Anaesthesia Product News

Genetic Predisposition To Sepsis: Chickens, Eggs And SNPs

Report from a symposium at the 36th Congress of the Society for Critical Care Medicine, Orlando Florida February 2007
Author: Dr Karen Stuart-Smith, Consultant Anaesthetist, Glan Clwyd Hospital, Denbighshire, Wales.

Coverage of the 3rd National Meeting of the Anaesthesia Research Trust
Meeting organiser: Dr Karen Stuart-Smith, Consultant Anaesthetist, Glan Clwyd Hospital, Denbighshire, Wales.

Balancing High Quality Patient Care And Costs In The Operating Theatre
Author: Dräger Medical

The Role Of The Bonfils Laryngoscope In Anaesthesia
Authors: Dr Mark Halligan and Dr Pete Charters, Consultant Anaesthetists, University Hospital Aintree, Liverpool.

Genetic Predisposition To Sepsis: Chickens, Eggs And SNPs

Report from a symposium at the 36th Congress of the Society for Critical Care Medicine, Orlando Florida February 2007
Author: Dr Karen Stuart-Smith, Consultant Anaesthetist, Glan Clwyd Hospital, Denbighshire, Wales.

The topics covered at the SCCM Congress in February this year were broadly similar (even down to the speakers, in some cases) as the ESICM meeting that I reported on in previous issues of this magazine. However one of the most interesting symposia I attended in Florida was low-key, sparsely attended, and inevitably on the last day of the conference. The reason for the low attendance etc, etc, was probably down to two factors. Firstly, it was not about an immediate change you could make to your clinical practice, thereby impressing your colleagues and friends. Secondly, the subject was presented in such a way that only a complete anorak could get excited about the content, and would bore the pants off anyone he spoke to about it. Nevertheless it is potentially one of the most promising areas of sepsis research, and may ultimately be worth more than a hundred international trials on whether you should give steroids or not. I am talking about the renewed attempts to understand the genetic regulation of the response to sepsis. In this article I will discuss some of the issues discussed at the meeting in broad terms, and try to unravel the anorak sufficiently to persuade you of the relevance of this topic.

Anorak heaven: the Human Genome Project

The promise of the Human Genome Project was that unravelling the DNA sequences that make up a human being would predict an individual’s future in terms of susceptibility to disease. For example, if you have a particular alteration in your DNA sequence (a ‘genetic polymorphism’), so that one myocardial protein is made rather than another, you might have weaker cardiac muscle and therefore be more prone to heart failure. (I made that example up, by the way). Thus, all the people in a community with that particular polymorphism who will develop heart failure in later life could be identified by whole population DNA sampling. This can be termed ‘genomics’. Finding a way to either change the DNA sequence or replace the errant protein so that a different protein is made, so that the individual is ‘cured’ as a adult or saved from disease by intervention in utero (!) is loosely what ‘proteomics’ is about.

Thus the Human Genome Project has been set up with the very best of intentions. Human DNA has indeed been sequenced. However, so far, that’s it. A problem has arisen which is very similar to the one in the Hitchhiker’s Guide to the Galaxy. In that story, a large computer was built to find the answer to Life, the Universe and Everything. When the answer turned out to be 42, an even bigger computer had to be built to find out what the question was. As the first computer points out in the story, looking for the answer is an expensive waste of time if you don’t know what the question is. DNA sequencing is not difficult, but it is methodical and time-consuming, and requires pristine laboratory conditions so that you really are detecting a human gene sequence and not a hair from your Labrador that fell off your T-shirt into the test-tube. If you’re spending all this money finding out the answer, you better know what the question is.

In the context of our fictitious weak myocardial protein example, you would need to undertake the following steps:

Find a city of several thousand inhabitants and round up as many people as possible with clinically proven heart failure. A couple of thousand patients at least will be required (we’ll come to the statistics in a minute).
Take DNA samples from all of them, to determine whether they share a common DNA variant (genetic polymorphism) at the site on the gene where the myocardial protein you think is responsible for precipitating heart failure is made.
Biopsy the heart muscle of all these patients to determine whether this same protein (made by the DNA variant that you think makes it) is present in all the patients and correlates with the DNA sequencing.

You can see how complicated this could get. In order to ‘blame’ a particular polymorphism for a disease, you have to know the exact mechanism of a disease, it has to be dependent on one protein or group of proteins (say in an enzyme cascade, for example), and everyone who has the disease has to have a small number of DNA variants in common. In other words, you have to be holding the chicken (the disease) and the egg (the DNA) simultaneously. In addition, in order to have a chance of effecting a cure, you better be sure that disturbing one gene sequence doesn’t have disastrous consequences for another. Of course, there are a few diseases where straightforward polymorphisms are predictive: early onset breast and colon cancers are good examples. For the rest, both the chicken and the egg remain elusive. Insurance companies and scaremongering editors of The Sun need to apply their energies elsewhere.

So what’s the point?

If you’re still awake, you’re probably wondering what all this has got to do with sepsis. Everyone who works in Intensive Care can remember the 80 year-old with faecal peritonitis who miraculously survived and the 50 year-old who died rapidly of an overwhelming respiratory tract infection. Clearly there is a wide variation in susceptibility to sepsis within the community. The question is, is there a genetic predisposition to sepsis?

Earlier attempts to answer this question have run into the sorts of problems described in our fictitious example above. Not knowing the mechanism of sepsis (the chicken) is of course a big handicap. Without a clear understanding of the proteins and cells affected by sepsis, or even a very clear definition of the sepsis syndrome itself, many studies in the past have had to use a ‘scattergun’ approach, looking at several different genes which might be involved in the inflammatory response, and attempting to find an association between variants of these genes and outcome in sepsis. This can be described as looking for a polymorphism in a haystack, and until recently has had very poor results.

A recent systematic review of this type of investigation1 makes depressing reading. 76 studies, investigating 51 polymorphisms

(in genes coding for various sepsis-related proteins such as tumour necrosis factor alpha (TNFa), various interleukins and heat shock protein (HSP)), were identified as meeting basic study criteria, although just barely so in some cases. The most common flaw was underpowering, or to put it simply, not enough patients. The majority of trials contained less than fifty patients, and only 3 out of the original 76 were sufficiently powered to detect an 80% level of association between susceptibility to sepsis and a particular polymorphism in an inflammation-related gene. The rest wasted an awful lot of money on DNA kits from pharmaceutical companies.

The review further suggests that only half of these studies had an adequate control group, although my personal view is that none of them had. Strictly speaking, there are two possible control groups, one of healthy individuals who have never had sepsis, and, more relevant, a group of patients who had severe sepsis and survived versus a physiologically matched group which died.

The statistics that were performed were also of dubious value, and this is where the issue of patient numbers is crucial. As doctors all we can remember of our statistics swotted at the last minute for exam purposes is that a p value less than 0.05 is statistically significant. Most of the studies do indeed reach a significance of p < 0.05, so that’s all right then. Except that it isn’t. Because sepsis is a syndrome expressed in many different organ systems, and because there are so many potential polymorphisms for each individual inflammatory protein, the statistics need to be tightly conducted in a large well-defined population. The huge number of potential factors, and the large number of unknowns (e.g. the exact role of TNFa-protective or not?) means that only Bayesian analysis is likely to be suitable (NOT a paired Students t-test!). At least 2000 patients are estimated to be required1, as in our hypothetical example above. None of the trials examined by this review achieved these parameters, with the twin results that a) genetic associations with sepsis could not be replicated between studies, and b) the chance that an individual result was a false positive was very high. Indeed, this systematic review estimates that the majority of reported studies contained false positive results.

A good example of this problem lies in two papers published by the same group, seeking associations between genetic polymorphisms in sepsis-related proteins and risk of severe sepsis following burn injury2,3. The quite reasonable premise of these studies was that patients with isolated burn injuries would form a more cohesive population than the general ITU patient. The first study contained 159 patients with a severe burn injury (>20%), or significant smoke inhalation injury. To avoid confounding factors, patients with any additional trauma-related injuries were excluded. To cut a long story short, of the five genetic polymorphisms tested, two of them, a specific variant of the DNA coding for TNFa, and one coding for toll-like receptor 4 (TLR4, trust me for the moment) seemed to correlate with a greatly increased risk of developing severe sepsis in burns patients. Unfortunately the second paper, which includes the original 159 patients plus an additional 69, showed not only that the apparent risk associated with these variants was lower than in the original paper, but that other sepsis-related proteins, apparently not associated with increased risk the first time round, now appeared to be relevant to burns-related sepsis. In other words, adding 69 patients radically changed the conclusions.

Confused? You should be. The problem is the very small patient numbers (underpowered), the statistics (non-Bayesian and p values too high), and the fact that the inflammatory response to burns and sepsis is quite simply not understood. The false positive rate is probably quite high, particularly in the first smaller study. A lot of chickens and eggs are missing. To be fair to the authors, these problems are highlighted in the discussion section of their papers.

The potential solution-understanding a SNP

How can this mess be sorted out? There are two issues. First, the sepsis cascade must be understood. Second, the technology for detecting polymorphisms has had to be improved. Let us deal with the sepsis cascade first.

A simplified view of the sepsis cascade in a leucocyte is shown in figure 1. The details don’t matter, but the point is that lipopolysaccharide, which is the outer coating of the bacterium, binds to the acute phase protein lipopolysaccharide binding protein (LBP). The LPS/LBP complex presents itself to the surface of the leucocyte, where it binds to a receptor called toll-like receptor 4 (TLR4) on the leucocyte cell surface, setting off a second messenger cascade which ultimately results in release of inflammatory cytokines such as interleukins and TNFa, triggering the full inflammatory response. LPS also interacts with endothelial cell receptors that cause the expression of adhesion molecules and hence the attachment of neutrophils and monocytes to blood vessels4. The point is that genetic polymorphisms in any part of this cascade process to make an individual more or less vulnerable to sepsis.

Figure 1: Cell recognition of lipopolysaccharide (LPS). See text for details. LBP, lipopolysaccharide binding protein; TLR4, Toll-like receptor 4; IRAK, IL-1 receptor-associated kinase; Tollip, Toll interacting protein; MD2, myeloid differentiation protein-2; MyD88, myeloid differentiation primary response 88; TIRAP, TIR domain-containing adapter protein (also known as MYD88 adaptor-like protein); TIFA, TRAF-interacting protein with a forkheadassociated domain; TRAF6, TNF receptor-associated factor-6; IKKs, I£eB kinases; NF-£eB, nuclear factor kappa B; I£eB, kappa B inhibitor. Figure 1 is taken from reference 4, with kind permission from Jesus Villar, MD, PhD, FCCM, Director, Canarian Institute for Biomedical Research.

I’m assuming here that you all know what a double helix looks like. Base pairs link within the double helix in a specific pattern (the genetic code), and parts of the helix unwind to link with RNA molecules which then trundle off to join amino acids together to make the relevant protein (I’m paraphrasing 50 years of molecular biology here). Most variations in the genetic code involve a single base pair, with the result that a single amino acid may be substituted for another in a protein, with either good or bad results. A bad result in the context of sepsis would be that an important receptor protein such as TLR4 would be defective and fail to implement the immune response to sepsis adequately.

To be more exact, the vast majority of variants (polymorphisms) in the genetic code involve a single nucleotide within a base pair. This is called a Single Nucleotide Polymorphism or SNP. There is approximately 1 SNP every 1000 base pairs, most of which are irrelevant noise, but still present the polymorphism in a haystack problem alluded to earlier. However recent advances in technology, driven by private genetics companies, have allowed hundreds of SNPs in any one genome to be detected much more rapidly. In these circumstances the Human Genome Project finally comes into its own. Since we now know where most of the inflammation-related proteins are coded in the DNA sequence, looking for SNPs in these sequences in a large population becomes much more feasible. Up or down regulation of individual cytokines and receptors (i.e. changes in gene expression) can be traced by changes in RNA transcription and translation into individual proteins. All you need now is a large enough population to perform an adequate clinical trial, and this is what the symposium (at last!) was all about.

Inflammation and the host response to injury: an NIH-funded large-scale collaborative research programme

Several of the speakers at the symposium described the first steps that have been taken in a hugely ambitious research programme to understand the genomic basis of inflammation and injury, including sepsis, trauma, haemorrhage and burns. The early years of the study have been taken up with careful efforts to avoid the mistakes of the past, especially the issue of population numbers. It is a large multicentre trial, and great care has been taken to educate participating centres in the collection, labelling and storage of samples for genomic analysis, as well as adequate record keeping with regard to individual patients5. A number of standard operating procedures has been developed, which are of sufficient quality that possibly other clinical trials should consider following this methodology.

The first results report changes in gene expression within the various ‘white cells’, i.e. leucocytes, monocytes and T cells in patients with sepsis as compared to normal individuals. I will describe one study to show how it works6.

Patients with severe traumatic injury and multiple organ failure have long been known to have a reduced T cell population. You will know from your clinical experience that a low white count in an injured, septic patient is a very bad sign. In these patients T cells die rapidly (apoptosis) and the ones that remain migrate poorly (anergy). Genomic studies have shown an increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic genes, i.e. the patients’ immune balance is tipped in favour of T cell destruction. Further, while in normal individuals monocytes stimulate T cell activity, monocytes from these individuals showed downregulation of genes that stimulate T cell activity. In other words, the T cell anergy may be partly accounted for by this genetically programmed decrease in monocyte function. Clearly, the next step will be to compare this genetic picture with other less severely compromised patients to determine whether there are similar changes in gene expression, or whether survivors don’t make these changes at all. It’s a complicated but fascinating story, with a long way to go. All I can say is, after attending this symposium, I feel less sceptical and more optimistic about genomic research. Watch this space.

References

Clark MF and Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med 2006;32:1706-12
Barber RC et al. TLR4 and TNF-a polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet 2004;41:808-13
Barber RC et al, Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res 2006;4:250-5
Villar J et al. Bench-to-bedside review: understanding genetic predisposition to sepsis. Crit Care 2004;8:180-9
Cobb JP et al. Application of genome-wide expression analysis to human health and disease. PNAS 2005;102:4801-6
Laudanski K et al. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. PNAS 2006;103:15564-9

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The 3rd National Anaesthesia Research Meeting (NARM) took place in the splendid surroundings of the Bosworth Hall Hotel in Market Bosworth, Warwickshire on 18th-20th April 2007. NARM is the flagship meeting of the Anaesthesia Research Trust, which is a registered charity dedicated to improving the understanding of the relevance of research among junior anaesthetists, and to provide informed advice from experienced researchers on the design, execution and presentation of audit and research projects. The overriding philosophy of NARM is complete informality, so that all audience members, junior and senior, may feel free to interrupt speakers (politely) to ask for clarification of a point or put forward a different point of view. Free discussion is encouraged. Junior anaesthetists may also give either oral or poster presentations on case reports, audit projects or original research. The abstracts presented to the meeting are printed here, and I am very grateful to Anaesthesia Product News for allowing these abstracts to be published here.

The programme extended over three days, and for the sake of preserving space, I must ask the reader to refer to the full programme on the Anaesthesia Research Trust website at www.anaesthesiaresearch.org.uk The range of the programme was very extensive, covering the use of intralipid in local anaesthetic toxicity (Dr Tim Meek), current understanding of clotting (Dr Paula Bolton-Maggs), the use of thromboelastography in the labour suite (Dr Gordon Lyons), early goal-directed therapy (Professor David Bennett), genomics and proteomics (Professor Don Tindall), writing papers and presenting posters (Professor Virginia Miller), patient perceptions of PCA (Professor George Hall), ischaemia-reperfusion injury (Dr Mahesh Nirmalan), pre-operative assessment (Mrs Jane Jackson and Mrs Amanda Bassett from the Pre-operative Association), pre-operative drinking rules and how to implement them (Dr Eileen Williams), and of course the hard-working crew from Glan Clwyd who gave the basic and advanced airway workshops (Dr Catherine Gardner-Thorpe, Dr Eileen Williams, Dr Manish Adke and Mr Richard Owen).

In addition to all of this, some of the sponsoring companies provided workshops on their products. This included Datascope and Deminax, who were able to describe their products in an informal manner in a tutorial session. The philosophy of this is that you can view the company products and make up your own mind in a relaxed fashion, rather than grabbing a few pens and running off, which satisfies neither side!

The evening entertainment consisted on the first evening of a sumptuous buffet dinner to the accompaniment of a string quartet, and the second night included a pre-dinner falconry display on the vast lawns of the hotel.

The overall atmosphere of the meeting was very conducive to relaxed discussion, and was particularly enjoyed by the juniors who attended, who I think were quite surprised by the format of the meeting. The evaluation forms are not yet completely analysed, but show a very satisfying number of ‘5 out of 5’s from attendees.

Next year’s meeting of NARM will probably be in October 2008, and you are all cordially invited to attend. Watch the website for details and/or sign up for the Anaesthesia Research Trust e-newsletter for further details.

The meeting would not have been possible without the generosity of the sponsors. These were; GE Healthcare, Datascope, Deminax Medical Instruments, Medicell, Intavent Orthofix, KarlStorz, Trucorp, Cook, Deltex Medical Group and LiDCO, and of course, Anaesthesia Product News.

Title: Anaesthetic Management of a Ventilator Dependent Parturient: A Case Report

Authors: Sujesh Bansal, Richard Wadsworth
Institution: Anaesthetic Department, St. Mary’s Hospital & Manchester Royal Infirmary

Case History
A 19-year-old (BMI=13.5) wheelchair bound parturient with severe kyphoscoliosis and flexion deformities was referred to us at 13 weeks gestation. She was diagnosed with congenital muscular dystrophy (CMD) at the age of three years, and developed type 2 respiratory failure by the age of fourteen, necessitating non-invasive nasal BiPAP ventilation at night. A multidisciplinary case conference discussed various issues including the high risk of maternal morbidity & mortality and the desirability of an advanced directive. By the 17th week of gestation despite being on 24 hours ventilatory support, she was distressed with increasing breathlessness and demanded a CS as soon as possible.

CS was planned at 28-weeks gestation in the main theatre adjoining ITU. In addition to standard monitoring, invasive arterial pressure monitoring was used. It was decided to provide regional anaesthesia by lumbar epidural. During epidural insertion at L4/5 interspace, accidental dural tap by Tuohy needle occurred, due to difficult spinal anatomy. It was decided to place a 17-gauge multi-orifice epidural catheter intrathecally and use it as a spinal catheter. Titrated doses of hyperbaric 0.5% bupivacaine totalling 4.0 mL over 30 min resulted in an adequate surgical anaesthesia. The patient continued to use her own non-invasive nasal BiPAP ventilator during regional blockade and through out surgery. The rest of the perioperative course was uneventful.

Discussion
CMD is an autosomal recessive genetic condition, so females are usually asymptomatic carriers. Due to her ventilator dependence and muscular dystrophy, we wished to avoid GA. We chose epidural and not intrathecal anaesthesia in the first instance because of uncertainty of her spinal cord anatomy as well as history of failed lumbar puncture in the past.

Conclusion
We found continuous spinal anaesthesia to be a reliable, rapidly titrable technique, in this ventilator-dependent parturient, thus avoiding GA and the risk of prolonged post-operative ventilation.

Title: A prospective Audit of Postoperative Vomiting in Paediatric Adenotonsillectomy

Authors: Lorraine Alderson, Simon Courtman, Anna Johnson, Tim Hooper
Institution: Derriford Hospital. Plymouth

Introduction
Paediatric adenotonsillectomy is increasingly becoming a day case procedure hampered by a high incidence of postoperative vomiting. There is a wide variation of techniques used to anaesthetise these patients. This prospective audit looked at the anaesthetic and analgesic regimes used in 100 consecutive children undergoing adenotonsillectomy. This was then analysed in conjunction with the incidence and treatment of post operative vomiting.

Method
Using a data collection sheet, the anaesthetist recorded: 1) induction agent, 2) use of nitrous oxide, 3) type of airway, 4) intravenous fluids, 5) analgesics and 6) antiemetics given intraoperatively. The use of analgesics and antiemetics in conjunction with the number of vomits and time of first oral intake were recorded for the first 24 hours post operatively.

Results
Twenty-five percent of the patients vomited in the first 24 hours postoperatively. Of these 8% vomited more than once. Vomiting was more common in those receiving nitrous oxide (31%) compared with those who didn’t (15%). Vomiting was also associated with use of perioperative morphine.

Perioperative opioids	Incidence of recurrent vomiting
Intraoperative fentanyl only	0% (n=51)
Intraoperative fentanyl/post op oramorph	6% (n=30)
Intraoperative morphine only	38% (n=9)
Intraoperative morphine/post op oramorph	33% (n=10)

Recurrent vomiting was more common in those receiving only one antiemetic perioperatively (27% if given dexamethasone, 12% with ondansetron, 4% if given both dexamethasone and ondansetron). Induction agent and type of intraoperative airway did not appear to affect the incidence of postoperative vomiting. All patients were given combined paracetamol and voltarol perioperatively in addition to intraoperative intravenous fluids.

Conclusion
Postoperative vomiting in children undergoing adenotonsillectomy is multifactorial. Postoperative vomiting was more common in those who received nitrous oxide and in those who received perioperative morphine. Is nitrous oxide now obsolete? Should fentanyl be the intraoperative analgesic of choice for this procedure? The routine use of combined antiemetics and regular postoperative antiemetics for those with additional risk factors for postoperative vomiting is advocated.

Title: Effectiveness of Continuous Vancomycin Infusion in Achieving Therapeutic Plasma Levels in Critical Care

Authors: R Gupta, J Marriott, T Gallacher

Introduction
Vancomycin is a glycopeptide antibiotic effective against gram positive organisms including methicillin resistant Staphylococcus Aureus (MRSA). When used in clinical practice plasma levels of the drug are routinely monitored to minimise the risks of renal toxicity.

Critical care patients requiring vancomycin at University Hospital Birmingham NHS Foundation Trust (UHB) had traditionally received a bolus dose twice daily. Following publications by James1 and Wysocki2, this treatment regime was changed to a bolus loading dose followed by a continuous infusion to maintain a steady therapeutic plasma level.

The new regime was introduced in May 2005 in all four Critical Care Units within UHB. A retrospective audit was carried out – from December 2005 to May 2006 – to establish the reliability of the new regime in achieving and maintaining therapeutic plasma vancomycin levels.

One hundred and fifty five patients were studied, resulting in 1426 patient episodes with a mean time on Vancomycin of 7.125 days. Table 1 shows a summary of the results.

(% samples)	All Units	Unit 1	Unit 2	Unit 3	Unit 4
Therapeutic range plasma concentration	46	54	50	43	15
Sub-therapeutic plasma concentration	41	31	36	51	80
Potentially toxic plasma concentration	13	15	14	6	5

Once achieved, all units had difficulty maintaining therapeutic plasma levels.

Three of the four intensive care units provide renal support, with Unit 4, the unit with the lowest prevalence of therapeutic plasma vancomycin levels the unit which did not provide renal support.

This audit demonstrated that the current previously validated regime is ineffective in providing therapeutic vancomycin levels for the critical care patient population at UHB. A review of the current regime is required to provide a guideline which is effective in achieving and maintaing therapeutic vancomycin levels.

References

James JK, Palmer SM, Levine DP, Rybak MJ. Comparison of Conventional Dosing versus Continuous-Infusion Vancomycin Therapy for Patients with Suspected or Documented Gram-Positive Infections. Antimicrobial Agents and Chemotherapy 1996;40(3):696-700.

Wysocki M, Delatour F, Faurisson F et al. Continuous versus Intermittent Infusion of Vancomycin in Severe Staphylococcal Infections: Prospective Multicenter Randomised Study. Antimicrobial Agents and Chemotherapy 2001;45(9):2460-2467.

Title: A Case of Fictitious Methhaemoglobinaemia

Authors: Kumaresh Venkatesan, N Matthews
Institution: University Hospital of North Staffordshire

Aim
Sentinel lymph node biopsy is now becoming a standard procedure to identify nodal spread and staging of various tumours. We present a case of factitious methaemoglobinemia after peri-tumoural injection of patent blue V dye for the purpose of sentinel lymph node detection.

Case Report
A 40 year old lady presented for an elective L mastectomy, sentinel node biopsy and axillary clearance. Apart from smoking, she was generally fit with no other relevant past medical history. After uneventful induction & maintenance of general anaesthesia, the patient desaturated to 90% in spite of FiO2 of 100% following intradermal injection of 2 mls of 2.5% Patent blue V close to the tumour site. After ensuring adequacy of ventilation, analysis of arterial blood gas revealed a normal oxygen saturation (estimated) and partial pressure, but elevated methaemoglobin levels in the co-oximetry. As she remained haemodynamically stable surgery was continued to completion and her saturation gradually improved to 94%. Following extubation she was conscious, comfortable with no signs of respiratory distress and remained on 6 litres/ min of supplemental oxygen via face mask. This case report illustrates interference of patent blue V dye with the pulse oximetry and co-oximetry.

Discussion
Sentinel lymph node biopsy is a new, valuable technique to assess the nodal status of patients with various malignant tumours. The accuracy of the technique is improved by injection of a blue dye around the tumour immediately before the operation to aid visual identification of the afferent lymphatics and sentinel lymph node by the surgeon. Patent Blue V, a rosaniline dye is now commonly used to facilitate visual identification of sentinel nodes.

The dye has an in vitro peak light absorption at 640 nm in plasma and 622-636 nm in whole blood. This closely corresponds to the wavelength of the red light used in the pulse oximetry. In the presence of patent blue V dye in the plasma, the amount of reduced haemoglobin is overestimated, resulting in falsely low saturation reading in our patient. The blood gas analyzers, apart from directly measuring pH, pO2 and pCO2, also estimates oxygen saturation (known as O2Sat) from pO2, pH and the standard oxygen haemoglobin dissociation (ODC) curve. This estimated value was normal in our patient. The spectrophotometric method of measuring various fractions of normal and dyshaemoglobins by the co-oximeter resulted in elevated levels of methaemoglobin. What is the likely reason for this increase in detected methaemoglobin? A peak absorbance of light near 630 nm is used to characterize MetHb in the co-oximeters. Since the peak absorption of patent blue V is 640 nm, the presence of the dye in the blood led to the co-oximeter algorithm interpreting the changes of the absorbances as an increase of fractional methaemoglobin (FMetHb) and a spurious overestimation of methaemoglobin in our patient.

Title: Anaesthetic Trainee Satisfaction After the Implementation of the European Working Time Directive (EWTD) – A Questionnaire Survey

Authors: Prabhu Gandhimani, Simon Old
Institution: The Heart of England NHS Trust

Aim
To take a snap shot survey of the influence of EWTD on training, academic and social life of anaesthetic trainees.

Method
A questionnaire was sent to all the anaesthetic Registrars (155) in the Yorkshire Region.

Results
Out of the 80 Registrars (51.6%) that responded, the majority did not prefer the shift system (67.5%), did fewer training lists per week than recommended (83.75%), felt they spend the majority of their social hours in the hospital (67%) and were unable to rest adequately in the day during their night shifts (85%). About a third of registrars felt that they do not get enough solo exposure.

Discussion
The EWTD, designed to improve the working conditions of doctors in training, is in reality threatening to damage the quality of training and disrupt social life1. Solo lists enhance both the organisational and management skills of an Anaesthetist and it is worrying that more than a third are not getting that experience. Only 15% of registrars slept adequately during their set of night on calls. Sleep deprivation can contribute significantly to cognitive impairment and medical errors and although the onus is on the individual to limit their fatigue, measures should be taken to educate them.

References

Connolly c, N.M., Working pattern in anaesthesia – The current position. The RCOA Bulletin 12, March 2002: p. 585-7

Title: A Case of Emergency Caesarean Section Under Local Infiltration Anaesthesia in a Morbidly Obese Parturient

Author: Dr Sangram Patil
Institution: Morriston Hospital, Swansea

Introduction
We report a case of a morbidly obese parturient who needed emergency caesarean section for foetal distress. General anaesthetic failed due to ‘can’t intubate can’t ventilate’. Regional anaesthesia was tried after waking the patient with no success.

Case Report
Twenty-five year old lady at term pregnancy was admitted to the labour ward. She was morbidly obese with a body mass index of 49. She had no medical problems. Amniotic fluid was heavily meconium stained with fetal heart rate of 80beats/min, hence the obstetrician decided to do an emergency caesarean section.

Rapid sequence induction was done. On direct laryngoscopy the patient could not be intubated. Sp02 reduced to 50% from 99% preinduction in about 20 seconds. Mask ventilation, 100% oxygen and Geudel’s airway was tried. This was unsuccessful and Sp02 was still around 50%. Ventilation was attempted with size 3 laryngeal mask airway which was in vain. By then the patient started breathing spontaneously and Sp02 increased to 96%. Since the fetal heart rate improved to 120-140 beats /min it was decided the wake the patient up and proceed with regional anaesthesia.

Combined spinal epidural was tried but after multiple failed attempts it was abandoned. The fetal heart rate started decelerating again. After getting consent from the patient the team decided to carryout the caesarean section under local anaesthesia.

Patient was given 50% oxygen and 50% nitrous oxide. 40 mls of 0.5% plain bupivacaine was injected to the skin and subcutaneous tissue. Pain control in the postoperative period was with PCA morphine.

Discussion
In this modern anaesthetic era local anaesthetic for caesarean section cannot be advocated. However in a real emergency and difficult situation where no other option is available abdominal infiltration may be performed quickly.

Conclusion
This case report highlights importance of local anaesthetic as a lifesaving technique in emergency caesarean section in morbidly obese patients if rapid establishment of general or regional anaesthesia is difficult or impossible.

Title: Evaluation of the Use of a Medium Fidelity Simulator to Teach Airway Skills to Undergraduate Medical Students

Authors: Seema Quasim, Cyprian Mendonca
Institution: University Hospital, Coventry

Background
Medical students from the Warwick Medical School undertake a joint anaesthetic and orthopaedic module lasting 8 weeks. During this time they are expected to acquire a range of skills, in particular airway skills. Theatre opportunities are variable so a medium fidelity simulator is used to facilitate the acquisition of airway skills.

Method
Medical students attending a 3-hour simulator session in small groups were asked to complete an anonymous feedback questionnaire at then end of the session.

Results
Fifty-nine out of 60 questionnaires were returned.

Students generally rated the session very highly. Fifty students (85%) found the session useful or very useful and 54 (92%) rated the content of the session as good or excellent. With regard to the overall value of simulator-based teaching, 50 (85%) felt that the experience was valuable or very valuable. Only two students rated the experience as poor.

However, the students were divided as to whether a simulator should form part of the end-of-block assessment. Thirty-nine students (66%) felt that a simulator would be either good or very good as an assessment tool, but 5 students felt that it would not be useful at all. Fifteen (25%) were undecided on this matter.

Discussion
The medical students valued the opportunity to acquire and practise airway skills using a simulator in a skills laboratory. It is recognised that these skills, particularly intubation skills, are difficult to acquire as a medical student, even more so with the use of the laryngeal mask airway. Many students commented that the session should be undertaken as early as possible in the block, indicating perhaps that the session allows the students to gain confidence in a non-threatening environment. Simulator-based training is an important adjunct to theatre-based training, but there is some resistance to it being used as an assessment tool. This should be explored in further studies.

Title: A Survey of Advanced Airway Skills in Warwickshire School Specialist Registrars (SpRs)

Authors: M Ranganathan, E Powell, C Mendonca
Institution: UHCW

Background
In 2004 a survey of trainees at University Hospitals Coventry and Warwickshire revealed a poor experience of advanced airway skills. This led to the development of an airway management course and cricothyrotomy training. This survey investigates the confidence of Warwickshire SpRs in advanced airway skills. The skills investigated are required for the use of the Difficult Airway Society’s guidelines on the management of an unanticipated difficult airway.

Method
Sixty-two SpRs were sent a questionnaire. The skills investigated were; McCoy laryngoscope, fibreoptic intubation (FOI) through Intubating laryngeal mask airway (ILMA) and laryngeal mask airway (LMA), asleep FOI and needle cricothyroidotomy.

Results
Thirty-seven SpRs replied to the survey, (60%). 100% of SpRs felt confident in using the McCoy laryngoscope. The majority of SpRs in years 4 and 5 are confident at performing asleep FOI and needle cricothyrotomy. The confidence amongst the SpR1 -3 is variable. 49% of SpRs had attended an airway course.

Percentage of SpRs confident in skill

Airway Skill	Year 1	Year 2	Year 3	Year 4	Year 5
McCoy	100	100	100	100	100
FOI ILMA	0	40	43	62	50
FOI LMA	0	40	43	55	50
Asleep FOI	0	80	43	93	100
Needle crico	0	100	100	79	88

Discussion
The results show that although SpRs years 4 and 5 are confident in asleep FOI, the experience in using secondary intubation devices (FOI through ILMA and LMA) remains low. This suggests that SPRs need more training in these skills. Reduced number of working hours1 and reduced supervision of trainees may contribute to SpRs not achieving the required competence.

Reference

Underwood SM, MacIndoe AK. British Journal of Anaesthesia 2005, 95: 616-21.

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There is no doubt that a hospital’s success is challenged by many complex factors including mounting cost pressures, fluctuations in personnel and increasing pressure on resources. More and more we hear phrases like surgery manager, surgery management and surgery as a cost or profit centre. As cost and quality get weighted against each other, how can perioperative care areas maintain a high quality of patient care? It is also true that surgical procedures can take varying amounts of time to complete for different patients even if the indications are the same. All these issues present a huge challenge to a responsible and forward-looking hospital management team in the costly realm of surgery. Therefore, hospital administration must continually evaluate the delivery of its operating theatre services for efficiency and effectiveness.

It is widely known that operating theatres account for up to fifty percent of the overall cost of a surgical patient and so supplier solutions to address the ever-increasing quality and cost pressures are always welcome. Within the marketplace, leading medical device companies are busy looking at solutions to these issues. One such company is Dräger Medical. Building on more than a century of anaesthesia expertise, Dräger Medical’s solution exists in the form of an integrated combination of medical systems and services designed to improve efficiency in the operating theatre. Anaesthesia, therapy, monitoring, information management, architectural systems and complementary products combine to help operating theatre personnel redefine process efficiency and so increase productivity and patient care. The impact of this type of comprehensive solution on the perioperative care area process has in fact proven to lead to a reduction in operating theatre turnover time. Additionally, it gives medical staff access to data anytime/anywhere, allows more time for patient care, improves active safety, simplifies patient transport and as a result, improves overall patient care.

In the operating theatre you are always under pressure to handle a wider range of patients and more complex procedures, but at the same time cost reduction remains a key driver. Standardisation of procedures and structures helps increase cost efficiency. This is also true for investments in medical technologies, anaesthesia systems and patient monitoring. etc. The integration of new anaesthesia devices with continuous patient monitoring and comprehensive hospital information system access is a positive move forward and important in contributing towards the long-term economic viability of the operating theatre.

A number of studies have already established that anaesthesia induction in a designated induction area increases the number of surgical cases performed during a normal working day. This practice is commonplace in the UK and to support this Dräger Medical designed the Fabius TiroTM. This device meets the specific needs of the Induction Room. It makes the latest technology available to a hospital but at a much lower cost. As part of the Fabius family, it has the same technology and performance as other Dräger anaesthesia systems. These include advanced safety features, a space saving modular design, manoeuverability and its cylinder operation proves practical for extended periods, since the E-vent electronic ventilator consumes no drive gas.

The Fabius® GS premium anaesthesia delivery system is another example of response to market needs in an effort to redefine the price/performance ratio. It offers features previously unavailable in its price category, with components and sensor technologies that make it inexpensive to operate. Contrary to traditional pneumatically driven ventilators, the E-vent is electronically driven and software controlled and provides an open platform for future software upgrades without the need for hardware changes. As ventilation technologies evolve, upgrading the existing platform will be possible without replacing the entire machine.

The balance between patient safety and cost is difficult and patient safety is obviously always paramount. Adverse incidents cannot be completely eliminated from complex modern healthcare environments and Trusts will always seek to acquire innovative devices that minimise risk to patients. Renowned as a medical breakthrough, Primus was the first anaesthetic machine of its kind to be used in Europe. All anaesthetic machines have basic alarms but the Primus has built-in safety systems that continually monitor a patient’s condition.

St George’s Hospital in Tooting, London is a 1,200 bedded hospital with 30 Operating Theatres. It was the first hospital in the UK to purchase Primus and, in fact, replaced its entire fleet of anaesthetic machines. Dr Linda Murdoch, Consultant Anaesthetist at St George’s says: “The Primus anaesthetic machine is a great all round device. It delivers ITU quality ventilation and all the necessary safety and back up alarms, providing the highest quality anaesthesia delivery. This allows the anaesthetist to concentrate on patient care safe in the knowledge that the Primus alarms are triggered if the ventilatory status of the patient changes.”

The cost saving possibilities continue with Dräger’s most recent addition, Zeus® – the supreme ruler. Aptly named, the Zeus does in fact open the door to endless possibilities in therapy, patient monitoring and documentation. By combining inhalational and intravenous anaesthesia with ICU quality ventilation and patient monitoring, it provides not only an individual workplace solution but also access to a hospital-wide information management system. Besides offering manually controlled fresh-gas delivery, Zeus can automatically administer oxygen, carrier gas and volatile agents to make Target Controlled Anaesthesia (TCA) possible. It is equipped for everything from balanced anaesthesia to state-of-the-art Total Intravenous Anaesthesia (TIVA).

St George’s Hospital continues to work closely with Dräger Medical and has recently purchased five Zeus anaesthetic workstations. Dr Linda Murdoch also explains the reasons why the Trust chose Zeus:

“The Zeus contains innovative technology to help improve the practice of low flow anaesthesia. The main features are a turbine driven ventilator and an injection system for the delivery of anaesthetic agents. The device has an automatic control mode option by which the anaesthetist sets the concentrations of inspired oxygen and expired anaesthetic agent that they require in the circle system. The Zeus then regulates the gas flow using the turbine to provide an even mix of the injected agent and oxygen to the patient in the most safe and economical mode possible. Simply put, this mode delivers Target Controlled Anaesthesia and therefore saves the department money on anaesthetic agents and improves patient care.”

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We were introduced to the Bonfils laryngoscope in 2001 when Dr Mark Halligan was looking for a subject for a research project. The Storz representative told us something of the background of the instrument and the difficulty they were having marketing the product because certain anaesthetists who tried it had had limited success. Bonfils himself had worked in Berne, Switzerland and the instrument was first marketed in 1982. There were no English language publications about its clinical use and after its introduction it had not appeared to have attracted much attention. Christian Rudolf had apparently re-discovered the instrument when looking through the Storz instrument catalogue a few years after the reunification of Germany. His department in Leipzig was the only place where it was in regular clinical use. We visited him to observe his techniques first hand in early February 2002. We saw it being used for routine intubations as well as difficult cases. They had no special indications or contra-indications for its use. In addition to the theatre practice we observed, we were shown a recording of its use in an awake patient. In some of the GA cases a Macintosh laryngoscope was used to assist with Bonfils placement. Our starting point was that this was effectively defeating the object and we determined to learn to use the instrument on its own.

After we returned back to Merseyside, our first study was to determine the learning curve in routine GA cases where difficult intubation was not expected. A learning curve was evident and for consistent intubation times of less than 30 seconds this required an experience of about 25 cases1. In retrospect, much of this requirement was taken up by us evolving our own individual techniques. We expect shorter times for current in-house training. We have also realised that it is possible to achieve some success with a less than optimal technique, though this usually catches practitioners out in due course. The ideal is obviously to learn a good technique from the start and this is especially important before taking on difficult cases. Ideally all teaching should be by someone already expert with the instrument and who can teach by observing the trainees efforts with a camera stack system.

Before we looked at any difficult cases we did a second study investigating the effect on the airway of cricoid pressure. This was particularly useful because it showed us how to use the instrument for extensive examination of the airway in the sort of detail that a surgeon might use to perform an exploratory panendoscopy. By this stage we had already started to impress our ENT surgical colleagues with the clear and close up views of the relevant anatomical features. (In this context the most impressive feature of the instrument is a panoramic view of the subglottis which is second to none of their instruments as far as we are concerned.) Our third study involved laryngeal tumours which we again approached with a panendoscopic examination prior to intubation. As before we used an apnoeic technique but combined this with a light plane of anaesthesia to allow for problems that might be associated with difficult ventilation. Even in the few cases when the latter occurred intubation was rapidly effected and there was no need to alter the technique otherwise. We now have a combined experience of over 100 cases of successful pharyngo-glottic tumours intubated with no failures. In laryngeal and supraglottic tumour cases the most impressive feature of the instrument is its semi-rigid structure. Unlike a conventional flexible fibrescope the view is not only wider, sharper and bigger but it is the ability to push the tumour to one side in order to be able to see and intubate the glottic inlet that makes the instrument so useful in these cases (Figure 1).

Figure 1: The Bonfils can be used to push solid tumours aside. The left image shows a tight glottic opening due to a supraglottic tumour and next to it the result of twisting the instrument to the right to open up the glottis.

In describing technique in use, the first thing to realise is that both hands will be important to be able to control the tongue and epiglottis. The instrument itself is not handed and as such is one of the few airway implements to leave the naturally left handed person at no disadvantage. The design has been modified over time but the usual adult version comes in a straight metallic cylinder that is curved toward the tip (Figure 2).The diameter allows a size 6.0mm tracheal tube for intubation but there is a smaller version with a 3.5mm diameter. The earlier suction /oxygen insufflation channel is removed in newer models to allow for improvements in the optics and lighting. Secretions are best dealt with by learning to avoid sputum or blood pools but with experience it is possible to clear the end of the instrument by gently wiping it against the tissues. When setting up the instrument the tracheal tube is placed over the laryngoscope and fixed into the locking device. The ideal relationship between the tube tip and ‘scope is to have the tube extending a few millimetres in front which gives a view down the instrument of a small cresent representing the tube tip. For a right-handed anaesthetist the grip should be around the T-junction where the light source is connected. The patient should be on a trolley or table that can be adjusted to a lower height than would be needed for conventional laryngoscopy.

Figure 2: The profile of the Bonfils and its distal curve. Here the angle of the eyepiece is adjustable and there is an adjustable mount to lock the tracheal tube into.

When the patient is ready, the mouth is opened widely to gain access to the posterior pharyngeal wall. This can then be used as an antero-posterior depth marker while turning the instrument through 90Þ and progress down the airway. In the meantime the left hand is used to lift the mandible and epiglottis forward. There are two ways of doing this. The anterior approach has the thumb applied to the floor of the mouth while gripping the mandible to be able to pull it forward. The posterior alternative position uses the thumb like a Macintosh laryngoscope in that it is placed more laterally in the mouth to get behind the tongue so as to pull it and the mandible forward together (Figure 3). Competence with either technique is when the operator can show his/her trainer that the epiglottis can be lifted further forward by simple movements of the thumb.

In certain circumstances it will prove difficult to get any movement of the epiglottis off the posterior wall. Even under these circumstances a view of the epiglottis is usually possible and this will suggest the best strategy for getting the Bonfils under it. Again there are two possibilities. Firstly the instrument can be flipped under the epiglottis by swinging it sharply to one side, or alternatively, going a bit further onward usually opens up a natural space to one side of the epiglottis (where it starts to fold down from in front of the glottis). The trick to learn with the former technique is stopping the flicking movement before the instrument ends up being repositioned on the other side by overshooting the target. When the glottis is visualised the instrument is advanced with care and the bevel is used to sweep the right vocal cord to one side while advancing between through. Once the instrument is just beyond the cords the left hand can be released and the view will be maintained. The left hand is then used to release the tube from the locking device and the tube is advanced over the ‘scope under direct vision into the trachea.

Figure 3: These figures demonstrate the alternative positions for the supporting hand to lift the jaw forward. The thumb is inserted into the mouth either just behind the lower incisors as in the left diagram or further back inside the mouth behind the tongue.

Figure 4: Here the Bonfils is represented as a thick bold line. In the left diagram the mandible and soft tissues limit forward rotation of the tip (with the upper incisor acting as a pivot). On the left, the instrument is turned through 90degrees so that it appears flat in profile and positioned further back in the mouth. Now the maxillary molars act as the pivoting point so the tip is easily rotated further more anteriorly.

Novices usually rest the instrument on the upper incisors to help steady it and ensure better control. Retromolar refers to the not infrequent need to move the instrument to the corner of the mouth2. This allows a more anterior position when the mandible would otherwise be in the way. Effectively the pivoting position is changed and position of the curve of the instrument is changed accordingly (Figure 4). With edentulous patients, learners do better if they keep the instrument pressed against the left hand and move this across the mouth as required for any retromolar re-positioning. In general, advancement of the instrument is very similar to a flexible fibrescope in that small movements can be very effective and are associated with greater control. With experience there is less need for any support for the instrument and as a result it hardly makes contact with any tissues other than the tongue. The most impressive feature of the instrument is the absence of pressing on the tissues making its use particularly atraumatic.

The Bonfils is not suitable for nasal intubations or severely limited mouth opening (say 2cm). In our practice it is not used for awake intubations so this necessitates use of an apnoeic technique. Our preference has been for total intravenous anaesthesia (TIVA) based anaesthetic techniques. In our view the particular indications for use of the Bonfils are problem cases with laryngo-pharyngeal or base of tongue pathothologies. At the same time we would include any patients in whom conventional Macintosh laryngoscopy results in a “peardrop” effect3 i.e. macroglossia, micrognathy, lingual tonsil, rigid neck, bull neck, poor jaw translation etc. This would therefore include the majority of cases where difficult intubation was not predicted pre-operatively.

References

Halligan M, Charters P. A clinical evaluation of the Bonfils intubation fibrescope. Anaesthesia 2003; 58(11): 1087-91.
Rudolf C. Gentle and reliable intubation of problem patients. Experience with the Bonfils Retromolar Intubation Fibrescope. Storz company literature 09-2000.1
Horton WA, Fahy L, Charters P. Factor Analysis in Difficult Intubation: Laryngoscopy Induced Airway Obstruction. B J Anaes 1990; 65: 801-5.

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