sodium-bicarbonate and Disease-Models--Animal

Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Contrast Media; Disease Models, Animal; Erythropoietin; Free Radical Scavengers; Humans; Research Design; Sodium Bicarbonate; Translational Research, Biomedical

To date, there is no evidence showing a benefit from any advanced cardiac life support (ACLS) medication in out-of-hospital cardiac arrest (OOHCA), despite animal data to the contrary. One explanation may be a difference in the time to first drug administration. Our previous work has shown the mean time to first drug administration in clinical trials is 19.4min. We hypothesized that the average time to drug administration in large animal experiments occurs earlier than in OOHCA clinical trials.. We conducted a literature review between 1990 and 2006 in MEDLINE using the following MeSH headings: swine, dogs, resuscitation, heart arrest, EMS, EMT, ambulance, ventricular fibrillation, drug therapy, epinephrine, vasopressin, amiodarone, lidocaine, magnesium, and sodium bicarbonate. We reviewed the abstracts of 331 studies and 197 full manuscripts. Exclusion criteria included: non-peer reviewed, all without primary animal data, and traumatic models. From these, we identified 119 papers that contained unique information on time to medication administration. The data are reported as mean, ranges, and 95% confidence intervals. Mean time to first drug administration in animal laboratory studies and clinical trials was compared with a t-test. Regression analysis was performed to determine if time to drug predicted ROSC.. Mean time to first drug administration in 2378 animals was 9.5min (range 3.0-28.0; 95% CI around mean 2.78, 16.22). This is less than the time reported in clinical trials (19.4min, p<0.001). Time to drug predicted ROSC (odds ratio 0.844; 95% CI 0.738, 0.966).. Shorter drug delivery time in animal models of cardiac arrest may be one reason for the failure of animal studies to translate successfully into the clinical arena.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Administration Schedule; Epinephrine; Heart Arrest; Humans; Lidocaine; Life Support Care; Magnesium Sulfate; Regression Analysis; Sodium Bicarbonate; Time Factors; Vasoconstrictor Agents; Vasopressins

The routine use of sodium bicarbonate in patients with cardiac arrest has been discouraged, with the benefit of outcome evaluation. Current recommendations include an elaborate stratification of circumstances in which bicarbonate is to be used. The physiological and clinical aspects of bicarbonate administration during cardiopulmonary resuscitation in animal and human studies were reviewed. The onset of significant acidemia or alkalemia is associated with adverse system specific effects. The administration of bicarbonate may mitigate the adverse physiological effects of acidemia, improve response to exogenously administered vasopressor agents, or simply increase venous return due to an osmolar effect, resulting in increased coronary perfusion pressure. Likewise, bicarbonate may have adverse effects in each of these areas. The preponderance of evidence suggests that bicarbonate is not detrimental and may be helpful to outcome from cardiac arrest. An objective reappraisal of the empirical use of bicarbonate or other buffer agents in the appropriate "therapeutic window" for cardiac patients may be warranted.

Topics: Acid-Base Equilibrium; Acidosis; Animals; Central Nervous System; Disease Models, Animal; Heart; Heart Arrest; Hemodynamics; Humans; Lung; Myocardium; Sodium Bicarbonate

Diphenhydramine is a moderately lipophilic antihistamine with sodium channel blockade properties. It is consumed recreationally for mild hallucinogenic and hypnotic effects and causes dysrhythmias, seizures, and death with overdose. Intravenous lipid emulsion is a novel agent used to treat lipophilic drug overdose. Two case reports describe clinical improvement with intravenous lipid emulsion after diphenhydramine toxicity, but no prospective studies have been reported. Our objective is to determine whether intravenous lipid emulsion improved hypotension compared with sodium bicarbonate for severe diphenhydramine toxicity in a model of critically ill swine.. Twenty-four swine weighing 45 to 55 kg were infused with diphenhydramine at 1 mg/kg per minute until the mean arterial pressure reached 60% of baseline. Subjects were randomized to receive intravenous lipid emulsion (bolus of 7 mL/kg and then 0.25 mL/kg per minute) or sodium bicarbonate (2 mEq/kg plus an equal volume of normal saline solution). We measured pulse rate, systolic blood pressure, mean arterial pressure, cardiac output, QRS interval, and serum diphenhydramine level. Twelve animals per group provided a power of 0.8 and α of .05 to detect a 50% difference in mean arterial pressure. We assessed differences between groups with a repeated-measures linear model (MIXED) and Kaplan-Meier estimation methods. We compared systolic blood pressure, mean arterial pressure, and cardiac output with repeated measures ANOVA.. Baseline weight, hemodynamic parameters, QRS interval, time to hypotension, and diphenhydramine dose required to achieve hypotension were similar between groups. After hypotension was reached, there was no overall difference between intravenous lipid emulsion and sodium bicarbonate groups for cardiac output or QRS intervals; however, there were transient differences in mean arterial pressure and systolic blood pressure, favoring intravenous lipid emulsion (difference: mean arterial pressure, sodium bicarbonate versus intravenous lipid emulsion -20.7 [95% confidence interval -31.6 to -9.8]; systolic blood pressure, sodium bicarbonate versus intravenous lipid emulsion -24.8 [95% confidence interval -37.6 to -12.1]). Time to death was similar. One intravenous lipid emulsion and 2 sodium bicarbonate pigs survived. End-of-study mean total serum diphenhydramine levels were similar. The mean lipid layer diphenhydramine level was 6.8 μg/mL (SD 3.1 μg/mL) and mean aqueous layer level 8.6 μg/mL (SD 5.5 μg/mL).. In our study of diphenhydramine-induced hypotensive swine, we found no difference in hypotension, QRS widening, or diphenhydramine levels in aqueous layers between intravenous lipid emulsion and sodium bicarbonate.

Topics: Animals; Diphenhydramine; Disease Models, Animal; Fat Emulsions, Intravenous; Female; Hemodynamics; Hypotension; Pilot Projects; Sodium Bicarbonate; Swine

Carbicarb, sodium bicarbonate, and 5% dextrose were compared for effects on resuscitability in a canine model of electromechanical dissociation after ventricular fibrillation.. 21 healthy mongrel dogs were anesthetized with pentobarbital, intubated, and mechanically supported. They were instrumented to measure heart rate, arterial pressure, pulmonary artery pressure, right atrial pressure, cardiac output, and arterial and mixed venous blood gases. The dogs were then subjected to a protocol that consisted of three successive CPR episodes. During each episode they were treated with repeated injections of one of the three substances, randomly chosen. After two minutes of ventricular fibrillation and four minutes of electromechanical dissociation, CPR was started with a thumper (rate, 60; duty cycle, 50%). If recovery was not obtained after five minutes of CPR, 1 mEq/kg carbicarb or sodium bicarbonate or 5 mL D5W was injected in the right atrium. Half the dose of the same substance was injected every five minutes thereafter; 1 mg epinephrine was also injected every five minutes until recovery. Hemodynamic and gasometric evaluations were performed five and 20 minutes after recovery. This later evaluation served as baseline for the next CPR episode.. The duration and success rates of CPR are similar in the three CPR groups. Hemodynamic parameters were also similar during recovery. Bicarbicarb and sodium bicarbonate increased bicarbonate levels and corrected pH in the arterial and mixed venous blood. There was no difference in the blood gas values after carbicarb and sodium bicarbonate.. In this model of cardiac arrest, carbicarb was not superior to sodium bicarbonate in the correction of metabolic acidosis during CPR.

Topics: Acidosis, Lactic; Animals; Bicarbonates; Blood Gas Analysis; Carbonates; Clinical Protocols; Disease Models, Animal; Dogs; Drug Combinations; Glucose; Heart Arrest; Hemodynamics; Resuscitation; Sodium; Sodium Bicarbonate

Hepatic injury induced by ischemia and reperfusion (HIRI) is a major clinical problem after liver resection or transplantation. The polarization of macrophages plays an important role in regulating the severity of hepatic ischemia/reperfusion injury. Recent evidence had indicated that the ischemia induces an acidic microenvironment by causing increased anaerobic glycolysis and accumulation of lactic acid. We hypothesize that the acidic microenvironment might cause the imbalance of intrahepatic immunity which aggravated HIRI. The hepatic ischemia/reperfusion injury model was established to investigate the effect of the acidic microenvironment to liver injury. Liposomes were used to deplete macrophages

Topics: Animals; Benzophenones; Cells, Cultured; Cellular Microenvironment; Disease Models, Animal; Hydrogen-Ion Concentration; Immunity, Innate; Kupffer Cells; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Reperfusion Injury; Severity of Illness Index; Signal Transduction; Sodium Bicarbonate; Tyrosine

We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation.. We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage.. Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked.. This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Topics: Animals; Cations, Monovalent; Disease Models, Animal; Dogs; Female; Humans; Hydrogen-Ion Concentration; Hypertonic Solutions; Infusions, Intravenous; Kidney; Renal Elimination; Sodium; Sodium Bicarbonate; Tissue Distribution; Water-Electrolyte Imbalance

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have potential advantages over sutures and staples for wound closure, hemostasis, and integration of implantable devices onto wet tissues. However, existing bioadhesives display several limitations including slow adhesion formation, weak bonding, low biocompatibility, poor mechanical match with tissues, and/or lack of triggerable benign detachment. Here, we report a bioadhesive that can form instant tough adhesion on various wet dynamic tissues and can be benignly detached from the adhered tissues on demand with a biocompatible triggering solution. The adhesion of the bioadhesive relies on the removal of interfacial water from the tissue surface, followed by physical and covalent cross-linking with the tissue surface. The triggerable detachment of the bioadhesive results from the cleavage of bioadhesive's cross-links with the tissue surface by the triggering solution. After it is adhered to wet tissues, the bioadhesive becomes a tough hydrogel with mechanical compliance and stretchability comparable with those of soft tissues. We validate in vivo biocompatibility of the bioadhesive and the triggering solution in a rat model and demonstrate potential applications of the bioadhesive with triggerable benign detachment in ex vivo porcine models.

Topics: Adhesiveness; Animals; Biocompatible Materials; Cross-Linking Reagents; Disease Models, Animal; Female; Hydrogels; Materials Testing; Rats; Sodium Bicarbonate; Solutions; Succinimides; Surgical Wound; Swine; Tissue Adhesives; Wound Closure Techniques

Bupivacaine cardiotoxicity mainly manifests as inhibition of the cardiac sodium channel, which slows conduction, particularly at the ventricular level. Experimental studies have demonstrated that intravenous lipid emulsions (ILEs) can reduce the cardiotoxic effects of bupivacaine, but the extent of these effects is controversial. Sodium bicarbonate (B) represents the standard treatment of toxicity related to sodium channel-blocking drugs. The aim of this study was to compare the effects of ILEs and B on the speed of recovery from bupivacaine-induced effects on the electrocardiographic parameters.. Bupivacaine 4 mg/kg was administered to 24 anesthetized pigs. Three minutes after delivering the bupivacaine bolus, the animals were given the following: ILE 1.5 mL/kg followed by 0.25 mL/kg/min (ILE group) and B 2 mEq/kg followed by 1 mEq/kg/h (B group). Controls (C group) were given saline solution, 50 mL followed by 1 mL/kg/h. Electrophysiological parameters were evaluated in sinus rhythm and during right ventricular pacing at several time intervals up to 30 minutes. Data were analyzed as the area under the curve (AUC) for the first 10 minutes (AUC10) or 30 minutes (AUC30).. Bupivacaine increased the sinus cycle length, PR interval, and QRS duration. AUC30 of the sinus rhythm QRS duration after antidote administration was significantly different among the 3 groups (P = .003). B group experienced faster recovery from intoxication than the C group (AUC10, P = .003; AUC30, P = .003) or the ILE group (AUC10, P = .018). During the first minute, 50% of the B group (versus 0% of the ILE and C groups) had recovered >30% of QRS duration (P = .011). The trend toward faster recovery in the ILE group than in the C group did not reach significance (AUC10, P = .23; AUC30, P = .06). Effects on the paced QRS duration at a rate of 150 bpm were more intense but with similar results (B versus C group: AUC10, P = .009; AUC30, P = .009; B versus ILE: AUC10, P = .015; AUC30, P = .024). The recovery process of the paced QRS tended to be slower for all antidotes.. In a closed-chest swine model, B was an effective treatment for electrophysiological alterations caused by established bupivacaine toxicity. At clinical doses, B ameliorated bupivacaine electrocardiographic toxicity faster than ILE. Use-dependent effects of bupivacaine are prominent and delay the effects of both antidotes, but B produces faster recovery than ILE.

Topics: Action Potentials; Anesthetics, Local; Animals; Antidotes; Arrhythmias, Cardiac; Bupivacaine; Cardiotoxicity; Disease Models, Animal; Fat Emulsions, Intravenous; Heart Conduction System; Heart Rate; Recovery of Function; Sodium Bicarbonate; Sus scrofa; Time Factors

The Edelman equation has long guided the expected response of plasma [Na+] to changes in sodium, potassium, and water balance, but recent short-term studies challenged its validity. Plasma [Na+] following hypertonic NaCl infusion in individuals on low-sodium diet fell short of the Edelman predictions supposedly because sodium restriction caused progressive osmotic inactivation of 50% of retained sodium. Here, we examine the validity of this challenge.. We evaluated baseline total body water (TBW) and Na+ space following acute hypertonic NaHCO3 infusion in dogs with variable sodium and potassium stores, including normal stores, moderate depletion (chronic HCl feeding), or severe depletion (diuretics and dietary NaCl deprivation).. TBW (percentage body weight) averaged 65.9 in normals, 62.6 in HCl-induced metabolic acidosis and moderate sodium and potassium depletion, and 57.6 in diuretic-induced metabolic alkalosis and severe sodium and potassium depletion (p < 0.02). Na+ space (percentage body weight) at 30, 60, and 90 min postinfusion averaged 61.1, 59.8, and 56.1, respectively, in normals (p = 0.49); 70.0, 74.4, and 72.1, respectively, in acidotic animals (p = 0.21); and 56.4, 55.1, and 54.2, respectively, in alkalotic animals (p = 0.41). Absence of progressive expansion of Na+ space in each group disproves progressive osmotic inactivation of retained sodium. Na+ space at each time point was not significantly different from baseline TBW in normal and alkalotic animals indicating that retained sodium remained osmotically active in its entirety. However, Na+ space in acidotic animals at all times exceeded by ∼16% baseline TBW (p < 0.01) signifying an early, but nonprogressive, osmotic inactivation of retained sodium, which we link to baseline bone-sodium depletion incurred during acid buffering.. Our investigation affirms the validity of the Edelman construct in normal dogs and dogs with variable sodium and potassium depletion and, consequently, refutes the recent observations in human volunteers subjected to dietary NaCl restriction.

Topics: Animals; Body Water; Diet, Sodium-Restricted; Disease Models, Animal; Dogs; Female; Humans; Hypertonic Solutions; Infusions, Intravenous; Potassium; Sodium Bicarbonate; Water-Electrolyte Imbalance

Tricyclic antidepressants (TCAs) are a major cause of fatal drug poisoning due to their cardiotoxicity. Alkalinization by sodium bicarbonate (NaHCO3) administration, the first-line therapy for TCA-induced cardiotoxicity, can occasionally yield insufficient efficacy in severe cases. Because most TCAs are highly lipophilic, lipid emulsion may be more effective than alkalinization. However, it remains to be determined whether lipid emulsion is more beneficial than alkalinization in reversing amitriptyline-induced cardiotoxicity.. Hemodynamic variables were recorded from in vivo guinea pig models and Langendorff-perfused hearts. Whole-cell patch-clamp experiments were conducted on enzymatically isolated ventricular cardiomyocytes to record fast sodium currents (INa). Lipid solutions were prepared using 20% Intralipid. The pH of the alkaline solution was set at 7.55. We assessed the effect of lipid emulsion on reversing amitriptyline-induced cardiotoxicity, in vivo and in vitro, compared to alkalinization. The data were evaluated by Student t test, 1-way repeated-measures analysis of variance, or analysis of covariance (covariate = amitriptyline concentration); we considered data statistically significant when P < .05.. In the in vivo model, intervention with lipids significantly reversed the amitriptyline-induced depression of mean arterial pressure and prolongation of QRS duration on electrocardiogram more than alkalinization (mean arterial pressure, mean difference [95% confidence interval]: 19.0 mm Hg [8.5-29.4]; QRS duration, mean difference [95% confidence interval] -12.0 milliseconds [-16.1 to -7.8]). In the Langendorff experiments, perfusion with 1% and 2% lipid solutions demonstrated significant recovery in left ventricular developed pressure (LVdevP), maximum change rate of increase of LVdevP (dP/dtmax) and rate-pressure product compared with alkaline solution (LVdevP [mm Hg], alkaline 57 ± 35, 1% lipid 94 ± 12, 2% lipid 110 ± 14; dP/dtmax [mm Hg/s], alkaline 748 ± 441, 1% lipid 1502 ± 334, 2% lipid 1753 ± 389; rate-pressure product [mm Hg·beats·minute], alkaline 11,214 ± 8272, 1% lipid 19,025 ± 8427, 2% lipid 25,261 ± 4803 with analysis of covariance). Furthermore, lipid solutions (0.5%-4%) resulted in greater recovery of hemodynamic parameters at 3 μM amitriptyline. Amitriptyline inhibited INa in a dose-dependent manner: the half-maximal inhibitory concentration (IC50) was 0.39 μM. The IC50 increased to 0.75 μM in the alkaline solution, 3.2 μM in 1% lipid solution, and 6.1 μM in 2% lipid solution. Furthermore, the lipid solution attenuated the use-dependent block of sodium channels by amitriptyline more than alkaline solution. On 30 consecutive pulses at 1 Hz, the current decreased to 50.1 ± 2.1, 60.3 ± 1.9, and 90.4% ± 1.8% in standard, alkaline, and 1% lipid solution, respectively. Even 0.5% lipid solution showed greater effects than the alkaline solution in all experiments.. Lipid emulsion significantly suppressed amitriptyline-induced INa, inhibition, which was likely related to the marked improvement in hemodynamic status observed in vivo and in isolated perfused hearts. These results suggest the superiority of lipid emulsion as the first-line therapy for TCA-induced cardiotoxicity compared to alkalinization therapy.

Topics: Acid-Base Equilibrium; Action Potentials; Alkalies; Amitriptyline; Animals; Arterial Pressure; Cardiotoxicity; Disease Models, Animal; Emulsions; Guinea Pigs; Heart Diseases; Heart Rate; Hydrogen-Ion Concentration; Infusions, Intravenous; Isolated Heart Preparation; Kinetics; Male; Myocytes, Cardiac; Phospholipids; Recovery of Function; Sodium; Sodium Bicarbonate; Soybean Oil; Ventricular Function, Left

Sodium bicarbonate (NaHCO

Topics: Acids; Animals; Blood Glucose; Disease Models, Animal; Fibrosis; Glomerulosclerosis, Focal Segmental; Hemodynamics; Hydrogen-Ion Concentration; Ion Channels; Kidney Tubules; Male; Proteinuria; Rats, Inbred Dahl; Rats, Mutant Strains; Sodium Bicarbonate; Sodium Chloride, Dietary

Chronic ingestion of the acid (H⁺)-producing diets that are typical of developed societies appears to pose a long-term threat to kidney health. Mechanisms employed by kidneys to excrete this high dietary H⁺ load appear to cause long-term kidney injury when deployed over many years. In addition, cumulative urine H⁺ excretion is less than the cumulative increment in dietary H⁺, consistent with H⁺ retention. This H⁺ retention associated with the described high dietary H⁺ worsens as the glomerular filtration rate (GFR) declines which further exacerbates kidney injury. Modest H⁺ retention does not measurably change plasma acid⁻base parameters but, nevertheless, causes kidney injury and might contribute to progressive nephropathy. Current clinical methods do not detect H⁺ retention in its early stages but the condition manifests as metabolic acidosis as it worsens, with progressive decline of the glomerular filtration rate. We discuss this spectrum of H⁺ injury, which we characterize as “H⁺ stress”, and the emerging evidence that high dietary H⁺ constitutes a threat to long-term kidney health.

Topics: Acid-Base Equilibrium; Acidosis; Animals; Diet; Dietary Proteins; Disease Models, Animal; Glomerular Filtration Rate; Homeostasis; Humans; Hydrogen; Kidney; Kidney Diseases; Nephrectomy; Protons; Sodium Bicarbonate; Stress, Physiological

Heat stress and rhabdomyolysis are major risk factors for the occurrence of repeated acute kidney injury in workers exposed to heat and strenuous work. These episodes, in turn, may progress to chronic kidney disease.. The purpose of this study was to test the effect of allopurinol (AP) and sodium bicarbonate on the kidney injury induced by recurrent heat stress dehydration with concomitant repeated episodes of rhabdomyolysis.. The model consisted of heat stress exposure (1 h, 37°C) plus rhabdomyolysis (R) induced by repetitive IM injections of glycerol (7.5 mL/kg BW days) in the rat. In addition, to replicate the human situation, uricase was inhibited (oxonic acid [OA] 750 mg/K/d) to increase uric acid (UA) levels. Additional groups were treated either with AP 150 mg/L, n = 10, bicarbonate (BC; 160 mM, n = 10), or both (AP + BC, n = 10) in drinking water. We also included 2 control groups consisting of normal controls (N-Ref, n = 5) and uricase-inhibited rats (OA, n = 5) that were not exposed to heat or muscle injury. Groups were studied for 35 days.. Uricase-inhibited rats exposed to heat and rhabdomyolysis developed pathway and increased intrarenal oxidative stress and inflammasome activation. Kidney injury could be largely prevented by AP, and also BC, although the treatments were not synergistic.. Increased levels of UA may play an important role in the renal alterations induced by heat stress and continuous episodes of rhabdomyolysis. Therefore, treatments aimed to reduce hyperuricemia may help to decrease the renal burden in these conditions. Clinical trials are suggested to test whether this is also true in humans.

Topics: Acute Kidney Injury; Allopurinol; Animals; Disease Models, Animal; Disease Progression; Glycerol; Heat-Shock Response; Hot Temperature; Humans; Kidney; Male; Occupational Exposure; Oxidative Stress; Oxonic Acid; Rats; Renal Insufficiency, Chronic; Rhabdomyolysis; Sodium Bicarbonate; Treatment Outcome; Urate Oxidase; Uric Acid

Bone defects created after curettage of benign bone tumors are customarily filled with solid poly(methyl methacrylate) (PMMA) or other bone substitutes. In this study, we depicted a porous PMMA-based cement (produced by mixing sodium bicarbonate and citric acid) and evaluated the prospect of its clinic application. Cement samples were characterized by high-performance liquid chromatography (HPLC) coupled to mass spectrometry and its cytotoxicity evaluated in fibroblast cultures. Implantation in rabbits allowed the histologic analysis of bone, kidneys, and liver for toxicity and coagulation tests, and MRI images for hemostasis evaluation. Osseointegration was analyzed through radiography, microtomography (micro-CT), SEM, and histology of sheep specimens. Rabbit specimens were analyzed 1, 4, and 7 days after implantation of porous or solid bone cement in 6.0 mm femoral defects. Sheep specimens were analyzed 3 and 6 months after implantation or not of porous or solid cement in 15.0 mm subchondral tibial defects. The production process did not release any detectable toxic substance but slightly reduced fibroblast proliferation in vitro. Until 7 days after surgery, no local or systemic alterations could be detected in histology, or hematoma formation in histology or MRI. Sheep implants showed 6 mm linear ingrowth from the bone-cement interface and 20% bone ingrowth considering the whole defect area. Radiography, micro-CT, SEM, and histology confirmed these findings. We conclude that our porous PMMA-based cement is an attractive alternative treatment for bone defect filling that combines osseointegration and early weight bearing. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 649-658, 2018.

Topics: Animals; Bone Cements; Bone Substitutes; Bone Transplantation; Cell Line; Cell Survival; Citric Acid; Disease Models, Animal; Humans; Kidney; Liver; Male; Mice; NIH 3T3 Cells; Osseointegration; Polymethyl Methacrylate; Porosity; Rabbits; Sheep; Sodium Bicarbonate

A reliable measurement of brain water content (wet-to-dry ratio) is an important prerequisite for conducting research on mechanisms of brain edema formation. The conventionally used oven-drying method suffers from several limitations, especially in small samples. A technically demanding and time-consuming alternative is freeze-drying.. Centrifugal vacuum concentrators (e.g. SpeedVac/speed-vacuum drying) are a combination of vacuum-drying and centrifugation, used to reduce the boiling temperature. These concentrators have the key advantages of improving the freeze-drying speed and maintaining the integrity of dried samples, thus, allowing e.g. DNA analyses. In the present study, we compared the heat-oven with speed-vacuum technique with regard to efficacy to remove moisture from water and brain samples and their effectiveness to distinguish treatment paradigms after experimental traumatic brain injury (TBI) caused by controlled cortical impact (CCI).. Both techniques effectively removed water, the oven technique taking 24h and vacuum-drying taking 48h. Vacuum-drying showed lower variations in small samples (30-45mg) and was suitable for genomic analysis as exemplified by sex genotyping. The effect of sodium bicarbonate (NaBic8.4%) on brain edema formation after CCI was investigated in small samples (2×1mm). Only vacuum-drying showed low variation and significant improvement under NaBic8.4% treatment.. The receiver operating curves (ROC) analysis demonstrated that vacuum-drying (area under the curve (AUC):0.867-0.967) was superior to the conventional heat-drying method (AUC:0.367-0.567).. The vacuum method is superior in terms of quantifying water content in small samples. In addition, vacuum-dried samples can also be used for subsequent analyses, e.g., PCR analysis.

Topics: Animals; Area Under Curve; Brain Chemistry; Brain Edema; Brain Injuries, Traumatic; Centrifugation; Desiccation; Disease Models, Animal; Feasibility Studies; Genotyping Techniques; Hot Temperature; Male; Mice, Inbred C57BL; Neuroprotective Agents; ROC Curve; Sodium Bicarbonate; Time Factors; Vacuum; Water

Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to mucormycosis, an angioinvasive fungal infection with high mortality. Previously, we demonstrated that Rhizopus invades the endothelium via binding of fungal CotH proteins to the host receptor GRP78. Here, we report that surface expression of GRP78 is increased in endothelial cells exposed to physiological concentrations of β-hydroxy butyrate (BHB), glucose, and iron that are similar to those found in DKA patients. Additionally, expression of R. oryzae CotH was increased within hours of incubation with DKA-associated concentrations of BHB, glucose, and iron, augmenting the ability of R. oryzae to invade and subsequently damage endothelial cells in vitro. BHB exposure also increased fungal growth and attenuated R. oryzae neutrophil-mediated damage. Further, mice given BHB developed clinical acidosis and became extremely susceptible to mucormycosis, but not aspergillosis, while sodium bicarbonate reversed this susceptibility. BHB-related acidosis exerted a direct effect on both GRP78 and CotH expression, an effect not seen with lactic acidosis. However, BHB also indirectly compromised the ability of transferrin to chelate iron, as iron chelation combined with sodium bicarbonate completely protected endothelial cells from Rhizopus-mediated invasion and damage. Our results dissect the pathogenesis of mucormycosis during ketoacidosis and reinforce the importance of careful metabolic control of the acidosis to prevent and manage this infection.

Topics: 3-Hydroxybutyric Acid; Animals; Diabetic Ketoacidosis; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endothelial Cells; Fungal Proteins; Glucose; Heat-Shock Proteins; Host-Pathogen Interactions; Humans; Iron; Male; Mice; Mice, Inbred ICR; Mucormycosis; Rhizopus; Sodium Bicarbonate; Virulence

Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase cobinamide binding, further enhancing antidote effectiveness.. Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxocobinamide or dinitrocobinamide (250 mM). Red blood cell cyanide concentration, plasma cobinamide, and thiocyanate concentrations were measured from blood samples.. In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. Aquohydroxocobinamide and dinitrocobinamide increased survival time to 64 ± 41 (p < 0.05) and 75 ± 16.4 min (p < 0.001), respectively. Compared to aquohydroxocobinamide, dinitrocobinamide showed greater systemic absorption and reduced blood pressure. Dinitrocobinamide also markedly increased the red blood cell cyanide concentration. Under all conditions, the plasma thiocyanate concentration gradually increased with time.. This study demonstrates a promising new approach to treat high-dose cyanide ingestion, with gastric alkalinization alone and in combination with oral cobinamide for treating a supra-lethal dose of orally administered cyanide in rabbits.

Topics: Administration, Oral; Analysis of Variance; Animals; Antacids; Antidotes; Blood Pressure; Cobamides; Cyanides; Disease Models, Animal; Eating; Erythrocytes; Humans; Male; Rabbits; Sodium Bicarbonate; Spectrum Analysis; Survival Rate; Thiocyanates; Time Factors

Angiotensin II (AII) mediates glomerular filtration rate (GFR) decline in animals with subtotal nephrectomy (Nx), but the mechanisms for increased AII activity are unknown. Because reduced GFR of Nx is associated with acid (H(+)) retention that increases kidney AII, AII-mediated GFR decline might be induced by H(+) retention.. We measured GFR and kidney microdialyzate H(+) and AII content in Sham and 2/3 Nx rats in response to amelioration of H(+) retention with dietary NaHCO3, to AII receptor antagonism and to both.. GFR was lower in Nx than that in Sham. Nx but not Sham GFR was lower at Week 24 than that at Week 1. Despite no differences in plasma acid-base parameters or urine net acid excretion, kidney H(+) content was higher in Nx than that in Sham, consistent with H(+) retention. Plasma and kidney microdialyzate AII were higher in Nx than that in Sham and dietary NaHCO3 reduced each in Nx but not in Sham. AII receptor antagonism was associated with higher Week 24 GFR in Nx with H(+) retention but not in Sham or in Nx in which H(+) retention had been corrected with dietary NaHCO3. Week 24 GFR after dietary NaHCO3 was higher than after AII receptor antagonism. Week 24 GFR was not different after adding AII receptor antagonism to dietary NaHCO3.. AII-mediated GFR decline in 2/3 Nx was induced by H(+) retention and its amelioration with dietary HCO3 conserved GFR better than AII receptor antagonism in this CKD model. H(+) retention might induce AII-mediated GFR decline in patients with reduced GFR, even without metabolic acidosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animal Feed; Animals; Disease Models, Animal; Female; Glomerular Filtration Rate; Kidney; Male; Microdialysis; Nephrectomy; Protons; Rats; Rats, Wistar; Sodium Bicarbonate; Tetrazoles; Valine; Valsartan

Administration of NaHCO3 does not improve cellular function or reduce the mortality of acute lactic acidosis. This might be related to aggravation of intracellular acidosis, but it could also be due to activation of Na+/H+ exchanger with a deleterious increment in intracellular calcium ([Ca2+]i). This study examined the impact of coadministration of NaHCO3 and a selective inhibitor of Na+/H+ exchanger, sabiporide on cardiovascular function, changes in proinflammatory cytokines, and organ function in a model of acute lactic acidosis produced by hemorrhagic hypotension followed by infusion of lactic acid.. Experimental, prospective study.. Medical Center research laboratory.. Male Yorkshire pigs.. Anesthetized pigs were subjected to hypovolemia for 30 minutes and followed by DL-lactic acid infusion, and then either saline or sodium bicarbonate was infused.. Hypovolemia followed by a DL-lactic acid infusion resulted in severe acidemia with a blood pH~6.8. Administration of NaHCO3 did not improve cardiovascular performance or decrease the levels of proinflammatory responses, whereas administration of sabiporide prior to acid or NaHCO3 infusion improved cardiopulmonary performance and blood oxygenation, reduced nuclear factor-κB activation, neutrophil accumulation, and proinflammatory cytokine production, and attenuated organ injury. Exposure of rat cardiac myocytes to a pH of 7.2 led to a marked increase of [Ca2+]i, and release of lactate dehydrogenase from cells which were further augmented after increase in external pH by addition of NaHCO3. Both the increase in [Ca2+]i and release of lactate dehydrogenase were attenuated in the presence of sabiporide.. Coadministration of Na/H exchanger inhibitor with sodium bicarbonate improves cardiovascular performances, reduces proinflammatory responses, and attenuates organ injury. This improvement in these variables appears to be related to prevention of a rise in intracellular calcium occurring after both exposures to acid and bicarbonate.

Topics: Acidosis; Animals; Blood Gas Analysis; Calcium; Cytokines; Disease Models, Animal; Guanidines; Hemodynamics; Hydrogen-Ion Concentration; L-Lactate Dehydrogenase; Male; Sodium Bicarbonate; Sodium-Hydrogen Exchangers; Swine

To be effective, orally administered live Salmonella vaccines must first survive their encounter with the low pH environment of the stomach. To enhance survival, an antacid is often given to neutralize the acidic environment of the stomach just prior to or concomitant with administration of the vaccine. One drawback of this approach, from the perspective of the clinical trial volunteer, is that the taste of a bicarbonate-based acid neutralization system can be unpleasant. Thus, we explored an alternative method that would be at least as effective as bicarbonate and with a potentially more acceptable taste. Because ingestion of protein can rapidly buffer stomach pH, we examined the possibility that the protein-rich Ensure® Nutrition shakes would be effective alternatives to bicarbonate.. We tested one Salmonella enterica serovar Typhimurium and three Salmonella Typhi vaccine strains and found that all strains survived equally well when incubated in either Ensure® or bicarbonate. In a low gastric pH mouse model, Ensure® worked as well or better than bicarbonate to enhance survival through the intestinal tract, although neither agent enhanced the survival of the S. Typhi test strain possessing a rpoS mutation.. Our data show that a protein-rich drink such as Ensure® Nutrition shakes can serve as an alternative to bicarbonate for reducing gastric pH prior to administration of a live Salmonella vaccine.

Topics: Animals; Antacids; Bacterial Proteins; Dietary Sucrose; Disease Models, Animal; Food, Formulated; Gene Expression; Hydrogen-Ion Concentration; Mice; Microbial Viability; Mutation; Salmonella Infections; Salmonella typhi; Salmonella typhimurium; Salmonella Vaccines; Sigma Factor; Sodium Bicarbonate; Stomach; Vaccination; Vaccines, Attenuated

Topics: Ammonium Chloride; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Female; Hydrogen-Ion Concentration; Intracellular Fluid; Kaplan-Meier Estimate; Mice; Mice, Transgenic; Motor Neurons; Sodium Bicarbonate; Superoxide Dismutase

Lactic acidosis is associated with cardiovascular failure. Buffering with sodium bicarbonate is proposed in severe lactic acidosis. Bicarbonate induces carbon dioxide generation and hypocalcemia, both cardiovascular depressant factors. The authors thus investigated the cardiovascular and metabolic effects of an adapted sodium bicarbonate therapy, including prevention of carbon dioxide increase with hyperventilation and ionized calcium decrease with calcium administration.. Lactic acidosis was induced by hemorrhagic shock. Twenty animals were randomized into five groups: (1) standard resuscitation with blood retransfusion and norepinephrine (2) adapted sodium bicarbonate therapy (3) nonadapted sodium bicarbonate therapy (4) standard resuscitation plus calcium administration (5) hyperventilation. Evaluation was focused in vivo on extracellular pH, on intracellular pH estimated by P nuclear magnetic resonance and on myocardial contractility by conductance catheter. Aortic rings and mesenteric arteries were isolated and mounted in a myograph, after which arterial contractility was measured.. All animals in the hyperventilation group died prematurely and were not included in the statistical analysis. When compared with sham rats, shock induced extracellular (median, 7.13; interquartile range, [0.10] vs. 7.30 [0.01]; P = 0.0007) and intracellular acidosis (7.26 [0.18] vs. 7.05 [0.13]; P = 0.0001), hyperlactatemia (7.30 [0.01] vs. 7.13 [0.10]; P = 0.0008), depressed myocardial elastance (2.87 [1.31] vs. 0.5 [0.53] mmHg/μl; P = 0.0001), and vascular hyporesponsiveness to vasoconstrictors. Compared with nonadapted therapy, adapted bicarbonate therapy normalized extracellular pH (7.03 [0.12] vs. 7.36 [0.04]; P < 0.05), increased intracellular pH to supraphysiological values, improved myocardial elastance (1.68 [0.41] vs. 0.72 [0.44] mmHg/μl; P < 0.05), and improved aortic and mesenteric vasoreactivity.. A therapeutic strategy based on alkalinization with sodium bicarbonate along with hyperventilation and calcium administration increases pH and improves cardiovascular function.

Topics: Acidosis, Lactic; Adrenergic alpha-Agonists; Animals; Blood Transfusion; Calcium; Disease Models, Animal; Heart; Hydrogen-Ion Concentration; Hyperventilation; Magnetic Resonance Spectroscopy; Male; Norepinephrine; Random Allocation; Rats; Rats, Wistar; Severity of Illness Index; Shock, Hemorrhagic; Sodium Bicarbonate

Cisplatin, a platinum-derived chemotherapeutic agent, produces antineoplastic effects coupled with toxic neuropathic pain and impaired general health status. These side-effects complicate long term studies of neuropathy or analgesic interventions in animals. We recently demonstrated that pretreatment with sodium bicarbonate (4% NaHCO3) prior to cisplatin (3 mg/kg i.p. weekly up to 5 weeks) was associated with improved health status (i.e. normal weight gain, body temperature, creatinine and ketone levels, and kidney weight ratio) in rats (Neurosci Lett 544:41-46, 2013). To reduce the nephrotoxic effects of cisplatin treatment in mice, we compared effects of sodium bicarbonate (4% NaHCO3 s.c.), vitamin C (25 mg/kg s.c.), resveratrol (25 mg/kg s.c.) and saline (0.9% NaCl) pretreatment on cisplatin-induced changes in animal health status, neuropathic pain and proinflammatory cytokine levels in spinal cord and kidney.. Cisplatin-treated mice receiving saline pretreatment exhibited elevated ketone, creatinine and kidney weight ratios, representative of nephrotoxicity. Vitamin C and sodium bicarbonate lowered creatinine/ketone levels and kidney weight ratio whereas resveratrol normalized creatinine levels and kidney weight ratios similar to saline pretreatment. All pretreatments were associated with decreased ketone levels compared to saline pretreatment. Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in all pretreatment groups and was similarly reversed by either morphine (6 mg/kg i.p.) or ibuprofen (6 mg/kg i.p.) treatment. RT-PCR showed that mRNA levels for IL-1β were increased in lumbar spinal cord of cisplatin-treated groups pretreated with either saline, NaHCO3 or resveratrol/cisplatin-treated groups. However, IL-6 and TNF-alpha were elevated in the kidneys in all cisplatin-treated groups. Our studies also demonstrate that 60 days after the last cisplatin treatment, body weight, body temperature, kidney functions and mRNA levels have returned to baseline although the neuropathic pain (mechanical and cold) is maintained.. Studies employing cisplatin should include NaHCO3 or vitamin C pretreatment to improve animal health status and reduce nephrotoxicity (lower creatinine and kidney weight ratio) without affecting the development of chemotherapy-induced neuropathy or analgesic efficacy.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Blood Glucose; Body Temperature; Body Weight; Cisplatin; Creatinine; Disease Models, Animal; Drug Administration Schedule; Health Status; Hyperalgesia; Ketones; Male; Mice; Mice, Inbred C57BL; Pain Threshold; Peripheral Nervous System Diseases; Sodium Bicarbonate; Vitamins

Tricyclic antidepressants (TCAs) are highly lipophilic medications used to treat posttraumatic stress disorder and chronic pain. Intravenous lipid emulsion (ILE) is a recent antidote for lipophilic drug overdose with unclear effectiveness. ILE has been studied in TCA overdose in small animals, and cases are reported in humans, but controlled studies in a larger animal model are lacking. Given the high lipophilicity of amitriptyline, a TCA, the hypothesis was that ILE would be more effective than the standard antidote sodium bicarbonate in improving amitriptyline-induced hypotension. The objective was to determine if ILE improved hypotension (defined by a mean arterial pressure [MAP] < 60% baseline) compared to sodium bicarbonate for amitriptyline overdose in a critically ill porcine model.. In this prospective, randomized, controlled trial, 24 female Sus scrofa swine weighing 45 to 55 kg were infused with amitriptyline at 0.5 mg/kg/min until the MAP reached 60% of baseline values. Animals were randomized to the experimental treatment group (ILE 7 mL/kg bolus, then 0.25 mL/kg/min) or the standard treatment group (sodium bicarbonate 2 mEq/kg plus an equal volume of saline). The primary outcome was a 50% improvement in MAP after ILE administration. We continuously monitored heart rate (HR), systolic blood pressure (sBP), MAP, and cardiac output. Electrocardiograms were recorded every 15 minutes. Serum pH, pCO2 , bicarbonate, lactate, and electrolytes were measured. Amitriptyline levels were measured by liquid chromatography/tandem mass spectrometry. Statistical methods used to detect a difference in MAP between the two treatment groups included repeated-measures analysis of variance, adjusted for treatment, time, and the interaction of treatment by time. A sample size of 12 animals per group provided a power of 0.8 and an alpha of 0.05 to detect a 50% difference in MAP.. There was no difference at baseline between ILE and sodium bicarbonate groups in mean HR, sBP, MAP, or cardiac output. Mean amounts of amitriptyline to reach hypotension and time to hypotension were similar between groups. After hypotension there was no difference between groups for mean HR, sBP, MAP, or cardiac output. The median time from hypotension to death was greater for the sodium bicarbonate group (10 minutes [IQR = 6 to 61 minutes] vs. 5 minutes [IQR = 4.5 to 6 minutes] for the ILE group; p = 0.003), but overall survival was not different. One ILE and four sodium bicarbonate pigs survived. Additionally, no difference was detected in QRS intervals between the two groups. The mean (±SD) amitriptyline level in the lipid layer was 3.34 (±2.12) μg/mL, and in the aqueous layer, 4.69 (±2.44) μg/mL. The ILE fatty layer contained 38.2% of total measurable amitriptyline, while the aqueous layer contained 53.6%.. Intravenous lipid emulsion treatment failed to improve amitriptyline-induced hypotension when compared to the standard treatment of sodium bicarbonate in a large animal model of severe TCA overdose. Larger groups with better survival may yield different results from the high mortality observed in this pilot study. Similar amounts of amitriptyline were found in the aqueous and lipid layers. These conclusions are limited to a single ILE regimen.

Topics: Animals; Antidepressive Agents, Tricyclic; Blood Pressure; Disease Models, Animal; Fat Emulsions, Intravenous; Female; Hypotension; Pilot Projects; Prospective Studies; Sodium Bicarbonate; Swine

The use of intravenous lipid emulsion (ILE) as an antidote in non-local, anaesthetic drug toxicity has generated considerable interest. Flecainide is a lipophilic anti-arrhythmic with a significant cardiotoxic profile, with blockade of sodium and potassium channels causing arrhythmias and shock in severe toxicity. ILE has been proposed as a treatment option in severe flecainide toxicity refractory to other modalities.. We compared the effects of ILE and hypertonic sodium bicarbonate in a rabbit model of flecainide toxicity.. Twenty sedated and ventilated New Zealand White Rabbits received flecainide infusion titrated to a mean arterial pressure (MAP) of 60% baseline, which was defined as toxicity. The rabbits then received either sodium bicarbonate or ILE, and the flecainide infusion was reduced in an attempt to model ongoing enteric absorption. MAP and heart rate were recorded every minute for 15 min and plasma flecainide concentration was measured at toxicity and 15 min. ECG QRS duration was recorded at baseline, toxicity and at 5, 10 and 15 min post-toxicity.. No difference was observed in heart rate (p = 0.2804), MAP (p = 0.1802) or QRS duration (p = 0.7471) between groups. The immediate rate of rise in MAP was greatest in the bicarbonate group in the 5 min immediately post-toxicity.. In this study, no differences were observed between an active control of hypertonic sodium bicarbonate and ILE for the primary endpoint of MAP at 15 min nor for QRS duration at any timepoint. There was a transient rapid increase in blood pressure seen in the sodium bicarbonate group that was not sustained. No increase was seen in blood concentration of flecainide in the ILE group, suggesting no 'lipid sink' for flecainide in this model. More research is warranted to define any role for ILE in flecainide toxicity.

Topics: Animals; Anti-Arrhythmia Agents; Antidotes; Blood Pressure; Disease Models, Animal; Endpoint Determination; Fat Emulsions, Intravenous; Female; Flecainide; Heart Rate; Hypertonic Solutions; Male; Poisoning; Rabbits; Sodium Bicarbonate

Hypoxia and acidosis develop in in situ tumors as cellular expansion increases the diffusion distance of substrates and metabolites from blood vessels deep to the basement membrane. Prior studies of breast and cervical cancer revealed that cellular adaptation to microenvironmental hypoxia and acidosis is associated with the transition from in situ to invasive cancer. We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer.. A total of 37 C57BL/6 TRAMP mice were randomized to a control group or to 1 of 4 treatment groups. In the latter groups 200 mM sodium bicarbonate were added to drinking water starting between ages 4 and 10 weeks.. In all 18 controls prostate cancer developed that was visible on 3-dimensional ultrasound at a mean age of 13 weeks. They died within 52 weeks (median 37). When sodium bicarbonate therapy commenced before age 6 weeks in 10 mice, all reached senescence (age 76 weeks) without radiographic evidence of prostate cancer. Histological sections of the prostates in this cohort showed hyperplasia but no cancer in 70% of mice and minimal well differentiated cancer in the remainder. When therapy commenced after age 6 weeks in 9 mice, prostate cancer development was no different from that in controls.. Immunohistochemical staining for carbonic anhydrase 9 in regions of ductal hyperplasia showed increased expression in controls vs the early treatment group. Regional pH perturbation in in situ tumors may be a simple, inexpensive and effective cancer prevention strategy.

Topics: Acid-Base Equilibrium; Adaptation, Physiological; Animals; Buffers; Cell Hypoxia; Cell Transformation, Neoplastic; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Transplantation; Phenotype; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Sodium Bicarbonate; Transplantation, Heterologous

The effectiveness of sodium bicarbonate (SB) has recently been questioned although it is often used to correct metabolic acidosis of neonates. The aim of the present study was to examine its effect on hemodynamic changes and hydrogen peroxide (H(2)O(2)) generation in the resuscitation of hypoxic newborn animals with severe acidosis.. Newborn piglets were block-randomized into a sham-operated control group without hypoxia (n = 6) and two hypoxia-reoxygenation groups (2 h normocapnic alveolar hypoxia followed by 4 h room-air reoxygenation, n = 8/group). At 10 min after reoxygenation, piglets were given either i.v. SB (2 mEq/kg), or saline (hypoxia-reoxygenation controls) in a blinded, randomized fashion. Hemodynamic data and blood gas were collected at specific time points and cerebral cortical H(2)O(2) production was continuously monitored throughout experimental period. Plasma superoxide dismutase and catalase and brain tissue glutathione, superoxide dismutase, catalase, nitrotyrosine and lactate levels were assayed.. Two hours of normocapnic alveolar hypoxia caused cardiogenic shock with metabolic acidosis (PH: 6.99 ± 0.07, HCO(3)(-): 8.5 ± 1.6 mmol/L). Upon resuscitation, systemic hemodynamics immediately recovered and then gradually deteriorated with normalization of acid-base imbalance over 4 h of reoxygenation. SB administration significantly enhanced the recovery of both pH and HCO(3-) recovery within the first hour of reoxygenation but did not cause any significant effect in the acid-base at 4 h of reoxygenation and the temporal hemodynamic changes. SB administration significantly suppressed the increase in H(2)O(2) accumulation in the brain with inhibition of superoxide dismutase, but not catalase, activity during hypoxia-reoxygenation as compared to those of saline-treated controls.. Despite enhancing the normalization of acid-base imbalance, SB administration during resuscitation did not provide any beneficial effects on hemodynamic recovery in asphyxiated newborn piglets. SB treatment also reduced the H(2)O(2) accumulation in the cerebral cortex without significant effects on oxidative stress markers presumably by suppressing superoxide dismutase but not catalase activity.

Topics: Acid-Base Equilibrium; Acidosis; Animals; Animals, Newborn; Blood Gas Analysis; Catalase; Cerebral Cortex; Disease Models, Animal; Female; Glutathione; Hemodynamics; Hydrogen Peroxide; Hypoxia; Infusions, Intravenous; Lactic Acid; Male; Oxidation-Reduction; Oxidative Stress; Oxygen; Pulmonary Alveoli; Resuscitation; Sodium Bicarbonate; Superoxide Dismutase; Swine; Tyrosine

We have identified a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 (NBC1) in a patient with isolated proximal renal tubular acidosis (pRTA). To specifically address the pathogenesis of this mutation, we created NBC1 W516X knock-in mice to match the patient's abnormalities. The expression of NBC1 mRNA and protein in the kidneys of NBC1(W516X/W516X) mice were virtually absent, indicating that nonsense-mediated mRNA decay (NMD) is involved in the defective transcription and translation of this mutation. These mice not only recapitulated the phenotypes of this patient with growth retardation, pRTA, and ocular abnormalities, but also showed anemia, volume depletion, prerenal azotemia, and several organ abnormalities, culminating in dehydration and renal failure with early lethality before weaning. In isolated renal proximal tubules, both NBC1 activity and the rate of bicarbonate absorption were markedly reduced. Unexpectedly, there was no compensatory increase in mRNA of distal acid/base transporters. Sodium bicarbonate but not saline administration to these mutant mice markedly prolonged their survival, decreased their protein catabolism and attenuated organ abnormalities. The prolonged survival time uncovered the development of corneal opacities due to corneal edema. Thus, NBC1(W516X/W516X) mice with pRTA represent an animal model for metabolic acidosis and may be useful for testing therapeutic inhibition of NMD in vivo.

Topics: Acidosis; Acidosis, Renal Tubular; Age Factors; Aging; Analysis of Variance; Anemia; Animals; Aquaporin 2; Bicarbonates; Codon, Nonsense; Corneal Opacity; Disease Models, Animal; Female; Gene Knock-In Techniques; Genotype; Growth Disorders; Homozygote; Humans; Hydrogen-Ion Concentration; Kidney Tubules, Proximal; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phenotype; RNA, Messenger; Severity of Illness Index; Sodium Bicarbonate; Sodium-Bicarbonate Symporters; Transcription, Genetic

A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO(3)(-). It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O(2)(·-)) production induced by oleic acid-bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb-induced O(2)(·-) production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O(2)(·-) production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO(3) feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O(2)(·-)-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.

Topics: Albumins; Animals; Apoptosis; Cell Line; Disease Models, Animal; Disease Progression; DNA Damage; Female; Focal Adhesion Kinase 2; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases; Oleic Acid; Oxidative Stress; Oxygen; Proteinuria; Reactive Oxygen Species; Sodium Bicarbonate

The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.. We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.. Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.. DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Bicarbonates; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Dichloroacetic Acid; Disease Models, Animal; Female; Humans; Hydrogen-Ion Concentration; Lactates; Lung Neoplasms; Mice; Mice, SCID; Sodium Bicarbonate; Survival Analysis; Tumor Burden; Tumor Microenvironment

It is well known that acid/base disturbances modulate proton/bicarbonate transport in the cortical collecting duct. To study the adaptation further we measured the effect of three days of acidosis followed by the rapid recovery from this acidosis on the number and type of intercalated cells in the rabbit cortical collecting duct. Immunofluorescence was used to determine the expression of apical pendrin in β-intercalated cells and the basolateral anion exchanger (AE1) in α-intercalated cells. Acidosis resulted in decreased bicarbonate and increased proton secretion, which correlated with reduced pendrin expression and the number of pendrin-positive cells, as well as decreased pendrin mRNA and protein abundance in this nephron segment. There was a concomitant increase of basolateral AE1 and α-cell number. Intercalated cell proliferation did not seem to play a role in the adaptation to acidosis. Alkali loading for 6-20 h after acidosis doubled the bicarbonate secretory flux and reduced proton secretion. Pendrin and AE1 expression patterns returned to control levels, demonstrating that adaptive changes by intercalated cells are rapidly reversible. Thus, regulation of intercalated cell anion exchanger expression and distribution plays a key role in adaptation of the cortical collecting duct to perturbations of acid/base.

Topics: Acid-Base Equilibrium; Acidosis; Adaptation, Physiological; Alkalosis; Animals; Anion Exchange Protein 1, Erythrocyte; Anion Transport Proteins; Disease Models, Animal; Female; Kidney Tubules, Collecting; Membrane Transport Proteins; Proton-Translocating ATPases; Rabbits; Sodium Bicarbonate

The aim of this study is to investigate the efficacy and mechanism of action of intravenous (IV) bicarbonate in preventing radiocontrast nephropathy (RCN).. Twenty-eight Wistar rats were randomized into four groups including control (group 1), radiocontrast (group 2), bicarbonate (group 3), and radiocontrast plus bicarbonate (group 4). Once blood chemistry and arterial blood gases were examined and 24 h urine samples were collected, all rats were administered furosemide (2 mg/kg subcutaneous) and deprived of water for 24 h. Iothalamate sodium (6 mL/kg) was administered to group 2 and group 4. IV bicarbonate (8.4%) was administered to group 3 and group 4 (3 h before the administration of iothalamate). On the fourth day, 24 h urine was collected, and at the end of the day rats were sacrificed and blood chemistry and arterial blood gases were reexamined. Myeloperoxidase (MPO), nitric oxide (NO), total glutathione, and malondialdehyde were quantified on the renal tissue. H&E slides were examined.. Basal creatinine and creatinine clearance were similar between groups. There was no significant difference between creatinine and creatinine clearance by the end of the experiment. Glutathione level in group 2 was lower than in group 4. Histopathologically, there was no injury in the control group (group 1) whereas there was an intermediate-severe injury (71.4%) in the radiocontrast group (group 2). The percentage of intermediate-severe injury was significantly lower (71.4% vs. 28.6%, p = 0.02) in the radiocontrast plus bicarbonate group (group 4).. Sodium bicarbonate attenuates the development of radiocontrast-induced tubular necrosis.

Topics: Animals; Contrast Media; Disease Models, Animal; Female; Infusions, Intravenous; Ioxaglic Acid; Kidney Diseases; Kidney Function Tests; Oxidative Stress; Rats; Rats, Wistar; Sodium Bicarbonate

Intracellular acidosis during early reperfusion after coronary artery occlusion was recently linked to cardioprotection resulting from myocardial ischemic postconditioning. We tested the hypotheses that transient alkalosis during early reperfusion abolishes helium preconditioning and that the mitochondrial permeability transition pore inhibitor cyclosporin A (CsA) restores the cardioprotective effects of helium during alkalosis in vivo.. Rabbits (n = 36) instrumented for hemodynamics measurement were subjected to a 30-min left anterior descending coronary artery occlusion and 3-h reperfusion. The rabbits received 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before left anterior descending coronary artery occlusion in the absence or presence of transient alkalosis (pH = 7.5) produced by administration of IV sodium bicarbonate (10 mEq) 2 min before reperfusion. Other rabbits preconditioned with helium received CsA (5 mg/kg) in the presence of alkalosis or CsA alone.. Helium reduced myocardial infarct size (25% +/- 4% of left ventricular area at risk; P < 0.05) compared with control (44% +/- 6%). Alkalosis during early reperfusion did not alter infarct size alone (46% +/- 2%), but this intervention abolished helium-induced cardioprotection (45% +/- 3%). CsA restored reductions in infarct size produced by helium preconditioning in the presence of alkalosis (28% +/- 6%; P < 0.05 versus control) but did not affect myocardial necrosis alone (43% +/- 6%).. The results demonstrate that transient alkalosis during early reperfusion abolishes helium preconditioning in rabbits. CsA restored helium-induced cardioprotection during alkalosis, suggesting that helium preconditioning inhibits mitochondrial permeability transition pore formation by maintaining intracellular acidosis during early reperfusion.

Topics: Acidosis; Administration, Inhalation; Alkalosis; Animals; Cyclosporine; Disease Models, Animal; Drug Administration Schedule; Helium; Hemodynamics; Male; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Rabbits; Sodium Bicarbonate

Dietary factors play essential roles in gastric carcinogenesis. We recently found that dietary supplementation with NaHCO(3) significantly increased the development of gastric cancer in a rat gastric stump model. Here, we analysed nontransformed gastric mucosa for expression of the cancer-related proteins cyclooxygenase-2 (COX-2) and ornithine decarboxylase (ODC), and we examined the relationship between expression levels of those proteins and mucosal proliferation. Research has shown that COX-2 is upregulated in gastric mucosal inflammation and is strongly associated with gastrointestinal cancer. ODC is the key enzyme in polyamine synthesis and a regulator of cell proliferation. We performed gastric resections on 48 Wistar rats to induce spontaneous gastric cancer; half of these animals were given a normal diet, and the other half received a diet supplemented with NaHCO(3). Twenty-four unoperated rats served as a control group. The surgical procedure per se led to a significant rise in mucosal expression of COX-2 and an associated increase in cell proliferation. However, the COX-2 level in gastric mucosa was not further affected by dietary supplementation of carbonate. Interestingly, nontransformed gastric mucosa in the operated rats receiving a carbonate-supplemented diet showed a pronounced increase in ODC expression that was strongly correlated with a further enhanced cell proliferation. These results indicate that carbonate ions, which represent a major constituent of intestinal reflux into the stomach, increase the expression of ODC and thereby enhance cell proliferation in nontransformed mucosa, and consequently elevate the risk of gastric cancer.

Topics: Adenocarcinoma; Animals; Cell Proliferation; Cyclooxygenase 2; Dietary Supplements; Disease Models, Animal; Gastric Mucosa; Gastric Stump; Immunoenzyme Techniques; Male; Ornithine Decarboxylase; Rats; Rats, Wistar; Sodium Bicarbonate; Stomach Neoplasms

Acid-sensing ion channels (ASICs), newly discovered members of epithelial Na+ channels/degenirin superfamily, are widely distributed throughout the mammalian peripheral and central nervous system and have been implicated in many physiological and pathophysiological processes. We have recently shown that activation of calcium-permeable ASIC1a is involved in acidosis-mediated, glutamate independent, ischaemic brain injury. In this study the neuroprotective time window for ASIC1a blockade in a mouse model of focal ischaemia is examined and the role of acidosis per se addressed by continuous pH measurements in penumbral cortex and post-ischaemic alkalization of brain. The effects of NMDA receptor blockade and ASIC1a blockade were compared. Specific ASIC1a blockade by the tarantula toxin psalmotoxin, PcTX, administered intracerebroventricularly as late as 5 h after 60 min of transient middle cerebral artery occlusion (MCAO) reduced infarct volume by >50%; the protection persisted for at least 7 days. Protection was also demonstrated after permanent MCAO. In penumbral cortex alkaline pH preceded acid pH and infarction. Attenuating brain acidosis by NaHCO3 or blocking ASIC1a with PcTX were both protective. NMDA blockade produced additive neuroprotection and the presence of PcTX prolonged the time window of effectiveness of NMDA blockade. Neuroprotection by PcTX was also achievable by intranasal administration. These findings further suggest that ASIC1a is a novel molecular target involved in ischaemic brain injury. Post-ischaemic administration of an ASIC1a blocker may prove to be an effective neuroprotective strategy for stroke patients.

Topics: Acid Sensing Ion Channels; Acidosis; Animals; Brain; Brain Ischemia; Cerebral Cortex; Cerebral Ventricles; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Infarction, Middle Cerebral Artery; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; N-Methylaspartate; Nerve Tissue Proteins; Neuroprotective Agents; Sodium Bicarbonate; Sodium Channels; Spider Venoms; Time Factors

In the human setting, it has been shown that acute increase in the concentration of ketone bodies by infusion of beta-hydroxybutyrate increased the cerebral blood flow (CBF) without affecting the overall cerebral metabolic activity. The mechanism by which this effect of ketone bodies was mediated is not known. Alterations in several parameters may possibly explain the increase in CBF and the resetting of the relation between CBF and cerebral metabolism. To study this phenomenon further, we measured global CBF and global cerebral metabolism with the Kety-Schmidt technique in the wakeful rat before and during infusion of ketone bodies. During acute hyperketonemia (average concentration of beta-hydroxybutyrate: 6 mmol/L), global CBF increased 65% from 108 to 178 mL/100 g min and the cerebral metabolic rates for both oxygen and glucose remained constant. This resetting of the relation between CBF and cerebral metabolism could not be explained by alterations in blood pH or arterial CO2 tension. By measuring cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy, it could further be concluded that the brain pH was unchanged during acute hyperketonemia. These observations indicate that the mechanism responsible for the increase in CBF is rather a direct effect on the cerebral endothelium than via some metabolic interactions.

Topics: 3-Hydroxybutyric Acid; Acute Disease; Anesthesia; Animals; Brain; Cerebrovascular Circulation; Disease Models, Animal; Hydrogen-Ion Concentration; Infusions, Intravenous; Ketone Bodies; Magnetic Resonance Spectroscopy; Male; Phosphorus Isotopes; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Sodium Bicarbonate; Wakefulness

Our recent study demonstrated that sodium bicarbonate improved cardiac function in macaque models with early-phase endotoxic shock. In the present study, we investigated further the ryanodine receptor/calcium release-channel (RyR) and calcium pump after fluid resuscitation of macaques with early-phase endotoxic shock.. Twenty-four anaesthetised macaques were assigned to four groups. Nineteen animals were given an intravenous dose of 2.8 mgkg(-1) lipopolysaccharide (LPS). Sixty minutes after the LPS challenge, the animals were given (i) 5 mLkg(-1) normal saline (Ns group, n = 6), (ii) 5 mLkg(-1) of 5% sodium bicarbonate (Sb group, n = 6) or (iii) 5 mLkg(-1) of 3.5% hypertonic sodium chloride (Hs group, n = 7). The control group (Co group, n = 5) received 1 mLkg(-1) normal saline and then with 5 mLkg(-1) normal saline 60 min later.. Endotoxin produced a reduction of the density of RyR but did not alter the affinity of RyR. Compared with normal saline, sodium bicarbonate or hypertonic saline induced a restoration of density of RyR but did not influence the affinity of RyR and the calcium pump.. Up-regulation of RyR performance in myocardium following administration of sodium bicarbonate contributes to the improvement of cardiac function in macaques in the early phase of endotoxic shock.

Topics: Animals; Calcium-Transporting ATPases; Disease Models, Animal; Escherichia coli; Female; Fluid Therapy; Lipopolysaccharides; Macaca; Male; Myocardium; Resuscitation; Ryanodine Receptor Calcium Release Channel; Saline Solution, Hypertonic; Shock, Septic; Sodium Bicarbonate; Up-Regulation

Antiarrhythmics can have devastating effects in cardiotoxic poisonings. Amiodarone is recommended for treatment of wide complex tachycardia, but its hemodynamic effects in wide complex tachycardia induced by tricyclic antidepressant poisoning are unknown. The objective of this study was to compare the effects of sodium bicarbonate, amiodarone, and normal saline in treating wide complex tachycardia secondary to nortriptyline poisoning.. This unblended randomized controlled animal study involved 18 anesthetized, intubated pigs with arterial and venous lines. Nortriptyline (2 mg/mL) was infused at 20 mg/min until the onset of toxicity, defined as a systolic blood pressure < or =50 mmHg or QRS > or =120 ms. At that point, the pigs were randomized into three groups of six. Group I received 0.9% normal saline, 10 ml/kg. Group II received hypertonic sodium bicarbonate, 1 mEq/kg. Group III received amiodarone, 15 mg/kg. The pigs were observed until death or survival at 60 minutes.. After treatment, the changes in QRS were as follows: Group I, -2.0 ms; Group II, -33.0 ms; Group III, -21.7 ms. ANOVA demonstrated no significant difference between the groups (p = 0.28). Mean arterial pressures 10 minutes after treatment were as follows: Group I, 19.4 mmHg; Group II, 23.7 mmHg; Group III, 12.5 mmHg. Based on ANOVA, there was no significant difference between any of the groups (p = 0.50).. In this model of nortriptyline poisoning, the administration of amiodarone to correct wide complex tachycardia did not have a harmful effect.

Topics: Action Potentials; Amiodarone; Animals; Anti-Arrhythmia Agents; Antidepressive Agents, Tricyclic; Blood Pressure; Disease Models, Animal; Heart Conduction System; Nortriptyline; Research Design; Sodium Bicarbonate; Swine; Tachycardia; Time Factors

Systemic acidosis induces preretinal neovascularization (NV) analogous to retinopathy of prematurity (ROP) in the neonatal rat. Sodium bicarbonate is used in human neonates to treat acidosis. The effects of alkali administration on the developing retinal vasculature and on acidosis-induced retinopathy (AIR) are unknown. We investigated the effect of sodium bicarbonate gavage on the retinal vasculature of normal and acidotic neonatal rats to determine (1) whether bicarbonate treatment is associated with preretinal NV and (2) whether AIR can be prevented with systemic bicarbonate treatment.. The extent of acidosis and alkalosis were initially determined from carotid arterial blood samples. In the bicarbonate-alone study, newborn rats were randomized into litters of 25 and received bicarbonate doses of 15 mmol/kg twice daily and 20 mmol/kg once daily from days 2 to 7. Control animals received saline gavage. In the AIR treatment study, acidosis was induced in neonatal rats by intraperitoneal injection of acetazolamide 200 mg/kg from days 2 to 7. Acetazolamide-treated rats received either additional bicarbonate gavage or no additional treatment. Eyes were enucleated on day 13, and the retinal vasculature was assessed for NV using ADPase staining techniques and light microscopy.. Systemic alkalosis (peak pH 7.55+/-0.02; mean +/- SD) was confirmed with bicarbonate gavage, and partial reversal of acidosis was confirmed when acetazolamide-treated rats received bicarbonate. Surviving rats receiving bicarbonate 15 mmol/kg twice daily (28% survival) and 20 mmol/kg bicarbonate once daily (45% survival) had an incidence of preretinal NV of 9% and 8%, respectively. No NV was seen in saline-control rats. In the acetazolamide-treated rats, the incidence of preretinal NV in surviving rats was numerically lower in bicarbonate-treated rats than acetazolamide-only controls (8% versus 24%, p=0.065) but with only 19% survival in the bicarbonate-treated rats.. In the neonatal rat, alkalosis induced by bicarbonate gavage is associated with a low incidence of mild, preretinal NV similar to ROP. Although treating acidotic rats with bicarbonate may reduce the incidence of preretinal NV, treatment was associated with an unacceptable mortality rate.

Topics: Acetazolamide; Acid-Base Equilibrium; Acidosis; Animals; Animals, Newborn; Carbonic Anhydrase Inhibitors; Disease Models, Animal; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Injections, Intraperitoneal; Rats; Rats, Sprague-Dawley; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity; Sodium Bicarbonate

The objective of this study was to develop an experimental animal model of fulminant hepatic failure to test the efficacy of the bioartificial liver system. The portal vein and the hepatic artery were clamped intermittently and then the hepatic artery was ligated (ligation group, n=5). Pigs whose hepatic arteries were not ligated after clamping were assigned to the non-ligation group (n=5). The biochemical changes in blood, histologic alterations of the liver and neurologic examination for pigs were checked up. All animals died within 17 hr in the ligation group. On the other hand, all animals survived more than 7 days in the non-ligation group. In the ligation group, the levels of ammonia, lactic acid and creatinine showed a progressively increasing pattern. Prothrombin time was also prolonged gradually. Cytoplasmic condensation and nuclear pyknosis of hepatocytes were detected histologically at autopsy. Neurologic findings such as decreased pain sensation, tachypnea and no light reflex of pupils were observed. The findings shown in the ligation group are similar to the clinical features of fulminant hepatic failure in human and this animal model is reproducible. Therefore, this can be a suitable animal model to evaluate the efficacy of the bioartificial liver system for treating fulminant hepatic failure.

Topics: Acidosis; Ammonia; Animals; Aspartate Aminotransferases; Bilirubin; Blood Glucose; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Female; Hepatic Artery; Lactic Acid; Ligation; Liver Failure, Acute; Portal Vein; Potassium; Prothrombin Time; Sodium Bicarbonate; Swine

These studies established a macaque model of early-phase endotoxic shock, and investigated the resuscitation effects of three different solutions. Twenty-four macaques were assigned to four groups. Nineteen animals were given an intravenous dose of 2.8 mg/kg lipopolysaccharide (LPS). At 60 min after LPS challenge, the animals were given (i) 5 mL/kg normal saline (Ns group, n=6), (ii) 5% of 5 mL/kg sodium bicarbonate (Sb group, n=6), (iii) hypertonic 3.5% sodium chloride of 5 mL/kg (Hs group, n=7). The control group (Co group, n=5) was first injected with 1 mL/kg Ns and with 5 mL/kg Ns 60 min later. Haemodynamic parameters and blood gases were measured during the experiment, and myocardial morphology was examined on termination of the experiment. Administration of LPS caused hypotension and decreases of the left ventricular work index (LVWI). In the Sb group, mean arterial pressure, cardiac index, systemic vascular resistance index, LVWI and right ventricular work index were significantly higher than those of the Ns group. Pathological changes of myocardium were identified in all of the LPS groups. The studies suggest that macaques are suitable models for studying endotoxic shock and potential fluid therapies.

Topics: Analysis of Variance; Animals; Blood Gas Analysis; Disease Models, Animal; Hemodynamics; Heparin; Hydrogen-Ion Concentration; Lipopolysaccharides; Macaca mulatta; Myocardium; Saline Solution, Hypertonic; Shock, Septic; Sodium Bicarbonate; Ventricular Function, Left

Sodium bicarbonate is the most physiological alkalinizing agent. The effect of a new bicarbonated Ringer's solution (BRS) containing Mg2+, on metabolic acidosis and serum magnesium abnormality were evaluated and compared with those of acetated Ringer's (ARS), lactated Ringer's (LRS) and Ringer's (RS) solutions in an experimental haemorrhagic shock model with dogs.. Animals were randomly divided into six groups (n = 6 in each group), a sham-operated group, an operated group without infusion, and 4 operated groups with infusion (BRS, ARS, LRS and RS groups). Each RS was intravenously administered at 60 mL kg(-1) h(-1) for 1.5 h. Arterial blood gases, plasma electrolytes and cardiovascular parameters were analysed.. BRS significantly improved blood base excess values, which were decreased by blood-letting, faster and more markedly than did LRS and RS (BRS--6.3 +/- 0.5 mEq L(-1); LRS--9.2 +/- 1.1 mEq L(-1); RS--12.4 +/- 1.0 mEq L(-1) at the end of infusion). The alkalinizing effect of BRS tended to be better than that of ARS but not significantly so. The serum Mg2+ concentration was well-maintained by BRS as compared to other RS (BRS 1.5 +/- 0.0 mgdL(-1); ARS 1.2 +/- 0.0mgdL(-1); LRS 1.1 +/- 0.0mgdL(-1); RS 1.3 +/- 0.1 mgdL(-1), at the end of infusion).. These results suggest that BRS is a suitable perioperative solution for metabolic acidosis and serum electrolyte balance among RS tested.

Topics: Acid-Base Equilibrium; Acidosis; Animals; Blood Pressure; Carbon Dioxide; Disease Models, Animal; Dogs; Heart Rate; Hematocrit; Hemoglobins; Hemorrhage; Infusions, Intravenous; Isotonic Solutions; Lactic Acid; Magnesium; Male; Oxygen; Random Allocation; Ringer's Lactate; Ringer's Solution; Shock; Sodium Bicarbonate; Time Factors

Topics: Animals; Antidepressive Agents, Tricyclic; Cardiovascular Diseases; Disease Models, Animal; Drug Overdose; Humans; Hyperventilation; Saline Solution, Hypertonic; Sodium Bicarbonate

To explore the effects of alkaline buffers on cerebral perfusion and cerebral acidosis during and after cardiopulmonary resuscitation (CPR), 45 anaesthetized piglets were studied. The animals were subjected to 5 min non-interventional circulatory arrest followed by 7 min closed chest CPR and received either 1 mmol/kg of sodium bicarbonate, 1 mmol/kg of tris buffer mixture, or the same volume of saline (n=15 in all groups), adrenaline (epinephrine) boluses and finally external defibrillatory shocks. Systemic haemodynamic variables, cerebral cortical blood flow, arterial, mixed venous, and internal jugular bulb blood acid-base status and blood gases as well as cerebral tissue pH and PCO(2) were monitored. Cerebral tissue acidosis was recorded much earlier than arterial acidaemia. After restoration of spontaneous circulation, during and after temporary arterial hypotension, pH in internal jugular bulb blood and in cerebral tissue as well as cerebral cortical blood flow was lower after saline than in animals receiving alkaline buffer. Buffer administration during CPR promoted cerebral cortical reperfusion and mitigated subsequent post-resuscitation cerebral acidosis during lower blood pressure and flow in the reperfusion phase. The arterial alkalosis often noticed during CPR after the administration of alkaline buffers was caused by low systemic blood flow, which also results in poor outcome.

Topics: Acidosis; Animals; Bicarbonates; Brain; Buffers; Carbon Dioxide; Cardiopulmonary Resuscitation; Cerebrovascular Circulation; Disease Models, Animal; Heart Arrest; Hydrogen-Ion Concentration; Isotonic Solutions; Sodium Bicarbonate; Sodium Chloride; Sus scrofa; Tromethamine

To determine whether intravenous (IV) hypertonic sodium bicarbonate is effective in the reversal of QRS widening associated with severe Taxus intoxication.. Seventeen anesthetized and instrumented swine were poisoned with an IV extract of Taxus media until doubling of the QRS interval on electrocardiography was achieved. After poisoning (time zero), the animals received either 4 mL/kg IV 8.4% sodium bicarbonate (experimental group; 6 animals), a similar volume of 0.7% NaCl in 10% mannitol (mannitol group; 6 animals), or nothing (control group; 5 animals). The main outcome parameter was QRS duration. Secondary outcome parameters were mean arterial pressure (MAP), heart rate (HR), and cardiac index (CI = cardiac output/kg). Additionally, arterial pH, partial pressure of carbon dioxide (pCO(2)), and plasma-ionized calcium, sodium, and potassium were monitored.. Taxus toxicity, defined as a 100% increase in QRS duration, was produced in all animals. The animals were similar in regard to baseline and time 0 physiologic parameters as well as amount of Taxus media extract administered. From times 5 through 30 minutes, following assigned treatment, significant increases in QRS duration were detected in the experimental and mannitol groups compared with the control group. A significant lowering of MAP was found in the experimental group compared with the control group. No significant difference between groups was noted in HR or CI. The swine treated with hypertonic sodium bicarbonate had a statistically significant increase in pH, plasma sodium concentration, and base excess compared with the other groups.. Hypertonic sodium bicarbonate was ineffective in reversing the widening of QRS interval associated with Taxus poisoning in this swine model.

Topics: Animals; Blood Pressure; Calcium; Disease Models, Animal; Electrocardiography; Heart Rate; Hydrogen-Ion Concentration; Hypertonic Solutions; Infusions, Intravenous; Male; Mannitol; Poisoning; Potassium; Sodium; Sodium Bicarbonate; Swine; Taxus

Epidemiological studies have suggested an association between antacid therapy and development of listeriosis in humans. In this study we used a neutropenic mouse model to demonstrate that oral administration of sodium bicarbonate shortly before intragastric (i.g.) inoculation with Listeria monocytogenes EGD (serotype 1/2a) significantly increased the severity of the resulting systemic infection. An explanation for this observation is provided by evidence that L. monocytogenes EGD is rapidly inactivated in synthetic gastric fluid at pH below 5. A second strain of L. monocytogenes (CM [serotype 1/2b]) exhibited little ability to cause systemic infection following i.g. inoculation and was not significantly enhanced by administration of sodium bicarbonate. Strain CM was readily inactivated in synthetic gastric fluid even at pH 7. These data suggest that gastric acidity and enzymes provide some innate defense against gastrointestinal listeriosis in neutropenic mice.

Topics: Animals; Animals, Outbred Strains; Disease Models, Animal; Disease Susceptibility; Female; Gastric Acid; Listeriosis; Liver; Mice; Mice, Inbred ICR; Neutropenia; Sodium Bicarbonate; Spleen

Controversy surrounds the use of buffers during cardiac arrest to correct acidosis. The objective of this study was to determine whether attenuation or neutralization of cerebral acidosis by Carbicarb alters hippocampal glutamate levels, neuronal cell death, and neurologic deficits after reperfusion from asphyxial cardiac arrest in rats.. Rats were prospectively randomized to either a control (n=45), low-dose Carbicarb (LDC; 3 mL/kg, n=45), or high-dose Carbicarb (HDC; 6 mL/kg, n=45) group in a blinded fashion during resuscitation after 8 minutes of asphyxial cardiac arrest. Microdialysis was used to assess brain pH and glutamate. A neurologic deficit score and neuronal cell death in the hippocampus were determined at day 7.. Resuscitation was greatest in LDC rats (42/45) and least in HDC rats (28/45) versus that in control rats (34/45). Brain pH was higher in the LDC and HDC rats 10 minutes after resuscitation and remained higher than that of control rats for 120 minutes after resuscitation. Glutamate levels at 10 to 120 minutes after reperfusion were lowest in the LDC rats. LDC rats had the lowest neurologic deficit score (1+/-2) versus that of control rats (13+/-8) and HDC rats (19+/-6). Hippocampal neuronal cell death was lowest in LDC rats (30+/-20) versus that in control rats (86+/-47) and HDC rats (233+/-85).. LDC administered during resuscitation from asphyxial cardiac arrest attenuated acidosis, improved resuscitation, and reduced neurologic deficits and the number of dead hippocampal neurons. Neutralization of cerebral acidosis with HDC increased the number of dead hippocampal neurons and neurologic deficits after resuscitation from cardiac arrest in rats.

Topics: Acidosis; Animals; Asphyxia; Brain; Brain Ischemia; Carbonates; Cell Death; Disease Models, Animal; Drug Combinations; Glutamic Acid; Heart Arrest; Hippocampus; Neurons; Rats; Recovery of Function; Reperfusion Injury; Sodium Bicarbonate; Treatment Outcome

To examine the impact of administration of NaHCO3 on contractility and energy metabolism of the myocardium during hypoxemia.. Regional myocardial hypoxia was induced in the left anterior descending (LAD) artery myocardium in anesthetized, open-chest dogs, using a perfusion circuit between the right atrium and the LAD artery, and a membrane oxygenator. The rate of flow in LAD artery was maintained constant with the use of a roller pump. During hypoxia, eight dogs were administered isotonic NaHCO3 in the circuit and six other dogs received equimolar NaCl. Myocardial contractile function was assessed using sonomicrometry for measurement of percentage of systolic shortening and preload recruitable stroke work. Oxygen consumption and the rate of appearance of lactate were measured. Clamp-frozen tissue samples were obtained at the end of the experiment from the hypoxic LAD myocardium and the nonhypoxic circumflex myocardium for measurement of tissue lactate level.. During hypoxia, there was a significant decrease in oxygen consumption by the LAD myocardium (35 +/- 7 micromol/min in the NaCl group and 40 +/- 7 micromol/min in the NaHCO3 group during hypoxia vs. 131 +/- 11 micromol/min during aerobic perfusion). There was also a significant decrease in myocardial contractility as measured by percentage of systolic shortening (14 +/- 3% to -8 +/- 3%); NaHCO3 infusion during hypoxia did not improve myocardial contractility (-7 +/- 2%). Similar results were obtained with measurements of preload recruitable stroke work. The rate of production of lactate during hypoxia was substantially lower than expected, based on the calculated oxygen deficit, and was not significantly increased by the administration of NaHCO3 (33 +/- 9 micromol/min in the NaCl group and 51 +/- 5 micromol/min in the NaHCO3 group). Tissue lactate was not statistically different in the hypoxic myocardium supplied by the LAD artery and the nonhypoxic myocardium supplied by the circumflex artery in either group.. The response of the myocardium to hypoxia is to decrease its mechanical work and metabolic demand. The infusion of NaHCO3 did not enhance myocardial contractile function or flux in glycolysis during hypoxia. We speculate that this diminished mechanical work and metabolic demand may represent an adaptive response to preserve cellular integrity until oxygen delivery is restored.

Topics: Acidosis, Lactic; Analysis of Variance; Animals; Blood Gas Analysis; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Energy Metabolism; Female; Hemodynamics; Hydrogen-Ion Concentration; Hypoxia; Lactic Acid; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Stunning; Oxygen Consumption; Sodium Bicarbonate; Stroke Volume

The experiments presented here were done to evaluate whether the levels of CO2 in respiratory air during the 13C-bicarbonate breath test (13C-BBT) may be used as a marker of non-invasive diagnosis of the levels of atrophic gastritis. Twenty-eight patients with chronic gastritis and five healthy volunteers were enrolled in the study. Moreover, experimental gastritis was induced in rats by N-methy-N-nitro-N-nitrosoguanidine. In human, the levels of atrophic gastritis were evaluated from the vascular pattern of the gastric fornix. Total delta 13CO2 calculated from the 13C-BBT and the mucosal thickness ratio (MTR) were measured in rats with experimental gastritis. The levels of 13CO2 were significantly higher from patients with a vascular pattern at the fornix than in those without a vascular pattern (p<0.01). There was a good correlation between MTR and the levels of 13CO2, in rats with experimental gastritis (p<0.01). These findings indicate that the levels of 13CO2 during 13C-BBT reflect the levels of atrophic gastritis and show its clinical significance for non-invasive evaluation of atrophic gastritis. This has important clinical implications in selecting Helicobacter pylori-positive cases for therapy and follow-up.

Topics: Age Factors; Animals; Body Height; Body Weight; Breath Tests; Buffers; Carbon Dioxide; Carbon Isotopes; Disease Models, Animal; Gastric Mucosa; Gastritis, Atrophic; Humans; Male; Methylnitronitrosoguanidine; Rats; Rats, Wistar; Sex Factors; Sodium Bicarbonate

Administration of ammonium chloride aggravates, while short-term administration of sodium or potassium bicarbonate lessens the development of polycystic kidney disease in Han:SPRD rats. We have conducted studies to determine whether the protection afforded by the administration of sodium bicarbonate is sustained and prevents development of uremia during chronic administration and whether the effects of the administration of ammonium chloride and sodium bicarbonate are also observed in a different model of polycystic kidney disease, the CD1-pcy/pcy mouse. We found that chronic administration of 200 mM sodium bicarbonate to Han:SPRD rats inhibited cystic enlargement and prevented the subsequent development of interstitial inflammation, chronic fibrosis, and uremia. We also found that, while the administration of ammonium chloride has similar effects in Han:SPRD rats and CD1-pcy/pcy mice, the administration of sodium bicarbonate is only protective in the Han:SPRD rats. This probably reflects differences in these models (predominately involvement of proximal tubules in Han:SPRD rats and of collecting ducts and distal tubules in pcy/pcy mice) and the different location and nature of the renal metabolic responses to the administration of acid or alkaline load.

Topics: Ammonia; Ammonium Chloride; Animals; Bicarbonates; Disease Models, Animal; Female; Fibrosis; Inflammation; Kidney; Male; Mice; Mice, Inbred Strains; Microscopy, Electron, Scanning; Organ Size; Polycystic Kidney Diseases; Rats; Rats, Inbred Strains; Sodium Bicarbonate; Species Specificity; Time Factors; Uremia

To develop an animal model to study dose-response relationships of enteropathogenic bacteria.. Adult, male Wistar Unilever rats were exposed orally to different doses of Salmonella enterica serovar Enteritidis after overnight starvation and neutralization of gastric acid by sodium bicarbonate. The spleen was the most sensitive and reproducible organ for detection of dose-dependent systemic infection. Illness was only observed in animals exposed to doses of 10(8) cfu or more. At lower doses, histopathological changes in the gastro-intestinal tract were observed, but these were not accompanied by illness. Marked changes in numbers and types of white blood cells, as well as delayed-type hyperresponsiveness, indicated a strong, dose-dependent cellular immune response to Salm. Enteritidis.. The rat model is a sensitive and reproducible tool for studying the effects of oral exposure to Salm. Enteritidis over a wide dose range.. The rat model allows controlled quantification of different factors related to the host, pathogen and food matrix on initial stages of infection by food-borne bacterial pathogens.

Topics: Administration, Oral; Animals; Disease Models, Animal; Fasting; Feces; Gastric Acid; Gastric Acidity Determination; Hydrogen-Ion Concentration; Hypersensitivity, Delayed; Leukocyte Count; Male; Rats; Rats, Wistar; Salmonella enteritidis; Salmonella Infections, Animal; Sodium Bicarbonate; Spleen

The changes of vitreous pH values under acute glaucoma status have never been reported. In this study, we measured the changes of vitreous pH values in an acute glaucoma rabbit model. Under ketamine and xylazine anesthesia, the anterior chamber of the right eye of New Zealand white rabbits was cannulated and connected to a polygraph for continuous intraocular pressure (IOP) monitoring and a mini-pump for persistent injection of viscoelastic substance, Healon GV. The measurement of vitreous pH was done by inserting a pH probe via a third opening through the sclera into the vitreous. Different IOP levels were maintained by varied amounts of Healon GV injections into the anterior chamber. The changes of vitreous pH values following the intracameral injections were recorded and evaluated. The changes of vitreous pH values were minimal when IOPs were maintained at lower than 35 mmHg. Vitreous pH values decreased significantly from 7.32 to less than 7.03, when the IOPs were kept at 70 mmHg or higher. However, the decrease of pH values was reversible if IOP was held at 70 mmHg for less than 10 minutes and then reduced to normal level at once. In addition, with MTT viability assay, it was noted that the decrease in vitreous pH was associated with a higher percentage of retinal cell death.

Topics: Acidosis; Acute Disease; Animals; Cell Death; Disease Models, Animal; Glaucoma; Hyaluronic Acid; Hydrogen-Ion Concentration; Intraocular Pressure; Male; Ocular Hypertension; Rabbits; Retina; Retinal Diseases; Sodium Bicarbonate; Vitreous Body

Advanced cardiac life support (ACLS) guidelines recommend a 3- to 5-minute interval between repeated doses of epinephrine. This recommendation does not take into account the dose of epinephrine used, and only very limited data exist regarding the hemodynamic responses to repeated "high" doses of epinephrine. The objective of this study was to analyze the hemodynamic responses to repeated, equal, high doses of epinephrine administered during cardiopulmonary resuscitation (CPR) in a canine model of ventricular fibrillation (VF).. This study used a secondary analysis of data collected in a prospective, randomized study, primarily designed to assess the effects of acid buffers in a canine model of cardiac arrest. VF was electrically induced. After 10 minutes, CPR was initiated, including ventilation with FIO(2)=1.0, external chest compressions, administration of epinephrine (0.1 mg/kg repeated every 5 minutes) and defibrillation. Animals were randomized to receive either NaHCO(3), Carbicarb, tromethamine (THAM), or NaCl. The hemodynamic variables were sampled from each experiment's paper chart at 1-minute intervals, and the responses to the first 4 doses of epinephrine were compared.. Thirty-six animals (9 in each buffer group) were included in this analysis. Systolic, diastolic, and coronary perfusion pressures increased steeply (by 100%, 130%, and 190%, respectively) only after the first epinephrine dose. These pressures peaked at 2 to 3 minutes and decreased only slightly and insignificantly during the rest of the 5-minute interval, until the next epinephrine dose. No further significant increases in arterial pressures were observed in response to the next 3 doses of epinephrine, administered 5 minutes apart.. The hemodynamic effects of high-dose epinephrine (0.1 mg/kg) during CPR appear to last longer than 5 minutes. Therefore, longer intervals between doses may be justified with high doses of epinephrine.

Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Buffers; Carbonates; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Drug Administration Schedule; Drug Combinations; Drug Evaluation, Preclinical; Drug Therapy, Combination; Epinephrine; Practice Guidelines as Topic; Random Allocation; Sodium Bicarbonate; Sodium Chloride; Time Factors; Tromethamine; Vasoconstrictor Agents; Ventricular Fibrillation

To evaluate the potential utility of sodium bicarbonate in an established model of acute propranolol toxicity.. Two minutes after the completion of a propranolol infusion (10 mg/kg), a bolus of 1.5 mEq/kg of sodium bicarbonate solution (1 mEq/mL) followed by an infusion of 1.5 mEq/kg over the next 26 minutes (n = 6) or an equivalent timing and volume of 5% dextrose solution (n = 6) was administered in each dog. Targeted cardiovascular parameters included heart rate, mean arterial pressure, left ventricular dP/dtmax, and QRS interval.. Propranolol infusion significantly depressed heart rate (p < 0.0001), mean arterial pressure (p < 0.0001), dP/dtmax (p < 0.0001) and prolonged the QRS interval (p < 0.0001). Sodium bicarbonate failed to significantly improve these targeted parameters when compared to control animals.. In this canine model of propranolol toxicity, intravenous sodium bicarbonate appears to be an ineffective single therapy. Furthermore, these results may suggest a different mechanism of sodium channel blockade for propanolol than that of type IA antiarrhythmic agents.

Topics: Animals; Bicarbonates; Blood Pressure; Cardiovascular Diseases; Disease Models, Animal; Dogs; Electrocardiography; Heart Conduction System; Heart Rate; Infusions, Intravenous; Poisoning; Propranolol; Sodium; Sodium Bicarbonate; Treatment Outcome; Ventricular Function, Left

This study was conducted to determine whether hypertonic sodium bicarbonate would improve the hypotension associated with severe verapamil toxicity compared with volume expansion.. The study design used a nonblinded acute animal preparation. Twenty-four anesthetized and instrumented swine were poisoned with verapamil delivered at a rate of 1 mg/kg per hour for 10 minutes followed by incremental increases of 1 mg/kg per hour every 10 minutes until the endpoint of a mean arterial blood pressure of 45% of baseline was achieved. Animals alternately received either 4 mEq/kg of hypertonic sodium bicarbonate intravenously over 4 minutes or similar volumes of 0.6% sodium chloride in 10% mannitol (control). The main outcome parameter followed was mean arterial pressure. In addition, physiologic parameters including cardiac output, heart rate, pH, PCO (2), PO (2), plasma ionized calcium, sodium, and potassium were monitored.. Verapamil toxicity, as defined by a mean arterial pressure of 45% of baseline, was produced in all animals following an average verapamil infusion dose of 0.6+/-0.12 mg/kg. This dose produced an average plasma verapamil concentration of 728.1+/-155.4 microgram/L, with no significant difference between groups. Swine treated with hypertonic sodium bicarbonate experienced a significant increase in mean arterial pressure (>50%) and cardiac output (>30%) over the first 20 minutes that slowly equilibrated with the control group over the remainder of the experiment. As expected, plasma sodium concentrations were elevated significantly in the sodium bicarbonate group while plasma potassium concentrations were decreased significantly. Finally, there was a significant decrease in plasma ionized calcium concentration in the sodium bicarbonate-treated group compared with controls.. Hypertonic sodium bicarbonate reversed the hypotension and cardiac output depression of severe verapamil toxicity in a swine model.

Topics: Animals; Blood Pressure Determination; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Hemodynamics; Hypertonic Solutions; Hypotension; Infusions, Intravenous; Male; Reference Values; Severity of Illness Index; Sodium Bicarbonate; Sodium Chloride; Survival Rate; Swine; Verapamil

The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E214k, were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO3 did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for >/=24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.

Topics: Acidosis; Adrenalectomy; Animals; Corticosterone; Cysteine Endopeptidases; Dexamethasone; Diabetes Mellitus, Experimental; Disease Models, Animal; Enzyme Activation; Glucocorticoids; Insulin; Male; Multienzyme Complexes; Muscle Proteins; Muscular Atrophy; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sodium Bicarbonate; Ubiquitins

Topics: Animals; Buffers; Carbonates; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Drug Combinations; Heart Arrest; Humans; Sodium Bicarbonate; Tromethamine; Ventricular Fibrillation

During cardiopulmonary resuscitation (CPR), elimination of CO2 was shown to be limited by low tissue perfusion, especially when very low perfusion pressures were generated. It has therefore been suggested that sodium bicarbonate (NaHCO3), by producing CO2, might aggravate the hypercarbic component of the existing acidosis and thereby worsen CPR outcome. The objectives of this study were to evaluate the effects of CO2 producing and non-CO2 producing buffers in a canine model of prolonged ventricular fibrillation followed by effective CPR.. Prospective, randomized, controlled, blinded trial.. Experimental animal research laboratory in a university research center.. Thirty-eight adult dogs, weighing 20 to 35 kg.. Animals were prepared for study with thiopental followed by halothane, diazepam, and pancuronium. Ventricular fibrillation was electrically induced, and after 10 mins, CPR was initiated, including ventilation with an FIO2 of 1.0, manual chest compressions, administration of epinephrine (0.1 mg/kg every 5 mins), and defibrillation. A dose of buffer, equivalent to 1 mmol/kg of NaHCO3, was administered every 10 mins from start of CPR. Animals were randomized to receive either NaHCO3, Carbicarb, THAM, or 0.9% sodium chloride (NaCl). CPR was continued for up to 40 mins or until return of spontaneous circulation.. Buffer-treated animals had a higher resuscitability rate compared with NaCl controls. Spontaneous circulation returned earlier and at a significantly higher rate after NaHCO3 (in seven of nine dogs), and after Carbicarb (six of ten dogs) compared with NaCl controls (two of ten dogs). Spontaneous circulation was achieved twice as fast after NaHCO3 compared with NaCl (14.6 vs. 28 mins, respectively). Hydrogen ion (H+) concentration and base excess, obtained 2 mins after the first buffer dose, were the best predictors of resuscitability. Arterial and mixed venous Pco2 did not increase after NaHCO3 or Carbicarb compared with NaCl.. Buffer therapy promotes successful resuscitation after prolonged cardiac arrest, regardless of coronary perfusion pressure. NaHCO3, and to a lesser degree, Carbicarb, are beneficial in promoting early return of spontaneous circulation. When epinephrine is used to promote tissue perfusion, there is no evidence for hypercarbic venous acidosis associated with the use of these CO2 generating buffers.

Topics: Animals; Blood Gas Analysis; Buffers; Carbonates; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Drug Combinations; Epinephrine; Heart Arrest; Hemodynamics; Infusions, Intravenous; Prospective Studies; Random Allocation; Sodium Bicarbonate; Treatment Outcome; Tromethamine; Ventricular Fibrillation

We sought to compare the effects of hypertonic sodium chloride solution (HTS), sodium bicarbonate solution, and hyperventilation (HV) on severe tricyclic antidepressant (TCA) toxicity in a swine model.. Twenty-four mixed-breed, domestic swine of either sex were given an intravenous infusion of nortriptyline (NT) until development of both a QRS duration longer than 120 ms and a systolic blood pressure (SBP) less than or equal to 50 mm Hg. Animals were randomly assigned to 1 of 4 groups. On reaching toxicity, the control group received 10 mL/kg of 5% dextrose in water (D5W); the HTS group received 10 mL/kg of 7.5% NaCl solution (15 mEq Na+/kg); the NaHCO3 group received 3 mEq/kg of 8.4% sodium bicarbonate solution followed by enough D5W solution to equal 10 mL/kg of total volume; and the HV group was mechanically hyperventilated to maintain arterial pH between 7.50 and 7.60 and given 10 mL/kg of D5W.. The mean SBP 10 minutes after treatment was 54+/-18 mm Hg in the control group, 134+/-21 mm Hg in the HTS group, 85+/-19 mm Hg in the NaHCO3 group, and 60+/-12 mm Hg in the HV group (P<.05). Mean QRS duration 10 minutes after treatment was 144+/-38 ms in the control group, 80+/-14 ms in the HTS group, 105+/-38 ms in the NaHCO3 group, and 125+/-46 ms in the HV group (P<.05).. In this model of TCA, toxicity HTS was more effective than sodium bicarbonate. Hyperventilation had little effect. Sodium loading may be the most important factor in reversing TCA toxicity.

Topics: Animals; Antidepressive Agents, Tricyclic; Blood Pressure; Buffers; Disease Models, Animal; Electrocardiography; Female; Fluid Therapy; Glucose; Hydrogen-Ion Concentration; Injections, Intravenous; Male; Nortriptyline; Random Allocation; Respiration, Artificial; Saline Solution, Hypertonic; Sodium; Sodium Bicarbonate; Swine; Tachycardia, Ventricular

To determine whether alkalinization with sodium bicarbonate (NaHCO3) in near-lethal hyperkalemia either lowers potassium (K) rapidly or shortens duration of cardiac conduction disturbances.. A controlled canine laboratory investigation of 3 treatments for severe hyperkalemia. Conditioned dogs (n = 8; 17-30 kg) received, in random order, 2 mmol/kg of each of 3 treatments (matched in sodium and water) in separate experiments > or = 1 week apart: 1.05% NaHCO3 over 60 minutes (infusion therapy); 8.4% NaHCO3 over 5 minutes, then 14 mL/kg sterile water over 55 minutes (bolus therapy); 8.4% NaCl over 5 minutes, then 14 mL/kg sterile water over 55 minutes (saline therapy). Prior to administering one of the above therapies, the animals were anesthetized with 0.5-2.5% isoflurane and ventilated to maintain a normal PCO2. After 30 minutes of equilibration, 2 mmol/kg/hr (loading dose) of a 2-mmol/mL KCl solution was given until idioventricular or relative junctional bradycardic dysrhythmias were sustained for 15 minutes. Then KCl was decreased to 1 mmol/kg/hr (maintenance dose) for 2 hours and 45 minutes. Treatment was begun after 45 minutes of maintenance KCl infusion.. The pretreatment K level (all studies) was 9.06 +/- 0.82 mmol/L (mean +/- SD). Although the mean K level decreased more after saline therapy than after bolus therapy at every time, differences were neither statistically significant nor clinically important during the first 30 minutes. The means of the differences in decreases (saline minus bolus) were small, 0.26 (95% CI, -0.48 to 1.00) at 15 minutes, 0.16 (95% CI, -0.67 to 0.98) at 30 minutes. Dysrhythmia duration was shorter with bolus therapy than for saline therapy in only 1 of 5 dogs (p = 0.38).. Hypertonic saline bolus lowered plasma K as effectively as NaHCO3 bolus in this animal model within the first 30 minutes. Clinically meaningful decreases due to alkalinization alone within 30 minutes are unlikely.

Topics: Animals; Disease Models, Animal; Dogs; Hyperkalemia; Osmolar Concentration; Sodium Bicarbonate

Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to investigate whether treatment with epinephrine or norepinephrine increases survival as compared with standard treatment with sodium bicarbonate in experimental amitriptyline poisoning.. Nonrandomized, controlled intervention trial.. University laboratory.. Male, anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 91).. Rats subjected to a 60-min infusion of amitriptyline (2 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, sodium bicarbonate, epinephrine plus sodium bicarbonate, norepinephrine plus sodium bicarbonate, or placebo.. Inotropic drug treatment was associated with an increased survival rate as compared with treatment with sodium bicarbonate and treatment with placebo. Epinephrine treatment was superior to norepinephrine. Additional treatment with sodium bicarbonate increased survival rate for each inotropic drug. Sodium bicarbonate and inotropic drug treatment independently increased the survival rate (p < .001 for both effects). No interaction between these two treatment effects was observed.. Both epinephrine and norepinephrine increased the survival rate in tricyclic antidepressant poisoning in rats. Sodium bicarbonate increased the survival rate independent of inotropic drug treatment. Furthermore, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment was epinephrine plus sodium bicarbonate.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Arrhythmias, Cardiac; Disease Models, Animal; Drug Combinations; Electrolytes; Epinephrine; Hemodynamics; Humans; Male; Norepinephrine; Poisoning; Rats; Rats, Sprague-Dawley; Sodium Bicarbonate; Survival Rate; Sympathomimetics

The effectiveness of 5 different brands of dentifrices on caries and plaque were tested in rats in 2 experiments. 10 litters of rats each were infected with Streptococcus sobrinus OMZ-176 and Actinomyces viscosus Ny1. The rats were offered the diet 2000a containing either 40% of sucrose (study I) or 10% of sucrose (study II). The following products were tested topically: (1) H2O, (negative control); (2) chlorhexidine diacetate, (positive control); (3) Parodontax NF; (4) Meridol; (5) Colgate Total; (6) Mentadent C; (7) Dent Xpress. Comparisons with the water control in study I showed that plaque extent was decreased by chlorhexidine diacetate, Dent Xpress and by Mentadent C only. All fluoride-containing dentifrices tested reduced caries. In study II, comparisons with the water control showed that plaque extent was reduced by chlorhexidine diacetate, Parodontax, Meridol, Dent Xpress and by Mentadent C. All dentifrices reduced caries, however, the incidence was low. These 2 studies confirm that fluorides incorporated in dentifrices decrease dental caries in the rat. Differences in the effectiveness of caries inhibition between the 5 dentifrices could not be explained either by the form of fluoride utilized or by the antimicrobials added. Rather, the performance of a given dentifrice depended upon the concerted action of the particular ingredients. It appears that the effect of antiplaque agents should be evaluated in the rat model using a diet containing sucrose at a low level.

Topics: Actinomyces viscosus; Administration, Topical; Amines; Animals; Anti-Infective Agents, Local; Cariostatic Agents; Chlorhexidine; Dental Caries; Dental Plaque; Dentifrices; Diet, Cariogenic; Dietary Sucrose; Disease Models, Animal; Drug Combinations; Drug Interactions; Fluorides; Hydrogen Peroxide; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; Silicic Acid; Silicon Dioxide; Sodium Bicarbonate; Sodium Fluoride; Streptococcus sobrinus; Tin Fluorides; Toothpastes; Water

To determine efficacy of hypertonic sodium bicarbonate in narrowing QRS prolongation produced by chloroquine.. Randomized, controlled animal experiment using an accepted rat model of sodium channel blockade.. Hypotension and widening of QRS complexes (lead II) of the ECG were produced in 16 rats by administration of a total of 87 mg/kg chloroquine intravenously over 20 minutes. Eight rats were treated with 6 mL/kg 1 M sodium bicarbonate intravenously over two minutes beginning ten minutes into the chloroquine infusion. Serial measurements of QRS duration and systolic blood pressure were obtained for 30 minutes.. QRS intervals narrowed more rapidly in animals receiving sodium bicarbonate (p = .045), although the difference in mean rate of narrowing between groups was modest at only .23 msec/min. Because of large variances, no statistically significant differences could be demonstrated in systolic blood pressure.. Hypertonic sodium bicarbonate partially reversed sodium channel blockade and resultant QRS interval prolongation produced by chloroquine in rats. These data should be interpreted with caution, given the need to extrapolate to humans and the modest effect of sodium bicarbonate on QRS narrowing.

Topics: Amebicides; Animals; Antimalarials; Chloroquine; Disease Models, Animal; Electrocardiography; Heart Rate; Male; Rats; Rats, Sprague-Dawley; Sodium Bicarbonate

To determine whether changes in cardiac output, regional blood flow, and intracranial pressure during permissive hypercapnia are blood pH-dependent and can be attenuated by correction of intravascular acidemia.. Prospective, controlled study.. Research laboratory.. Female Marino ewes.. Animals were instrumented with a pulmonary artery catheter, femoral arterial and venous catheters, a catheter in the third cerebral ventricle, and ultrasonic flow probes on the left carotid, superior mesenteric, and left renal arteries 1 wk before experimentation. At initiation of the protocol, ewes underwent endotracheal intubation and mechanical ventilation under general anesthesia. Minute ventilation was reduced to induce hypercapnia with a target PaCO2 of 80 torr (10.7 kPa). In the pH-uncorrected group (n = 6), arterial blood pH was allowed to decreased without treatment. In the pH-corrected group (n = 5), 14.4 mEq/kg of sodium bicarbonate was given intravenously as a bolus to correct arterial blood pH toward a target arterial pH of 7.40 (dose calculated by the Henderson-Hasselbalch equation).. Arterial blood pH, PCO2, cardiac output, intracranial pressure, and carotid, superior mesenteric, and renal artery blood flow rates were measured at normocapnic baseline and at every hour during hypercapnia for 6 hrs. In the pH-uncorrected group, arterial blood pH decreased from 7.41 +/- 0.03 at normocapnia to 7.14 +/- 0.01 (p < .01 vs. normocapnia) as blood PCO2 increased to 81.2 +/- 1.8 torr (10.8 +/- 0.2 kPa). In the pH-corrected group, arterial blood pH was 7.42 +/- 0.02 at normocapnia and was maintained at 7.37 +/- 0.01 while PaCO2 was increased to 80.3 +/- 0.9 torr (10.7 +/- 0.1 kPa). Significant increases in cardiac output occurred with the initiation of hypercapnia for both groups (pH-uncorrected group: 4.3 +/- 0.6 L/min at normocapnia vs. 6.8 +/- 1.0 L/min at 1 hr [p < .05]; pH-corrected group: 4.1 +/- 0.4 at normocapnia vs. 5.7 +/- 0.4 L/min at 1 hr [p < .05]). However, this increase was sustained only in the uncorrected group. Changes in carotid and mesenteric artery blood flow rates, as a percent of baseline values, showed sustained significant increases in the pH-uncorrected groups (p < .05) and only transient (carotid at 1 hr) or no (superior mesenteric) significant change in the pH-corrected groups. Conversely, significant increases in renal artery blood flow were seen only in the pH-uncorrected group during the last 2 hrs of the experiment (p < .05). Organ blood flow, as a percent of cardiac output, did not change significantly in either group. Intracranial pressure increased significantly in the pH-uncorrected group (9.0 +/- 1.5 mm Hg at normocapnia vs. 26.8 +/- 5.1 at 1 hr, p < .05), and remained increased, while showing no significant change in the pH-corrected group (8.5 +/- 1.6 mm Hg at normocapnia to 7.7 +/- 4.2 at 1 hr).. Acute hypercapnia, induced within 1 hr, is associated with significant increases in cardiac output, organ blood flow, and intracranial pressure. These changes can be significantly attenuated by correction of blood pH with the administration of sodium bicarbonate, without adverse effects on hemodynamics.

Topics: Acute Disease; Animals; Blood Gas Analysis; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Hemodynamics; Hydrogen-Ion Concentration; Hypercapnia; Positive-Pressure Respiration; Prospective Studies; Random Allocation; Respiratory Distress Syndrome; Sheep; Sodium Bicarbonate; Time Factors

Hypotension is a major contributor to mortality in tricyclic antidepressant overdose. Recent data suggest that tricyclic antidepressants inhibit calcium influx in some tissues. This study addressed the potential role of calcium channel blockade in tricyclic antidepressant-induced hypotension.. Two interventions were studied that have been shown previously to improve blood pressure with calcium channel blocker overdose. CaCl2 and 4-aminopyridine. Anesthetized rats received the tricyclic antidepressant desipramine IP to produce hypotension, QRS prolongation, and bradycardia. Fifteen min later, animals received CaCl2, NaHCO3, or saline. In a second experiment, rats received tricyclic antidepressant desipramine IP followed in 15 min by 4-aminopyridine or saline.. NaHCO3 briefly (5 min) reversed hypotension and QRS prolongation. CaCl2 and 4-aminopyridine failed to improve blood pressure. The incidence of ventricular arrhythmias (p = 0.004) and seizures (p = 0.03) in the CaCl2 group was higher than the other groups.. The administration of CaCl2 or 4-aminopyridine did not reverse tricyclic antidepressant-induced hypotension in rats. CaCl2 therapy may possibly worsen both cardiovascular and central nervous system toxicity. These findings do not support a role for calcium channel inhibition in the pathogenesis of tricyclic antidepressant-induced hypotension.

Topics: 4-Aminopyridine; Animals; Antidepressive Agents, Tricyclic; Arrhythmias, Cardiac; Blood Pressure; Bradycardia; Calcium Channels; Calcium Chloride; Desipramine; Disease Models, Animal; Electrocardiography; Hypotension; Male; Rats; Saline Solution, Hypertonic; Sodium Bicarbonate

The purpose of this study was to evaluate the plasma potassium (K+) response after administration of tromethamine (THAM) or sodium bicarbonate (NaHCO3) in an acidotic rabbit model. Eighteen healthy, adult female New Zealand White rabbits were subjected to severe hypoxia until a base deficit of -10 mEq/L resulted. Rabbits were then randomized to receive THAM solution, NaHCO3, or no drug (control). The drug was administered over 2 min in quantities calculated to correct a base deficit of 10 or greater. Plasma K+ and sodium (Na+) were measured for 45 min after drug administration. No difference in K+ response was noted after THAM, NaHCO3, or no drug. In contrast, THAM resulted in significantly lower Na+ concentrations when compared to the NaHCO3 or the control group (P < 0.05). In this rabbit model, alkalinization after THAM administration results in K+ changes similar to those after NaHCO3. THAM should be considered when treating acidosis in patients where hypernatremia is a concern.

Topics: Acidosis; Alkalies; Analysis of Variance; Animals; Blood Pressure; Buffers; Carbon Dioxide; Disease Models, Animal; Female; Hydrogen-Ion Concentration; Hypoxia; Linear Models; Potassium; Rabbits; Random Allocation; Sodium; Sodium Bicarbonate; Tromethamine

Flecainide occasionally produces incessant ventricular tachycardia that is difficult to treat. Reports of uncontrolled clinical studies have suggested a therapeutic role for hypertonic sodium bicarbonate (NaHCO3). To test this observation, spontaneous and pacing-induced arrhythmia canine models were designed. In the spontaneous model, flecainide was infused at 0.5 mg/kg/min until ventricular tachycardia occurred spontaneously. In the pacing-induced model, flecainide was infused at 1.0 mg/kg/min load (0.5 mg/kg/min maintenance) stepwise until the QRS was widened 50%, 75%, and 100%, with programmed ventricular stimulation at each step until ventricular arrhythmia was induced. Dogs who developed spontaneous arrhythmia were treated blindly with three doses of either NaHCO3 (3 mEq/kg/dose, with 1 minute between doses) or normal saline. Dogs who were induced in the second model were treated with the same three doses, 10 minutes apart, with programmed stimulation between each dose. Before unblinding in both protocols, dogs were classified as "responders" or "nonresponders" to therapy. In the spontaneous model, of 14 dogs with spontaneous ventricular tachycardia, all 7 dogs treated with NaHCO3 showed response, compared with only 1 of 7 dogs treated with saline (P < .01). Ventricular QRS complexes/min were reduced by NaHCO3 in that protocol. In the induced arrhythmia protocol, of 14 dogs with inducible arrhythmia, 6 of 7 responded to NaHCO3, and 1 of 7 responded to placebo (P < .05). In both protocols, arterial pH and the serum sodium concentration were increased by NaHCO3 but not by normal saline control treatment. QRS interval duration was shortened by NaHCO3 therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Electrocardiography; Flecainide; Hypertonic Solutions; Sodium Bicarbonate; Sodium Chloride; Tachycardia, Ventricular

Effects of amrinone (AMR), a phosphodiesterase inhibitor, alone and in combination with dobutamine (DOB), on hemodynamics and O2 delivery were studied during porcine endotoxemia. Pentobarbital-anesthetized pigs were randomly administered either Escherichia coli lipopolysaccharide (endotoxin) or equivolumetric .9% NaCl (control) as a continuous infusion for 4 h. From 2 to 4 h (T = 120-240 min) of endotoxin infusion, pigs were randomly administered one of the following treatments; AMR infusion (40 micrograms/kg/min) (AMRlow); DOB (10 micrograms/kg/min) (DOB); AMR infusion (40 micrograms/kg/min) + DOB (AMRlow+DOB); AMR bolus (.75 mg/kg) followed by AMR infusion (40 micrograms/kg/min) (AMRhigh); or AMR bolus (.75 mg/kg) followed by infusion (40 micrograms/kg/min) + DOB (AMRhigh+DOB). Myocardial samples were obtained at the end of the experiment and flash-frozen for beta-adrenergic receptor analysis. Endotoxin significantly (p < .05) decreased cardiac index, right ventricular ejection fraction, stroke volume index, maximum rate of rise of left ventricular pressure (dP/dtmax), mean arterial pressure, and O2 delivery, and increased pulmonary vascular resistance and mean pulmonary arterial pressure (p < .05). AMRlow+DOB significantly (p < .05) increased cardiac index, dP/dtmax, right ventricular ejection fraction, stroke volume index, O2 delivery and consumption, and decreased mean pulmonary arterial pressure, pulmonary vascular resistance, mean arterial pressure, and systemic vascular resistance. beta-Adrenergic receptor density (Bmax) and binding equilibrium dissociation constant (KD) for [3H]dihydroalprenolol were not affected by endotoxin or any treatment (p < .05). Endotoxin-induced hemodynamic deterioration and decreased O2 delivery was attenuated by AMRlow+DOB. Potential applications of this combination may exist in treatment of septic patients with inadequate myocardial performance and reduction in O2 delivery complicated by pulmonary hypertension.

Topics: Amrinone; Animals; Disease Models, Animal; Dobutamine; Down-Regulation; Drug Therapy, Combination; Hemodynamics; Hydrogen-Ion Concentration; Oxygen Consumption; Radioligand Assay; Receptors, Adrenergic, beta; Shock, Septic; Sodium Bicarbonate; Swine; Ventricular Function, Right

Paraplegia or paraparesis caused by temporary cross-clamping of the aorta is a devastating sequela in patients after surgery of the thoracoabdominal aorta. No effective clinical method is available to protect the spinal cord from ischemic reperfusion injury. A small animal (rat) model of spinal cord ischemia is established to better understand the pathophysiological events and to evaluate potential treatments. Eighty-one male Sprague-Dawley rats weighing 300 g to 350 g were used for model development (45) and treatment evaluation (36). The heparinized and anesthetized rat was supported by a respirator following tracheostomy. The thoracic aorta was cannulated via the left carotid artery for post-clamping intra-aortic treatment solution administration. After thoracotomy, the aorta was freed and temporarily clamped just distal to the left subclavian artery and just proximal to the diaphragm for different time intervals: 0, 5, 10, 15, 20, 25, 30, 35, and 40 minutes (five animals per group). The motor function of the lower extremities postoperatively showed consistent impairment after 30 minutes clamping (5/5 rats were paralyzed), and this time interval was used for treatment evaluation. For each treatment, six animals per group were used, and direct local intra-aortic infusion of physiologic solution (2 mL) at different temperatures with or without buffer substances was given immediately after double cross-clamp to protect the ischemic spinal cord. Arterial blood (2 mL) was infused in the control group. The data indicate that the addition of HCO3-(20 mM) to the hypothermic (15 degrees C) solution offered complete protection of the spinal cord from ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetates; Animals; Aorta; Cardioplegic Solutions; Disease Models, Animal; Drug Evaluation, Preclinical; Gluconates; HEPES; Hypothermia, Induced; Magnesium Chloride; Male; Paraplegia; Postoperative Complications; Potassium Chloride; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Reproducibility of Results; Sodium Acetate; Sodium Bicarbonate; Sodium Chloride; Spinal Cord; Time Factors

The effects of HCO3Na load on acid-base balance and muscle intracellular bioenergetics have been investigated using 31P-magnetic resonance spectroscopy in an experimental model of endotoxinic shock. Anesthetized, mechanically ventilated, and paralyzed rats (n = 16) were given an intravenous bolus of Escherichia coli lipopolysaccharide (15 mg/kg). When shock was established they were randomly assigned to receive either HCO3Na intravenously (2 mmol/kg in 2 min) or an equimolar saline injection. Lipopolysaccharide induced a significant decrease in the levels of mean arterial pressure (58 +/- 6 vs. 120 +/- 8 mmHg), arterial pH (7.20 +/- .03 vs. 7.35 +/- .01), intracellular pH (6.86 +/- .04 vs. 7.08 +/- .01), a marked hyperlactatemia (7 +/- 3 vs. 1.2 +/- .2 mmol/L) and a drop in the phosphocreatine-inorganic phosphate ratio. In the bicarbonate-loaded rats, mean arterial pressure further decreased whereas it remained unchanged in the saline group. Bicarbonate increased arterial pH and PaCO2 transiently. In the saline group, arterial pH decreased and PaCO2 remained stable. In both groups, intracellular pH and high energy phosphates had a similar evolution. In this model of septic shock, partial correction of arterial pH using HCO3Na did not reduce the metabolic cellular injury in skeletal muscle. Based on these results, HCO3Na may be of limited therapeutic value in severe septic metabolic acidosis.

Topics: Acidosis, Lactic; Animals; Blood Pressure; Disease Models, Animal; Hindlimb; Hydrogen-Ion Concentration; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Muscle, Skeletal; Physical Phenomena; Physics; Rats; Rats, Sprague-Dawley; Shock, Septic; Sodium Bicarbonate; Sodium Chloride

To compare the effects of hypertonic saline, sodium bicarbonate, and Carbicarb resuscitation on acid-base balance, hemodynamics, and oxygen dynamics in a reperfused, canine hemorrhagic shock model.. Prospective, randomized trial.. Laboratory at a university medical center.. Thirty-five anesthetized, mongrel dogs.. After the administration of anesthesia, the dogs were intubated and mechanically ventilated. Vascular catheters were inserted into each femoral artery, for continuous blood pressure monitoring, intermittent blood sampling, and for establishing controlled hemorrhage. A pulmonary artery catheter was inserted via the right jugular vein. Inhaled and exhaled gases were continuously analyzed using a metabolic gas monitor. The animals were subjected to 90 mins of controlled hemorrhagic shock. They were then randomly given a 2.5-mL/kg equimolar injection of 8.4% sodium bicarbonate, Carbicarb, or 5.84% hypertonic saline. The sodium load per kilogram of body weight was identical in all three groups. Thirty minutes later, the animals were retransfused with the shed blood over 15 mins and further observed for 120 mins.. Carbicarb and sodium bicarbonate both significantly increased bicarbonate concentrations compared with saline. Arterial and venous blood pH increased more with Carbicarb than with bicarbonate but this increase was not statistically significant. After shock but before retransfusion, all three treatments moderately increased blood pressure, cardiac index, oxygen delivery index, and oxygen consumption index to a similar extent. After retransfusion, blood pressure, cardiac index, and oxygen dynamics temporarily improved in all groups, without significant improvement in the bicarbonate and Carbicarb-treated animals, despite their excellent acid-base status.. In severe canine hemorrhagic shock, Carbicarb, bicarbonate, and hypertonic saline appear to possess similar hemodynamic properties despite the buffering properties of bicarbonate and Carbicarb. The similar responses may be due to their identical sodium content. Arterial pH correction does not appear to further improve the responses to blood retransfusion.

Topics: Acid-Base Imbalance; Animals; Carbonates; Disease Models, Animal; Dogs; Drug Combinations; Hemodynamics; Hydrogen-Ion Concentration; Oxygen; Prospective Studies; Random Allocation; Resuscitation; Saline Solution, Hypertonic; Shock, Hemorrhagic; Sodium Bicarbonate

Sodium bicarbonate is administered during cardiopulmonary resuscitation (CPR) for the treatment of systemic acidemia. However, the effect of administering standard-dose sodium bicarbonate on the vasopressor effect of epinephrine is unknown. This study compared the effects of sodium bicarbonate or normal saline on the vasopressor effect of epinephrine in 18 pigs. After 10 minutes of unassisted ventricular fibrillation, CPR was started using a pneumatic chest compression device. Two minutes after the start of CPR, sodium bicarbonate (1 mEq/kg) or normal saline (1 mL/kg) was administered into the right ventricule followed 1 minute later by epinephrine (0.2 mg/kg). Defibrillation was attempted at 8 minutes of CPR (18 minutes of ventricular fibrillation). Results demonstrated no significant differences in aortic systolic, aortic diastolic, or coronary perfusion pressure (CPP) between the two groups (1 minute after epinephrine, CPP was 22.6 +/- 13.3 mm Hg versus 21.1 +/- 20.7 mm Hg for the sodium bicarbonate and normal saline groups, respectively). However, when the data were stratified according to pH < 7.4 and pH > 7.4, the peak change in CPP was 12.7 +/- 21 mm Hg when pH < 7.4 and was 5.2 +/- 7.4 when pH > 7.4 (P = .33). Resuscitation was also similar between the two groups (two of nine for sodium bicarbonate and one of nine for normal saline). In conclusion, the standard recommended dose of sodium bicarbonate did not alter the vasopressor effect of epinephrine or resuscitation compared with normal saline in this closed chest model of ventricular fibrillation and CPR.

Topics: Acidosis; Animals; Aorta; Bicarbonates; Blood Gas Analysis; Blood Pressure; Cardiopulmonary Resuscitation; Coronary Vessels; Diastole; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Electric Countershock; Epinephrine; Heart Ventricles; Injections; Random Allocation; Sodium; Sodium Bicarbonate; Sodium Chloride; Swine; Systole; Ventricular Fibrillation

Systemic acidosis occurs during cardiac arrest and cardiopulmonary resuscitation (CPR). The present study investigated the effect of different modes of sodium bicarbonate administration on blood gas parameters during CPR. Arterial and venous blood gases were obtained during 10 minutes of CPR which was preceded by 3 minutes of unassisted ventricular fibrillation in 36 dogs. Following 1 minute of CPR, the animals received one of four treatments in a randomized and blinded manner: normal saline (NS), sodium bicarbonate bolus dose 1 mEq/kg (B), sodium bicarbonate continuous infusion 0.1 mEq/kg/min (I), and sodium bicarbonate bolus dose (0.5 mEq/kg) plus continuous infusion 0.1 mEq/kg/min (L+I). Eleven dogs completed NS, 8 B, 8 I, and 9 L+I protocol. Following NS infusion, both arterial and venous pH declined consistently over time. Significant differences compared with NS treatment in venous pH were observed at 12 minutes of ventricular fibrillation (L+I, 7.27 +/- 0.05; NS, 7.15 +/- 0.05; B, 7.20 +/- 0.05; I, 7.24 +/- 0.04, each bicarbonate treatment versus NS, and L+I versus B, (P < .05). The B group had an elevated venous PCO2 (mm Hg) concentration following 6 minutes of ventricular fibrillation compared with NS, L+I, and I groups (81 +/- 14 versus 69 +/- 10 versus 68 +/- 10 versus 71 +/- 8, respectively, (P = .07). Arterial pH and PCO2 values showed a similar trend as the venous data with the L+I group demonstrating arterial alkalosis (pH > 7.45) at 12 minutes of ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animals; Bicarbonates; Blood; Carbon Dioxide; Cardiopulmonary Resuscitation; Disease Models, Animal; Dogs; Heart Arrest; Hydrogen-Ion Concentration; Infusions, Intravenous; Injections, Intravenous; Random Allocation; Sodium; Sodium Bicarbonate; Sodium Chloride

We investigated the effects of carbon dioxide-producing and carbon dioxide-consuming buffers on intramyocardial pH and on cardiac resuscitability. In 29 pigs, intramyocardial pH was continuously measured with a glass electrode advanced into the midmyocardium of the posterior left ventricle through a diaphragmatic window. Ventricular fibrillation (VF) was electrically induced by alternating current applied to the epicardium of the left ventricle. After 3 minutes of VF, precordial compression was begun and continued for an interval of 8 minutes. Sodium bicarbonate (a carbon dioxide-generating buffer), Carbicarb (a carbon dioxide-consuming buffer), and hypertonic sodium chloride (control solution) were infused into the right atrium during cardiac resuscitation. Defibrillation was attempted by transthoracic direct-current shock after 11 minutes of VF. Intramyocardial pH progressively decreased from an average value of 7.26 before VF to 6.87 before infusion of buffers. Systemic circulation and great cardiac vein pH significantly increased after administration of the two buffer agents. However, intramyocardial pH continued to decline to an average of 6.62 after 11 minutes of VF, and this decline was not altered by either buffer solution or by the saline control. As in previous studies, resuscitability was closely related to coronary perfusion pressure at the time of direct-current countershock but not to pH. Accordingly, the rationale of reversing acidosis by the administration of these buffer agents is not supported. Even more important, neither carbon dioxide-consuming nor carbon dioxide-producing buffers altered myocardial acidosis or improved myocardial resuscitability under controlled experimental conditions of cardiac arrest.

Topics: Acidosis; Animals; Bicarbonates; Blood; Buffers; Carbon Dioxide; Carbonates; Disease Models, Animal; Drug Combinations; Heart Arrest; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Myocardium; Resuscitation; Saline Solution, Hypertonic; Sodium; Sodium Bicarbonate; Swine

In rats, single intravenous doses of folic acid induce damage to renal tubular epithelium, deposition of folic acid in tubular lumens, increase in wet kidney weight, oliguria and interstitial connective tissue proliferation. Separation of the nephrotoxic and obstructive effects of folic acid was attempted by pretreatment with NH4Cl or NaHCO3. These effects of folic acid were unaltered by pretreatment with NH4Cl and there was, in addition, accumulation of eosinophilic droplets in papillary collecting duct epithelium. After pretreatment with NaHCO3, folic acid deposition is decreased or absent; there is a smaller increase in wet kidney weight; the rats are polyuric rather than oliguric; interstitial connective tissue proliferation is reduced; and no droplets form in papillary collecting ducts, but lesions are still present in proximal convoluted tubule epithelial cells. These findings indicate that folic acid has direct nephrotoxic effects independent of intraluminal folic acid deposition, and that damage to renal epithelium, unlike that induced by many nephrotoxins, occurs at several levels of the nephron.

Topics: Ammonium Chloride; Animals; Bicarbonates; Disease Models, Animal; Female; Folic Acid; Kidney; Kidney Diseases; Rats; Sodium; Sodium Bicarbonate

Central to the controversy that surrounds the treatment of accidental severe hypothermia is the question of how the method of rewarming affects myocardial performance, and therefore survival. We induced severe hypothermia and cardiac arrest in 15 mongrel dogs. Each dog was rewarmed by one of three methods: partial cardiac bypass (Group I); peritoneal dialysis (Group II); or external rewarming with a fluid-circulated blanket (Group III). The cardiac arrest state was supported by partial cardiac bypass in Group I and by standard mechanical cardiopulmonary resuscitation (CPR) in Groups II and III. In all dogs, the hypothermically depressed myocardial performance returned to normal upon rewarming. Groups I and II had similar rewarming times and required similar volumes of crystalloid and bicarbonate solutions to maintain adequate cardiac filling pressures and arterial pH. However, Group III had a significantly slower rewarming time and required significantly greater volumes of crystalloid and bicarbonate solutions. The sole procedural death occurred in Group III. Our results show that partial cardiac bypass, peritoneal dialysis, and the fluid-circulated blanket are equally effective in rewarming severely hypothemic dogs with cardiac arrest, provided that the cardiac arrest is relieved by partial cardiac bypass or standard mechanical CPR and that physiologic levels of intravascular volume, oxygenation, and pH are maintained.

Topics: Accidents; Animals; Bicarbonates; Body Temperature; Cardiac Output; Crystalloid Solutions; Disease Models, Animal; Dogs; Electrocardiography; Heart Arrest; Heart Rate; Hypothermia; Infusions, Parenteral; Isotonic Solutions; Peritoneal Dialysis; Plasma Substitutes; Resuscitation; Sodium; Sodium Bicarbonate

Gastric ulceration has been induced after stress, combining 24 h of fasting and 48 h of restraint in 9 groups of 20 rats with or without a pyloroplasty or a pylorojejunostomy combined with atropine and gastric infusion of NaHCO3 or taurocholic acid. After death or sacrifice at 48 h, ulcer index and blood in the jejunum were determined. Gastric mucosal blood flow was measured semi-continuously by a laser Doppler velocimeter. There were 45% deaths after 48 h of restraint alone, and 70% in the group combining pylorojejunostomy with taurocholic acid. Mortality was lower (p less than or equal to 0.01) pylorojejunostomy alone and more significantly so (p less than or equal to 0.001) when associated with NaHCO3. There was no death when NaHCO3 and atropine were combined with restraint. The mucosal blood flow increased significantly during the first 12 h of restraint in the taurocholic acid group. Both groups with NaHCO3 had mucosal blood flows similar to the controls. Gastric acid and gastric emptying, mucosal ischemia and bile reflux are joint factors inducing gastric stress ulcer. The 100% survival and the low ulcer index after a treatment by atropine and gastric infusion of NaHCO3 suggest that these well-known drugs should be used more frequently.

Topics: Animals; Atropine; Bicarbonates; Bile Reflux; Biliary Tract Diseases; Blood Flow Velocity; Disease Models, Animal; Gastric Mucosa; Jejunum; Male; Peptic Ulcer Hemorrhage; Pylorus; Rats; Rats, Inbred Strains; Restraint, Physical; Sodium; Sodium Bicarbonate; Stomach Ulcer; Stress, Physiological; Taurocholic Acid