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The safety profile of neuraxial magnesium has not been properly addressed


Academic year: 2021

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Monitoring anaesthetic gas concentrations

in the exhaust of the cardiopulmonary

bypass oxygenator

Editor—Nitzschke and colleagues1recently studied sevoflur-ane plasma concentrations during cardiopulmonary bypass (CPB). The authors found no relationship between sevoflurane plasma concentrations and either sevoflurane concentrations in the exhaust of the oxygenator or bispectral index (BIS) values, prompting them to conclude that ‘Measuring the concentration of sevoflurane in the exhaust from the oxygen-ator is not useful for monitoring sevoflurane administration during bypass’.

However, the authors failed to take into account the conse-quences of Henry’s law: at a constant temperature, the amount of a given gas that dissolves in a given type and volume of liquid is directly proportional to the partial pressure of that gas in equilibrium with that liquid. Blood/gas partition coefficient changes for sevoflurane during CPB were not measured, and may have been considerable given the acute changes in blood temperature and haematocrit that routinely occur.2 For this reason, the partial pressure in the blood remains unknown. This is the important variable, because, like all gases, inhaled anaesthetics are transported down a partial pressure gradient (not a concentration gradient), and be-cause their clinical effects correlate with the partial pressure. The appropriate technique to use is double headspace equili-bration of blood samples, as described by many previous authors, which allows simultaneous measurement of partial pressure and solubility.3–6

To summarize, reporting plasma concentrations without blood solubility does not allow meaningful clinical recom-mendations to be made. By implication, trying to find a relationship between plasma sevoflurane concentration and BIS with these data is futile. Therefore we argue that the conclusions by Nitzschke and colleagues are premature: pending further evidence, it remains reasonable practice to monitor anaesthetic gas concentrations in the exhaust of the oxygenator.

Declaration of interest

None declared. J. F. A. Hendrickx1* R. Carette1 P. Peyton2 A. De Wolf3

, members of www.navat.org research consortium 1Aalst, Belgium

2Melbourne, Australia 3Chicago, USA

*E-mail: jcnwahendrickx@yahoo.com

1 Nitzschke R, Wilgusch J, Kersten JF, et al. Changes in sevoflurane plasma concentration with delivery through the oxygenator during on-pump cardiac surgery. Br J Anaesth 2013; 110: 957 –65

2 Alliot PR, Steward A, Flook V, Mapleson WW. Variation with tempera-ture of the solubilities of inhaled anesthetics in water, oil and bio-logical media. Br J Anaesth 1973; 45: 294 –300

3 Fink BR, Morikawa K. A simplified method for the measurement of volatile anesthetics in blood by gas chromatography. Anesthesiology 1970; 32: 451 –5

4 Wagner PD, Naumann PF, Lavaruso RB. Simultaneous measurement of eight foreign gases in blood by gas chromatography. J Appl Physiol 1974; 36: 600 –5

5 Smith MA, Sapsed-Byrne SM, Lockwood GG. A new method for meas-urement of anesthetic partial pressure in blood. Br J Anesth 1997; 78: 449 –52

6 Peyton P, Chong M, Stuart-Andrews C, Robinson G, Pierce R, Thompson B. Measurement of anesthetic agents in blood using a conventional infrared clinical gas analyzer. Anesth Analg 2007; 105: 680– 7


The safety profile of neuraxial magnesium

has not been properly addressed

Editor—We read with interest the recent meta-analysis by Mor-rison and colleagues,1in which the authors reviewed the effect of intrathecal administration of magnesium on the duration of spinal anaesthesia. After a thorough subgroup analysis, the authors concluded that the addition of intrathecal magnesium to lipophilic opioids with or without local anaesthetic is asso-ciated with an increased duration of spinal anaesthesia in the non-obstetric population, defined as time to first analgesic request. They also encouraged authors to perform additional randomized controlled trials (RCTs) to better define the role of intrathecal magnesium when administered with local anaes-thetics alone, and more specifically, in the obstetric population. However, we would like to raise an important issue. As stated recently in another meta-analysis investigating the an-algesic efficacy of perioperative neuraxial magnesium,2the safety profile of this mode of administration has not been prop-erly addressed. This previous review supported the clinical con-clusions of Morrison and colleagues, demonstrating that intrathecal magnesium increased the time to first analgesic request by a mean difference of 39.6 min, reduced morphine consumption at 24 h after operation, and reduced early post-operative pain scores. Of concern, however, only four of the 18 included trials, representing a total of only 140 patients, specifically sought evidence of neurological complications. Indeed, the bolus doses used of 50–100 mg may be neurotoxic. Animal studies have demonstrated pain on injection, motor dysfunction, and histological dose-dependent changes in rabbit neurones after intrathecal doses of 0.3, 1, 2, and 3 mg kg21.3These doses closely mirror human doses studied on a per kilogram basis (0.7– 1.4 mg kg21, based on an estimated 70 kg mass). Moreover, two case reports have described patients suffering from disorientation4and continuous peri-umbilical burning pain5with continuous infusion of neuraxial magnesium.

In summary, most human trials investigating the efficacy of intrathecal magnesium have failed to monitor for neurological




complications and the potential neurotoxicity of intrathecal magnesium has not been adequately addressed in animals. Morrison and colleagues rightly qualify their review with the caveat that magnesium sulphate is not currently licensed in the UK for intrathecal administration. We urge clinicians to con-sider these concerns. Rather than proceeding with additional RCTs to answer the questions raised by this meta-analysis, we advocate additional basic science studies to strengthen our understanding of the risk-to-benefit balance from the use of this intrathecal adjunct.

Declaration of interest

None declared. E. Albrecht1* C. Kern1 K. R. Kirkham2 1Lausanne, Switzerland 2Toronto, Canada *E-mail: eric.albrecht@chuv.ch

1 Morrison AP, Hunter JM, Halpern SH, Banerjee A. Effect of intrathecal magnesium in the presence or absence of local anaesthetic with and without lipophilic opioids: a systematic review and meta-analysis. Br J Anaesth 2013; 110: 702– 12

2 Albrecht E, Kirkham KR, Liu SS, Brull R. The analgesic efficacy and safety of neuraxial magnesium sulphate: a quantitative review. Anaesthesia 2013; 68: 190– 202

3 Saeki H, Matsumoto M, Kaneko S, et al. Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits? Anesth Analg 2004; 99: 1805–12

4 Goodman EJ, Haas AJ, Kantor GS. Inadvertent administration of magnesium sulfate through the epidural catheter: report and ana-lysis of a drug error. Int J Obstet Anesth 2006; 15: 63– 7

5 Dror A, Henriksen E. Accidental epidural magnesium sulfate injec-tion. Anesth Analg 1987; 66: 1020–1


Reply from the authors

Editor—We thank Dr Albrecht and colleagues for their thoughtful comments regarding our recent meta-analysis of the effect of intrathecal magnesium on the duration of spinal anaesthesia.1They are justified in raising concerns regarding the safety of using intrathecal magnesium and, in particular, of neurotoxicity. We did mention neurotoxicity within the Dis-cussion section, including the study from Saeki and colleagues2 which demonstrated the destruction of laminae V–VII at doses of magnesium 1 mg kg21or more. In contrast, a study from Chanimov and colleagues3demonstrated no histological differences in the spinal cord when serial intrathecal injections of up to 12.6% magnesium sulphate, lidocaine, or saline were given to rats.

Other animal studies have also shown conflicting evidence regarding neurotoxicity. In contrast to Saeki and colleagues, Simpson and colleagues4demonstrated that administering

intrathecal magnesium before thoracic aortic cross-clamping reduced the incidence of paraplegia from spinal cord ischae-mia in animals. A recent study has shown, however, that in animals, 15% magnesium sulphate given via the intrathecal route is associated with some degeneration of the mitochon-dria, and neuronal degenerative changes on repeated injec-tions.5 The trials included within our meta-analysis either used 50% magnesium6–9 or 15% magnesium sulphate.10 There were no reported events suggestive of neurotoxicity within these or any other studies in our meta-analysis, al-though undoubtedly the length of follow-up may not have been sufficient to uncover all the possible neurological effects. Given the inconsistency regarding the potential neuro-toxicity, we would advocate that the safety profile of magne-sium sulphate should perhaps be confirmed with further well-designed safe dose finding studies in clinical research.

Dr Albrecht and colleagues also raise the issue of disorien-tation after epidural administration of magnesium sulphate that was administered as an infusion inadvertently.11We did not investigate the effect of continuous epidural magnesium sulphate; hence, we cannot speculate as to whether the symp-toms are applicable to the intrathecal route. Furthermore, the authors of the case report attributed the symptoms to a supra-therapeutic serum magnesium concentration having received 9 g in just over 1 h.

Declaration of interest

None declared. A. P. Morrison1 J. M. Hunter1 S. H. Halpern2 A. Banerjee1* 1Liverpool, UK 2Toronto, Canada *E-mail: abanerjeeuk@gmail.com

1 Morrison AP, Hunter JM, Halpern SH, Banerjee A. Effect of intrathecal magnesium in the presence or absence of local anaesthetic with and without lipophilic opioids: a systematic review and meta-analysis. Br J Anaesth 2013; 110: 702–12

2 Saeki H, Matsumoto M, Kaneko S, et al. Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits? Anesth Analg 2004; 99: 1805–12

3 Chanimov M, Cohen ML, Grinspun Y, et al. Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate. An experimental study in a rat model. Anaesthesia 1997; 52: 223 –8

4 Simpson JI, Elde TR, Schiff GA, et al. Intrathecal magnesium sul-phate protects the spinal cord from ischemic injury during thoracic aortic cross-clamping. Anesthesiology 1994; 81: 1493–9

5 Ozdogan L, Sastim H, Ornek D. Neurotoxic effects of intrathecal magnesium sulphate. Braz J Anesthesiol 2013; 63: 139 –48 6 Khalili G, Janghorbani M, Sajedi P, Ahmadi G. Effects of adjunct

intra-thecal magnesium sulfate to bupivacaine for spinal anesthesia: a randomized, double-blind trial in patients undergoing lower ex-tremity surgery. J Anesth 2011; 25: 892 –7




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