Skip Navigation



BJA Advance Access published online on February 15, 2007
British Journal of Anaesthesia, doi:10.1093/bja/ael373
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
98/4/497    most recent
ael373v1
Right arrow E-Letters: Submit a response to the article
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by McLeod, G. A.
Right arrow Articles by Columb, M. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McLeod, G. A.
Right arrow Articles by Columb, M. O.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

An isobolographic analysis of diamorphine and levobupivacaine for epidural analgesia in early labour

G. A. McLeod1,*, B. Munishankar1 and M. O. Columb2

1 Department of Anaesthetics, Ninewells Hospital and Medical School, Dundee, Scotland, UK
2 Acute Block Intensive Care Unit, South Manchester University Hospital, Wythenshawe, UK

* Corresponding author: Department of Anaesthetics, Ninewells Hospital and Medical School, Dundee, Scotland. E-mail: g.a.mcleod{at}dundee.ac.uk

Accepted for publication December 2, 2006.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
BACKGROUND: Few data describe the pharmacological interactions between local anaesthetics and opioids. The aim of this study was to measure the median effective concentration (MEC) of diamorphine and levobupivacaine when given separately and as mixtures for epidural analgesia, and determine whether the combination is additive or synergistic.

METHODS: One hundred and twenty patients were enrolled in this prospective randomized, two-phase, double-blind study. In the first phase, 60 women were randomized to receive a fixed 20 ml volume of either levobupivacaine or diamorphine epidurally . Dosing was determined using up-down sequential allocation with testing intervals, respectively, of 0.01%w/v and 12.5 µg ml–1. After estimations of the MEC of levobupivacaine and diamorphine, a further 60 patients were randomized in the second phase to one of the three mixtures: (a) diamorphine 70 µg ml–1 (fixed) and levobupivacaine (testing interval 0.004%w/v, starting at 0.044%w/v); (b) levobupivacaine 0.044%w/v (fixed) and diamorphine (testing interval 7 µg ml–1, starting at 70 µg ml–1); and (c) bivariate diamorphine and levobupivacaine (testing intervals of 7 µg ml–1 and 0.004%w/v starting at 70 µg ml–1 and 0.044% w/v respectively).

RESULTS: The MEC estimates from the first phase were 143.8 µg ml–1 (95% CI 122.2–165.3) for diamorphine and 0.083%w/v (95% CI 0.071–0.095) for levobupivacaine. In the second phase, the MEC and interaction index ({gamma}) of the three combinations were: diamorphine 65.5 µg ml–1 (56.8–74.2), {gamma} = 0.99; levobupivacaine 0.041%w/v (0.037–0.049), {gamma} = 0.98; and for the fixed combination diamorphine 69.5 µg ml–1 (60.5–78.5) and levobupivacaine 0.044%w/v (0.039–0.049), {gamma} = 1.02.

CONCLUSION: The combination of diamorphine and levobupivacaine is additive and not synergistic when used for epidural analgesia in the first stage of labour.

Keywords: anaesthesia, obstetric;; anaesthetic techniques, epidural;; anaesthetics local, levobupivacaine;; analgesics opioid, diamorphine


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
The clinical efficacies of local anaesthetics1 and opioids2 have been shown to be concentration-dependent when used as the sole epidural analgesic in labour. However, in practice, epidural administration of a mixture of local anaesthetic and opioid is more commonplace during labour3 4 or after surgery.5 6 Use of a combined approach often decreases the incidence of side-effects while maintaining a similar level of pain relief.7 Despite widespread use of combinations of local anaesthetics and opioids, there are few data describing the pharmacological interactions between these drug groups,8 9 and a wide range of combination therapies are used clinically. Therefore, the aim of this study was to measure the median effective concentration (MEC) of diamorphine and levobupivacaine when given separately and as mixtures for epidural analgesia, and determine whether the combination is additive or synergistic.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
One hundred and twenty patients were enrolled in his prospective randomized, two-phase, double-blind study after informed, written consent, and approval by the Tayside Committee on Medical Ethics. Patient information sheets describing the study protocol and procedure were distributed within the antenatal clinic to patients between 36 and 38 weeks gestation. Patients were approached for consent early in labour and before induction. Criteria for inclusion in the study were request for epidural analgesia when in active labour, cervical dilatation ≤5 cm, no opioids administered within the previous 12 h and no history of significant antenatal or maternal illness.

After i.v. infusion of crystalloid solution, and with the patient in the left lateral position, a lumbar epidural catheter was inserted caudally at the L 2/3 interspace using loss of resistance to saline. Saline injection was minimized to <2 ml. All epidural injections were performed by one anaesthetist (B.M.), using the standard technique.

In the first phase, 60 women were randomized, using computer-generated numbers and sealed envelopes, to receive a fixed 20 ml volume of either epidural levobupivacaine (n = 30) or diamorphine (n = 30). No test dose was given and time zero was designated as the time at which the epidural injection was completed. Once the injection was given, the anaesthetist left the room. Both the patient and midwife were blinded to the syringe contents. Non-invasive blood pressure was measured every 5 min for the first 20 min according to the labour ward epidural protocol. The pressure at 15 min was used for analysis.

Labour pain was measured using the same method as previous, similar studies1 2 investigating the MEC of local anaesthetics in early labour. Pain after epidural injection was measured every 5 min for 30 min by midwives with a visual analogue pain score (VAPS) corresponding to the peak pain associated with the previous contraction. The outcomes of the study were defined as:

  • Successful—VAPS ≤10 mm at any time within the 30 min study period.
  • Unsuccessful—VAPS >10 mm within the 30 min study period, but pain relief after bolus rescue with a 10 ml solution of 0.25%w/v bupivacaine.
  • Technical failure—VAPS >10 mm within the 30-min study period, but no pain relief after bolus rescue with a 10 ml solution of 0.25%w/v bupivacaine. After a technical failure, the next patient was randomized to the same solution and concentration.

Dosing was started at 0.12%w/v levobupivacaine and 200 µg ml–1 diamorphine and continued using up-down sequential allocation with testing intervals of 0.01%w/v and 12.5 µg ml–1 for levobupivacaine and diamorphine, respectively. Testing intervals approximating to 10% of the initial dose were used in accordance with previous methodology.1 2

After estimations of the MEC of levobupivacaine and diamorphine, a further 60 patients were randomized in the second phase to one of three mixtures (n = 20):

  • diamorphine 70 µg ml–1 (fixed) and levobupivacaine (testing interval 0.004%w/v, starting at 0.044%w/v);
  • levobupivacaine 0.044%w/v (fixed) and diamorphine (testing interval 7 µg ml–1, starting at 70 µg ml–1);
  • bivariate diamorphine and levobupivacaine (fixed testing intervals of diamorphine 7 µg ml–1 and levobupivacaine 0.004%w/v, starting at a combination dose of diamorphine 70 µg ml–1 and levobupivacaine 0.044%w/v, respectively).

Measurement of the efficacy of analgesia in phase two used the same criteria as phase one. After the study, pain relief was maintained throughout labour with patient controlled epidural boluses of 15 ml bupivacaine 0.1%w/v. Hourly monitoring of maternal heart rate, non-invasive arterial pressure, ventilatory frequency, nausea, and vomiting was undertaken until 2 h after delivery. In addition, fetal welfare was assessed using continuous cardiotocography, Apgar scores, umbilical arterial, and venous pH.

Data are presented as mean (SD), median (IQR), and count, and were analysed using Student's t-test, one-way analysis of variance (ANOVA), repeated measures ANOVA, Kruskal–Wallis ANOVA on ranks, Fisher's exact test, and {chi}2 test as appropriate. Up-down analysis of paired reversals and probit regression were used to estimate MEC with 95% CI. The interaction index {gamma},10 defined by the isobolar relation a/A+b/B, where A is the concentration of drug A (alone), B is the concentration of drug B (alone), and (a,b) is the combination that produces the same clinical effect, was used to quantify any interaction. If {gamma} = 1 the combination is additive, if {gamma}>1 the combination is sub additive, and if {gamma}<1 the combination is synergistic. The isoboles were plotted on isobolographic plots and compared with the 95% CI to the line of addition. Analyses were carried out using Excel 2000 (Microsoft Inc., Redmond, WA, USA), Number Cruncher Statistical Software (NCSS 2001, Inc., Kaysville, UT, USA) and Minitab 14.13 (Minitab Inc., State College, PA, USA).


View this table:
[in this window]
[in a new window]

  		Table 1 Patient characteristics of those receiving diamorphine alone, levobupivacaine alone, and the combination of diamorphine and levobupivacaine (three groups combined). Continuous data analysed using one-way ANOVA; nominal data{dagger} analysed using {chi}2 or Fisher's exact test

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Patient characteristics (Table 1), obstetric data and fetal outcomes (Table 2) were similar in all groups. No patient had a measured ventilatory frequency <12 bpm at any time during or after labour. There was no difference in systolic arterial pressure between patients receiving diamorphine, levobupivacaine, or the combination, either before or after epidural injection (F-ratio 0.4, P = 0.92). In contrast, diastolic arterial pressure consistently reduced 15 min after epidural injection in all groups (F-ratio 11.7, P < 0.001). Nausea and vomiting was more common in women who received diamorphine (P < 0.01). One patient spontaneously complained of itching.


View this table:
[in this window]
[in a new window]

  		Table 2 Maternal and fetal outcomes for patients receiving diamorphine alone, levobupivacaine alone and the combination of diamorphine and levobupivacaine (three groups combined). Continuous, parametric data analysed using one-way ANOVA and presented as mean (SD) and F-ratio. Continuous, non-parametric data* analysed using Kruskal–Wallis one-way ANOVA on ranks and presented as median (IQR) and {chi}2. Nominal data{dagger} analysed using {chi}2 or Fisher's exact test. SVD, spontaneous vaginal delivery

 
The MEC estimates from the first phase (Fig. 1) were 143.8 µg ml–1 (95% CI 122.2–165.3) for diamorphine and 0.083%w/v (95% CI 0.071–0.095) for levobupivacaine using up-down analysis. The results of the probit regression are shown in Table 3.


Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig 1 First phase: patient sequences with MEC (95% CI) are plotted (n = 30 per group). (A) MEC for diamorphine was 143.8 (122.2–165.3) µg ml–1 (testing interval 12.5 µg ml–1). (B) MEC for levobupivacaine was 0.083 (0.071–0.095)%w/v (testing interval 0.01%w/v).

 


View this table:
[in this window]
[in a new window]

  		Table 3 MEC (95% CI) estimates of isoboles

 
In the second phase, the MEC of three combinations were estimated (Table 3). Results using up-down analysis were: diamorphine 65.5 µg ml–1 (56.8–74.2), {gamma} = 0.99 (Fig. 2); levobupivacaine 0.041%w/v (0.037–0.049), {gamma} = 0.98 (Fig. 2); and for the fixed combination (Fig. 2) diamorphine 69.5 µg ml–1 (60.5–78.5) and levobupivacaine 0.044%w/v (0.039–0.049), {gamma} = 1.02. Figure 3 shows an isobologram of each single drug MEC on the x- and y-axes with the three mixed isoboles and the line of addition joining the single drug MEC estimates. Each mixed isobole with 95% CI is contained wholly within the 95% CI of the line of addition. The mixed isoboles were combined using probit analysis (Table 4) and also plotted as an isobologram, yielding {gamma} = 1.00 (Fig. 3). The results show that the combination of levobupivacaine and diamorphine is additive and not synergistic for analgesia in the first stage of labour.


Figure 2
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig 2 Second phase: patient sequences with MEC (95% CI are plotted (n = 20 per group). (A) MEC for diamorphine with levobupivacaine fixed at 0.044%w/v was 65.5 µg ml–1 (56.8–74.2), {gamma} = 0.99 (testing interval; 7 µg). (B) MEC for levobupivacaine with diamorphine fixed at 70 µg ml–1 was 0.041%w/v (0.037–0.049), {gamma} = 0.98 (testing interval 0.004%w/v). (C) MEC estimates for fixed ratio of diamorphine and levobupivacaine were 69.5 µg ml–1 (60.5–78.5) and 0.044%w/v (0.039–0.049) respectively, {gamma} = 1.02, (testing intervals 7 µg and 0.004%w/v).

 


Figure 3
View larger version (28K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig 3 Isobolograms are plotted with isoboles (95% CI error bars) and line of addition with 95% CI. (A) The up-down analysis plot shows the isoboles from the first phase with the three isoboles from the second phase. (B) Probit analysis is used to combine the isoboles from the second phase to give a summarized estimate of the second phase. The overall interaction index {gamma} = 1.00 confirms that addition, not synergy, best categorizes the interaction.

 


View this table:
[in this window]
[in a new window]

  		Table 4 Probit results of MEC (95% CI) for the combined isobolographic plot

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
This study has shown that the efficacy of levobupivacaine and diamorphine is purely additive ({gamma} = 1.00) when used in combination for analgesia in the first stage of labour. There was no evidence of synergism with these drugs.

Results from the first stage of our study support results from previous work investigating the potency of levobupivacaine. Our MEC for levobupivacaine of 0.083%w/v (95% CI 0.071–0.095) is similar to previous studies.17 However, our MEC for diamorphine was almost half that of our preceding study in the labour ward which used a fixed dose of 3 mg diamorphine. The MEC of diamorphine in our present study was 143.8 µg ml–1 (95% CI 122.2–165.3) compared with an overall MEC of 244.2 µg ml–1 (95% CI 230.8–257.2) in the fixed dose study.2 The difference in MEC may be explained by the differences in injection volumes. In our current study, injection volume was standardized to a fixed volume of 20 ml, whereas in our previous fixed dose study,2 the volume (and concentration) injected varied according to the response of the previous patient and varied between 10 and 15 ml.

Examination of data from both studies2 suggests that the pharmacodynamic profile of diamorphine is more complex than presumed. There is a widespread assumption that the effectiveness of epidural drugs is dependent entirely on dose. However, in this study using a fixed volume design, efficacy improved, as expected, by increasing dose, but in the previous study2 using a fixed dose design, improvement followed increasing concentration. For example, in the current study, efficacy was improved from the MEC of 144 µg ml –1 in 20 ml by increasing dose, while in the previous fixed dose study,2 efficacy was improved by increasing concentration from 150 µg ml–1 (in 20 ml) to 600 µg ml–1 (in 5 ml). Thus, the two studies together suggest that enhancing the clinical efficacy of diamorphine is dependent on both the dose and the concentration of drug. Our studies would suggest that presenting a fixed mass of diamorphine to the epidural space may not necessarily provide good clinical pain relief, unless it is mixed in a small volume (of high concentration).

The data from these and other studies also suggest that the optimum volumes for dosing efficiency are different for local anaesthetics and diamorphine in the epidural space. Fixed dose studies of bupivacaine11 and chloroprocaine12 have shown improved efficacy with high volume (>20 ml), low concentration solutions, whereas our studies investigating diamorphine have shown efficacy is improved with higher concentrations and lower volumes. Differences in optimal volume between local anaesthetics and diamorphine almost certainly reflects their respective sites of action; the former in the epidural space requires adequate volume for dermatomal coverage, while the latter, presumably acting at spinal opioid receptors, is more concentration gradient rather than volume dependent.

This apparent conflict may partly explain a failure to find any synergy ({gamma}>1.00) for the combination, but the fixed volume design of the current study probably also precludes findings of {gamma}<1.00, and by fixing volume (which is usual clinical practice) we are biasing to addition. Choice of drug ratios and clinical endpoints may also influence the results of isobolography. Our results pertain to the relatively fixed ratio of levobupivacaine and diamorphine (approximately 50:50) and a commonly used endpoint (VAPS score ≤10 mm). As the 50:50 ratio is the combination where interactions are best defined, it is likely that our results are generally representative of the nature of the interaction for these two drugs.

We chose diamorphine because we have previously shown that it provides good pain relief equivalent to that of local anaesthetics for pain in the first stage of labour and had pharmacological properties that would allow us to construct a clinical isobologram. The interaction between the more commonly used opioids, fentanyl and sufentanil, and local anaesthetics is not known. Two studies investigating the dose response of local anaesthetics when combined with fentanyl13 and sufentanil14 have indicated that the combination of fentanyl to bupivacaine is additive, but that the combination of sufentanil and ropivacaine may be synergistic. A recent study has shown that both fentanyl and sufentanil may provide analgesia in labour equivalent to a VAPS ≤10 mm, although using high doses.15 The minimum analgesic dose for sufentanil was 21.1 µg (95% CI, 20.2–21.9 µg) and 124.2 µg (95% CI, 118.1–130.6 µg) for fentanyl.

Side-effects in this study such as nausea and vomiting and sedation were associated with opioid use, alone or in combination, but not with local anaesthetic use. No differences were seen in systolic or diastolic arterial pressure between groups, although diastolic pressure was reduced in all groups 15 min after epidural injection. Importantly, there were no differences in fetal outcome. These findings contrast with a study investigating the efficacy and side-effects of epidural bupivacaine, morphine, or the combination when used for abdominal surgery,8 where the combination group had the best balance of efficacy against side-effects. It may be that our results may simply reflect the different patient populations. Of interest, side-effects were greater in this fixed 20 ml volume study compared with our previous fixed dose study2 using high concentration, low volume solutions.

Despite observing an additive effect of the combination, the value of our isobologram is relatively limited. Variations in relative potencies between dose pairs may occur with different drug ratios or alternative endpoints. Thus, our results pertain to the relatively fixed ratio of levobupivacaine and diamorphine (approximately 50:50) and the endpoint we used in this study (VAPS score ≤10 mm). The 50:50 ratio is, however, the combination where interactions are best defined.

Variations in relative potency may be determined by building a three-dimensional construct, plotting drug concentrations on the x- and y-axes, and plotting effect on the vertical z-axis. The advantage of using a response surface11 is that plotting of individual dose-effects creates an additive linear or non-linear reference surface relative to which combination effects may be viewed. Such methods require continuous measures and are not as suited to binary outcomes. Alternative methods of determining the optimal combination of local anaesthetic and opioid include direct search or optimization models such as the simplex method and Berenbaum's partition method.12 Irrespective of the method chosen, the concentrations and mixes of drugs cannot be assumed to be the optimum. Techniques such as optimization models, surface response analysis, and isobolography, provide a spectrum of tools, whereby the number of potential combinations is constrained from larger to smaller numbers, leading to qualitative and quantitative descriptions of interactions, which can be then evaluated in randomized controlled study designs.

In summary, we have shown that the combination of diamorphine and levobupivacaine is additive and not synergistic when used for epidural analgesia in the first stage of labour.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
We wish to thank the Obstetric Anaesthetists Association for funding B.M. during the conduct of this study.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
1 Lyons G, Columb M, Wilson RC, Johnson RV. (1998) Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 81:899–901.[Abstract/Free Full Text]

2 McLeod GA, Munishankar B, Columb MO. (2005) Is the clinical efficacy of epidural diamorphine concentration-dependent when used as analgesia for labour? Br J Anaesth 94:229–33.[Abstract/Free Full Text]

3 Bernard JM, Le Roux D, Barthe A, Jourdain O, Vizquel L, Michel C. (2001) The dose-range effects of sufentanil added to 0.125% bupivacaine on the quality of patient-controlled epidural analgesia during labor. Anesth Analg 92:184–8.[Abstract/Free Full Text]

4 Gogarten W, Van de Velde M, Soetens E, et al. (2004) A multicentre trial comparing different concentrations of ropivacaine plus sufentanil with bupivacaine plus sufentanil for patient-controlled epidural analgesia in labour. Eur J Anaesthesiol 21:38–45.[CrossRef][Web of Science][Medline]

5 Paech MJ, Pavy TJ, Orlikowski CE, Lim W, Evans SF. (1997) Postoperative epidural infusion: a randomized, double-blind, dose-finding trial of clonidine in combination with bupivacaine and fentanyl. Anesth Analg 84:1323–8.[Abstract]

6 Niemi G and Breivik H. (2003) The minimally effective concentration of adrenaline in a low-concentration thoracic epidural analgesic infusion of bupivacaine, fentanyl and adrenaline after major surgery. A randomized, double-blind, dose-finding study. Acta Anaesthesiol Scand 47:439–50.[CrossRef][Web of Science][Medline]

7 Liu SS, Carpenter RL, Mackey DC, et al. (1995) Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology 83:757–65.[CrossRef][Web of Science][Medline]

8 Robinson AP, Lyons GR, Wilson RC, Gorton HJ, Columb MO. (2001) Levobupivacaine for epidural analgesia in labor: the sparing effect of epidural fentanyl. Anesth Analg 92:410–4.[Abstract/Free Full Text]

9 Curatolo M, Schnider TW, Petersen-Felix S, et al. (2000) A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia. Anesthesiology 92:325–37.[CrossRef][Web of Science][Medline]

10 Tallarida RJ. (2002) The interaction index: a measure of drug synergism. Pain 98:163–8.[CrossRef][Web of Science][Medline]

11 Tallarida RJ. (2001) Drug synergism: its detection and applications. J Pharmacol Exp Ther 298:865–72.[Abstract/Free Full Text]

12 Curatolo M and Sveticic G. (2002) Drug combinations in pain treatment: a review of the published evidence and a method for finding the optimal combination. Best Pract Res Clin Anaesthesiol 16:507–19.

13 Robinson AP, Lyons GR, Wilson RC, Gorton HJ, Columb MO. (2001) Levobupivacaine for epidural analgesia in labor: the sparing effect of epidural fentanyl. Anesth Analg 92:410–4.[Abstract/Free Full Text]

14 Polley LS, Columb MO, Wagner DS, Naughton NN. (1998) Dose-dependent reduction of the minimum local analgesic concentration of bupivacaine by sufentanil for epidural analgesia in labor. Anesthesiology 89:626–32.[CrossRef][Web of Science][Medline]

15 Capogna G, Camorcia M, Columb MO. (2003) Minimum analgesic doses of fentanyl and sufentanil for epidural analgesia in the first stage of labor. Anesth Analg 96:1178–82.[Abstract/Free Full Text]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
98/4/497    most recent
ael373v1
Right arrow E-Letters: Submit a response to the article
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by McLeod, G. A.
Right arrow Articles by Columb, M. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McLeod, G. A.
Right arrow Articles by Columb, M. O.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?