaving? Curr Opin Anesth. 2009;22:667-671.

McLeod G.A., Burke D. Levobupivacaine. Anaesthesia. 2001;56:331-341.

Picard J., Harrop-Griffith W. Lipid emulsion to treat drug overdose: past, present and future. Anaesthesia. 2009;64:119-121.

Whiteside J.B., Wildsmith J.A.W. Developments in local anaesthetic drugs. Br J Anaesth. 2001;87:27-35.

Neuromuscular Blockade

Neuromuscular blocking drugs

Tubocurarine (dTC). Long-acting non-depolarizing quaternary ammonium compound. The first neuromuscular blocker was used clinically by Griffiths and Johnson in Montreal in 1942. Prepared from the plant Chondrodendron tomentosum; 50% protein bound. Hypotension secondary to histamine release and also SNS > PNS blockade, causing bradycardia. Minimal metabolism. Excreted in bile and urine.

Gallamine. Blocks vagus and acts as β₁-agonist to cause tachycardia and hypertension. Crosses placenta, so contraindicated in obstetrics. Renal excretion 85%; therefore avoid in renal failure.

Benzylisoquinoliniums

Doxacurium. Long-acting non-depolarizing drug with no cardiovascular side-effects; 25% recovery of twitch height in 2–3 h. Excreted by the kidney unchanged, with minor pathway via the liver. Therefore prolonged action in hepatic and renal failure.

Mivacurium. Short-acting non-depolarizing drug. Consists of three stereo-isomers, two with short elimination half-lives of 1.8–1.9 min, the third with an elimination half-life of 53 min but only one-tenth as potent. Hydrolysed by plasma cholinesterases to inactive metabolites. Duration of action prolonged by same factors that affect suxamethonium, e.g. atypical enzymes. Weak ability to release histamine.

Atracurium. Intermediate-acting non-depolarizing drug. Minimal cardiovascular effects. Amount of histamine release is proportional to the rate of injection. Spontaneous degradation by ester hydrolysis and Hofmann degradation. Breakdown product of laudanosine is known to cause cerebral irritation which may accumulate to significant levels when using prolonged infusions, e.g. ITU.

Cisatracurium. Purified form (1R-cis, 1R′-cis isomer) of one of the 10 stereoisomers of atracurium, accounting for about 15% of the racemic mixture. Intermediate-acting non-depolarizing drug. It is more potent and has a slightly longer duration of action than atracurium. It provides greater cardiovascular stability because it lacks histamine-releasing effects. Mostly broken down by Hofmann degradation to form laudanosine, with a small amount removed by the liver and kidney. Plasma esterases do not appear to hydrolyse cisatracurium directly. Hepatic or renal impairment have little pharmacokinetic effect.

Steroid derivatives

Pancuronium. Long-acting non-depolarizing drug; 80% protein bound. Deacetylated by liver to three inactive metabolites: 75% excreted in urine, 25% via bile. Indirect SNS effects (via release of noradrenaline from nerve endings) to cause ↑ CO, ↑ HR and ↑ BP. Potentiated by its additional vagal blockade. Minimal histamine release.

Vecuronium. Intermediate-acting non-depolarizing drug. No cardiovascular side-effects. Safe in liver failure. No histamine release. 60% eliminated in bile, half of which is broken down to the 3 OH-metabolite.

Pipecuronium. Long-acting non-depolarizing drug with no cardiovascular side-effects. Excreted by the kidney unchanged with minor pathway via the liver. Therefore prolonged in hepatic and renal failure. No histamine release.

Rocuronium. Intermediate-acting non-depolarizing drug. Neuromuscular blocking drugs of low potency are thought to have a faster onset of action because of the higher concentration gradient between plasma and postsynaptic nicotinic receptor (Bowman 1988). Similar kinetics to vecuronium but with faster biphasic onset (80% of block within 60 s followed by remainder over 2–3 min). Vagolytic action may cause 10–12% increase in HR. Does not cause histamine release. Not metabolized, and excreted unchanged in urine and bile. Prolonged action in liver failure but not in renal failure. Rocuronium 1.0 mg/kg can be used as an alternative to suxamethonium 1.0 mg/kg for rapid sequence induction provided there is no anticipated difficulty in intubation. The clinical duration of this dose of rocuronium is, however, 60 min. Classed as intermediate in its risk of causing anaphylaxis.

Table 11.3 Short-acting non-depolarizing neuromuscular blocking drugs

Table 11.4 Long-acting non-depolarizing neuromuscular blocking drugs

Priming

Priming accelerates onset of block by ≈︀30 s. Use dose of 20% ED₉₅, pre-oxygenate and keep priming interval <2 min. Also accelerate onset of block by using large (2–3 times ED₉₅) single doses of non-depolarizer, e.g. increasing dose of vecuronium from 0.1 to 0.4 mg/kg speeds onset from 3.5 to 1.5 min.

Suxamethonium

Stimulates all sympathetic and parasympathetic ganglia, cholinergic autonomic receptors, muscarinic receptors in the sinus node of the heart and nicotine receptors. In low doses, causes negative inotropic and chronotropic effects, attenuated by atropine.

Side-effects include:

• masseter muscle rigidity and malignant hyperthermia

• increased intraocular pressure

• increased intragastric pressure but increased lower oesophageal sphincter pressure

• increased intracerebral pressure

• myalgia and muscle damage

• anaphylactic reactions

• hyperkalaemia – raises plasma K⁺ by 0.5–0.8 mmol, particularly in burns and renal failure

• bradycardia, particularly with second doses in neonates

• dual block.

Metabolized by plasma cholinesterase (t_½ = 2–4 min). Decreased plasma cholinesterase with congenital and acquired conditions.

Congenital. Several genes control the structure of plasma cholinesterase (Table 11.5). Normal homozygote genetic structure is E1^U, E1^U. Common abnormal variants are:

• atypical gene E1^a

• fluoride gene E1^f

• silent gene E1^s.

Table 11.5 Common genotypes of plasma cholinesterase

Commonest abnormality is the heterozygous state for the atypical gene (E1^U, E1^a) present in 4% of the Caucasian population. This results in prolongation of neuromuscular blockade for ≈︀30 min. Heterozygous forms of the other abnormal genes result in prolongation of neuromuscular blockade for >3 h.

In vitro, dibucaine prevents normal plasma cholinesterase breaking down benzoylcholine. Normal benzoylcholine breakdown produces a colour change, the percentage inhibition of which is related to the dibucaine number (DN). A dibucaine number >77 is present in normal homozygotes; lower numbers suggest impaired plasma cholinesterase activity. Use of fluoride instead of dibucaine allows detection of the abnormal fluoride gene, by measuring the fluoride number (FN).

Onset of neuromuscular blockade

Relative sensitivity of muscles to neuromuscular blockade is as follows: muscles of upper airway > peripheral muscle and intercostal muscles > diaphragm. Therefore, optimal intubating conditions develop earlier than a similar depth of block in the hand. Sufficient relaxation for intubation is usually present well before complete loss of the TO4 in the adductor pollicis.

A normal tidal volume requires just 15% of maximum diaphragm strength, so adequate respiratory effort can still occur while limbs are still paralysed. Forearm/hand muscles are of comparable sensitivity to intercostals and may explain why ventilatory weakness is still present until the adductor pollicis muscle has recovered completely. Any weakness detectable in peripheral muscles is likely to be associated with difficulty in maintaining an airway.

Neonatal diaphragmatic paralysis occurs at the same time as peripheral muscle groups, making peripheral neuromuscular monitoring a good indicator of respiratory muscle reversal.

Reversal of neuromuscular blockade

Sustained head lift, tongue protrusion, hand grip, coughing and vital capacity of >10 mL/kg require patient cooperation and are only crude measures.

Inspiratory effort > −25 cmH₂O is required before spontaneous respiration becomes adequate (equates with 15 mL/kg vital capacity). Adequate gag/swallowing correlates with > −40 cmH₂O. Five-second head lift equates to –55 cmH₂O inspiratory pressure.

In neonates and infants, hip flexion to >90° equates with a maximum inspiratory force of –30 cmH₂O, which is adequate for spontaneous respiration.

Anticholinesterase agents

Main reversal agent is neostigmine, which inhibits acetylcholinesterase, preventing the breakdown of acetylcholine and resulting in re-establishment of neuromuscular transmission. Neostigmine causes muscarinic side-effect, necessitating the co-administration of anticholinergic drugs. Unable to reverse deep block and also associated with persistence of residual block.

Sugammadex

Sugammadex is a modified γ-cyclodextrin, a selective NMB binding agent, specifically developed to reverse aminosteroid NMBs (rocuronium/vecuronium). Block induced by rocuronium or vecuronium can be reversed from superficial or deep levels within 2–3 min using 4–8 mg.kg⁻¹ or 16 mg.kg⁻¹ sugammadex, respectively. The ability of sugammadex to reverse deep block with 3–5 min of administering 1.0–1.2 mg.kg⁻¹ rocuronium makes use of rocuronium as an alternative to suxamethonium for rapid sequence induction a possibility. May bind to progestagen (oral contraceptive pill), fusidic acid and flucloxacillin to reduce their efficacy.

Neuromuscular blockade by other drugs

• Aminoglycosides – pre-junctional block

• Tetracyclines – post-junctional block

• Calcium-channel blockers – interfere with pre-junctional Ca²⁺ flux

• Magnesium – potentiates block

• Metoclopramide – prolongs action of suxamethonium by 50%.

Monitoring

Monitor to assess degree of relaxation, help adjust dosage, assess development of phase II block, provide early recognition of patients with abnormal cholinesterases, and to assess cause of apnoea.

Stimulate peripheral nerve and assess visually, by feeling the strength of contraction or mechanically (mechanomyography, electromyography). Ulnar nerve in forearm is motor only to adductor pollicis in hand, which is easily accessible. Facial nerve stimulation is a better indicator than ulnar nerve to predict when intubation is possible.

Patterns of nerve stimulation

All stimulation should be supramaximal. Achieved by increasing the intensity of the stimulus until twitch height increases no further.

• Single twitch. A 2 ms stimulus is applied every few seconds and subsequent contractions monitored. Insensitive since >75% of postsynaptic receptors must be blocked before there is any diminution in twitch height.

• Train of four. A 2 Hz stimulus is applied no more often than every 10 s. Compare first (T₁) and last twitch (T₄). TO4 ratio (T₁:T₄) indicates degree of neuromuscular blockade:

– T₄ disappears at 75% depression of T₁ (1st, 2nd and 3rd twitches present)

– T₃ disappears at 80% depression of T₁ (1st and 2nd twitches present)

– T₂ disappears at 90% depression of T₁ (1st twitch only)

– T₁ disappears at 100% depression of T₁ (no twitches).

A TO4 count of 0–1 is needed for adequate intubating conditions, but a count of three twitches provides adequate relaxation for most surgery. A TO4 ratio >0.70, or T₁:T₀ >0.75, corresponds to adequate clinical recovery, but normal pharyngeal function requires a ratio >0.90.

Neuromuscular reversal can be given when T₂ has reappeared, i.e. when T₁ is about 20% of its control height.

• Tetanic stimulation. Supramaximal stimulation of 50 Hz for 5 s. With non-depolarizing block, peak height is reduced and fades. Release of acetylcholine is reduced (possibly presynaptic effect) and postsynaptic receptors are blocked, limiting sustained contraction.

• Post-tetanic count. A 1 Hz stimulus is applied 5–10 s after tetanic stimulus. May result in response (post-tetanic potentiation), even if none is seen with original TO4. Due to increased synthesis and mobilization of acetylcholine following tetanus. Appearance of post-tetanic count precedes return of TO4 by 30–40 min.

• Double-burst stimulation (Engbaek et al 1989). Three 0.2 ms bursts of 50 Hz tetanus, each burst separated by 20 ms and repeated after 750 ms. Similar to TO4, but tactile evaluation is more sensitive because fade of the two resultant contractions is more marked.

Table 11.6 Depolarizing versus non-depolarizing block

Depolarizing block	Non-depolarizing block
Reduced twitch height	Reduced twitch height
No fade of TO4/tetanus	Fade of TO4/tetanus
No post-tetanic potentiation	Post-tetanic potentiation

Bibliography

Donati F., Bevan D.R. Not all muscles are the same. Editorial,. Br J Anaesth. 1992;68:235-236.

Fuchs-Buder T., Schreiber J.U., Meistelman C. Monitoring neuromuscular block: an update. Anaesthesia. 2009;64(Suppl 1):82-89.

Kopman A.F., Eikermann M. Antagonism of non-depolarising neuromuscular block: current practice. Anaesthesia. 2009;64(Suppl 1):22-30.

Kopman A.F. Sugammadex: A revolutionary approach to neuromuscular antagonism. Anesthesiology. 2006;104:631-633.

Martyn J.A.J., Fagerlund M.J., Eriksson L.I. Basic principles of neuromuscular transmission. Anaesthesia. 2009;64(Suppl 1):1-9.

Martyn J., Durieux M.E. Succinylcholine: new insights into mechanisms of action of an old drug. Anesthesiology. 2006;104:633-634.

McGrath C.D., Hunter J.M. Monitoring of neuromuscular block. Contin Educ Anaesthesia, Crit Care Pain. 2006;6:7-12.

Mirakhur R.K. Sugammadex in clinical practice. Anaesthesia. 2009;64(Suppl 1):45-54.

Mirakhur R.K., Harrop-Griffiths W. Management of neuromuscular block: time for a change? Anaesthesia. 2009;64(Suppl 1):iv-v.

Opioids and Other Analgesics

Fentanyl (anilino-piperidine)

Fentanyl was the first of the potent anilino-piperidine opioids, being 200 times as potent as morphine with a high therapeutic index. Its high lipid solubility causes accumulation of the drug in lipophilic tissues, particularly the lungs on first pass, with a resultant prolongation in elimination half-life (150–400 min); 84% is protein bound to albumin and α- and β-globulins; 80% undergoes N-dealkylation by liver metabolism to inactive norfentanyl, so it has prolonged duration of action with liver disease. Little change in drug kinetics in patients with renal disease.

Alfentanil (anilino-piperidine)

Alfentanil has 20% of the potency of fentanyl. Less lipid-soluble than fentanyl, with 90% bound to α₁-acid glycoprotein. It is shorter acting and 80% is biotransformed by liver metabolism, so has prolonged duration of action with liver disease. Little change in drug kinetics in patients with renal disease.

Sufentanil (anilino-piperidine)

Shorter acting than fentanyl, with an elimination half-life of 140–200 min. Some 80% is biotransformed by liver metabolism, so has prolonged duration of action with liver disease. Little change in drug kinetics in patients with renal disease except in uraemic patients.

Remifentanil (anilino-piperidine)

Remifentanil is an ultra-short-acting synthetic opioid with µ-specific opioid activity. Vials of remifentanil contain glycine which is an inhibitory neurotransmitter, making it unsuitable for subarachnoid and extradural injection; 70% bound to α₁-acid glycoprotein. It has cardiovascular and side-effect profiles similar to fentanyl. Not associated with histamine release. The ester linkage (shown by the dotted line) makes remifentanil susceptible to rapid hydrolysis by tissue and blood non-specific esterases (distinct from pseudocholinesterase) and it therefore has a rapid clearance (elimination t_½ = 5 min) independent of renal and hepatic function. The major metabolite is a pure µ-opioid agonist excreted by the kidney, but with a potency 1/4600 of the parent compound. Placental transfer occurs rapidly, but metabolism and redistribution prevent adverse neonatal effects. Prolonged duration of action with liver disease. Little change in drug kinetics in patients with renal disease.

Allows more rapid recovery, but associated with increased postoperative analgesia requirements. Less nausea and vomiting than with other longer-acting opioids. As with other opioids, muscle rigidity at high dose may occur. When assessed by the effect on reduction in MAC, the relative potencies of sufentanil, fentanyl, remifentanil and alfentanil are 1:10:10:80.

Pethidine

Greater (>70%) protein binding (mostly α₁-acid glycoprotein) than morphine. Metabolized by N-demethylation to the active metabolite, norpethidine and inactive pethidinic acid and norpethidinic acid. Accumulation of norpethidine in renal impairment may prolong the action of pethidine and cause tremor, agitation and seizures. Despite significant pulmonary clearance, 80% is biotransformed by liver metabolism, so liver disease is associated with increased elimination half-life.

Said to be the opioid of choice for biliary colic because its atropine-like effect will counteract the opioid action on smooth muscle. Topical atropine, however, does not relax a contracted gall bladder and there no is evidence that pethidine is any better than equianalgesic doses of other opioids.

Morphine

Metabolized to morphine 3-glucuronide (M3G) and the active metabolite morphine 6-glucuronide (M6G). 10% of morphine conjugation occurs in extrahepatic and GI tissues; 80% biotransformed by liver metabolism, but kinetics of morphine remain unaltered until end-stage liver disease. Renal failure is associated with accumulation of M3G and M6G and prolonged action.

Diamorphine

3,6-diacetylmorphine (heroin). Hydrolysed in liver and blood to 6-monoacetyl morphine, a potent opioid.

Codeine

3-methoxymorphine. Approximately 10–20% of the potency of morphine. Methyl ether group reduces metabolism so increasing oral bioavailability. Undergoes extensive hepatic metabolism, mostly to inactive conjugated compounds but 10–20% metabolized to morphine.

Tramadol

A phenylpiperidine derivative with a structure similar to pethidine and elimination t_½ of 5–7 h. Same analgesic potency as pethidine. Analgesic effects through:

• moderate affinity at μ-receptors and weak activity at κ-receptors

• enhancing the function of the spinal descending inhibitory pathways and blocking spinal nociceptive pathways by inhibition of reuptake of both 5HT and norepinephrine at synapses

• presynaptic stimulation of 5HT release.

As it enhances monoaminergic transmission, it is contraindicated in patients taking MAOIs. Does not cause significant respiratory depression or histamine release. Exists as a chiral mixture with (+) form acting at μ-receptors and (–) form causing monoamine reuptake inhibition. Has 10–20% of the potency of morphine but causes less respiratory depression and less depression; 20% bound to plasma protein with an elimination t_½ of 5 h. Demethylation by the liver (P₄₅₀) accounts for 86% of the metabolism. The O-desmethyl-tramadol metabolite is active with a t_½ of 9 h. Most metabolites are excreted in the urine. Hepatic and renal impairment causes significant prolongation of action.

For moderate/severe pain, 3 mg/kg is an effective initial dose. Associated with common but mild side-effects of headache, nausea, vomiting and dizziness. Reduced side-effects with oral slow-release preparations.

Committee on Safety of Medicines (CSM) has received 27 reports of convulsions possibly associated with tramadol, although many of the patients were known epileptics. Some reports have shown interaction with coumarin anticoagulants to prolong the INR and there have also been reports of drug abuse.

Bibliography

Budd K., Langford R. Tramadol revisited. Br J Anaesth. 1999;82:493-496.

Komatsu R., Turan A.M., Orhan-Sungur M., et al. Remifentanil for general anaesthesia: a systematic review. Anaesthesia. 2007;62:1266-1280.

Sear J.W. Recent advances and developments in the clinical use of i.v. opioids during the preoperative period. Br J Anaesth. 1998;81:38-50.

Volatile Agents

Table 11.7 Physical properties of volatile agents

Halothane

Instability in light is improved by the addition of 0.01% thymol. Arrhythmogenicity associated with alkane structure. Maximum recommended safe dose of adrenaline is 0.1 mg/10 min. Least irritant of all the volatiles for gas induction.

Halothane hepatitis

The National Halothane Study (USA 1966) studied 750 000 anaesthetics. Spectrum of damage from minor derangement of LFTs to fulminant hepatic failure (FHF). There were seven cases of unexplained FHF (1:35 000 halothane exposures). Hepatitis was associated with more than one exposure to halothane, recent exposure to halothane, family history of halothane hepatotoxicity, obesity, female sex and drug allergies. Eosinophilia and autoantibodies were common.

There are two patterns of hepatitis:

• mild – usually subclinical with transient derangement in LFTs

• fulminant hepatic failure – defined by Neuberger & Williams (1988) as ‘the appearance of liver damage within 28 days of halothane exposure in a person in whom other known causes of liver disease had been excluded’.

Some 75% of patients with halothane hepatitis have antibodies reacting to halothane-altered antigens. Route of metabolism of halothane depends upon O₂ tension in liver. At high O₂ tension, an oxidative route generates trifluoroacetyl halide (TFAH) (Fig. 11.3), which covalently binds to liver proteins, forming haptens. Halothane-directed antibodies detectable by ELISA test have been identified that are directed against TFAH antigens. Present in 70% of cases of halothane-induced FHF. The significance of the more minor reductive route at low O₂ tension is debated. It may be associated with direct liver damage with release of fluoride. National database of FHF patients set up at St Mary’s Hospital, London (Prof. R.M. Jones), to whom these patients should be reported.