Garry McDowell

Factors predicting anaphylaxis to peanuts and tree nuts in patients referred to a specialist center

BACKGROUND Although acute allergic reactions after ingestion of peanuts and tree nuts are common, fatalities are rare. Other than patients with coexisting asthma, it is currently not possible to predict which patients are most likely to develop severe reactions. OBJECTIVE The aim of this study was to determine which clinical and laboratory parameters best predict the likelihood of severe allergic reactions. METHODS From 1992 to 2004, we collected detailed information on the clinical severity and allergy test results of 1094 patients with peanut and tree nut allergy attending a regional allergy center. In a subgroup of 122 patients, sera were assayed for activity of enzymes involved in the catabolism of bradykinin. RESULTS Severe pharyngeal edema was 3.8 (2.1-6.9) times more common in patients with severe rhinitis and 2.6 (1.8-3.7) more common after ingestion of tree nuts compared with peanuts. Patients with serum angiotensin-converting enzyme concentrations <37.0 mmol/L had a 9.6 (1.6-57)-fold risk of severe pharyngeal edema. Life-threatening bronchospasm was most likely in patients with severe asthma (relative risk, 6.8 [4.1-11.3]) and less so in patients with milder asthma (2.7 [1.7-4.0]). Altered levels of consciousness were more likely in patients with severe eczema (3.1 [1.1-8.4]). CONCLUSION Severity of coexisting atopic diseases predicted which patients attending a tertiary referral clinic were most likely to develop life-threatening allergic reactions to peanuts and tree nuts. Patients with the lowest serum angiotensin-converting enzyme concentrations were more likely to develop life-threatening pharyngeal edema, suggesting that this complication may be partly mediated by bradykinin.

Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are known to be elevated in patients with chronic heart failure at rest. While it is known that during exercise the circulating level of ANP increases in patients with heart failure, the response of BNP to exercise in these patients relative to control subjects is unclear. Ten patients with stable chronic heart failure and 10 normal control subjects performed symptom‐limited exercise with respired gas analysis. All patients had depressed left ventricular ejection fractions (LVEF). Patients had lower peak oxygen consumption PV˙O2) than the control group [median (range) 1.18 (0.98–1.76) vs. 1.94 (1.53–2.31) L min−1; P < 0.001]. Circulating plasma levels of ANP and BNP were higher at rest in patients than in control subjects [ANP 335 (140–700) vs. 90 (25–500) pg mL−1; BNP 42 (25–50) vs. 20 (10–20) pg mL−1], and at peak exercise [ANP 400 (200–1000) vs. 130 (10–590); BNP 46 (40–51) vs. 20 (10–30)]. The rise in ANP at peak exercise was significant in patients compared with the resting level, but not in control subjects. For BNP, there was a significant rise in patients but no change in control subjects. The circulating plasma levels of both peptides showed a strong negative correlation with LVEF (ANP, P < 0.005; BNP, P < 0.0001) and, to a less extent, with RVEF. It is possible that BNP may give a better indication of cardiac function.

The Manchester Acute Coronary Syndromes (MACS) decision rule for suspected cardiac chest pain: derivation and external validation

Objective We aimed to derive and validate a clinical decision rule (CDR) for suspected cardiac chest pain in the emergency department (ED). Incorporating information available at the time of first presentation, this CDR would effectively risk-stratify patients and immediately identify: (A) patients for whom hospitalisation may be safely avoided; and (B) high-risk patients, facilitating judicious use of resources. Methods In two sequential prospective observational cohort studies at heterogeneous centres, we included ED patients with suspected cardiac chest pain. We recorded clinical features and drew blood on arrival. The primary outcome was major adverse cardiac events (MACE) (death, prevalent or incident acute myocardial infarction, coronary revascularisation or new coronary stenosis >50%) within 30 days. The CDR was derived by logistic regression, considering reliable (κ>0.6) univariate predictors (p<0.05) for inclusion. Results In the derivation study (n=698) we derived a CDR including eight variables (high sensitivity troponin T; heart-type fatty acid binding protein; ECG ischaemia; diaphoresis observed; vomiting; pain radiation to right arm/shoulder; worsening angina; hypotension), which had a C-statistic of 0.95 (95% CI 0.93 to 0.97) implying near perfect diagnostic performance. On external validation (n=463) the CDR identified 27.0% of patients as ‘very low risk’ and potentially suitable for discharge from the ED. 0.0% of these patients had prevalent acute myocardial infarction and 1.6% developed MACE (n=2; both coronary stenoses without revascularisation). 9.9% of patients were classified as ‘high-risk’, 95.7% of whom developed MACE. Conclusions The Manchester Acute Coronary Syndromes (MACS) rule has the potential to safely reduce unnecessary hospital admissions and facilitate judicious use of high dependency resources.

Do risk factors for chronic coronary heart disease help diagnose acute myocardial infarction in the Emergency Department

BACKGROUND Hypertension, hyperlipidaemia, diabetes mellitus, tobacco smoking and a family history of premature coronary artery disease are known to be risk factors for the development of coronary artery disease. We sought to determine whether these traditional risk factors aid the diagnosis of acute myocardial infarction (AMI) in the Emergency Department (ED). METHODS We performed a prospective diagnostic cohort study within the ED at Manchester Royal Infirmary, a university-affiliated teaching hospital with an annual ED census of approximately 145,000 patients. We recruited 804 patients who had presented to the ED with suspected cardiac chest pain. All patients had the presence or absence of traditional cardiac risk factors documented at the time of presentation using a custom-designed clinical report form. All patients subsequently underwent 12-h troponin T testing to provide a robust gold standard for the diagnosis of AMI according to revised World Health Organisation criteria. RESULTS The absence of any traditional cardiac risk factors carried a negative likelihood ratio of 0.61 for the diagnosis of AMI. 12.2% of patients with no cardiac risk factors had AMI, compared with 21.3% of patients with four or five risk factors. The area under the receiver-operating characteristic curve was 0.49. CONCLUSIONS Traditional cardiac risk factors are not helpful for the confirmation or exclusion of AMI within the ED. Future Emergency Medicine research should focus on those clinical and diagnostic features that are likely to alter during the acute phase of illness.

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer.

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml−1 has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin–antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group.

Can a modified thrombolysis in myocardial infarction risk score outperform the original for risk stratifying emergency department patients with chest pain

Background: The thrombolysis in myocardial infarction (TIMI) risk score has been shown to risk stratify patients with suspected acute coronary syndromes (ACS) effectively in the emergency department (ED) but cannot be used to guide patient disposition. We aimed to evaluate whether modifying the TIMI risk score to give greater weighting to ischaemic ECG changes and troponin elevations would enhance its risk stratification and thus potentially facilitate safe patient discharge after 12-h troponin testing. Methods: A prospective diagnostic cohort study was performed within the ED at Manchester Royal Infirmary, a university-affiliated teaching hospital with an annual ED census of approximately 145 000 patients. 804 patients who had presented to the ED with suspected cardiac chest pain were recruited. All patients underwent 12-h troponin T testing and were followed up by telephone and chart review after 30 days for the composite primary outcome of death, acute myocardial infarction (AMI) or urgent coronary revascularisation. Results: The modified TIMI risk score outperformed the original (area under the receiver operator characteristic curve 0.87 versus 0.77, p<0.001). Using a cut-off of more than 2 points the score had a sensitivity of 96.4% for the prediction of 30-day events. The specificity of the score was only 51.0%, suggesting that in practice over 40% of patients would be ineligible for discharge even after troponin testing. Conclusions: Modifications to the TIMI risk score can improve its performance in the risk stratification of patients presenting to the ED with chest pain. However, a lack of specificity may still limit its use for guiding patient disposition after troponin testing.

The endopeptidase inhibitor, candoxatril, and its therapeutic potential in the treatment of chronic cardiac failure in man.

Candoxatril (UK-79300) is the orally-active prodrug of candoxatrilat (UK-73967), the active enantiomer of (+/-)candoxatrilat (UK-69578), a potent neutral endopeptidase (NEP) inhibitor. This article describes the rationale behind the use of such a drug in the treatment of chronic heart failure in man. It further describes the pharmacokinetics and pharmacodynamics of candoxatril in normal healthy individuals and in patients with chronic cardiac failure. In addition, we describe the initial results comparing candoxatril with furosemide and captopril in human heart failure.

Neuroendocrine changes in chronic cardiac failure

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

The natriuretic peptide family.

For several decades there has been a search for an endogenous natriuretic-diuretic hormone. As early as 1935, Peters proposed that the ‘fullness’ of the bloodstream may provide a diuretic response on part of the kidney. Experiments by De Wardener et al. [l] provided evidence in support of a hormonal mechanism influencing sodium excretion. If blood from a dog, in which volume expansion with normal saline had been performed, was used to perfuse the kidney of another dog, natriuresis occurred which was independent of the effect of aldosterone or renal perfusion pressure. Other experiments [2] showed that distension of the left atrium with a balloon in an anaesthetized dog led to an increase in urine output, suggesting a specific link between the heart and kidney. The concept that the heart might secrete a hormone which might play a role in the control of sodium and water excretion, and thereby blood volume, was reinforced by the observation of endocrine-like granules in atrial muscle cells [3] and by a change in the degree of granulation with the alteration of sodium and water balance [4]. These experiments led DeBold and co-workers to carry out the key experiments in which they injected rats with extracts prepared from rat atria and ventricles [5]. The natriuretic peptide family currently consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Each peptide exhibits natriuretic-diuretic, vasorelaxant and other functions designed to lower blood pressure and to control electrolyte homeostasis. The natriuretic peptides exert their physiological actions via a series of cellular receptors. Ligand occupancy of the extracellular domain results in the activation of an intracellular guanylate cyclase with an associated rise in cGMP, which is thought to act as the second messenger for the peptides.

Choline for diagnosis and prognostication of acute coronary syndromes in the Emergency Department

OBJECTIVES Choline has been identified as a promising marker of coronary inflammation, plaque destabilisation and ischaemia. We sought to evaluate plasma choline levels for rapid confirmation or exclusion of acute myocardial infarction (AMI) in the Emergency Department (ED) and for predicting major adverse cardiac events (MACE). METHODS We prospectively recruited 361 patients who presented to the ED with suspected cardiac chest pain within the previous 24 h. Blood was drawn at the time of presentation for plasma choline levels. All patients underwent troponin T testing > or = 12 h after symptom onset and were followed up for the occurrence of MACE within 6 months. Whole blood choline (WBCho) levels were also measured in a convenience sample of 39 patients. RESULTS Plasma choline levels did not help to predict a diagnosis of AMI (odds ratio (OR) 1.00 (95% confidence intervals (CI) 0.91-1.10, p = 0.98). For a diagnosis of AMI the area under the receiver operating characteristic (ROC) curve was 0.48. Plasma choline was not predictive of the combined endpoint of MACE (OR 1.03, 95% CI 0.95-1.12, p = 0.45) but predicted AMI within 6 months (OR 1.31, 95% CI 1.09-1.56, p = 0.003). WBCho levels were significantly different to plasma levels and were predictive of MACE. CONCLUSIONS Plasma choline, measured at the time of ED presentation, is not a diagnostic marker of AMI but predicts AMI within 6 months. While plasma choline failed to predict MACE, WBCho was predictive and warrants further evaluation.