Measured Mean Arterial Pressure Research Articles

Effects of sodium-glucose transporter-2 inhibition on systemic hemodynamics, renal function, and intra-renal oxygenation in sepsis-associated acute kidney injury.

People with type 2 diabetes mellitus treated with sodium-glucose transporter-2 inhibitors (SGLT2i) have lower rates of acute kidney injury (AKI). Sepsis is responsible for the majority of AKI in critically ill patients. This study investigated whether SGLT2i is renoprotective in an ovine model of Gram-negative septic AKI. Sixteen healthy merino ewes were surgically instrumented to enable measurement of mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion, and oxygenation. After a 5-day recovery period, sepsis was induced via slow and continuous intravenous infusion of live Escherichia coli. Twenty-three hours later, sheep were randomized to receive an intravenous bolus of 0.2 mg/kg empagliflozin (n = 8) or a fluid-matched vehicle (n = 8). Empagliflozin treatment did not significantly reduce renal medullary hypoperfusion or hypoxia, improve kidney function, or induce histological changes. Renal cortical oxygenation during the intervention period was 47.6 ± 5.9mmHg in the empagliflozin group compared with 40.6 ± 8.2mmHg in the placebo group (P = 0.16). Renal medullary oxygenation was 28.0 ± 18.5mmHg in the empagliflozin compared with 25.7 ± 16.3mmHg (P = 0.82). Empagliflozin treatment did not result in significant between-group differences in renal blood flow, kidney function, or renal histopathological changes. In a large mammalian model of septic AKI, a single dose of empagliflozin did not improve renal microcirculatory perfusion, oxygenation, kidney function, or histopathology.

A prediction model for stillbirth based on first trimester pre-eclampsia combined screening.

To evaluate the accuracy of combined models of maternal biophysical factors, ultrasound, and biochemical markers for predicting stillbirths. A retrospective cohort study of pregnant women undergoing first-trimester pre-eclampsia screening at 11-13 gestational weeks was conducted. Maternal characteristics and history, mean arterial pressure (MAP) measurement, uterine artery pulsatility index (UtA-PI) ultrasound, maternal ophthalmic peak ratio Doppler, and placental growth factor (PlGF) serum were collected during the visit. Stillbirth was classified as placental dysfunction-related when it occurred with pre-eclampsia or birth weight <10th percentile. Combined prediction models were developed from significant variables in stillbirths, placental dysfunction-related, and controls. We used the area under the receiver-operating-characteristics curve (AUC), sensitivity, and specificity based on a specific cutoff to evaluate the model's predictive performance by measuring the capacity to distinguish between stillbirths and live births. There were 13 (0.79%) cases of stillbirth in 1643 women included in the analysis. The combination of maternal factors, MAP, UtA-PI, and PlGF, significantly contributed to the prediction of stillbirth. This model was a good predictor for all (including controls) types of stillbirth (AUC 0.879, 95% CI: 0.799-0.959, sensitivity of 99.3%, specificity of 38.5%), and an excellent predictor for placental dysfunction-related stillbirth (AUC 0.984, 95% CI: 0.960-1.000, sensitivity of 98.5, specificity of 85.7). Screening at 11-13 weeks' gestation by combining maternal factors, MAP, UtA-PI, and PlGF, can predict a high proportion of stillbirths. Our model has good accuracy for predicting stillbirths, predominantly placental dysfunction-related stillbirths.

The left ventricle increases contractility in response to baroreceptor unloading, which is sympathetically-mediated in the anesthetized rat.

Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardio-vagal arms. Since sympathetic post-ganglionic neurons also innervate the left ventricle (LV), it is oft-assumed that the LV produces a sympathetically-mediated increase in contractility during baroreceptor unloading, but this has not been characterized using a load-independent index of contractility. We aimed to determine a) whether LV contractility increases in response to baroreceptor unloading, and b) whether such increases are mediated via the sympathetic or parasympathetic arm of the autonomic nervous system. Ten male Wistar rats were anesthetized (urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and load-independent LV contractility [maximal rate of increase in pressure adjusted to end-diastolic volume (PAdP/dtmax)], respectively. Rats were placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% for 60s to mechanically unload baroreceptors under control conditions. LBNP was repeated in each animal following infusions of cardiac autonomic blockers using esmolol (sympathetic), atropine (parasympathetic), and esmolol+atropine. Under control conditions, PAdP/dtmax increased during baroreceptor unloading (26±6 vs. 31±9 mmHg·s-1·μL-1, p=0.031). During esmolol, there was no increase in LV contractility during baroreceptor unloading (11±2 vs. 12±2, p=0.125); however, during atropine, there was an increase in LV contractility during baroreceptor unloading (26±6 vs. 31±9, p=0.019). During combined esmolol and atropine, there was a small increase in contractility vs control (13±3 vs. 15±4, p=0.046). Our results demonstrate that, in anesthetized rats, LV contractility increases in response to baroreceptor unloading, which is largely sympathetically mediated.

Chronic inhibition of angiotensin converting enzyme lowers blood pressure in spontaneously hypertensive rats by attenuation of sympathetic tone: The role of enhanced baroreflex sensitivity

Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.

Physiologic Determinants of Near-Infrared Spectroscopy-Derived Cerebral and Tissue Oxygen Saturation Measurements in Critically Ill Patients.

Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. Two ICUs in the United Kingdom. Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO2) and quadriceps muscle tissue saturations (SmtO2). Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo2) measurements were recorded alongside NIRS data. Arterial Paco2, Pao2, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco2, Spo2, MAP, and HR were weakly associated with SctO2 but only explained 7.1% of the total variation. Spo2 and MAP were associated with SmtO2, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.

Ketamine Sedation Decreases Survival after Extremity Trauma and Moderate Hemorrhage in Rats

Objective: Traumatic hemorrhage (HEM) is often associated with pain. The use of ketamine (KET) has increased both on the battlefield and in civilian emergency care for analgesia and sedation. We have reported that an analgesic dose of KET does not impact cardiorespiratory responses or survival after HEM (JAP 130: 1583-1593, 2021). In this study, we measured the effects of a larger, sedative, dose of KET on cardiovascular responses and survival to moderate (37% blood volume) HEM combined with extremity trauma (ET), and whether midazolam (MDZ), a drug often given in combination with KET alters these responses. Hypothesis: We hypothesized that either KET (50 mg/kg) or KET+MDZ (5 mg/kg) would compromise cardiovascular responses to HEM and thereby decrease survival. Methods: Male rats were implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine SR was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized using isoflurane, and a carotid catheter was implanted. The next day, rats were briefly anesthetized using isoflurane to perform ET (fibular fracture + hindlimb soft tissue crush injury) and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min). Rats received either 1) saline vehicle (VEH, n=8); 2) KET (n=8); or 3) KET followed by MDZ (KET+MDZ; n=9) during a 15 min infusion (t = 25-40 min). The study continued for 200 minutes (time = 40-240 min). Data are mean ± SD. Results: There were no differences between groups in MAP or HR at either baseline (t = 0 min) or at end of HEM (t = 25 min). However, during the 20 min after treatment (t = 40-60 min), MAP and HR were significantly lower (P≤0.05) in KET (46 ± 3 mmHg; 220 ± 11 bpm) and KET+MDZ (45 ± 10 mmHg; 212 ± 24 bpm) compared to VEH (68 ± 20 mmHg; 297 ± 37 bpm). During this time, only 3 of 8 rats in the KET group survived HEM, while all rats survived in VEH and KET+MDZ groups. At the end of the study (t = 240 min), survival rate was significantly lower (P=0.003) in KET (37.5%) compared to VEH (87.5%) or KET+MDZ (100%). Similarly, survival time was significantly lower (P=0.004) in KET (115 ± 103 min) compared to VEH (227 ± 37 min) or KET+MDZ (240 ± 0 min). Summary of Results: A sedative dose of KET decreased survival following HEM, but the same dose of KET followed by MDZ was protective. The MDZ effect was not due to improvements in cardiovascular responses to the HEM. Conclusion: Sedation with ketamine alone after trauma and moderate HEM decreased survival. Further studies of the effects of sedation with KET alone or KET+MDZ on respiration and metabolic responses to HEM may provide insight on the overall effect on survival. Congressionally Directed Medical Research Program (CDMRP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise Pressor Reflex Function Is Exacerbated in Decerebrate Adenine-Induced Chronic Kidney Disease Rats

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). While the underlying mechanisms are not completely understood, elevated sympathetic nerve activity (SNA) and exercise intolerance are thought to play an important role. In normal physiological conditions, sympathetic modulation of the cardiovascular system during physical activity is largely governed by a peripheral neural reflex originating in contracting skeletal muscle, known as the exercise pressor reflex (EPR). Pioneering work by Park et al. demonstrated that CKD patients exhibited abnormal SNA and blood pressure (BP) elevations during both static and rhythmic handgrip exercise, suggesting an overactive EPR. However, due to experimental design constraints inherent to humans, the contribution of the EPR to the augmented SNA and BP responses to exercise could not be fully addressed. Therefore, the purpose of this study was to specifically test EPR function in CKD using a reduced animal model. Sprague-Dawley rats were randomly assigned to receive either a powdered chow diet containing adenine (0.25%w/w in feed) to induce CKD or a powdered chow diet alone (control group) for 12 weeks. Subsequently, in decerbrate animals, we measured mean arterial pressure (MAP) and renal SNA (RSNA) in response to isolated EPR activation during hindlimb muscle contraction (i.e., simulated exercise). We further assessed cardiovascular and sympathetic responses to passive muscle stretch to stimulate the mechanoreflex (i.e., activation of the mechanically-sesnsitive component of the EPR), and intra-arterial capsaicin administratration to activate the metaboflex (i.e., stimulation of the metabolically-sensitive component of the EPR). After completion of the diet, levels of plasma creatinine were significantly increased in adenine-fed rats compared to control rats (2.57±1.05 vs. 0.34±0.05 mg/dL, P&lt;0.01), suggesting impaired renal function (i.e., adenine-induced CKD). We found that CKD animals exhibited augmentations in RSNA (Δ=153±75 vs. 61±50 %, P&lt;0.05) and MAP (Δ=35±18 vs. 17±8 mmHg, P&lt;0.05) in response to muscle contraction when compared to control animals. Importantly, the muscle tension developed during contraction was similar between the two groups (Δ=0.9±0.2 vs. 1.0±0.3 kg, P&gt;0.1, CKD vs. control). During stimulation of the mechanoreflex, CKD rats also exhibited significantly greater RSNA (Δ=100±54 vs. 32±26 %, P&lt;0.05) and MAP responses (Δ=25±14 vs. 10±7 mmHg, P&lt;0.05) than control rats. The developed muscle tension during passive stretch was similar between the two groups (Δ=0.9±0.2 vs. 1.0±0.4 kg, P&gt;0.1, CKD vs. control). There was a tendency for the responses to metaboreflex activation to be heightened in the CKD group compared with the control group, but the difference did not reach statistical significance (ΔRSNA=212±68 vs. 107±105 %, P=0.06, ΔMAP=67±12 vs. 48±21 mmHg, P=0.06, CKD vs. control, respectively). Our findings suggest that EPR function, particularly muscle mechanoreflex function, is exaggerated in CKD, leading to sympathetic activation and hypertensive responses during exercise. P30 DK079307 Subaward to H.K. and R01HL-133179 to W.V. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle contractions attenuate the norepinephrine-related reduction in interstitial oxygen pressures in the rat spinotrapezius

Increased sympathetic nerve activity with exercise plays a key role in the control of arterial blood pressure and redistribution of blood flow. Within the microcirculation, elevated sympathetic outflow promotes the release of norepinephrine and smooth muscle contraction. Exercise-induced attenuation of sympathetic vasoconstriction (i.e., functional sympatholysis) is thus critical for active muscle oxygen delivery-utilization matching. However, the extent to which muscle contractions impact noradrenergic regulation of interstitial oxygen pressures (PO2is) is unknown. This is important because, as dictated by Fick’s law, PO2is provides the sole driving force for oxygen diffusion into the myocyte thereby supporting oxidative phosphorylation. PURPOSE: To determine the effects of norepinephrine administration on resting and contracting rat skeletal muscle PO2is. We tested the hypothesis that topical application (superfusion) of norepinephrine would result in blunted decreases in skeletal muscle PO2is during contractions compared to rest. METHODS: PO2is was determined via phosphorescence quenching in the exposed spinotrapezius muscle of anesthetized male Sprague-Dawley rats (n=7, 2-3 months old) at rest and during electrically-induced submaximal contractions (0.5 Hz, 3-6 V) for 6 minutes in response to norepinephrine superfusion (5x10−4 M). Functional sympatholysis was determined as the difference between the norepinephrine-induced changes in PO2is at rest and during the contraction steady-state (i.e., 2 min following the onset of muscle contractions) using (i) the absolute PO2is fall with norepinephrine (ΔPO2is), and (ii) the area under the PO2is curve plotted as a function of time (AUC). The tail (caudal) artery was cannulated for measurements of mean arterial pressure (MAP) and heart rate (HR). RESULTS: Consistent with our hypothesis, skeletal muscle contractions attenuated norepinephrine-evoked reductions in spinotrapezius interstitial oxygenation as evaluated by ΔPO2is (rest: -8.7±1.4, contractions: -4.3±1.1 mmHg, p&lt;0.05) and AUC (rest: 2246±368, contractions: 1066±273 mmHg·s, p&lt;0.05). Although MAP increased significantly with norepinephrine both at rest (+5±1%, p&lt;0.05) and during contractions (+8±1%, p&lt;0.05), this mild hypertensive response to norepinephrine was not different between conditions (p&gt;0.05). Norepinephrine superfusion did not affect HR at rest or during contractions (p&gt;0.05). CONCLUSIONS: That muscle contractions blunted the decrease in spinotrapezius PO2is with norepinephrine compared to the resting condition is consistent with functional sympatholysis. The latter serves to match active muscle O2 delivery-utilization in the face of elevated sympathetic nerve activity during exercise. The current results indicate that a novel combination of phosphorescence quenching (interstitial oxygenation, PO2is) and superfusion techniques may be used to evaluate functional sympatholysis in the intact rat spinotrapezius muscle. Showalter Research Trust, Purdue University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Investigation of Hydrogen Sulfide Therapy as a Strategy to Preserve Erectile Health During Androgen Deprivation

Severe erectile dysfunction is prevalent in men with prostate cancer that undergo androgen deprivation therapy (ADT). Androgen deprivation drives drastic changes in the erectile tissues of the corpus cavernosum and pre-penile arteries, which include endothelial dysfunction, vascular remodeling, and diminished vascular smooth muscle quality. Restorative therapies are desperately needed to preserve tissue function and quality during the ADT period. Hydrogen sulfide (H2S) is a gaseous cell signaling molecule with vasodilatory, antioxidant, and anti-inflammatory properties that promote endothelial and vascular health. Recent advancements suggest that H2S may influence cellular health through stimulation of autophagy and regulation of mitochondrial dynamics. Therefore, the objective of this study was to investigate the ability of SG1002, an H2S pro-drug, to preserve erectile function following prolonged ADT. We hypothesized that SG1002 would have a positive effect on erectile function associated with a stimulation of protective pathways related to cellular antioxidant defense, mitochondrial fusion, and autophagy in the corpus cavernosum. Male C57Bl/6 mice were divided into four cohorts, one cohort that underwent sham castration surgery and three cohorts that underwent castration. Castrations were performed at 14 weeks of age. The sham group and one castrated cohort were placed on a control diet. The other two cohorts were placed on identical diets at the time of castration that were supplemented with SG1002 at approximately 20 mg/kg/day or 100 mg/kg/day. Mice were studied 5 weeks following surgery. Erectile function was assessed in vivo by measurements of intracavernous pressure (ICP) and mean arterial pressure (MAP) in response to stimulation of the cavernous nerve. Relative content of 19 proteins in the corpus cavernosum tissue was determined by western blot. Group differences were determined by one-way or two-way ANOVA followed by Tukey’s post hoc test, with an α-level of 0.05. Erectile function was severely diminished among all castrated cohorts compared to sham mice (p&lt;0.01). SG1002 administration elicited a modest but statistically significant augmentation of erectile function (p&lt;0.05) that was equivalent between the two doses. Castration was associated with a significant decrease in the antioxidant proteins GCLC, SOD3, and TRX1, as well as the mediators of mitochondrial fusion MFN1 and MFN2, and the autophagy stimulatory protein ATG7 (p&lt;0.05). There were no significant effects of SG1002 treatment on any of the proteins investigated. In conclusion, H2S therapy elicited a modest protective effect on erectile function that may have been mediated by its direct vasodilatory potential or neurological mechanisms. Further study will be needed to determine if any adverse structural changes associated with castration were affected by H2S therapy. Funding From the National Institutes of Health Grant numbers: R03DK131242 and R03DK131242-01S1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

An Acute Bout of Subconcussive Head Impacts Does Not Change Intracranial Pressure

Purpose: Subconcussive head impacts (SHI) are known to cause a variety of negative sequelae including increased plasma concentrations of neuronal structural and glial proteins, attenuated neurovascular coupling, and impaired vestibular function. Traumatic brain injuries are associated with an increase in intracranial pressure (ICP). However, it is unknown whether an acute bout of SHI increases ICP. We tested the hypothesis that estimates of ICP via ultrasound assessments of optic nerve sheath diameter (ONSD) would be greater following a single session of repetitive SHI versus a control condition. Methods: 14 healthy participants (age: 19±2 y; BMI: 21±4 kg/m2, 3 women) with at least 3 y of soccer heading experience completed two experimental conditions in a randomized crossover design. 20 soccer headings were used to induce repetitive SHI and 20 soccer kicks were used as the control condition. A soccer ball was projected from a soccer JUGS machine (40 km/h, 12.2 m away) every 30 s for both conditions. ONSD assessed via ultrasound is associated with direct measures of ICP. Subjects were in the supine position during ONSD (transverse plane, each eye; B-mode linear array ultrasound), heart rate (HR; 3-lead ECG), and mean arterial blood pressure (MAP; photoplethysmography) measurements conducted at baseline prior to heading/kicking and at 2 h, 24 h, and 72 h post. ONSDs were measured 3 mm under the bulb in triplicate for each eye and the mean values were used for analyses. Inter-eye ONSD values were also averaged for analyses. Clinical intervention to alleviate elevated ICP is indicated when ONSD is &gt; 5.0 mm. Data were analyzed using a mixed-effects model with repeated measures with time and condition as within subject factors. Data are presented as mean ± SD if statistically significant. Results: No subjects had an ONSD &gt; 5.0 mm in either eye following heading or kicking. Left ONSD was greater than baseline at 2 h post heading (2.89 ± 0.25 mm vs. 2.99 ± 0.27 mm; p = 0.0157) and greater than baseline at 2 h (2.92 ± 0.37 mm vs. 2.98 ± 0.31 mm; p = 0.0352) and 72 h (3.08 ± 0.26 mm; p = 0.0067) post kicking. Left ONSD at 72 h post kicking was greater than heading (3.08 ± 0.26 mm vs. 2.93 ± 0.25 mm; p = 0.0022). There were no interaction effects for right ONSD (p = 0.4686), average ONSD (p = 0.1178), HR (p = 0.1039) or MAP (p = 0.3889). Conclusion: Neither the heading nor kicking intervention elicited a clinically relevant ONSD that would require medical attention. Contrary to our hypothesis, an acute bout of 20 soccer headers did not evoke greater ONSD in healthy subjects versus kicking. Therefore, our data indicate that a single session of SHI does not increase ICP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

A Parameter Identification Approach towards Hemodynamics based on Capnography

Research question Pulse detection decisions during cardiopulmonary resuscitation (CPR) are commonly augmented by end-tidal CO2-concentration (etCO2) levels and trend as etCO2 is a surrogate measure of systemic blood flow during (CPR)1. However, ventilatory and circulatory parameters influence the interpretability of etCO2 heavily. Recently developed methods of continuous cardiac output measurement based on capnography are not applicable during CPR due to the required controlled ventilation settings2. In this study, a parameter identification for a model of CO2 transport during resuscitation is used to estimate cardiac output based on capnography and tidal flow. Methodology After development of a compartmental ordinary differential equation (ODE) model to represent CO2 transport during CPR, parameters such as airway dead space and the level of systemic perfusion are estimated by a multishooting parameter identification approach3. To evaluate the method, tests are conducted on experimental data from a porcine model (approved by an ethics committee vote of the Austrian Federal Ministry of Education, Science and Research (GZ: 2021-0.895.386)). The estimated level of systemic perfusion is compared visually to invasively measured mean arterial pressure due to a lack of continuous cardiac output measurements as a ground truth. Results For exemplary data from a female pig (weight 50.4 kg), airway resistance was estimated to 20.8 hPa s /L, compliance: 25.2 mL/hPa, and dead space: 109 mL. Changes in cardiac output can be identified qualitatively as shown in Fig. 1. Conclusion A validated, simple ODE model for CO2 extraction during CPR could contribute quantifying the impact of ventilatory parameters on etCO2 and elucidate CO2 production, storage and transport during cardiac arrest. Assumptions on CO2 production during cardiac arrest and redistribution in the body, and the lacking cardiac output measurements complicate the analysis. Conflicts of Interest All authors have no conflict of interest to declare.

544 Interleukin-6 protects renal dysfunction in mouse models of hypertension and salt-sensitive hypertension

OBJECTIVES/GOALS: We are investigating the role of IL-6 in regulating renal function by measuring mean arterial pressure (MAP), renal plasma flow (RPF) and glomerular filtration rate (GFR) in wild type (WT) and IL-6-knockout (KO) mice in established mouse models of angiotensin II (AII)-dependent- hypertension and -salt-sensitive hypertension. METHODS/STUDY POPULATION: Twelve-week-old male WT and KO mice on the C57BL6 background strain were infused with vehicle (V; saline) or angiotensin II (AII; 200 ng/kg/min) for 12-14 days. Half of the AII-treatment groups were maintained on a high salt (HS; 6% NaCl) diet for the duration of the experiment, while the other half of the AII treatment groups and both vehicle groups were fed normal rat chow. MAP was continuously measured by a fluid filled catheter in conscious mice for the duration of the experiment. RPF and GFR were measured on days 12-14 in anesthetized mice by the para-aminohippurate, and fluorescein isothiocynate-Inulin techniques, respectively. All data were analyzed by 2-way ANOVA; *p&lt;0.05 vs. WT, same treatment; #p&lt;0.05 vs.V, same genotype; ^p&lt;0.05, AII vs. AII+HS, same genotype. RESULTS/ANTICIPATED RESULTS: MAP was 31% lower in KO vs WT mice. AII increased MAP (1.2-fold) in WT but not KO mice. HS diet magnified AII-induced increases in MAP in WT and moderately increased MAP in AII-KO mice: [MAP (mmHg): WT+V, 130±7.0; KO+V, 91.0+4.0*; WT+AII, 153±5.0#; KO+AII, 83.0±4.0*; WT+AII+HS, 150±11#; KO+AII+HS, 93.0±4.0#]. AII infusion reduced RPF in the KO but not WT mice. Addition of HS reduced RPF in WT and exacerbated AII-induced reductions in RPF in KO mice [RPF (ml/min/g): WT+V, 1.82±0.23; KO+V, 1.91+0.40; WT+AII, 3.16±0.75#; KO+AII, 1.65±0.42*; WT+AII+HS, 1.10±0.31#^; KO+AII+HS, 1.13±0.XX#^]. The HS diet reduced GFR in AII-infused KO but not WT mice [GFR (µl/min/g): WT+V, 756±XX; KO+V, 788±XX; WT+AII, 1010±63*#; KO+AII, 756±23*; WT+AII+HS, 1100±150#; KO+AII+HS: 540±210*#^]. DISCUSSION/SIGNIFICANCE: The absence of IL-6 in male mice attenuated AII- and/or AII+HS-induced increases in MAP; however, it exacerbated HS-induced reductions in RPF and GFR. These findings suggest inhibiting IL-6 has therapeutic potential as an antihypertensive but not as a renal protective agent in hypertension and salt-sensitive hypertension disease states.

First Trimester Preeclampsia Screening and Prevention: Perspective in Chinese Mainland

Abstract Preeclampsia (PE), a multisystem disorder in pregnancy, is one of the leading causes of perinatal morbidity and mortality that poses financial and physical burdens worldwide. Preterm PE with delivery at &lt;37 weeks of gestation is associated with a higher risk of adverse maternal and perinatal outcomes than term PE with delivery at ≥37 weeks of gestation. A myriad of first trimester screening models have been developed to identifying women at risk of preterm PE. In fact, the Fetal Medicine Foundation (FMF) first trimester prediction model has undergone successful internal and external validation. The FMF triple test enables the estimation of patient-specific risks, using Bayes theorem to combine maternal characteristics and medical history together with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor. Establishing a quality control process for regular monitoring and to ensure data standardization, reliability, and accuracy is key to maintaining optimal screening performance. The rate of preterm PE can be reduced by 62% by using the FMF prediction model, followed by the administration of low-dose aspirin. Recent evidence has also demonstrated that metformin has the potential for preventing PE in patients at high-risk of the disorder. In this article, we will summarize the existing literature on the different screening methods, different components of risk assessment, therapeutic interventions, and clinical implementation of the first trimester screening and prevention program for PE with specific considerations for Chinese mainland.

IMPACT OF NOREPINEPHRINE DOSAGE INCREASE AND VOLUME EXPANSION ON CAPILLARY REFILL TIME IN SEPTIC SHOCK PATIENTS

Background: When evaluating patients with acute circulatory failure, one clinical feature that may be quickly determined at the bedside is the capillary refill time (CRT).Objective: The objective of this observational study was to describe the changes in CRT that occur as a result of volume expansion and increased dosages of norepinephrine, along with related macro-circulatory variables, in patients suffering from septic shock. Study Design: This was an observational study. Setting: The study was conducted at Bahria Town International Hospital Lahore and Services Institute of Medical Sciences. Duration of Study: The study was conducted over six months from January 2, 2023, to July 30, 2023. Methods: We measured mean arterial pressure (MAP), cardiac index (CI), and five consecutive CRT readings in 40 septic shock patients. These measurements were taken before and after a 500 mL saline infusion in 20 patients and before and after an increase in norepinephrine dosage in another 20 patients. Results: The "norepinephrine" group had lower SAPS II and SOFA scores than the "volume expansion" group. When all patients were assessed together, volume expansion significantly lowered heart rate while increasing MAP, diastolic arterial pressure, CI, CVP, and CRT. Fluid-induced increases in CI of ≥ 15% were observed in 11 patients (55%). In fluid responders, fluid infusion significantly raised MAP by 31% (11-49%) and CI by 26% (20-42%). Increased norepinephrine levels may lower CRT in patients with a baseline value of fewer than 3 seconds. Increasing norepinephrine has a low possibility of decreasing CRT in patients with baseline CRT ≥ 3 seconds if the MAP increase is &lt;15%. However, the decrease in CRT is inconsistent in patients with baseline CRT ≥ 3 seconds when norepinephrine increases MAP by ≥ 15%. Univariate regression analysis revealed a correlation between the absolute value of CRT and lactate levels, heart rate, norepinephrine dosage, gender, SAPS II, and ICU mortality. In a multivariate analysis that included all physiological parameters with a p-value &lt;0.1 in univariate linear regression, only lactate upon admission had a significant association with the absolute value of CRT. Conclusion: CRT uncommonly improves with therapy in individuals with septic shock and prolonged CRT when volume expansion raises cardiac output by &lt;15% and increasing the dosage of norepinephrine increases MAP by &lt;15%. CRT's response varies when there are significant effects of fluid infusion on cardiac output and norepinephrine on MAP; in some patients, it decreases while remaining consistent in others. CRT functions as an indicator of microcirculation in this context.

Emergency Medical Services Protocols for Assessment and Treatment of Patients with Ventricular Assist Devices.

Patients with ventricular assist devices (VADs) represent a growing population presenting to Emergency Medical Services (EMS), but little is known about their prehospital care. This study aimed to characterize current EMS protocols in the United States for patients with VADs. States with state-wide EMS protocols were included. Protocols were obtained from the state EMS website. If not available, the office of the state medical director was contacted. For each state, protocols were analyzed for patient and VAD assessment and treatment variables. Of 32 states with state-wide EMS protocols, 21 had VAD-specific protocols. With 17 (81%) states noting a pulse may not be palpable, protocols recommended assessing alternate measures of perfusion and mean arterial pressure (MAP; 15 [71%]). Assessment of VAD was advised through listening for pump hum (20 [95%]) and alarms (20 [95%]) and checking the power supply (15 [71%]). For treatment, EMS prehospital consultation was required to begin chest compression in three (14%) states, and mechanical (device) chest compressions were not permitted in two (10%) states. Contact information for VAD coordinator was listed in a minority of five (24%) states. Transport of VAD equipment/backup bag was advised in 18 (86%) states. This national analysis of EMS protocols found VAD-specific EMS protocols are not universally adopted in the United States and are variable when implemented, highlighting a need for VAD teams to partner with EMS agencies to inform standardized protocols that optimize these patients' care.

Incidence and first trimester risk factors of stillbirth in Indonesia.

To determine the incidence and the risk factors of stillbirth from maternal biophysical, ultrasound, and biochemical markers at 11-13weeks of gestation in the Indonesian population. This was a retrospective cohort study of pregnant women for first-trimester preeclampsia screening at 11-13weeks of gestation in some clinics and hospital in Jakarta. Maternal characteristics and history, mean arterial pressure (MAP) measurement, uterine artery pulsatility index (UtA-PI) ultrasound, maternal ophthalmic peak ratio (Oph-PR) Doppler, and placental growth factor (PlGF) serum were collected during the visit. Stillbirth was classified into placental dysfunction-related when it occurred with preeclampsia or birth weight <10th percentile and non-placental dysfunction-related. Bivariate and multivariate logistic regression analyses were employed to determine the risk factors associated with stillbirth. Of 1,643 eligible participants, 13 (0.79 %) stillbirth cases were reported. More than half of the stillbirths (7) were placental dysfunction-related. After adjusted with maternal age, body mass index (BMI), and parity status, chronic hypertension (aOR (adjusted odds ratio)) 24.41, 95 % CI {confidence interval} 5.93-100.43), previous pregnancy with preeclampsia (aOR 15.79, 95 % CI 4.42-56.41), MAP >101.85 (aOR 26.67, 95 % CI 8.26-86.06), UtA-PI >1.90 (aOR 10.68, 95 % CI 2.34-48.58, and PlGF <28.77 pg/mL (aOR 18.60, 95 % CI 5.59-61.92) were associated with stillbirth. The incidence of stillbirth in the population is comparable to studies conducted in developed countries. Most routine variables assessed at the 11-13weeks combined screening for preeclampsia are associated with the risk of stillbirth.

Vagotomy blunts cardiorespiratory responses to vagal afferent stimulation via pre- and postsynaptic effects in the nucleus tractus solitarii.

Viscerosensory information travels to the brain via vagal afferents, where it is first integrated within the brainstem nucleus tractus solitarii (nTS), a critical contributor to cardiorespiratory function and site of neuroplasticity. We have shown that decreasing input to the nTS via unilateral vagus nerve transection (vagotomy) induces morphological changes in nTS glia and reduces sighs during hypoxia. The mechanisms behind post-vagotomy changes are not well understood. We hypothesized that chronic vagotomy alters cardiorespiratory responses to vagal afferent stimulation via blunted nTS neuronal activity. Male Sprague-Dawley rats (6weeks old) underwent right cervical vagotomy caudal to the nodose ganglion, or sham surgery. After 1week, rats were anaesthetized, ventilated and instrumented to measure mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively). Vagal afferent stimulation (2-50Hz) decreased cardiorespiratory parameters and increased neuronal Ca2+ measured by in vivo photometry and in vitro slice imaging of nTS GCaMP8m. Vagotomy attenuated both these reflex and neuronal Ca2+ responses compared to shams. Vagotomy also reduced presynaptic Ca2+ responses to stimulation (Cal-520 imaging) in the nTS slice. The decrease in HR, SSNA and PhrNA due to nTS nanoinjection of exogenous glutamate also was tempered following vagotomy. This effect was not restored by blocking excitatory amino acid transporters. However, the blunted responses were mimicked by NMDA, not AMPA, nanoinjection and were associated with reduced NR1 subunits in the nTS. Altogether, these results demonstrate that vagotomy induces multiple changes within the nTS tripartite synapse that influence cardiorespiratory reflex responses to afferent stimulation. KEY POINTS: Multiple mechanisms within the nucleus tractus solitarii (nTS) contribute to functional changes following vagal nerve transection. Vagotomy results in reduced cardiorespiratory reflex responses to vagal afferent stimulation and nTS glutamate nanoinjection. Blunted responses occur via reduced presynaptic Ca2+ activation and attenuated NMDA receptor expression and function, leading to a reduction in nTS neuronal activation. These results provide insight into the control of autonomic and respiratory function, as well as the plasticity that can occur in response to nerve damage and cardiorespiratory disease.

Maternal cardiovascular function at mid-gestation is related to placental angiogenesis.

To investigate whether placental function, reflected in the levels of angiogenic factors, is associated with maternal cardiac function and hemodynamic responses at 19 to 24 weeks' gestation after adjustment for maternal risk factors and pregnancy complications. Prospective study on women with singleton pregnancies attending Kings' College Hospital, London, UK for a routine hospital visit at 19-24 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, maternal heart rate, serum placental growth factor and soluble fms-like tyrosine kinase 1 (sFLT-1).We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. Our cohort included 4006 women.Lower placental growth factor (PlGF) values were significantly associated with higher mean arterial pressure (MAP) (p<0.001), lower maternal heart rate (p<0.001), lower mitral valve s' velocity (p= 0.027) and higher left atrial volume (p=0.022) after adjustment for maternal characteristics and pregnancy complications. sFLT-1 was positively related to relative wall thickness (p= 0.012), whereas sFLT-1/ PlGF ratio was negatively associated with mitral valve A (p= 0.006) and positively associated with left atrial volume (p= 0.015) and MAP (p= 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors from their obstetric and medical history. A continuous link of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present at mid-gestation, independently of preexisting maternal risk factors and pregnancy complications. Impaired placental function appears to be related to a mild systolic and diastolic dysfunction and cardiac remodeling. This article is protected by copyright. All rights reserved.

Three ultrasound guided plane blocks for perioperative analgesia in patients undergoing radical cystectomy: a randomized clinical trial

Background &amp;objective: Transmuscular quadratus lumborum plane block (QLPB), paravertebral plane block (PVPB), and erector spinae plane block (ESPB) are three regional anesthesia techniques for management of perioperative pain for surgical procedures on the trunk, including thorax and abdomen. We compared the effectiveness of PVPB, QLPB type III (QL3), and ESPB for perioperative analgesia during radical cystectomy performed for bladder cancer.&#x0D; Methodology: This randomized double-blind trial was performed on 120 patients, aged above 18 years, undergoing radical cystectomy under general anesthesia. Individuals were randomly divided into 3 equal groups: ESPB, PVPB, and QLPB. Blocks were performed under ultrasound guidance preoperatively on each side with 30 ml of 0.25% bupivacaine. Time to perform block and time to the first dose of morphine postoperatively, were noted. Intra-operative hemodynamic data, including MAP and heart rate (HR) were noted every 10 min for an hour, and then at 30 min intervals. Postoperatively, MAP and HR were recorded at 0, 2, 6, 12 and 24 hours. The connection between qualitative factors was investigated using the chi-square test and Fisher's exact test. For the purpose of comparing the groups, one-way ANOVA and the Bonferroni correction were used. A two-tailed P value &lt; 0.05 was considered significant.&#x0D; Results: Time to perform block was substantially reduced in ESPB and QL3 groups compared to PVPB group. Time to the first dose of morphine was substantially delayed in the PVPB group than ESPB and QL3 groups. Total 24 h morphine consumption was substantially lower in the PVPB group than ESPB and QL3 groups. Postoperative visual analog scale measurements were substantially lower at 15 min, 30 min, and 12 h in the PVPB group than ESPB and QL3 groups and at 6 h in the ESPB and QL3 groups than in PVPB group. Postoperative mean arterial blood pressure and heart rate measurements were substantially reduced at 0 and 12 h in the PVPB group than in ESPB and QL3 groups and at 6 h in the ESPB and QL3 groups than in PVPB group.&#x0D; Conclusions: The ultrasound guided paravertebral plane block was superior to quadratus lumborum plane block type III and erector spinae plane block in providing more effective analgesia but with higher time to perform block.&#x0D; Abbreviations: ESPB- Erector Spinae Plane Block; PVPB- Paravertebral Plane Block; QLPB- Quadratus Lumborum Plane Block; QL3- Quadratus Lumborum Plane Block Type III&#x0D; Keywords: Paravertebral Plane Block; Quadratus Lumborum Plane Block; Erector Spinae Plane Block; Ultrasound; Radical Cystectomy&#x0D; Citation: Seif NE, El-Kholy MM, Ali AR, Zalat MM, Elshazly M. Three ultrasound guided plane blocks for perioperative analgesia in patients undergoing radical cystectomy: a randomized clinical trial. Anaesth. pain intensive care 2024;28(1):85-91; DOI: 10.35975/apic.v28i1.2381&#x0D; Received: September 28, 2023; Reviewed: October 31, 2023; Accepted: October 31, 2023