Metabolic acidosis regulates RGS16 and G protein signaling in osteoblasts.

Chronic metabolic acidosis stimulates cell-mediated net Ca2+ efflux from bone mediated by increased osteoblastic cyclooxygenase 2, leading to prostaglandin E2-induced stimulation of receptor activator of NF-κB ligand-induced osteoclastic bone resorption. Ovarian cancer G protein-coupled receptor-1 (OGR1), an osteoblastic H+-sensing G protein-coupled receptor, is activated by acidosis and leads to increased bone resorption. As regulator of G protein signaling (RGS) proteins limit GPCR signaling, we tested whether RGS proteins themselves are regulated by metabolic acidosis. Primary osteoblasts were isolated from neonatal mouse calvariae and incubated in physiological neutral or acidic (MET) medium. Cells were collected, and RNA was extracted for real-time PCR analysis with mRNA levels normalized to ribosomal protein L13a. RGS1, RGS2, RGS3, RGS4, RGS10, RGS11, and RGS18 mRNA did not differ between MET and neutral medium; however, by 30 min, MET decreased RGS16, which persisted for 60 min and 3 h. Incubation of osteoblasts with the OGR1 inhibitor CuCl2 inhibited the MET-induced increase in RGS16 mRNA. Gallein, a specific inhibitor of Gßγ signaling, was used to determine if downstream signaling by the ßγ-subunit was critical for the response to acidosis. Gallein decreased net Ca2+ efflux from calvariae and cyclooxygenase 2 and receptor activator of NF-κB ligand gene expression from isolated osteoblasts. These results indicate that regulation of RGS16 plays an important role in modulating the response of the osteoblastic GPCR OGR1 to metabolic acidosis and subsequent stimulation of osteoclastic bone resorption.NEW & NOTEWORTHY The results presented in this study indicate that regulation of regulator of G protein signaling 16 and G protein signaling in the osteoblast plays an important role in modulating the response of osteoblastic ovarian cancer G protein-coupled receptor 1 (OGR1) to metabolic acidosis and the subsequent stimulation of osteoclastic bone resorption. Further characterization of the regulation of OGR1 in metabolic acidosis-induced bone resorption will help in understanding bone loss in acidotic patients with chronic kidney disease.

EndoPil: A Magnetically Actuated Swallowable Capsule for Weight Management: Development and Trials.

Intragastric balloons (IGBs), by occupying the stomach space and prolonging satiety, is a promising method to treat obesity and consequently improves its associated comorbidities, e.g. coronary heart disease, diabetes, and cancer. However, existing IGBs are often tethered with tubes for gas or liquid delivery or require endoscopic assistance for device delivery or removal, which are usually uncomfortable, costly, and may cause complications. This paper presents a novel tetherless, magnetically actuated capsule (EndoPil) which can deploy an IGB inside the stomach after being swallowed and being activated by an external magnet. The external magnet attracts a small magnet inside the EndoPil to open a valve, triggering the chemical reaction of citric acid and potassium bicarbonate to produce carbon dioxide gas, which inflates a biocompatible balloon (around 120 mL). A prototype, 13 mm in diameter and 35 mm in length, was developed. Simulations and bench-top tests were conducted to test the force capability of the magnetic actuation mechanism, the required force to activate the valve, and the repeatability of balloon inflation. Experiments on animal and human were successfully conducted to demonstrate the safety and feasibility of inflating a balloon inside the stomach by an external magnet.

Half Saline-Bicarbonate Solution as Intraoperative Fluid Replacement Therapy Leads to Less Acidosis and Better Early Renal Function During Deceased-Donor Transplant.

OBJECTIVES: Normal saline is the most common crystalloid solution that is used in renal transplant surgery. In this study, our aim was to determine the effects of a combination of half saline and bicarbonate versus normal saline as a routine solution. MATERIALS AND METHODS: For this double-blind random-ized clinical trial, we enrolled 100 adult patients undergoing kidney transplant. Patients were divided into 2 groups: those who received normal saline and those who received half saline and bicarbonate infusion as fluid replacement therapy during renal transplant. All patients received about 40 mL/kg of crystalloids during surgery. Serial creatinine con-centrations (primary outcomes) were compared between groups at 1, 2, 3, and 7 days after surgery. Urine output (secondary outcome) was compared between groups at recovery and at 6 and 24 hours after surgery. In addition, base excess, chloride, and sodium levels were measured before and 6 hours after surgery. Each liter of half saline-bircarbonate, which is relatively isoosmotic to human plasma, was composed of 70 mEq bicarbonate, 77 mEq chloride, and 147 mEq sodium. RESULTS: Patients who received half saline-bicarbonate had significantly lower postoperative creatinine levels at all time points than patients who received normal saline (P = .019). Serum chloride and sodium levels (P = .001) were significantly higher and base excess (P = .007) was significantly lower in the normal saline group at 6 hours after transplant. At all time points, urine output levels were significantly higher in the half saline-bicarbonate group (P = .001). CONCLUSIONS: The use of half saline-bicarbonate was associated with better early graft function compared with normal saline in the first 7 days after transplant.

Efficacy of buffered local anaesthetics in head and neck infections.

Lignocaine is one of the most commonly-used agents to anaesthetise an area preoperatively. It can, however, cause undesirable effects such as burning on injection, relatively slow onset, and unreliable, or lack of, numbness when injected into infected tissues as a result of the acidic pH of commercial preparations (the pH is between 3.5 and 7.0 compared with the physiological pH, which is between 7.35 and 7.45). The aim of this comparative study was to evaluate the efficacy of buffered local anaesthetic on infected areas by altering the pH with 8.4% sodium bicarbonate, to measure the pain before and after the injection, and to record the time of onset of anaesthesia. All 60 patients were given 2% lignocaine hydrochloride with adrenaline 1:80,000 and 30 patients were randomly allocated to have 10:1 dilution of 8.4% sodium bicarbonate (study group). Pain was assessed on a visual analogue scale and a verbal rating scale. There was a significant difference in the amount of pain between control and study groups (p=0.025). The mean (SD) time (minutes) to onset of local anaesthesia in the study group was 1.06 (0.25) compared with 2.96 (0.81) in the control group (p<0.001). Our results confirm the efficacy of the buffered local anaesthetic solution in reducing pain on injection and resulting in quicker onset of anaesthesia. Increasing the pH of lignocaine solutions with bicarbonate immediately before use, therefore, should be considered when treating various acute infections of the head and neck.

Can an amino acid-based oral rehydration solution be effective in managing immune therapy-induced diarrhea?

Immune checkpoint inhibitor (ICPi) therapy has transformed the way we treat cancer. However, its immune related adverse events (irAEs) can be debilitating and life threatening. Immune therapy-induced diarrhea (ITID) is one of the most commonly encountered irAEs and can lead to expensive and prolonged hospitalizations. The current standard of care for grade 3 or 4 ITID involves ICPi discontinuation, the initiation of steroids, and infliximab for refractory disease. This treatment regimen reverses the desired anti-tumor effect of ICPis, can lead to side effects, and is cost-ineffective. We report the first case of the successful treatment of grade 3 ITID with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients. We hypothesize that an AA-ORS may mitigate ITID via safer and more economically viable means than the current standard of care, but more controlled trials are needed to test this hypothesis.

Comparative studies between longitudinal and torsional modes in phacoemulsification, using active fluidics technology along with the intrepid balanced tip.

PURPOSE: To compare and report the intra- and postoperative outcomes of phacoemulsification between longitudinal (LPKE) and torsional (TPKE) mode, using active fluidics along with the intrepid balanced tip. METHODS: This single center prospective randomized comparative study comprised a total 108 consecutive eyes of 108 patients having senile cataract subdivided into nuclear opalescence (NO) grades II-IV according to the lens opacities classification system III (LOCS III). Cataracts of each grade were randomly assigned to two groups LPKE (n = 54) and TPKE (n = 54) mode, who were operated on by the same surgeon using same machine (Centurion® Alcon Laboratories, Inc., USA) having features of both active fluidics and intrepid balanced tip. Pre-, intra-, and postoperative evaluations were done independently by a different author, who was masked to the surgical procedures. Patients were evaluated on the postoperative days (PODs) 1, 7, 15, and 28. Intraoperative outcome measures were cumulative dissipated energy (CDE) and ultrasound time (UST). Postoperative outcome measures were endothelial cell loss (ECL), central corneal thickness (CCT), and best-corrected visual acuity (BCVA). RESULTS: Age, gender, and NO-grade distribution among two modes were comparable (P > 0.05). Difference of CDE and UST between modes were found to be significant (P < 0.001) in favor of TPKE with all NO-grades. TPKE mode performs better than LPKE mode with regard to ECL, CCT-change, and BCVA-change, although the differences were found to be insignificant (P > 0.05). CONCLUSION: When using active fluidics along with the intrepid balanced tip, TPKE mode appeared to be a more efficient mode of PKE with reduced mean UST and CDE across all NO-grades, as compared to LPKE mode. However, ECL, CCT-change, and BCVA-change were seemed to be comparable between the two modes.

Positron Emission Tomography Imaging of Lesions pH Using 11C-Labeled Bicarbonate.

OBJECTIVES: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11C-labeled bicarbonate (H11CO3-) buffer and positron emission tomography (PET). METHODS: H11CO3- was produced by on-column NaOH adsorption. Biodistribution of H11CO3- in normal mice was determined. In addition, uptake studies and inhibition experiments of H11CO3- in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode. RESULTS: PET imaging demonstrated the high uptake of H11CO3- in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H11CO3- in mice model tissues had no change. Similarly, administration with ammonium chloride (NH4Cl) decreased the pH, whereas the unchanged uptake of H11CO3- in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H11CO3- in mice model tissues was observed. CONCLUSIONS: H11CO3- solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H11CO3- PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation.

Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model.

BACKGROUND: Long-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown. MATERIALS AND METHODS: In a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation. RESULTS: Daily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4+ IL-17+ cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFß1, TNFα, INFγ, and MIP-1ß were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS. CONCLUSION: Development of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4+ IL-17+ cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.

A Phase 4, multicentre, randomized, single-blind clinical trial to evaluate the immunogenicity of the live, attenuated, oral rotavirus vaccine (116E), ROTAVAC®, administered simultaneously with or without the buffering agent in healthy infants in India.

BACKGROUND: The World Health Organization recommends that rotavirus vaccines should be included in all national immunization programs. Some currently licensed oral rotavirus vaccines contain a buffering agent (either as part of a ready-to-use liquid formulation or added during reconstitution) to reduce possible degradation of the vaccine virus in the infant gut, which poses several programmatic challenges (the large dose volume or the reconstitution requirement) during vaccine administration. Because ROTAVAC®, a WHO prequalified vaccine, was derived from the 116E neonatal strain, we evaluated the immunogenicity and safety of ROTAVAC® without buffer and ROTAVAC® with buffer in a phase 4, multicentre, single-blind, randomized clinical trial in healthy infants in India. METHODS: 900 infants, approximately 6, 10 and 14 weeks of age, were assigned to 3 groups to receive ROTAVAC® (0.5 mL dose) orally: (i) 2.5 mL of citrate-bicarbonate buffer 5 minutes prior to administration of ROTAVAC® (Group I), (ii) ROTAVAC®, alone, without any buffer (Group II), or (iii) ROTAVAC®, mixed with buffer immediately before administration (Group III). Non-inferiority was compared among the groups for differences in serological responses (detected by serum anti-rotavirus IgA) and safety. RESULTS: Geometric mean titers post vaccination at day 84 (28 days after dose 3) were 19.6 (95%CI: 17.0, 22.7), 20.7 (95%CI: 17.9, 24) and 19.2 (95%CI: 16.8, 22.1) for groups I, II and III respectively. Further, seroconversion rates and distribution of adverse events were similar among groups. CONCLUSIONS: Administration of ROTAVAC® at a 0.5 mL dose volume without buffering agent was shown to be well tolerated and immunogenic. Given the homologous nature of the strain, it is plausible that ROTAVAC® replicates well and confers immunity even without buffer administration.

HYDration and Bicarbonate to Prevent Acute Renal Injury After Endovascular Aneurysm Repair With Suprarenal Fixation: Pilot/Feasibility Randomised Controlled Study (HYDRA Pilot Trial).

OBJECTIVE/BACKGROUND: Up to 25% of patients undergoing elective endovascular aneurysm repair (EVAR) develop acute kidney injury (AKI), which is associated with short and long-term morbidity and mortality. There is no high quality randomised evidence regarding prevention of EVAR related AKI. METHODS: A novel AKI prevention strategy for EVAR was devised, based on best evidence and an expert consensus group. This included a bolus of high dose sodium bicarbonate (NaHCO3) immediately before EVAR (1 mL/kg of 8.4% NaHCO3) and standardised crystalloid based hydration pre- and post-EVAR. A pilot/feasibility randomised controlled trial (RCT) was performed in two centres to assess the safety of the intervention, potential impact on AKI prevention, and feasibility of a national RCT; the primary end point was the proportion of eligible patients recruited into the study. AKI was defined using "Kidney Disease Improving Global Outcomes" and "Acute Kidney Injury Network" criteria based on National Institute for Health and Clinical Excellence AKI recommendations, using serum creatinine and hourly urine output. RESULTS: Fifty-eight patients (84% of those screened; median age 75 years [range 57-89 years], 10% female) were randomised to receive the standardised intravenous hydration with (intervention) or without (control) NaHCO3. Groups were comparable in terms of AKI risk factors; 56 of 58 participants had a device with suprarenal fixation. Overall, 33% of patients in the control arm developed AKI versus 7% in the intervention arm (as treated analysis). None of the patients receiving NaHCO3 developed a serious intervention related adverse event; five patients did not attend their 30 day follow-up. CONCLUSION: Bolus high dose NaHCO3 and hydration is a promising EVAR related AKI prevention method. This trial has confirmed the feasibility of delivering a definitive large RCT to confirm the efficacy of this novel intervention, in preventing EVAR related AKI.

Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine-epinephrine combination.

OBJECTIVE: To investigate the nociceptive and clinical effects of buffering a lidocaine-epinephrine solution with sodium bicarbonate in caudal epidural block in mares. STUDY DESIGN: Prospective randomized controlled trial. ANIMALS: Six mixed-breed mares weighing 350-440 kg. METHODS: Each animal was administered two caudal epidural injections, 72 hours apart, using different solutions prepared immediately before injection. The control solution was 7 mL 2% lidocaine hydrochloride with epinephrine hemitartrate (1:200,000) added to 3 mL sterile water for injection (pH 2.9). The alkalinized solution was 7 mL of lidocaine-epinephrine solution added to 2.3 mL sterile water for injection and 0.7 mL 8.4% sodium bicarbonate (pH 7.4). Nociception was evaluated by response to skin pinching at 31 sites in the sacral region and around the perimeter of the anogenital area (distances of 10, 15 and 20 cm) before, and 5, 10 and 15 minutes after epidural injection, then every 15 minutes until the return of nociception in all evaluated sites. The onset and duration times, and intensity of ataxia (grades 0 to 3) were recorded. The paired t test was used to compare the onset and duration of anesthesia and ataxia (p<0.05). RESULTS: Alkalization of the solution resulted in significant decreases in the average time of onset of loss of nociception in the sacral region (40%) and around the perimeter of the anogenital area extending up to 5 cm (36%) and from 5 to 10 cm (32%) from the anus and vulva. Alkalization also decreased the average duration of ataxia (33%), without affecting the duration and extent of anesthesia or the degree of ataxia. CONCLUSIONS AND CLINICAL RELEVANCE: Alkalization of lidocaine-epinephrine solution is advantageous in shortening the duration of ataxia and hastening the onset of anesthesia in areas adjacent to the anogenital area, without reducing the duration of epidural anesthesia, in mares.

Single-Dose Lignocaine-Based Blood Cardioplegia in Single Valve Replacement Patients.

OBJECTIVE:: Myocardial protection is the most important in cardiac surgery. We compared our modified single-dose long-acting lignocaine-based blood cardioplegia with short-acting St Thomas 1 blood cardioplegia in patients undergoing single valve replacement. METHODS:: A total of 110 patients who underwent single (aortic or mitral) valve replacement surgery were enrolled. Patients were divided in two groups based on the cardioplegia solution used. In group 1 (56 patients), long-acting lignocaine based-blood cardioplegia solution was administered as a single dose while in group 2 (54 patients), standard St Thomas IB (short-acting blood-based cardioplegia solution) was administered and repeated every 20 minutes. All the patients were compared for preoperative baseline parameters, intraoperative and all the postoperative parameters. RESULTS:: We did not find any statistically significant difference in preoperative baseline parameters. Cardiopulmonary bypass time were 73.8±16.5 and 76.4±16.9 minutes (P=0.43) and cross clamp time were 58.9±10.3 and 66.3±11.2 minutes (P=0.23) in group 1 and group 2, respectively. Mean of maximum inotrope score was 6.3±2.52 and 6.1±2.13 (P=0.65) in group 1 and group 2, respectively. We also did not find any statistically significant difference in creatine-phosphokinase-MB (CPK-MB), Troponin-I levels, lactate level and cardiac functions postoperatively. CONCLUSION:: This study proves the safety and efficacy of long-acting lignocaine-based single-dose blood cardioplegia compared to the standard short-acting multi-dose blood cardioplegia in patients requiring the single valve replacement. Further studies need to be undertaken to establish this non-inferiority in situations of complex cardiac procedures especially in compromised patients.

Single-dose lignocaine-based blood cardioplegia in single valve replacement patients

Abstract OBJECTIVE: Myocardial protection is the most important in cardiac surgery. We compared our modified single-dose long-acting lignocaine-based blood cardioplegia with short-acting St Thomas 1 blood cardioplegia in patients undergoing single valve replacement. METHODS: A total of 110 patients who underwent single (aortic or mitral) valve replacement surgery were enrolled. Patients were divided in two groups based on the cardioplegia solution used. In group 1 (56 patients), long-acting lignocaine based-blood cardioplegia solution was administered as a single dose while in group 2 (54 patients), standard St Thomas IB (short-acting blood-based cardioplegia solution) was administered and repeated every 20 minutes. All the patients were compared for preoperative baseline parameters, intraoperative and all the postoperative parameters. RESULTS: We did not find any statistically significant difference in preoperative baseline parameters. Cardiopulmonary bypass time were 73.8±16.5 and 76.4±16.9 minutes (P=0.43) and cross clamp time were 58.9±10.3 and 66.3±11.2 minutes (P=0.23) in group 1 and group 2, respectively. Mean of maximum inotrope score was 6.3±2.52 and 6.1±2.13 (P=0.65) in group 1 and group 2, respectively. We also did not find any statistically significant difference in creatine-phosphokinase-MB (CPK-MB), Troponin-I levels, lactate level and cardiac functions postoperatively. CONCLUSION: This study proves the safety and efficacy of long-acting lignocaine-based single-dose blood cardioplegia compared to the standard short-acting multi-dose blood cardioplegia in patients requiring the single valve replacement. Further studies need to be undertaken to establish this non-inferiority in situations of complex cardiac procedures especially in compromised patients.

Gastric Fluid Volume Change After Oral Rehydration Solution Intake in Morbidly Obese and Normal Controls: A Magnetic Resonance Imaging-Based Analysis.

BACKGROUND: Although preoperative fluid intake 2 hours before anesthesia is generally considered safe, there are concerns about delayed gastric emptying in obese subjects. In this study, the gastric fluid volume (GFV) change in morbidly obese subjects was investigated after ingesting an oral rehydration solution (ORS) and then compared with that in nonobese subjects. METHODS: GFV change over time after the ingestion of 500 mL of ORS containing 2.5% carbohydrate (OS-1) was measured in 10 morbidly obese subjects (body mass index [BMI], >35) scheduled for bariatric surgery and 10 nonobese (BMI, 19-24) using magnetic resonance imaging. After 9 hours of fasting, magnetic resonance imaging scans were performed at preingestion, 0 min (just after ingestion), and every 30 minutes up to 120 minutes. GFV values were compared between morbidly obese and control groups and also between preingestion and postingestion time points. RESULTS: The morbidly obese group had a significantly higher body weight and BMI than the control group (mean body weight and BMI in morbidly obese, 129.6 kg and 46.3 kg/m, respectively; control, 59.5 kg and 21.6 kg/m, respectively). GFV was significantly higher in the morbidly obese subjects compared with the control group at preingestion (73 ± 30.8 mL vs 31 ± 19.9 mL, P = .001) and at 0 minutes after ingestion (561 ± 30.8 mL vs 486 ± 42.8 mL; P < .001). GFV declined rapidly in both groups and reached fasting baseline levels by 120 minutes (morbidly obese, 50 ± 29.5 mL; control, 30 ± 11.6 mL). A significant correlation was observed between preingestion residual GFV and body weight (r = .66; P = .001). CONCLUSIONS: Morbidly obese subjects have a higher residual gastric volume after 9 hours of fasting compared with subjects with a normal BMI. However, no differences were observed in gastric emptying after ORS ingestion in the 2 populations, and GFVs reached baseline within 2 hours after ORS ingestion. Further studies are required to confirm whether the preoperative fasting and fluid management that are recommended for nonobese patients could also be applied to morbidly obese patients.

D-lactic acidosis - case report and review of the literature.

D-lactic acidosis is a rare complication that occurs mainly in patients with malabsorption due to a surgically altered gastrointestinal tract anatomy, namely in short bowel syndrome or after bariatric surgery. It is characterized by rapid development of neurological symptoms and severe metabolic acidosis, often with a high serum anion gap. Malabsorbed carbohydrates can be fermented by colonic microbiota capable of producing D-lactic acid. Routine clinical assessment of serum lactate covers only L-lactic acid; when clinical suspicion for D-lactic acidosis is high, special assays for D-lactic acid are called for. A serum level of more than 3 mmol/L of D-lactate confirms the diagnosis. Management includes correction of metabolic acidosis by intravenous bicarbonate, restriction of carbohydrates or fasting, and antibiotics to eliminate intestinal bacteria that produce D-lactic acid. We report a case of D-lactic acidosis in a patient with short bowel syndrome and review the pathophysiology of D-lactic acidosis with its biochemical and clinical features. D-lactic acidosis should be considered when patients with short bowel syndrome or other malabsorption syndromes due to an altered gastrointestinal tract anatomy present with metabolic acidosis and neurological symptoms that cannot be attributed to other causes. With the growing popularity of bariatric surgery, this metabolic derangement may be seen more frequently in the future.

A head to head evaluation of 8 biochemical scanning tools for unmeasured ions.

We aimed to evaluate the sensitivity and specificity of 8 biochemical scanning tools in signalling the presence of unmeasured anions. We used blood gas and biochemical data from 15 patients during and after cardio-pulmonary bypass. Sampling time-points were pre-bypass (T1), 2 min post equilibration with priming fluid containing acetate and gluconate anions (T2), late bypass (T3) and 4 h after surgery (T4). We calculated the anion gap (AG), albumin-corrected anion gap (AGc), whole blood base excess (BE) gap, plasma BE gap, standard BE gap and the strong ion gap (SIG), plus 2 new indices-the unmeasured ion index (UIX) and unmeasured plasma anions according to the interstitial, plasma and erythrocyte acid-base model (IPEua). Total measured plasma concentrations of acetate and gluconate [XA] were proxies for unmeasured plasma anions. [XA] values (mmol/L) were 1.41 (0.87) at T1, 11.73 (3.28) at T2, 4.80 (1.49) at T3 and 1.36 (0.73) at T4. Corresponding [albumin] values (g/L) were 32.3 (2.0), 19.8 (2.6), 21.3 (2.5) and 29.1 (2.3) respectively. Only the AG failed to increase significantly at T2 in response to a mean [XA] surge of >10 mEq/L. At an [XA] threshold of 6 mEq/L, areas under receiver -operator characteristic curves in rank order were IPEua and UIX (0.88 and 0.87 respectively), SIG (0.81), AGc (0.79), standard BE gap (0.77), plasma BE gap (0.71), BE gap (0.70) and AG (0.59). Similar ranking hierarchies applied to positive and negative predictive values. We conclude that during acute hemodilution UIX and IPEua are superior to the anion gap (with and without albumin correction) and 4 other indices as scanning tools for unmeasured anions.

A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis.

Background: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) study. Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%­10.9%] vs 45.6% [28.9%­72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. Conclusions: Bicarbonate markedly enhances the anticancer activity of TACE. Funding: Funded by National Natural Science Foundation of China. Clinical trial number: ChiCTR-IOR-14005319.

Surgery is the main treatment for liver cancer, but the most common liver cancer ­ called hepatocellular carcinoma ­ can sometimes become too large to remove safely. An alternative option to kill the tumor is to block its blood supply via a process called embolization. This procedure deprives the tumor cells of oxygen and nutrients such as glucose. However, embolization also prevents a chemical called lactic acid ­ which is commonly found around tumors ­ from being removed. Lactic acid actually helps to protect cancer cells and also aids the growth of new blood vessels, and so the "trapped" lactic acid may reduce the anticancer activity of embolization. Previous works suggested that neutralizing the acidic environment in a tumor while depriving it of glucose via embolization could become a new treatment option for cancer patients. Chao et al. now report a small clinical trial that tested this idea and involved patients with large hepatocellular carcinomas. First, a group of thirty patients received the embolization treatment together with an injection of bicarbonate ­ a basic compound used to neutralize the lactic acid ­ that was delivered directly to the tumor. The neutralization killed these large tumors more effectively than what is typically seen in patients who just undergo embolization Chao et al. then recruited another twenty patients and randomly assigned them to receive either just the embolization or the embolization with bicarbonate treatment. This randomized trial showed that the tumors died more and patients survived for longer if they received the bicarbonate together with the embolization treatment compared to those patients that were only embolized. In fact, four patients initially assigned to, and treated in, the embolization-only group subsequently asked to cross over to, and indeed received, the bicarbonate treatment as well. These data indicate that this bicarbonate therapy may indeed be effective for patients with large tumors that are not amenable to surgery. In future, larger clinical trials will need to be carried out to verify these initial findings.

Treatment of patients with uric acid stones.

Uric acid nephrolithiasis and unduly acidic urinary pH are both considered a renal manifestation of insulin resistance but the underlying mechanisms for the development of low urinary pH and the propensity for uric acid stone formation are not completely elucidated. Nevertheless, excessive dietary acid intake, increased endogenous acid production and/or defective NH4+ excretion play an important role, among other factors. The main principles of therapy for uric acid nephrolithiasis are aimed at urinary alkalinization through diet modification or pharmacologic agents, increase of urinary volume, and less importantly at the reduction of uric acid excretion.

Sodium reduction during cardiopulmonary bypass: Plasma-Lyte 148 versus trial fluid as pump primes.

OBJECTIVES: We compared effects on plasma sodium concentrations plus calculated plasma tonicity of two "balanced" crystalloid solutions used as 2 L pump primes during cardiopulmonary bypass (CPB): Plasma-Lyte 148 (sodium concentration, 140 mmol/L; potassium concentration, 5 mmol/L) versus a bicarbonate-balanced fluid (sodium concentration, 140 mmol/L; potassium concentration, 0 mmol/L). DESIGN, SETTING AND PARTICIPANTS: We analysed pooled data from two prospective interventional studies performed in university-affiliated hospitals, from 50 patients undergoing elective cardiac surgery. INTERVENTIONS: Participants were allocated equally to Plasma-Lyte 148 or bicarbonate-balanced fluid, with plasma electrolytes measured by direct ion selective electrodes immediately before bypass (pre-CPB), within 3 minutes of commencement (T2), and before bypass cessation (end-CPB). RESULTS: Plasma sodium fell at T2 in 46 patients (92%) (P<0.0005). With Plasma-Lyte 148, the mean sodium decreased by 3.0 mmol/L (SD, 1.7 mmol/L), and with bicarbonate-balanced fluid it decreased by 2.2 mmol/L (SD, 1.1 mmol/L) (P=0.002). The mean tonicity fell by >5 mOsm/kg for both groups (P<0.0005). At end-CPB, the mean sodium for both groups remained reduced by >2 mmol/L (P<0.0005). In the group receiving Plasma-Lyte 148, 52% of patients were hyponatraemic (sodium<135 mmol/L) at T2 and end-CPB. CONCLUSIONS: Sodium reductions were common with both priming solutions, but more severe with Plasma-Lyte 148. Crystalloid priming solutions require sodium concentrations>140mmol/L to ensure normonatraemia throughout CPB.

Efficacy of chlorhexidine, dexpanthenol, allantoin and chitosan gel in comparison with bicarbonate oral rinse in controlling post-interventional inflammation, pain and cicatrization in subjects undergoing dental surgery.

INTRODUCTION: Reducing post-interventional inflammation and pain in odontostomatological surgery procedures, such as tooth extractions, implants or oral biopsies is a relevant clinical goal. Chlorhexidine oral rinse is commonly used with this aim. Recently a new product containing chlorhexidine, dexpanthenol, allantoin and chitosan (Bexident Post [BP]) in a gel formulation has been developed. We evaluated the efficacy of BP in controlling postsurgical inflammation and pain and in promoting cicatrization in subjects undergoing molar extractions. SUBJECTS AND METHODS: We conducted a prospective sequential cross-over, randomized controlled study in patients undergoing surgical removal of at least two impacted mandibular third molars (teeth numbers 38 and 48) (numbers 17 and 32 in the Universal Tooth Numbering System), in two separate sessions, to determine the effect of BP in comparison with bicarbonate (BC) oral rinse (one spoonful in 200 ml of water), both used three times daily. Each subject utilized both products in a randomized sequential manner after each tooth extraction. Primary outcomes of the study were post-procedure pain and inflammation. Secondary outcomes were analgesic pill rescue use (metamizole 1 cap every 8 hours if needed) and an assessor-blinded evaluation of cicatrization with a semi-quantitative scale (good, satisfactory and insufficient). Post-procedure pain was assessed 6 hours after tooth extraction and for seven consecutive days by means of a 10 cm visual analogue scale (VAS) (from 0: no pain to 10: extreme pain). The extent of inflammation was evaluated through metric measurements of facial perimeter using standardized anatomical reference points. RESULTS: A total of 47 patients (22 men and 25 women; mean age 34 years) were enrolled with a total of 94 molars extracted. Nineteen subjects applied BC as the first sequential treatment and 28 BP as the first. Before surgery no mean differences in the two treatments in inflammation measurements were observed. After surgery mean VAS pain score was similar between the two treatments in the first 6 hours (VAS score = 6.5). A marked progressive reduction in pain intensity with the use of BP was observed throughout the treatment period in comparison with BC (7 day mean scores 3.7 vs. 5.3; p = 0.0001). BP was superior to BC in reducing inflammation with -50% of the inflammation-related measurement (6 mm vs. 12 mm; p = 0.0001). Analgesic pill consumption was lower with BP in comparison with BC (13 pills vs. 24; p < 0.05). Cicatrization was scored 'good' in a higher percentage of subjects during BP use (64%) in comparison with the BC group (13%) (p = 0.0001). No serious side effects were reported with either treatment regimen. CONCLUSION: In this trial BP performed better than BC in controlling pain and inflammation in subjects undergoing dental surgery, reducing the consumption of analgesics and favoring better cicatrization.