Acute Hypotension Research Articles

Dynamic changes in the relationship of microglia to cardiovascular neurons in response to increases and decreases in blood pressure

Microglia are present throughout the central nervous system (CNS) and express receptors for every known neurotransmitter. During inflammation, microglia change into a state that either promotes removal of debris (M1), or into a state that promotes soothing (M2). Caudal- and rostral- ventrolateral medullary regions (CVLM and RVLM, respectively) of the brainstem are key nuclei involved in all aspects of the cardiovascular system. In this study, we investigate a novel role for microglia in cardiovascular control in the brainstem of adult male Sprague–Dawley (SD) rat. Here we show, that increases and decreases in blood pressure (BP) triggers alertness in the physiology of microglia in the brainstem region; inducing changes in microglial spatial distribution and the number of synapses in contact with microglial end processes. Following 6h of acute hypertension, the number of synapses in contact with microglia increased by ≈30% in both regions of the brainstem, CVLM and RVLM. Induction of acute hypotension for 6h causes microglia to reduce the number of synaptic contacts by >20% in both, CVLM and RVLM, nuclei of the brainstem. Our analysis of the morphological characteristics of microglia, and expression levels of M1 and M2, reveals that the changes induced in microglial behavior do not require any obvious dramatic changes in their morphology. Taken together, our findings suggest that microglia play a novel, unexpected, physiological role in the uninjured autonomic nuclei of CNS; we therefore speculate that microglia act cooperatively with brainstem cardiovascular neurons to maintain them in a physiologically receptive state.

Pediatric sports-related traumatic brain injury in United States trauma centers.

OBJECTIVE Traumatic brain injury (TBI) in children is a significant public health concern estimated to result in over 500,000 emergency department (ED) visits and more than 60,000 hospitalizations in the United States annually. Sports activities are one important mechanism leading to pediatric TBI. In this study, the authors characterize the demographics of sports-related TBI in the pediatric population and identify predictors of prolonged hospitalization and of increased morbidity and mortality rates. METHODS Utilizing the National Sample Program of the National Trauma Data Bank (NTDB), the authors retrospectively analyzed sports-related TBI data from children (age 0-17 years) across 5 sports categories: fall or interpersonal contact (FIC), roller sports, skiing/snowboarding, equestrian sports, and aquatic sports. Multivariable regression analysis was used to identify predictors of prolonged length of stay (LOS) in the hospital or intensive care unit (ICU), medical complications, inpatient mortality rates, and hospital discharge disposition. Statistical significance was assessed at α < 0.05, and the Bonferroni correction (set at significance threshold p = 0.01) for multiple comparisons was applied in each outcome analysis. RESULTS From 2003 to 2012, in total 3046 pediatric sports-related TBIs were recorded in the NTDB, and these injuries represented 11,614 incidents nationally after sample weighting. Fall or interpersonal contact events were the greatest contributors to sports-related TBI (47.4%). Mild TBI represented 87.1% of the injuries overall. Mean (± SEM) LOSs in the hospital and ICU were 2.68 ± 0.07 days and 2.73 ± 0.12 days, respectively. The overall mortality rate was 0.8%, and the prevalence of medical complications was 2.1% across all patients. Severities of head and extracranial injuries were significant predictors of prolonged hospital and ICU LOSs, medical complications, failure to discharge to home, and death. Hypotension on admission to the ED was a significant predictor of failure to discharge to home (OR 0.05, 95% CI 0.03-0.07, p < 0.001). Traumatic brain injury incurred during roller sports was independently associated with prolonged hospital LOS compared with FIC events (mean increase 0.54 ± 0.15 days, p < 0.001). CONCLUSIONS In pediatric sports-related TBI, the severities of head and extracranial traumas are important predictors of patients developing acute medical complications, prolonged hospital and ICU LOSs, in-hospital mortality rates, and failure to discharge to home. Acute hypotension after a TBI event decreases the probability of successful discharge to home. Increasing TBI awareness and use of head-protective gear, particularly in high-velocity sports in older age groups, is necessary to prevent pediatric sports-related TBI or to improve outcomes after a TBI.

Vasovagal-related stress immediately before FDG injection may increase bilateral adrenal FDG uptake.

To evaluate the relationship between vasovagal-related stress on positron emission tomography (PET)/CT and adrenal fludeoxyglucose (FDG) uptake. We reviewed the medical records of 1358 consecutive patients who underwent FDG PET/CT examinations and selected those who presented with vasovagal-related symptoms and acute hypotension immediately before FDG injection (vasovagal reflex group). Patients who underwent FDG PET/CT examinations on the same days as the vasovagal reflex group without new complaints or any adrenal lesion were used as controls. We evaluated adrenal FDG uptake visually and by means of adrenal maximum standardized uptake value (SUV(max)) and adrenal/liver (A/L) SUV(max) ratio. Next, we reviewed the FDG PET/CT images of the same 1358 patients and selected the cases presenting with bilateral avid FDG uptake. 4 patients were included in the vasovagal reflex group, and all of them showed bilateral avid adrenal FDG uptake visually, while 19 patients in the control group did not. The mean adrenal SUV(max) and the mean A/L SUV(max) ratio were significantly higher in the vasovagal reflex group than in the control group (p < 0.001). 10 (0.74%) patients, including 4 patients from the vasovagal reflex group, showed bilateral avid FDG uptake with normal adrenal configuration on CT. Vasovagal-related stress immediately before FDG injection may increase bilateral adrenal FDG uptake. Vasovagal-related stress may be included in the differential diagnosis of the cause of bilateral avid adrenal FDG uptake.

METHOD FOR PREDICTING OF ACUTE HYPOTENSIVE EPISODES

Hypotension is type of secondary insult and it is related to poor outcome. The ability to predict adverse hypotensive events, where a patient’s arterial blood pressure drops to abnormally low levels, would be of major benefit to the fields of primary and secondary health care. The aim of the paper is to present the novel method for predicting of acute hypotensive episodes, based on ECG analysis by the complex system theory approach. 45 patients (in four neurointensive care facilities throughout Europe) data were selected for the analysis. 11 patients had EUSIG-defined hypotensive events. The method includes determining of time varying biomarkers corresponding to plurality of physiological processes in patient’s organism as a non-linear dynamic complex system and generating an acute hypotension prediction classifier. The calculations of biomarkers are based on complex system approach and algebraic matrix analysis of ECG parameters. The classifier is based on the comparison of biomarkers behaviour in 3D images. It is demonstrated that the presented method allows us to predict arterial hypotension events 40-50 minutes ahead with a sensitivity of 81 %, specificity 94 %. This result was obtained from prospective real-time data collection in a live clinical intensive care environment.

Case File: Shocking out with severe hypoxia

Clinical Vignette: 36 year old presented in acute respiratory distress, hypotension (BP 70/40 with HR 120), and severe hypoxia (SpO2 80s with partial rebreather). Thoracic auscultation was normal though the heart sounds were masked by her breath sounds. The jugular venous pulse (JVP) was grossly distended with no leg edema.

Factors associated with maternal death in an intensive care unit.

ObjectiveTo identify factors associated with maternal death in patients admitted to an intensive care unit.MethodsA cross-sectional study was conducted in a maternal intensive care unit. All medical records of patients admitted from January 2012 to December 2014 were reviewed. Pregnant and puerperal women were included; those with diagnoses of hydatidiform mole, ectopic pregnancy, or anembryonic pregnancy were excluded, as were patients admitted for non-obstetrical reasons. Death and hospital discharge were the outcomes subjected to comparative analysis.ResultsA total of 373 patients aged 13 to 45 years were included. The causes for admission to the intensive care unit were hypertensive disorders of pregnancy, followed by heart disease, respiratory failure, and sepsis; complications included acute kidney injury (24.1%), hypotension (15.5%), bleeding (10.2%), and sepsis (6.7%). A total of 28 patients died (7.5%). Causes of death were hemorrhagic shock, multiple organ failure, respiratory failure, and sepsis. The independent risk factors associated with death were acute kidney injury (odds ratio [OR] = 6.77), hypotension (OR = 15.08), and respiratory failure (OR = 3.65).ConclusionThe frequency of deaths was low. Acute kidney injury, hypotension, and respiratory insufficiency were independent risk factors for maternal death.

Stunned Myocardium due to Decompensation from Hypovolemic Shock in a Pregnant Woman with Uterine Atony Following Cesarean Section

Transient post ischemic left ventricular dysfunction has been called stunned myocardium. The stunned myocardium can lead cardiac problems such as arrhythmias, left ventricular dysfunction, and a myocardial infarction. Stunned myocardium is a reversible condition. In this case, a 25 year old female patient with a history of mild intermittent asthma became hypovolemic and got into shock after developing uterine atony following a cesarean section. The patient did not respond to rapid volume replacement therapy. Subsequently, the patient had acute pulmonary edema, hypotension, and tachycardia developed. Echocardiogram was done showing severe left ventricular dysfunction (ejection fraction (EF), 25-35%) with left inferobasal wall hypokinesis and no right ventricular dysfunction or severe tricuspid regurgitation or right ventricular hypertrophy. Chest x-ray showed newly diagnosed cardiomegaly and bilateral pulmonary congestion. Initial troponin I was elevated, however, the level of troponin I remained stable with the same baseline value. Patient was at high risk for pulmonary embolism (PE) based on risk assessment, therefore, anticoagulation was started. Chest CT for pulmonary embolism was performed, and the result was negative. Two days after, repeated echocardiogram showed improved EF was 35%. Patient was discharged with beta –blocker to reduce oxygen demand of myocardium. This case supports hypovolemic shock not responding to volume replacement therapy can cause myocardium damage which is able to be diagnosed with stunned myocardium.

Subarachnoid Hemorrhage-Triggered Acute Hypotension Is Associated with Left Ventricular Cardiomyocyte Apoptosis in a Rat Model.

Whether hypotension that occurs due to neurogenic stunned myocardium after subarachnoid hemorrhage (SAH) is associated with cardiomyocyte apoptotic cell death remains unknown. In this study, 18 male rats were subjected to sham or the endovascular perforation model of SAH surgery. Based on the mean arterial pressure (MAP) after SAH, rats were separated into SAH with hypotension (SAH hypotension) or SAH with blood pressure preservation (SAH BP preservation) groups. All animals were euthanized 2 h after the surgical procedure. Hearts were removed and separated transversely into base and apex parts, then Western blot analyses and immunohistochemistry were performed only in the apex part. One rat died as a result of severe SAH and two rats with mild SAH were excluded. We analyzed data from 15 rats that were divided into three groups: sham, SAH hypotension, and SAH BP preservation (n = 5, each). There was a significantly higher cleaved caspase-3/caspase-3 ratio in the SAH hypotension group compared with sham and the SAH BP preservation group. Cardiomyocyte apoptosis was demonstrated in the SAH rats. This is the first experimental report that describes SAH-induced neurogenic stunned myocardium with ensuing hypotension may result from the acute apoptotic cardiomyocyte cell death in the left ventricle.

Risk of ischemic stroke during the initiation period of α-blocker therapy among older men.

Alpha-blockers are notorious for their first-dose effect of acute hypotension during the early initiation period. Because acute cerebral hypoperfusion may precipitate an episode of ischemic stroke, we aimed to provide a quantitative estimate of the risk of ischemic stroke during the early initiation period of α-blocker therapy, using a self-controlled case series design. We identified all men aged 50 years or more as of 2007 who were incident users of α-blockers and had a diagnosis of ischemic stroke during the 2007-2009 study period using claims data from Taiwan's National Health Insurance claims database. The first day on which the α-blocker was prescribed was the index date. We partitioned different risk periods according to their relationship to the index date (pre-exposure risk periods 1 and 2 = ≤ 21 d and 22-60 d before index date, respectively; post-exposure risk periods 1 and 2 = ≤ 21 d and 22-60 d after index date, respectively); the remainder of the study period was defined as the unexposed period. We estimated the incidence rate ratio (IRR) of ischemic stroke in each risk period relative to the unexposed period using a conditional Poisson regression model. A total of 7502 men were included. Compared with the risk in the unexposed period, the risk of ischemic stroke was increased in post-exposure risk period 1 among all patients in the study population (adjusted IRR 1.40, 95% confidence interval [CI], 1.22-1.61) and among patients without concomitant prescriptions for other antihypertensive agents (adjusted IRR 2.11, 95% CI 1.73-2.57). Alpha-blocker therapy was associated with an increased risk of ischemic stroke during the early initiation period, especially among patients who were not taking other antihypertensive agents.

Amniotic fluid embolism: an Australian-New Zealand population-based study.

BackgroundAmniotic fluid embolism (AFE) is a major cause of direct maternal mortality in Australia and New Zealand. There has been no national population study of AFE in either country. The aim of this study was to estimate the incidence of amniotic fluid embolism in Australia and New Zealand and to describe risk factors, management, and perinatal outcomes.MethodsA population-based descriptive study using the Australasian Maternity Outcomes Surveillance System (AMOSS) carried out in 263 eligible sites (>50 births per year) covering an estimated 96 % of women giving birth in Australia and all 24 New Zealand maternity units (100 % of women giving birth in hospitals) between January 1 2010-December 31 2011. A case of AFE was defined either as a clinical diagnosis (acute hypotension or cardiac arrest, acute hypoxia and coagulopathy in the absence of any other potential explanation for the symptoms and signs observed) or as a post mortem diagnosis (presence of fetal squames/debris in the pulmonary circulation).ResultsThirty-three cases of AFE were reported from an estimated cohort of 613,731women giving birth, with an estimated incidence of 5.4 cases per 100 000 women giving birth (95 % CI 3.5 to 7.2 per 100 000). Two (6 %) events occurred at home whilst 46 % (n = 15) occurred in the birth suite and 46 % (n = 15) in the operating theatre (location not reported in one case). Fourteen women (42 %) underwent either an induction or augmentation of labour and 22 (67 %) underwent a caesarean section. Eight women (24 %) conceived using assisted reproduction technology.Thirteen (42 %) women required cardiopulmonary resuscitation, 18 % (n = 6) had a hysterectomy and 85 % (n = 28) received a transfusion of blood or blood products. Twenty (61 %) were admitted to an Intensive Care Unit (ICU), eight (24 %) were admitted to a High Dependency Unit (HDU) and seven (21 %) were transferred to another hospital for further management. Five woman died (case fatality rate 15 %) giving an estimated maternal mortality rate due to AFE of 0.8 per 100 000 women giving birth (95 % CI 0.1 % to 1.5 %). There were two deaths among 36 infants.ConclusionsA coordinated emergency response requiring resource intense multi-disciplinary input is required in the management of women with AFE. Although the case fatality rate is lower than in previously published studies, high rates of hysterectomy, resuscitation, and admission to higher care settings reflect the significant morbidity associated with AFE. Active, ongoing surveillance to document the risk factors and short and long-term outcomes of women and their babies following AFE may be helpful to guide best practice, management, counselling and service planning. A potential link between AFE and assisted reproductive technology warrants further investigation.

Flubromazolam – A new life-threatening designer benzodiazepine

Context: In addition to designer benzodiazepines such as etizolam, deschloroetizolam, pyrazolam, diclazepam, nifoxipam, or clonazolam, a new psychoactive substance like flubromazolam, triazole of flubromazepam has become available. Flubromazolam is currently not marketed as a medication but rather as a research chemical and recreational drug. It mostly causes sedative effects but also has moderate anti-anxiety and muscle relaxant effects. A case of a severe intoxication of flubromazolam has been reported. Case details: A 27-year-old man, presented with deep coma, bilateral pinpoint unreactive pupils, acute respiratory failure and hypotension, complicated by hypoxic ischemic changes in the central nervous system. A positive result of a urine screening test confirmed the presence of benzodiazepines, which resulted in administration of flumazenil and improved patient consciousness. Quantitative method of liquid chromatography indicated flubromazolam in the patient’s serum at 59 ng/mL and urine at 105 ng/mL about 19 h after ingestion of 3 mg dose. On admission, serum creatine kinase was 15 960 U/L. The patient was treated with mechanical ventilation, intravenous fluids, flumazenil and continuous infusion of norepinephrine at a dose of 0.12 µg/kg/min. The patient survived and on the ninth day of hospitalization he was transferred to the Department of Neurology. Discussion: Flubromazolam is a new designer drug. Recreational use may be a cause of prolonged, severe intoxication associated with coma, hypotension, and rhabdomyolysis.

Amlodipine and clarithromycin co-prescription.

Dear Editor Concerns have recently been raised about the concomitant use of calcium-channel blockers and macrolide antibiotics, particularly clarithromycin. Two recent cases of deliberate amlodipine overdose, complicated by community-acquired pneumonia, managed on our intensive care unit have highlighted to us this significant, potential drug interaction. Both received benzyl penicillin and clarithromycin as per hospital protocol alongside organ support in the form of inotropes. One patient required positive pressure ventilation, and both showed evidence of hepatic and renal dysfunction, one requiring haemofiltration. Clarithromycin is a potent liver enzyme inhibitor and thus potentiates the action of amlodipine. An increased risk of acute kidney injury, hypotension and all-cause mortality amongst patients in whom these drugs are co-prescribed has been suggested. This is surely all the more concerning in cases of amlodipine overdose, particularly in the context of hepatorenal injury. Hospital protocols promote the routine use of clarithromycin in the treatment of community-acquired pneumonia, and dosing regimes of other drugs with the potential for interaction such as warfarin are judiciously adjusted. In our experience, clinicians and pharmacists often neglect amlodipine when considering these potentially deleterious interactions. We feel more needs to be done to raise awareness of this important patient safety issue.

Intramural Colonic Hematoma

Introduction: Intramural colonic hematomas are extremely rare, accounting for 5% of all intramural hematomas, and are usually found after acute trauma or in the setting of bleeding diatheses. Spontaneous intestinal intramural hematomas in patients on oral anticoagulant therapy occur in 1/2500 patients. We report here a rare and dramatic case of an intramural colonic hematoma in an 89-year-old male taking anti-platelet agents with a colonic hematoma. Case Report: An 89-year-old male with history notable for ischemic cardiomyopathy (on aspirin and Clopidogrel) and chronic constipation presented to the hospital with urosepsis. His hospital course was complicated by 3 episodes of bright red blood per rectum and hypotension. He had no history of past gastrointestinal hemorrhage or abdominal trauma. He had a remote history of subtotal colectomy for colonic volvulus. He had never undergone any prior endoscopic evaluation. His physical exam was notable for moderate cachexia and a normal abdomen. There was bright red blood within the vault and external hemorrhoids, but no rectal mass. His hematocrit was 39.0% and INR was 1.1. Colonoscopy revealed a 19 cm intra-colonic hematoma extending to the recto-sigmoid junction (Fig. 1) with near complete obstruction. Computed tomography revealed the hematoma to be 8.0 cm x 8.8 cm in crosssection (Fig. 2). There was no intra-abdominal blood. The patient was successfully managed conservatively with a titrated bowel regimen and cessation of Clopidogrel. There was no evidence of colonic ischemia or recurrent bleeding.Figure 1Figure 2Discussion: We present here a rare case of an intramural colonic hematoma in the setting of anti-platelet agents. Although there was no obvious abdominal trauma, it is possible that increased intra-abdominal pressure due to constipation played an etiologic role. Intramural colonic hematomas should be considered in patients presenting with acute hypotension in setting of a bleeding diathesis, abdominal pain, and an acute drop in hematocrit, particularly when no gross GI bleeding is present. Our patient is unusual because he had no abdominal pain and exhibited rectal bleeding. The latter was a result of the hematoma tearing into the colonic lumen. Rare potential complications include obstruction and ischemia. Intracolonic hematomas are most often managed conservatively but may require surgical management in the setting of ischemia.

Pulse detection with a single accelerometer placed at the carotid artery: Performance in a real-life diagnostic test during acute hypotension.

Pulse detection via palpation is a basic and essential procedure in daily medical practice. We have been investigating the performance of a single accelerometer placed above the carotid artery, which is one of the recommended locations for manual palpation. A low-cost sensor attached by an adhesive measures accelerations due to carotid dilatations and whole body vibrations. A real-time demonstrator has been developed to classify 10 second- windows in "Pulse", "Motion" and "No Pulse" and to infer pulse rate. Data were obtained during a scheduled head-up tilt table test (HUTT). Our results show for a subgroup of 10 patients with acute hypotension a wide spread of "good" signal coverage ranging from as low as 37% up to 100%. Key factors compromising the performance in HUTT are motion artifacts, arrhythmias, sensor placement and sensor-skin coupling. In conclusion, pulse detection with a single accelerometer is sufficiently accurate, if good signal coverage can be achieved.

Pulmonary edema and acute respiratory distress syndrome in a child with Plasmodium falciparum malaria

We report the case of a 12-year-old girl who had returned to the UK from Nigeria two days prior to presenting with fever and breathing difficulties. She had high-grade pyrexia, was mildly dehydrated and lethargic but there were no abnormal findings on auscultation. Initially she required 5l/min of oxygen to maintain adequate oxygenation. The chest X-ray showed bilateral shadowing consistent with pulmonary edema and early acute respiratory distress syndrome (ARDS). The patient was admitted to pediatric intensive care unit and intubated six hours later due to increasing oxygen requirement and deteriorating level of consciousness. Thin blood films revealed Plasmodium falciparum infection with high-grade parasitemia (13%). The girl was commenced on intravenous quinine. No further complications were observed, apart from mild renal impairment. She made a remarkable recovery, was extubated after four days of ventilation and discharged without residual problems five days later. Lung function tests at follow up revealed no abnormalities. Acute lung injury (ALI) secondary to P. falciparum malaria, which includes pulmonary edema and ARDS at the severe end of the spectrum, is not uncommon in adults, and has been reported to occur in up to 30% of malaria patients who require admission to the intensive care unit. In contrast, ALI is a relatively rare complication in pediatric patients. Many of these patients with ALI simultaneously develop other complications of malaria including acute renal failure, hypotension and cerebral malaria. Adult studies have reported overall mortality rates of approximately 50% in patients with ALI secondary to malaria; however, the majority of survivors have no long-term respiratory sequelae.

The effect of an acute increase in central blood volume on the response of cerebral blood flow to acute hypotension.

The purpose of the present study was to examine whether the response of cerebral blood flow to an acute change in perfusion pressure is modified by an acute increase in central blood volume. Nine young, healthy subjects voluntarily participated in this study. To measure dynamic cerebral autoregulation during normocapnic and hypercapnic (5%) conditions, the change in middle cerebral artery mean blood flow velocity was analyzed during acute hypotension caused by two methods: 1) thigh-cuff occlusion release (without change in central blood volume); and 2) during the recovery phase immediately following release of lower body negative pressure (LBNP; -50 mmHg) that initiated an acute increase in central blood volume. In the thigh-cuff occlusion release protocol, as expected, hypercapnia decreased the rate of regulation, as an index of dynamic cerebral autoregulation (0.236 ± 0.018 and 0.167 ± 0.025 s(-1), P = 0.024). Compared with the cuff-occlusion release, the acute increase in central blood volume (relative to the LBNP condition) with LBNP release attenuated dynamic cerebral autoregulation (P = 0.009). Therefore, the hypercapnia-induced attenuation of dynamic cerebral autoregulation was not observed in the LBNP release protocol (P = 0.574). These findings suggest that an acute change in systemic blood distribution modifies dynamic cerebral autoregulation during acute hypotension.

Hypotension Risk Prediction via Sequential Contrast Patterns of ICU Blood Pressure.

Acute hypotension is a significant risk factor for in-hospital mortality at intensive care units. Prolonged hypotension can cause tissue hypoperfusion, leading to cellular dysfunction and severe injuries to multiple organs. Prompt medical interventions are thus extremely important for dealing with acute hypotensive episodes (AHE). Population level prognostic scoring systems for risk stratification of patients are suboptimal in such scenarios. However, the design of an efficient risk prediction system can significantly help in the identification of critical care patients, who are at risk of developing an AHE within a future time span. Toward this objective, a pattern mining algorithm is employed to extract informative sequential contrast patterns from hemodynamic data, for the prediction of hypotensive episodes. The hypotensive and normotensive patient groups are extracted from the MIMIC-II critical care research database, following an appropriate clinical inclusion criteria. The proposed method consists of a data preprocessing step to convert the blood pressure time series into symbolic sequences, using a symbolic aggregate approximation algorithm. Then, distinguishing subsequences are identified using the sequential contrast mining algorithm. These subsequences are used to predict the occurrence of an AHE in a future time window separated by a user-defined gap interval. Results indicate that the method performs well in terms of the prediction performance as well as in the generation of sequential patterns of clinical significance. Hence, the novelty of sequential patterns is in their usefulness as potential physiological biomarkers for building optimal patient risk stratification systems and for further clinical investigation of interesting patterns in critical care patients.

Dual renin-angiotensin system blockade and outcome benefits in hypertension: a narrative review.

Inhibition of the renin-angiotensin system (RASi) lowers blood pressure, reduces cardiovascular outcomes and blunts the progressive course of heart failure and of chronic kidney disease. This narrative article summarizes why the hypothesis came up that more complete RASi with two different agents should be more beneficial compared with one agent and how this hypothesis was deflated in randomized clinical trials (RCTs). The hypothesis was based on experimental findings and surrogate endpoints in patients, namely lowering of blood pressure and reduction of proteinuria. Three large RCTs in patients with atherosclerotic vascular disease or in diabetic kidney disease randomized almost 40, 000 patients. RASi with one agent was compared with RASi with two agents. All three RCTs ruled out benefits of dual RASi on major cardiovascular outcomes and reported substantial adverse effects of dual RASi. The latter included hyperkalemia, acute kidney injury, symptomatic hypotension and syncope. There was also no substantial advantage of dual over monotherapy on decline in kidney function. In one RCT, there was a hint of nonsustained, early benefit on kidney outcomes with dual therapy. Outside heart failure, RASi with two agents is not indicated to treat hypertension because of substantial safety concerns and lack of benefit on major cardiovascular and kidney outcomes.

The Effect Of An Acute Increase In Central Blood Volume On Dynamic Cerebral Autoregulation

Previous investigations demonstrated that cerebral blood flow was influenced by changes in central blood volume and arterial blood pressure even within the range of cerebral autoregulation (60-150 mmHg). Recently, we found that during acute microgravity (parabolic flight condition), the acute increase in central blood volume decreased gradually arterial blood pressure via the arterial and cardiopulmonary baroreflexes. Despite the acute hypotension and central hypervolemia, steady-state cerebral blood flow was well maintained during this condition. However, the dynamic relationship between central blood volume and cerebrovascular control remains unclear. PURPOSE: The purpose of the present study was to examine dynamic cerebral autoregulation during an acute hypotension with central hypervolemia. METHODS: Nine young healthy subjects voluntarily participated in this study. In order to measure dynamic cerebral autoregulation, change in middle cerebral artery mean blood flow velocity (MCA Vmean) was analyzed during acute hypotension caused by two methods: 1) thigh-cuff occlusion release (without change in central blood volume) and 2) lower body negative pressure (-50 mmHg, LBNP) release (with acute increase in central blood volume). RESULTS: As expected, the thigh-cuff occlusion release caused acute hypotension and decrease in MCA Vmean accordingly, but MCA Vmean returned to the baseline value quickly. LBNP release increased and then decreased arterial blood pressure acutely. During the phase of decreased arterial blood pressure, however, the rate of regulation, as an index of dynamic cerebral autoregulation during LBNP release, was significantly lower than that during cuff release (0.112 ± 0.116 and 0.236 ± 0.053 sec-1, respectively, P=0.030). CONCLUSIONS: These findings suggest that an acute change in central blood volume modifies dynamic cerebral autoregulation.

The effect of an acute increase in central blood volume on hypercapnia‐induced attenuation in dynamic cerebral autoregulation

It is well established that hypercapnia attenuates dynamic cerebral autoregulation. The impact of central blood volume on cerebral blood flow is controversial. The purpose of the present study was to examine whether hypercapnia‐induced attenuation in dynamic cerebral autoregulation is modified by acute central hypervolemia. Nine young healthy subjects voluntarily participated in this study. In order to measure dynamic cerebral autoregulation during normocapnic and hypercapnic (5%) conditions, the change in middle cerebral artery mean blood flow velocity (MCA Vmean) was analyzed during acute hypotension caused by two methods: 1) thigh‐cuff occlusion release (without change in central blood volume) and 2) lower body negative pressure (‐50 mmHg, LBNP) release (with acute increase in central blood volume). As expected, hypercapnia decreased the rate of regulation, as an index of dynamic cerebral autoregulation (0.236±0.053 and 0.167±0.074 sec‐1, respectively, P=0.025). In contrast, this attenuation was disappeared during central hypervolemia (P=0.574). This phenomenon may be associated with hypervolemia‐induced attenuation of dynamic cerebral autoregulation (P=0.009). These findings suggest that an acute change in central blood volume modifies carbon dioxide‐induced changes in dynamic cerebral autoregulation.