Genomic investigation and clinical correlates of the in vitro ß-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.

Effects of sodium bicarbonate solution on hypergravity-induced Fos expression in neurons of the amygdala in rats: Implication of sodium bicarbonate therapy for vertigo.

OBJECTIVE: In Japan, intravenous injection of a 7 % solution of sodium bicarbonate (NaHCO3) had been originally developed to inhibit motion sickness and then have long been used to treat vertigo. Previously, we reported that Fos-positive neurons appear in the amygdala after hypergravity stimulation in rats. In the present study, we examined whether injection of 7 % NaHCO3 inhibits hypergravity-induced Fos expression in the neurons in the central nucleus of the amygdala in rats. METHODS: Rats were exposed to 2 G hypergravity in an animal centrifuge device for 3 h. A solution of 7 % NaHCO3 at a dose of 4 mM/kg was injected intraperitoneally before 2 G hypergraviy. Fos-positive neurons in the amygdala were stained immunohistochemically. RESULTS: The number of Fos-positive neurons in the central nucleus of the amygdala was significantly increased after 2 G hypergravity in rats that received no drugs or saline, compared to that in rats exposed only to the noise of the centrifuge and received 7 % NaHCO3 solution. The number of Fos-positive neurons in the central nucleus of the amygdala after 2 G hypergravity was significantly decreased in rats that received 7 % NaHCO3 solution, compared to that in rats that received no drugs or saline. CONCLUSION: Since Fos expression is a marker of activated neurons, the present findings suggest that hypergravity activates the amygdala and that administration of 7 % NaHCO3 suppresses hypergravity-induced activation of the amygdala. Hypergravity disturbs spatial orientation to produce motion sickness and the amygdala is involved in fear response. Recently, Ziemann et al. suggested that fear-evoking stimuli reduce the pH in the amygdala to activate it, leading to induction of fear behavior and that administering HCO3- attenuates fear behavior [Cell 2009; 139: 1012-1021]. Therefore, it is possible that hypergravity reduces the pH in the amygdala to activate it, thereby inducing the fear associated with motion sickness and that administration of 7 % NaHCO3 increases the brain pH thereby suppressing hypergravity-induced activation of the amygdala and inhibiting the fear associated with motion sickness. In patients with vertigo, 7 % NaHCO3 therapy may increase the brain pH thereby suppressing the activation of the amygdala and inhibiting the fear associated with vertigo to elicit a beneficial clinical effect.

13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.

Alkalinization Using Sodium Bicarbonate for COVID-19 Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: A systematic review and meta-analysis have been conducted to evaluate the efficacy of alkalinization for COVID-19 patients based on current evidence to determine the impact of alkalinization on COVID-19 outcomes. METHODS: We searched MEDLINE (Pubmed), Web of Science, Cochrane Library, and Clinicaltrials.gov for studies evaluating the efficacy of alkalinization up to 30 April 2023. Based on the PRISMA 2020 statement criteria a systematic review and meta-analysis of studies were performed. RESULTS: The results of our meta-analysis showed a significant reduction in mortality rate in the alkalinization group compared to controls (RR 0.73, 95% CI: 0.56-0.95; I2 = 0%). However, our subgroup analysis showed no significant improvement in RCT-only studies (RR 0.78, 95% CI: 0.59-1.05; I2 = 0%), the recovery rate was significantly higher in the alkalinization group (RR 2.13, 95% CI: 1.39-3.26; I2 = 0%), duration of recovery also has improved in alkalinization group (SMD 0.76, 95% CI: 0.33-1.18; I2 = 0%). The results of our meta-analysis showed a significant reduction in the duration of hospitalization in the alkalinization group compared to controls with very low certainty of evidence (SMD -0.66, 95% CI: -0.97 to -0.35; I2 = 36%). CONCLUSION: With low certainty of evidence, alkalinization (by sodium bicarbonate) can be an efficient and safe adjuvant treatment for COVID-19 patients. Future randomized controlled trials are needed to strengthen the available evidence.

Temporal Transcriptomic Profiling Reveals Dynamic Changes in Gene Expression of Giant Freshwater Prawn upon Acute Saline-Alkaline Stresses.

Bicarbonate and sulfate are among two primary ion constituents of saline-alkaline water, with excessive levels potentially causing metabolic disorders in crustaceans, affecting their molting and interrupting development. As an economically important crustacean species, the molecular adaptive mechanism of giant freshwater prawn Macrobrachium rosenbergii in response to the stress of bicarbonate and sulfate remains unexplored. To investigate the mechanism underlying NaHCO3, Na2SO4, and mixed NaHCO3, Na2SO4 stresses, M. rosenbergii larvae were exposed to the above three stress conditions, followed by total RNA extraction and high-throughput sequencing at eight distinct time points (0, 4, 8, 12, 24, 48, 72, and 96 h). Subsequent analysis revealed 13, 16, and 13 consistently identified differentially expressed genes (DEGs) across eight time points under three stress conditions. These consistently identified DEGs were significantly involved in the Gene Ontology (GO) terms of chitin-based cuticle development, protein-carbohydrate complex, structural constituent of cuticle, carnitine biosynthetic process, extracellular matrix, and polysaccharide catabolic process, indicating that alkaline stresses might potentially impact the energy metabolism, growth, and molting of M. rosenbergii larvae. Particularly, the transcriptome data revealed that DEGs associated with energy metabolism, immunity, and amino acid metabolism were enriched across multiple time points under three stress conditions. These DEGs are linked to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including glycolysis/glucogenesis, amino sugar and nucleotide sugar metabolism, and lysine degradation. Consistent enrichment findings across the three stress conditions support conclusions above. Together, these insights are instrumental in enhancing our understanding of the molecular mechanisms underlying the alkaline response in M. rosenbergii larvae. Additionally, they offer valuable perspectives on the regulatory mechanisms of freshwater crustaceans amid saline-alkaline water development.

Lyophilized rumen fluid as a ruminal fermentation modifier in high grain-fed acidotic goats.

Rumen cud transfaunation re-establishes rumen micro environment and improves fermentation in recipient animals affected with digestive disorders. Preserving rumen cud or fluid will increase its availability for the treatment of rumen fermentation disorders, without having to maintain donor animals. Rumen fluid collected from healthy goats, fed standard ration having roughage 70% and concentrate 30%, was lyophilized (prefreezing -80 °C, 48 h; lyophilization -45 °C, 32 h) using 5% glycerol as cryoprotectant. The 16 S metagenome analysis of the lyophilized rumen fluid (LRF) revealed an abundance of Prevotella (33.2%). Selenomonas ruminantium (1.87%) and Megasphaera elsdenii (0.23%) were also present. Twenty-four goats having history of high grain feeding and exhibiting clinical symptoms of rumen fermentation disorders were randomly distributed into either one of the two treatment groups viz., T1 = oral administration of LRF 31 g/animal/day and T2 = oral administration of sodium bicarbonate (SB) 15 g/animal/day. Post intervention LRF and SB, improved animal body condition, feed intake, fecal consistency, elevated the ruminal pH at 48 h, reduced propionate and lactate at 48 h, reduced total volatile fatty acids (TVFA) and ammonia nitrogen at 24 h. Significant reduction in serum blood urea nitrogen (BUN) and urea levels were observed even from 24 h post intervention irrespective of the treatments. LRF significantly improved acetate and decreased propionate production compared to SB. LRF at 7.5% (v/v) can thus be used to counteract ruminal fermentation disorders in goats sequel to high grain ration.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice.

We previously reported that mice with low neuronal pH drink more alcohol, demonstrating the importance of pH for alcohol reward and motivation. In this study, we tested whether systemic pH affects alcohol consumption and if so, whether it occurs by changing the alcohol reward. C57BL/6J mice were given NaHCO3 to raise their blood pH, and the animals' alcohol consumption was measured in the drinking-in-the-dark and two-bottle free choice paradigms. Alcohol consumption was also assessed after suppressing the bitterness of NaHCO3 with sucrose. Alcohol reward was evaluated using a conditioned place preference. In addition, taste sensitivity was assessed by determining quinine and sucrose preference. The results revealed that a pH increase by NaHCO3 caused mice to decrease their alcohol consumption. The decrease in high alcohol contents (20%) was significant and observed at different ages, as well as in both males and females. Alcohol consumption was also decreased after suppressing NaHCO3 bitterness. Oral gavage of NaHCO3 did not alter quinine and sucrose preference. In the conditioned place preference, NaHCO3-treated mice spent less time in the alcohol-injected chamber. Conclusively, the results show that raising systemic pH with NaHCO3 decreases alcohol consumption, as it decreases the alcohol reward value.

Metabolic Acidosis in CKD: Pathogenesis, Adverse Effects, and Treatment Effects.

Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor musculoskeletal health, cardiovascular events, and death. Mechanisms that prevent metabolic acidosis detrimentally promote further kidney damage, creating a cycle between acid accumulation and acid-mediated kidney injury. Disrupting this cycle through the provision of alkali, most commonly using sodium bicarbonate, is hypothesized to preserve kidney function while also mitigating adverse effects of excess acid on bone and muscle. However, results from clinical trials have been conflicting. There is also significant interest to determine whether sodium bicarbonate might improve patient outcomes for those who do not have overt metabolic acidosis. Such individuals are hypothesized to be experiencing acid-mediated organ damage despite having a normal serum bicarbonate concentration, a state often referred to as subclinical metabolic acidosis. Results from small- to medium-sized trials in individuals with subclinical metabolic acidosis have also been inconclusive. Well-powered clinical trials to determine the efficacy and safety of sodium bicarbonate are necessary to determine if this intervention improves patient outcomes.

Sodium bicarbonate and intubation in severe diabetic ketoacidosis: are we too quick to dismiss them?

Management of diabetic ketoacidosis (DKA) has internationally established guidelines. However, management of severe, refractory DKA with multiple contributors to acidosis, and management of DKA in patients with altered mentation, remain ambiguous. Use of sodium bicarbonate and intubation in DKA are unpopular treatment practices, but warrant consideration in these unique clinical scenarios. This paper describes a 61-year-old Sri Lankan female who presented with severe DKA, seizures and altered level of consciousness. In her case, the acidosis was secondary to DKA, hyperlactatemia, hyperchloraemic acidosis and acute kidney injury (AKI). Intravenous sodium bicarbonate was used in the management of acidosis. She was intubated due to altered level of consciousness with inadequate respiratory drive to compensate for metabolic acidosis. The outcome in her case was favorable. Intravenous sodium bicarbonate in DKA should be considered for patients with severe, refractory acidosis with hemodynamic instability, hyperkalemia and compounding acidosis due to normal anion gap acidosis or AKI. Intubation should be considered for patients with obtunded mentation unable to achieve respiratory compensation and obtunded mentation where reversal of DKA is unlikely to improve consciousness. Both strategies should be personalized with consideration of individual risk vs benefit.

Prevalence, Risk Factors, and Management of Metabolic Acidosis in Chronic Kidney Disease Patients: A Multicenter Retrospective Study in Malaysia.

Background Metabolic acidosis in chronic kidney disease (CKD) patients has lately gained attention due to the growing evidence of its treatment benefits. This study aims to provide baseline data on the prevalence, risk factors, and current management of metabolic acidosis among the pre-dialysis adult Malaysian CKD population. Methodology This multicenter cross-sectional retrospective study involved pre-dialysis CKD patients above 18 years old on regular nephrology clinic follow-up at three Malaysian government hospitals with nephrology subspecialty. Demographic data, clinical information, laboratory data, and a list of concomitant medications were collected. Factors associated with the occurrence of metabolic acidosis were identified via multiple logistic regression. Results Six hundred and fifty-seven CKD patients were screened for this study, in which only 39.4% (n=259) had available bicarbonate levels. From this, a total of 86.1% (n=223) had metabolic acidosis. Higher estimated glomerular filtration rate (odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-1.00, p=0.043) and those with cardiovascular disease (OR 0.33, 95% CI 0.15-0.73; p=0.007) were significantly associated with lower odds of metabolic acidosis. There were 43.0% (n=96) on alkali therapy with sodium bicarbonate solution being the most common (n=91, 94.8%). Among those receiving alkali therapy, only 19.8% (n=19) achieved bicarbonate levels of ≥ 22 mEq/L. Conclusion Our study showed that metabolic acidosis was highly prevalent, although few achieved target levels despite supplementation, supporting the need for focused management of metabolic acidosis in the CKD population.

Effect of partial substitution of complex phosphates with sodium bicarbonate on aggregation, conformation and gel properties of beef-pork-chicken complex myofibrillar proteins.

BACKGROUND: Complex phosphates (CP) can improve the physicochemical properties and gelation properties of myofibrillar fibrous protein (MP) in mixed meat products, but an excessive intake of phosphates over a long period of time is harmful to health. The present study investigated the effects of partial or complete substitution of CP with sodium bicarbonate (SB) on the physicochemical properties and gel properties of beef-pork-chicken mixed myofibrillar protein (BPC-MP), aiming to evaluate the feasibility of this method in reducing the amount of phosphate in mixed meat products. RESULTS: Under the optimal substitution conditions, the turbidity of BPC-MP was reduced by 37.8%, the net negative potential was increased by 28.9% and the modulus of elasticity (G') was increased. The tertiary structure indexes of protein (including fluorescence intensity, surface hydrophobicity and active thiol content) were significantly changed, whereas the α-helix and ß-turn angle contents in the secondary structure of protein were significantly increased. In addition, the water retention ability and strength of gel were also improved, which were increased by 20.7% and 42.6%, respectively. The results of scanning electron microscopy showed that the SB substitution group had a more compact and ordered microstructure. CONCLUSION: The results showed that partial substitution of CP with SB reduced the amount of phosphate added to BPC-MP and had a positive effect on the physicochemical and gel properties of BPC-MP. © 2024 Society of Chemical Industry.

The electroneutral Na+-HCO3- cotransporter NBCn1 (SLC4A7) modulates colonic enterocyte pHi, proliferation, and migration.

NBCn1 (SLC4A7) is one of the two major Na+-HCO3- cotransporters in the human colonic epithelium, expressed predominantly in the highly proliferating colonocytes at the cryptal base. Increased NBCn1 expression levels are reported in tumors, including colorectal cancer. The study explores its importance for maintenance of the intracellular pH (pHi), as well as the proliferative, adhesive, and migratory behavior of the self-differentiating Caco2BBe colonic tumor cell line. In the self-differentiating Caco2BBe cells, NBCn1 mRNA was highly expressed from the proliferative stage until full differentiation. The downregulation of NBCn1 expression by RNA interference affected proliferation and differentiation and decreased intracellular pH (pHi) of the cells in correlation with the degree of knockdown. In addition, a disturbed cell adhesion and reduced migratory speed were associated with NBCn1 knockdown. Murine colonic Nbcn1-/- enteroids also displayed reduced proliferative activity. In the migrating Caco2BBe cells, NBCn1 was found at the leading edge and in colocalization with the focal adhesion markers vinculin and paxillin, which suggests that NBCn1 is involved in the establishment of cell-matrix adhesion. Our data highlight the physiological significance of NBCn1 in modulating epithelial pH homeostasis and cell-matrix interactions in the proliferative region of the colonic epithelium and unravel the molecular mechanism behind pathological overexpression of this transporter in human colorectal cancers.NEW & NOTEWORTHY The transporter NBCn1 plays a central role in maintaining homeostasis within Caco2BBe colonic epithelial cells through its regulation of intracellular pH, matrix adhesion, migration, and proliferation. These observations yield valuable insights into the molecular mechanism of the aberrant upregulation of this transporter in human colorectal cancers.

K+-Driven Cl-/HCO3- Exchange Mediated by Slc4a8 and Slc4a10.

Slc4a genes encode various types of transporters, including Na+-HCO3- cotransporters, Cl-/HCO3- exchangers, or Na+-driven Cl-/HCO3- exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl-/HCO3- exchanger, which can be driven by either Na+ or K+, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na+ or K+ drive Cl-/HCO3- exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl-/HCO3- exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl- and HCO3--dependent K+ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K+ at the Na+ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K+ in the same direction as HCO3- ions in a similar fashion to that described for Na+ transport in the rat Slc4a8 structure.

pH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain.

Strict homeostatic control of pH in both intra- and extracellular compartments of the brain is fundamentally important, primarily due to the profound impact of free protons ([H+]) on neuronal activity and overall brain function. Astrocytes, crucial players in the homeostasis of various ions in the brain, actively regulate their intracellular [H+] (pHi) through multiple membrane transporters and carbonic anhydrases. The activation of astroglial pHi regulating mechanisms also leads to corresponding alterations in the acid-base status of the extracellular fluid. Notably, astrocyte pH regulators are modulated by various neuronal signals, suggesting their pivotal role in regulating brain acid-base balance in both health and disease. This review presents the mechanisms involved in pH regulation in astrocytes and discusses their potential impact on extracellular pH under physiological conditions and in brain disorders. Targeting astrocytic pH regulatory mechanisms represents a promising therapeutic approach for modulating brain acid-base balance in diseases, offering a potential critical contribution to neuroprotection.

Endoscopic lithotripsy combined with drug lithotripsy vs. drug lithotripsy for the treatment of phytobezoars: analysis of 165 cases.

AIM: To analyze efficacy of endoscopic lithotripsy combined with drug lithotripsy as compared with drug lithotripsy for the treatment of phytobezoars. METHODS: We collected and evaluated case records of 165 patients with phytobezoars from 2014 to 2023. And we analyzed demographic and clinical characteristics, imaging features, endoscopic features, complications of phytobezoars, and compared efficacy between endoscopic lithotripsy combined with drug lithotripsy (Group A) and drug lithotripsy (sodium bicarbonate combined with proton pump inhibitor) (Group B). RESULTS: The median age of patients with phytobezoars was 67.84 ± 4.286 years old. Abdominal pain was the most common symptom and peptic ulcers (67.5%) were the most common complication. Bezoar-induced ulcers were more frequent in the gastric angle. The success rate of phytobezoars vanishing in Group A and Group B were similar (92.3% vs. 85.1% within 48 h, 98.7% vs. 97.7% within a week), while the average hospitalization period, average hospitalization cost, second endoscopy rate, and average endoscopic operation time were significantly lower in patients in Group B than in Group A. CONCLUSION: Drug lithotripsy is the preferred effective and safe treatment option for phytobezoars. We advise that an endoscopy should be completed after 48 h for drug lithotripsy.

Equisetum arvense as a silica fertilizer.

The aim was to use the agricultural weed and silica (Si) hyperaccumulator Equisetum arvense as Si fertilizer in plant cultivation. We investigated (1) the Si uptake in various Equisetum species, (2) where Si accumulates in the Equisetum plant, (3) processing methods to release as much Si as possible from dried, ground E. arvense plants and (4) which treatment yields gives the highest uptake of Si in young wheat plants cultivated in soil containing ground E. arvense. The results showed that E. arvense containes 22% Si and was among the best Si accumulators. Equisetum arvense accumulates Si as both soluble and firmly bound fractions. Amorphous silica (SiO2) accumulates in the outer cell walls of epidermis of the entire plant. Regarding the processing method, a longer treatment time, greater concentration of Equisetum, boiling, and the addition of sodium bicarbonate increased the Si availability in ground, dried E. arvense. The addition of untreated, ground, dried E. arvense to the soil, corresponding to 160 kg Si ha-1, increased the available Si in the soil and the Si uptake in wheat plants by five-fold, compared with the control. Boiling the ground E. arvense increased the Si uptake by 10 times, and the of sodium bicarbonate increased the availability and uptake by 40 times, compared with the control. In conclusion, dried, ground E. arvense can be used as a Si fertilizer as is, after boiling for a slightly better effect, or with sodium bicarbonate (up to a similar amount as the ground material) for best effect.

Common pitfalls in the use of hypertonic sodium bicarbonate for cardiac toxic drug poisonings.

BACKGROUND: Hypertonic sodium bicarbonate is advocated for the treatment of sodium channel blocker poisoning, but its efficacy varies amongst different sodium channel blockers. This Commentary addresses common pitfalls and appropriate usage of hypertonic sodium bicarbonate therapy in cardiotoxic drug poisonings. SODIUM BICARBONATE WORKS SYNERGISTICALLY WITH HYPERVENTILATION: Serum alkalinization is best achieved by the synergistic effect of hypertonic sodium bicarbonate and hyperventilation (PCO2 ∼ 30-35 mmHg [0.47-0.6 kPa]). This reduces the dose of sodium bicarbonate required to achieve serum alkalinization (pH ∼ 7.45-7.55) and avoids adverse effects from excessive doses of hypertonic sodium bicarbonate. VARIABILITY IN RESPONSE TO SODIUM BICARBONATE TREATMENT: Tricyclic antidepressant poisoning responds well to sodium bicarbonate therapy, but many other sodium channel blockers may not. For instance, drugs that block the intercellular gap junctions, such as bupropion, do not respond well to alkalinization. For sodium channel blocker poisonings in which the expected response is unknown, a bolus of 1-2 mmol/kg sodium bicarbonate can be used to assess the response to alkalinization. SODIUM BICARBONATE CAN EXACERBATE TOXICITY FROM DRUGS ACTING ON MULTIPLE CARDIAC CHANNELS: Hypertonic sodium bicarbonate can cause electrolyte abnormalities such as hypokalaemia and hypocalcaemia, leading to QT interval prolongation and torsade de pointes in poisonings with drugs that have mixed sodium and potassium cardiac channel properties, such as hydroxychloroquine and flecainide. THE GOAL FOR HYPERTONIC SODIUM BICARBONATE IS TO ACHIEVE THE ALKALINIZATION TARGET (∼PH 7.5), NOT COMPLETE CORRECTION OF QRS COMPLEX PROLONGATION: Excessive doses of hypertonic sodium bicarbonate commonly occur if it is administered until the QRS complex duration is < 100 ms. A prolonged QRS complex duration is not specific for sodium channel blocker toxicity. Some sodium channel blockers do not respond, and even when there is a response, it takes a few hours for the QRS complex duration to return completely to normal. In addition, QRS complex prolongation can be due to a rate-dependent bundle branch block. So, no further doses should be given after achieving serum alkalinization (pH ∼ 7.45-7.55). MAXIMAL DOSING FOR HYPERTONIC SODIUM BICARBONATE: A further strategy to avoid overdosing patients with hypertonic sodium bicarbonate is to set maximum doses. Exceeding 6 mmol/kg is likely to cause hypernatremia, fluid overload, metabolic alkalosis, and cerebral oedema in many patients and potentially be lethal. RECOMMENDATION FOR THE USE OF HYPERTONIC SODIUM BICARBONATE IN SODIUM CHANNEL BLOCKER POISONING: We propose that hypertonic sodium bicarbonate therapy be used in patients with sodium channel blocker poisoning who have clinically significant toxicities such as seizures, shock (systolic blood pressure < 90 mmHg, mean arterial pressure <65 mmHg) or ventricular dysrhythmia. We recommend initial bolus dosing of hypertonic sodium bicarbonate of 1-2 mmol/kg, which can be repeated if the patient remains unstable, up to a maximum dose of 6 mmol/kg. This is recommended to be administered in conjunction with mechanical ventilation and hyperventilation to achieve serum alkalinization (PCO2∼30-35 mmHg [4-4.7 kPa]) and a pH of ∼7.45-7.55. With repeated bolus doses of hypertonic sodium bicarbonate, it is imperative to monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the electrocardiogram. CONCLUSIONS: Hypertonic sodium bicarbonate is an effective antidote for certain sodium channel blocker poisonings, such as tricyclic antidepressants, and when used in appropriate dosing, it works synergistically with hyperventilation to achieve serum alkalinization and to reduce sodium channel blockade. However, there are many pitfalls that can lead to excessive sodium bicarbonate therapy and severe adverse effects.

Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis.

BACKGROUND: Bicarbonate has recently been identified as a crucial factor affecting peptidylarginine deiminase (PAD) activity; however, the mechanism underlying its role in rheumatoid arthritis (RA) remains unclear. Iguratimod (IGU), a small-molecule disease-modifying anti-rheumatic drug, requires further investigation. This study aimed to explore the mechanism by which bicarbonate affects citrullination and inflammation in RA and identify new targets for IGU. METHODS: We enrolled 20 patients with RA in the study. Sodium bicarbonate cotransporter 2 (NBCe2) was detected in the peripheral blood neutrophils and peripheral blood mononuclear cells (PBMCs) of these patients. The effects of varying concentrations of IGU, methotrexate (MTX), dexamethasone (DXM), and S0859 (an NBCe2 inhibitor) on NBCe2, PAD2, PAD4, and citrullinated histone H3 (cit-H3) levels in, migration ability of, and cytokine production from neutrophils and PBMCs were examined. RESULTS: Our findings showed that in patients with RA, citrullinated protein production by peripheral blood neutrophils instead of PBMCs, which showed higher NBCe2 expression levels, increased with an increase in the bicarbonate concentration. In addition, tumor necrosis factor-alpha (TNF-α) promoted NBCe2 expression in neutrophils from patients with RA. Furthermore, we revealed that the inhibitory effects of IGU on neutrophil NBCe2 and cit-H3 levels, degrees of inhibition of neutrophil and PBMC migration, and suppression of interleukin 6, TNF-α, and metalloproteinase-9 secretion from neutrophil-like differentiated HL-60 cells did not substantially differ from those of MTX, DXM, and S0859 at specific doses. CONCLUSIONS: Bicarbonate promotes protein citrullination and inflammation in RA via NBCe2, and IGU can downregulate NBCe2.

Effects of different types of Ringer's solution on patients with traumatic haemorrhagic shock: a prospective cohort study.

OBJECTIVE: To compare the fluid resuscitation effect of sodium acetate Ringer's solution and sodium bicarbonate Ringer's solution on patients with traumatic haemorrhagic shock. METHOD: We conducted a prospective cohort study in our emergency department on a total of 71 patients with traumatic haemorrhagic shock admitted between 1 December 2020 and 28 February 2022. Based on the time of admission, patients were randomly divided into a sodium bicarbonate Ringer's solution group and sodium acetate Ringer's solution group, and a limited rehydration resuscitation strategy was adopted in both groups. General data were collected separately, and the patients' vital signs (body temperature, respiration, blood pressure and mean arterial pressure (MAP)), blood gas indices (pH, calculated bicarbonate (cHCO3-), partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (pCO2) and clearance of lactate (CLac)), shock indices, peripheral platelet counts, prothrombin times and plasma fibrinogen levels were measured and compared before and 1 h after resuscitation. RESULTS: The post-resuscitation heart rate of the sodium bicarbonate Ringer's solution group was significantly lower than that of the sodium acetate Ringer's solution group (p < 0.05), and the MAP was also significantly lower (p < 0.05). The patients in the sodium bicarbonate Ringer's solution group had significantly higher pH, cHCO3- and PaO2 values and lower pCO2 and CLac values (p < 0.05) than those in the sodium acetate Ringer's solution group, and the post-resuscitation peripheral platelet counts and fibrinogen levels were significantly higher, with shorter plasma prothrombin times and smaller shock indices (p < 0.001). CONCLUSION: Sodium bicarbonate Ringer's solution is beneficial for maintaining MAP at a low level after resuscitation. The use of sodium bicarbonate Ringer's solution in limited fluid resuscitation has positive results and is of high clinical value.