Procalcitonin kinetics following abdominal aortic surgery and its value for postoperative intestinal ischaemia detection.

OBJECTIVE: The purpose of our study was to describe perioperative kinetics of procalcitonin (PCT) in patients undergoing aortic surgery, to compare the kinetics in the open abdominal aortic aneurysm (AAA) repair and aortobifemoral bypass for aortoiliac occlusive disease (AIOD), and to evaluate the ability of PCT to detect intestinal ischaemia. METHODS: A prospective non-randomized observational cohort study in 80 patients (62 men and 18 women) undergoing elective aortic surgery was performed. Serum PCT was measured at baseline and defined intraoperative and postoperative timepoints up to postoperative day 7. MRI contrast-enhanced imaging was used to detect intestinal ischaemia. RESULTS: The comparison of the AAA and AIOD cohort did not show any significant difference in PCT levels. Patients with intestinal ischaemia had higher serum PCT at multiple timepoints postoperatively. The most accurate timepoints for early diagnosis were postoperative day 3, followed by 24 h after declamping of the vascular reconstruction, and postoperative day 7. The sensitivity and negative predictive values were 100% in all mentioned timepoints. However, event at the best timepoint the specificity was 89% and the positive predictive value 43%. CONCLUSIONS: Procalcitonin levels in the postoperative period at proper timepoints might help to detect postoperative intestinal ischaemia. The limitation of this marker is its low specificity for intestinal ischaemia and low positive predictive value. The highest value of this marker is that it can rule out this complication because normal PCT levels mean that intestinal ischaemia is very unlikely.

Kinetics of d-lactate and ischemia-modified albumin after abdominal aortic surgery and their ability to predict intestinal ischemia.

OBJECTIVES: Acute intestinal ischemia is a severe complication of abdominal aortic surgery that is difficult to diagnose early and therefore to treat adequately and timely. In this study the perioperative kinetics of d-lactate and ischemia-modified albumin (IMA) are described and the predictive value of these markers for the early diagnosis of acute intestinal ischemia is assessed. DESIGN & METHODS: This non-randomised, single-centre cohort study enrolled 50 patients with abdominal aortic aneurysm (AAA) and 30 patients with aortoiliac occlusive disease (AOID). Serum d-lactate and IMA were assessed pre-, intra-, and postoperatively at eight defined time points. RESULTS: The highest serum d-lactate was at 6 h after complete declamping of the vascular graft. The highest predictive power of d-lactate was at 3 h after complete declamping (AUC 0.857). IMA was found to be higher in the AAA group in ischemic patients 10 min after complete declamping than in the AOID group. The highest predictive values of IMA were at 1 h after aortic cross-clamping (AUC 0.758) and 3 and 6 h after complete declamping (0.745 and 0.721, respectively). Moreover, the multivariate model with both markers at 3 h after complete declamping improved the detection of intestinal ischemia (AUC 0.894). CONCLUSIONS: Serum levels of IMA and d-lactate seem to be influential predictive markers for postoperative intestinal ischemia, especially after 3 h from complete declamping of vascular reconstruction.

l-lactate kinetics after abdominal aortic surgery and intestinal ischemia - An observational cohort study.

BACKGROUND: Postoperative intestinal ischemia is a severe complication in abdominal aortic surgery. Early diagnosis is needed for adequate and timely treatment. We studied the postoperative kinetics of l-lactate in vascular patients to assess its value as a marker for early postoperative intestinal ischemia detection. MATERIAL AND METHODS: We performed a prospective non-randomized single-center observational cohort study in eighty elective patients, fifty operated on for abdominal aortic aneurysm (AAA) and thirty for aortoiliac occlusive disease (AIOD). Serum l-lactate was measured preoperatively, intraoperatively, and postoperatively at defined timepoints up to postoperative day 7. Intestinal ischemia was detected using MRI enterocolography. We have used univariate logistic regression and receiver operating characteristics curves for the evaluation of marker accuracy. RESULTS: We recorded 6 cases of postoperative intestinal ischemia (7.5%), five non-transmural and one transmural. Two patients died because of this complication (mortality 33%). The comparison of AAA and AIOD cohorts showed a significant difference in l-lactate levels at one intraoperative timepoint, which was attributable to procedure differences. The only preoperative factor associated with higher l-lactate levels at some timepoints was chronic kidney disease. Patients suffering postoperative intestinal ischemia had elevated serum l-lactate levels at multiple timepoints. The most accurate timepoint for diagnosis was 24 h after the declamping of the vascular reconstruction (DC24H), the second was 10 min after declamping. Sensitivity, specificity, positive and negative predictive values at timepoint DC24H were 100%, 82%, 32%, and 100%, respectively. CONCLUSION: Serum l-lactate levels might help in the early detection of postoperative intestinal ischemia after aortic surgery if proper timepoints are used. Cutoff values need to be established in large-scale prospective studies.

Experience with VariClose® vein sealing system in the Czech Republic.

OBJECTIVES: The aim of this study was to assess occlusion rates of saphenous veins treated with the VariClose vein sealing system. METHODS: A retrospective analysis including a total of 64 patients from four centres from the Czech Republic. Occlusion was defined as a non-compressible vein with absence of flow with exception to the first 3 cm from the saphenofemoral or saphenopopliteal junction on duplex ultrasound. RESULTS: In 64 patients a total of 79 veins were treated. Technical success of the procedure was achieved in 74 (94%) of cases. The mean follow-up was 5.5 months. The closure rates calculated by the Kaplan-Meier method at 1, 3, 6 and 12 months were 94%, 85%, 69% and 36%, respectively, and there were no significant differences between centers. The average difference in VCSS score before and after the procedure was 1.8. CONCLUSIONS: The present study demonstrated surprisingly worse occlusion rates than the current literature.

Constitutive models and failure properties of fibrous tissues of carotid artery atheroma based on their uniaxial testing.

To obtain an experimental background for the description of mechanical properties of fibrous tissues of carotid atheroma, a cohort of 141 specimens harvested from 44 patients during endarterectomies, were tested. Uniaxial stress-strain curves and ultimate stress and strain at rupture were recorded. With this cohort, the impact of the direction of load, presence of calcifications, specimen location, patient's age and sex were investigated. A significant impact of sex was revealed for the stress-strain curves and ultimate strains. The response was significantly stiffer for females than for males but, in contrast to ultimate strain, the strength was not significantly different. The differences in strength between calcified and non-calcified atheromas have reached statistical significance in the female group. At most of the analysed stress levels, the loading direction was found significant for the male cohort which was also confirmed by large differences in ultimate strains. The representative uniaxial stress-strain curves (given by median values of strains at chosen stress levels) were fitted with an isotropic hyperelastic model for different groups specified by the investigated factors while the observed differences between circumferential and longitudinal direction were captured by an anisotropic hyperelastic model. The obtained results should be valid also for the tissue of the fibrous cap, the rupture of which is to be predicted in clinics using computational modelling because it may induce arterial thrombosis and consequently a brain stroke.

Failure properties of abdominal aortic aneurysm tissue are orientation dependent.

INTRODUCTION: Biomechanical rupture risk assessment of abdominal aortic aneurysm (AAA) requires information about failure properties of aneurysmal tissue. There are large differences between reported values. Among others, studies vary in using either axially or circumferentially oriented samples. This study investigates the effect of sample orientation on failure properties. METHODS: Aneurysmal tissues from 45 patients (11 females) were harvested during open AAA repair, cut into uniaxial samples (90) and tested mechanically within 3 h. If possible, the samples were cut in both axial (49 samples) and circumferential (41 samples) directions. Wall thickness, First Piola-Kirchhoff strength Pult and ultimate tension Tult were recorded. Influence of sample orientation and other clinical parameters were investigated using non parametric tests. RESULTS: Medians of Pult (values 1100 kPa for circumferential vs. 715 kPa for axial direction, p < 10-4) and Tult (17.4 N/cm in circumferential vs. 11.2 N/cm in axial direction, p < 10-4) were significantly higher in circumferential direction. For paired data, the median of difference was 411 kPa (p < 10-3) in Pult and 7.4 N/cm (p < 10-4) in Tult in favor of circumferential direction. CONCLUSIONS: In this first study of anisotropy in AAA wall failure properties using paired comparisons, the strength in circumferential orientation was found to be higher than in axial orientation.

Biomechanical indices are more sensitive than diameter in predicting rupture of asymptomatic abdominal aortic aneurysms.

OBJECTIVE: Several studies of biomechanical rupture risk assessment (BRRA) showed its advantage over the diameter criterion in rupture risk assessment of abdominal aortic aneurysm (AAA). However, BRRA studies have not investigated the predictability of biomechanical risk indices at different time points ahead of rupture, nor have they been performed blinded for biomechanical analysts. The objective of this study was to test the predictability of the BRRA method against diameter-based risk indices in a quasi-prospective patient cohort study. METHODS: In total, 12 women and 31 men with intact AAAs at baseline have been selected retrospectively at two medical centers. Within 56 months, 19 cases ruptured, whereas 24 cases remained intact within 2 to 56 months. This outcome was kept confidential until all biomechanical activities in this study were finished. The biomechanical AAA rupture risk was calculated at baseline using high-fidelity and low-fidelity finite element method models. The capability of biomechanics-based and diameter-based risk indices to predict the known outcomes at 1 month, 3 months, 6 months, 9 months, and 12 months after baseline was validated. Besides common cohort statistics, the area under the curve (AUC) of receiver operating characteristic curves has been used to grade the different rupture risk indices. RESULTS: Up to 9 months ahead of rupture, the receiver operating characteristic analysis of biomechanics-based risk indices showed a higher AUC than diameter-based indices. Six months ahead of rupture, the largest difference was observed with an AUC of 0.878 for the high-fidelity biomechanical risk index, 0.859 for the low-fidelity biomechanical risk index, 0.789 for the diameter, and 0.821 for the sex-adjusted diameter. In predictions beyond 9 months, none of the risk indices proved to be superior. CONCLUSIONS: High-fidelity biomechanical modeling improves the predictability of AAA rupture. Asymptomatic AAA patients with high biomechanical AAA rupture risk indices have an increased risk of rupture. Integrating biomechanics-based diagnostic indices may significantly decrease the false-positive rate in AAA treatment. CLINICAL RELEVANCE: Rupture of abdominal aortic aneurysm (AAA) is the tenth leading cause of death in men older than 60 years; however, the currently used maximal diameter criterion has a high false-positive rate. In this study, we have compared this criterion with biomechanical rupture risk assessment on the unique data set of 43 asymptomatic AAAs, of which 19 ruptured later. Moreover, the AAA outcome was blinded to the operator for the first time. Our data demonstrated that the biomechanical rupture risk assessment is superior to maximal diameter in predicting AAA rupture up to 9 months ahead and significantly decreases the false-positive rate.

Current vascular allograft procurement, cryopreservation and transplantation techniques in the Czech Republic.

BACKGROUND: Vascular allotransplantations are performed worldwide in selected patients suffering from vascular prosthesis infection or critical limb ischemia. Either fresh or cryopreserved vascular allograft may be used. OBJECTIVES: In various points, we address several aspects (allograft procurement, cryopreservation and transplantation technique) of the program of vascular allotransplantations in the Czech Republic. MATERIAL AND METHODS: Vascular grafts retrieval has been done within multiorgan harvests using no-touch technique. Very short time of cold ischemia is achieved due to close cooperation with Tissue Establishment where the following processing of cryopreservation is performed. Meeting all necessary quality criteria is a prerequisity for releasing grafts for clinical application. Standardized thawing protocol and surgical handling aims to minimize microfractures before implantation. RESULTS: Based on experimental and clinical work, the first validation of cryopreserved arterial and venous grafts for clinical use was performed between 2011 and 2013 in the Czech Republic. The developement of storage of vascular tissue in banks was stimulated in 2000-2010 by the issue of EU directives and national harmonized norms, aimed at assurance of high quality and safety of cells and tissues used for transplantations in humans. CONCLUSIONS: There are several crucial moments affecting final quality, including graft retrieval within a multiorgan harvest, short ischemic time, cryopreservation and thawing technique used. The recommended surgical handling during implantation may also affect results and graft-related complications.

Organization model for allotransplantations of cryopreserved vascular grafts in Czech Republic.

The transplantation of fresh or cryopreserved vascular allografts in patients with a prosthetic graft infection or critical limb ischemia is necessary for their limb salvage and, in many cases, represents a lifesaving procedure. While transplantation of fresh allografts has a long history in the Czech Republic, the standard use of cryopreserved vascular allografts was introduced into the clinical practice in 2011 as a result of the implementation of EU Directive 2004/23/EC into national legislation (Human Cell and Tissue Act No. 296/2008 Coll.). The authors present an organizational model based on cooperation between the majority of Czech Transplant Centers with a tissue establishment licensed by the national competent authority. In various points, we are addressing individual aspects of experimental and clinical studies which affect clinical practice. Based on experimental and clinical work, the first validation of cryopreserved arterial and venous grafts for clinical use was performed between 2011 and 2013. The growing number of centers participating in this programme led to a growing number of patients who underwent transplantation of vascular allografts. In 2015 the numbers of transplanted fresh versus cryopreserved allografts in the Czech Republic were almost equal. Cooperation of the participating centers in the Czech Republic with the licensed Tissue Establishment made it possible to achieve a full compliance with the European Union Directives, and harmonized national legal norms and assured a high quality of cryopreserved vascular allografts.

Correlation between transversal and orthogonal maximal diameters of abdominal aortic aneurysms and alternative rupture risk predictors.

PURPOSE: There is no standard for measuring maximal diameter (Dmax) of abdominal aortic aneurysm (AAA) from computer tomography (CT) images although differences between Dmax evaluated from transversal (axialDmax) or orthogonal (orthoDmax) planes can be large especially for angulated AAAs. Therefore we investigated their correlations with alternative rupture risk indicators as peak wall stress (PWS) and peak wall rupture risk (PWRR) to decide which Dmax is more relevant in AAA rupture risk assessment. MATERIAL AND METHODS: The Dmax values were measured by a trained radiologist from 70 collected CT scans, and the corresponding PWS and PWRR were evaluated using Finite Element Analysis (FEA). The cohort was ordered according to the difference between axialDmax and orthoDmax (Da-o) quantifying the aneurysm angulation, and Spearman's correlation coefficients between PWS/PWRR - orthoDmax/axialDmax were calculated. RESULTS: The calculated correlations PWS/PWRR vs. orthoDmax were substantially higher for angulated AAAs (with Da-o≥3mm). Under this limit, the correlations were almost the same for both Dmax values. Analysis of AAAs divided into two groups of angulated (n=38) and straight (n=32) cases revealed that both groups are similar in all parameters (orthoDmax, PWS, PWRR) with the exception of axialDmax (p=0.024). CONCLUSIONS: It was confirmed that orthoDmax is better correlated with the alternative rupture risk predictors PWS and PWRR for angulated AAAs (DA-O≥3mm) while there is no difference between orthoDmax and axialDmax for straight AAAs (DA-O<3mm). As angulated AAAs represent a significant portion of cases it can be recommended to use orthoDmax as the only Dmax parameter for AAA rupture risk assessment.

Pseudoaneurysm of the Dorsalis Pedis Artery: Case Report and Literature Review.

Aneurysms and pseudoaneurysms of the dorsalis pedis artery are rare vascular entities usually caused by traumatic injury or iatrogenic intervention, producing a focal soft pulsatile tissue mass in the dorsal foot. Gradual expansion of the fibrous capsule can produce secondary physical signs through the pressure exerted on surrounding structures. We report the case of a 57-year-old male with an idiopathic pseudoaneurysm of the dorsalis pedis artery. A focused history found a low-grade blunt trauma to the dorsal foot that had occurred 2 years previously. The diagnosis of a pseudoaneurysm was confirmed by ultrasound examinations and computed tomography angiograms. The pseudoaneurysm was treated with resection, and a short reversed great saphenous vein interposition graft was placed. He recovered well after surgery and remained free of symptoms 18 months postoperatively. The literature review of this uncommon vascular pathologic entity and the diagnosis and management are discussed.

Infrared thermography as option for evaluating the treatment effect of percutaneous transluminal angioplasty by patients with peripheral arterial disease.

Aim of this study was to evaluate the possible use of infrared thermography as a supplementary method to the ankle-brachial index used in assessing the treatment effect of percutaneous transluminal angioplasty. The study included 21 patients, mean age was 60.22 years. Healthy control group included 20 persons, mean age was 55.60 years. Patients with symptomatic peripheral arterial disease (Fontaine stages I-III) were admitted for endovascular treatment by percutaneous transluminal angioplasty. Thermal images and ankle-brachial index values were obtained before and after treatment by percutaneous transluminal angioplasty. Median temperature change in the treated limb was 0.4℃, for non-treated limb was -0.5℃. The median value of ankle-brachial index in the treated limb increased by 0.17 from 0.81 after the procedure. The median value of ankle-brachial index in the non-treated limb decreased by 0.03 from the value of 1.01. Significant difference between treated limb and non-treated limb in change of ankle-brachial index was found with p value = .0035. The surface temperature obtained by the infrared thermography correlates with ankle-brachial index. We present data showing that the increase of ankle-brachial index is associated with increase of skin temperature in the case of limbs treated by percutaneous transluminal angioplasty. Our results also suggest potential of the use of infrared thermography for monitoring foot temperature as a means of early detection of onset of foot ischemic disorders.

Using Noncontact Infrared Thermography for Long-term Monitoring of Foot Temperatures in a Patient with Diabetes Mellitus.

Foot complications in persons with diabetes mellitus (DM) are associated with substantial costs and loss of quality of life. Increasing evidence suggests changes in skin temperature, measured using an infrared thermographic system (IRT), may be a predictor of foot ulcer development in patients with DM. The purpose of this case study is to describe the long-term IRT findings and overall clinical outcomes of a patient with DM and peripheral vascular disease. Foot temperature measurements using IRT were obtained slightly more than 1 year before and immediately following endovascular treatment of a 76-year-old man, a nonsmoker with type 2 DM, hypertension, and ischemic heart disease with cardiac arrhythmia. Although he was otherwise asymptomatic, the infrared measurement showed an average temperature difference of 2.3˚ C between the left and right foot until he developed a small, trauma-induced wound on the left foot, at which time left foot temperature increased. He was diagnosed with rectosigmoid adenocarcinoma, underwent surgery and chemotherapy, and subsequently was evaluated for peripheral vascular disease. Before undergoing peripheral angiography and percutaneous transluminal angioplasty, IRT evaluation showed a hot spot on the left heel. Immediately following endovascular treatment, the mean temperature difference between the right and left foot was low (0.2˚ C), but a Stage I pressure ulcer was visible on the left heel. Skin breakdown in that area was observed 2 months later, and the wound continued to increase in size and depth. The patient died shortly thereafter due to complications of cancer. In this case study, a series of infrared images of foot skin temperatures appeared to show a relationship with blood circulation and wound/ulcer development and presentation. IRT has the ability to instantaneously measure the absolute temperature of the skin surface over a large area without direct skin contact. However, the devices are very sensitive and prospective clinical studies to determine the validity, reliability, sensitivity, and specificity of these measurements for routine use in patients who are at risk for vascular disease and/or foot ulcers are needed.

Evaluation of a novel vascular graft with a distal bifurcation designed to reduce the development of intimal hyperplasia. Experimental study in a porcine aorta model.

OBJECTIVE: Abnormal haemodynamics is commonly agreed to be a major contributor to the development of distal anastomotic intimal hyperplasia. A new vascular graft design proposed by computational studies was used to demonstrate its surgical feasibility and to compare it with the conventional graft in a porcine model. METHOD: The device was used in 12 eight-month-old pigs, six received the new graft and six had a conventional graft. The proximal graft end was implanted into the aorta, the distal graft end was implanted into the iliac artery. The host artery was ligated in order to simulate occlusion. At 20 weeks after surgery the pigs were killed and the device was excised for histological and morphometric analysis. RESULTS: In five experimental grafts the reconstruction was occluded due to thrombosis; only one prosthesis was patent showing a minimum of neointimal hyperplasia. In the control group too only three of the six grafts were patent. A histological analysis revealed, as the cause of occlusion, fibrous tissue overgrowth corresponding in structure to neointimal hyperplasia. Differences in the number of obliterations and in occlusion rates between the profiles of the two groups were evaluated using the median test (P<0.05). The results were not statistically significant. CONCLUSION: Although mathematical modelling had shown significant haemodynamic benefits of a naturally bifurcated graft, our study did not confirm its superiority over conventionally used prostheses.

Automatic identification and validation of planar collagen organization in the aorta wall with application to abdominal aortic aneurysm.

Arterial physiology relies on a delicate three-dimensional (3D) organization of cells and extracellular matrix, which is remarkably altered by vascular diseases like abdominal aortic aneurysms (AAA). The ability to explore the micro-histology of the aorta wall is important in the study of vascular pathologies and in the development of vascular constitutive models, i.e., mathematical descriptions of biomechanical properties of the wall. The present study reports and validates a fast image processing sequence capable of quantifying collagen fiber organization from histological stains. Powering and re-normalizing the histogram of the classical fast Fourier transformation (FFT) is a key step in the proposed analysis sequence. This modification introduces a powering parameter w, which was calibrated to best fit the reference data obtained using classical FFT and polarized light microscopy (PLM) of stained histological slices of AAA wall samples. The values of w = 3 and 7 give the best correlation (Pearson's correlation coefficient larger than 0.7, R 2 about 0.7) with the classical FFT approach and PLM measurements. A fast and operator independent method to identify collagen organization in the arterial wall was developed and validated. This overcomes severe limitations of currently applied methods like PLM to identify collagen organization in the arterial wall.

A numerical implementation to predict residual strains from the homogeneous stress hypothesis with application to abdominal aortic aneurysms.

Wall stress analysis of abdominal aortic aneurysm (AAA) is a promising method of identifying AAAs at high risk of rupture. However, neglecting residual strains (RS) in the load-free configuration of patient-specific finite element analysis models is a sever limitation that strongly affects the computed wall stresses. Although several methods for including RS have been proposed, they cannot be directly applied to patient-specific AAA simulations. RS in the AAA wall are predicted through volumetric tissue growth that aims at satisfying the homogeneous stress hypothesis at mean arterial pressure load. Tissue growth is interpolated linearly across the wall thickness and aneurysm tissues are described by isotropic constitutive formulations. The total deformation is multiplicatively split into elastic and growth contributions, and a staggered schema is used to solve the field variables. The algorithm is validated qualitatively at a cylindrical artery model and then applied to patient-specific AAAs (n = 5). The induced RS state is fully three-dimensional and in qualitative agreement with experimental observations, i.e., wall strips that were excised from the load-free wall showed stress-releasing-deformations that are typically seen in laboratory experiments. Compared to RS-free simulations, the proposed algorithm reduced the von Mises stress gradient across the wall by a tenfold. Accounting for RS leads to homogenized wall stresses, which apart from reducing the peak wall stress (PWS) also shifted its location in some cases. The present study demonstrated that the homogeneous stress hypothesis can be effectively used to predict RS in the load-free configuration of the vascular wall. The proposed algorithm leads to a fast and robust prediction of RS, which is fully capable for a patient-specific AAA rupture risk assessment. Neglecting RS leads to non-realistic wall stress values that severely overestimate the PWS.

Importance of material model in wall stress prediction in abdominal aortic aneurysms.

BACKGROUND: Results of biomechanical simulation of the abdominal aortic aneurysm (AAA) depend on the constitutive description of the wall. Based on in vitro and in vivo experimental data several constitutive models for the AAA wall have been proposed in the literature. Those models differ strongly from each other and their impact on the computed stress in biomechanical simulation is not clearly understood. METHODS: Finite element (FE) models of AAAs from 7 patients who underwent elective surgical repair were used to compute wall stresses. AAA geometry was reconstructed from CT angiography (CT-A) data and patient-specific (PS) constitutive descriptions of the wall were derived from planar biaxial testing of anterior wall tissue samples. In total 28 FE models were used, where the wall was described by either patient-specific or previously reported study-average properties. This data was derived from either uniaxial or biaxial in vitro testing. Computed wall stress fields were compared on node-by-node basis. RESULTS: Different constitutive models for the AAA wall cause significantly different predictions of wall stress. While study-average data from biaxial testing gives globally the same stress field as the patient-specific wall properties, the material model based on uniaxial test data overestimates the wall stress on average by 30 kPa or about 67% of the mean stress. A quasi-linear description based on the in vivo measured distensibility of the AAA wall leads to a completely altered stress field and overestimates the wall stress by about 75 kPa or about 167% of the mean stress. CONCLUSION: The present study demonstrated that the constitutive description of the wall is crucial for AAA wall stress prediction. Consequently, results obtained using different models should not be mutually compared unless different stress gradients across the wall are not taken into account. Highly nonlinear material models should be preferred when the response of AAA to increased blood pressure is investigated, while the quasi-linear model with high initial stiffness produces negligible stress gradients across the wall and thus, it is more appropriate when response to mean blood pressure is calculated.