Local infiltration analgesia with ropivacaine, ketorolac, and epinephrine is a technically simple method for postoperative pain management after knee and hip replacement,1 which has gained popularity in many countries.2 Local infiltration analgesia not only improves postoperative pain but also reduces the need for opioid analgesic drugs and leads to faster rehabilitation and earlier discharge from hospital.3–7 Information regarding the pharmacokinetics and safety margin of ropivacaine and area under the curve after local infiltration analgesia is still sparse. Ropivacaine binds mainly to alpha-1-acid glycoprotein (AAG),8 a plasma protein, which increases during trauma.8–14
A generalized grand mal seizure has been reported at an IV concentration of 3.68 mg/L of ropivacaine, 15 minutes after an ultrasound-guided and peripheral nerve stimulator–assisted interscalene brachial plexus blockade, with no sign of intravascular placement, with 75 mg of ropivacaine, a dose considered to be safe.15 Large surgical incisions and soft-tissue dissection, typical of major orthopedic surgery, may lead to peak plasma levels of local anesthetics16 with increased risk for central nervous system and cardiovascular toxicity.17
The aim of this study was to determine the maximal plasma concentration of unbound ropivacaine for 30 hours after elective primary total hip arthroplasty using local infiltration analgesia for postoperative analgesia. In addition, we assessed whether the level of AAG during the first postoperative day after local infiltration analgesia correlates with the fraction of unbound ropivacaine.
This study, conducted between 2010 and 2011, was approved by the IRB and the medical product agency of Sweden. This study was conducted with written informed consent from the study subjects. We included 15 adult patients, ASA grade I to III, without allergies to any of the study drugs, creatinine plasma concentration <100 mmol/L, and QT-interval <450 milliseconds. Access to research staff limited inclusion of patients. No eligible patient refused participation.
All patients had spinal anesthesia at L2-L3 or L3-L4 with isobaric bupivacaine (Marcain Spinal®, AstraZeneca, Stockholm, Sweden). Local infiltration analgesia consisted of peri- and intra-articular infiltration with a mixture of 100 mL ropivacaine (2 mg/mL; Narop®, AstraZeneca), 1 mL ketorolac (30 mg/mL; Toradol®, Roche), and 5 mL epinephrine (0.1 mg/mL; Adrenalin®, NM Pharma): 20 mL was injected subcutaneously at the start of the operation and the remaining 86 mL in the capsula, the resutured short outward rotators and the gluteus maximus.
Quantification of Total and Unbound Ropivacaine
Sampling started 10 minutes after completing local infiltration analgesia at 10, 20, 30, 45 minutes and 1, 2, 3, 4, 6, 8, 12, 24, and 30 hours, respectively. Liquid chromatography-mass spectrometry (Agilent 1100 MSD; Agilent Technologies, CA) was used. The limits of quantification were 0.0053 to 2.66 mg/L. The internal standard was doxepine (Sigma-Aldrich, St. Louis, MD). The unbound ropivacaine concentration was determined after centrifugation at 5500g for 10 minutes at 37°C using an Amicon ULTRA centrifugal filter.
Quantification of AAG
Plasma AAG, collected before moving the patient to the operating room and 1, 4, 12, and 24 hours after surgery, was analyzed with nephelometry (IMMAGE by Beckman Coulter, Stockholm, Sweden).
Electrocardiograph changes and neurological symptoms of local anesthetic toxicity were monitored according to clinical routine.
This pilot study without prior power calculation used a sample size of 15 based on previous experience.18 Prism 6.0 software (GraphPad Software, San Diego, CA) was used to calculate area under the curve. The upper prediction bound for maximal unbound ropivacaine was 2.22 SD based on normal distribution. Since zero adverse events were observed, we calculated the Clopper-Pearson exact value.19 Statistica 12 (StatSoft, Tulsa, OK) was used to calculate linear correlation and estimate the statistical power. P < 0.05 and a power of at least 80% were required to draw any conclusion on correlation.
All patients completed the study. Demographic data and individual results are presented in Table 1, the pharmacokinetic profile for ropivacaine in Figure 1, the AAG profile over time in Figure 2, and percentage of unbound ropivacaine versus AAG in Figure 3, respectively. The 95% upper prediction bound for unbound ropivacaine was 0.032 mg/L. The statistical power of the linear correlation of maximal concentration versus age or creatinine clearance was 53% and 50%, respectively. Neither tachycardia, nor arrhythmias on electrocardiogram, nor neurological signs of local anesthetic toxicity (circumoral paresthesia, tinnitus, muscle twitch, or seizure) were detected. The Clopper-Pearson 95% upper confidence limit for adverse signs was 0.218.
Two hours after surgery, no prolongation of QT-interval >450 milliseconds was observed in any patient.
The 95% upper prediction bound for maximal unbound plasma concentration after injection of 200 mg ropivacaine in local infiltration analgesia was 0.032 mg/L. This level is comparable with levels observed after local infiltration analgesia without epinephrine20 and half as high as after 400 mg.21 Plasma concentrations within the same range,22–27 or considerably higher,28,29 without adverse reactions have been reported during epidural infusion or peripheral nerve block with ropivacaine. Side effects sufficient to stop an IV infusion were reported at arterial concentrations of 0.34 to 0.85 mg/L.30 This range has been considered a relevant safety limit in studies reporting the venous plasma concentration of unbound ropivacaine.26,29
With increasing age, total body water, peripheral circulation, and renal function decrease.31 These changes may affect the pharmacokinetics of ropivacaine after local infiltration analgesia. Using a 2-sided test based on our data, at least 29 individuals are needed to get a power of 80% to test the hypotheses that the maximal unbound ropivacaine concentration correlates with age and creatinine clearance. Thus, our sample size of 15 individuals was insufficient to test this hypothesis.
Ropivacaine binds mainly to AAG,12,14 but previous studies on ropivacaine after local infiltration analgesia16,21,32 have not reported the plasma level of AAG. We detected AAG levels similar to those in young healthy adults.33 After 24 hours, AAG had increased by <40%. However, we did not find any correlation between the plasma concentration of AAG and the percentage of unbound plasma concentration of ropivacaine during the first 24 hours after local infiltration analgesia. AAG levels may double approximately 4 days postoperatively and seem to reach a maximal concentration at postoperative days 6 to 12.11,13 An increase of AAG sufficient to decrease the unbound concentration of ropivacaine has been observed later than 24 hours after surgical trauma.8,22,28,34 Not only the unbound plasma concentration but also physiological, anatomical, and pharmacokinetic factors contribute to toxicity of local anesthetic.35
The unbound ropivacaine concentration after 200 mg of ropivacaine administered during local infiltration analgesia seems to be below plasma concentrations linked to adverse cardiac or neurological reactions in the patient population included in this study. Inclusion of more elderly patients with decreased renal function is needed to determine cutoff levels for decreased doses of ropivacaine in local infiltration analgesia required for safety concerns. AAG levels are of minor importance for unbound ropivacaine plasma concentration during the first 24 hours after total hip arthroplasty with local infiltration analgesia. Larger studies are needed to test the hypothesis that the unbound ropivacaine concentration correlates with age and creatinine clearance.
Name: Fatin Affas, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Fatin Affas has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Staffan Eksborg, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Staffan Eksborg has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Per Wretenberg, MD, PhD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Per Wretenberg has seen the original study data and approved the final manuscript.
Name: Christina Olofsson, MD, PhD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Christina Olofsson has seen the original study data and approved the final manuscript.
Name: Carl-Olav Stiller, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Carl-Olav Stiller has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Terese T. Horlocker, MD.
The authors thank Professor Olof Beck, chemist, and Tommy Petterson, laboratory engineer, Department of Clinical Pharmacology, Karolinska University Hospital Laboratory, for analysis of ropivacaine; Lena Sandlund, Center for Laboratory Medicine Karolinska University Hospital, for analysis of alpha-1-acid glycoprotein; and Anna Granström and Anna Schening, research nurses, Karolinska University Hospital, Department of Anesthesia and Intensive Care, for technical assistance.
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