Perfusion Research Articles

Clinical, sonographic and molecular changes in calcific tendinitis of the shoulder following extracorporeal shockwave therapy: a prospective case-control study.

Extracorporeal shockwave therapy (ESWT) is the primary treatment for calcific tendinitis of the shoulders, but what are the effects of clinical, sonographic, and molecular markers following ESWT in treating calcific tendinitis of the shoulder? Twenty-eight patients were categorized into radiodense and radiolucent subgroups. In addition, clinical assessments included the visual analogue scale (VAS), Constant-Murley (CM) score, American Shoulder and Elbow Surgeon (ASES) score, sonographic evaluation, and serum enzyme-linked immunosorbent assay (ELISA). The participants completed a one-year follow-up. All data were collected before and after treatment. After one year of follow-up, all patients showed notable improvement in VAS, CM, and ASES scores, with no significant clinical variations among the subgroups. However, the radiolucent group showed significant complete resorption and size reduction at the final follow-up. Sonographic evaluation revealed improved tissue perfusion and reduced calcification from 3 to 12 months in all patients, including those in the radiolucent group, but complete resorption of calcific deposits did not occur. The percentage of tissue perfusion was improved at 1 and 3 months after ESWT. There were no significant differences in the levels of the molecular markers interleukin-1 beta (IL-1 β) or IL-33, but the level of insulin-like growth factor 1 (IGF-1) was notably increased at 1 and 3 months post-ESWT. The BMP7 level was increased at 3 months and was then decreased significantly at 6 and 12 months. ESWT improved symptoms, reduced calcification, enhanced tissue perfusion, and promoted angiogenesis and BMP7 activity. In particular, it benefited radiolucent type patients with better calcification resorption. Partial resorption led to improvements in transparency, and a second ESWT session at 3 months was recommended for optimal results.

Veno-venous extracorporeal membrane oxygenation-assisted treatment of severe airway stenosis due to goiter: Two case reports.

Extracorporeal membrane oxygenation (ECMO) is a critical care intervention that acts as a temporary substitute for the heart and lungs, facilitating adequate tissue perfusion and gas exchange. The 2 primary configurations, veno-arterial and veno-venous ECMO, are tailored to support either the heart and lungs or the lungs alone, respectively. The case report details patients with tumor-induced airway stenosis who encountered limitations with standard treatments, which were either insufficient or carried the risk of severe complications such as hypoxia and asphyxia. Patients were diagnosed with severe airway stenosis caused by goiter, a condition that required innovative treatment approaches to prevent complications during the management process. Veno-venous ECMO was implemented as a bridging therapy to provide vital respiratory support during the tumor resection procedure. This intervention was crucial in reducing the risks associated with airway edema or tumor rupture. With the use of veno-venous ECMO, the patients successfully underwent tumor resection. They were subsequently weaned off the ECMO support, and after a course of treatment, they were discharged in good condition. The case demonstrates the efficacy of veno-venous ECMO as a bridging therapy for managing severe airway stenosis caused by goiter. Its use facilitated the successful resection of tumors and led to positive patient outcomes, highlighting its potential as a valuable treatment option in similar scenarios.

Peculiarities of cerebral blood flow and vascular reactivity in patients with large and giant tumors of the cerebello-pontine angle

Background. Vestibular schwannomas and posterior fossa meningiomas are one of the most difficult tumors for surgical treatment. The mortality rate after their removal reaches 13,5 %. The main causes of death are hemorrhagic and ischemic complications. There are no studies in the literature on tissue perfusion of brainstem structures and cerebellum and reactivity of vertebral and basilar arteries in patients with extraaxial tumors of the posterior cranial fossa. Therefore, the study of the blood supply of the brainstem structures and cerebellum, as well as the functional characteristics of the vertebral and basilar arteries in these patients is of considerable interest.Aim. To evaluate tissue perfusion of the pons and cerebellum, as well asthe reactivity of the vertebral and basilar arteries in patients with large and giant vestibular schwannomas and posterior fossa meningiomas.Materials and methods. Eighty-two patients with large and giant extraaxial tumors of the base of the posterior cranial fossa were examined. The median age was 54 [44; 61] years. Vestibular schwannomas were diagnosed in 52.4 % of patients, and meningiomas of the posterior cranial fossa were diagnosed in 47.6 %. All patients underwent duplex scanning of the basilar and vertebral arteries. We evaluated linear blood flow and coefficients of reactivity and index of vasomotor reactivity. We investigated the metabolic reactivity of cerebral blood flow by conducting hyper- and hypocapnic tests. Computed tomography perfusion imaging was performed in 18 patients. We detected cerebral blood volume, cerebral blood flow, mean transit time of contrast agent and time to peak of contrast agent. Measurements were carried out in six regions of interest located symmetrically on the pons and in the white matter of the cerebellar hemispheres on the side of the tumor and on the opposite side.Results. Linear blood flow rates in the intracranial segments of the vertebral and the basilar arteries in patients with tumors were higher than in the comparison group (p<0.05). These patients are characterized by a decrease of reactivity coefficients in the vertebral and basilar arteries, especially when performing hypercapnic tests (p <0.05). Paradoxical reactivity and areactivity were diagnosed in 34.9 % of patients with vestibularschwannomas and 25.6 % with meningiomas. In the pons on the side of the tumor in patients with vestibularschwannomas, a decrease in cerebral blood flow by 19.3 %, an increase in cerebral blood volume by 33.3 % and an increase in mean transit time of contrast agent and in time to peak of contrast agent by 48.1 % and 71.1 % (p <0.05) were found. In patients with meningiomas in the pons on the side of the tumor, all perfusion parameters were higher (p<0.05). In the deep regions of the cerebellar hemisphere on the side of the tumor in patients with tumors, all perfusion parameters were higher compared to the opposite side.Conclusion. The results of the study made it possible to quantify cerebral blood flow in patients with large and giant vestibular schwannomas and meningiomas of the posterior cranial fossa base. The revealed changes indicate the risk of developing pathological vascular reactions and disorders of cerebral blood flow in the postoperative period.

Flap-Based Reconstruction in Patients with Autoimmune Disease: An Institutional Experience with the Deep Inferior Epigastric Perforator Flap and Review of the Literature.

Autoimmune diseases are associated with characteristic chronic inflammation, aberrations in tissue perfusion, and hypercoagulability, and thus have considerable implications for local and free-flap reconstruction. We seek to summarize the current evidence on outcomes of flap-based reconstruction in patients with pre-existing autoimmune disease and present our experience with autologous breast reconstruction in this population. PubMed, Embase, Scopus, Cochrane, and Web of Science were searched for relevant articles, and pertinent data were presented qualitatively. Institutional data were queried for patients who underwent autologous breast reconstruction with deep inferior epigastric perforator (DIEP) flaps between 2015 and 2024. A retrospective review was conducted to identify DIEP patients with a history of autoimmune disease. Data on patient demographics, medication history, flap outcomes, and perioperative complications were collected. The majority of existing studies found no increased independent risk of flap complications. However, other complications, predominantly wound dehiscence, were independently associated with autoimmune disease. Regarding immunosuppressant therapy, the literature demonstrated that perioperative glucocorticoid use was consistently associated with all complications, including seroma, infection, wound disruption, and partial flap loss.Our 13-patient institutional experience identified no cases of total flap loss or microvascular thrombotic complications. There was one case of partial flap necrosis further complicated by abdominal site cellulitis, and one case of recipient-site dehiscence managed with local wound care. No patients required re-operation for flap or donor-site complications. The literature suggests that flap reconstruction can be performed safely in patients with autoimmune conditions, which was also supported by our institutional experience. While there is likely minimal risk of microsurgical complications in the context of free tissue transfer, donor-site morbidity and wound dehiscence remain major concerns for patients with a history of autoimmune disease. Limiting the use of immunosuppressive agents, especially corticosteroids, may potentially improve outcomes of flap reconstruction.

Is time to first CT scan in patients with isolated severe traumatic brain injury prolonged when prehospital arterial cannulation is performed? A retrospective non-inferiority study

BackgroundInvasive blood pressure measurement is the in-hospital gold standard to guide hemodynamic management and consecutively cerebral perfusion pressure in patients with traumatic brain injury (TBI). Its prehospital use is controversial since it may delay further care. The primary aim of this study was to test the hypothesis that patients with severe traumatic brain injury who receive prehospital arterial cannulation, compared to those with in-hospital cannulation, do not have a prolonged time between on-scene arrival and first computed tomography (CT) of the head by more than ten minutes.MethodsThis retrospective study included patients 18 years and older with isolated severe TBI and prehospital induction of emergency anaesthesia who received treatment in the resuscitation room of the University Hospital of Graz between January 1st, 2015, and December 31st, 2022. A Wilcoxon rank-sum test was used to test for non-inferiority (margin = ten minutes) of the time interval between on-scene arrival and first head CT.ResultsWe included data of 181 patients in the final analysis. Prehospital arterial line insertion was performed in 87 patients (48%). Median (25–75th percentile) durations between on-scene arrival and first head CT were 73 (61–92) min for prehospital arterial cannulation and 75 (60–93) min for arterial cannulation in the resuscitation room. Prehospital arterial line insertion was significantly non-inferior within a margin of ten minutes with a median difference of 1 min (95% CI − 6 to 7, p = 0.003).ConclusionTime-interval between on-scene arrival and first head CT in patients with isolated severe traumatic brain injury who received prehospital arterial cannulation was not prolonged compared to those with in-hospital cannulation. This supports early out-of-hospital arterial cannulation performed by experienced providers.

Cerebral physiologic insult burden in acute traumatic neural injury: a Canadian High Resolution-TBI (CAHR-TBI) descriptive analysis

BackgroundOver the recent decades, continuous multi-modal monitoring of cerebral physiology has gained increasing interest for its potential to help minimize secondary brain injury following moderate-to-severe acute traumatic neural injury (also termed traumatic brain injury; TBI). Despite this heightened interest, there has yet to be a comprehensive evaluation of the effects of derangements in multimodal cerebral physiology on global cerebral physiologic insult burden. In this study, we offer a multi-center descriptive analysis of the associations between deranged cerebral physiology and cerebral physiologic insult burden.MethodsUsing data from the Canadian High-Resolution TBI (CAHR-TBI) Research Collaborative, a total of 369 complete patient datasets were acquired for the purposes of this study. For various cerebral physiologic metrics, patients were trichotomized into low, intermediate, and high cohorts based on mean values. Jonckheere–Terpstra testing was then used to assess for directional relationships between these cerebral physiologic metrics and various measures of cerebral physiologic insult burden. Contour plots were then created to illustrate the impact of preserved vs impaired cerebrovascular reactivity on these relationships.ResultsIt was found that elevated intracranial pressure (ICP) was associated with more time spent with cerebral perfusion pressure (CPP) < 60 mmHg and more time with impaired cerebrovascular reactivity. Low CPP was associated with more time spent with ICP > 20 or 22 mmHg and more time spent with impaired cerebrovascular reactivity. Elevated cerebrovascular reactivity indices were associated with more time spent with CPP < 60 mmHg as well as ICP > 20 or 22 mmHg. Low brain tissue oxygenation (PbtO2) only demonstrated a significant association with more time spent with CPP < 60 mmHg. Low regional oxygen saturation (rSO2) failed to produce a statistically significant association with any particular measure of cerebral physiologic insult burden.ConclusionsMean ICP, CPP and, cerebrovascular reactivity values demonstrate statistically significant associations with global cerebral physiologic insult burden; however, it is uncertain whether measures of oxygen delivery provide any significant insight into such insult burden.

Effects of Telmisartan on Intraocular Pressure, Blood Pressure, and Ocular Perfusion Pressure in Normal and Glaucomatous Cats.

To determine the effect of telmisartan on intraocular pressure (IOP), blood pressure (BP), and ocular perfusion pressure (OPP) in normal and glaucomatous cats. A four-week study was conducted in six normal adult cats, followed by a longer six-month study performed in 37 cats with spontaneous glaucoma and 11 age-matched normal cats. Telmisartan (1 mg/kg/day) or placebo-vehicle were administered orally once daily. IOP was measured by rebound tonometry. BP readings were obtained by oscillometric method. OPP was calculated as mean arterial pressure (MAP) - IOP. IOP and BP were obtained three times a week for the first study and weekly for the second study. Baseline IOP was significantly higher, and OPP was significantly lower in glaucomatous cats than in normal cats (P < 0.0001). These differences between glaucomatous and normal cats persisted throughout the study, regardless of treatment (P < 0.001). No significant differences in IOP, BP, or OPP were detected between any study phases in the first, normal feline cohort or between telmisartan- and placebo-treated glaucomatous cats at any timepoint in the second study. Oral telmisartan was well tolerated and did not have a detrimental effect on BP or OPP in cats but did not lower IOP or improve OPP in cats with glaucoma. While showing telmisartan could not be used as a sole therapy for IOP lowering, our data affirmed a lack of detrimental effects of telmisartan on BP and OPP in a translationally-relevant, spontaneous, large animal glaucoma model.

Role of arterial blood glucose and interstitial fluid glucose difference in evaluating microcirculation and clinical prognosis of patients with septic shock: a prospective observational study

BackgroundMicrocirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA−I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock.MethodsThe present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA−I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA−I interval was analyzed.ResultsA total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6–16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9–40), of whom 18 died during ICU stay. The GA−I levels were negative correlation with CRT (r = 0.369, P < 0.001), Lac (r = -0.269, P < 0.001), skin mottling score (r=-0.223, P < 0.001), and were positively associated with urine volume (r = 0.135, P < 0.05). The ICU mortality rate of patients with septic shock presenting GA−I ≤ 0.30 mmol/L and ≥ 2.14 mmol/L was significantly higher than that of patients with GA−I at 0.30–2.14 mmol/L [65.2% vs. 15.0%, odds ratio (OR) = 10.625, 95% confidence interval (CI): 2.355–47.503].ConclusionGA−I was correlated with microcirculation parameters, and with differences in survival. Future studies are needed to further explore the potential impact of GA−I on microcirculation and clinical prognosis of septic shock, and the bedside monitoring of GA−I may be beneficial for clinicians to identify high-risk patients.

GPER Stimulation Attenuates Cardiac Dysfunction in a Rat Model of Preeclampsia.

Preeclampsia poses a substantial clinical challenge, characterized by maternal hypertension, cardiac dysfunction, and persistent cardiovascular risks for both the mother and offspring. Despite the known roles of the estrogen receptor (GPER [G protein-coupled estrogen receptor]) in placental development, its impact on cardiovascular aspects within a preeclampsia animal model remains unexplored. We propose that G-1, a GPER agonist, could have the potential to regulate not only hypertension but also cardiac dysfunction in rats with preeclampsia. To explore the influence of G-1 on preeclampsia, we used the reduced uterine perfusion pressure (RUPP) model. RUPP rats were administered either G-1 (100 µg/kg per day) or hydralazine (25 mg/kg per day). We conducted echocardiography to probe the intricate cardiac effects of G-1. The RUPP rat model revealed signs of hypertension and cardiac dysfunction and alterations in gene and protein expression within placental and heart tissues. G-1 treatment reduced blood pressure and reversed cardiac dysfunction in rats with preeclampsia. In contrast, administration of the vasodilator hydralazine reduced blood pressure without an improvement in cardiac function. In addition, while G-1 treatment restored the levels of sFLT-1 (soluble fms-like tyrosine kinase-1) in RUPP rats, hydralazine did not normalize this antiangiogenic factor. The therapeutic intervention of G-1 significantly mitigated the cardiovascular dysfunction observed in the RUPP rat model of preeclampsia. This discovery underscores the broader significance of understanding GPER's role in the context of preeclampsia-related cardiovascular complications.

Optimal target mean arterial pressure for patients with sepsis-associated encephalopathy: a retrospective cohort study

BackgroundSepsis-associated encephalopathy (SAE) patients often experience changes in intracranial pressure and impaired cerebral autoregulation. Mean arterial pressure (MAP) plays a crucial role in cerebral perfusion pressure, but its relationship with mortality in SAE patients remains unclear. This study aims to investigate the relationship between MAP and the risk of 28-day and in-hospital mortality in SAE patients, providing clinicians with the optimal MAP target.MethodsWe retrospectively collected clinical data of patients diagnosed with SAE on the first day of ICU admission from the MIMIC-IV (v2.2) database. Patients were divided into four groups based on MAP quartiles. Kruskal-Wallis H test and Chi-square test were used to compare clinical characteristics among the groups. Restricted cubic spline and segmented Cox regression models, both unadjusted and adjusted for multiple variables, were employed to elucidate the relationship between MAP and the risk of 28-day and in-hospital mortality in SAE patients and to identify the optimal MAP. Subgroup analyses were conducted to assess the stability of the results.ResultsA total of 3,816 SAE patients were included. The Q1 group had higher rates of acute kidney injury and vasoactive drug use on the first day of ICU admission compared to other groups (P < 0.01). The Q1 and Q4 groups had longer ICU and hospital stays (P < 0.01). The 28-day and in-hospital mortality rates were highest in the Q1 group and lowest in the Q3 group. Multivariable adjustment restricted cubic spline curves indicated a nonlinear relationship between MAP and mortality risk (P for nonlinearity < 0.05). The MAP ranges associated with HRs below 1 for 28-day and in-hospital mortality were 74.6–90.2 mmHg and 74.6–89.3 mmHg, respectively.The inflection point for mortality risk, determined by the minimum hazard ratio (HR), was identified at a MAP of 81.5 mmHg. The multivariable adjusted segmented Cox regression models showed that for MAP < 81.5 mmHg, an increase in MAP was associated with a decreased risk of 28-day and in-hospital mortality (P < 0.05). In Model 4, each 5 mmHg increase in MAP was associated with a 15% decrease in 28-day mortality risk (HR: 0.85, 95% CI: 0.79–0.91, p < 0.05) and a 14% decrease in in-hospital mortality risk (HR: 0.86, 95% CI: 0.80–0.93, p < 0.05). However, for MAP ≥ 81.5 mmHg, there was no significant association between MAP and mortality risk (P > 0.05). Subgroup analyses based on age, congestive heart failure, use of vasoactive drugs, and acute kidney injury showed consistent results across different subgroups.Subsequent analysis of SAE patients with septic shock also showed results similar to those of the original cohort.However, for comatose SAE patients (GCS ≤ 8), there was a negative correlation between MAP and the risk of 28-day and in-hospital mortality when MAP was < 81.5 mmHg, but a positive correlation when MAP was ≥ 81.5 mmHg in adjusted models 2 and 4.ConclusionThere is a nonlinear relationship between MAP and the risk of 28-day and in-hospital mortality in SAE patients. The optimal MAP target for SAE patients in clinical practice appears to be 81.5 mmHg.

Nitroglycerin challenge identifies microcirculatory target for improved resuscitation in patients with circulatory shock

BackgroundCirculatory shock and multi-organ failure remain major contributors to morbidity and mortality in critically ill patients and are associated with insufficient oxygen availability in the tissue. Intrinsic mechanisms to improve tissue perfusion, such as up-regulation of functional capillary density (FCD) and red blood cell velocity (RBCv), have been identified as maneuvers to improve oxygen extraction by the tissues; however, their role in circulatory shock and potential use as resuscitation targets remains unknown. To fill this gap, we examined the baseline and maximum recruitable FCD and RBCv in response to a topical nitroglycerin stimulus (FCDNG, RBCvNG) in patients with and without circulatory shock to test whether this may be a method to identify the presence and magnitude of a microcirculatory reserve capacity important for identifying a resuscitation target.MethodsSublingual handheld vital microscopy was performed after initial resuscitation in mechanically ventilated patients consecutively admitted to a tertiary medical ICU. FCD and RBCv were quantified using an automated computer vision algorithm (MicroTools). Patients with circulatory shock were retrospectively identified via standardized hemodynamic and clinical criteria and compared to patients without circulatory shock.Results54 patients (57 ± 14y, BMI 26.3 ± 4.9 kg/m2, SAPS 56 ± 19, 65% male) were included, 13 of whom presented with circulatory shock. Both groups had similar cardiac index, mean arterial pressure, RBCv, and RBCvNG. Heart rate (p < 0.001), central venous pressure (p = 0.02), lactate (p < 0.001), capillary refill time (p < 0.01), and Mottling score (p < 0.001) were higher in circulatory shock after initial resuscitation, while FCD and FCDNG were 10% lower (16.9 ± 4.2 and 18.9 ± 3.2, p < 0.01; 19.3 ± 3.1 and 21.3 ± 2.9, p = 0.03). Nitroglycerin response was similar in both groups, and circulatory shock patients reached FCDNG similar to baseline FCD found in patients without shock.ConclusionCritically ill patients suffering from circulatory shock were found to present with a lower sublingual FCD. The preserved nitroglycerin response suggests a dysfunction of intrinsic regulation mechanisms to increase the microcirculatory oxygen extraction capacity associated with circulatory shock and identifies a potential resuscitation target. These differences in microcirculatory hemodynamic function between patients with and without circulatory shock were not reflected in blood pressure or cardiac index.

Comparing The Effects of Compression Contrast Therapy and Dry Needling on Muscle Functionality, Pressure Pain Threshold, and Perfusion after Isometric Fatigue in Forearm Muscles of Combat Sports Athletes: A Single-Blind Randomized Controlled Trial.

The aim of this study was to compare the acute effects of compression contrast therapy (CT) and dry needling therapy (DN) on muscle tension (MT), muscle strength (Fmax), pressure pain threshold (PPT), and perfusion (PU) following fatigue of forearm muscles (e.g., flexor carpi radialis) in combat sports athletes. A single-blind randomized controlled trial was employed. Participants first underwent muscle fatigue induction, which involved sustaining an isometric handgrip at 60% of their maximum voluntary contraction in 5-second cycles. This was followed by exposure to one of the regenerative therapies. Forty-five participants were randomly assigned to one of three groups: CT/DN (n = 15), CT/ShDN (n = 15), and ShCT/DN (n = 15). The sham condition (Sh) involved a simulated version of the technique. Measurements were taken at four time points: (i) at rest; (ii) immediately after exercise that led to a state of fatigue; (iii) 5 minutes after therapy (PostTh5min); and (iv) 24 hours after therapy (PostTh24h). Each participant was exposed to one experimental condition and one control condition, thereby undergoing evaluation in two sessions. Significant differences between groups were found in MT during the PostTh5min (p = 0.005), as well as in PU during the PostTh5min (p < 0.001) and PU during the PostTh24h (p < 0.001). All groups showed significant improvements at 5 minutes post-therapy compared to immediately post-muscle fatigue. As conclusions, CT/DN seems to be significantly better for enhancing MT and PU after 5 minutes of muscle fatigue induction. Using either CT, DN, or both combined is recommended to enhance the recovery of muscle functionality and properties, favoring recovery and potentially speeding up performance enhancement.

Risk Factors Related to the Development of Full-thickness Pressure Injuries in Hospitalized Pediatric Patients.

Current pediatric pressure injury (PI) prevention measures are based on risk factors related to PI development in adults. Children offer a unique concern for PI development because their bodies are still developing, and their skin responds differently to external pressure. To explore risk factors for the development of full-thickness PIs in children aged 21 weeks' gestation to 21 years. This retrospective, observational, correlational study included 799 hospitalized children who developed a PI. The pediatric and adult PI risk factors used in the study were identified from the International Pressure Ulcer Prevention and Treatment Guideline. A stepwise multivariate logistic regression model was used. Multivariate analyses revealed that risk factors for predicting a full-thickness PI varied by age. For children aged 38 weeks to 12 months, risk factors included tissue perfusion and oxygenation: generalized edema, conditions of the OR, and nutrition deficits. For children aged 1 to 7 years, fragile skin status was a risk factor. For youth aged 8 to 21 years, the two risk factors were tissue perfusion and oxygenation: decreased oxygenation and extracorporeal membrane oxygenation. Across the total sample, extracorporeal membrane oxygenation, tissue perfusion and oxygenation: decreased oxygenation and malnutrition were risk factors for predicting a full-thickness PI. Full-thickness PI risk factors differ among the ages of pediatric patients.

In vivo optical assessment of cerebral and skeletal muscle microvascular response to phenylephrine.

This study aimed to investigate the simultaneous response of the cerebral and skeletal muscle microvasculature to the same phenylephrine (PE) boluses. A hybrid optical system that combines hyperspectral near-infrared spectroscopy (hs-NIRS) and diffuse correlation spectroscopy (DCS) was used to monitor changes in tissue oxygenation and perfusion. Data were collected from the head and hind limb of seven male Sprague-Dawley rats while administering intravenous (IV) injections of PE or saline to all animals. The response to saline was used as a control. Skeletal muscle oxygenation decreased significantly after PE injection, while a statistically underpowered decrease in perfusion was observed, followed by an increase beyond baseline. Vascular conductance also decreased in the muscle reflecting the drug's vasoconstrictive effects. Tissue oxygenation and perfusion increased in the brain in response to PE. Initially, there was a sharp increase in cerebral perfusion but no changes in cerebral vascular conductance. Subsequently, cerebral flow and vascular conductance decreased significantly below baseline, likely reflecting autoregulatory mechanisms to manage the excess flow. Further, fitting an exponential function to the secondary decrease in cerebral perfusion and increase in muscular blood flow revealed a quicker kinetic response in the brain to adjust blood flow. In the skeletal muscle, PE caused a transient decrease in blood volume due to vasoconstriction, which resulted in an overall decrease in hemoglobin content and tissue oxygen saturation. Since PE does not directly affect cerebral vessels, this peripheral vasoconstriction shunted blood into the brain, resulting in an initial increase in oxygenated hemoglobin and oxygen saturation.

Abstract P434: Piezo2 Channels in JG cells do not Regulate Renin Expression or Renin Release to the Circulation

Kidneys are central to blood pressure regulation through the renin-angiotensin system. Renin-producing juxtaglomerular (JG) cells act as renal baroreceptors by controlling renin release according to the changes in perfusion pressure. Recent studies suggest that Piezo2 calcium channels may regulate the baroreceptor mechanism of renin release. However, our single-cell RNAseq and RNAScope analysis on adult kidneys showed a very low expression for Piezo2 in the JG cells. Since it is unclear if Piezo2 in the JG cells regulates renin expression and release, we defined the in vivo role of Piezo2 in the current study using Piezo2 conditional mutant mice. For this we generated Piezo2 fl/fl ;Ren1 d Cre, Piezo2 fl/del ;Ren1 d Cre and Piezo2 fl/fl ;Akr1b7.Cre-Er T2 mice. Though we detected an efficient deletion of Piezo2 by RNAScope in the JG cells of the mutant kidneys, we did not observe a significant difference in the renin signals between the control and the mutant groups by renin immunostaining. q-RT-PCR of the kidney cortices to measure renin mRNA levels and renin-specific ELISA to quantify plasma renin levels also indicated no significant differences (NS) between the control and the mutant groups ( Piezo2 fl/fl ;Ren1 d Cre - Relative renin mRNA levels: Control (n=11) 1.05±0.113 Mutants (n=6) 0.90±0.20, NS; Plasma renin levels (pg/ml): Control (n=11) 17472±3712 Mutants (n=6) 14934±3547, NS; Piezo2 fl/del ;Ren1 d Cre - Relative renin mRNA levels: Control (n=3) 0.98±0.13 Mutants (n=4) 1.04±0.19, NS; Plasma renin levels (pg/ml): Control (n=3) 20221±4303 Mutants (n=4) 15014±1901, NS). Furthermore, subjecting the mice to hypotension and volume depletion with captopril and a low salt diet for one week did not affect the renin expression due to Piezo2 deletion in the renin cells. Finally, our results from the aortic coarctation surgery model showed that Piezo2 deletion in the adult JG cells of Piezo2 fl/fl ;Akr1b7.Cre-Er T2 mice did not affect the changes in renin expression between the left and right kidneys in response to perfusion pressure (Relative renin mRNA levels: Control (n=11) LK-1.102 ±0.173 RK-0.316±0.046, p=0.002 Mutants (n=9) LK-1.191±0.266 RK-0.524±0.212, p=0.05). Collectively, our in vivo data shows that renin expression is unaffected during normal conditions and when homeostasis is threatened by hypotension, sodium depletion, or changes in blood pressure, indicating that Piezo2 channels are not necessary for renin synthesis and release to circulation in JG cells.

O107 A LONGITUDINAL STUDY ON THE IMPACT OF CHILDHOOD ELEVATED BLOOD PRESSURE ON TARGET ORGAN HEALTH IN ADOLESCENCE: THE EXAMIN YOUTH SA STUDY

Background and objective: Primary hypertension in children is becoming a global threat for the growing economic burden of hypertension management in adulthood and sustainable healthcare. We determined the associations of adolescent blood pressure (BP) with target organ damage markers (carotid intima-media thickness (CIMT) and left ventricular mass index (ilVM)) over a four year period, stratified by childhood BP status at baseline. Methods: We included 421 Black and 307 White South African adolescents (mean age: 11.04 years) with complete follow-up data for BP, CIMT and iLVM. Standard anthropometric measures and basic demographic information were collected. Results: Children were stratified by baseline BP status, i.e., normotensive; n=454 (57.5% Black and 57.7% female) and elevated BP; n=274 (58.4% Black and 52.2% female), with comparable proportions of ethnicity (p=0.81) and sex (p=0.15). Systolic BP (by 6mmHg; p&lt;0.001), diastolic BP (by 3mmHg; p&lt;0.001) and perfusion pressure (by 4mmHg; p&lt;0.001) as well as sex-specific body mass index for age z-scores (BAZ; p&lt;0.001) were all higher in the elevated BP compared to normotensive group. Groups were comparable for age (p=0.78), CIMT (p=0.28) and iLVM (p=0.64). In partial regression analysis (adjusting for ethnicity, sex, follow-up age and BAZ), systolic BP correlated positively with CIMT (r=0.125; p=0.041) and iLVM (r=0.184; p=0.002) in the elevated BP group only. Backward multiple adjusted linear regression analysis (adjustment for perfusion pressure at baseline, age, sex, ethnicity and BAZ) showed adverse associations of systolic BP with CIMT (β=0.126; p=0.046) and iLVM (β=0.199; p=0.001), and diastolic BP with iLVM (β=0.130; p=0.002), only in children with elevated BP at baseline. Conclusion: Elevated BP in early childhood contributes to the long-term impact on target organ health during adolescence independent of sex and ethnicity, while the association of BP with iLVM seems to be moderated by excess adiposity.

Abstract P338: Impaired Endothelial-Dependent Vasorelaxation and Myogenic Response in Renal Afferent Arterioles of Diabetic mice: Role of Endothelial NOX1, and New Gene Pathways.

Diabetes increases the risk of cardiovascular disease and hypertension, in part, by decreasing arterial vasodilation through decreased NO bioavailability and increased superoxide. In the kidney, type 1 diabetes induces a decrease in renal filtration, proteinuria, inflammation, and fibrosis, increasing the incidence of kidney disease. In diabetic rats and rabbits, prone to renal disease, diabetes blunts acetylcholine (Ach)-induced vasorelaxation of afferent arterioles, in part, by enhancing endothelial superoxide. However, it is unclear whether diabetes affects afferent arteriole vasodilation and myogenic response in mice. We hypothesize that diabetes increases endothelial NOX1 mediated superoxide production in mouse afferent arterioles, decreasing Ach-induced vasodilation. We dissected and perfused afferent arterioles from male diabetic Akita mice 12-14 weeks of age and measured the effect Ach (10 -7 -10 -5 M) on luminal diameter after pre-constriction with norepinephrine. Diabetic Akita mice had a largely reduced Ach-induced dilation at all doses of Ach (80±6% average inhibition in dilation, p&lt;0.025, n=6). To study the role of NOX1, we used the inhibitor ML171 (5µM). When added to the endothelial lumen, NOX1 inhibition completely restored Ach-induced dilation of diabetic Akita mice, which was not different from WT controls. In Control C57 mice, ML171 did not change Ach-induced dilation in Aff-Art (n=6). We then examined the myogenic response in diabetic mice by measuring lumen diameter after step increases in perfusion pressure (60-140 mmHg). Afferent arterioles of diabetic Akita mice did not constrict when pressure was increased, even at 140 mmHg, whereas WT mice showed normal myogenic response (delta constriction 60-140 mmHg WT: 2.15±0.41 vs Akita: 0.37±0.32 µm, WT p&lt;0.01 from baseline, Akita n.s from baseline). To understand the mechanisms behind these effects we performed RNAseq in manually micro-dissected afferent arterioles from 12-week-old Akita and WT mice. Bioinformatics analysis showed 530 DEGs (FDR pAdj&lt;0.05, n=6). Most of the DEGs are involved in endothelial cell function/metabolism, smooth muscle cell contractility, activated inflammatory pathways, and free radical/NO production. We conclude that early diabetes has a large effect on renal afferent arteriole reactivity by affecting the expression of hundreds of genes. These effects are likely involved in hypertension and kidney damage progression in type 1 diabetes.

Abstract P429: Stronger Association of Angiotensinogen with Mortality than Renin or Lactate in Critical Illness

Introduction: Sepsis and septic shock remain global healthcare issues associated with high mortality rates affecting millions every year despite best care efforts. Activation of the renin-angiotensin-system (RAS) is an early event in sepsis, and renin levels may more strongly associate with mortality than serum lactate, a widely accepted index of patient status. We postulated that reduced levels of Angiotensinogen (AGT) may reflect a dysfunctional RAS driven by high renin levels but an attenuated expression of Ang II to adequately support tissue perfusion and blood pressure. This study compared the association with mortality of AGT to serum lactate and active renin in a subset of the VICTAS (Vitamin C, Thiamine, and Steroids in Sepsis) cohort (N=103) at baseline (day 0) prior to treatment. Methods: Serum levels of intact AGT and active renin protein were quantified by separate ELISAs. Biomarker discrimination for all-cause 30-day mortality was compared by receiver operating characteristic (ROC) curves generated by logistic regression models adjusted for age, sex, sequential organ failure assessment (SOFA) score, systolic blood pressure, and in-hospital vasopressor support. Association of serum AGT, renin, and lactate with mortality was assessed by Kaplan-Meier curves with log rank test and hazard ratios derived from Cox regression. Results: Median [interquartile range] serum levels for AGT were: 114 [78.2-205.4] nM; renin: 4.9 [2.2-13.6] pM; and lactate: 2.6 [1.7-3.8] mM. ROC curves revealed better discrimination of AGT for mortality than either active renin or lactate. The area under the curve (AUC) of AGT (0.82, 95% CI: 0.70, 0.93) was greater than lactate (AUC=0.68, 95% CI: 0.57, 0.80; p=0.022). Kaplan-Meier curves and log rank test also revealed that AGT levels below 114 nM associated with reduced survival. Renin levels greater than 4.9 pM were also associated with patient mortality albeit less than that for AGT while higher lactate levels (&gt;2.6 mM) were not associated with mortality in this cohort. Conclusion: AGT levels more strongly associated with 30-day mortality than renin or lactate in the VICTAS cohort. Reduced AGT may reflect increased consumption by high renin coupled with reduced expression by the liver ultimately impairing Ang II-AT 1 R tone in critically ill patients. The prospective assessment of circulating AGT may facilitate more precise therapeutic approaches treatment to restore a dysfunctional RAS and improve overall mortality in sepsis.

Abstract P418: Placental small-RNA sequencing reveals a distinct microRNA signature and its functional relevance in a preeclamptic rat model

Introduction: Despite considerable research over the last few decades, molecular mechanisms that govern preeclamptic (PE) pathogenesis are poorly understood. Recent studies focussed on mechanistic exploration documented that microRNAs (miRNAs) regulate critical processes (endothelial dysfunction, inflammation, oxidative stress) pertinent to PE pathology. However, to the best of our knowledge, a complete placental miRNA expression profiling has not been undertaken. Given the complexity surrounding miRNA biology, a comprehensive miRNA profiling would greatly aid our efforts in better understanding PE pathology. Objective: The objective of the current study was to perform a comprehensive profiling of placental miRNAs in PE rat (reduced perfusion pressure;RUPP) model, and identify their functional relevance. Methods: RUPP surgery was performed on gestational day (GD)14. Blood pressures (carotid catheterization) were collected on GD19, and placenta (~5mg) was used to isolate miRNA (Qiagen’s miRNeasy Micro Kit). Small RNA sequencing (s-RNA seq) was performed by Illumina sequencer(NEXTFLEX Kit). Enrichment analysis was performed using Cytoscape(BINGO, overrepresentation, p=0.05). Functional associations were retrieved using TAM2.0. Results: RUPP rats showed higher MAP (123.8±1.51 vs.98.70±1.53 mmHg, n=10, p&lt;0.0001) vs.control rats. S-RNA seq revealed a total of 142 (40 up and 102 down) differentially regulated (diff-reg) miRNAs in RUPPs. Of these, the top 5 diff-reg miRNAs were; miR-211-3p, miR-628, miR-6324, miR-363-5p, miR-6329 (up) and miR-3587, miR-29b-3p, miR-3556a, miR-29a-3p, miR-21-3p (down). Interestingly, TAM2.0 revealed that these miRNAs are involved in immune response (miR-363, miR-21, miR-29), B-cell differentiation (miR-628), T-cell activation (miR-21), adipogenesis, lipid metabolism (miR-211, miR-29, miR-21), and angiogenesis (miR-363, miR-21) all of which are relevant to PE. Further, enrichment analysis revealed that the top 10 significantly enriched terms include, regulation of transport, cell-cell signaling, calcium ion-dependent exocytosis (BP); synaptic vesicle, perinuclear region of cytoplasm, membrane bound/clathrin-coated vesicle (CC); glycoprotein binding, protein dimerization activity, myosin head/neck binding (MF). Conclusions: Our findings demonstrate that dysregulated placental miRNAs may be involved in PE pathogenesis. Future studies building on these preliminary findings may help identify candidate miRNA for therapeutic manipulation.

Abstract 16: A Novel H2 Relaxin B-Chain-Only Peptide Variant B7-33 Improves The Pathophysiology Of Placental Ischemia In The Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia

Background: Preeclampsia (PE) is a hypertensive pregnancy disorder, which occurs in approximately 10% of all gestations. The literature suggests the potential therapeutic role of H2 relaxin in PE. A novel H2 relaxin B-chain-only peptide variant B7-33 (27 amino acids without any disulfide bonds) has recently been developed. Objective: The goal of this study was to test the hypothesis that a novel H2 relaxin B-chain-only peptide variant B7-33 could improve the pathophysiology of placental ischemia in the Reduced Uterine Perfusion Pressure (RUPP) rat model of PE. Methods: The efficacy of B7-33 was evaluated in the RUPP model as described previously. RUPP rats are randomly assigned to 4 groups (N=8/group): 1) vehicle, 2) B733; 3) B733-Fc; and 4) B733-HSA. Rats are dosed twice weekly (i.v.) from GD10 to GD 20. On GD 18, rats are anesthetized with isoflurane, and carotid arterial catheters are inserted into the carotid artery, tunneled under the skin, and externalized at the back of the neck. On the following day, mean arterial pressure (MAP) is monitored with a pressure transducer (Cobe III Tranducer CDX Sema) and recorded continuously for 30 min. On GD18, uterine artery resistance index (UARI) of rats is measured by Doppler sonography. The nitric oxide bioavailability, soluble fms-like tyrosine kinase-1 (sFlt-1), and TNF-α) were measured by commercially available kits. Statistical comparisons were performed using analysis of variance with Duncan’s post hoc test. Results: The RUPP rats have increased MAP (122.2 ± 8.1 mm Hg), plasma TNF-α (223 ±11.4 pg/mL), and plasma sFlt-1(863 ±18.2 pg/mL) along with decreased NO index (14±2 µM) compared to normal pregnancy: MAP (102 ± 5.2 mm Hg); plasma TNF-α (28 ± 4.1 pg/mL); plasma sFlt-1(244 ± 9.4 pg/mL) and NO index (26 ±4.1 µM). Treatment with B733 and B7-33 fusion proteins significantly (*p&lt;0.05) lowers MAP, plasma TNF-α, and plasma sFlt-1 and increased NO index back to that of normal pregnancy. The B7-33 data are consistent with earlier data with serelaxin in the RUPP model. All fusions tested ameliorate hypertension in the RUPP animals. B7-33 normalizes BP and proteinuria in the DOCA rat model of preE. Conclusion: The conclusion of the study is that both B7-33 and B7-33 fusion proteins demonstrate efficacy in attenuating the symptoms of PE including hypertension and inflammation in RUPP model. We conclude that B7-33 is an ideal candidate for development as a novel therapeutic in preE.