Inhibition of iNOS augments cutaneous endothelial NO-dependent vasodilation in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks.

We tested the hypothesis that inducible nitric oxide synthase (iNOS) contributes to reduced nitric oxide (NO)-dependent vasodilation in non-Hispanic Blacks and prehypertensive non-Hispanic Whites. Twenty Black and twenty White participants (10 normotensive, 10 prehypertensive per group; n = 40 total) participated in this study. Participants were instrumented with two microdialysis fibers, and each site was randomized as control (lactated Ringer) or iNOS inhibition (0.1 mM 1400W). Laser-Doppler flow probes and local heaters were used to measure skin blood flow and heat the skin to induce vasodilation, respectively. Each site was heated from 33°C to 39°C (rate: 0.1°C/s). Once a plateau was established, 20 mM nitro-l-arginine methyl ester (l-NAME), a nonspecific NOS inhibitor, was infused at each site to quantify NO-dependent vasodilation. At control sites, %NO-dependent vasodilation was reduced in prehypertensive Whites (47 ± 10%NO) and in both normotensive and prehypertensive Blacks (39 ± 9%NO and 28 ± 5%NO, respectively) relative to normotensive Whites (73 ± 8%NO; P < 0.0001 for all comparisons). Compared with respective control sites, iNOS inhibition increased NO-dependent vasodilation in prehypertensive Whites (68 ± 8%NO) and in both normotensive and prehypertensive Blacks (78 ± 8%NO and 55 ± 6%NO, respectively; P < 0.0001 for all comparisons). We failed to find an effect for normotensive Whites (77 ± 7%NO). After iNOS inhibition, %NO-dependent vasodilation was similar between normotensive Whites, prehypertensive Whites, and normotensive Blacks. Inhibition of iNOS increased NO-dependent vasodilation to a lesser extent in prehypertensive Blacks. These data suggest that iNOS contributes to reduced NO-dependent vasodilation in prehypertension and in Black participants.NEW & NOTEWORTHY Inducible nitric oxide synthase (iNOS) is typically upregulated in conditions of increased oxidative stress and may have detrimental effects on the vasculature. Endothelial nitric oxide (NO), which is cardioprotective, is reduced in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks. We found that inhibition of iNOS can increase endothelial NO-dependent vasodilation in prehypertensive White participants and in both normotensive and prehypertensive Black participants.Inducible nitric oxide (NO) synthase (iNOS) can be upregulated under conditions of increased oxidative stress and may have detrimental effects on the vasculature. Endothelial NO, which is cardioprotective, is reduced in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks. We found that inhibition of iNOS can increase endothelial NO-dependent vasodilation in prehypertensive White participants and in both normotensive and prehypertensive Black participants.

Impact of Obesity on Tranexamic Acid Efficacy in Adult Patients With Major Bleeding.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic used for prophylaxis and treatment of acute bleeding. Although fixed dosing is often used in practice, weight-based dosing is sometimes used in the operating room (OR). The efficacy and safety of fixed-dose TXA is not well established in patients with above average weight or body mass index. OBJECTIVE: To characterize the efficacy and safety of intravenous TXA in obese patients with major bleeding. METHODS: This was a retrospective review of 165 patients receiving fixed-dose TXA for acute bleeding outside the OR. Blood product administration (BPA) before and after TXA was collected, along with demographic and bleed-related information. Thrombotic events were the major safety end point. A prespecified subgroup analysis was conducted in patients weighing at least 100 kg compared with a lower weight. Logistic regression was performed to determine whether an association exists between body weight and blood product requirement after TXA administration. RESULTS: In the 24 hours after TXA, patients received an average of 4.17 units of blood product. Patients weighing at least 100 kg averaged 4.04 total units, compared with 4.19 units in the lower weight group (P = 0.603). Administration of individual blood products did not differ between groups, and thrombotic events were similar. Regression analysis did not associate weight with total BPA. CONCLUSION AND RELEVANCE: In patients receiving fixed-dose TXA, weight does not appear to alter blood product requirements or rates of adverse thrombotic events. These data support continued use of fixed-dose TXA for treatment of acute major bleeding in obese patients.

Sensory nerve-mediated and nitric oxide-dependent cutaneous vasodilation in normotensive and prehypertensive non-Hispanic blacks and whites.

The purpose of this study was to investigate the effect of race and subclinical elevations in blood pressure (i.e., prehypertension) on cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation. We recruited participants who self-identified as either non-Hispanic black (n = 16) or non-Hispanic white (n = 16). Within each group, participants were subdivided as either normotensive (n = 8 per group) or prehypertensive (n = 8 per group). Each participant was instrumented with four intradermal microdialysis fibers: 1) control (lactated Ringer's), 2) 5% lidocaine (sensory nerve inhibition), 3) 20 mM Nω-nitro-l-arginine methyl ester (l-NAME) (NO synthase inhibition), and 4) lidocaine + l-NAME. Skin blood flow was assessed via laser-Doppler flowmetry, and each site underwent local heating from 33°C to 39°C. At the plateau, 20 mM l-NAME were infused at control and lidocaine sites to quantify NO-dependent vasodilation. Maximal vasodilation was induced via 54 mM sodium nitroprusside and local heating to 43°C. Data are means ± SD. Sensory nerve-mediated cutaneous vasodilation was reduced in prehypertensive non-Hispanic white (34 ± 7%) and both non-Hispanic black groups (normotensive, 20 ± 9%, prehypertensive, 24 ± 15%) relative to normotensive non-Hispanic whites (54 ± 12%). NO-dependent vasodilation was also reduced in prehypertensive non-Hispanic white (41 ± 7%) and both non-Hispanic black groups (normotensive, 44 ± 7%, prehypertensive, 19 ± 7%) relative to normotensive non-Hispanic whites (60 ± 11%). The decrease in NO-dependent vasodilation in prehypertensive non-Hispanic blacks was further reduced relative to all other groups. These data suggest subclinical increases in blood pressure adversely affect sensory-mediated and NO-dependent vasodilation in both non-Hispanic blacks and whites.NEW & NOTEWORTHY Overt hypertension is known to reduce cutaneous sensory nerve-mediated and nitric oxide (NO)-dependent vasodilation, but the effect of subclinical increases in blood pressure (i.e., prehypertension) is unknown. The combined effect of race and prehypertension is also unknown. In this study, we found that prehypertension reduces cutaneous sensory nerve-mediated and NO-dependent vasodilation in both non-Hispanic white and black populations, with the greatest reductions observed in prehypertensive non-Hispanic blacks.

Pharmacologic Reversal of Direct Oral Anticoagulants.

Direct oral anticoagulants are becoming increasingly popular in outpatient use. These medications have lacked specific reversal agents. However, this is changing. The Federal Food and Drug Administration approved idarucizumab for reversal of dabigatran in 2016, and another agent, andexanet alfa, is currently in clinical trials for reversal of rivaroxaban and apixaban. This article examines the efficacy and safety of these emerging reversal agents, as well as other historical agents for reversal of direct oral anticoagulants.

The effect of heating rate on the cutaneous vasomotion responses of forearm and leg skin in humans.

We examined skin blood flow (SkBF) and vasomotion in the forearm and leg using laser-Doppler fluxmetry (LDF) and spectral analysis to investigate endothelial, sympathetic, and myogenic activities in response to slow (0.1 °C·10 s(-1)) and fast (0.5 °C·10 s(-1)) local heating. At 33 °C (thermoneutral) endothelial activity was higher in the legs than the forearms (P ≤ 0.02). Fast-heating increased SkBF more than slow heating (P=0.037 forearm; P=0.002 leg). At onset of 42 °C, endothelial (P=0.043 forearm; P=0.48 leg) activity increased in both regions during the fast-heating protocol. Following prolonged heating (42 °C) endothelial activity was higher in both the forearm (P=0.002) and leg (P<0.001) following fast-heating. These results confirm regional differences in the response to local heating and suggest that the greater increase in SkBF in response to fast local heating is initially due to increased endothelial and sympathetic activity. Furthermore, with sustained local skin heating, greater vasodilatation was observed with fast heating compared to slow heating. These data indicate that this difference is due to greater endothelial activity following fast heating compared to slow heating, suggesting that the rate of skin heating may alter the mechanisms contributing to cutaneous vasodilatation.

Pharmacologic Strategies to Prevent Blood Loss and Transfusion in Orthotopic Liver Transplantation.

Patients undergoing orthotopic liver transplantation are at risk of both life-threatening blood loss and thrombosis due to preexisting liver dysfunction and major intra- and postoperative coagulopathy. Traditional laboratory markers of hemostasis and coagulopathy are often inadequate to describe the alterations. Whole blood global viscoelastic tests, thromboelastography, and thromboelastometry may provide more complete pictures of the hematologic derangements and allow for more targeted therapy to prevent blood loss and massive transfusion. Antifibrinolytic medications such as aprotinin, tranexamic acid, and [Latin Small Letter Open E]-aminocaproic acid have been used successfully to reduce blood loss and the need for transfusion, although most published data are from small prospective trials or larger retrospective cohorts. Recombinant factor VIIa has not been shown to improve outcomes. Although transfusion needs have been associated with adverse outcomes, no studied medications for prevention of blood loss and transfusion have been associated with improved mortality or graft survival post-liver transplant.

Adverse Hemodynamic Effects of Dexmedetomidine in Critically Ill Elderly Adults.

Background: Dexmedetomidine is a currently recommended first-line sedative agent for critically ill patients requiring mechanical ventilation. Recent trials demonstrated no difference in clinical outcomes between patients treated with dexmedetomidine vs usual care, but significantly more hemodynamic adverse effects in the dexmedetomidine group. One subgroup analysis suggested a 90-day mortality benefit in elderly patients, but no distinction was made between groups regarding age when reporting adverse effects. Given potential decreased baroreceptor function in the elderly, adverse hemodynamic effects of dexmedetomidine may impact them more. Objective: To assess the incidence of adverse hemodynamic effects of dexmedetomidine in elderly ICU patients compared to other sedative agents to clarify the role of dexmedetomidine in this patient population. Methods: This was a single-center, retrospective study including mechanically ventilated elderly patients requiring sedative agents for ≥12 hours. The primary outcome evaluated was composite end point of incidence of bradycardia and hypotension. Secondary outcomes included incidence of each adverse event individually, hospital and ICU length of stay, and duration of mechanical ventilation. Results: There was no difference in adverse events between the two groups (58.7% vs 74.1% in the dexmedetomidine vs usual care groups, P =.074). There was no difference in hospital or ICU length of stay. Patients in the dexmedetomidine group were on the ventilator longer than patients in the usual care group with a median of 6 vs 3 days, respectively (P = 0.004). Conclusion: In this single-center, retrospective study dexmedetomidine had a similar incidence of adverse events in elderly patients compare to the usual care group.

Association Between Sedative Medication Administration and Delirium Development in a Medical Intensive Care Unit.

Background: Delirium develops frequently in intensive care unit (ICU) patients. Societal guidelines have suggested that benzodiazepines may cause delirium. This study investigates if a change in sedation administration use over time is associated with changes in delirium incidence. Methods: This was a retrospective cohort study conducted over a 4 year time period in a medical ICU. All data was abstracted from a local data warehouse. The primary outcome of the study was the association between annual cumulative benzodiazepine use and incidence of delirium during the study period. Data was analyzed using descriptive characteristics and Spearman's correlation coefficient. Additionally, multivariate logistic regression was performed to identify independent risk factors for delirium development. Results: From 2015 to 2018, annual total benzodiazepine administration decreased from 62,215 mg to 18,105 mg lorazepam equivalents (p = <.01). The cumulative dose of dexmedetomidine increased, with 657,262 mcg administered in 2015 and 1,476,951 mcg in 2018 (p < .01). No differences in annual delirium incidence were found. Risk factors that were significantly correlated with delirium following multivariate logistic regression included acute respiratory distress syndrome, renal failure, hepatic failure, septic shock, severe alcohol withdrawal, vasopressor use, corticosteroid use, benzodiazepine use, antipsychotic use, opiate use, and propofol use. Conclusions: A profound change in sedation medication paradigm did not influence delirium rates in a medical ICU.

Cutaneous sensory nerve-mediated microvascular vasodilation in normotensive and prehypertensive non-Hispanic Blacks and Whites.

Relative to non-Hispanic Whites, non-Hispanic Blacks are disproportionately affected by elevated blood pressure (BP). It is unknown whether race or subclinical increases in BP affect the ability of cutaneous sensory nerves to induce cutaneous microvascular vasodilation. Sixteen participants who self-identified as non-Hispanic Black (n = 8) or non-Hispanic White (n = 8) were subgrouped as normotensive or prehypertensive. Participants were instrumented with three intradermal microdialysis fibers: (a) control, (b) 1 µM sodium nitroprusside (SNP), an exogenous nitric oxide (NO) donor, and (c) 20 mM NG -nitro-l-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. A slow local heating protocol (33-40°C, 0.1°C/min) was used to assess the onset of cutaneous sensory nerve-mediated vasodilation (temperature threshold) and skin blood flow was measured using laser-Doppler flowmetry. At control sites, the temperature threshold occurred at a higher temperature in non-Hispanic Blacks (normotensive: 37.2 ± 0.6°C, prehypertensive: 38.9 ± 0.5°C) compared to non-Hispanic Whites (normotensive: 35.2 ± 0.8°C, prehypertensive: 35.2 ± 0.9°C). L-NAME shifted the temperature threshold higher in non-Hispanic Whites (normotensive: 37.8 ± 0.7°C, prehypertensive: 38.2 ± 0.8°C), but there was no observed effect in non-Hispanic Blacks. SNP did not affect temperature threshold in non-Hispanic Whites, but shifted the temperature threshold lower in non-Hispanic Blacks (normotensive: 34.6 ± 1.2°C, prehypertensive: 34.8 ± 1.1°C). SNP mitigated differences in temperature threshold across all groups. There was no effect found for BP status in either the non-Hispanic Black or non-Hispanic White groups. These data suggest that reduced NO bioavailability affects the ability of cutaneous sensory nerves to induce microvascular vasodilation in young, otherwise healthy non-Hispanic Blacks.

Oxandrolone treatment in adults with severe thermal injury.

Severe thermal injury is associated with hypermetabolism and hypercatabolism, leading to skeletal muscle breakdown, lean body mass loss, weight loss, and negative nitrogen balance. Muscle protein catabolism in patients with severe thermal injury is the result of stress-induced increased release of cytokines and counterregulatory hormones. Coupled with decreased serum anabolic hormone concentrations such as testosterone and growth hormone along with the presence of insulin resistance, anabolism in patients with severe thermal injury is inefficient or impossible during the acute postburn period. This causes difficulty in restoring lean body mass and regaining lost body weight, as well as poor healing of the burn wound and delayed patient recovery. Oxandrolone, a synthetic derivative of testosterone, has been used in adult patients with severe thermal injury to enhance lean body mass accretion, restore body weight, and accelerate wound healing. In clinical studies, oxandrolone 10 mg orally twice/day improved wound healing, restored lean body mass, and accelerated body weight gain. During the rehabilitation period, oxandrolone therapy with adequate nutrition and exercise improved lean body mass, increased muscle strength, and restored body weight. However, most data on oxandrolone use in adult patients with severe thermal injury are derived from single-center studies, many of which enrolled a relatively small number of subjects and some of which had a poor design. Multicenter, prospective, randomized studies are needed to better define the optimal oxandrolone dosage and to confirm the efficacy and safety of this drug in adult patients with severe thermal injury.

Incidence of Rebound Hypertension after Discontinuation of Dexmedetomidine.

INTRODUCTION: To date, no studies have evaluated the incidence of rebound hypertension occurring with the discontinuation of long-term (> 72 hrs) dexmedetomidine infusions. Rebound hypertension has been documented in the literature with clonidine, a structurally and pharmacologically similar medication. OBJECTIVES: To compare the incidence of rebound hypertension associated with cessation of dexmedetomidine infusion with other sedative medications. METHODS: This retrospective, matched cohort study evaluated the incidence of rebound hypertension in intensive care unit patients receiving continuous infusions of at least 72 hours in duration of dexmedetomidine, propofol, or midazolam. RESULTS: The study population consisted of 216 patients: 54 treated with dexmedetomidine and 162 treated with propofol or midazolam. Rebound hypertension occurred significantly more often in patients with a history of hypertension (71.1%) than in patients with no prior hypertension (28.9%; p<0.001).There was no difference in incidence of rebound hypertension in the dexmedetomidine or propofol and midazolam arms (16.7% vs 17.9%, p=0.837). The titration timeframe for the dexmedetomidine infusion, defined as the time from peak infusion rate until discontinuation, was significantly shorter in patients with rebound hypertension (median duration, 4 hrs) compared with patients who did not have rebound hypertension (median duration, 17 hrs; p=0.011). CONCLUSION: There was no difference in the incidence of rebound hypertension observed with dexmedetomidine discontinuation compared with propofol or midazolam. Instead, history of hypertension and a shorter weaning duration appear to be associated with increased risk of rebound hypertension regardless of the sedative used.

Oxandrolone in pediatric patients with severe thermal burn injury.

OBJECTIVE: To review the role of oxandrolone in pediatric patients with severe thermal burn injury. DATA SOURCES: MEDLINE (1950-April 2008) and Science Citation Index (1900-April 2008) searches were performed using the key terms oxandrolone, burn, and children. STUDY SELECTION AND DATA EXTRACTION: All English-language articles that evaluated the efficacy and safety of oxandrolone in pediatric patients with severe thermal burn injury were included in this review. DATA SYNTHESIS: Oxandrolone stimulates protein synthesis by binding to androgen receptors. The efficacy and safety of adjunct oxandrolone therapy in pediatric patients (20%) were evaluated in 8 clinical studies. Oral oxandrolone 0.1 mg/kg twice daily increased protein synthesis, lean body mass accretion, and muscle strength; improved serum visceral protein concentrations; promoted weight gain; and increased bone mineral content. During the postburn rehabilitation period, oxandrolone 0.1 mg/kg/day improved muscle strength, especially when combined with exercise. Based on clinical studies, oxandrolone 0.1 mg/kg twice daily is safe when given for up to 12 months. However, mild increases in serum liver transaminase concentrations and reversible sexual changes were observed during therapy. Although data on the efficacy and safety of oxandrolone in severely burned children are supported by prospective, randomized, controlled studies, limitations of available data are that they originated from a single study center and that wound healing measurement is lacking in children with severe thermal burns. CONCLUSIONS: The benefits of adjunct oxandrolone therapy in severely burned pediatric patients have been demonstrated in the acute postburn injury and long-term postburn rehabilitation periods. Close monitoring of liver function, sexual development, and growth pattern is recommended during oxandrolone treatment.

Does body weight impact the efficacy of vasopressin therapy in the management of septic shock?

BACKGROUND: Vasopressors used for the management of septic shock are often dosed according to body weight. Use of vasopressin for physiologic replacement in patients with septic shock is usually administered as a standard non-weight-based dose. We hypothesized that the efficacy of vasopressin may be influenced by body weight. PURPOSE: The primary objective was to determine if the effects of vasopressin on other vasopressor dosing requirements is related to body weight. Secondary objectives included evaluation of blood pressure and heart rate after the start of vasopressin infusion. METHODS: A retrospective, cohort study in a large academic health center was conducted. Sixty-four adult inpatients with septic shock (26 medical intensive care unit and 38 surgical intensive care unit) who required vasopressor administration including vasopressin therapy were included. Dosing requirements of vasopressors were captured 1 hour before and during the hour of vasopressin initiation and 2 and 4 hours later. Other information collected during the study period included blood pressure, mean arterial pressure, and heart rate. RESULTS: Most of the patients (n = 61) received vasopressin at a dose of 0.04 U/min. Changes in vasopressor dosing were significantly correlated with weight-adjusted vasopressin at 2 hours (correlation coefficient = -0.36, P = .03) and 4 hours (correlation coefficient = -0.46, P < .001). Use of vasopressin was associated with significant increases in systolic blood pressure, diastolic blood pressure, and mean arterial pressure at each time point compared with baseline. CONCLUSIONS: Effects of vasopressin on catecholamine dosing requirements in the setting of septic shock may be influenced by body weight. Prospective studies are needed to examine weight-based dosing of vasopressin in this setting.

Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression.

STUDY OBJECTIVE: To evaluate the efficacy, safety, and costs of rabbit antithymocyte globulin (TMG) induction in patients who received kidney transplants from living unrelated donors. DESIGN: Retrospective cohort study. SETTING: Large academic medical center. PATIENTS: Eighty-seven patients who received kidney transplants from living unrelated donors: 40 of the recipients underwent transplantation between January 1, 2003, and December 31, 2004, and did not receive TMG induction (no induction group); 47 underwent transplantation between January 1, 2005, and June 30, 2006, and received TMG induction (induction group). All patients received cyclosporine-based immunosuppression. MEASUREMENTS AND MAIN RESULTS: Biopsy-proven acute rejection, posttransplantation complications, and inpatient hospital costs for the first 12 months after transplantation were compared between groups using standard univariate statistical analyses. Induction significantly decreased the occurrence of biopsy-proven acute rejection versus no induction (2% vs 48%, p<0.001). Fifty percent of rejection episodes in the no induction group required hospitalization, and 46% of rejection episodes required TMG treatment. Slightly elevated initial costs associated with TMG induction were offset by lower costs related to rejection treatment. Total inpatient costs for the 12 months after transplantation were comparable between the groups (no induction $66,038 vs induction $74,183, p>0.05). For the no induction versus induction groups, no significant differences in cytomegalovirus disease (5% vs 6%), malignancy (3% vs 2%), graft failures (5% vs 6%), mortality (5% vs 4%), and serum creatinine concentrations (mean +/- SD 1.4 +/- 0.3 vs 1.5 +/- 0.3 mg/dl) were observed at 12 months (p>0.05 for all comparisons). CONCLUSION: Five-day TMG induction effectively reduced the 1-year acute rejection rate without significantly increasing total inpatient costs or posttransplantation complications among recipients of kidney transplants from living unrelated donors.