A small-molecule Fenton reagent for self-augmented chemodynamic therapy by intelligently regulating intracellular acidosis.

A small-molecule Fenton reagent, integrating ferrocene with a carbonic anhydrase inhibitor, was designed to intelligently regulate intracellular acidosis for self-augmented chemodynamic therapy. Acidosis coupled with up-regulated ROS levels demonstrated potent cytotoxicity and effective tumor suppression.

Myelotoxicity and kidney dysfunction related to the use of trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia: a case report of severe adverse events with a common drug.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are common side effects, with hyperkalemia being uncommon in patients without kidney dysfunction, and myelotoxicity being even rarer. We present the case of a male patient with hypertension and a recent diagnosis of non-Hodgkin lymphoma, undergoing rituximab treatment for two months. He was admitted to the intensive care unit due to dyspnea, tachypnea, and pleuritic pain, requiring mechanical ventilation. Chest computed tomography showed bilateral and multilobed ground-glass opacities, compromising more than 80% of the lung parenchyma. Pulmonary tuberculosis and COVID-19 were ruled out. An angiotomography and Doppler ultrasound revealed an extensive pulmonary thrombus and deep venous thrombosis. Empiric treatment with TMP-SMX for PCP was initiated, but within four days, the patient experienced metabolic acidosis and severe hyperkalemia, necessitating hemodialysis. He also presented with progressive pancytopenia and critical levels of leukopenia and thrombocytopenia. The hypothesis of TMP-SMX-induced myelotoxicity was suspected. Considering the unavailability of an alternative treatment, it was opted to continue TMP-SMX and initiate a granulocyte-colony-stimulating factor. However, the patient maintained medullary deterioration, becoming refractory to the transfusion of blood derivates. On the 17th day of treatment, a clinical decision was made to suspend TMP-SMX, leading to improvements within 48 hours in marrow and kidney functions, metabolic acidosis, and hyperkalemia. Despite all efforts, the patient died after 35 days of hospitalization due to hospital-acquired infections. This case highlights the importance of clinicians recognizing potential myelotoxicity with TMP-SMX and promptly discontinuing the drug if necessary.

An engineered nanoplatform cascade to relieve extracellular acidity and enhance resistance-free chemotherapy.

Tumor extracellular acidity and chemoresistance are regarded as the main obstacles to achieving optimal chemotherapeutic efficacy in tumor therapy. Herein, a new kind of acid-cascade P-S-Z nanoparticles (NPs) is developed to relieve extracellular acidosis and enhance chemotherapy without causing drug resistance. The P-S-Z NPs selectively accumulate in tumors and then regulate the release of S-Z NPs containing syrosingopine (Syr) and acid-activated prodrug ZMC1-Pt depending on the extracellular acidity. Benefiting from their small size and positive surface charge, S-Z NPs are easily internalized by tumor cells in deep tumor tissue, facilitating the release of Syr to inhibit lactic acid excretion and ultimately enhance cell acidosis. The prolonged intracellular acidosis not only inhibits tumor cell proliferation, but also continuously triggers the activation of ZMC1-Pt prodrug, a platinum-based chemotherapeutic drug that effectively eliminates cancer cells and restores wild-type p53 function to prevent tumor chemoresistance. As a proof of concept, this is a promising strategy to transfer the adverse effect of intracellular acidosis to facilitate chemotherapy. This well-designed delivery system effectively kills tumor cells without causing significant tumor drug resistance, thus opening a new window to treat cancer.

Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease: a systematic review and meta-analysis.

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2 , and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P < 0.001) and functionality assessed with the sit-to-stand test (SMD -0.31 [95% CI -0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.

Evaluation of the efficacy and associated complications of regional citrate anticoagulation in neonates: experience from a fourth level neonatal intensive care unit.

Continuous kidney replacement therapy (CKRT) use has increased in recent years, but anticoagulation is a challenge for neonates. Regional citrate anticoagulation (RCA) is rarely preferred in neonates because of citrate accumulation (CA) and metabolic complications. We aimed to demonstrate the efficacy and safety of RCA in neonates. We retrospectively analyzed the medical records of 11 neonates treated with RCA-CKRT between 2018 and 2023. The initial dose of RCA was 2.1-3 mmol/l, and then, its dose was increased according to the level of ionized calcium (iCa+2) in the circuit and patients. The total/iCa+2 ratio after-treatment > 2.5 was indicated as CA. We evaluated to citrate dose, CA, circuit lifespan, and dialysis effectivity. The median gestational age was 39 (36.4-41.5) weeks, the median body weight (BW) was 3200 (2400-4000) grams, and the mean postnatal age was 4 (2-24) days. The most common indication for CKRT was hyperammonemia (73%). All neonates had metabolic acidosis and hypocalcemia during CKRT. Other common metabolic complications were hypophosphatemia (90%), hypokalemia (81%), and hypomagnesemia (63%). High dialysate rates with a median of 5765 ml/h/1.73 m2 allowed for a rapid decrease in ammonia levels to normal. Four patients (36.3%) had CA, and seven (63.7%) did not (non-citrate accumulation, NCA). Mean BW, median postnatal age, biochemical parameters, coagulation tests, and ammonia levels were similar between the CA and NCA groups. Low pH, low HCO3, high lactate, and SNAPPE-II scores could be associated with a higher T/iCa ratio. CONCLUSION:  RCA was an efficient and safe anticoagulation for neonates requiring CKRT. Metabolic complications may occur, but they could be managed with adequate supplementation. WHAT IS KNOWN: • Continuous kidney replacement therapy (CKRT) has become popular in recent years due to its successful treatment of fluid overload, electrolyte imbalance, metabolic acidosis, multi-organ failure, and hyperleucinemia/hyperammonemia associated with inborn errors of metabolism. • The need for anticoagulation is the major difficulty in neonatal CKRT. In adult and pediatric patients, regional citrate anticoagulation has been shown to be effective. WHAT IS NEW: • RCA is an effective and safe anticoagulation method for neonates who require CKRT. • Electrolyte imbalances and metabolic acidosis could be managed with adequate supplementation and appropriate treatment parameters such as citrate dose, blood flow rate, and dialysate flow rate.

Metabolic acidosis during the relapse treatment of idiopathic intracranial hypertension.

We herein present a 40-year-old female physician who was diagnosed with idiopathic intracranial hypertension (IIH) 4 years ago. In the last years, the patient was in remission without any medications. Since the onset of COVID-19 pandemic, she has been stressfully working in the high-risk area, therefore using personal protective equipment (N95 mask, protective clothing, goggles, and protective cap) during the day for extended periods. Her headaches recurred and the patient was diagnosed with a relapse of IIH; acetazolamide and afterward topiramate were initiated, with diet treatment. Symptomatic metabolic acidosis, which is otherwise a rare side effect of the IIH treatment and not seen in her first attack even with higher doses, developed during the follow-up, presenting with shortness of breath and chest tightening. The emerging problems of IIH diagnosis and management during the COVID-19 pandemic will be discussed.

An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA , the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis.

BACKGROUND: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. METHODS: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. RESULTS: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. CONCLUSIONS: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

[A case of pyroglutamic metabolic acidosis after cotreatment by flucloxacillin and paracetamol]. / Un cas d'acidose métabolique pyroglutamique sur comédication par flucloxacilline et paracétamol.

We report on the case of a 73-year-old man, who was referred to our emergency department for confusion and dyspnea. He had been under a treatment of flucloxacillin for six weeks because of a possible methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis that was complicated by an acute late infection of a knee prosthesis. The laboratory work-up revealed a metabolic acidosis with a high anion gap. After exclusion of the other explanations, we retained a pyroglutamic metabolic acidosis due to concomitant intake of paracetamol and flucloxacillin, favoured by several risk factors. This diagnosis was confirmed by an organic acid dosage in the urine. After discontinuation of the drugs and a treatment with N-acetylcysteine, the evolution was favourable with correction of the metabolic acidosis and the confusional state.

Nous rapportons le cas d'un homme de 73 ans, sous traitement de flucloxacilline depuis 6 semaines pour une possible endocardite à Staphylococcus aureus sensible à la méticilline (SASM) compliquée d'une infection aiguë tardive d'une prothèse de genou. Il est adressé à notre service d'urgences pour un état confusionnel et une dyspnée. Le bilan met en évidence une acidose métabolique à trou anionique élevé. Après exclusion des différentes étiologies, nous retenons une acidose métabolique pyroglutamique d'origine médicamenteuse sur prise concomitante de paracétamol et flucloxacilline, favorisée par plusieurs facteurs précipitants. Ce diagnostic est confirmé par un dosage d'acide organique dans les urines. Après arrêt des médicaments incriminés et traitement par N-acétylcystéine, l'évolution est favorable avec correction de l'acidose métabolique et de l'état confusionnel.

Bicarbonato de sodio intravenoso ¿Cuándo, cómo y por qué utilizarlo? / Intravenous sodium bicarbonate. When, how and why to use it?

Severe metabolic acidosis is defined by a pH < 7.2 with HCO3− < 8 mE- q/L in plasma. Its best treatment is to correct the underlying cause. However, acidemia produces multiple complications such as resistance to the action of catecholamines, pulmonary vasoconstriction, impaired cardiovascular function, hyperkalemia, immunological dysregulation, respiratory muscle fatigue, neurological impairment, cellular dysfunction, and finally, it contributes to multisystemic failure. Intravenous NaHCO3 buffers severe acidemia, preventing the associated damage and gains time while the causal disease is corrected. Its indication requires a risk-benefit assessment, considering its complications. These are hypernatremia, hypokalemia, ionic hypocalcemia, rebound alkalosis, and intracellular acidosis. For this reason, therapy must be "adapted" and administered judiciously. The patient will require monitoring with serial evaluation of the internal environment, especially arterial blood gases, plasma electrolytes, and ionized calcium. Isotonic solutions should be preferred instead of hypertonic bicarbonate. The development of hypernatremia must be prevented, calcium must be provided for hypocalcemia to improve cardiovascular function. Furthermore, in mechanically ventilated patients, a respiratory response similar to the one that would develop physiologically, must be established to be able to extract excess CO2 and thus avoid intracellular acidosis. It is possible to estimate the bicarbonate deficit, speed, and volume of its infusion. However, the calculations are only for reference. More important is to start intravenous NaHCO3 when needed, administer it judiciously, manage its side effects, and continue it to a safe goal. In this review we address all the necessary elements to consider in the administration of intravenous NaHCO3, highlighting why it is the best buffer for the management of severe metabolic acidosis.

Eltrombopag-induced Metabolic Acidosis and Hepatic Encephalopathy in Pediatric ITP.

Eltrombopag is approved for the treatment of chronic immune thrombocytopenia purpura (ITP) in pediatric patients 1 year and older who have demonstrated an insufficient response to corticosteroids and intravenous immunoglobulin. We present the case of a 2-year-old boy with chronic immune thrombocytopenia purpura who developed life-threatening adverse effects of acute liver failure, metabolic acidosis and encephalopathy with standard drug dosing. To our knowledge, this is the first case of eltrombopag-induced hepatic encephalopathy highlighting the critical need for prescribers to exercise caution when prescribing eltrombopag in the pediatric setting.

Extracellular Acidification Induces Lysosomal Dysregulation.

Many invasive cancers emerge through a years-long process of somatic evolution, characterized by an accumulation of heritable genetic and epigenetic changes and the emergence of increasingly aggressive clonal populations. In solid tumors, such as breast ductal carcinoma, the extracellular environment for cells within the nascent tumor is harsh and imposes different types of stress on cells, such as hypoxia, nutrient deprivation, and cytokine inflammation. Acidosis is a constant stressor of most cancer cells due to its production through fermentation of glucose to lactic acid in hypoxic or normoxic regions (Warburg effect). Over a short period of time, acid stress can have a profound effect on the function of lysosomes within the cells exposed to this environment, and after long term exposure, lysosomal function of the cancer cells can become completely dysregulated. Whether this dysregulation is due to an epigenetic change or evolutionary selection has yet to be determined, but understanding the mechanisms behind this dysregulation could identify therapeutic opportunities.

Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists.

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis.

Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.

Effect of sodium bicarbonate supplementation on the renin-angiotensin system in patients with chronic kidney disease and acidosis: a randomized clinical trial.

BACKGROUND: Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. METHODS: Patients with CKD stage G4 and plasma bicarbonate 15-24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. RESULTS: Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P < 0.05). Furthermore, a trend towards lower plasma aldosterone (291 to 204 ng/L, P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P < 0.05). CONCLUSIONS: Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity.

Eucalyptus oil poisoning: two case reports.

BACKGROUND: Eucalyptus oil poisoning is rare in adults but is not that uncommon in children. The common side effects in children include depression in the level of consciousness, ataxia, seizures, and vomiting. Unlike in children, seizures are unusual in adult patients with eucalyptus oil poisoning. We report the cases of two patients with eucalyptus oil poisoning, both adults who unintentionally took eucalyptus oil and presented to the emergency room of our institution with seizures. CASE PRESENTATION: Two adult Indian men who unintentionally consumed eucalyptus oil presented to the emergency room of our institution with seizures. In both patients, arterial blood gas analysis showed the presence of severe metabolic acidosis. Both the patients were managed in the intensive care unit and received standard supportive care. Metabolic acidosis was corrected with intravenous bicarbonate infusion. They were successfully discharged on the fourth day. CONCLUSIONS: All physicians should be aware of the toxic effects of eucalyptus oil, which is used often in daily life in India. Supportive care in an intensive care unit, including rapid correction of metabolic acidosis and adequate maintenance of hemodynamic parameters, will lead to a rapid recovery. Warning labels should be made mandatory on all products that contain eucalyptus oil.

Association Between the Use of Sodium Bicarbonate and Mortality in Acute Kidney Injury Using Marginal Structural Cox Model.

OBJECTIVE: Acute kidney injury with metabolic acidosis is common in critically ill patients. This study assessed the associations between the use of IV sodium bicarbonate and mortality of patients with acute kidney injury and acidosis. DESIGN: The study was conducted by using data from Beth Israel Deaconess Medical Center, which included several ICUs such as coronary care unit, cardiac surgery recovery unit, medical ICU, surgical ICU, and trauma-neuro ICU. Marginal structural Cox model was used to assess the relationship between receipt of sodium bicarbonate and hospital mortality, allowing pH, PaCO2, creatinine, and bicarbonate concentration as time-varying predictors of sodium bicarbonate exposure while adjusting for baseline characteristics of age, gender, Sequential Organ Failure Assessment score, acute kidney injury stage, Elixhauser score, quick Sequential Organ Failure Assessment, and Simplified Acute Physiology Score II. SETTING: A large U.S.-based critical care database named Medical Information Mart for Intensive Care. PATIENTS: Patients with Kidney Disease: Improving Global Outcomes acute kidney injury stage greater than or equal to 1 (> 1.5 (Equation is included in full-text article.)baseline creatinine) and one measurement of acidosis (pH ≤ 7.2). Baseline creatinine was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 3,406 eligible patients, 836 (24.5%) had received sodium bicarbonate treatment. Patients who received sodium bicarbonate treatment had a higher Sequential Organ Failure Assessment (9 vs 7; p < 0.001), lower pH (7.16 vs 7.18; p < 0.001), and bicarbonate concentration (16.51 ± 7.04 vs 20.57 ± 6.29 mmol/L; p < 0.001) compared with those who did not receive sodium bicarbonate. In the marginal structural Cox model by weighing observations with inverse probability of receiving sodium bicarbonate, sodium bicarbonate treatment was not associated with mortality in the overall population (hazard ratio, 1.16; 95% CI, 0.98-1.42; p = 0.132), but it appeared to be beneficial in subgroups of pancreatitis (hazard ratio, 0.53; 95% CI, 0.28-0.98; p = 0.044) and severe acidosis (pH < 7.15; hazard ratio, 0.75; 95% CI, 0.58-0.96; p = 0.024). Furthermore, sodium bicarbonate appeared to be beneficial in patients with severe bicarbonate deficit (< -50 kg·mmol/L). CONCLUSIONS: In the analysis by adjusting for potential confounders, there is no evidence that IV sodium bicarbonate is beneficial for patients with acute kidney injury and acidosis. Although the study suggested potential beneficial effects in some highly selected subgroups, the results need to be validated in experimental trials.

Blockade of Acid-Sensing Ion Channels Attenuates Recurrent Hypoglycemia-Induced Potentiation of Ischemic Brain Damage in Treated Diabetic Rats.

Diabetes is a chronic metabolic disease and cerebral ischemia is a serious complication of diabetes. Anti-diabetic therapy mitigates this complication but increases the risk of exposure to recurrent hypoglycemia (RH). We showed previously that RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. The present study evaluated the hypothesis that increased intra-ischemic acidosis in RH-exposed ITD rats leads to pronounced post-ischemic hypoperfusion via activation of acid-sensing (proton-gated) ion channels (ASICs). Streptozotocin-diabetic rats treated with insulin were considered ITD rats. ITD rats were exposed to RH for 5 days and were randomized into Psalmotoxin1 (PcTx1, ASIC1a inhibitor), APETx2 (ASIC3 inhibitor), or vehicle groups. Transient global cerebral ischemia was induced overnight after RH. Cerebral blood flow was measured using laser Doppler flowmetry. Ischemic brain injury in hippocampus was evaluated using histopathology. Post-ischemic hypoperfusion in RH-exposed rats was of greater extent than that in control rats. Inhibition of ASICs prevented RH-induced increase in the extent of post-ischemic hypoperfusion and ischemic brain injury. Since ASIC activation-induced store-operated calcium entry (SOCE) plays a role in vascular tone, next we tested if acidosis activates SOCE via activating ASICs in vascular smooth muscle cells (VSMCs). We observed that SOCE in VSMCs at lower pH is ASIC3 dependent. The results show the role of ASIC in post-ischemic hypoperfusion and increased ischemic damage in RH-exposed ITD rats. Understanding the pathways mediating exacerbated ischemic brain injury in RH-exposed ITD rats may help lower diabetic aggravation of ischemic brain damage.

Oral Sodium Bicarbonate Supplementation Does Not Affect Serum Calcification Propensity in Patients with Chronic Kidney Disease and Chronic Metabolic Acidosis.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T50 calcification inhibition test (T50-test) is a global functional test analyzing the overall propensity of calcification in serum, and low T50-time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T50-time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T50-time in CKD patients. MATERIAL AND METHODS: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO3- ≤21 mmol/L), in which patients are randomized to either achieve serum HCO3- levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T50-time was assessed. RESULTS: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T50-time was 275 (± 64) min. After 4 weeks, the mean change of T50-time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (ß = -25; 95% CI: -71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T50-time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T50-time (ß = -145; 95% CI: -237 to -52). CONCLUSION: Oral sodium bicarbonate supplementation showed no effect on T50-time in acidotic CKD patients.