Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Stress in new graduates: can the profession do more to help?

Richard Halliwell and colleagues believe that it can, on the basis of a survey they conducted to assess the incidence of poor mental health and wellbeing in recent veterinary graduates, and workplace factors that might be associated with this.

Cardiac assessment prior to non-cardiac surgery.

BACKGROUND: Increasingly, patients undergoing non-cardiac surgery are older and have more comorbidities yet preoperative cardiac assessment appears haphazard and unsystematic. We hypothesised that patients at high cardiac risk were not receiving adequate cardiac assessment, and patients with low-cardiac risk were being over-investigated. AIMS: To compare in a representative sample of patients undergoing non-cardiac surgery the use of cardiac investigations in patients at high and low preoperative cardiac risk. METHODS: We examined cardiac assessment patterns prior to elective non-cardiac surgery in a representative sample of patients. Cardiac risk was calculated using the Revised Cardiac Risk Index. RESULTS: Of 671 patients, 589 (88%) were low risk and 82 (12%) were high risk. We found that nearly 14% of low-risk and 45% of high-risk patients had investigations for coronary ischaemia prior to surgery. Vascular surgery had the highest rate of investigation (38%) and thoracic patients the lowest rate (14%). Whilst 78% of high-risk patients had coronary disease, only 46% were on beta-blockers, 49% on aspirin and 77% on statins. For current smokers (17.3% of cohort, n = 98), 60% were advised to quit pre-op. CONCLUSIONS: Practice patterns varied across surgical sub-types with low-risk patients tending to be over-investigated and high-risk patients under-investigated. A more systemised approach to this large group of patients could improve clinical outcomes, and more judicious use of investigations could lower healthcare costs and increase efficiency in managing this cohort.

Uptake of guidelines in the management of patients taking anticoagulants and antiplatelet agents presenting for elective surgery.

Management guidelines for patients on antithrombotic agents presenting for surgery have long been disseminated. Clinical practice, however, does not always follow published guidelines in a timely manner, despite their dissemination. This project is an audit of the management of patients on anticoagulants or antiplatelet agents presenting for elective surgery in a large metropolitan teaching hospital. An audit was conducted of the management of patients on anticoagulants or antiplatelet agents presenting for elective surgery at Westmead Hospital to determine the percentage of patients whose management complied with guidelines, and to identify the prevailing reasons for guideline deviation. This was an observational study with qualitative and quantitative aspects. Data was collected for the 102 patients who fulfilled the inclusion criteria: 55.4% of decisions by surgeons and 51.4% of decisions by anaesthetists made in this study matched guidelines; 31.4% of decisions made by anaesthetists were fully compliant with guidelines; 20% of anaesthetic decisions were unintentionally compliant and 48.6% of anaesthetic decisions were noncompliant. A variety of reasons were cited for decisions made without the use of guidelines such as other clinical imperatives, lack of guideline awareness and a belief that it is not the role of the anaesthetist to manage perioperative antithrombotic therapy, amongst others. It is evident from this audit that compliance with guidelines remains an area where there is an opportunity for further practice improvement.

Beta-blocker management in high-risk patients presenting for non-cardiac surgery: before and after the POISE Trial.

The POISE Trial was a randomised, placebo-controlled, double-blind study of the effectiveness of perioperative beta-blockade in preventing cardiac events including death in 8351 patients. Our hypothesis was that knowledge of the results of the POISE Trial would either increase or decrease the use of effective perioperative beta-blockade, depending on the result. Patients presenting for non-cardiac surgery and at risk of perioperative cardiac events were recruited in two cohorts before and after the release of the POISE Trial results. Effective perioperative beta-blockade was defined as heart rate <65 beats per minute for at least 80% of the perioperative period in patients prescribed beta-blockers. Effective perioperative beta-blockade was achieved in 22 (11.5%) of 191 patients prescribed perioperative beta-blockade in the first cohort (n=392) and seven (6%) of 118 patients in the second cohort (n=241) (P=0.10). Effective heart rate control was achieved in 29 (9%) patients prescribed perioperative beta-blockers compared with 10 (3%) patients not prescribed perioperative beta-blockers (P=0.001). The rate of implementation of effective beta-blockade was low before POISE and this did not change significantly after publication. Our finding does not provide reliable evidence of a change in practice as a result of the POISE Trial.

Acute subdural haematoma in the presence of an intrathecal catheter placed for the prevention of post-dural puncture headache.

A 31-year-old term primigravid woman had an intrathecal catheter placed following a dural puncture during attempted epidural analgesia during labour. After 23 hours she developed sudden loss of consciousness and an urgent brain computed tomography scan demonstrated a large left hyper-acute subdural haematoma. Craniotomy revealed active bleeding from a ruptured left temporal bridging vein. She was extubated 12 hours after surgery and was discharged home 11 days later without neurological deficit. Although subdural haematoma is a recognised complication of dural puncture, it has not been reported in the presence of an intrathecal catheter. An intrathecal catheter may not always prevent cerebrospinal fluid efflux, so subdural haematoma remains a potential complication of inadvertent dural puncture.

The responsibilities of veterinary educators in responding to emerging needs in veterinary medicine.

It is an unfortunate fact that not only has veterinary education failed to adapt in the face of likely future needs, but it has also failed to respond to societal changes that have already taken place and that have affected the requirements for veterinary services and veterinary capability. The responsibility is primarily that of educators, although vision and foresight require a co-ordinated approach involving national and international veterinary organisations. Once it is accepted by all parties that change is essential, the implementation will fail unless there is a unified programme involving the schools and colleges, the accrediting agencies, the licensing authorities, governments, the professional organisations and corporate veterinary medicine. All have a role to play, and any one can readily block progress. A unified approach is an absolute requirement. The developed countries must take a leading role, but the issues are global, and ways must be found to facilitate change in all parts of the world. Disease knows no boundaries, and any strategy is only as strong as its weakest link.

Is our divided profession a profession in decline?

Richard Halliwell is concerned by criticisms of the veterinary profession in the recent select committee report on a new Veterinary Surgeons Act. He fears that a lack of leadership and division within the veterinary profession may have contributed to loss of influence, and makes some suggestions for putting that right.

Reducing the suicide rate among veterinary surgeons: how the profession can help.

A short communication on page 415 of this issue of The Veterinary Record draws attention to the high suicide rate among members of the veterinary profession. In this article, Professor Richard Halliwell, who has recently chaired a series of meetings on this matter at the Royal College of Veterinary Surgeons, and Mr Brian Hoskin, chairman of the Veterinary Benevolent Fund, describe some of the support mechanisms available to veterinary surgeons and discuss what more might be done.

The effects of endoparasitism on the immune response to orally administered antigen in cats.

The aim of the study was to assess whether infection with Toxocara cati (T. cati) facilitates the induction of immunoglobulin (Ig) E or other antibody responses to a specific antigen administered with food in kittens. Two groups of 10 cats each, either experimentally infected with T. cati or parasite-free, were dosed with human serum albumin (HSA) added daily to their food from day 7 to 28 inclusive. Levels of HSA-specific IgE, IgG, IgA and IgM were assessed in the serum by enzyme-linked immunosorbent assay (ELISA) in both groups of cats at weeks 0, 2, 4 and 8. Although weak, an IgE response was detected in most of the cats 1 week after exposure to HSA. However, HSA-specific IgG and IgA could only be detected from the third week after exposure to HSA. The group of parasitized cats had significantly higher levels of HSA-specific antibodies of the IgG and IgA at weeks 4 and 8 (p<0.05 by Mann-Whitney) and IgE isotypes at weeks 2 and 4 (p<0.05 by analysis of variance (ANOVA)) than did the group of parasite-free cats. Specific IgM antibody was not detected in the sera of any of the 20 cats. These findings are supportive of a role of T. cati infection in enhancing the IgE response to orally administered antigens, and hence possibly, in genetically susceptible individuals, in the development of food hypersensitivity.

Human embryonal carcinoma stem cells expressing green fluorescent protein form functioning neurons in vitro: a research tool for co-culture studies.

Neural differentiation is controlled by complex molecular mechanisms that determine cell fate and diversity within the nervous system. Interactions between developing tissues play an important role in regulating this process. In vitro co-culture experiments offer a method to study cell differentiation and function under controlled conditions, with the additional benefit of investigating how interactions between populations of cells influence cell growth and behavior. However, it can often be difficult to distinguish between populations of co-cultured cells. Here we report the development of a human embryonal carcinoma (EC) stem cell line (named TERA2.cl.SP12-GFP) that expresses the genetic marker, green fluorescent protein (GFP). Here, we demonstrate that TERA2.cl.SP12-GFP stem cells stably express GFP and that this remains detectable during retinoic acid-induced differentiation. Regulated expression of neural markers during cell development correlated with the formation of morphologically identifiable neurons. Populations of post-mitotic GFP-positive neurons were readily purified and electrophysiological characterization confirmed that such neurons were functionally active. Thus, cultured TERA2.cl.SP12-GFP cells can be readily distinguished from alternative cell types in vitro and provide an amenable system for live cell imaging to study the development and function of human neurons in isolation, and in co-culture with other tissue types.

Cutaneous hypersensitivity reactions to Psoroptes ovis and Der p 1 in sheep previously infested with P. ovis--the sheep scab mite.

We have previously shown that infestation with Psoroptes ovis induces an IgE response and intense tissue eosinophilia, typical of a Type I hypersensitivity response [Parasite Immunol. 22 (2000) 407]. Intradermal tests (IDSTs) suggest that there are also delayed and Arthus-type responses to this parasite. In order to study the nature of ovine cutaneous reactions to P. ovis, naïve controls and experimentally infested sheep (n = 5) were challenged intradermally with mite antigen. Challenge elicited immediate (P < 0.001) and delayed (P < 0.005) wheal reactions in sensitised sheep. At 6 (P < 0.02) and 30 h (P < 0.001) the predominant infiltrating cells were eosinophils. To explore the role of circulating antibodies, naïve sheep (n = 5) were subjected to Prausnitz-Kustner (PK) tests. These elicited immediate (P < 0.02) but not delayed wheal reactions. At 6 h eosinophils (P < 0.001) dominated the infiltrate. These results suggest that P. ovis allergens provoke an IgE-dependent immediate and late phase response and a cell-mediated eosinophil-rich delayed-type hypersensitivity response (ER-DTH).

Characterization of the interaction between a novel convulsant agent, norbiphen, and GABA(A) and other ligand-gated ion channels.

A hybrid molecule composed of the antimicrobial, norfloxacin, linked to the non-steroidal anti-inflammatory drug (NSAID), biphenylacetic acid, which we have termed norbiphen, is a lethal convulsant in vivo and an antagonist of rodent GABA(A) receptors in vitro. In the present study, the selectivity, molecular site(s) and mechanism of action of this novel convulsant were investigated using electrophysiological techniques. Sub-maximal GABA-evoked currents recorded from rodent hippocampal neurons were reversibly inhibited by norbiphen (1 microM) to 5+/-2% of control whereas glutamate, NMDA and glycine activated responses were little or unaffected. Sub-maximal GABA-evoked currents recorded from oocytes expressing recombinant human alpha1beta2gamma2s or alpha1beta2 GABA(A) receptors were also reversibly inhibited by norbiphen (1-1000 nM) with an IC(50) (+/-s.e.m.) of 5.7+/-1 and 8.8+/-1 nM, respectively. Similarly, GABA currents recorded from alpha1beta1gamma2s, alpha1beta1 and beta2gamma2s receptors were inhibited with IC(50)s of 16.1+/-1, 18.8+/-1 and 4.2+/-1 nM, respectively. In contrast, norbiphen (100 nM) had little or no effect at rho1 GABA(C) homomers. At alpha1beta2gamma2s receptors, norbiphen had no affect on the GABA reversal potential, and inhibition was not voltage-dependent, suggesting that this compound does not act at the ion channel. The GABA concentration response curve was shifted in a competitive-like fashion by norbiphen (10-300 nM) and a Schild analysis of these data yielded a slope of 0.94+/-0.1 and a pA(2) of 7.77. Our data reveal a novel, selective and highly potent antagonist of GABA(A) receptors. Norbiphen should be a valuable agent in future studies of this receptor complex.

The ACVD task force on canine atopic dermatitis (III): the role of antibodies in canine atopic dermatitis.

Although an important pathogenic role for IgE is established in the case of allergic asthma and rhinitis in man, its role in atopic dermatitis is less clear. There are many studies where allergists and immunologists have provided evidence in favour of such a role, whereas dermatologists are less than convinced. In dogs, however, there is an abundance of clinical evidence implying that atopic dermatitis is antigen driven, and recent studies suggest that there may be a role for IgE, not only in the effector pathway, but also in antigen capture. Although an IgG response often accompanies an IgE response in dogs with atopic dermatitis, there is little evidence in support of a pathogenic role in respect of the former isotype.

The ACVD task force on canine atopic dermatitis (XI): the relationship between arthropod hypersensitivity and atopic dermatitis in the dog.

The relationship between arthropod allergen hypersensitivity and the development of canine atopic dermatitis (AD) is unclear. It has been shown that dogs with AD are more likely to exhibit positive intradermal reactivity to flea allergens than non-pruritic dogs from the same flea-endemic geographic region. Also, dogs in a flea endemic region are four times more likely to suffer from flea allergy dermatitis (FAD) and AD than from FAD alone. These results provide indirect evidence to support the hypothesis that, in the canine species, atopy predisposes to the development of hypersensitivity to flea allergens and eventually to FAD. A causal relationship between insects other than fleas and canine AD has not been identified with certainty.

An electrophysiological study of the effects of propofol on native neuronal ligand-gated ion channels.

1. Pharmacological evidence suggests that some of the clinical actions of propofol may be mediated, at least in part, by positive modulation of the GABA(A) receptor chloride channel. The effect of propofol at other native neuronal ligand-gated ion channels is unclear. 2. To gain some insight into the effects of propofol at a range of native neuronal receptors, the present study has used an extracellular recording technique and determined its effects at GABA(A), 5-HT3, P2X and nicotinic acetylcholine (nACh) receptors of the rat isolated vagus nerve and the GABA(A) and strychnine-sensitive glycine receptor of the rat isolated optic nerve. In addition, we have used patch-clamp recording techniques to further investigate the effects of propofol at the GABA(A) and strychnine-sensitive glycine receptors in rat cultured hippocampal neurons. 3. Propofol (0.3-100 micromol/L) concentration-dependently potentiated submaximal GABA-evoked responses in the vagus nerve and shifted the GABA concentration-response curve to the left. In contrast, propofol at concentrations ranging from 1 to 10 micromol/L had little or no effect on 5-HT3, P2X or nACh receptor-mediated responses in the vagus nerve but, at 100 micromol/L, propofol inhibited these responses to approximately 50% of control. In the optic nerve, EC20 GABA-evoked responses were also potentiated by propofol (10 micromol/L), while EC20 glycine-evoked responses were minimally enhanced. 4. Further investigations using cultured hippocampal neurons showed that submaximal (10 micromol/L) GABA-evoked currents were potentiated by propofol (1-10 micromol/L), in a non-voltage-dependent manner, whereas submaximal (100 micromol/L) glycine-evoked currents were unaffected. 5. These data suggest that propofol, at therapeutic concentrations, exerts its principle pharmacological actions at GABA(A) receptors with relatively little effect at other neuronal ligand-gated ion channels.