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Anesth Analg 2002;94:1621-1624 © 2002 International Anesthesia Research Society
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Abstract |
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IMPLICATIONS: Manipulating the density of local anesthetic solutions by using a simple formula may be clinically useful in producing optimal density solutions for spinal anesthesia under a variety of clinical conditions.
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Introduction |
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The density of intrathecally administered drugs is believed to be an important factor in determining spread within the subarachnoid space (1,2). Adding glucose to local anesthetic solutions increases density and is used to manufacture hyperbaric bupivacaine solutions, the most popular intrathecal local anesthetic for spinal anesthesia. Injected in the lateral position, hyperbaric solutions produce a greater maximum height of sensory block, with a consequent more frequent incidence of hypotension, but with less variation in spread compared with glucose-free (plain) bupivacaine 0.5% (3,4).
These and similar studies suggest that the optimal density of intrathecal bupivacaine, producing adequate anesthesia without excessive hypotension, for different clinical circumstances may lie between the densities of the two currently available commercial preparations of hyperbaric and hypobaric bupivacaine. The aim of our laboratory study was to produce solutions of variable but predictable density at 37°C by altering the final glucose concentration of bupivacaine before studies investigating such optimal density solutions for different clinical situations are undertaken.
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Methods |
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The densities of all drugs tested were determined at 37°C (±0.01°C) by using a density meter (DMA 450; Paar Scientific Ltd., London, UK). The DMA 450 uses the mechanical oscillation resonance frequency technique (5) and is accurate to ±0.00001 g/mL (range, 0–3 g/mL). The DMA 450 was calibrated daily with desiccated air and distilled water. Study drugs included 5% glucose (Macoflex®; Macopharma, Twickenham, Middlesex, UK), distilled water (Antigen, Hillside, Southport, UK), 0.9% saline (Antigen), 0.5% bupivacaine (Antigen), and 0.5% bupivacaine (Marcain Plain®; AstraZeneca, King’s Langley, Herts, UK).
The first part of the study protocol was designed to measure density variations between multiple and single drug lots. For each drug, one ampule was either removed from five different drug lots (multiple lots) or five ampules were removed from the same lot (single lots), and a mean density value was obtained from five density measurements. All subsequent experiments were performed by using drugs from a single lot.
The second part of the study protocol determined the effect of adding glucose to Astra (BupAstra) and Antigen (BupAntigen) bupivacaine, which are both used in our institution. Various 2-mL saline/glucose mixtures, calculated to produce a final glucose concentration ranging from 0 to 10 mg/mL, were added to either 8 mL of BupAntigen or 8 mL of BupAstra (0.5%). This dilution was chosen to simulate mixtures used in clinical practice, where an opioid such as morphine or diamorphine is added to the bupivacaine, producing a final bupivacaine concentration of 0.4%.
The final part of the study protocol was designed to determine the effect of adding glucose to commonly used spinal drug combinations, such as that used for cesarean delivery within our own institution. One such bupivacaine/opioid mixture consists of 2 mL of 0.5% plain BupAntigen and 250 µg of diamorphine powder (Evans, Leatherhead, Surrey, UK) diluted in 0.5 mL of 0.9% saline (Antigen), resulting in a spinal injectate volume of 2.5 mL. This produces a final bupivacaine concentration of 4 mg/mL (0.4%), with a final diamorphine concentration of 100 µg/mL. This was reproduced for the study by adding 1000 µg of diamorphine to 8 mL of 0.5% BupAntigen, followed by 2 mL of the same saline/glucose combinations used in the previous experiment. In this way, the density of this bupivacaine/opioid combination was measured throughout a range of glucose concentrations. Because fentanyl is also a commonly used intrathecal drug, the previous experiment was repeated with 20 µg of fentanyl (Sublimaze®, 50 µg/mL; Janssen-Cilag, High Wycombe, Bucks, UK) in place of diamorphine, producing a final fentanyl concentration of 2 µg/mL within the same bupivacaine/saline/glucose combinations. The dose of fentanyl used in the study protocol was chosen for ease of dilution. Throughout the study period, a mean density result for each solution under test was generated by five consecutive individual density measurements.
The densities of all solutions tested are expressed as mean and SD, with variations in density within multiple and single lots analyzed with analysis of variance. A Student’s t-test was used to analyze the mean difference in density between undiluted Antigen and Astra bupivacaine. Analysis of variance was used to analyze density variations between bupivacaine/opioid and bupivacaine-only solutions across a range of glucose concentrations. Linear regression analysis was used to define the relationship between the final glucose concentration of a solution and its measured density. P < 0.05 was considered to be statistically significant.
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Results |
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There were no statistically significant differences in the measured densities of multiple or single lots of any drugs tested (Table 1). Study solution densities are shown in Table 2.
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The mean densities of undiluted BupAntigen and BupAstra were significantly different (mean difference, 0.00019 g/mL; 95% confidence interval [CI], 0.000186–0.000194 g/mL; P < 0.0001). Adding glucose to BupAntigen and BupAstra resulted in a linear increase in density with increasing glucose concentration (BupAntigen: R2 = 0.998, P < 0.0001; BupAstra: R2 = 0.979, P < 0.0001) (Fig. 1). There was a statistically significant difference in the mean densities of BupAntigen and BupAstra throughout the range of glucose dilutions (P < 0.0001). The presence of opioid had a minimal, although statistically significant, effect on the mean density of BupAntigen throughout the range of glucose concentrations (P < 0.0001; Fig. 2).
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All linear regression lines were expressed by using the formula y = a + bx (y = final solution density, b = line slope, x = final glucose concentration, a = y axis intercept). The mean slope (95% CI) for the regression lines corresponding to BupAntigen only, BupAntigen with diamorphine, and BupAntigen with fentanyl were 0.00026 (0.00025–0.00028; R2 = 0.998; P < 0.0001), 0.00026 (0.00025–0.00027; R2 = 0.996;P < 0.0001), and 0.00026 (0.00025–0.00027; R2 = 0.998; P < 0.0001), respectively. For BupAstra alone, the corresponding mean slope (95% CI) was 0.00026 (0.00025–0.00027; R2 = 0.998; P < 0.0001).
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Discussion |
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As in previous studies (5–7), all our non-glucose-containing solutions were hypobaric at body temperature (Table 2), with 0.5% BupAstra differing significantly in its mean density from the 0.5% BupAntigen (P < 0.0001). The reason why different commercial preparations of glucose-free bupivacaine should differ in their densities is unclear, but these differences were consistent between and within different lots. The study has also demonstrated that the addition of glucose to bupivacaine produced solutions of predictable density in a linear manner (Figs. 1 and 2), with the addition of opioid having a minimal, although significant, effect. Within 95% CIs, the slope (b) of all regression lines varied from 0.00025 to 0.00028, with the value a closely corresponding to the mean density of undiluted bupivacaine. By using the information derived from our experiments, a new modified formula for bupivacaine can now be expressed in the form of the following equation:
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If the final glucose concentration of the solution and the density of the undiluted local anesthetic are known, the density of any intrathecally administered solution can now be determined without the need for direct measurement. The fact that the densities of the two preparations of bupivacaine varied in parallel throughout the range of glucose dilutions makes it more likely that other local anesthetics would respond in the same way (i.e., the slope would be the same for any drug when glucose is used). Because anesthesiologists often add opioids to intrathecal local anesthetics, dilutions with glucose/saline mixtures, instead of saline, can create solutions with a desired density. Because the final glucose concentration (not the opioid) largely determines a solution’s density, the same principle should apply for other hypobaric opioids, including morphine.
Currently there are only two commercially available preparations of bupivacaine in the United Kingdom, namely, bupivacaine 0.5%, containing 8% glucose (Marcain Heavy®; AstraZeneca), which is hyperbaric; and glucose-free bupivacaine 0.5%, which is hypobaric. Although there is extensive clinical experience with both drugs for spinal anesthesia, they are not without problems. Hyperbaric bupivacaine is more predictable in its spread than glucose-free bupivacaine, but its higher spread is associated with an increased incidence of hypotension (3,4). These studies also found that bupivacaine solutions containing 5% glucose were clinically indistinguishable in terms of their spread from the 8% solution. Bannister et al. (8) compared bupivacaine containing final concentrations of 0.33%, 0.83%, or 8% glucose and found a significant difference in the maximal height of block between the 8% group and both the 0.33% and 0.83% groups, with the most frequent incidence of hypotension in the 8% group. It should be noted that the block was adequate for surgery in all but 1 of the 30 patients studied.
The optimal density of intrathecal bupivacaine, producing adequate anesthesia without excessive hypotension, may therefore lie between the densities of the preparations used in these studies. Although different final glucose concentrations of bupivacaine solutions have been studied, no study has looked at the effect on the spread of bupivacaine solutions containing from 1% to 5% glucose. The formula provides a simple way of calculating the density of common intrathecal combinations to facilitate research in this area.
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Acknowledgments |
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Stephen Hallworth was supported by a research fellowship grant from SIMS Portex Ltd., Hythe, Kent, UK. Gary Stocks was supported by a research fellowship grant from the Obstetric Anaesthetists’ Association, London, UK (registered charity 272190).
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References |
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- Stienstra R, Greene NM. Factors affecting the subarachnoid spread of local anesthetic solutions. Reg Anesth 1991; 16: 1–6.
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Greene NM. Distribution of local anesthetic solutions within the subarachnoid space. Anesth Analg 1985; 64: 715–30.
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Chambers WA, Edstrom HH, Scott DB. Effect of baricity on spinal anaesthesia with bupivacaine. Br J Anaesth 1981; 53: 279–82.
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Moller IW, Fernandes A, Edstrom HH. Subarachnoid anaesthesia with 0.5% bupivacaine: effects of density. Br J Anaesth 1984; 56: 1191–5.
[Abstract/Free Full Text] - Richardson MG, Wissler RN. Densities of dextrose-free intrathecal local anesthetics, opioids, and combinations measured at 37 degrees C. Anesth Analg 1997; 84: 95–9.[Abstract]
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Horlocker TT, Wedel DJ. Density, specific gravity, and baricity of spinal anesthetic solutions at body temperature. Anesth Analg 1993; 76: 1015–8.
[Abstract/Free Full Text] - Lui AC, Polis TZ, Cicutti NJ. Densities of cerebrospinal fluid and spinal anaesthetic solutions in surgical patients at body temperature. Can J Anaesth 1998; 45: 297–303.[Web of Science][Medline]
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Bannister J, McClure JH, Wildsmith JA. Effect of glucose concentration on the intrathecal spread of 0.5% bupivacaine. Br J Anaesth 1990; 64: 232–4.
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