Analgesia to acidosis: metabolic acidosis due to chronic acetaminophen (paracetamol) use.

This case describes a rare occurrence of high anion gap metabolic acidosis due to chronic acetaminophen (paracetamol) usage, which can be confirmed by measuring 5-oxoproline (pyroglutamate), an organic acid metabolite. As acetaminophen is an extremely common drug prescribed in both inpatient and outpatient settings, a high degree of clinical suspicion is required to isolate it as the aetiology for metabolic acidosis. Management includes discontinuation of acetaminophen use and at times the supplementation of oral bicarbonate. Metabolic acidosis due to a high anion gap is commonly described by the mnemonic 'MUDPILES' in daily practice. A newer mnemonic, 'GOLD MARK' is proposed to be a more inclusive tool to assist in determining the cause of high anion gap metabolic acidosis, especially with such cases being reported.

Short-term effects of small volume saline infusion on acid base equilibrium in critically ill patients.

BACKGROUND: Short-term acid-base effects of 0.9% saline solution infusion are not well described. Aim of this study was to assess the effects of a fluid challenge with 0.9% saline in critically ill patients according to the Stewart's approach, which allows a precise determination of acid base equilibrium. METHODS: In 40 mechanically ventilated critically ill patients, acid-base variables according to Stewart's approach were measured before and after 30 minutes from the infusion of 0.5L of 0.9% saline. Patients were divided in saline responder (fractional sodium excretion increase <0.5) and non-responders, and in patients with (estimated glomerular filtration rate >63 mL/min) and without renal impairment. RESULTS: After saline infusion, plasma sodium concentration did not change (138 [135-141] vs. 138 [135-140] mEq/L, P=0.646), while chloride concentration significantly increased (102 [100-106] vs. 104 [191-106] mEq/L, P=0.003), reducing strong ion difference (37.0 [34.9-38.0] vs. 35.4 [32.7-37.5] mEq/L, P=0.004) without any impact on pH, due to the concomitant albumin dilution. In saline non-responders, the increase of plasma chloride concentration caused a reduction in strong ion difference, while in saline responders both plasma chloride concentration and strong ion difference remained similar. Patients with and without renal impairment presented a similar acid-base response. CONCLUSIONS: The infusion of 0.9% saline reduced strong ion difference by increasing plasma chloride concentration, with no effect on pH due to concomitant albumin dilution. Saline non-responders, characterized by the ability to excrete the sodium excess, were more likely to suffer the acidifying effects of saline infusion, while renal function did not affect the acid-base response to saline infusion.

Osmolal and anion gaps after acute self-poisoning with agricultural formulations of the organophosphorus insecticides profenofos and diazinon: A pilot study.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases.

Vitamin B6 prevents Isocarbophos-induced posterior cerebral artery injury in offspring rats through up-regulating S1P receptor expression.

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment.

Is carbonic anhydrase inhibition useful as a complementary therapy of Covid-19 infection?

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.

Effects of post-exercise sodium bicarbonate ingestion on acid-base balance recovery and time-to-exhaustion running performance: a randomised crossover trial in recreational athletes.

This study investigated the effect of post-exercise sodium bicarbonate (NaHCO3) ingestion on acid-base balance recovery and time-to-exhaustion (TTE) running performance. Eleven male runners (stature, 1.80 ± 0.05 m; body mass, 74.4 ± 6.5 kg; maximal oxygen consumption, 51.7 ± 5.4 mL·kg-1·min-1) participated in this randomised, single-blind, counterbalanced and crossover design study. Maximal running velocity (v-V̇O2max) was identified from a graded exercise test. During experimental trials, participants repeated 100% v-V̇O2max TTE protocols (TTE1, TTE2) separated by 40 min following the ingestion of either 0.3 g·kg-1 body mass NaHCO3 (SB) or 0.03 g·kg-1 body mass sodium chloride (PLA) at the start of TTE1 recovery. Acid-base balance (blood pH and bicarbonate, HCO3-) data were studied at baseline, post-TTE1, after 35 min recovery and post-TTE2. Blood pH and HCO3- concentration were unchanged at 35 min recovery (p > 0.05), but HCO3- concentration was elevated post-TTE2 for SB vs. PLA (+2.6 mmol·L-1; p = 0.005; g = 0.99). No significant differences were observed for TTE2 performance (p > 0.05), although a moderate effect size was present for SB vs. PLA (+14.3 s; g = 0.56). Post-exercise NaHCO3 ingestion is not an effective strategy for accelerating the restoration of acid-base balance or improving subsequent TTE performance when limited recovery is available. Novelty: Post-exercise sodium bicarbonate ingestion did not accelerate the restoration of blood pH or bicarbonate after 35 min. Performance enhancing effects of sodium bicarbonate ingestion may display a high degree of inter-individual variation. Small-to-moderate changes in performance were likely due to greater up-regulation of glycolytic activation during exercise.

[Accidental feeding of the coccidiostat nicarbazin in layer breeder flocks - A case report]. / Versehentliche Fütterung von Legehennen-Elterntier-Herden mit dem Kokzidiostatikum Nicarbazin.

Following the accidental feeding of a compound feed containing the coccidiostat nicarbacin in layer breeder flocks (Lohmann Brown Classic), the birds displayed distinct clinical signs within a few hours. Mortality increased during the following 5 days, whereas laying performance and hatching rate of eggs during this period decreased markedly. Egg shell discoloration was observed as early as during the first day. As a consequence, an association between feeding of the coccidiostat nicarbacin and the observed symptoms was assumed. Recent studies indicate that Nicarbacin reduces the activity of aminolevulinic acid synthase type 1 (ALAS 1), which is responsible for the synthesis of protoporphyrin IX in the shell gland as main compound of brown egg shells. Reduced laying performance and increased mortality was likely due to nicarbacin-induced deregulated body temperature homeostasis and concomitant imbalances in acid-base status of the animals. The case reveals that the accidental feeding of nicarbacin to non-target animals such as laying hens and their parents may result in acute clinical symptoms. This highlights the necessity of appropriate care in handling feed additives and their premixes for specific non-target animals and should sensitize farmers and veterinarians.

Life-threatening triclopyr poisoning due to diethylene glycol monoethyl ether solvent.

INTRODUCTION: Triclopyr is a synthetic auxin-like herbicide. It is considered to have low toxicity and there are few reports of poisoning. We report two cases of life-threatening toxicity following ingestions of 250 mL of 50 g/L triclopyr co-formulated with diethylene glycol monoethyl ether (DEGEE). CASE REPORTS: A 79-year-old male with a background of hypertension and atrial fibrillation presented two hours after ingestion with sedation, a severe high anion gap metabolic acidosis, raised osmolar gap and an aspiration pneumonitis. He was ventilated and dialysed for 10 h with resolution of the acidaemia. He was discharged home on day 33. A 66-year-old male with a past history of alcoholism and hypertension presented following a collapse. He had sedation, a severe high anion gap metabolic acidosis with a raised osmolar gap, acute kidney injury and vasodilatory shock. He was ventilated and received dialysis for 43 h. He had poor neurological recovery and died on day 10. DISCUSSION: Ingestion of triclopyr formulations can produce life-threatening toxicity. In large poisonings of triclopyr co-formulated with DEGEE, a high anion gap metabolic acidosis appears to be due to the glycol ether solvent rather than triclopyr itself. Management should focus on good supportive care including dialysis for significant metabolic acidosis.

The therapeutic importance of acid-base balance.

Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.

Citrate Supplementation Restores the Impaired Mineralisation Resulting from the Acidic Microenvironment: An In Vitro Study.

Chronic metabolic acidosis leads to bone-remodelling disorders based on excessive mineral matrix resorption and inhibition of bone formation, but also affects the homeostasis of citrate, which is an essential player in maintaining the acid-base balance and in driving the mineralisation process. This study aimed to investigate the impact of acidosis on the osteogenic properties of bone-forming cells and the effects of citrate supplementation in restoring the osteogenic features impaired by the acidic milieu. For this purpose, human mesenchymal stromal cells were cultured in an osteogenic medium and the extracellular matrix mineralisation was analysed at the micro- and nano-level, both in neutral and acidic conditions and after treatment with calcium citrate and potassium citrate. The acidic milieu significantly decreased the citrate release and hindered the organisation of the extracellular matrix, but the citrate supplementation increased collagen production and, particularly calcium citrate, promoted the mineralisation process. Moreover, the positive effect of citrate supplementation was observed also in the physiological microenvironment. This in vitro study proves that the mineral matrix organisation is influenced by citrate availability in the microenvironment surrounding bone-forming cells, thus providing a biological basis for using citrate-based supplements in the management of bone-remodelling disorders related to chronic low-grade acidosis.

Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection?

Sodium bicarbonate (NaHCO3) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO3 or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO3 treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO3 or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO3 protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO3 in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO3 and other alkali in slowing kidney disease progression and their relationship to acid-base status. Then, we discuss the physiological pathways that have been proposed to underlie these renoprotective effects and highlight strengths and weaknesses in the data supporting each pathway. Finally, we discuss how answering key questions regarding the physiological mechanism(s) mediating the beneficial actions of NaHCO3 therapy in CKD is likely to be important in the design of future clinical trials. We conclude that basic research in animal models is likely to be critical in identifying the physiological mechanisms underlying the benefits of NaHCO3 treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO3 as a therapy in CKD and perhaps other disease states.

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes.

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 µmol/day (IQR 17-138), and ß-hydroxybutyrate by 59 µmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin.

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

Acetazolamide causes renal [Formula: see text] wasting but inhibits ammoniagenesis and prevents the correction of metabolic acidosis by the kidney.

Carbonic anhydrase (CAII) binds to the electrogenic basolateral Na+-[Formula: see text] cotransporter (NBCe1) and facilitates [Formula: see text] reabsorption across the proximal tubule. However, whether the inhibition of CAII with acetazolamide (ACTZ) alters NBCe1 activity and interferes with the ammoniagenesis pathway remains elusive. To address this issue, we compared the renal adaptation of rats treated with ACTZ to NH4Cl loading for up to 2 wk. The results indicated that ACTZ-treated rats exhibited a sustained metabolic acidosis for up to 2 wk, whereas in NH4Cl-loaded rats, metabolic acidosis was corrected within 2 wk of treatment. [Formula: see text] excretion increased by 10-fold in NH4Cl-loaded rats but only slightly (1.7-fold) in ACTZ-treated rats during the first week despite a similar degree of acidosis. Immunoblot experiments showed that the protein abundance of glutaminase (4-fold), glutamate dehydrogenase (6-fold), and SN1 (8-fold) increased significantly in NH4Cl-loaded rats but remained unchanged in ACTZ-treated rats. Na+/H+ exchanger 3 and NBCe1 proteins were upregulated in response to NH4Cl loading but not ACTZ treatment and were rather sharply downregulated after 2 wk of ACTZ treatment. ACTZ causes renal [Formula: see text] wasting and induces metabolic acidosis but inhibits the upregulation of glutamine transporter and ammoniagenic enzymes and thus suppresses ammonia synthesis and secretion in the proximal tubule, which prevented the correction of acidosis. This effect is likely mediated through the inhibition of the CA-NBCe1 metabolon complex, which results in cell alkalinization. During chronic ACTZ treatment, the downregulation of both NBCe1 and Na+/H+ exchanger 3, along with the inhibition of ammoniagenesis and [Formula: see text] generation, contributes to the maintenance of metabolic acidosis.

Topiramate Decelerates Bicarbonate-Driven Acid-Elimination of Human Neocortical Neurons: Strategic Significance for its Antiepileptic, Antimigraine and Neuroprotective Properties.

BACKGROUND: Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability. OBJECTIVE: For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs. METHODS: In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP). RESULTS: Among 17 pyramidal neurons exposed to 50 µM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3 -- driven pHi-regulation by TPM, favoring a stimulation of the passive Cl-/HCO3 --antiporter (CBT) - an acid-loader predominantly in more alkaline neurons. CONCLUSION: TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits.

Enteric-coated sodium bicarbonate supplementation improves high-intensity cycling performance in trained cyclists.

PURPOSE: Enteric-coated sodium bicarbonate (NaHCO3) can attenuate gastrointestinal (GI) symptoms following acute bicarbonate loading, although the subsequent effects on exercise performance have not been investigated. The purpose of this study was to examine the effects of enteric-coated NaHCO3 supplementation on high-intensity exercise performance and GI symptoms. METHODS: Eleven trained male cyclists completed three 4 km time trials after consuming; a placebo or 0.3 g∙kg-1 body mass NaHCO3 in enteric-coated or gelatin capsules. Exercise trials were timed with individual peak blood bicarbonate ion concentration ([HCO3-]). Blood acid-base balance was measured pre-ingestion, pre-exercise, and post-exercise, whereas GI symptoms were recorded pre-ingestion and immediately pre-exercise. RESULTS: Pre-exercise blood [HCO3-] and potential hydrogen (pH) were greater for both NaHCO3 conditions (P < 0.0005) when compared to placebo. Performance time was faster with enteric-coated (- 8.5 ± 9.6 s, P = 0.044) and gelatin (- 9.6 ± 7.2 s, P = 0.004) NaHCO3 compared to placebo, with no significant difference between conditions (mean difference = 1.1 ± 5.3 s, P = 1.000). Physiological responses were similar between conditions, although blood lactate ion concentration was higher with gelatin NaHCO3 (2.4 ± 1.7 mmol∙L-1, P = 0.003) compared with placebo. Furthermore, fewer participants experienced GI symptoms with enteric-coated (n = 3) compared to gelatin (n = 7) NaHCO3. DISCUSSION: Acute enteric-coated NaHCO3 consumption mitigates GI symptoms at the onset of exercise and improves subsequent 4 km cycling TT performance. Athletes who experience GI side-effects after acute bicarbonate loading may, therefore, benefit from enteric-coated NaHCO3 supplementation prior to exercise performance.

Effects of daily ingestion of sodium bicarbonate on acid-base status and anaerobic performance during an altitude sojourn at high altitude: a randomized controlled trial.

BACKGROUND: The present study investigated the effects of chronic sodium bicarbonate (NaHCO3) ingestion on a single bout of high-intensity exercise and on acid-base balance during 7-day high-altitude exposure. METHODS: Ten recreationally active subjects participated in a pre-test at sea level and a 7-day hiking tour in the Swiss Alps up to 4554 m above sea level. Subjects received either a daily dose of 0.3 g/kg NaHCO3 solution (n = 5) or water as a placebo (n = 5) for 7 days. Anaerobic high-intensity exercise performance was assessed using the portable tethered sprint running (PTSR) test under normoxic and hypoxic conditions (3585 m). PTSR tests assessed overall peak force, mean force, and fatigue index. Blood lactate levels and blood gas parameters were assessed pre- and post-PTSR. Urinary pH and blood gas parameters were further analyzed daily at rest in early morning samples under normoxic and hypoxic conditions. RESULTS: There were no significant differences between the bicarbonate and control group in any of the PTSR-related parameters. However, urinary pH (p = 0.003, ηp2 = 0.458), early morning blood bicarbonate concentration (p < 0.001, ηp2 = 0.457) and base excess (p = 0.002, ηp2 = 0.436) were significantly higher in the bicarbonate group compared with the control group under hypoxic conditions. CONCLUSIONS: These results indicate that oral NaHCO3 ingestion does not ameliorate the hypoxia-induced impairment in anaerobic, high-intensity exercise performance, represented by PTSR-related test parameters, under hypobaric, hypoxic conditions, but the maximal performance measurements may have been negatively affected by other factors, such as poor implementation of PTSR test instructions, pre-acclimatization, the time course of hypoxia-induced renal [HCO3-] compensation, changes in the concentrations of intra- and extracellular ions others than [H+] and [HCO3-], or gastrointestinal disturbances caused by NaHCO3 ingestion. However, chronic NaHCO3 ingestion improves blood bicarbonate concentration and base excess at altitude, which partially represent the blood buffering capacity.

The Renal Physiology of Pendrin-Positive Intercalated Cells.

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl- absorption and HCO3- secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl-/HCO3- exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3 administration. In some rodent models, pendrin-mediated HCO3- secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl- absorption, as well as their effect on the epithelial Na+ channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+ and Cl- balance, pendrin affects the balance of other ions, such as K+ and I-. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.

Acid-base effects of continuous infusion furosemide in clinically stable surgical ICU patients: an analysis based on the Stewart model.

OBJECTIVES: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included. MAIN OUTCOMES AND MEASURES: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient. RESULTS: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (rs = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.