Decline In Mean Arterial Pressure Research Articles

Effect of Dietary Sodium on Blood Pressure

Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied. To examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use. Prospectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets. High-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets. Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure. Among the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants' median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P < .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as "salt sensitive." At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P < .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively. Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events. ClinicalTrials.gov Identifier: NCT04258332.

Monoclonal antibodies neutralizing alpha-hemolysin, bicomponent leukocidins, and clumping factor A protected against Staphylococcus aureus-induced acute circulatory failure in a mechanically ventilated rabbit model of hyperdynamic septic shock.

Patients with septic shock caused by Staphylococcus aureus have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of S. aureus septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression. Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after S. aureus intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with S. aureus. Rabbits challenged with S. aureus, but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (P<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury. These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock.

Balanced volatile sedation with isoflurane in critically ill patients with aneurysmal subarachnoid hemorrhage - a retrospective observational study.

In patients with severe aneurysmal subarachnoid hemorrhage (SAH) deep sedation is often used early in the course of the disease in order to control brain edema formation and thus intracranial hypertension. However, some patients do not reach an adequate sedation depth despite high doses of common intravenous sedatives. Balanced sedation protocols incorporating low-dose volatile isoflurane administration might improve insufficient sedation depth in these patients. We retrospectively analyzed ICU patients with severe aneurysmal SAH who received isoflurane in addition to intravenous anesthetics in order to improve insufficient sedation depth. Routinely recorded data from neuromonitoring, laboratory and hemodynamic parameters were compared before and up to 6 days after initiation of isoflurane. Sedation depth measured using the bispectral index improved in thirty-six SAH patients (-15.16; p = 0.005) who received additional isoflurane for a mean period of 9.73 ± 7.56 days. Initiation of isoflurane sedation caused a decline in mean arterial pressure (-4.67 mmHg; p = 0.014) and cerebral perfusion pressure (-4.21 mmHg; p = 0.013) which had to be balanced by increased doses of vasopressors. Patients required increased minute ventilation in order to adjust for the increase in PaCO2 (+2.90 mmHg; p < 0.001). We did not detect significant increases in mean intracranial pressure. However, isoflurane therapy had to be terminated prematurely in 25% of the patients after a median of 30 h due to episodes of intracranial hypertension or refractory hypercapnia. A balanced sedation protocol including isoflurane is feasible for SAH patients experiencing inadequately shallow sedation. However, therapy should be restricted to patients without impaired lung function, hemodynamic instability and impending intracranial hypertension.

Non-dipping heart rate &amp; major adverse cardiovascular events in type 2 diabetes mellitus

Abstract Background Type 2 diabetes mellitus (T2DM) is a known major risk factor for cardiovascular disease. Whilst the influence of traditional risk factors such as hypertension, hyperlipidaemia and smoking are well-established determinants of major adverse cardiovascular events (MACE) in subjects with T2DM, the impact of insulin resistance, non-dipping blood pressure and heart rate status have not been adequately investigated. Purpose To determine predictors of MACE in a population of T2DM with underlying target-organ damage at baseline. Methods This study included 196 subjects with T2DM with advanced proliferative diabetic retinopathy. These subjects were recruited in 2008–2009 and were consequently followed up till February 2022 to determine independent predictors of MACE. At baseline, the median age of the participants was 64 years (IQR: 59–71 years) and the median diabetes duration was 18 years (IQR: 10–25 years). At baseline, all underwent 24-hour blood pressure and heart rate (HR) monitoring, and were assessed for markers of inflammation, insulin resistance, albuminuria, presence of peripheral neuropathy and peripheral vascular disease. Subjects whose night-time HR did not decrease by more than 10% as compared to daytime readings were classified as non-dippers. Similarly, a non-dipping BP profile was defined as a nocturnal decline of mean arterial pressure of less than 10%. At follow-up, the all-cause death rate was noted as well as MACE. The latter was defined as all-cause death, non-fatal MI, non-fatal stroke, coronary revascularisation or hospitalisation for unstable angina pectoris or heart failure. Univariate followed by multivariate Cox-regression analysis was performed to determine independent predictors of both all-cause mortality and MACE. Results At follow-up, 46% of the study participants had died whilst 63.1% had exhibited MACE. Multivariate analysis revealed age (OR: 1.05, 95% CI 1.02–1.07, p&amp;lt;0.001), ESR (OR: 1.012, 95% CI: 1.001–1.02, p=0.035), GGT (OR: 1.005, 95% CI 1.001–1.009, p=0.025) and eGFR (OR: 0.99, 95% CI 0.98–0.99, p=0.016) at baseline to be independent determinants of all-cause death. With regards MACE, likewise, age (OR: 1.028, 95% CI 1.007–1.05, p=0.009), GGT (OR: 1.004, 95% CI 1.001–1.008, p=0.017) and eGFR (OR: 0.99, 95% CI 0.98–0.99, p=0.022) were shown to be independent determinants together with diabetes duration (OR: 1.034, 95% CI 1.014–1.055, p=0.001) and presence of non-dipping heart rate at baseline. The latter was shown to be the strongest predictor of MACE (OR: 1.55, 95% CI 1.06–2.26, p=0.024). Conclusion Whereas increasing age and impaired renal function are known risk factors for cardiovascular disease, this long-term follow-up study has highlighted the relevance of non-dipping heart rate in type 2 diabetes mellitus. Previous studies had shown an association between non-dipping heart rate and target-organ damage in diabetic subjects. The impact on MACE merits further investigation. Funding Acknowledgement Type of funding sources: None.

Angiotensin II and the Renal Hemodynamic Response to an Isolated Increased Renal Venous Pressure in Rats.

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min, p<0.05) and GFR (−0.77±0.18ml/min, p<0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (−22.4±4.1 vs. −9.9±2.3mmHg, p<0.05), whereas the decrease in heart rate (HR) was less (−5±6bpm vs. −23±4bpm, p<0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (−0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction.

Safety Profile of Endoscopist-directed Balanced Propofol Sedation for Procedural Sedation: An Experience at a Hospital-based Endoscopy Unit.

Nurse-administered propofol sedation was restricted to anesthesiologists in 2009, a practice that has contributed to spiraling health care costs in the United States. The aim of this study was to evaluate the safety of endoscopist-directed balanced propofol sedation (EDBPS). We identified patients undergoing endoscopy with EDBPS from January 1, 2017, to June 20, 2017, and abstracted their medical records. Adverse events (AEs) included: hypoxia (oxygen saturation < 90%); hypotension [(a) systolic blood pressure < 90 mm Hg, (b) systolic blood pressure decline of >50 mm Hg, (c) decline in mean arterial pressure of >30%]; bradycardia (heart rate of < 40 beats/min). Logistic regression identified factors independently associated with AEs. A total of 1897 patients received EDBPS during the study period [mean age: 55 y (SD=11.4 y); 56.4% women]. Patients received median doses of 50 µg fentanyl, 2 mg of midazolam, and a mean propofol dose of 160±99 mg. There were no major complications (upper 95% confidence interval, 0.19%). Overall, 334 patients (17.6%) experienced a clinically insignificant AE: 65 (3.4%) experienced transient hypoxia, 277 patients (14.6%) experienced hypotension, 2 had transient bradycardia. In bivariate analysis, older age was associated with risk for hypotension, propofol dose was associated with transient hypoxemia, and procedure duration was associated with both hypotension and transient hypoxia. In multivariate analysis, only procedure length was associated with AEs (odds ratio scale 10; odds ratio=1.07; 95% confidence interval, 1.05-1.09, P<0.001). EDBPS is safe for endoscopic sedation. Given the higher cost of anesthesia-administered propofol, endoscopists should reinstate EDBPS by revising institutional sedation policies.

Pegylated Carboxyhemoglobin (SANGUINATE®) Restores Blood Flow and Tissue Oxygenation in a Novel Rat Model of Acute Vaso-Occlusive Crisis

INTRODUCTION: Sickle Cell Disease (SCD) hemoglobin S (HbS) promotes hemoglobin polymerization and red blood cell (RBC) sickling during hypoxia. PEGylated carboxyhemoglobin bovine (PEG-COHb; SANGUINATE®) has been previously shown to reverse sickling of SCD RBC in vitro by directed gas transfer to hypoxic RBC. A rat model was used to evaluate the capability of SANGUINATE® to restore cardiovascular rheology and tissue oxygenation (PISFO2) at sites distal to acute Vaso-Occlusions (VOC).OBJECTIVES: Evaluate the in vivo capability of PEG-COHb to improve rheology in rats placed in active VOC through transfusion of human SCD RBC while monitoring treatment effects on PISFO2 and systemic functions.METHODS: Human homozygous (HbSS) whole blood was obtained from consented SCD volunteers. The SCD RBC were isolated by centrifugation, triple-washed and resuspended in lactated Ringer's saline (LRS). Male Sprague Dawley rats were anesthetized, cannulated for fluid transfer, and surgically prepared for microscopic study of the spinotrapezius microcirculation. Isovolemic exchange transfusion of rat blood with suspended SC RBCs (27.5 ± 3.5% total blood volume) was conducted until PISFO2 at the distal portion of the spinotrapezius muscle was < 1 mmHg. VOC was visually confirmed as wide-spread precapillary arteriolar flow-arrest. Animals in VOC were subsequently treated 15 minutes later with PEG-COHb or LRS administered as a bolus of 8.0 ml/kg over 5 minutes. Animals were observed for up to 4 hours post-treatment and then euthanized. Measurements included systemic cardiovascular parameters, survival, blood chemistry, and PISFO2 via phosphorescence quenching microscopy and were obtained across treatment groups and the no treatment [Sham] control group.RESULTS: Exchange transfusion successfully produced a reduction in PISFO2 in the distal portion of the spinotrapezius muscle for all animals to <1 mmHg presumably through Vaso-Occlusions. VOC was visually apparent as flow arrest was initially observed in capillaries and most small venules and arterioles, and then progressed proximally into sites with larger feed vessels and higher intravascular pressures with subsequent declines in local PISFO2. Intervention with PEG-COHb and LRS both showed a visual improvement in microvascular flow, but yielded differential effects on PISFO2 in all sites (average return to 96 ± 6% and 64 ± 20% of baseline, respectively). PEG-COHb -treated animals survived the entire 4 h observation phase with a final global spinotrapezius PISFO2 level within 10% of baseline values. In contrast, global spinotrapezius PISFO2 declined to 0 mmHg for LRS treated animals by 3 h with rapid decline in mean arterial pressure and death occurring prior to 4 h. Serum lactate levels were monitored to provide an assessment of systemic ischemia from time 0 after exchange transfusion to the last collection point near the end of the experiment. Lactate increased for untreated Sham (34 ± 4.5 to 124 ± 43.0 mg/dl) and LRS groups (48 ± 15.0 to 110 ± 43.0 mg/dl), but remained stable for SANGUINATE®-treated animals (42 ± 1.5 to 40 ± 4.5 mg/dl). Total microcirculatory collapse occurred in Sham animals by 3h along with a null-reading of PISFO2, which was followed by a rapid decline in mean arterial pressure and death at 3.5 h similar to the LRS group.SUMMARY: This study was conducted in a novel rat model providing the ability to monitor real-time microcirculatory events and systemic parameters, which is difficult in murine models due to their smaller stature. PEG-COHb treatment promoted VOC resolution as evidenced through improved blood flow and concomitant effects on PISFO2. Importantly, the gas transfer properties of SANGUINATE® not only acutely resolved VOC, but provided the added benefit of restoring PISFO2 to near baseline values. In contrast, LRS animals showed transient rheology and minimal PISFO2 improvements, but levels declined over time and outcomes were similar to sham controls. Restoring blood flow and PISFO2 are key events to limiting VOC pain and complications and the treatment with PEG-COHb demonstrated the ability to achieve these critical functions suggesting it may provide improvements in treating acute VOC in human SCD individuals. DisclosuresSong:Prolong Pharmaceuticals: Consultancy, Research Funding. Nugent:Prolong Pharmaceuticals: Consultancy, Research Funding.

Studies to Evaluate the Safety of Constant Rate Infusions of Dexmedetomidine, Ketamine and Lidocaine Alone or in Combination during Isoflurane Anesthesia in Horses

Background: Horses mount a huge stress response to anesthesia when compared to other animals, hence are risky candidates for anesthesia. Inhalant anesthetic agents offer more control to anesthetic depth and facilitate rapid recovery, hence are considered to be safer than intravenous agents for surgical procedures requiring more than an hour, however, newer drug combinations are being explored to minimize the undesired consequences and dose rate of inhalant agents. The present study explored the safety of dexmedetomidine, ketamine and lidocaine constant rate infusion alone or as a combination along with Isoflurane for safer anesthesia in horses.Methods: The study was conducted on 28 horses divided into S, D, DK and DKL groups having 7 animals in each. Xylazine (1 mg/kg) and butorphanol (0.05mg/kg) were given intravenously for premedication. Ketamine (2 mg/kg) and midazolam (0.2 mg/kg) were used for induction and anesthesia was maintained with isoflurane. Normal saline (1000ml/hour), Dexmedetomidine (2µg/kg/hr), Dexmedetomidine and ketamine (2 µg/kg/hr and 2 mg/kg/hr) and Dexmedetomidine, ketamine and lidocaine (2 µg/kg/hr, 2 mg/kg/hr and 2 mg/kg/h) were given as CRI in groups S, D, DK and DKL, respectively. Thiopentone sodium (250mg bolus, 5%) was given as a fast intravenous bolus whenever required. Anesthetic efficacy was evaluated based on clinical, haemato-biochemical, hemodynamic, and endocrine variables.Result: A significant decline in mean arterial pressure was noticed in group DKL but changes in CVP and SpO2 in different groups were non-significant. Higher Blood glucose and low Insulin levels were seen in group DK during 45-60 min. Constant rate infusions of Dexmedetomidine, Ketamine and Lidocaine alone or in combination produced a significant sparing effect on Isoflurane and thiopentone while they improved peri-operative quality of anesthesia in horses.

INITIAL EGFR DECLINE AND LONG-TERM RENAL FUNCTION DURING BLOOD PRESSURE LOWERING THERAPY: A PATIENT LEVEL META-ANALYSIS OF THE SPRINT AND ACCORD-BP RANDOMIZED CONTROLLED TRIALS

Objective: Lowering blood pressure (BP) can lead to an initial decline in renal function. Guidelines recommend treatment adjustment when the estimated glomerular filtration rate (eGFR) decreases by more than 20%. However, there is ongoing debate how much can be accepted. We determined the relation between initial eGFR and BP decrease, and subsequent eGFR during follow-up in participants from ACCORD-BP and SPRINT. Design and method: Diabetic and non-diabetic patients at increased cardiovascular risk were randomized to intensive (&lt;120) or standard (&lt;140 mmHg) systolic BP-targets. We determined the relation between initial decline in mean arterial pressure (MAP) and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR-decline after 1 year. Results: In total 13266 patients, aged 66.2 year, 39% female and with mean eGFR 76.4 ml/min/1.73m2, with 41126 eGFR measurements were analyzed. The &gt;20% stratum consisted of 669 (10%) in the intensive and 334 (5%) participants in the standard group. Up to 10 mmHg MAP decrease, there was no significant change in eGFR, with a lower bound of 26% based on 95% of the participants. Hereafter, there was a linear association between MAP and eGFR with an initial eGFR decrease of 3.4% (95%CI 2.9–3.9%) per 10 mmHg MAP decrease, with a lower eGFR bound increasing to 46% after 40 mmHg MAP decrease (figure 1). There was no significant difference in eGFR slope (p = 0.37) after stratification to treatment allocation and initial eGFR decline, with an annual eGFR decrease of 1.24 (95%CI 1.09–1.39), 1.20 (95%CI 0.97–1.43) and 1.14 (95%CI 0.77–1.50) in the 5, 5–20% and &gt;20% stratum during intensive and 0.95 (95%CI 0.81–1.09), 1.23 (95%CI 0.97–1.49) and 1.17 (95%CI 0.65–1.69) ml/min/1.73m2/year during standard treatment. Conclusions: In patients at high cardiovascular risk, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. The observed degree of initial eGFR decline was strongly dependent on the achieved BP decrease, suggesting that the achieved BP difference should be taking into account when interpreting the eGFR decline during antihypertensive therapy.

The effect of high-dose intramuscular epinephrine on the recovery of spontaneous circulation in an asphyxia\u2010induced cardiac arrest rat model

BackgroundObtaining vascular access can be challenging during resuscitation following cardiac arrest, and it is particularly difficult and time-consuming in paediatric patients. We aimed to compare the efficacy of high-dose intramuscular (IM) versus intravascular (IV) epinephrine administration with regard to the return of spontaneous circulation (ROSC) in an asphyxia-induced cardiac arrest rat model.Methods Forty-five male Sprague-Dawley rats were used for these experiments. Cardiac arrest was induced by asphyxia, and defined as a decline in mean arterial pressure (MAP) to 20 mmHg. After asphyxia-induced cardiac arrest, the rats were randomly allocated into one of 3 groups (control saline group, IV epinephrine group, and IM epinephrine group). After 540 s of cardiac arrest, cardiopulmonary resuscitation was performed, and IV saline (0.01 cc/kg), IV (0.01 mg/kg, 1:100,000) epinephrine or IM (0.05 mg/kg, 1:100,000) epinephrine was administered. ROSC was defined as the achievement of an MAP above 40 mmHg for more than 1 minute. Rates of ROSC, haemodynamics, and arterial blood gas analysis were serially observed.ResultsThe ROSC rate (61.5%) of the IM epinephrine group was less than that in the IV epinephrine group (100%) but was higher than that of the control saline group (15.4%) (log-rank test). There were no differences in MAP between the two groups, but HR in the IM epinephrine group (beta coefficient = 1.02) decreased to a lesser extent than that in the IV epinephrine group with time.ConclusionsIM epinephrine induced better ROSC rates compared to the control saline group in asphyxia-induced cardiac arrest, but not compared to IV epinephrine. The IM route of epinephrine administration may be a promising option in an asphyxia-induced cardiac arrest.

Initial Estimated Glomerular Filtration Rate Decline and Long-Term Renal Function During Intensive Antihypertensive Therapy: A Post Hoc Analysis of the SPRINT and ACCORD-BP Randomized Controlled Trials.

Lowering blood pressure (BP) can lead to an initial decline in estimated glomerular filtration rate (eGFR). However, there is debate how much eGFR decline is acceptable. We performed a post hoc analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial), which randomized patients to intensive or standard systolic BP-targets. We determined the relation between initial decline in mean arterial pressure and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR decline after 1 year. A total of 13 266 patients with 41 126 eGFR measurements were analyzed. Up to 10 mm Hg of BP-lowering, eGFR did not change. Hereafter, there was a linear decrease of 3.4% eGFR (95% CI, 2.9%-3.9%) per 10 mm Hg mean arterial pressure decrease. The observed eGFR decline based on 95% of the subjects varied from 26% after 0 mm Hg to 46% with a 40 mm Hg mean arterial pressure decrease. There was no difference in eGFR slope (P=0.37) according to initial eGFR decline and BP-target, with a decrease of 1.24 (95% CI, 1.09-1.39), 1.20 (95% CI, 0.97-1.43), and 1.14 (95% CI, 0.77-1.50) in the 5%, 5% to 20%, and >20% stratum during intensive and 0.95 (95% CI, 0.81-1.09), 1.23 (95% CI, 0.97-1.49), and 1.17 (95% CI, 0.65-1.69) mL/minute per 1.73 m2 per year during standard treatment. In patients at high cardiovascular risk with and without diabetes mellitus, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. Our results support that an eGFR decrease up to 20% after BP lowering can be accepted and suggest that the limit can be extended up to 46% depending on the achieved BP reduction. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000620, NCT01206062.

Transcapillary fluid flux and inflammatory response during neonatal therapeutic hypothermia: an open, longitudinal, observational study

BackgroundTherapeutic hypothermia is neuroprotective in asphyxiated neonates by counteracting mechanisms contributing to brain injury. Although an initial increased permeability is part of an inflammatory reaction and thereby a natural healing process, an excessive endothelial permeability with edema formation may result in impaired hemodynamics. Reduced permeability may, however, benefit healing. Although plasma and interstitial colloid osmotic pressure are accessible and essential parameters for understanding fluid imbalance, the mechanisms of fluid exchange remain poorly understood. The potential influence of therapeutic hypothermia on plasma and interstitial colloid osmotic pressure, and the relationship between inflammatory markers and colloid osmotic pressure in asphyxiated neonates, was investigated.MethodsSeventeen neonates with moderate to severe hypoxic ischemic encephalopathy, born after 35 weeks gestation, received servo-controlled whole body cooling before 6 h of age, followed by gradual rewarming after 72 h. All infants were treated according to a national hypothermia protocol. Interstitial fluid in the skin was collected at 7, 13, 25, 49, and 73 h after birth by subcutaneous implantation of multifilamentous nylon wicks with 60 min of implantation time. Biomarkers of inflammation and colloid osmotic pressure were measured in serum and interstitial fluid.ResultsA modest decrease in serum and interstitial colloid osmotic pressure was measured, leaving an unaltered difference in colloid osmotic pressure gradient. A decline in mean arterial pressure was observed between 7 and 13 h of life, with a concomitant decrease in positive fluid balance within the same time frame. White blood cell count and leukocyte subclasses dropped significantly throughout treatment, with elevated interstitial interleukin (IL)-1α and decreased serum IL-1RA, IL-6, and IL-10 during treatment time points.ConclusionsColloid osmotic pressures measured in serum and interstitial fluid during asphyxia is lower than previously reported, with small alteration of pressure differences across capillaries, reducing vascular filtration. An inherent local and systemic regulation of inflammation together with changes in colloid osmotic pressure may indicate a possible preventive mechanism of edema generation during neonatal asphyxia and therapeutic hypothermia.Trial registrationClinicalTrials.gov Identifier: NCT01044940. Date of registration: January 8, 2010.

Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22mg/kg) infusion or the same volume saline, 30min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

Anesthetic Management of Transapical Off-Pump Mitral Valve Repair With NeoChord Implantation.

Various minimally invasive surgical approaches have been used in mitral valve (MV) surgery. The transapical off-pump mitral valve intervention with NeoChord implantation (TOP-MINI) is a minimally invasive, alternative procedure for the treatment of degenerative mitral regurgitation. There are several special considerations for the anesthesiologist during the TOP-MINI procedure. The main purpose of this study was to present the anesthetic management of the TOP-MINI procedure. An observational study. Training and research hospital. Adult patients who underwent MV repair with the NeoChord DS1000 system (NeoChord Inc, St Louis Park, MN). The study included 12 consecutive patients who underwent MV repair with the NeoChord DS1000 system at the Antalya Training and Research Hospital, Antalya, Turkey, between June 2014 and December 2015. A record was made of preoperative demographic details, comorbidities, preoperative and postoperative mitral regurgitation severity, preoperative and postoperative forced expiratory volume in 1 second values, use of blood products and vasoactive drugs, surgical times, mechanical ventilation times, intensive care unit (ICU) and hospital length of stay, visual analog scale scores, analgesic requirement in ICU and perioperative complications. TOP-MINI was performed completely off-pump in 12 patients. Intraoperative salvaged blood via cell-saver was 660±196 mL. Patients required 0.8±0.7 U of red blood cells and 2.0±0.9 U of fresh frozen plasma in the ICU. Inotropic support was used in 5 patients. There was a significant decline in mean arterial pressure from before surgery to during implantation (70.9±4.5 mmHg v 51.7±5.8 mmHg, respectively). A statistically significant increase was demonstrated in mean arterial pressure from during implantation to postimplantation (51.7±5.8 mmHg v 67.0±6.8 mmHg, respectively). There were no significant differences in preoperative and postoperative forced expiratory volume in 1 second values. Defibrillation was required in 1 patient, and temporary atrial fibrillation was observed in 1 patient during the procedure. Atelectasis occurred in the postoperative period in 1 patient. The mean visual analog scale score was 3.6±1.4, and the mean tramadol consumption was 77±39 mg in the ICU. Extubation time and the mean length of stay in the ICU and hospital were 2.6±0.5 hours, 19.8±2.7 hours, 5±1 days, respectively. The TOP-MINI procedure requires complex anesthetic management. Transesophageal echocardiographic guidance is essential for this procedure. One-lung ventilation, fluid administration, avoidance of hypothermia, and pain management are the bases for anesthetic management.

Anterior spinal cord infarction in a 77-year-old male after a right hemicolectomy: A case report

A 77-year-old man underwent an exploratory laparotomy and right hemicolectomy for bowel ischemia. An etiology that has been investigated was hypotension leading to hypoperfusion. Intraoperatively, the patient experienced hypotension with a decline in mean arterial pressure from 150 mmHg to 30 mmHg for a duration of 20 minutes. Postoperatively the patient had another episode of hypotension with a decline in mean arterial pressure from 80 mmHg to 55 mmHg for a-15-minute period. On post-operative day three the patient was paraplegic with spinal cord infarction seen on magnetic resonance imaging from T10 to the conus medullaris. The blood supply to this region appeared unobstructed on imaging and therefore it is likely that intermittent hypotension was associated with insufficient blood flow to this region.

Clonidine Restores Pressor Responsiveness to Phenylephrine and Angiotensin II in Ovine Sepsis.

In sepsis, prolonged, sympathetic overstimulation may lead to vasopressor-refractory hypotension. We therefore examined the effects of the α2-adrenergic agonist clonidine on mean arterial pressure, renal sympathetic nerve activity, and pressor responsiveness to phenylephrine and angiotensin II during hypotensive sepsis in conscious sheep. Interventional study. Research institute. Twelve adult Merino ewes (n = 6 per group). Sepsis was induced by IV infusion of Escherichia coli for 32 hours. Pressor responses to increasing doses of phenylephrine and angiotensin II were measured at baseline and at 24, 28, and 32 hours of sepsis. Sheep were treated with clonidine (1 μg/kg/hr) or saline-vehicle from 24 to 32 hours of sepsis. Sepsis was characterized by hypotension (~12 mm Hg), increased heart rate (~80 beats/min), increased renal sympathetic nerve activity (~70%), and blunted pressor responses to phenylephrine and angiotensin II. In vehicle-treated sheep, mean arterial pressure progressively declined from 25 to 32 hours of sepsis (73 ± 3 to 66 ± 3 mm Hg; p = 0.013) while the elevations in heart rate and renal sympathetic nerve activity and reduced pressor responsiveness to vasopressors persisted. Clonidine treatment prevented the further decline in mean arterial pressure, substantially reduced heart rate and renal sympathetic nerve activity and restored pressor responsiveness to both phenylephrine and angiotensin II toward preseptic levels. Administration of clonidine during hypotensive sepsis reduced renal sympathetic nerve activity, restored vascular sensitivity to both phenylephrine and angiotensin II, and resulted in better preservation of arterial pressure. Considering these findings, a clinical trial for the use of clonidine in the treatment of persistent vasopressor-refractory hypotension in patients with septic shock would be worthwhile.

Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure.

The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (Rictor(aP2KO)) mice generated using adipocyte protein-2 gene promoter-driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in Rictor(aP2KO) mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of Rictor(aP2KO) mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity.

Abstract 210: A Phase I Clinical Trial of Sildenafil for the Treatment of Cerebral Vasospasm Following Subarachnoid Hemorrhage

Introduction: Animal studies have indicated that phosophodiesterase V (PDE-V) inhibition reduces cerebral vasospasm and improves outcomes following subarachnoid hemorrhage (SAH). Hypothesis: We hypothesize that sildenafil (an FDA-approved PDE-V inhibitor) is safe when given to patients with aneurysmal SAH and improves cerebral vasospasm. Methods: A prospective, non-randomized proof-of-principle trial using a two-phase dose escalation scheme was implemented. Patients with SAH underwent day-7 screening angiography to assess for vasospasm. In phase I, those with moderate to severe vasospasm were given 10mg (low dose) of intravenous sildenafil, followed by repeat angiography 30 mins after infusion. In phase II, patients with any degree of vasospasm were given 30mg (high dose) of sildenafil, followed by repeat angiography. Safety was assessed by analyzing vital signs, intracranial pressure (ICP) monitoring neurological status, and observing for the development of adverse reactions attributable to sildenafil. Two blinded reviewers compared pre- and post-sildenafil angiographic images to admission angiography and subjectively graded them as “improvement” or “no improvement” in vasospasm. Unblinded quantitative measurements of vessel diameter change were also made between pre- and post-sildenafil angiograms. Results: Eleven of 23 patients enrolled had vasospasm, received sildenafil and underwent repeat angiography (5 received the 10mg dose and 6 the 30mg dose). There were no adverse effects upon heart rate, ICP, or neurologic status. Sildenafil infusion did result in a transient decline in mean arterial pressure (MAP). With the low dose there was a 16% decline in MAP with an average time to return to baseline of 16 mins. For the high dose the decline was 19% with an average of 33 mins to return to baseline. Seven of 11 (64%) had angiographic improvement in vasospasm, with 3 of 5 (60%) from the low dose group and 4 of 6 (67%) from the high dose group. The average vessel dilatation in responders was 1.25 mm. Conclusions: Sildenafil is safe and well tolerated when given for the acute treatment of SAH-related cerebral vasospasm. These findings provide preliminary evidence that angiograpic vasospasm is improved in select patients following sildenafil infusion.

Mathematical Modeling of Thermal and Circulatory Effects During Hemodialysis

Intradialytic hypotension (IDH) is one of the most common complications of hemodialysis (HD) treatment. The initiating factor of IDH is a decrease in blood volume, which is related to an imbalance between ultrafiltration (UF) and refilling rate. Impaired reactivity of resistance and capacitance vessels in reaction to hypovolemia plays possibly a major role in the occurrence of IDH. These vessels also fulfill an important function in body temperature regulation. UF-induced cutaneous vasoconstriction would result in a reduced surface heat loss and an increase in core temperature. To release body heat, skin blood flow is increased at a later stage of the HD treatment, whereby possibly IDH can occur. The aim of the study is to develop a mathematical model that can provide insight into the impact of thermoregulatory processes on the cardiovascular (CV) system during HD treatment. The mathematical procedure has been created by coupling a thermo-physiological model with a CV model to study regulation mechanisms in the human body during HD + UF. Model simulations for isothermal versus thermoneutral HD + UF were compared with measurement data of patients on chronic intermittent HD (n = 13). Core temperature during simulated HD + UF sessions increased within the range of measurement data (0.23°C vs. 0.32 ± 0.41°C). The model showed a decline in mean arterial pressure of -7% for thermoneutral HD + UF versus -4% for isothermal HD + UF after 200 min during which relative blood volume changed by -13%. In conclusion, simulation results of the combined model show possibilities for predicting circulatory and thermal responses during HD + UF.

TNF-α blockade improves early post-resuscitation survival and hemodynamics in a swine model of ischemic ventricular fibrillation

Aim of the studyInflammatory cytokines have been implicated in the pathophysiology of post cardiac arrest syndrome, including myocardial dysfunction and hypotension, often leading to multi-organ system dysfunction and death. We hypothesized that administration of infliximab after return of spontaneous circulation (ROSC) would ameliorate hypotension and myocardial dysfunction and prolong survival. MethodsDomestic swine were anesthetized and instrumented. Balloon occlusion of the LAD coronary artery just distal to the first septal perforator was performed and VF followed spontaneously in all animals. After 7min, chest compressions, defibrillation, and standard ACLS resuscitation was performed. Animals achieving ROSC (N=32) were randomized to receive infliximab (5mg/kg, n=16) or vehicle (250mL normal saline, n=16) immediately post-ROSC and survival and hemodynamics were monitored for 3h. ResultsThere were no differences in prearrest hemodynamic variables, TNF-α levels, or resuscitation variables between groups. Both groups demonstrated a time dependent decline in mean arterial pressure (MAP) and stroke work (SW) post-ROSC with a nadir at 1h followed by recovery over hours 2 and 3. This decline was blunted in infliximab-treated swine (1-h between group difference in MAP 21mm Hg, 95% CI 3–38mm Hg and SW 6.7gm-m, 95% CI 0.4–13 at 1h). Left ventricular systolic dp/dt fell in the vehicle group (−437mm Hg/s, 95% CI −183 to −690) but did not in the infliximab group. Tau rose only in the vehicle group (44ms, 95% CI 1–87). Short-term survival was higher in the infliximab group (Kaplan–Meier p=0.022). ConclusionsBlockade of TNF-α in the immediate post-ROSC period improved survival and hemodynamic parameters in this swine model of ischemic VF.