Hypotensive Response Research Articles

Correlation between nongenomic action of C19-steroids and COVID-19 severity.

The recent COVID-19 pandemic is the defining global health crisis of our time and little is known about this disease. It has been reported that advanced age is considered a major risk factor for COVID-19 complications, and data suggest that this disease is deadlier for men than women but these observations are currently unclear. Regarding androgen action, it has been shown that certain smooth muscles are a target for androgens by inducing an acute relaxing effect in airway and vascular tissues that is nongenomically mediated; likewise, androgens are capable of inducing genomic anti-inflammatory and nongenomic hypotensive responses. The aim of this report is to associate the relationship between COVID-19 and aging men as well as the comorbidities presented in this group of patients linked with androgen deficiency. Remarkably, the nongenomic mechanisms of androgens as potential protectors are reviewed. On this basis, it is suggested that hypotestosteronemia may be a risk factor for COVID-19 severity.

Perivascular histamine receptors mediate vasosensory reflex responses elicited by thermal nociceptive stimuli in anaesthetised rat models

Objectives: Reflex responses elicited by intra-arterial (i.a) instillation of nociceptive agents are known as vasosensory reflex responses. The present study was designed to demonstrate the vasosensory reflex responses evoked by thermal nociceptive stimuli in anaesthetised rat models and to examine the role of perivascular histamine receptors in mediating these responses. Materials and Methods: In this study, saline at different temperatures (0°C/30°C/55°C) was instilled retrogradely into the femoral artery to stimulate the perivascular nociceptive terminals and the respiratory movements, BP and ECG were recorded for 10 min. Experiments were performed in four groups of rats. Two groups were dedicated to study the temperature-induced reflex cardiorespiratory (CVR) responses after i.a instillation of cold (0°C) and warm saline (55°C). The responses in these groups were compared with the responses after instillation of normal saline at room temperature (30°C) in a separate group of rats that served as time matched control group. Another group of rats was pre-treated with pheniramine and the responses elicited by warm saline were studied. Results: Instillation of warm saline produced immediate (2–6 s) hyperventilatory, hypotensive and bradycardiac responses which were short-lived, while equivolume of normal saline at room temperature did not. Cold saline also elicited the CVR changes of similar quality as that of warm saline but of lesser quantity which were not significantly different from the control group. Pre-treatment with pheniramine significantly attenuated the warm saline-induced reflex responses. Conclusion: Activation of perivascular sensory nerve terminals by thermal nociceptive stimuli elicits vasosensory reflex responses altering CVR parameters. Perivascular histamine receptors play a significant role in mediating the temperature-induced vasosensory reflex responses.

Gene-gene interactions in the protein kinase C/endothelial nitric oxide synthase axis impact the hypotensive effects of propofol.

Anaesthesia with propofol is frequently associated with hypotension, which is at least partially attributable to increased nitric oxide (NO) formation derived from the activation of protein kinase C (PKC)/endothelial NO synthase (NOS3) axis. In this cross-sectional study, we tested whether PRKCA (which encodes PKCα) polymorphisms, or haplotypes, and interactions among PRKCA and NOS3 polymorphisms affect the hypotensive responses to propofol. We collected venous blood samples from 164 patients before and 10 min after propofol administration. Genotypes were determined by PCR and haplotype frequencies were estimated. Nitrite and NOx (nitrites+nitrates) levels were measured by using an ozone-based chemiluminescence assay and the Griess reaction, respectively. We used multifactor dimensionality reduction to test interactions among PRKCA and NOS3 polymorphisms. Propofol promoted enhanced blood pressure-lowering effects and increased nitrite levels in subjects carrying GA + AA genotypes for the rs16960228 and TC + CC genotypes for the rs1010544 PRKCA polymorphisms, and the CCG haplotype. Moreover, genotypes for the rs1010544 PRKCA polymorphism were associated with higher or lower blood pressure decreases in response to propofol depending on the genotypes for the rs2070744 NOS3 polymorphism. Our findings suggest that PRKCA genotypes and haplotypes impact the hypotensive responses to propofol, possibly by modifying NO bioavailability, and that PRKCA-NOS3 interactions modify the blood pressure-lowering effects of propofol.

Haemodynamic effects of a prehospital emergency anaesthesia protocol consisting of fentanyl, ketamine and rocuronium in patients with trauma: a retrospective analysis of data from a Helicopter Emergency Medical Service

ObjectivesPrehospital rapid sequence induction (RSI) of anaesthesia is an intervention with significant associated risk. In this study, we aimed to investigate the haemodynamic response over time of a prehospital RSI...

Association of 5-aminolevulinic acid with intraoperative hypotension in malignant glioma surgery

BackgroundUse of 5-aminolevulinic acid for photodynamic malignant tumor diagnosis reportedly causes intraoperative hypotension (systolic blood pressure < 70 mmHg) during urologic surgery. However, its association with intraoperative hypotension in malignant glioma surgery and underlying mechanisms has not yet been elucidated.. This study aimed to investigate whether 5-aminolevulinic acid administration is associated with intraoperative hypotension in malignant glioma surgery and explore the mechanisms of 5-aminolevulinic acid-induced hypotension in vitro. MethodsIn this retrospective multicenter cohort study, we investigated intracellular nitric oxide as a candidate mediator of hypotension in response to 5-aminolevulinic acid in vitro in human umbilical vein endothelial cell cultures. ResultsOf 142 patients, 94 underwent 5-aminolevulinic acid-guided surgery. Systolic blood pressure was significantly lower throughout surgery with 5-aminolevulinic acid administration. 5-Aminolevulinic acid administration was an independent risk factor for intraoperative hypotension according to multivariable logistic regression analysis (89% vs. 56%; odds ratio = 6.72, 95% confidence interval [2.05–22.1], P = 002). In subgroup analysis of the 5-aminolevulinic acid group, increasing age and use of renin-angiotensin system inhibitors had a synergistic effect with 5-aminolevulinic acid on decreased blood pressure. In the vascular endothelial cell culture study, 5-aminolevulinic acid induced a significant increase in intracellular nitric oxide generation. Conclusions5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells.

Abstract 12310: Metabolic Gain Index is Associated With Adverse Clinical Outcomes Independently of Peak VO 2 in Patients With Heart Failure With Reduced Ejection Fraction Undergoing Cardiopulmonary Exercise Stress Testing

Introduction: Cardiopulmonary exercise stress test (CPET) is an essential prognostic tool in patients with heart failure with reduced ejection fraction (HFrEF) for advanced therapy evaluation. We studied the predictive utility of the metabolic gain index (MGI), which reflects the relative gain of the CPET-estimated stroke volume by the relative change in the product of VO 2 and heart rate (HR) from resting to peak exercise. This novel MGI aims to reflect cardiac reserve function, and, overall prognosis in HFrEF patients. Hypothesis: The MGI is an independent predictor of adverse outcomes in patients with HFrEF. Methods: We reviewed electronic medical records of 843 HFrEF patients (LVEF ≤40%) undergoing CPET from 12/2012 to 9/2020. The MGI was calculated using the formula, [(Peak VO 2 x Peak HR)-(Resting VO 2 x Resting HR)]/(Resting VO 2 x Resting HR). Patients with hypotensive or bradycardia response during exercise were excluded. Primary outcome was the composite of all-cause mortality, LVAD implantation, and heart transplantation. Multivariable Cox proportional hazard models and log rank test were used. For subgroup analysis, patients were stratified by the RER, age, sex, BMI, and beta-blocker use. Results: In our study cohort (mean age 56.2±12.2 years, 73% men, 85% with beta-blockers, mean LVEF 24.8±8.0 %, 16% with BMI ≥35 kg/m 2 , and 75% with RER &gt;1.05), there were 279 (33.1%) patients developed adverse events during median follow up time of 897 days. Lower MGI was independently associated with increased risk of the adverse outcomes with adjustment for age, sex, comorbidities, LVEF, and peak VO 2 (quartile 1 vs 4, hazard ratio 1.83, 95% CI 1.03-3.25, p =0.040, Figure 1A ), especially in patients with RER &gt; 1.05, BMI &lt; 35 kg/m 2 , and without beta-blocker use ( Figure 1B ). Conclusions: Lower MGI is associated with poor prognosis independently of peak VO 2 . The prognostic value of MGI needs to be further corroborated in other multicenter HFrEF cohorts.

Acute cardiometabolic effects of brief active breaks in sitting for patients with rheumatoid arthritis.

Exercise is a treatment in rheumatoid arthritis, but participation in moderate-to-vigorous exercise is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. We compared the acute effects of active breaks in sitting with those of moderate-to-vigorous exercise on cardiometabolic risk markers in patients with rheumatoid arthritis. In a crossover fashion, 15 women with rheumatoid arthritis underwent three 8-h experimental conditions: prolonged sitting (SIT), 30-min bout of moderate-to-vigorous exercise followed by prolonged sitting (EX), and 3-min bouts of light-intensity walking every 30 min of sitting (BR). Postprandial glucose, insulin, c-peptide, triglycerides, cytokines, lipid classes/subclasses (lipidomics), and blood pressure responses were assessed. Muscle biopsies were collected following each session to assess targeted proteins/genes. Glucose [-28% in area under the curve (AUC), P = 0.036], insulin (-28% in AUC, P = 0.016), and c-peptide (-27% in AUC, P = 0.006) postprandial responses were attenuated in BR versus SIT, whereas only c-peptide was lower in EX versus SIT (-20% in AUC, P = 0.002). IL-1β decreased during BR, but increased during EX and SIT (P = 0.027 and P = 0.085, respectively). IL-1ra was increased during EX versus BR (P = 0.002). TNF-α concentrations decreased during BR versus EX (P = 0.022). EX, but not BR, reduced systolic blood pressure (P = 0.013). Lipidomic analysis showed that 7 of 36 lipid classes/subclasses were significantly different between conditions, with greater changes being observed in EX. No differences were observed for protein/gene expression. Brief active breaks in sitting can offset markers of cardiometabolic disturbance, which may be particularly useful for patients who may find it difficult to adhere to exercise.NEW & NOTEWORTHY Exercise is a treatment in rheumatoid arthritis but is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. Our findings show beneficial, but differential, cardiometabolic effects of active breaks in sitting and exercise in patients with rheumatoid arthritis. Breaks in sitting mainly improved glycemic and inflammatory markers, whereas exercise improved lipidomic and hypotensive responses. Breaks in sitting show promise in offsetting aspects of cardiometabolic disturbance associated with prolonged sitting in rheumatoid arthritis.

Postexercise hypotensive response in stroke patients following acute moderate or high intensity cycling session.

Hypertension is highly prevalent in stroke patients and reducing blood pressure is a priority. Aerobic exercise is known to induce postexercise hypotensive responses, but limited studies have documented this concept in stroke patients. The purpose was to investigate the effect of a single bout of moderate intensity continuous training (MICT) and high-intensity interval training (HIIT) on postexercise ambulatory blood pressure with patients with prior ischemic stroke or transient ischemic attack (TIA). Ten hypertensive adults (mean age: 70±9 years) with prior ischemic stroke or TIA participated using a randomized crossover design. Ambulatory blood pressure was monitored for up to 8 hours after either ergocycle MICT or HIIT of respectively 50% and 95% of peak power output. Blood pressure was compared to pre-exercise resting measure. HIIT and MICT induced a decrease of systolic blood pressure of -11.0±9.2 mmHg and -4.7±4.5 mmHg respectively (P=0.03) immediately after the exercise. Ambulatory systolic blood pressure showed a steady linear increase (R2=0.90; P<0.001) of ~1.2 mmHg/hour and returned to pre-exercise measure after 8 hours. Effect of the two exercise conditions over time did not significantly differ (P=0.278). Diastolic blood pressure was not affected by both exercises. Those results suggest that HIIT induce a systolic blood pressure reduction of greater magnitude than MICT immediately after cycling exercise among patients with prior ischemic stroke or TIA. For both exercises, effects on ambulatory blood pressure are similar and persist up to 8 hours.

Renal Deafferentation Prevents Progression of Hypertension and Changes to Sympathetic Reflexes in a Rabbit Model of Chronic Kidney Disease.

[Figure: see text].

Sympathoinhibition and vasodilation contribute to the acute hypotensive response of the superoxide dismutase mimic, MnTnBuOE-2-PyP5+, in hypertensive animals

The pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O2•−), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O2•− has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O2•− and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure.

Nischarin Is Not the Functional I1 Imidazoline Receptor Involved in Blood Pressure Regulation.

Imidazoline receptor antisera selected/Nischarin was proposed several years ago as the functional entity for the I1 medullary receptors (I1Rs) targeted, together with α2-adrenoceptors, by the centrally acting antihypertensive drugs, such as clonidine. The objective of this study was to test this assumption using a pyrroline analog of clonidine, LNP599, which, unlike clonidine and related compounds, displays high selectivity toward I1Rs. Cardiovascular effects of LNP599 (3 mg/kg intravenous) were evaluated in anesthetized, artificially ventilated nischarin mutant rats expressing a truncated form of nischarin lacking the putative imidazoline binding site. LNP599 induced a rapid and pronounced fall in arterial blood pressure in wild-type animals (-42.7% ± 11.0% after 15 minutes), associated with a ≈30% heart rate reduction. Similar effects were obtained in homozygous and heterozygous nischarin mutant rats. The observation that the hypotensive response to I1R activation is not affected by the absence of the putative imidazoline binding site on nischarin strongly suggests that nischarin cannot be regarded as the functional I1R. Carbohydrate regulation was improved in nischarin mutant rats, further supporting the conclusion that nischarin and I1R are 2 distinct molecular entities.

Post-exercise hypotension in response to high-intensity interval exercise: Potential mechanisms

Post-exercise hypotension in response to high-intensity interval exercise: Potential mechanisms

Cardiovascular responses to physical activity during work and leisure

ObjectivesRecent evidence suggests that occupational physical activity (OPA) is associated with adverse cardiovascular health, whereas leisure time physical activity is protective. This study explored explanatory physiological mechanisms.MethodsNineteen males (68% white,...

Hemiplegic migraine episode triggered by regadenoson

SPECT and PET myocardial perfusion imaging (MPI) are widely used to evaluate patients for coronary artery disease. Regadenoson (a selective A2A adenosine receptor agonist) is a commonly used vasodilator agent for stress MPI because of its safety profile and ease of use. Common adverse reactions such as headache, shortness of breath, flushing, and chest and abdominal discomfort are typically mild and can be effectively reversed using methylxanthines such as aminophylline and caffeine. Neurological adverse reactions such as seizure and stroke have rarely been reported with the use of regadenoson. The hemodynamic changes associated with regadenoson administration, such as an exaggerated hypotensive or hypertensive response, may be the cause for the reported cerebrovascular accidents. Activation of central nervous system A2A adenosine receptors is thought to be responsible for seizure episodes in patients with or without known histories of seizure. A2A adenosine receptors activation is also believed to play a role in headaches and migraine. This patient reported who has a history of hemiplegic migraine developed left side weakness and headache following the administration of regadenoson during a PET MPI study. Imaging work-up to rule out cerebrovascular accident was normal. After 1 hour from the onset of his symptoms, his weakness and headache significantly improved with complete resolution within 24 hours. We concluded that regadenoson triggered a hemiplegic migraine episode in this patient, which has not been previously reported in the literature. It may be prudent to avoid regadenoson and adenosine use in patients with a history of hemiplegic migraine.

Ipsilateral somatic nerves mediate histamine-induced vasosensory reflex responses involving perivascular afferents in rat models

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as ‘vasosensory reflex responses’. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2–7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.

Reduction in Hindquarter Vascular Resistance Supports 5-HT7 Receptor Mediated Hypotension.

The 5-HT7 receptor is the primary mediator of both the acute (<hours) and chronic (day-week) decreases in mean arterial pressure (MAP) during low dose 5-HT infusion in rats. Previous data show the hypotensive response during chronic 5-HT infusion is due to a decrease total peripheral resistance (TPR) and specifically splanchnic vascular resistance. We hypothesized that changes in vascular resistance in both the splanchnic and skeletal muscle vascular beds are critical to the cardiovascular effects mediated by the 5-HT7 receptor. Systemic and regional hemodynamic data were collected in conscious and anesthetized male rats using radiotelemetry, vascular catheters and transit-time flowmetry. Reversible antagonism of the 5-HT7 receptor was achieved with the selective antagonist SB269970 (33 μg/kg, iv). From the very beginning and throughout the duration (up to 5 days) of a low dose (25 μg/kg) infusion of 5-HT, TPR, and MAP were decreased while cardiac output (CO) was increased. In a separate group of rats, the contribution of the 5-HT7 receptor to the regional hemodynamic response was tested during 5-HT-induced hypertension. The decrease in MAP after 24 h of 5-HT (saline 83 ± 3 vs. 5-HT 72 ± 3 mmHg) was associated with a significant decrease in skeletal muscle vascular resistance (saline 6 ± 0.2 vs. 5-HT 4 ± 0.4 mmHg/min/mL) while splanchnic vascular resistance was similar in 5-HT and saline-treated rats. When SB269970 was administered acutely, MAP and skeletal muscle vascular resistance rapidly increased, whereas splanchnic resistance was unaffected. Our work suggests the most prominent regional hemodynamic response to 5-HT7 receptor activation paralleling the fall in MAP is a decrease in skeletal muscle vascular resistance.

Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl.

Fentanyl is a high-potency opioid receptor agonist that elicits profound analgesia and suppression of breathing in humans and animals. To date, there is limited evidence as to whether changes in oxidant stress are important factors in any of the actions of acutely administered fentanyl. This study determined whether the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), or a potent antioxidant, N-acetyl-L-cysteine methyl ester (L-NACme), modify the cardiorespiratory and analgesic actions of fentanyl. We examined whether the prior systemic injection of Tempol or L-NACme affects the cardiorespiratory and/or analgesic responses elicited by the subsequent injection of fentanyl in isoflurane-anesthetized and/or freely moving male Sprague-Dawley rats. Bolus injections of Tempol (25, 50 or 100 mg/kg, IV) elicited minor increases in frequency of breathing, tidal volume and minute ventilation. The ventilatory-depressant effects of fentanyl (5 μg/kg, IV) given 15 min later were dose-dependently inhibited by prior injections of Tempol. Tempol elicited dose-dependent and transient hypotension that had (except for the highest dose) resolved when fentanyl was injected. The hypotensive responses elicited by fentanyl were markedly blunted after Tempol pretreatment. The analgesic actions of fentanyl (25 μg/kg, IV) were not affected by Tempol (100 mg/kg, IV). L-NACme did not modify any of the effects of fentanyl. We conclude that prior administration of Tempol attenuates the cardiorespiratory actions of fentanyl without affecting the analgesic effects of this potent opioid. As such, Tempol may not directly affect opioid-receptors that elicit the effects of fentanyl. Whether, the effects of Tempol are solely due to alterations in oxidative stress is in doubt since the powerful antioxidant, L-NACme, did not affect fentanyl-induced suppression of breathing.

Pomegranate peel as a phytogenic in broiler chickens: Influence upon antioxidant, lipogenesis and hypotensive response.

The aim of this study was to evaluate antioxidant, antihyperlipidemic and hypotensive properties of pomegranate peel (PP) on antioxidant status, fat deposition, lipid peroxidation and pulmonary hypertensive response in broiler chickens. A total of 375 one‐day‐old male broilers (Cobb 500) were randomly assigned to five treatments included dietary PP levels of 0, 2.5, 5.0, 7.5 and 10 g/kg. Supplementation of PP at 7.5 and 10 g/kg resulted in significant upregulation of hepatic catalase (p < 0.004) and superoxide dismutase1 (SOD1; p < 0.05), which reflected in decreased concentration of circulatory malondialdehyde (MDA). Dietary inclusion of PP at 7.5 and 1.0 g/kg significantly decreased serum concentrations of triglycerides (p < 0.004) and cholesterol (p < 0.006) with concomitant decrease in abdominal fat deposition (p < 0.05). The antihyperlipidemic effect of PP was mediated through down‐regulation of peroxisome proliferator activated receptor alpha (PPARα). Hypotensive effect of PP was also observed at 7.5 and 10 g/kg as reduced heart weight and the right‐to‐total ventricular weight ratio (RV/TV) and decreased mortality from pulmonary hypertension. The hypotensive property of PP was associated with increased concentration of serum nitric oxide. In conclusion, this study revealed antioxidative, antihyperlipidemic and hypotensive effects of PP at 7.5 and 10 g/kg in broiler chickens exposed to hypobaric hypoxia. Health‐beneficial effects of PP suggest this product as a promising multi‐functional phytogenic feed additive for broiler chickens.

Fetal Cardiovascular Decompensation During Labor Predicted From the Individual Heart Rate Tracing: A Machine Learning Approach in Near-Term Fetal Sheep Model.

Background: When exposed to repetitive umbilical cord occlusions (UCO) with worsening acidemia, fetuses eventually develop cardiovascular decompensation manifesting as pathological hypotensive arterial blood pressure (ABP) responses to fetal heart rate (FHR) decelerations. Failure to maintain cardiac output during labor is a key event leading up to brain injury. We reported that the timing of the event when a fetus begins to exhibit this cardiovascular phenotype is highly individual and was impossible to predict.Objective: We hypothesized that this phenotype would be reflected in the individual behavior of heart rate variability (HRV) as measured by root mean square of successive differences of R-R intervals (RMSSD), a measure of vagal modulation of HRV, which is known to increase with worsening acidemia. This is clinically relevant because HRV can be computed in real-time intrapartum. Consequently, we aimed to predict the individual timing of the event when a hypotensive ABP pattern would emerge in a fetus from a series of continuous RMSSD data.Study Design: Fourteen near-term fetal sheep were chronically instrumented with vascular catheters to record fetal arterial blood pressure, umbilical cord occluder to mimic uterine contractions occurring during human labor and ECG electrodes to compute the ECG-derived HRV measure RMSSD. All animals were studied over a ~6 h period. After a 1–2 h baseline control period, the animals underwent mild, moderate, and severe series of repetitive UCO. We applied the recently developed machine learning algorithm to detect physiologically meaningful changes in RMSSD dynamics with worsening acidemia and hypotensive responses to FHR decelerations. To mimic clinical scenarios using an ultrasound-based 4 Hz FHR sampling rate, we recomputed RMSSD from FHR sampled at 4 Hz and compared the performance of our algorithm under both conditions (1,000 Hz vs. 4 Hz).Results: The RMSSD values were highly non-stationary, with four different regimes and three regime changes, corresponding to a baseline period followed by mild, moderate, and severe UCO series. Each time series was characterized by seemingly randomly occurring (in terms of timing of the individual onset) increase in RMSSD values at different time points during the moderate UCO series and at the start of the severe UCO series. This event manifested as an increasing trend in RMSSD values, which counter-intuitively emerged as a period of relative stationarity for the time series. Our algorithm identified these change points as the individual time points of cardiovascular decompensation with 92% sensitivity, 86% accuracy and 92% precision which corresponded to 14 ± 21 min before the visual identification. In the 4 Hz RMSSD time series, the algorithm detected the event with 3 times earlier detection times than at 1,000 Hz, i.e., producing false positive alarms with 50% sensitivity, 21% accuracy, and 27% precision. We identified the overestimation of baseline FHR variability by RMSSD at a 4 Hz sampling rate to be the cause of this phenomenon.Conclusions: The key finding is demonstration of FHR monitoring to detect fetal cardiovascular decompensation during labor. This validates the hypothesis that our HRV-based algorithm identifies individual time points of ABP responses to UCO with worsening acidemia by extracting change point information from the physiologically related fluctuations in the RMSSD signal. This performance depends on the acquisition accuracy of beat to beat fluctuations achieved in trans-abdominal ECG devices and fails at the sampling rate used clinically in ultrasound-based systems. This has implications for implementing such an approach in clinical practice.

The Influence of Anesthesia on the Cardiovascular Effects of Centrally Administered Clonidine

The α2 adrenergic receptor (α2AR) agonists are known to induce hypotensive responses when administered via intracerebroventricular (icv) route in normotensive rats anesthetized with either pentobarbital or urethane. However, the icv injection of α2AR agonists such as clonidine (CLO) produces hypertensive responses in normotensive conscious rats. To date, the effects icv administration of CLO in normotensive rats under ketamine/xylazine anesthesia, a commonly used anesthetic combination in experimental studies, is still unknown. We hypothesized that anesthetic drugs differentially modulate cardiovascular responses to centrally administered CLO. To evaluate this hypothesis, we assessed blood pressure (BP) and heart rate (HR) of normotensive male rats anesthetized with pentobarbital or ketamine/xylazine, both under mechanical ventilation. These animals received CLO (10 μg/5 μL) or dexmedetomidine (DEX; 0.6 μg/5 μL) by icv route. In additional experiments, yohimbine (5 μg/5 μL), a selective α2AR antagonist, was given by icv route 15 min before a second injection of CLO or DEX in ketamine/xylazine anesthetized rats. As widely described, the icv microinjection of CLO decreased the mean arterial pressure (MAP) and HR by 40.73 ± 6.3 mmHg and 134 ± 15 bpm in pentobarbital anesthetized rats (n = 5). On the other hand, in ketamine/xylazine anesthetized rats (n = 6) CLO increased MAP by 29.4 ± 5.1 mmHg and decreased HR by 34 ± 5 bpm, a less pronounced effect when compared with the pentobarbital group (p < 0.0001). Similarly, the icv microinjection of DEX in ketamine/xylazine anesthetized rats (n = 6) increased MAP by 20.8 ± 3.2 mmHg and decreased HR by 51 ± 16 bpm. Notably, yohimbine generated a pattern of hypotensive responses comparable to CLO and DEX. Additionally, after yohimbine administration, both CLO- and DEX-increased MAP were reduced to 9.9 ± 2.3 mmHg and 6.7 ± 1.1 mmHg, respectively (n = 6, p < 0.05), despite the lack of influence of yohimbine in the bradycardia induced by these α2AR agonists in ketamine/xylazine anesthetized rats. This study discloses that in normotensive rats under ketamine/xylazine anesthesia, central administration of CLO produces a hypertensive effect, opposing the findings obtained in pentobarbital-anesthetized rats and resembling the vascular responses described in conscious animals. This data was reproduced by DEX and reduced by yohimbine, suggesting that stimulation of central α2AR takes a preponderant role in this effect. Our results reinforce the relevance regarding the influence of anesthetic choice for studies involving cardiovascular parameters.