Jean-Xavier Mazoit

Pharmacokinetics of local anaesthetics in infants and children.

Amide local anaesthetics used for regional anaesthesia in paediatric patients are potent sodium channel blockers with marked stereospecificity, which consistently influences their action, especially their toxic action on the heart. At toxic concentrations, they induce severe arrhythmias with the potential for cardiac arrest. These agents are all bound to serum proteins, mainly to α1-acid glycoprotein (AAG), but also to human serum albumin. Protein binding ranges from 65% (lidocaine) to more than 95% (bupivacaine, ropivacaine). Because AAG is a major acute phase protein, its concentration rapidly increases when inflammatory processes develop, particularly during the postoperative period. Neonates and infants have a lower AAG concentration in serum as compared with adults; therefore, their free fraction of local anaesthetics is increased accordingly. This has important clinical implications since, at least at steady state, the toxic effects of local anaesthetics are directly related to the free (unbound) drug concentration.After injection into the epidural space, absorption into the bloodstream follows a biphasic process. The buffering properties of the epidural space are important and prevent a rapid rise in concentration. In infants and children, the epidural space seems to protect patients in a similar manner. Moreover, it has been observed that the peak plasma concentration (Cmax) of ropivacaine is delayed in infants and children when compared with adults. The time to Cmax decreases from 90–120 minutes in infants aged less than 6 months to 30 minutes in children aged more than 8 years.This delay in Cmax may also be related to the lower clearance observed in younger patients. Local anaesthetics are metabolised by cytochrome P450 (CYP). The main CYP isoforms involved are CYP3A4 for lidocaine and bupivacaine and CYP1A2 for ropivacaine. CYP3A4 is not mature at birth but is partly replaced by CYP3A7. The intrinsic clearance of bupivacaine is only one-third of that in adults at 1 month of age, and two-thirds at 6 months. CYP1A2 is not fully mature before the age of 3 years. Indeed, the clearance of ropivacaine does not reach its maximum before the age of 5 years. However, at birth this clearance is not as low as expected, and ropivacaine may be used even in younger patients.

Postoperative intravenous morphine titration

Relief of acute pain during the immediate postoperative period is an important task for anaesthetists. Morphine is widely used to control moderate-to-severe postoperative pain and the use of small i.v. boluses of morphine in the post-anaesthesia care unit allows a rapid titration of the dose needed for adequate pain relief. The essential principle of a titration regimen must be to adapt the morphine dose to the pain level. Although morphine would not appear to be the most appropriate choice for achieving rapid pain relief, this is the sole opioid assessed in many studies of immediate postoperative pain management using titration. More than 90% of the patients have pain relief using a protocol of morphine titration and the mean dose required to obtain pain relief is 12 (7) mg, after a median of four boluses. Sedation is frequent during i.v. morphine titration and should be considered as a morphine-related adverse event and not evidence of pain relief. The incidence of ventilatory depression is very low when the criteria to limit the dose of i.v. morphine are enforced. Morphine titration can be used with caution in elderly patients, in children, or in obese patients. In practice, i.v. morphine titration allows the physician to meet the needs of individual patients rapidly and limits the risk of overdose making this method the first step in postoperative pain management.

Analgesic efficacy and adverse effects of epidural morphine compared to parenteral opioids after elective caesarean section: A systematic review

Background: The optimal effective dose of epidural morphine that provides postoperative analgesia after caesarean section with minimal side effects remains debated.

Antinociceptive effect of resveratrol in carrageenan-evoked hyperalgesia in rats: prolonged effect related to COX-2 expression impairment.

Abstract Resveratrol is a natural polyphenol that protects from cancer and cardiovascular diseases. Resveratrol is able to induce apoptotic cell death and it inhibits the cyclooxygenase (COX) cascade. We measured the antinociceptive effect of resveratrol on carrageenan‐induced hyperalgesia, prostaglandin‐E2 (PGE2) concentration in CSF and COX‐1/COX‐2 gene expression in the spinal cord and dorsal root ganglion (DRG) in rats. Resveratrol induced a prolonged antinociceptive effect, which was correlated to the inhibition of COX‐2 mRNA increase in DRG and cord elicited by carrageenan. An increase in the basal threshold of mechanical nociception was also observed with resveratrol in the absence of any inflammatory insult. A rapid bilateralisation of COX‐2 mRNA production, not accompanied by a parallel increase in c‐Fos expression, was observed in spinal cord three hours after the inflammatory insult. This increase in COX‐2 mRNA concentration in the spinal cord on the opposite side of the inflammatory insult was abolished by resveratrol. In conclusion, the antinociceptive effect exhibited by resveratrol was related to the prevention of COX‐2 mRNA increase induced by carrageenan. Resveratrol also prevented the bilateralisation of COX‐2 expression. The later effect, together with the prolonged analgesia induced by a single injection, may be of great benefit for preventing chronic pain states often seen after inflammatory insults.

Adverse Effects of Regional Anaesthesia in Children

True complications of regional block procedures pertain to the performance of the block technique and the local anaesthetic. Such complications include lesions caused by the device used, and many of these complications can be avoided by using specifically designed devices.Complications related to the local anaesthetic solution mainly consist of local and systemic complications. Local toxicity has mainly been reported in adults following spinal administration of 5% lidocaine (lignocaine), a drug that is not usually used in children. Systemic toxicity consists of CNS and cardiovascular complications, methaemoglobinaemia and allergic reactions. Systemic toxicity has special features in children, especially in those <1 year old. Infants have a much higher free serum concentration of local anaesthetics than older children and adults, and are more prone to the deleterious effects of local anaesthetics. Additionally, as regional blocks are usually performed under general anaesthesia in children, signs of CNS toxicity may be concealed.Because of their higher heart rate, newborns and infants are thought to be more prone to the phasic block produced by tertiary amine agents such as bupivacaine than are adults. Serum concentrations at which bupivacaine (and etidocaine) exert cardiac toxicity seem to be similar to those producing CNS toxicity. As there is an increased threshold for CNS toxicity in infants plus an increased (or equal) sensitivity to bupivacaine cardiotoxicity, cardiac signs may not be preceded by any sign of CNS toxicity. Cardiac complications include: (i) arrhythmias with high degree conduction block, major QRS widening, torsade de pointes, and ventricular tachycardia related to re-entry phenomena; and (ii) major vascular collapse favoured by a concomitant decrease in the myocardial contractile force.Other complications of regional block procedures result from poor selection of agent, and inadequate safety precautions and monitoring of the patient, especially during the postoperative period. There are 2 other groups of disorders often reported as complications of regional anaesthetics: (i) effects that were not anticipated by the anaesthetist because of a lack of knowledge of all the consequences of the technique used; and (ii) complications attributed to a concomitant regional block procedure but with no established, sometimes even improbable, causal link with the regional technique.The overall morbidity of regional anaesthesia in children is low. Sound selection of local anaesthetics, insertion routes and block procedures, together with appropriate and careful monitoring, should prevent any major undesirable effects and enable regional anaesthesia to be a well tolerated and effective tool to overcome pain associated with minimal morbidity.

Local anesthetics and their adjuncts

Local anesthetics (LA) block propagation of impulses along nerve fibers by inactivation of voltage‐gated sodium channels, which initiate action potentials ( 1 ). They act on the cytosolic side of phospholipid membranes. Two main chemical compounds are used, amino esters and amino amides. Amino esters are degraded by pseudocholinesterases in plasma. Amino amides are metabolized exclusively by the liver. Only amide LAs will be considered in this article.

Ropivacaine in infants and children.

PURPOSE OF REVIEW Ropivacaine is considered less toxic than bupivacaine. In addition, at the low concentrations used for providing postoperative analgesia, ropivacaine seems to produce less motor blockade than bupivacaine. These two properties are of particular interest in paediatric practice. RECENT FINDINGS In paediatric practice regional anaesthesia is usually performed under general anaesthesia, and postoperative analgesia was until recently the major concern for most practitioners. The question now is: what is the right concentration to provide adequate intraoperative anaesthesia when ropivacaine is used in combination with volatile anaesthetic agents? The low concentration of ropivacaine used for postoperative analgesia seems to provide adequate intraoperative anaesthesia when general anaesthesia with a 0.5 minimum concentration of volatile anaesthetic is used in combination. However, potential toxicity is still the subject of debate because ropivacaine clearance is low in infancy and early childhood. Ropivacaine has a longer absorption process than bupivacaine, which leads to a lower maximum peak concentration with ropivacaine than with bupivacaine either after central or peripheral blocks, thus increasing the safety of the drug. The addition of adjuvant drugs also permits lower concentrations of ropivacaine, while providing excellent analgesia. The addition of adrenaline at very low concentrations has recently been found to increase the quality of epidural analgesia. SUMMARY Ropivacaine is now the reference drug for regional anaesthesia in paediatric patients, mainly because it is considered less toxic than bupivacaine and provides excellent postoperative analgesia even when used at low concentrations.

Median effective dose (ED50) of paracetamol and morphine for postoperative pain: a study of interaction

BACKGROUND Paracetamol is widely used to treat postoperative pain and is well known for its morphine-sparing effect. Therefore, the effect of morphine-paracetamol combination can be synergistic, additive, or infra-additive. The primary aim of our study is to define the median effective analgesic doses (ED₅₀s) of paracetamol, morphine, and the combination of both. Also, the nature of the interaction for postoperative pain after moderately painful surgery using an up-and-down method and isobolographic analysis was determined. METHODS Ninety patients, undergoing moderately painful surgery, were included in one of the three groups. Determination of the median ED₅₀s was performed by the Dixon and Mood up-and-down method. Initial doses were 1.5 g and 5 mg, with dose adjustment intervals of 0.5 g and 1 mg, in the paracetamol and morphine groups, respectively. The initial doses of paracetamol and morphine were 1.5 g and 3 mg, in the paracetamol-morphine combination group with dose adjustment intervals of 0.25 g for paracetamol and 0.5 mg for morphine. Analgesic efficacy was defined as a reduction to or <3 on a 0-10 numeric rating scale, 45 min after the beginning of drug administration. Isobolographic analysis was used to define the nature of their interaction. RESULTS The median ED₅₀s of paracetamol and morphine were 2.1 g and 5 mg, respectively. The median ED₅₀ of the combination was 1.3 g for paracetamol and 2.7 mg for morphine. CONCLUSIONS Our study showed that the combination of the paracetamol and morphine produces an additive analgesic effect. Clinical trial registration NCT01366313.

Ondansetron does not block paracetamol-induced analgesia in a mouse model of fracture pain

BACKGROUND The aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. METHODS In protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg⁻¹, paracetamol 50 mg kg⁻¹, paracetamol 100 mg kg⁻¹, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg⁻¹) plus saline (vehicle), paracetamol (100 mg kg⁻¹) plus ondansetron (1 mg kg⁻¹), paracetamol (100 mg kg⁻¹) plus ondansetron (2 mg kg⁻¹), saline plus ondansetron (2 mg kg⁻¹), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. RESULTS In protocol A, paracetamol (100 mg kg⁻¹)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg⁻¹ or saline [ED₅₀ paracetamol=46.3 (6.34) mg kg⁻¹]. No difference was found between paracetamol (30 mg kg⁻¹) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg⁻¹)+saline, paracetamol (100 mg kg⁻¹)+ondansetron (1 mg kg⁻¹), and paracetamol (100 mg kg⁻¹)+ondansetron (2 mg kg⁻¹), whereas in mice receiving saline+ondansetron (2 mg kg⁻¹) or saline+saline, there was no difference. CONCLUSION We found that paracetamol 100 mg kg⁻¹ blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.

Additivity of bupivacaine and morphine for peripheral analgesia in rats.

Abstract— Infiltration of the surgical wound is a classical technique for post‐operative analgesia. Recent studies have suggested that local anaesthetic may be combined with other drugs such as opioids. This study has evaluated, in rat, the infiltration with morphine, bupivacaine and their combination. In all groups, the two hind paws were injected with carrageenin. The left hind paw was used as control. The vocalisation threshold to paw pressure (VTPP) of both hind paws was evaluated 2 h after induction of carrageenin inflammation (baseline value), then every lOmin until the return to baseline value after injection of analgesic drugs. The development of oedema was evaluated in both hind paws by measurement of paw circumference (PC) before, then after, carrageenin injection. All analgesic drugs were injected in the right inflamed paw diluted in 0.2 mL of normal saline. The analgesic effect of bupivacaine (0.1, 0.25 and 0.5%), morphine (25, 50 and 100 μg) and their combination (bupivacaine 0.1%/morphine 20 μg, bupivacaine 0.2%/morphine 40 μg and bupivacaine 0.4 %/morphine 80 μg) was tested. The effect of naloxone on morphine induced analgesia was tested. The interaction between bupivacaine and morphine was evaluated with an isobolographic analysis. Bupivacaine produced a dose‐dependent antinociceptive effect. Morphine infiltration produced a peripheral, dose‐dependent analgesic effect antagonised by naloxone. This analgesic effect of morphine was associated with an anti‐inflammatory effect. The isobolographic analysis revealed only additivity between bupivacaine and morphine. The infiltration with morphine offers a peripheral analgesic effect which is additive with the effect of bupivacaine. An anti‐inflammatory effect of morphine participates in this peripheral analgesic effect.