Diuretics in States of Volume Overload: Core Curriculum 2022.

Volume overload, defined as excess total body sodium and water with expansion of extracellular fluid volume, characterizes common disorders such as congestive heart failure, end-stage liver disease, chronic kidney disease, and nephrotic syndrome. Diuretics are the cornerstone of therapy for volume overload and comprise several classes whose mechanisms of action, pharmacokinetics, indications, and adverse effects are essential principles of nephrology. Loop diuretics are typically the first-line treatment in the management of hypervolemia, with additional drug classes indicated in cases of diuretic resistance and electrolyte or acid-base disorders. Separately, clinical trials highlight improved outcomes in some states of volume overload, such as loop diuretics and sodium/glucose cotransporter 2 inhibitors in patients with congestive heart failure. Resistance to diuretics is a frequent, multifactorial clinical challenge that requires creative and physiology-based solutions. In this installment of AJKD's Core Curriculum in Nephrology, we discuss the pharmacology and therapeutic use of diuretics in states of volume overload and strategies to overcome diuretic resistance.

Pseudohyperchloremia and Negative Anion Gap - Think Salicylate!

BACKGROUND: Pseudohyperchloremia results in a very low or negative anion gap. Historically, the most common cause of this artifact was bromide poisoning. Bromide salts have been removed from most medications and bromism has become very uncommon. More recently, the introduction of chloride ion selective sensing electrodes (Cl-ISE) has generated a new cause of pseudohyperchloremia-salicylate poisoning. We describe 5 such patients and quantitate the error generated by this measurement artifact. METHODS: The magnitude of artifactual hyperchloremia generated by high salicylate levels was quantified in 5 patients by measuring chloride concentration with several Cl-ISEs from different manufacturers and with Cl-ISEs of different "ages," and comparing these results to measurements with a chloridometer (coulometric titration), which is free of the salicylate artifact. RESULTS: Cl-ISEs from different manufacturers generated a wide range of artifactual chloride concentration elevation. Furthermore, the same Cl-ISE generated increasingly severe pseudohyperchloremia as it was repeatedly reused over time and "aged." CONCLUSIONS: Salicylate interferes with measurement of the blood chloride concentration when a Cl-ISE is used. The severity of this artifact is related to the salicylate level, the specific Cl-ISE, and the "age" of the electrode. Toxic blood salicylate levels can generate marked pseudohyperchloremia, and consequently, an artifactual very small or negative anion gap. The large anion gap metabolic acidosis typical of salicylate poisoning is masked by this artifact. Salicylate has become the most common cause of pseudohyperchloremia, and physicians should immediately consider salicylate poisoning whenever the combination of hyperchloremia and a very small or negative anion gap is reported by the laboratory.

The Hypothesis of Circulus Hypoxicus and Its Clinical Relevance in Patients With Methanol Poisoning - An Observational Study of 35 Patients.

Methanol mass poisoning is a global problem with high fatality rates and often severe sequelae in survivors. Patients typically present late to the hospital with severe metabolic acidosis followed by a rapid deterioration in their clinical status. The hypothesis 'Circulus hypoxicus' describes the metabolic acidosis following methanol poisoning as a self-enhancing hypoxic circle responsible for methanol toxicity. We wanted to test the validity of this hypothesis by an observational study based on 35 patients from the methanol outbreaks in Norway (2004) and the Czech Republic (2012). Comprehensive laboratory values, including S(serum)-methanol, S-formate, S-lactate, arterial blood gases, anion and osmolal gaps, were used in the calculations. Laboratory values and calculated gaps were compared to each other using linear regression. S-lactate and S-formate correlated better with the increased base deficit and anion gap than did S-formate alone. Base deficit rose to about 20 mmol/L and S-formate rose to 12 mmol/L prior to a significant rise in S-lactate - most likely caused by formate inhibition of mitochondrial respiration (type B lactacidosis). The further rise in S-lactate was not linear to S-formate most likely due to the self-enhancing pathophysiology, but may also be associated with hypotension in critically ill patients and variable ethanol drinking habits. Our study suggests that the primary metabolic acidosis leads to a secondary lactic acidosis mainly due to the toxic effects of formate. The following decline in pH will further increase this toxicity. As such, a vicious and self-enhancing acidotic circle may explain the pathophysiology in methanol poisoning, namely the 'Circulus hypoxicus'.

Randomised double-blind comparison of bolus phenylephrine or ephedrine for treatment of hypotension in women with pre-eclampsia undergoing caesarean section.

Treatment of post-spinal hypotension during caesarean section assumes special concern in pre-eclamptic patients due to a compromised fetoplacental circulation and increased risk of placental hypoperfusion. Phenylephrine and ephedrine are the most commonly used vasopressors, although the best choice is still not clear. We studied 80 pre-eclamptic women with a singleton pregnancy who underwent caesarean section with spinal anaesthesia, and who developed hypotension defined as a decrease in systolic arterial pressure ≥ 20% from baseline or absolute value < 100 mmHg. Women were randomly allocated to receive phenylephrine 50 µg or ephedrine 4 mg boluses for treatment of hypotension. Blood pressure changes following vasopressor administration were similar in both groups, but heart rate remained higher after ephedrine at all time-points. The primary outcome measure of umbilical artery pH was 7.26 (0.11) in the phenylephrine group and 7.25 (0.09) in the ephedrine group (p = 0.86). The incidence of neonatal acidosis (umbilical artery pH < 7.20) was 9 (22.5%) in the phenylephrine group and 11 (27.5%) in the ephedrine group (p = 0.80). Other secondary outcome measures were comparable. In conclusion, phenylephrine 50 µg and ephedrine 4 mg, administered as intravenous boluses to treat post-spinal hypotension during caesarean section in pre-eclamptic patients, resulted in similar fetal acid-base values, were equally effective in treating hypotension and were associated with good maternal and neonatal outcome.

Isolated limb perfusion with cytostatic drug leakage. / Perfusión aislada de extremidad inferior con fuga de quimioterapéutico.

Isolated limb perfusion is the treatment of stage III melanoma with in-transit metastasis. This technique allows the administration of cytostatics at an effective concentration and temperature, which could not be administered systemically because of their toxicity. The toxicity due to leakage of the chemotherapy agent from the limb into the systemic circulation is the most serious short-term complication, and is manifested by a systemic inflammatory response syndrome in the immediate post-intervention period. Early detection of this complication and its peri-operative management requires a multidisciplinary approach, in which the anaesthesiologist plays a key role. A case of isolated lower limb perfusion is reported in which the procedure had to be interrupted due to the passage of tumour necrosis factor into the systemic circulation, with severe intra-operative haemodynamic repercussions.

Acid-base and electrolyte disorders associated with the use of antidiabetic drugs.

INTRODUCTION: The use of antidiabetic drugs is expected to substantially increase since diabetes mellitus incidence rises. Currently used antidiabetic drugs have a positive safety profile, but they are associated with certain acid-base and electrolyte abnormalities. The aim of the review is to present the current data regarding the antidiabetic drugs-associated acid-base and electrolyte abnormalities. Areas covered: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been linked with the scarce, but serious, complication of euglycemic diabetic ketoacidosis, as well as with an increase in serum potassium, magnesium and phosphorus levels. Metformin use has been associated with the development of lactic acidosis, although many studies have doubt the direct link with this serious complication. Additionally, metformin in some studies has been linked with a decrease in serum magnesium levels. Insulin administration is associated with a reduction in serum potassium, magnesium and phosphorus concentration, along with reduced renal magnesium excretion. Pioglitazone is associated with an increase in serum magnesium levels. Current data regarding the pathophysiological mechanisms, precipitants, risk factors and presentation of the above abnormalities are discussed in the present review. Expert opinion: Clinicians should choose appropriately between antidiabetic drugs based not only on their hypoglycemic efficacy and effects on cardiovascular risk but also based on the patient's specific risk to develop acid-base or electrolyte derangements.

Chloride toxicity in critically ill patients: What's the evidence?

Crystalloids have become the fluid of choice in critically ill patients and in the operating room both for fluid resuscitation and fluid maintenance. Among crystalloids, NaCl 0.9% has been the most widely used fluid. However, emerging evidence suggests that administration of 0.9% saline could be harmful mainly through high chloride content and that the use of fluid with low chloride content may be preferable in major surgery and intensive care patients. Administration of NaCl 0.9% is the leading cause of metabolic hyperchloraemic acidosis in critically ill patients and side effects might target coagulation, renal function, and ultimately increase mortality. More balanced solutions therefore may be used especially when large amount of fluids are administered in high-risk patients. In this review, we discuss physiological background favouring the use of balanced solutions as well as the most recent clinical data regarding the use of crystalloid solutions in critically ill patients and patients undergoing major surgery.

Approach to the Treatment of Methanol Intoxication.

Methanol intoxication is an uncommon but serious poisoning. Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia. Symptoms including abdominal pain and loss of vision can appear a few hours to a few days after exposure, reflecting the time necessary for accumulation of the toxic byproducts. In addition to a history of exposure, increases in serum osmolal and anion gaps can be clues to its presence. However, increments in both parameters can be absent depending on the nature of the toxic alcohol, time of exposure, and coingestion of ethanol. Definitive diagnosis requires measurement with gas or liquid chromatography, which are laborious and expensive procedures. Tests under study to detect methanol or its metabolite formate might facilitate the diagnosis of this poisoning. Treatment can include administration of ethanol or fomepizole, both inhibitors of the enzyme alcohol dehydrogenase to prevent formation of its metabolites, and hemodialysis to remove methanol and formate. In this Acid-Base and Electrolyte Teaching Case, a patient with methanol intoxication due to ingestion of model airplane fuel is described, and the value and limitations of current and new diagnostic and treatment measures are discussed.

Approach to the Patient With a Negative Anion Gap.

When anion gap calculation generates a very small or negative number, an explanation must be sought. Sporadic (nonreproducible) measurement errors and systematic (reproducible) laboratory errors must be considered. If an error is ruled out, 2 general possibilities exist. A true anion gap reduction can be generated by either reduced concentrations of unmeasured anions such as albumin or increased concentrations of unmeasured cations such as magnesium, calcium, or lithium. This teaching case describes a patient with aspirin (salicylate) poisoning whose anion gap was markedly reduced (-47 mEq/L). The discussion systematically reviews the possibilities and provides the explanation for this unusual laboratory result.

American Society of Nephrology quiz and questionnaire 2014: acid-base and electrolyte disorders.

The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. Once again, in 2014 the conference hall was overflowing with audience members and eager quiz participants. Topics covered by the expert discussants included electrolyte and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases from each of these categories along with single-best-answer questions were prepared and submitted by the panel of experts. Before the meeting, program directors of United States nephrology training programs and nephrology fellows answered the questions using an Internet-based questionnaire. During the live session, members of the audience tested their knowledge and judgment on a series of case-oriented questions prepared and discussed by the experts. They compared their answers in real time using audience response devices with the answers of the nephrology fellows and training program directors. The correct and incorrect answers were then discussed after the audience responses and the results of the questionnaire were displayed. As always, the audience, lecturers, and moderators enjoyed this educational session. This article recapitulates the acid-base and electrolyte disorders portion of the session and reproduces its educational value for the readers of the Clinical Journal of the American Society of Nephrology. Enjoy the clinical cases and expert discussions.

Drug-induced acid-base disorders.

The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal anti-inflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g., anesthetics, sedatives) or hyperventilation (e.g., salicylates, epinephrine, nicotine).

Diuretic-associated electrolyte disorders in the elderly: risk factors, impact, management and prevention.

Electrolyte and acid-base disorders are commonly encountered adverse effects of various diuretic agents, which are associated with considerable morbidity and mortality especially in elderly patients. Diuretic use is associated with hyponatraemia, hypernatraemia, hypokalaemia, hyperkalaemia, hyperuricaemia and alterations in magnesium, calcium, phosphate and acid-base homeostasis. Clinical studies have provided important data on the relative frequency and risk factors for these diuretic-associated electrolyte and acid-base disorders. Old age is one of the most recognized risk factors for diuretic-associated electrolyte and acid-base disorders. Hyponatraemia and hypokalaemia are the most common electrolyte abnormalities found among the elderly population taking diuretics. Both conditions are associated with short and long-term morbidity as well as mortality. This article presents an overview of the literature on diuretic-associated electrolyte disorders and suggested risk factors for their development especially in elderly patients when evidence is available. The impact of these electrolyte disorders on patients will be discussed. Strategies to prevent adverse outcomes related to these disorders should involve careful consideration of risk factors as well as ongoing clinical and laboratory evaluations in the course of using these diuretics.

[Intraperitoneal irrigation for pseudomyxoma peritonei-a case of critical metabolic alkalosis precipitated by irrigation with 101 of sodium bicarbonate--].

Pseudomyxoma peritonei causes marked accumulation of jelly-like ascites in the peritoneal cavity. Removal of much mucinous ascites by irrigating the cavity appears to be an effective treatment. We describe a patient who underwent the irrigation with sodium bicarbonate solution and developed critical alkalemia. A 68-year-old woman with normal renal function was operated on for recurrent pseudomyxoma peritonei. Fol- lowing the excision of primary lesion, her intraperitoneal cavity was irrigated with 10 1 of 7% sodium bicarbonate in about 45 minutes. Thirty minutes after irrigation, blood gas analysis revealed severe metabolic alkalosis (pH 7.714, BE 25.6 mmol x l-1 ) with electrolyte disorder (Na 157.8 mmol x l-1 K 2.31mmol x l-1, Ca 0.73 mmol x l-1). Hypotension (<60 mmHg) and sinus tachycardia (>130 beats x min -1) supervened 75 minutes later. Transferring to the ICU, she was given KC1 solution intravenously based on serial blood analysis while on mechanical ventilation. The next day acid-base disturbance returned spontaneously to normal (pH 7.45, BE 8.0mmol x l-1), leading to endotracheal extubation. Electrolyte imbalance was gradually resolved on 2nd POD and she was discharged from the ICU. Intraperitoneal irrigation with sodium bicarbonate requires special perioperative considerations for lifethreatening alkalemia, especially in a patient with renal impairment.

Cocaine induces a reversible stomatocytosis of red blood cells and increases blood viscosity.

Severe side effects of cocaine consumption are vasoocclusive events such as myocardial infarction and stroke. We have hypothesized that cocaine could affect red blood cells (RBCs) and alter the rheological behaviour of blood. Heparinized blood from healthy volunteers was incubated with a final hematocrit of 45% with increasing cocaine concentrations: 0, 10, 100, 1000, and 10'000 µmol/L plasma. Time dependence of the shape change was tested in phosphate buffered saline containing cocaine. RBCs were fixed in 1% glutaraldehyde for morphological analysis. Blood viscosity was measured with a Couette Viscometer (Contraves LS 30) at 37°C and a shear rate of 69.5 s⁻¹. RBC aggregation was assessed with a Myrenne aggregometer. Cocaine induced a dose-dependent stomatocytic shape transformation of RBCs, which was more pronounced in buffer than in plasma (plasma protein binding of the drug). Stomatocytosis occurs when a drug intercalates preferentially in the inner half of the membrane lipid bilayer. It was a time-dependent process with two components, an almost instant shape change occurring within 1 s, followed by a gradual further shape change during 10 min. Stomatocytosis was reversible by resuspension of the RBCs in cocaine-free buffer. This stomatocytic shape change increased whole blood viscosity at high shear rate from 5.69±0.31 mPa.s to 6.39±0.34 mPa.s for control and 10'000 µmol/L cocaine, respectively (p<0.01). RBC aggregation was not affected by the shape change. These effects occurred at a cocaine concentration, which is several-fold above those measured in vivo. Therefore, it is unlikely that hemorheological factors are involved in vascular events after cocaine consumption.

[Induction of the endoplasmic reticulum stress in conditions of acid-base imbalance in human cells of T-lymphoblastic leukemia].

Endoplasmic reticulum stress - typical molecular pathophysiological process that underlies many cardiovascular, endocrine and other diseases. Violations of the protein conformational maturation processes in the endoplasmic reticulum can cause proteotoxic stress. Compensatory mechanisms are activated in response to ER stress include increased expression of enzymes involved in the formation of disulfide bonds in proteins. The sulfhydryl groups oxidation in the electron transport chain (PDI-ERO1-O2) is associated with reactive oxygen species (ROS) generation. Increased activity of oxidoreductase ERO1 could be one of the mechanisms of oxidative stress - however, a direct relationship of ER stress with the overproduction of ROS remains a subject of debate. In this study we have shown that induced by dithiothreitol (DTT) violation of the redox balance with low ROS production leads to the endoplasmic reticulum stress in Jurkat cells. ER-stress in these cells is not associated with increased ROS production, DTT treatment leads to induction of apoptosis. Modulation of intracellular levels of ROS can influence the apoptosis-inducing effects of ER-stress. Given the possible involvement of ROS in the generation of disulfide bonds, the role of ROS in ER stress may be a modulation of disulfide proteome including client proteins.

Adverse effects of resuscitation with lactated ringer compared with ringer solution after severe hemorrhagic shock in rats.

Lactated Ringer (LR) is a widely used resuscitation fluid that is known to mediate beneficial effects on acid-base balance when compared with normal saline. We here compared LR with the more physiological Ringer solution (RS) regarding acid-base status, hemodynamics, survival, and organ injury following fluid resuscitation subsequent to severe hemorrhagic shock. Anesthetized rats were hemorrhaged to a mean arterial blood pressure of 25 to 30 mmHg within 30 min. After 60 min, they were resuscitated with either RS or LR (three times the shed blood volume) or with RS or LR plus blood (shed blood plus twice its volume) within 30 min. Subsequently, the animals were observed for further 150 min. When the rats were resuscitated with pure LR or RS, all animals of the shock/LR group, but only three of eight shock/RS group rats were dead 100 min later (median survival, 50 ± 13.1 vs. 120 ± 14.1 min; P < 0.05). Coadministration of the shed blood with RS or LR increased the survival rates to 100%. In these blood-resuscitated groups, organ injury, especially of the kidney, was diminished by the use of RS compared with LR. Time-matched acid-base parameters were not different in all shock groups until death of the animals or euthanasia at the end of experimental time. We conclude that, in severe hemorrhagic shock, resuscitation with RS leads to an improved outcome compared with resuscitation with LR, regardless whether blood is coadministered or not.

Evaluation of medetomidine-alfaxalone and medetomidine-ketamine in semi-free ranging Bennett's wallabies (Macropus rufogriseus).

Twenty-six adult semi-free-ranging Bennett's wallabies were anesthetized. Animals in group MA received medetomidine 0.1 mg/kg and alfaxalone 4 mg/kg i.m. in a 5-ml dart, whereas those in group MK received medetomidine 0.1 mg/kg and ketamine 5 mg/kg i.m. in a 3-ml dart. Dosages were based on estimated body weights. The wallabies were allowed to recover spontaneously or, if still nonresponsive at the end of the procedure, were given atipamezole 0.5 mg/kg (half the dose via i.m. and the other half via i.v.). Heart rate and respiratory rate were monitored at 5-min intervals, temperature at 10-min intervals, and two arterial blood samples were taken for blood gas analysis. Statistical analysis was performed by using analysis of variance (P < 0.05). The use of 5-ml darts in group MA compared with 3-ml darts in group MK could potentially increase the risk of iatrogenic trauma and should be considered. Induction and maintenance of anesthesia were satisfactory in both groups. There were no significant differences between the groups in mean time to first effect, recumbency, and approach, or to time to sternal recumbency and standing after reversal with atipamezole. Although bradycardia was present in both groups, no statistical differences were calculated for respiratory rate and heart rate, whereas the mean cloacal temperature was significantly lower in group MA (P = 0.01). Mixed acid-base disturbances occurred in both groups. All but one animal in group MK needed atipamezole at the end of the procedure. No adverse effects were observed after recovery.