Captopril Versus Hydralazine-Isosorbide Dinitrate Vasodilator Protocols in Patients With Acute Decompensated Heart Failure Transitioning From Sodium Nitroprusside.

BACKGROUND: The role of oral vasodilators in the management of acute decompensated heart failure (ADHF) is not clearly defined. We evaluated the use of captopril vs hydralazine-isosorbide dinitrate (H-ISDN) in the transition from sodium nitroprusside (SNP) in patients with ADHF. METHODS AND RESULTS: A retrospective chart review was performed of 369 consecutive adult patients in the intensive care unit with ADHF and reduced ejection fraction, who received either a captopril or an H-ISDN protocol to transition from SNP. Captopril patients were matched 1:2 to H-ISDN patients, based on serum creatinine and race (Black vs non-Black). Baseline demographics, serum chemistry and use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were similar in both groups. Time to SNP discontinuation (46.9 vs 40.4 hours, P = 0.11) and length of hospital stay (9.86 vs 7.99 days, P = 0.064) were similar in both groups. Length of hospital stay in the intensive care unit was statistically shorter in the H-ISDN group (4.11 vs 3.96 days, P = 0.038). Fewer H-ISDN protocol patients were discharged on ACEis/ARBs (82.9 % vs 69.9%, P = 0.003) despite similar kidney function at time of discharge (serum creatinine 1.1 vs 1.2, P = 0.113). No difference was observed in rates of readmission (40.7% vs 50%, P = 0.09) or mortality (16.3% vs 17.5 %, P = 0.77) at 1 year postdischarge. CONCLUSION: Similar inpatient and 1-year outcomes were observed between patients using H-ISDN vs ACEi when transitioning from SNP, even though fewer H-ISDN protocol patients were discharged taking ACEis/ARBs despite similar kidney function.

Characteristics of Heart Failure Patients With or Without Hypotension When Transitioning From Nitroprusside to Sacubitril-Valsartan.

BACKGROUND: Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Little is known about outcomes of HFrEF patients transitioned from sodium nitroprusside (SNP) to sacubitril-valsartan during an admission for acute decompensated heart failure. We sought to describe characteristics of patients initiated on sacubitril-valsartan while receiving SNP and, in particular, those patients who did and did not experience hypotension requiring interruption or discontinuation of sacubitril-valsartan. METHODS: We performed a retrospective case series of adult patients (>18 years) with HFrEF (left ventricular ejection fraction ≤40%) admitted to the University of Michigan cardiac intensive care unit between July 2018 to September 2020 who received sacubitril-valsartan while on SNP. RESULTS: A total of 15 patients with acute decompensated heart failure were initiated on sacubitril-valsartan while on SNP. The mean age was 57 ± 15.9 years. Seven (46.7%) patients experienced hypotension. The patients in the cohort who experienced hypotension were numerically older (60 ± 17 vs. 55 ± 15.5), and the majority were white (86%). Patients with hypotension had a numerically lower left ventricular ejection fraction (13 ± 4.2 vs. 18 ± 8.2) and higher serum creatinine (1.4 ± 0.54 vs. 0.88 ± 0.25). Seven (100%) patients received a diuretic on the day of sacubitril-valsartan initiation in those who experienced hypotension compared with 2 (25%) in those who did not experience hypotension. CONCLUSIONS: In almost half of patients admitted to the cardiac intensive care unit with acutely decompensated HFrEF, significant hypotension was seen when initiating sacubitril-valsartan while on SNP. Future studies should evaluate appropriate patients for this transition and delineate appropriate titration parameters.

S-Equol Protects Chondrocytes against Sodium Nitroprusside-Caused Matrix Loss and Apoptosis through Activating PI3K/Akt Pathway.

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.

Pharmacologic Control of Blood Pressure in Infants and Children.

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.

Incorporation of Nitroprusside on Silica Nanoparticles-A Strategy for Safer Use of This NO Donor in Therapy.

Silica-based nanoparticles have been developed as powerful platforms for drug delivery and might also prevent undesired side effects of drugs. Here, a fast method to synthesize positively charged mesoporous silica nanoparticles (ζ = 20 ± 0.5 mV, surface area = 678 m2 g-1, and 2.3 nm of porous size) was reported. This nanomaterial was employed to anchor sodium nitroprusside (SNP), a vasodilator drug with undesired cyanide release. A remarkable incorporation of 323.9 ± 7.55 µmol of SNP per gram of nanoparticle was achieved, and a series of studies of NO release were conducted, showing efficient release of NO along with major cyanide retention (ca. 64% bound to nanoparticle). Biological assays with mammalian cells showed only a slight drop in cell viability (13%) at the highest concentration (1000 µM), while SNP exhibited an LC50 of 228 µM. Moreover, pharmacological studies demonstrated similar efficacy for vasodilation and sGC-PKG-VASP pathway activation when compared to SNP alone. Altogether, this new SNP silica nanoparticle has great potential as an alternative for wider and safer use of SNP in medicine with lower cyanide toxicity.

t-Resveratrol Protects against Acute High Glucose Damage in Endothelial Cells.

Postprandial hyperglycemia in diabetic and nondiabetic subjects is associated with endothelial dysfunction. Evidence shows that high glucose generates oxidative stress and a pro-inflammatory state promoting the development of cardiovascular diseases. trans-Resveratrol (t-RV) has been shown to reduce cardiovascular risk. To determine whether t-RV acts as a protector against acute high glucose (AHG)-induced damage, two in vitro models, rat aortic rings (RAR) and human umbilical vein endothelial cells (HUVEC) were used. RAR pretreated with AHG (25 mM D-glucose) for 3 h dramatically decreased the endothelium-dependent relaxation (EDR) induced by acetylcholine in phenylephrine (PE)-precontracted vessels. However, coincubation with t-RV significantly mitigated the damage induced by AHG on EDR. Pretreatment with AHG did not affect the vasodilation induced by sodium nitroprusside. HUVEC treated with t-RV decreased cytotoxicity and reduced radical oxygen species production induced by AHG. Taken together, these results suggest that t-RV can mitigate the AHG-induced EDR damage through a mechanism involving ROS scavenging and probably an increase in the bioavailability of NO.

Metformin Exposure During Pregnancy and Lactation Did Not Cause Vascular Reactivity Alteration in Adult Male Offsprings.

Metformin has been used for the treatment of some metabolic diseases during gestation and the beneficial effects of metformin to the vascular system have been described in diabetic and obese animal models. Nevertheless, the long-term consequences to the vascular system of offsprings maternally exposed to metformin have not yet been characterized. Therefore, we want to test the hypothesis that gestational and lactational exposure to metformin would be safe for the vascular reactivity of male adult offsprings. Wistar female rats were treated with metformin 293 mg·kg·d, by gavage, from gestational day (GD) 0 to GD 21 (METG) or GD 0 until postnatal day 21 (METGL). Control dams received water by gavage in the same periods (CTRG and CTRGL). In male offsprings (75 days), the aortic reactivity to phenylephrine, acetylcholine, and sodium nitroprusside in the presence or absence of endothelium were evaluated. The results demonstrated that aortic contraction and relaxation were similar between groups. These data showed that metformin exposure during pregnancy and lactation did not interfere with aortic reactivity, suggesting that metformin exposure during gestational and lactation are safe for the offsprings' vascular system.

Thiocyanate Accumulation in Critically Ill Patients Receiving Nitroprusside Infusions.

PURPOSE: This study evaluated thiocyanate concentrations and factors associated with thiocyanate accumulation in intensive care unit patients receiving nitroprusside with and without sodium thiosulfate coadministration. MATERIALS AND METHODS: This retrospective study evaluated critically ill adults who received nitroprusside infusions and had at least one thiocyanate concentration. Patients with thiocyanate accumulation (concentrations ≥30 µg/mL) were compared to patients without accumulation. Factors associated with accumulation were determined by Spearman correlation and multivariate regression. RESULTS: Thiocyanate concentrations (n = 192) were obtained from 87 patients. Fourteen of the 87 (16%) patients experienced thiocyanate accumulation with a mean (SD) thiocyanate concentration of 44 ± 11 µg/mL. Patients with accumulation had received greater cumulative nitroprusside doses (28 vs 8.2 mg/kg, P < .01), greater cumulative sodium thiosulfate doses (16.8 vs 10.1 mg/kg, P < .01), and longer infusion durations (10.9 vs 6.0 days, P < .01), compared to patients without accumulation. Sodium thiosulfate coadministration resulted in greater thiocyanate concentrations (22.8 ± 16.7 vs 16.8 ± 14.9 µg/mL, P = .01), despite utilization of lower cumulative nitroprusside doses (10.2 vs 14.6 mg/kg, P = .03). Cumulative nitroprusside dose ( r2 .44, P < .001) and cumulative sodium thiosulfate dose ( r2 .32, P < .001) demonstrated a significant correlation with measured thiocyanate concentrations. Thiocyanate accumulation was independently associated with cumulative nitroprusside dose in mg/kg (regression coefficient 0.75, 95% CI 0.63-0.89; P < .01). No clinically significant adverse effects of cyanide or thiocyanate toxicity were observed. CONCLUSIONS: Cumulative nitroprusside dose was independently associated with thiocyanate accumulation. Despite elevated thiocyanate levels in 16% of patients, there was no clinical evidence of cyanide or thiocyanate toxicity. Routine monitoring of thiocyanate concentrations appears most warranted in patients receiving higher cumulative doses of nitroprusside.

Protective effects of melatonin on the activity of SOD, CAT, GSH-Px and GSH content in organs of mice after administration of SNP.

Sodium nitroprusside (SNP) is an antihypertensive drug with proven dose-dependent toxic effects attributed mainly to the production of cyanide but also excesive nitric oxide (NO) and derived reactive species. The present study evaluated whether melatonin administration would have time-dependent protective effect against SNP−induced toxicity. Male Swiss mice were used in this study. Control mice were treated with 0.9% NaCl; the second group was injected with 10 mg melatonin (MEL)/kg body weight (b.w.); the third group was given SNP at the dose of 3,6 mg/kg b.w.; the fourth group received both MEL and SNP at the same doses. In homogenates of brain, liver and kidneys, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were estimated after 3, 6 and 24 h of drugs administration. The concentration of reduced glutathione (GSH) was also evaluated in the blood, brain, liver and kidneys of mice at the same time intervals. In animals receiving MEL, the highest levels of GSH were observed in all the organs as compared to the control after 3, 6 h. Meanwhile, SNP decreased GSH concentration in the blood, brain, liver and kidneys in all time intervals. Administration of MEL in combination with SNP increased the GSH levels in all organs, as compared to the administration of SNP alone; this effect was observed after 3, 6 and 24 h. The activity of SOD, CAT and GSH-Px in the MEL-treated group increased after 3 h in all the organs, while in liver and kidney the increase was also observed after 6 h. Conversely, the SNP intoxication caused a decrease of the activity of enzymes in the tested organs in all intervals, while administration of MEL + SNP resulted in increased activities of SOD, CAT and GSH-Px in all the organs after 3 h and 6 h. The investigation carried out in the present study provide new data to add to the study of antioxidant properties of MEL and SNP-induced oxidative stress with regard to time-dependent properties in different types of tissues.

Rice bran extract improves mitochondrial dysfunction in brains of aged NMRI mice.

OBJECTIVES: Aging represents a major risk factor for neurodegenerative diseases such as Alzheimer's disease. Mitochondria are significantly involved in both the aging process and neurodegeneration. One strategy to protect the brain and to prevent neurodegeneration is a healthy lifestyle including a diet rich in antioxidants and polyphenols. Rice bran extract (RBE) contains various antioxidants including natural vitamin E forms (tocopherols and tocotrienols) and gamma-oryzanol. In this work, we examined the effects of a stabilized RBE on mitochondrial function in 18-month-old Naval Medical Research Institute mice (340 mg/kg body weight/day), which received the extract for 3 weeks via oral gavage. METHODS: Mitochondrial parameters were measured using high-resolution respirometry (Oroboros Oxygraph-2k), Western blot analysis, and photometric methods in dissociated brain cells, isolated mitochondria, and brain homogenate. Vitamin E concentrations in blood plasma and brain tissue were measured using HPLC with fluorescence detection. RESULTS: Aging leads to decreased mitochondrial function (decreased mitochondrial respiration and ATP production) and decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha). RBE administration increased alpha-tocopherol concentrations in the brain and compensated for age-related mitochondrial dysfunction by increasing mitochondrial respiration, membrane potential, PGC1alpha protein expression, and citrate synthase activity. Furthermore, resistance of brain cells to sodium nitroprusside-induced nitrosative stress was improved. DISCUSSION: According to these results, RBE is a promising candidate nutraceutical for the prevention of age-related neurodegenerative diseases.

Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients.

OBJECTIVE: Sodium nitroprusside is a direct-acting vasodilator used to lower blood pressure in the operating room and ICU. The efficacy of sodium nitroprusside has been analyzed in few pediatric randomized trials. This study assesses the efficacy and safety of sodium nitroprusside following at least 12 hours of IV infusion in children. DESIGN: Randomized, double-blind withdrawal to placebo study. SETTING: ICUs. PATIENTS: Pediatric patients younger than 17 years. INTERVENTIONS: Following 12-24 hours of open-label sodium nitroprusside titration, a blinded infusion of sodium nitroprusside or placebo was administered (at the stable rate used at the end of the open-label phase) for up to 30 minutes. MEASUREMENTS AND MAIN RESULTS: The primary efficacy measure was whether control of mean arterial blood pressure was lost, that is, increased above ambient baseline for two consecutive minutes during the blinded phase. The proportion of patients who lost mean arterial blood pressure control in the placebo group (15/19; 79%) was significantly different than those in the sodium nitroprusside group (9/20; 45%) (p = 0.048). Three patients experienced rebound hypertension during the blinded phase, and all were in the placebo group. Serious adverse event rates were low (7/52; 13%), and in only one patient was the serious adverse event determined to be related to sodium nitroprusside by the site investigator. Fourteen patients (27%) had whole blood cyanide levels above 0.5 µg/mL, with high correlation (0.7) between infusion rate and cyanide levels, but there were few clinical signs of cyanide toxicity. CONCLUSIONS: Sodium nitroprusside is efficacious in maintaining mean arterial blood pressure control in children following a 12-hour infusion. Although a high proportion of patients were found to have elevated cyanide levels, toxicity was not observed.

Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist.

Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open-label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra-arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 µg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8-3.2 µg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra-arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3-200 µg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230-320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra-arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.

Sodium nitroprusside infusion in patients with advanced heart failure.

AIMS: Advanced heart failure (AdvHF) poses significant treatment challenges, particularly when mechanical circulatory support or transplant options are unavailable, highlighting a gap in evidence-based medical management. The aim of this study was to evaluate the safety and effectiveness of sodium nitroprusside infusion (SNP) for enhancing systemic and renal perfusion in patients with AdvHF, with or without concomitant inotropic support. METHODS AND RESULTS: We retrospectively analyzed the medical records of 406 patients with AdvHF admitted between October 2014 and September 2018 who received nocturnal SNP infusions for at least one week. In 55 patients with symptomatic hypotension or signs of peripheral hypoperfusion (differential systemic BP < 15 mmHg), continuous dobutamine infusion was added. In a subset of 155 patients who required multiple hospitalizations (median 3), data from the last hospitalization were used. No symptomatic hypotension leading to discontinuation of SNP (mean dose: 0.5 ± 0.1 µg/kg/min) was reported. Patients showed a significant increase in differential systemic blood pressure after infusion (29.2 ± 8.1 to 36.8 ± 11.6 mmHg, p < 0.001) independent of dobutamine use. Administration of SNP and dobutamine resulted in greater weight loss compared to SNP alone (-5.33 ± 7.02 vs -3.32 ± 4.0 kg, p < 0.003), but it was also associated with a significant increase in creatinine levels compared to SNP alone (+0.24 ± 0.87 vs +0.02 ± 0.43, p = 0.005). CONCLUSIONS: The results show that SNP is a safe therapeutic choice in AdvHF patients with or without concomitant inotropic support and highlight the potential efficacy of nitroprusside in improving systemic and renal perfusion in these advanced patients.

The effect of sodium nitroprusside on cerebral hemodynamics and headache in healthy subjects.

INVESTIGATION: Sodium nitroprusside (SNP) is a powerful vasodilatory agent that, similarly to glyceryl trinitrate (GTN), releases nitric oxide (NO) but in contrast does not pass the blood-brain barrier. Nevertheless, it has already been used in animal models without any knowledge of its headache-inducing potential. We hypothesized that SNP would induce headache and vasodilation of cephalic and radial but not cerebral arteries. METHODS: Five healthy volunteers received intravenous infusions of SNP in a non-randomized dose-titration (1-5 µg/kg/min) study. We recorded headache intensity (verbal rating scale from 0 to 10), velocity in the middle cerebral artery (VMCA), and diameters of the superficial temporal artery (STA) and radial artery (RA). RESULTS: All participants reported a dose-related headache (median peak = 2.5, range 0-3). SNP dilated the STA and RA, caused a marked increase of heart rate and a decrease of mean arterial pressure (MAP) and partial pressure of end-tidal carbon dioxide (PetCO2). We found that SNP decreased the velocity of the VMCA, but this was canceled by a decrease of cerebral blood flow (CBF) due to hypocapnia. CONCLUSION: The present study shows that SNP is a headache-inducing agent with close similarities to headaches induced by GTN and probably without effect on intracerebral arteries.

Experimental study on the effect of controlled hypotension levels on rabbit CA1 neurons.

OBJECTIVE: The present study investigated the effect of controlled hypotension (CH) levels regulated by nitroprusside on hippocampal CA1 neurons. MATERIALS AND METHODS: All experimental rabbits were randomly divided into five groups to perform CH for recording their vital signs and survived for a certain time. The arterial blood was collected to measure the serum levels of interleukin 6 and tumor necrosis factor α and then the brain tissues were perfused and sectioned to carry out hematoxylin-eosin staining, TdT-mediated dUTP nick end labeling fluorescence, c-fos immunohistochemistry, and ultrastructural observation of hippocampal neuronal mitochondria. All data were analyzed with SPSS13.0 software, and P < 0.05 was indicated as statistically significant. RESULTS: Heart rate, mean arterial pressure, and the dosage of sodium nitroprusside were not statistically significant between groups, but at T2, heart rate levels in groups II-IV were lower than those in groups I and V. Simultaneously, interleukin 6 was remarkably overexpressed in group II than in other groups at T2, whereas tumor necrosis factor α was higher in groups I-III than in groups IV and V. At the light and electronic microscopic levels, the CA1 regional neurons of group IV were more seriously damaged and deranged compared with other groups so was the expression of c-fos. However, fluorescence from TdT-mediated dUTP nick end labeling assay was more intensive in groups II-IV than that in other groups. Results further showed that Flameng scores of mitochondria were the highest in group IV, but they were not statistically significant among the other groups. CONCLUSIONS: The different levels of CH remarkably affected the functional activities of hippocampal CA1 neurons; with the decrease of mean arterial pressure, neuronal apoptosis, and c-fos expression was gradually increased and reached the peak in 45% of basic values of blood pressure.

Sodium nitroprusside for advanced heart failure. A metanalysis of literature data.

Advanced heart failure (HF) is associated with a very poor prognosis and places a big burden on health-care services. The gold standard treatment, i.e. long-term mechanical circulatory support or heart transplantation, is precluded in many patients but observational studies suggest that the use of SNP might be associated with favourable long-term clinical outcomes. We performed a metanalysis of published studies that compared sodium nitroprusside (SNP) with optimal medical therapy to examine the safety and efficacy of SNP as part of the treatment regimen of patients hospitalized for advanced heart failure (HF). We searched PUBMED, EMBASE and WEB OF SCIENCE for studies that compared SNP with optimal medical therapy in advanced HF on July 2022. After screening 700 full-text articles, data from two original articles were included in a combined analysis. The analysis demonstrated a 66% reduction in the odds of death in advanced HF patients treated with SNP. The results show the potential importance of the inclusion of SNP in the treatment regimen of patients hospitalized because of advanced HF and underlines that controlled, randomized studies are still required in this condition.

The efficacy and safety of sodium nitroprusside in the treatment of schizophrenia: Protocol for an updated systematic review and meta-analysis.

BACKGROUND: Schizophrenia is a chronic persistent disease with high recurrence rate and high disability rate in the field of psychiatry. Sodium nitroprusside is a nitric oxide (NO) donor and considered a promising new compound for the treatment of schizophrenia. New high-quality clinical trials of sodium nitroprusside in the treatment of schizophrenia have been published in recent years. It is necessary to re-conduct the meta-analysis after the inclusion of these new clinical trials. Our study will conduct a systematic review and meta-analysis of the relevant literature in this field, so as to lay an evidence-based medicine foundation for the efficacy of sodium nitroprusside in the treatment of schizophrenia. METHODS AND ANALYSIS: Randomized controlled trials (RCTs) of sodium nitroprusside in the treatment of schizophrenia were searched through English databases (PubMed, Web of Science, Embase, and Cochrane Library) and Chinese databases (China Biology Medicine disc, VIP, WanFang Data, and CNKI). The extracted data will be inputted into Review Manager 5.3 for Meta-analysis. The included literature will be assessed for bias risk according to the bias risk assessment tools in the Cochrane Handbook for Systematic Reviews of Interventions. Funnel plots will be used to assess possible publication bias. Heterogeneity is tested by I2 and χ2 tests, and the existence of heterogeneity is defined as I2 ≥50% and P ≤0.1. If heterogeneity exists, the random-effect model will be used, and sensitivity analysis or subgroup analysis will be performed to further determine the source of heterogeneity. PROSPERO REGISTRATION NUMBER: CRD42022341681.

A biphasic response to nitric oxide donation in an ex vivo model of donation after cardiac death renal transplantation.

BACKGROUND: Donation after cardiac death (DCD) donors are vital to maximize the organ donor pool. Reperfusion injury (RI) is an important sequela in DCD organs due to warm and cold ischemia. RI manifests clinically as a high incidence of delayed graft function (DGF) and primary non-function (PNF) compared with donation after brain death organs. The importance of nitric oxide (NO) in the generation of reperfusion injury is pivotal. METHODS: Using an ex vivo porcine model of kidney transplantation the effects of reperfusion with and without NO supplementation on initial renal blood flow and function were compared. Real-time hemodynamic measurements were recorded and biochemical samples taken at set time-points. Molecular markers of reperfusion injury were also measured. Sodium nitroprusside was chosen as the NO donor. RESULTS: Results showed that NO donation initially improved renal blood flow significantly over controls; at the end of reperfusion this benefit was lost. In addition, there was an improvement in creatinine clearance, fractional excretion of sodium and renal oxygen consumption. There were observed to be higher levels of urinary nitrite/nitrate excretion, but no difference in isoprostane levels. CONCLUSION: This study represents a good model for the initial reperfusion period in large animal renal transplantation. The improvement in renal blood flow observed in the NO supplemented groups represents NO mediated vasodilatation. Later in reperfusion, accumulation of nitrogenous free radicals impairs renal blood flow. Clinically, NO supplementation during initial reperfusion of DCD kidneys improves renal blood flow but should be considered with caution due to potential deleterious effects of nitrogenous compound accumulation.

Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.

BACKGROUND: Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP) administration, accidental smoke inhalation, industrial mishaps, and bio-terrorism. In this study, we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate. METHODS: SNP study: A pilot study in 11 anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates, and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, 8 anesthetized pigs received a high-dose i.v. infusion of SNP (100 mg/h) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5 g i.v.) every hour after induction of severe CN toxicity, and 4 pigs received placebo. NaCN study: A pilot study was conducted in 4 spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of 6 pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g i.v.) followed by a repeat dose 60 minutes later in surviving animals. RESULTS: SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (P < 0.05) accompanied by severe lactic acidemia (P < 0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (P < 0.05), whereas the placebo-treated pigs deteriorated and did not survive (P < 0.05). NaCN study: NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote. CONCLUSIONS: CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.

Primary erythromelalgia in a 12-year-old boy: positive response to sodium channel blockers despite negative SCN9A mutations.

Erythromelalgia is a rare disorder characterized by recurrent pain attacks, swelling and redness in the distal extremities. The primary forms of the disorder are caused by mutations in voltage-gated sodium channels. Treatment is difficult and controlled therapeutic studies offer little to no guidance. We report on a 12-year-old boy and his first occurrence of primary erythromelalgia. Genetic findings for mutations in the SCN9A gene, which encodes for the α-subunit of sodium channel NaV1.7, were negative. Although initial treatment with sodium nitroprusside was ineffective, subsequent medication with lidocaine and mexiletine, in combination with gabapentin, was successful. Despite negative findings for mutations in the sodium channels, the use of sodium channel blockers should be considered in these patients.