BACKGROUND:There is paucity of information on coagulation parameters throughout pregnancy, the puerperium, and post-abortion - and how these relate to venous thromboembolism (VTE) risk. Guidance for thromboprophylaxis post-abortion is guided by expert opinion and extrapolated from post-birth, with recommendations varying from 0 to 6 weeks duration. METHODS:We conducted a study in a community abortion clinic in Edinburgh, UK March-August 2021. We recruited healthy pregnant women requesting medical abortion (<12 weeks gestation) and healthy, non-pregnant women (controls). Blood samples were taken prior to abortion and 10-14 days afterwards. Controls provided a single sample. We assessed laboratory markers of coagulation (Clauss-fibrinogen, prothrombin time, activated partial thromboplastin time, platelets) and viscoelastic measures using the ClotPro® system. We compared the control group with the pregnancy group pre- and post-abortion. RESULTS:We recruited 45 women (24 pregnant, 21 non-pregnant). Clauss-fibrinogen was significantly elevated pre-abortion compared to controls (3.4 g/L vs 2.8 g/L, p = 0.04), although remained within normal range. Two viscoelastic measures showed pro-coagulant changes, one pre-abortion and one post-abortion compared to controls. The absolute differences were small and remained within normal ranges. CONCLUSION:There were minimal differences in measures of coagulation in first trimester pregnancy, that largely resolved 10-14 days after medical abortion. Shorter courses of thromboprophylaxis might be sufficient compared to post-birth for those at high risk of VTE.

ABSTRACTDespite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Aims Point-of-care viscoelastic tests such as rotational thrombelastometry (ROTEM) and thromboelastography (TEG) give rapid information on the kinetics of clot formation, clot strength and fibrinolysis. We developed a ROTEM algorithm for the management of trauma patients at risk of massive haemorrhage using either 5 or 10 minute EXTEM and FIBTEM ROTEM thresholds. Study aims were (a) to compare time to results for ROTEM testing versus laboratory conventional coagulation testing (CCT) and (b) to compare incidence of Trauma-induced coagulopathy (TIC) for our 5 and 10 minute ROTEM algorithms versus both the CCT-based European guideline algorithm and the ROTEM-based iTACTIC study algorithm, in both MT and non-MT patients. Methods Single centre, prospective, observational Emergency Department based study. All trauma patients who underwent ROTEM testing were included. Data was collected from the ROTEM Sigma machine and hospital Electronic Patient Records and analysed. Results Between April 2016 and May 2019, 57 trauma patients were enrolled. Mean age was 47.4 years (SD 19.4) and 44 patients (77.2%) were male. Eleven patients (19.3%) required massive transfusion (MT), 5 patients died in ED (8.8%) and overall in-hospital mortality was 22.8% (n = 13). Median time from admission to CCT result was 83 minutes (IQR 60–93) compared to 51 minutes (IQR 32-93; p = 0.0006) for ROTEM A5 results. This time difference was present for both MT and non-MT patients. Trauma-induced coagulopathy (TIC) was identified in 14 (24.5%) patients using CCT compared to 22 (38.5%) using ROTEM (p = 0.11 ns). Conclusion Our ROTEM Sigma based algorithm enables a coagulation result to be obtained faster than laboratory CCT and could lead to earlier clinical intervention.

References 1. Klein AA, Meek T, Allcock E, et al. Recommendations for standards of monitoring during anaesthesia and recovery 2021. Anaesthesia 2021;76: 1212–23. 2. Audrey De Jong A, Pardo E, Rolle A, Bodin-Lario S, Pouzeratte Y, Jaber S. Airway management for COVID-19: a move towards universal videolaryngoscope?. Lancet Respiratory Medicine 2020;8: 555. 3. Sullivan EH, Gibson LE, Berra L, et al. In-hospital airway management of COVID-19 patients.Critical Care 2020;24: 292.

This guideline updates and replaces the 5th edition of the Standards of Monitoring published in 2015. The aim of this document is to provide guidance on the minimum standards for monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the UK and Ireland, but it is recognised that these guidelines may also be of use in other areas of the world. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and during transfer. There are new sections specifically discussing capnography, sedation and regional anaesthesia. In addition, the indications for processed electroencephalogram and neuromuscular monitoring have been updated.

1Consultant, Department of Anaesthesia, Guy’s and St. Thomas’NHS Foundation Trust, London, UK, Council Member, Association of Anaesthetists andCo-Chair of theWorking Party 2Consultant, Department of Anaesthesia, University Hospitals of Coventry andWarwickshire, Coventry, UK, Difficult Airway Society representative andCo-Chair of theWorking Party 3Consultant andHonoraryClinical Senior Lecturer, Imperial College London, London, UK 4Chair, TheAssociation for Anaesthetic and Respiratory Device Suppliers, Bromley, UK 5 Specialist Trainee, South East Scotland School of Anaesthesia, UK andMember of theAssociation of Anaesthetists TrainingCommittee 6 Ergonomics expert, Link Ergonomics, Nottingham, UK 7Consultant, Department of Anaesthesia, Guy’s and St. Thomas’NHS Foundation Trust, London, UK and President of Regional Anaesthesia (RA), UK 8Consultant, Department of Anaesthesia, Imperial CollegeHealthcareNHS Trust, London, UK, andCouncilMember, Royal College of Anaesthetists 9 Consultant inMedical Devices, Edinburgh, UK

Purpose of Review This review will summarize the current understanding of awareness with recall (AWR) after general anesthesia and draw ten lessons on its prevention and management from the largest study of AWR, the UK and Ireland National Audit Project 5 (NAP5). Recent Findings The results of NAP5 were published in 2014 and resulted in practice guidance on the prevention and management of AWR, “The NAP5 Handbook” which was published in 2019. NAP5 also led to the Guidelines for the Safe Practice of Total Intravenous Anaesthesia (TIVA) which were produced by the Association of Anaesthetists and the Society for Intravenous Anaesthesia (SIVA) and published in 2019. Summary Awareness with recall (AWR) after general anesthesia usually occurs when a neuromuscular blocking drug is given. The principal problem would be better described as awareness with recall after neuromuscular blockade (ARNB). Attempts to avoid or detect AWR should focus on preventing or detecting situations in which a neuromuscular blocking drug is acting but inadequate hypnotic anesthetic drug is given.

We thank the correspondents above for their interesting comments on the Association of Anaesthetists guidelines for the safe practice of total intravenous anaesthesia (TIVA) 1. We agree with Dr Whitaker that the use of pre-filled syringes can reduce the potential for intravenous (i.v.) drug administration errors. Indeed, this will apply to both i.v. drug infusions and i.v. bolus injections. In NAP5, among more than 160 cases of accidental awareness during general anaesthesia (AAGA), there were 18 cases due to error involving a drug swap 2. Only one of these involved a drug error during TIVA, whereas the other 17 were the result of a bolus injection of the wrong drug. This suggests that bolus administration may be at least as error prone as infusion anaesthesia. We also agree with Dr Whitaker that pre-filled syringes are likely to reduce the risk of contamination with micro-organisms and subsequent transmission of infection to patients. The recommendation in the quoted paper on propofol contamination by Zorrilla-Vaca et al. is to draw up propofol into a sterile syringe immediately before use after cleaning the top of the propofol vial with 70% isopropyl alcohol and while wearing gloves 3. However, it seems likely that the use of pre-filled syringes would be at least as effective. There are some barriers to the widespread use of pre-filled syringes. There are often competing pressures regarding safety and cost and pre-filled syringes may be considerably more expensive than ampoules or vials of the same drug. Moreover, some drugs are not stable in solution during storage in a syringe. The Association of Anaesthetists has established a Working Party to produce guidelines on injectable drug labelling and packaging which will consider the use of pre-filled syringes in anaesthesia. The first-generation target-controlled infusion (TCI) pumps for TIVA were controlled by Diprifusor microprocessors (AstraZeneca, Cambridge, UK) and contained a syringe recognition system. Diprifusor systems only operated if they were loaded with glass syringes, pre-filled with 1% or 2% propofol, that were supplied by one propofol manufacturer. Although this had safety benefits, eventually the high cost of the glass syringes relative to that of generic propofol drawn into ordinary syringes, and the restricted functionality of the Diprifusor pumps, resulted in most hospitals and anaesthetists abandoning their use. Although the glass pre-filled syringes are still being sold in Europe, the Diprifusor pumps specifically designed to use them are now only sold in Japan. As far as we are aware there are no other commercially available syringe-content recognition systems for IV anaesthetic infusions. Pre-filled syringes of remifentanil are not commercially available. Currently few, if any, hospitals in the UK, and very few hospitals in Europe, have a system where syringes are filled by pharmacists and supplied daily to anaesthetists. Widespread adoption of such a system would be financially and logistically challenging and the benefits would be limited unless syringe recognition technology was also incorporated. In our guidelines, we set out to recommend current best practice for the safe use of i.v. anaesthesia. There may be lessons from the experience with Diprifusor for future developments of syringe-content recognition systems and we would welcome the availability of such systems. Under the current circumstances, however, we do not feel that it is appropriate to recommend that pre-filled syringes should be used whenever using TIVA. We agree with Drs Carlos and de Boer that neuromuscular blockade monitoring should be used when neuromuscular blocking agents (NMBA) are administered. Although we do not specifically discuss neuromuscular blockade monitoring in our guidelines on TIVA, we do recommend in the guidelines that ‘monitoring of the patient during TIVA should be in accordance with the Association of Anaesthetists recommendations for standards of monitoring during anaesthesia and recovery 4.’ Those standards state ‘a peripheral nerve stimulator is mandatory for all patients receiving neuromuscular blockade drugs.’ Regarding the use of processed electroencephalography (pEEG) monitoring when administering TIVA with NMBAs, we are not the first to recommend this. In the UK and Ireland, it is also recommended in the NAP5 report 2 and in the Association of Anaesthetists’ standards of monitoring 4. There is a simple logic to this. We know that the incidence and severity of AAGA is increased by neuromuscular blockade 2, 5, which prevents patient movement that alerts the anaesthetist to the problem. During volatile-based maintenance of general anaesthesia, delivery of the anaesthetic agent is routinely monitored using end tidal gas monitoring. No similar confirmation of delivery is available with TIVA. However, pEEG monitoring, irrespective of its imperfections, provides monitoring of anaesthetic delivery by means of measuring the drug's effect on the cerebral cortex. We agree with Ward that there are advantages to using a titrated induction technique and that it is applicable in most patients. It may not be possible for rapid sequence induction anaesthesia but, otherwise, we consider it to be perfectly feasible for emergency patients, the obese or bariatric surgery and patients with predicted difficult airways. As propofol is a relatively slow onset drug, it is very important to understand and manage this appropriately, whether using TIVA or manual bolus injection, in order to avoid excessive dosing. As far as the issue of consent is concerned, any planned anaesthetic technique should be explained to the patient and the patient's consent obtained. However, we do not consider that a special or additional consent is needed in a situation where anaesthesia is not very rapidly induced. In our experience, patients find the relatively gradual and smooth titrated induction of anaesthesia with propofol a pleasant experience, with anxiolysis followed by sedation and then loss of consciousness. In fact, we usually administer low-dose propofol TCI before pre-oxygenation in elective surgery for this very reason. In low doses, propofol has a fairly powerful amnesic effect 6. In 30 years of our clinical experience, no patient administered TIVA has ever remarked on the duration of induction, or remembered any trauma around awake extubation. There is potential for airway manoeuvres to lead to complications in patients who are not adequately anaesthetised, but it has not been our experience that difficulty with bag-mask ventilation or supraglottic airway insertion is more common when a titrated induction technique is used rather than more rapid induction. As far as insertion of a supraglottic airway is concerned, we find that the lack of any movement in response to firm pressure on the angle of the mandible 7, together with relaxation of the masseter muscles, to be useful indications that insertion of the airway is likely to be well tolerated.

The use of cell salvage is recommended when it can be expected to reduce the likelihood of allogeneic (donor) red cell transfusion and/or severe postoperative anaemia. We support and encourage a continued increase in the appropriate use of peri-operative cell salvage and we recommend that it should be available for immediate use 24 h a day in any hospital undertaking surgery where blood loss is a recognised potential complication (other than minor/day case procedures).

Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at high altitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of specific coagulation factors in hypoxic humans have yielded conflicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to high altitude (5,200 m) using thromboelastometry and assays of platelet function to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent profiles, we detected a significant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter finding may be accounted for by the significant rise in platelet count and fibrinogen concentration that occurred during acclimatization. Platelet function assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normalization of coagulation following descent to sea level. These robust findings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events.

SummaryMajor vascular surgery is frequently associated with significant blood loss and coagulopathy. Existing evidence suggests hypofibrinogenaemia develops earlier than other haemostatic deficiencies during major blood loss. The purpose of this study was to assess whether the use of an infusion of fibrinogen concentrate to prevent and treat hypofibrinogenaemia during surgery resulted in satisfactory haemostasis, removing or reducing the need for blood component transfusion. Twenty patients undergoing elective extent‐4 thoraco‐abdominal aortic aneurysm repair were randomly allocated to receive either fresh frozen plasma or fibrinogen concentrate to treat hypofibrinogenaemia during surgery. Coagulation was assessed during and after surgery by point‐of‐care and laboratory testing, respectively, and treatment was guided by pre‐defined transfusion triggers. Despite blood losses of up to 11,800 ml in the patients who received the fibrinogen concentrate, none required fresh frozen plasma during surgery, and only two required platelet transfusions. The median (IQR [range]) allogeneic blood component administration during surgery and in the first 24 h postoperatively was 22.5 (14–28 [2–41]) units in patients allocated to fresh frozen plasma vs. 4.5 (3–11[0–17]) in patients allocated to fibrinogen concentrate (p = 0.011). All patients in both groups were assessed by the surgeon to have satisfactory haemostasis at the end of surgery. Mean (SD) postoperative fibrinogen concentrations were similar in patients allocated to fresh frozen plasma and fibrinogen concentrate (1.6 (0.3) g.l−1 vs. 1.6 (0.2) g.l−1; p = 0.36) but the mean (SD) international normalised ratio and activated partial thromboplastin time ratio were lower in patients allocated to fresh frozen plasma (1.1 (0.1) vs. 1.8 (0.3); p < 0.0001 and 1.1 (0.2) vs. 1.7 (0.5); p = 0.032, respectively). Fibrinogen concentrate may be used as an alternative to fresh frozen plasma in the treatment of coagulopathy during thoraco‐abdominal aortic aneurysm repair.

There are approximately 8.5 million Jehovah's Witnesses and around 150,000 live in Great Britain and Ireland. Based on their beliefs and core values, Jehovah's Witnesses refuse blood component transfusion (including red cells, plasma and platelets). They regard non-consensual transfusion as a physical violation. Consent to treatment is at the heart of this guideline. Refusal of treatment by an adult with capacity is lawful. The reasons why a patient might refuse transfusion and the implications are examined. The processes and products that are deemed acceptable or unacceptable to Jehovah's Witnesses are described. When a team is faced with a patient who refuses transfusion, a thorough review of the clinical situation is advocated and all options for treatment should be explored. After discussion, a plan should then be made that is acceptable to the patient and appropriate consent obtained. When agreement cannot be reached between the doctor and the patient, referral for a second opinion should be considered. When the patient is a child, the same strategy should be used but on occasion the clinical team may have to obtain legal help.

Guidelines are presented for safe practice in the use of intravenous drug infusions for general anaesthesia. When maintenance of general anaesthesia is by intravenous infusion, this is referred to as total intravenous anaesthesia. Although total intravenous anaesthesia has advantages for some patients, the commonest technique used for maintenance of anaesthesia in the UK and Ireland remains the administration of an inhaled volatile anaesthetic. However, the use of an inhalational technique is sometimes not possible, and in some situations, inhalational anaesthesia is contraindicated. Therefore, all anaesthetists should be able to deliver total intravenous anaesthesia competently and safely. For the purposes of simplicity, these guidelines will use the term total intravenous anaesthesia but also encompass techniques involving a combination of intravenous infusion and inhalational anaesthesia. This document is intended as a guideline for safe practice when total intravenous anaesthesia is being used, and not as a review of the pros and cons of total intravenous anaesthesia vs. inhalational anaesthesia in situations where both techniques are possible.

1. Consultant, Department of Anaesthesia, Royal Infirmary of Edinburgh, Edinburgh, UK. Society for Intravenous Anaesthesia. Co-chair of the guideline working party. 2. Professor, Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands. Society for Intravenous Anaesthesia. 3. Consultant, Department of Anaesthesia, Birmingham Children's Hospital, Birmingham, UK. Association of Paediatric Anaesthetists of Great Britain and Ireland. 4. Consultant, Department of Anaesthesia, Nottingham University Hospitals NHS Trust, Nottingham. UK. Society for Intravenous Anaesthesia 5. Professor, Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital NHS Trust, Bath, UK. Royal College of Anaesthetists. 6. Anaesthetic Registrar, Oxford School of Anaesthesia, UK. Group of Anaesthetists in Training. 7. Consultant, Department of Anaesthesia, Mid Western Regional Hospital, Dooradoyle, Limerick, Ireland. College of Anaesthetists of Ireland. 8. Consultant, Department of Anaesthesia, Derby Teaching Hospitals NHS Foundation Trust, Derby, UK; Society for Intravenous Anaesthesia. 9. Consultant, Department of Anaesthesia, North Bristol NHS Trust, Bristol, UK. Association of Anaesthetists of Great Britain and Ireland. Co-chair of the guideline working party. 10. Consultant, Department of Anaesthesia and Critical Care, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. Intensive Care Society. 11. Consultant, Department of Anaesthesia, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. Editor, Anaesthesia.

Pandit, J. J.*; Andrade, J.†; Bogod, D. G.‡; Hitchman, J. M.§; Jonker, W. R.∥; Lucas, N.¶; Mackay, J. H.#; Nimmo, A. F.**; O’connor, K.††; O’sullivan, E. P.‡‡; Paul, R. G.§§; Palmer, J. H. M. G.∥∥; Plaat, F.¶¶; Radcliffe, J. J.##; Sury, M. R. J.***; Torevell, H. E.†††; Wang, M.‡‡‡; Hainsworth, J.§§§; Cook, T. M.∥∥∥ on Behalf of the Royal College of Anaesthetists the Association of Anaesthetists of Great Britain And Ireland Author Information

Many more patients with heart disease undergo non-cardiac surgery than cardiac surgery. For this reason, the general anaesthesiologist needs to understand the pathophysiology of heart disease and it treatment. This chapter discusses the assessment and management of patients with coronary artery disease, cardiac failure, and valvular heart disease presenting for non-cardiac surgery. Risk modification is discussed including optimal use of drug therapies including statins, beta-blockers, and antiplatelet agents. The value of coronary artery bypass grafting surgery before elective non-cardiac surgery as is the management of patients with coronary stents, are addressed. Finally, the perioperative management including anaesthesia, monitoring, and postoperative care are reviewed.

Burdess, Anne MBChB; Nimmo, Alastair F. MD; Garden, O. James MD; Murie, John A. MD; Dawson, A. Raymond W. MD; Fox, Keith A. A. BSc(Hons), MBChB; Newby, David E. PhD Author Information

Endovascular technology now permits total endovascular thoracoabdominal aortic aneurysm (TAAA) repair with high volume centres reporting encouraging results. The long-term durability of such stent grafts is unknown, leading to concerns regarding their use in younger patients. This study reports contemporary outcomes of open repair in young patients.

We present the main findings of the 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia (AAGA). Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19,600 anaesthetics (95% confidence interval 1:16,700-23,450). However, there was considerable variation across subtypes of techniques or subspecialities. The incidence with neuromuscular block (NMB) was ~1:8200 (1:7030-9700), and without, it was ~1:135,900 (1:78,600-299,000). The cases of AAGA reported to NAP5 were overwhelmingly cases of unintended awareness during NMB. The incidence of accidental awareness during Caesarean section was ~1:670 (1:380-1300). Two-thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental, rapid sequence induction, obesity, difficult airway management, NMB, and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One-third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, mostly due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex, age (younger adults, but not children), obesity, anaesthetist seniority (junior trainees), previous awareness, out-of-hours operating, emergencies, type of surgery (obstetric, cardiac, thoracic), and use of NMB. The following factors were not risk factors for accidental awareness: ASA physical status, race, and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

BACKGROUND AND OBJECTIVE:Patients with critical limb ischemia have a perioperative cardiovascular morbidity comparable to patients with acute coronary syndromes. We hypothesized that perioperative dual antiplatelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischemia.METHODS:In a double-blind randomized controlled trial, 108 patients undergoing infrainguinal revascularization or amputation for critical limb ischemia were maintained on aspirin (75 mg daily) and randomized to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n = 50) or matched placebo (n = 58). Platelet activation and myocardial injury were assessed by flow cytometry and plasma troponin concentrations, respectively.RESULTS:Clopidogrel reduced platelet-monocyte aggregation before surgery (38%-30%; P = 0.007). This was sustained in the postoperative period (P = 0.0019). There were 18 troponin-positive events (8 [16.0%] clopidogrel vs. 10 [17.2%] placebo; relative risk [RR]: 0.93, 95% confidence interval [CI]: 0.39-2.17; P = 0.86). Half of troponin-positive events occurred preoperatively with clopidogrel causing a greater decline in troponin concentrations (P < 0.001). There was no increase in major life-threatening bleeding (7 [14%] vs. 6 [10%]; RR: 1.4, 95% CI: 0.49-3.76; P = 0.56) or minor bleeding (17 [34%] vs. 12 [21%]; RR 1.64, 95% CI: 0.87-3.1; P = 0.12), although blood transfusions were increased (28% vs. 12.6%, RR: 2.3, 95% CI: 1.0-5.29; P = 0.037).CONCLUSIONS:In patients with critical limb ischemia, perioperative dual antiplatelet therapy reduces biomarkers of atherothrombosis without causing unacceptable bleeding. Large-scale randomized controlled trials are needed to establish whether dual antiplatelet therapy improves clinical outcome in high-risk patients undergoing vascular surgery.