Redefining the perioperative stress response: a narrative review.

The systemic stress response triggered by surgical trauma is characterised by sterile inflammation preceding metabolic and neuroendocrine dysregulation. However, the relevance of the classically described 'stress response' is now highly questionable in an era where profound physiological deconditioning is common in older, frail surgical patients. Commonly used assessment techniques do not accurately reflect hypothalamic-pituitary-adrenal axis integrity after major surgery. Clinical interpretation of plasma concentrations of cortisol, the prototypical stress hormone, is rarely accurate, because of study heterogeneity, the inherently dynamic characteristics of cortisol production, and assay variability. Before surgery, chronic psychosocial stress and common cardiorespiratory co-morbidities are clinically relevant modifiers of neuroendocrine activation to acute stress/inflammation. The frequent development of multi-morbidity after major surgery further clouds the compartmentalised, discrete model of neuroendocrine activation after initial tissue injury. Starvation, impaired mobility, and sepsis after surgery generate distinct neuroendocrine profiles that challenge the conventional model of neuroendocrine activation. Basic science studies suggest that high circulating levels of cortisol may directly cause organ injury. Conversely, randomised controlled clinical trials investigating glucocorticoid supplementation have delivered contrasting results, with some suggesting a protective effect in the perioperative period. Here, we consider many of the confounding factors that have emerged to challenge the conventional model of the surgical stress response, and suggest that a more nuanced understanding of changes in hypothalamic-pituitary-adrenal axis physiology is warranted to advance perioperative medicine. Re-examining the perioperative stress response presents opportunities for improving outcomes through enhancing the understanding of the neuroendocrine aspects of preparation for and recovery from surgery.

Republished: 'Warm-Up Angina': harnessing the benefits of exercise and myocardial ischaemia.

The phenomenon of warm-up angina was first noted over 200 years ago. It describes the curious observation whereby exercise-induced ischaemia on second effort is significantly reduced or even abolished if separated from first effort by a brief rest period. However, the precise mechanism via which this cardio-protection occurs remains uncertain. Three possible explanations for reduced myocardial ischaemia on second effort include: first, an improvement in myocardial perfusion; second, increased myocardial resistance to ischaemia similar to ischaemic preconditioning; and third, reduced cardiac work through better ventricular-vascular coupling. Obtaining accurate coronary physiological measurements in the catheter laboratory throughout exercise demands a complex research protocol. In the 1980s, studies into warm-up angina relied on great cardiac vein thermo-dilution to estimate coronary blood flow. This technique has subsequently been shown to be inaccurate. However exercise physiology in the catheter laboratory has recently been resurrected with the advent of coronary artery wires that allow continuous measurement of distal coronary artery pressure and blood flow velocity. This review summarises the intriguing historical background to warm-up angina, and provides a concise critique of the important studies investigating mechanisms behind this captivating cardio-protective phenomenon.

The diagnostic accuracy of E6 & 7 mRNA detection as a primary screening test for the detection of severe cervical lesions.

PURPOSE: This prospective accuracy study aimed to assess the diagnostic accuracy of nucleic acid sequence amplification (NASBA) and flow cytometry for E6/7 human papillomavirus (HPV) mRNA detection as a primary screening test compared to cytology in the triage of severe cervical intraepithelial neoplasia (CIN) lesions. METHODS: 1083 women referred to our outpatient gynecology clinics for a routine Pap test were recruited. Residual material of the Pap smears was tested by NASBA and by flow cytometry for E6/7 mRNA expression. Biopsy results were used as reference standards. The accuracy indices of both techniques and of NASBA type-16 HPV were assessed for the detection of CIN2+ lesions and were compared to cytology. RESULTS: An increased lesion severity was associated with increased positivity rates of both NASBA and flow cytometry tests (x(2), p<0.001). A positive correlation between NASBA and flow cytometry was identified when these methods were examined with the Phi coefficient (value 0.369, 95% confidence interval [95%CI] : 0.307-0.426). Furthermore, NASBA (89.7 vs 57.7%, p<0.0005) and flow cytometry (77.3 vs 57.7%, p<0.0005) exhibited higher specificity rates than cytology. However, their sensitivity rates did not exceed those of cytology (NASBA:69.8 vs 84.6%, p=0.051; flow cytometry: 69.12 vs 84.6%, p=0.043). CONCLUSIONS: Both NASBA and flow cytometry exhibited increased specificity for the triage of CIN2+ lesions. However, their relatively lower sensitivity and higher positivity rates when compared to cytology do not make them ideal for a primary screening test. Hence, the role of mRNA detection in the screening for severe cervical lesions remains to be clarified.

Controversies in the management of endometriomas in patients undergoing assisted reproduction.

INTRODUCTION: The presence of an endometrioma has been proposed to affect the ovarian function in a negative way. Our aim was to present the key evidence on multiple aspects of endometriomas' management in subfertile couples scheduled for assisted reproduction technologies (ART). MATERIALS AND METHODS: A critical review of the existing literature was performed focusing on the need of endometrioma treatment prior to ART, the relevant options, the potentially participating surgeon's characteristics and the socioeconomic perspective. RESULTS: To date, we have no definitive data to suggest whether the damage to the ovaries observed in women with endometriomas may be related to the mere presence of the cyst, the surgical procedure to remove it, the combination of the two, or factors currently unknown. Moreover, there is no conclusive evidence that, for subfertile couples, removal of endometriomas increases the chance of having a baby. The uncertainty regarding the best treatment strategy and factors such as the limited number of tertiary centers for laparoscopic surgery throughout the world seems to further complicate the decision. CONCLUSIONS: Until research addresses the current "grey areas", the management of endometriomas in patients undergoing ART should be individualized and take into consideration numerous parameters.

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease.

Background Cold air inhalation during exercise increases cardiac mortality, but the pathophysiology is unclear. During cold and exercise, dual-sensor intracoronary wires measured coronary microvascular resistance ( MVR ) and blood flow velocity ( CBF ), and cardiac magnetic resonance measured subendocardial perfusion. Methods and Results Forty-two patients (62±9 years) undergoing cardiac catheterization, 32 with obstructive coronary stenoses and 10 without, performed either (1) 5 minutes of cold air inhalation (5°F) or (2) two 5-minute supine-cycling periods: 1 at room temperature and 1 during cold air inhalation (5°F) (randomized order). We compared rest and peak stress MVR , CBF , and subendocardial perfusion measurements. In patients with unobstructed coronary arteries (n=10), cold air inhalation at rest decreased MVR by 6% ( P=0.41), increasing CBF by 20% ( P<0.01). However, in patients with obstructive stenoses (n=10), cold air inhalation at rest increased MVR by 17% ( P<0.01), reducing CBF by 3% ( P=0.85). Consequently, in patients with obstructive stenoses undergoing the cardiac magnetic resonance protocol (n=10), cold air inhalation reduced subendocardial perfusion ( P<0.05). Only patients with obstructive stenoses performed this protocol (n=12). Cycling at room temperature decreased MVR by 29% ( P<0.001) and increased CBF by 61% ( P<0.001). However, cold air inhalation during cycling blunted these adaptations in MVR ( P=0.12) and CBF ( P<0.05), an effect attributable to defective early diastolic CBF acceleration ( P<0.05) and associated with greater ST -segment depression ( P<0.05). Conclusions In patients with obstructive coronary stenoses, cold air inhalation causes deleterious changes in MVR and CBF . These diminish or abolish the normal adaptations during exertion that ordinarily match myocardial blood supply to demand.

'Warm-up Angina': harnessing the benefits of exercise and myocardial ischaemia.

The phenomenon of warm-up angina was first noted over 200 years ago. It describes the curious observation whereby exercise-induced ischaemia on second effort is significantly reduced or even abolished if separated from first effort by a brief rest period. However, the precise mechanism via which this cardio-protection occurs remains uncertain. Three possible explanations for reduced myocardial ischaemia on second effort include: first, an improvement in myocardial perfusion; second, increased myocardial resistance to ischaemia similar to ischaemic preconditioning; and third, reduced cardiac work through better ventricular-vascular coupling. Obtaining accurate coronary physiological measurements in the catheter laboratory throughout exercise demands a complex research protocol. In the 1980s, studies into warm-up angina relied on great cardiac vein thermo-dilution to estimate coronary blood flow. This technique has subsequently been shown to be inaccurate. However exercise physiology in the catheter laboratory has recently been resurrected with the advent of coronary artery wires that allow continuous measurement of distal coronary artery pressure and blood flow velocity. This review summarises the intriguing historical background to warm-up angina, and provides a concise critique of the important studies investigating mechanisms behind this captivating cardio-protective phenomenon.