Medical knowledge | Anaesthetics » Per H. Rosenberg - Maximum Recommended doses of Local Anaesthetics

Source: http://www.doksinet Kirjeitä toimitukselle Per H. Rosenberg Department of Anaesthesiology and Intensive Care Medicine Helsinki University Hospital Helsinki, Finland Maximum recommended doses of local anaesthetics T he recommendations regarding maximum doses of local anaesthetics presented in physicians’ pharmaceutical reference books or in anaesthesiology text books are not evidence based. As a matter of fact, most of the recommendations are published by the manufacturer and are often very conservative. Usually, the recommendation of a maximum dose is expressed as the total amount of the local anaesthetic, e.g 200 mg for lidocaine in an adult The site of administration, size and age of the patient, concomitant diseases and medications are not taken into account. This controversy has been pointed out several times, and most strongly by Daniel C. Moore and co-workers 1 and by Bruce Scott 2. They questioned the validity of maximum dose recommendations because of the

completely ignored consideration of the various factors known or suspected, to affect absorption, metabolism and elimination of the drug. Drug-related factors Influence of site injection The vascularity and the binding of the local anaesthetic to the tissues will influence the rate of absorption into the circulating blood. Absorption from richly vascularized regions such as the pleura, the bronchial mucosa, and the scalp occurs rapidly 3. Intrinsic vasoactivity of the local anaesthetics The vasoactive potency of the clinically used amide-linked local anaesthetics varies. The effect is dose-dependent and as a rule, high concentrations cause dilatation and low concentrations cause constriction. The intrinsic vasoactivity of the 50 local anaesthetic does not play any greater role in influencing its absorption. Ropivacaine has been found to produce less vasodilatation than other commonly used amide-linked local anaesthetics 4, or even vasoconstriction, but whether this has any

clinically beneficial consequences remains open. As an example, plasma concentrations of ropivacaine in epidural anaesthesia are similar to those measured after a similar dose of bupivacaine 5, 6. Adrenaline Adrenaline slows the absorption of local anaesthetic and prolongs the anaesthetic action and increases the duration of the block. A suitable adrenaline concentration is 5 µg/ml which reduces the peak plasma concentration of the local anaesthetic, depending on the local anaesthetic, by 30–60 %. Higher adrenaline concentrations are commonly used in dentistry, but if one aims primarily at reducing the uptake of the local anaesthetic into blood, as low adrenaline concentration as 1.7 µg/ ml (1 : 600,000) has been shown to be effective with lidocaine 8. Patient-related factors Age Deterioration in morphology and nerve conduction by aging may increase the sensitivity to local anaesthetic block 8. In addition, because of reduced clearance, the doses of local anaesthetics need to be

reduced in adults, age-dependently between 10–20 % 9. In the newborn less than 4 months old, the low plasma concentrations of α1-acid glycoprotein (AAG), the local anaesthetic-binding acute phase protein, is related to an enhanced risk of toxicity. FINNANEST ,  () Source: http://www.doksinet When large doses of local anaesthetic are used in this group of patients, the dose per kilogram should be about 15 % lower than in older infants 9. Size Extremes in size need to be considered when regional anaesthetic blocks are used, both from the performance point of view and the pharmacokinetic/toxicity point of view. There is no evidence based recommendation or rule for proportional reduction of doses according to the weight but, obviously, dosing on milligram-perkilogram basis would be dangerous 10. Renal dysfunction In renal dysfunction, the clearance of local anaesthetics has been found to be lower than in nonuraemic patients 11. The concentration of AAG is

usually increased in uraemic patients 12 and this offers an important protection against toxicity. The initial absorption of local anaesthetic in uraemic patients is rapid 11 and the dose of a local anaesthetic should de reduced by 10–20 % when large doses are planned to be used. Furthermore, due to reduced elimination of the local anaesthetic and its metabolites, the doses used for continuous infusions should also be reduced by 10–20 %, according to the degree of renal dysfunction 9. Hepatic dysfunction The parmacokinetics of the majority of local anaesthetics is affected by a poorly functioning liver associated with concomitant alterations in circulation and body fluids. In end-stage liver dysfunction, the clearance of ropivacaine has been found to be about 60 % lower than in healthy volunteers 13. Patients with severe liver dysfunction often have other concomitant diseases (renal and cardiac), which may be even more important indications to reduce the dose of the local

anaesthetic. In mild liver dysfunction due to alcoholism, there is only minor alteration in the clearance of lidocaine 14. Single-dose local anaesthetic blocks can be performed without dose reduction in liver dysfunction. However, in repeat blocks (within short interval) and during continuous infusion blocks, the dose needs to be reduced by 10–50 %, depending on the stage of liver dysfunction 9. Heart failure In mild cardiac disease, there may be no reason to reduce the local anaesthetic dose in single- FINNANEST ,  () dose blocks. Due to decreased liver and kidney blood flow in advanced heart failure, causing slow elimination of drugs and metabolites, the dose of the local anaesthetic should be reduced at least in continuous infusion blocks, e.g, by 10–20 % 9 Large doses of adrenaline should be avoided in patients with cardiac disease with arrhythmias or hypokalaemia. Obviously, lidocaine should not be used to treat local anaesthetic-provoked ventricular

dysrhythmia because cardiac toxicity of local anaesthetic is additive 15. Pregnancy Regional anaesthetic blocks requiring large doses (e.g, brachial plexus block, epidural block) should be avoided during the first trimester of pregnancy. Dose reduction in epidural or spinal anaesthesia for caesarean section is necessary because of anatomical and physiological changes in the late stages of pregnancy and the enhanced sensitivity of nerves to local anaesthetics. Continuous infusion blocks are rarely used during pregnancy but, in principle, low doses for short periods could be used postoperatively, with the aim to reduce the need for analgesics such as opioid and cyclooxygenase inhibitors 9. Drug interactions The cytochrome P450 (CYP) isoenzymes primarily involved in the metabolism of local anaesthetics are CYP 3A4, CYP 2D6 and CYP 1A2 16, 17. In single dose blocks the impact of drug interactions (CYP enzymes) for toxicity of local anaesthetics is theoretical. In continuous infusions,

however, the decreased clearance of bupivacaine by strong CYP3A4 inhibitors (e.g, itraconazole and other conazole antimycotics) and of ropivacaine by strong CYP1A2 inhibitors (e.g, fluvoxamine, which also inhibits CYP 3A4) needs to be considered. If the patient receives such medication the continuous infusion doses of bupivacaine or ropivacaine needs to be reduced by 10–20 % 9. Conclusion None of the above mentioned recommendation is based on evidence classified higher than grade C (case series or poor quality cohort studies) 9. Therefore, exact recommendations regarding highest allowable dose of the local anaesthetics cannot be given. Recommendations regarding which factors need to be considered 51 Source: http://www.doksinet for the reduction of the dose are given in this presentation. The choice of a suitable (sufficient) dose for a particular type of regional anaesthetic block can be made with the guidance of modern highquality textbooks of regional anaesthesia. When large

doses are needed, the addition of low concentrations (1.7–5 µg/ml) of adrenaline is most useful in reducing the absorption of the local anaesthetic. The local anaesthetics are potentially toxic agents and, therefore, everyone who uses them must know which a suitable dose for a particular block in normal conditions is. In order to adjust the local anaesthetic dose properly one must also know how the drug-related factors and the patient-related factors can influence the absorption, distribution, metabolism and elimination. Finally, the maximum milligram dose recommendations for local anaesthetics by the pharmaceutical companies are illogical and needless.  References 1. Moore DC, Bridenbaugh LD, Thompson GE, et al Factors determining dosages of amide-type local anesthetic drugs. Anesthesiology 1977; 47: 263–268. 2. Scott DB Maximum recommended doses of local anaesthetic drugs (editorial). Br J Anaesth 1989; 63: 373–374 3. Covino BG, Vassallo H Local Anesthetics Mechanisms of

Action and Clinical Use. New York, New York, Grune & Stratton, 1976: 97. 4. Kopacz DJ, Capenter RL, Mackey DC Effect of ropivacaine on cutaneous capillary blood flow in pigs. Anesthesiology 1989; 71: 69–74. 52 5. Lee BB, Ngan Kee WD, Plummer JL, et al The effect of the addition of epinephrine on early systemic absorption of epidural ropivacaine in humans. Anesth Analg 2002; 95: 1402– 1407. 6. Burm AG, van Kleef JW, Gladines MP, et al Epidural anesthesia with lidocaine and bupivacaine: effects of epinephrine on the plasma concentration profiles. Anesth Analg 1986; 65: 1281– 1284. 7. Ohno H, Watanabe M, Saitoh J, et al Effect of epinephrine concentration on lidocaine disposition during epidural anesthesia. Anesthesiology 1988; 68: 625–629 8. Simon MJ, Veering BT, Stienstra R, et al The effect of age on neural blockade and hemodynamic changes after epidural administration of ropivacaine. Anesth Analg 2002; 94: 1325– 1330. 9. Rosenberg PH, Veering BT, Urmey WF Maximum

recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004; 29: 564–575. 10. Reynolds F Maximum recommended doses of local anesthetics: a constant cause of confusion (letter). Reg Anesth Pain Med 2005; 30: 314–316. 11. Pere P, Salonen M, Jokinen M, et al Pharmacokinetics of ropivacaine in uremic and nonuremic patients after axillary brachial plexus block. Anesth Analg 2002; 96: 563–569 12. Svensson CK, Woodruff MN, Baxter JG, et al Free drug concentration monitoring in clinical practice. Clin Pharmacokinet 1986;11: 450–469. 13. Jokinen M The pharmacokinetics of ropivacaine in hepatic and renal insufficiency. Best Pract Res Clin Anaesthesiol 2005; 19(2): 269–274. 14. Thomson PD, Melmon KL, Richardson JA, et al Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 1973; 78: 499–508 15. Toyoda Y, Kubota Y, Murakawa M, et al Prevention of hypokalemia during axillary nerve block vith 1%

lidocaine and epidnephrine 1:100,000. Anesthesiology 1988; 69: 109–112 16. Bowdle TA, Freund PR, Slattery JT Propranolol reduces bupivacaine clearance. Anesthesiology 1987; 66: 36–38 17. Oda Y, Furuichi K, Tanaka K, et al Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology 1994; 82: 214–220. FINNANEST ,  ()