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Sunday, January 30, 2011


A 30 year old ASA 1 patient weighing 70 kg  is scheduled for open reduction and internal fixation of fracture both bones on right upper limb. The pre anaesthetic check up was unremarkable except for mild nasal allergy.The patient received 3 mg intravenous midazolam in operation theatre for sedation and an interscalene brachial plexus block was attempted by the anaesthetist using 20 ml 1% lignocaine along with 20 ml 0.25% bupivacaine.Analgesia was adequate and  almost complete after 10 minutes of the block and the surgeon was about to operate. The patient complained of dizziness and vomited once.The blood pressure dropped below70 mm Hg systolic and the pulse was felt slow, feeble and thready. The chest on auscultation revealed equal and bilateral air entry.   Later on he complained of numbness of the face and began to convulse. Immediate support of airway and ventilation provided by mask ventilation and  intubation after intravenous thiopental.  Intravenous fluids administered  and intravenous ephedrine given at increments . Blood pressure dropped further down and patient  had a cardiac arrest following asystole. CPR  given as per ACLS protocols and a lipid emulsion was requested. The patient responded to resuscitative efforts and intralipid administration was not necessary. He was shifted to intensive care unit for close monitoring of vitals  and has fully recovered without any neurologic sequelae.

Local anaesthetics  are drugs used to prevent or relieve pain in specific regions of the body without producing unconsciousness. They  block pain sensation by blocking  conduction of pain impulses through nerves.Motor blockade and autonomic blockade are also observed as part of local anaesthetic action.Local anaesthetic drugs are widely used in dentistry and surgical specialities for providing surface anaesthesia, infiltrative anaesthesia or for nerve block. They are indispensable for the anaesthetist, in providing Regional Anaesthesia.The drug lignocaine find an unique place in crash cart for CPR and in emergency medicine trolley for treating arrhythmias.No pain management services can run without using local anaesthetics.However precaution must be taken while using them as chances of toxicity or side effects are high and may even be fatal. Manifestations of toxic reaction may range from minor urticaria or edema to very severe neurological toxcity or severe cardiovascular collapse.So basic resuscitation equipments and essential drugs should be kept ready before administering LAs to any patient. A brief review of local anaesthetic toxicity and its management, is given here.
 Pharmacology:  Structurally, all local anaesthetics are similar and consist of three parts: a lipiophilic (aromatic) end, a hydrophilic (amine) end, and a link between the two ends.[1] This intermediate link can be either an aminoester or an aminoamide bond, which classifies the local anaesthetics into two different groups: amides and esters. Esters include Procaine, Cocaine, Chlorprocaine, Amethocaine, etc .Amides include Lignocaine, Bupivacaine, Levobupivacaine, Ropivacaine etc.
All local anaesthetic drugs are weak bases  and exists in an equilibrium between ionised and non ionised forms in solution.The non-ionised form diffuses readily across the neuronal membranes into the axoplasm, where it ionises  and blocks sodium channels within the cell.

Factors affecting the anaesthetic activity of local anaesthetics include the dissociation constant (pKa),[2]
protein binding, lipid solubility, pH, and vascularity at the injection site.The pH at which the amount of ionised and nonionised drug is equal is known as the pka or diffusion constant , (the pKa of lignocaine is 7.8 but at a pH of 7.4, more than half of the drug exist as charged cation)  The onset of action of the drug is determined by the dissociation constant and pH of the medium. Anaesthetic with a pKa value near the physiological pH has a greater proportion of drug in the non-ionised form. The non ionised form  diffuses more readily across the nerve sheaths and membrane to its site of action. Therefore, local anaesthetics with pKa values close to physiological pH tend to have a more rapid onset of action as the non ionised content of the drug is more.  Factors that promote local extracellular acidosis (eg: infection) increase drug ionisation and therefore reduce local anaesthetic diffusion and penetration of the nerve membrane. Addition of sodium bicarbonate (1 ml 8.4%  sodium bicarbonate per 19 ml 1 % lignocaine)to local anaesthetics increases the pH of the solution, which increases the ratio of non-ionised to ionised form,resulting in a more rapid onset of action. The potency of local anaesthetics is affected by its lipid solubility  A highly lipid-soluble drug readily penetrates cell membranes and thus have higher potency compared to drugs having lower lipid  solubility

The degree of protein binding( alpha 1 acid glyco protein) and vascularity also affects the local anaesthetic’s
duration of action. Those with high plasma protein binding have longer durations of action. Addition
of a vasoconstrictor like epinephrine to lipid  soluble local anaesthetics decreases vascularity at the injection site, which prolongs the duration of action (via reduced absorption of the drug into the systemic circulation).

Mechanism of action:
LAs are membrane-stabilising drugs that reversibly decrease the rate of depolarisation and repolarisation of excitable membranes.Local anaesthetics block sensory and motor function by impeding the permeability of
neuronal cell membranes to sodium. This action prevents the rapid influx of sodium during the depolarisation phase of the action potential and its onward transmission.LAs selectively bind to inactivated closed sodium channels and stabilise them in order to prevent channel opening due to nerve stimulation and subsequent propagation of action potential.The primary electrophysiological effect of these compounds is to cause a local decrease in the rate and degree of depolarisation of the nerve membrane such that the threshold potential for transmission is not reached and the electrical impulse is not propagated down the nerve.[2]

Metabolism: The ester type local anaesthetics are hydrolysed by esterases in tissues and blood, while the amide types are metabolised primarily in the liver by cytochrome P450 enzymes and then excreted through kidney. Dosage adjustments may be made in hepatic and renal failure.[2]

Calculation of percentage  and dosage:

Concentration. Drug concentration is expressed as a percentage, i.e. grams per 100ml (e.g. 1%=1 g/100 ml (1 000 mg/100 ml) or 10 mg/ml). (Bupivacaine 0.25%=2.5 mg/
ml; lignocaine 1%=10 mg/ml.)
Dilution. When adrenaline is combined in an anaesthetic solution the result is expressed as a dilution (e.g. 1:100 000):
• 1:1 000 means 1 mg/1 ml (0.1%)
• 1:10 000 means 1 mg/10 ml (0.01%)
• 1:2 000 means 1 mg/2 ml (0.05%)
• 1:20 000 means 1 mg/20 ml (0.005%)
• 0.1 ml of 1:1 000 adrenaline added to 10ml of anaesthetic solution = 1:100 000 dilution or 0.01 mg/ml
• 50 ml of lignocaine 1% with adrenaline 1:100 000 contains lignocaine 500 mg and adrenaline 0.5 mg.
Adrenaline is the most commonly used vasoconstrictor, it is added to local anaesthetic solutions in concentrations ranging from 1 in 80,000 to 1 in 300,000, although most are usually prepared to contain a 1 in 200,000 (5 microgram /ml) concentration of adrenaline.[3]

Practical Point 
Adrenaline 1:1000 contains 1 gram of adrenaline per 1000mls solution i.e. 1mg/ml. To prepare a 1 in 200,000 solution the 1:1000 must be diluted 200 times. This is achieved by taking 0.1ml (= 0.1mg) and adding 19.9 mls of local anaesthetic solution.

Etiology of toxic reactions to Local Anaesthetics:[1]
  • Systemic: CNS  and CVS toxicity, termed as local anaesthetic systemic toxicity or LAST
  • Local toxicity: Neuronal damage or skeletal muscle damage
  • Others:   Methemoglobinemia (prilocaine) Hydrolysis of prilocaine initially leads to the formation of o-toluidine products that bind to haemoglobin and oxidises Hb to ferric form and cause methaemoglobinaemia.
  •  Allergy: Allergic reactions are rare even though IgE mediated reactions can occur and may be seen with ester linked LAs.
  • Addiction:  Cocaine  may lead to drug dependance.
  • Reaction to vasoconstrictors: Tachycardia, hypertension, headache,apprehension, which usually need no treatment.
  • Vasovagal reaction: Rapid onset of bradycardia, hypotension, pallor,faintness.Usually seen when patient assumes sitting position.
  • Anaphylaxis: Hypotension, bronchospasm, urticaria, oedema, needs treatment as per anaphylaxis algorithm
  • Transient nerve damage like persisting paraesthesia, prolonged anaesthesia etc will resolve spontaneously  and permanent nerve damage is rare. 
Local anaesthetic systemic toxicity (LAST)

Toxicity may occur due to[2]
  1. Accidental intravascular or intrathecal injection
  2. Relative overdosage of drug used
  3. Rapid systemic absorption  from the injected site
CNS Toxicity: Symptoms and signs of CNS  toxicity are  manifested as initial excitation  followed by depression. The pre excitation phase is characterised by tinnitus, light headedness ,confusion and circum oral numbness and paraesthesia. This progresses on to the excitation phase where the signs are shivering, tremor muscular twitchings  and convulsions .The final stage of depression is fatal as patients may loose consciousness and may go in for respiratory arrest. Blockade of inhibitory pathways  and inhibition of release of glutamate in cerebral cortex produce initial excitation.Blockade of inhibitory pathways allows facilitatory neurons to function in an unopposed fashion, which results in an increase in excitatory activity leading to convulsions. A further increase in the dose of local anesthetic leads to inhibition of activity of both the inhibitory and facilitatory circuits, which results in a generalized state of CNS depression.Respiratory or metabolic acidosis increases CNS toxicity by increased  cerebral blood flow and resulting in rapid delivery of anaesthetic agents to brain.Acidosis also decreases intracellular pH resulting in iron trapping, decreases the plasma protein binding making available more free form of the base. Seizures produce hypoventilation and a combined respiratory and metabolic acidosis, which further exacerbates the CNS toxicity. Hence immediate support of airway with proper ventilation and meticulous control of seizures advised,in LA toxicity

CVS Toxicity:  Direct cardiovascular effects  and direct peripheral vascular effects are observed .The direct CVS effects include bradycardia due to action on sodium channels which reduces action potential duration and effective refractory period.They increase PR interval and QRS complex duration resulting in prolongation of conduction time.They also exert dose-dependant negative inotropic action on cardiac muscle.Local anesthetics may depress myocardial contractility by affecting calcium influx and triggered release from the sarcoplasmic reticulum,[2] The direct peripheral vascular effects include a biphasic response on vascular smooth muscles characterised by initial vasoconstriction followed by vasodilatation.Thus there will be a reduction in blood pressure. The toxic effects are more pronounced with bupivacaine and remain sustained.Ventricular arrhythmias  including fibrllation are more common with bupivacaine  and cardiac resuscitation is more difficult after bupivacaine-induced cardiovascular collapse, and acidosis and hypoxia markedly potentiate the cardiotoxicity of bupivacaine.(4)

Treatment of  LAST:
In 2007, the Association of Anaesthetists of Great Britain and Ireland published guidelines for the
management of severe local anaesthetic toxicity.[5] In 2008, the American Society of Critical Care Anesthesiologists and the American Society of Anesthesiologists Committee on Critical CareMedicine,[6] as well as the Resuscitation Council of the United Kingdom[7] also published protocols for the treatment of LAST. In 2010, the American Society of  Regional Anesthesia and Pain Medicine published its practice advisory on LAST.[8] These guidelines emphasise the importance of airway management and early cardiopulmonary resuscitation, They also strongly  advise use of lipid emulsions along with resuscitative measures  and have incorporated the use of lipid emulsion therapy in their guidelines, in the management of LAST. The AAGBI  algorithm is shown below.

What is intra lipid?  How it helps?
Intralipid is a brand name for the first safe fat emulsion for human use, approved in 1962 in Europe and invented by Professor Arvid Wretlind, Sweden.   It is used as a component of parenteral nutrition for patients who are unable to get nutrition via an oral diet. It is an emulsion of soy bean oil, egg phospholipids and glycerin. It is available in a 10%, 20% and 30% concentration. The 30% concentration is not approved for direct intravenous infusion, but should be mixed with amino acids and dextrose as part of a total nutrient admixture.Intralipid provides essential fatty acids, Linolenic acid (LA), an omega-6 fatty acid,alpha-linolenic acid(ALA), an omega-3 fatty acid. Some preparations of the anaesthetic drugs propofol and etomidate (the vehicle for etomidate is propylene glycol) are supplied using Intralipid as a vehicle.[9] Intralipid is widely and freely available in all hospital intensive care units as this is one of the major constituent of parenteral nutrition

In 1998 Weinberg et al[10] first reported that lipid emulsion infused during resuscitation increased the
median lethal dose (LD50) of bupivacaine in rats by 50%. Followed by  in 2006 Rosenblatt et al[11] and
Litz et al[12] reported successful clinical use of lipid emulsion to reverse local anaesthetic induced cardiac
arrest.Many clinical reports released after this supported the use of lipid emulsion in the management of LAST[13,14,15] caused due to bupivacaine, levobupivacaine, and  ropivacaine.

The exact mechanism of action of lipid emulsion therapy is not known. It may serve as a“lipid sink”, providing a large lipid phase in the plasma, enabling capture of the local anaesthetic molecules and making them unavailable to tissues.Alternatively they prevent impaired fatty acid delivery caused by local anaesthetics in the mitochrondria, and enhance energy production. The commonly used lipid emulsion preparation is Intralipid 20%, and the efficacy of other preparations is not studied in detail . Propofol is not asuitable substitute for Intralipid. It is formulated in a 10% lipid emulsion as the amount of lipid emulsion is less compared to the concentration of propofol and higher doses of propofol have direct cardiovascular depressant effects. The recommended Intralipid regimen as given by AAGBI, entails an initial intravenous bolus injection of a 20% emulsion at 1.5 mL/kg over 1 minute, followed by an infusion of 15mL/kg/h. Cardiopulmonary resuscitation should be continued. If cardiovascular stability is not restored after 5minutes or if haemodynamics deteriorate, a maximum of two repeated boluses (1.5 mL/kg) may be given at 5-minute intervals. The intravenous infusion rate should also be doubled to 30 mL/kg/h. A maximum of three boluses can be given, and a cumulative dose of 12 mL/kg should not be exceeded.
It is seen that increasing the dose beyond 8 mL/kg is unlikely to be useful and in practice, resuscitation of an adult weighing 70 kg is  as follows:
    1. Use a 500-mL bag of fat emulsion (Intralipid 20%) and a 50-mL syringe.
    2. Draw up 50 mL and give it stat intravenously, and then draw up and give another 20 mL.
    3. Do exactly the same thing up to twice more as the epinephrine is given—if necessary or appropriate.
    4. Then, attach the fat emulsion bag to a giving set and administer it intravenously over the next 15 minutes.

Contra-indications to lipid emulsion therapy include lipid metabolism disorders and egg allergy, and caution is required for patients with anaemia, severe liver disease, coagulopathy, and pulmonary disease.  Potential complications include allergic reaction, fluid overload, impaired liver function, hypercoagulability and pancreatitis.
Here is the great and eminent personality whom i admire and salute,  Dr. Weinberg,a pioneer behind this experimentation and who first postulated that lipid emulsion has a role in the treatment of LA toxicity. Following his second report in 2003 stating that "Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity"., published in Regional Anesthesia and Pain Medicine 2003; 28: 198-202, many case reports have been published in support of the efficacy of lipid emulsions for reversing local anaesthetic toxicity.[13,14,15] He himself has designed a web site and shared his experience knowledge and invited people from all over the world for contributions in this regard .The site deals with local anaesthetic toxicity, literature, case reports,experiments, and treatment regimen.He has designed the lipid rescue kits and is running a laboratory for further research on this issue  watch this site:    www.lipidrescue.org
This figure shows a Home made lipid rescue kit .This kit designed by Mike Alway, RPh, from BonSecours Hospital.  "The container for the kit is a blue storage bin that has a clear hinged lid.  It contains the 20% Lipid bag (500 ml), IV tubing, 60cc Syringes (2), and needles. The protocol is attached to the Lipid bag inside the kit and  also pasted it on the outside.


So make your own rescue kits today and keep them in OR within your reach.

1.KC Lui;YF Chow, Safe use of local anaesthetics: prevention and management of systemic toxicity; Hong Kong Med J 2010;16:470-5
2. Miller's Anaesthesia,7th edition, R D Miller et al , Churchil Livingston
3.René du Plessis, MB ChB,Specialist Anaesthetist,Bloemfonte, Local anaesthetics: Characteris tics, uses
and toxicities;CME September 2009 Vol.27 No.9
4.Englesson S: The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. An experimental study in cats.  Acta Anaesthesiol Scand  1974; 18:79-87.
5.Guidelines for the management of severe local anaesthetic toxicity. The Association of Anaesthetists of Great Britain &Ireland; 2007.
6.Gabrielli A, O’Connor MF, Maccioli GA. Anesthesia Advanced Circulatory Life Support. The American Societyof Critical Care Anesthesiologists & The American Society of Anesthesiologists, Committee on Critical care Medicine;2008.
7.Cardiac arrest or cardiovascular collapse caused by local anesthetic. Resuscitation Council (UK); 2008.
8.Neal JM, Bernards CM, Butterworth JF 4th, et al. ASRA practice advisory on local anesthetic systemic toxicity. RegAnesth Pain Med 2010;35:152-61.
9.Wikipedia, en.wikipedia.org/wiki/Intralipid.
10.Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaineinduced
asystole in rats. Anesthesiology 1998;88:1071-5.
11. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, EisenkraftRosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest.Anesthesiology 2006;105:217-8.
12.Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006;61:800-1.
13.Julio A. Warren, MD,R. Brian Thoma, MD, Alexandru Georgescu, MD,Saurin J. Shah, MD
Intravenous Lipid Infusion in the Successful Resuscitation of Local Anesthetic-Induced Cardiovascular
Collapse After Supraclavicular Brachial Plexus Block (Anesth Analg 2008;106:1578 –80)
14.Meg A. Rosenblatt, M.D., Mark Abel, M.D., Gregory W. Fischer, M.D.,Chad J. Itzkovich, M.D.,James B. Eisenkraft, M.D; Successful Use of a 20% Lipid Emulsion to Resuscitate a Patient after a Presumed Bupivacaine-related Cardiac Arrest
15. R. J. Litz,M. Popp,S. N. Stehr,  Anaesthesia, Volume 61, Issue 8, pages 800–801, August2006, Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion.