CARDIAC EFFECTS OF SALBUTAMOL-INDUCED HYPOKALAEMIA IN THE CONSCIOUS DOG

1. Infusion of salbutamol (3.0 μg/min after a bolus injection of 100 μg) produced hypokalemia in conscious dogs. 2. Measurement of arterial and coronary sinus potassium differences revealed no significant potassium loss from the heart with established hypokalaemia. 3. Shortly after the initial salbutamol bolus and before steady-state hypokalaemia had been achieved during salbutamol infusion, a prolongation of QT_C occurred; this corresponded to a significant myocardial potassium loss of -0.12 mmol/1 plasma. 4. Urinary electrolyte excretions indicated that the hypokalaemia was not due to urinary potassium loss. 5. It was deduced that potassium had moved intracellularly. No change in hydrogen ion status occurred to account for this. Pronounced rises in plasma insulin immunoreactivities during salbutamol infusions suggested this as one mechanism for potassium shifts.     

Acute acetaminophen overdose is associated with dose-dependent hypokalaemia: a prospective study of 331 patients

Hypokalaemia is a recognized complication of acute acetaminophen overdose. It is unclear whether this might be a pharmacological effect of acetaminophen, or due to association with confounding factors. The present study sought to better characterize the relationship between acetaminophen concentrations and risk of hypokalaemia. A prospective study of patients received N-acetylcysteine treatment within 15 hr of acute acetaminophen ingestion. Serum potassium concentrations were determined before and after N-acetylcysteine. Serum acetaminophen concentrations were used to indicate overall drug exposure by comparison to the Rumack-Matthew nomogram. Hypokalaemia was pre-defined by serum concentrations <3.5 mmol/l, and groups compared by Mann-Whitney tests. There were 331 patients. Median (95% confidence interval) fall in serum potassium concentration after N-acetylcysteine was 0.05 mmol/l (-0.11-0.30 mmol/l) if acetaminophen concentrations were below the 'high-risk' treatment line, 0.30 mmol/l (0.17-0.40 mmol/l) if between the 'high-risk' and 'normal' treatment lines (P = 0.0358), and 0.40 mmol/l (0.20-0.50 mmol/l) if above the 'normal' treatment line (P = 0.0136). A receiver operating characteristic showed that high acetaminophen concentrations were predictive of hypokalaemia (P = 0.0001 versus zero discriminatory line), and 4 hr acetaminophen concentration >156 mmol/l gave 81% sensitivity and 48% specificity. The risk of hypokalaemia after acute acetaminophen overdose depends on the extent of acetaminophen exposure, irrespective of N-acetylcysteine administration and independent of whether vomiting occurred. Acetaminophen appears to cause concentration-dependent hypokalaemia after overdose, and the pharmacological basis requires further consideration.     

Síndrome de realimentación

Refeeding syndrome is a complex syndrome that occurs as a result of reintroducing nutrition (oral, enteral or parenteral) to patients who are starved or malnourished. Patients can develop fluid-balance abnormalities, electrolyte disorders (hypophosphataemia, hypokalaemia and hypomagnesaemia), abnormal glucose metabolism and certain vitamin deficiencies. Refeeding syndrome encompasses abnormalities affecting multiple organ systems, including neurological, pulmonary, cardiac, neuromuscular and haematological functions. Pathogenic mechanisms involved in the refeeding syndrome and clinical manifestations have been reviewed. We provide suggestions for the prevention and treatment of refeeding syndrome. The most important steps are to identify patients at risk, reintroduce nutrition cautiously and correct electrolyte and vitamin deficiencies properly.     

Treatment of fluid retention in cirrhosis: a comparison of bumetanide and frusemide.

Bumetanide and frusemide were compared in a crossover study of 10 patients with cirrhosis and fluid overload. Patients received each drug for 3 months. Doses of bumetide varied from 1 mg on alternate days to 3 mg daily (mean 1.3 mg/day), and for frusemide from 40 mg on alternate days to 160 mg daily (mean 72 mg/day). Both drugs proved effective in controlling ascites and oedema, 9 out of the 10 patients showing a satisfactory response. Minor side-effects, hypokalaemia and hyperuricaemia were common with both agents, and hypomagnesaemia and metabolic alkalosis developed in some patients.     

Thiazide-induced hypokalaemia; prevalence higher in women.

In 193 hypertensive patients taking bendrofluazide 5 mg daily, the mean serum potassium concentration was lower in women than in men (3.77 vs 3.99 mmol/l, P less than 0.001) and the prevalence of hypokalaemia (less than 3.5 mmol/l) was higher (25% vs 12%, P less than 0.05). This difference between the sexes was independent of age, body weight, renal function, the use of other antihypertensive drugs and compliance with treatment as judged by tablet counts. Severe hypokalaemia (less than 3.0 mmol/l) was uncommon and showed no difference between the sexes.     

Gitelman syndrome DD thiazide diuretics abuse

Introduction. Gitelman syndrome (GS) is a rare inherited disorder. Mutations in SLC12A3 gene that encode tubular Na+Cl-cotransporter (NCCT) cause hypokalemic metabolic alkalosis, salt loss, hypomagnesaemia and hypocalciuria. The symptoms include weakness, vertigo, hypotension, tetany, paresthesia and nausea. Diagnostic criteria are a normal urine concentrating ability, normal glomerular filtration rate (GFR), hypomagnesaemia (<0,65mmol/l), hypokalemia (<3,6mmol/l) and hypocalciuria (<0,1mmol/mmol creatinine). Previously, the diagnosis was made by exclusion. Today, genetic analysis can ensure diagnosis. Thiazide diuretics (TD) abuse with similar abnormalities can make the differential diagnosis difficult. Causal therapy of GS does not exist. The substitution of potassium and magnesium are therapeutic strategies. Case presentation. A 41-year-old obese woman presented at the emergency department with recurrent episodes of hypokalemia with concomitant weakness, muscle cramps, polyuria and collapse. The results of laboratory testing of blood and urine led to the suspected diagnosis of GS. In the follow-up examinations, the results were inconsistent. Therefore, a transient thiazide diuretics abuse was assumed. Discussion. This case demonstrates the difficulties in making the diagnosis of GS on the basis of only clinical and laboratory tests, without the use of genetic analysis. The differentiation between GS and thiazide diuretic abuse is especially difficult.     

Potassium conservation with amiloride/hydrochlorothiazide (‘Moduret’) in thiazide-induced hypokalaemia in hypertension

Summary

A double-blind study was carried out in 24 hypertensive patients with thiazide-induced hypokalaemia (serum potassium <3.2 mmol/l) to compare the effects of treatment with an amiloride/hydrochlorothiazide combination or hydrochlorothiazide alone. The study was divided into three phases: (i) potassium repletion (Weeks 0 to 4) with oral potassium chloride (40 mmol/day), (ii) stabilization (Weeks 4 to 6) of normokalaemia, and (Hi) active drug treatment (Weeks 6 to 14), patients being allocated at random to receive one or other of the two treatments. Dosage was 2 tablets per day of the 5?mg amiloride plus 50?mg hydrochlorothiazide combination or of 50?mg hydrochlorothiazide alone. The results showed that blood pressure control was comparable in both treatment groups but hydrochlorothiazide alone caused a statistically significant reduction in serum potassium levels compared to the drug combination. Apart from 1 patient who developed hypokalaemia on hydrochlorothiazide alone, no other side-effects of treatment were reported.     

Antihypertensive,saluretic and hypokalaemic effects of cyclothiazide in comparison with hydrochlorthiazide with amiloride supplement

Summary The antihypertensive, saluretic and hypokalaemic effects of a small dose of cyclothiazide (2.5 mg daily) were compared with those of a conventional dose of an hydrochlorthiazide-amiloride hydrochloride combination (50+5 mg daily). Both preparations were given to 13 patients with mild (WHO I) hypertension in a cross-over manner for six weeks, with an intervening wash-out phase of three weeks. The antihypertensive efficacy of cyclothiazide was well comparable to that of the hydrochlorthiazide-amiloride combination, although cyclothiazide tended to inhibit renal sodium reabsorption less than the combination. Cyclothiazide tended to cause hypokalaemia, apparently due to increased potassium loss, but with the present dosage none of the 13 patients developed marked hypokalaemia (serum potassium less than 3.3 mmol/l). Both drugs led to a comparable increase in serum urate concentration. Neither of the preparations affected creatinine or free-water clearance. The results suggest that even in relatively small doses thiazides effectively decrease blood pressure, and combining thiazides with potassium-sparing diuretics is advantageous only in patients with marked hypokalaemia and its associated risks.     

Inter-relationship between serum potassium and plasma catecholamines and 3':5' cyclic monophosphate in alcohol withdrawal

Serial analyses of serum potassium and plasma epinephrine, norepinephrine and adenosine 3':5'-cyclic monophosphate (cyclic AMP) concentrations were measured in 13 patients with alcohol withdrawal, six of whom presented delirium tremens. Patients with delirium showed at admission levels of potassium (3.45 +/- 0.45 mmol/l) lower (P less than 0.02) than patients without delirium (3.81 +/- 0.14 mmol/l). Three patients were hypokalemic, all of them with delirium. Serum potassium increased significantly in all the patients during evolution. A close negative correlation (r = -0.751) between the intensity of withdrawal and serum potassium was observed. Plasma epinephrine concentrations were increased at admission (623 +/- 192 pmol/l), patients with delirium showing greater values (705 +/- 137 pmol/l). As the alcohol withdrawal improved, plasma epinephrine concentration decreased. Plasma norepinephrine concentrations were also increased at admission (3422 +/- 1451 pmol/l), but did not change significantly during evolution, being similar in patients with and without delirium. Plasma cyclic AMP levels were high at admission (40.4 +/- 24.3 nmol/l) and increased significantly (P less than 0.05) during evolution. The data obtained suggest that in patients with alcohol withdrawal, as symptomatology improves, plasma epinephrine decreases, while plasma norepinephrine remains increased. The combined actions of the two facts--less beta-stimulus, maintaining of alpha-stimulus--would comprise a significant increase of kalemia, that in cases of initial hypokalemia would lead to normal values of serum potassium.     

Acid-base balance in alcohol users seen in an emergency room.

Over 10% of emergency room patients are diagnosed as having alcohol (6.0%) or drug intoxication. In the present study 196 alcohol intoxications treated in a hospital were studied retrospectively; 49.2% of the patients had abnormal acid-base values, alcoholics more often than non-alcoholics (p = 0.04). Mean blood ethanol concentration (BAC) was 310 mg/dl (SD 120); alcoholics had higher concentrations of alcohol. BAC was the higher the lower the serum pH was (p less than 0.002, r = -0.45). The deeper the coma the lower the serum pH (p less than 0.05) and the higher the BAC (p less than 0.0001). Respiratory acidosis (31.7%) was an important finding in those intoxicated. Metabolic acidosis (7.9%) could be explained by the presence metabolites of ethanol in the serum and by decreased extra-cellular fluid volume. Metabolic alkalosis related to vomiting and an extra-cellular fluid volume decrease was found in 7.9% of the patients. Respiratory alkalosis was a rare finding (1.6%). Hypokalemia (22.5%) and hypernatremia (15.3%) were the most important electrolyte changes. Chronic alcoholics had lower serum potassium than had non-alcoholics; 3.6% (n = 7) of the patients had to be intubated. Acid-base disturbances were frequent in adults with alcohol intoxication. Serum pH correlated well with the state of consciousness and the BAC.     

Treating severe metabolic alkalosis

The pathophysiology, symptomatology, and treatment of metabolic alkalosis are reviewed, with emphasis on treatment with intravenous hydrochloric acid. Three buffering systems are used by the body to correct an arterial pH above 7.45--tissue, respiratory, and renal systems. The kidneys have the primary responsibility for correcting a severe metabolic alkalosis, but several conditions (e.g., severe volume contraction) can interfere with the renal mechanisms. No unique symptoms are associated with metabolic alkalosis. Conventional conservative treatment of metabolic alkalosis involves meeting the patient's fluid and electrolyte needs and allowing the body to correct the alkalosis through its own mechanisms. However, when more rapid resolution of the alkalosis is needed or the patient cannot tolerate fluid and electrolyte therapy, mineral acids may be administered. Ammonium chloride and arginine monohydrochloride infusions may both be used; since both require hepatic conversion for full activity, patients with hepatic dysfunction may require alternative therapy. Dilute hydrochloric acid (0.1-0.2 N) may be given intravenously to these patients through a central-venous catheter. Dosage guidelines and formulation procedures are described in the paper, as are other possible therapeutic alternatives (dialysis, acetazolamide, cimetidine). Most cases of metabolic alkalosis can be managed with fluid and electrolyte therapy. When metabolic alkalosis needs to be resolved quickly or when conventional therapy cannot be tolerated, mineral acid administration should be instituted. The primary drug of choice for these patients is intravenous ammonium chloride; patients with hepatic or severe renal dysfunction should receive dilute hydrochloric acid via a central-venous catheter.     

Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels

1. Drug-induced block of the rapidly activating delayed rectifier K+ current (I(Kr)), encoded by human ether-a-go-go-related gene (hERG), has been linked to acquired long QT syndrome (aLQTS). Hypokalaemia is a recognized risk factor in aLQTS. To further understand why hypokalaemia is a risk factor in aLQTS, we examined the effect of [K+]o on drug block of the hERG potassium channel stably expressed in human embryonic kidney (HEK-293) cells using whole-cell voltage-clamp techniques. 2. The effects of selected [K+]o (1-20 mmol/L) on hERG block with four structurally diverse compounds (dofetilide, mesoridazine, quinidine and terfenadine) from different therapeutic classes were evaluated. Reducing [K+]o from 20 to 1 mmol/L had little effect on IC50 values for hERG current block for all four compounds. For example, evaluating quinidine in external potassium concentrations of 20, 10, 5 and 1 mmol/L resulted in IC50 values of 1.82 +/- 0.33, 2.04 +/- 0.28, 1.57 +/- 0.52 and 1.14 +/- 0.21 mmol/L, respectively. No statistically significant difference (P > 0.35, anova) was observed between drug block of hERG in different external potassium concentrations. These data are in contrast with previously reported results examining hERG channel modulation expressed in AT-1 cells under similar experimental conditions. 3. These results demonstrate that [K+]o does not directly modulate drug block of hERG channels expressed in an HEK-293 cell line. The enhanced risk of Torsades de Pointes associated with hypokalaemia in aLQTS may be due to reduction of other (non-hERG) potassium currents, further reducing the repolarization reserve, and not due to direct modulation of hERG block by [K+]o.     

Drug-induced hypomagnesaemia : scope and management.

Nearly 50 medications have been implicated as inducing hypomagnesaemia, sometimes based on insufficient data regarding clinical significance and frequency of occurrence. In fact, clinical effects attributed to hypomagnaesemia have been reported in only 17 of these drugs. A considerable amount of literature relating to individual drugs has been published, yet a comprehensive overview of this issue is not available and the hypomagnesaemic effect of a drug could be either overemphasised or under-rated. In addition, there are neither guidelines regarding treatment, prevention and monitoring of drug-induced hypomagnesaemia nor agreement as to what serum level of magnesium may actually be defined as 'hypomagnesaemia'. By compiling data from published papers, electronic databases, textbooks and product information leaflets, we attempted to assess the clinical significance of hypomagnesaemia induced by each drug. A practical approach for managing drug-induced hypomagnesaemia, incorporating both published literature and personal experience of the physician, is proposed. When drugs classified as inducing 'significant' hypomagnesaemia (cisplatin, amphotericin B, ciclosporin) are administered, routine magnesium monitoring is warranted, preventive treatment should be considered and treatment of hypomagnesaemia should be initiated with or without overt clinical manifestations. In drugs belonging to the 'potentially significant' category, among which are amikacin, gentamicin, laxatives, pentamidine, tobramycin, tacrolimus and carboplatin, magnesium monitoring is justified when either of the following occurs: clinical manifestations are apparent; persistent hypokalaemia, hypocalcaemia or alkalosis are present; other precipitating factors for hypomagnesaemia coexist; or treatment is with more than one potentially hypomagnesaemic drug. No preventive treatment is required and treatment should be initiated only if hypomagnesaemia is accompanied by symptoms or clinically significant relevant laboratory findings. In those drugs whose hypomagnesaemic effect is labelled as 'questionable', including furosemide and hydrochlorothiazide, routine monitoring and treatment are not required.     

Biochemical aberrations in hypertensive patients on antihypertensive drug therapy

This study focused on biochemical aberrations in newly diagnosed and long standing hypertensives on anti-hypertensive therapy. One hundred and seventy two hypertensives were studied. Hydrochlorthiazide was the most used drug (41 percent). Of the hypertensive patients, 44 percent and 13.4 percent were hypokalaemic when 3.5 and 3.0 ml/l serum potassium respectively was used as criterion for defining hypokalaemia. In addition 13.8 percent had serum sodium levels ranging between 110- 120 mmol/l. Renal dysfunction was found in 0.05 percent of the patients studied as judged by both raised serum urea and creatinine. Lipids and lipoproteins abnormalities were also apparent in the patient groups, cholesterol and triglycerides being significantly raised (p less than 0.05 and p less than 0.001 respectively). High density lipoprotein cholesterol was significantly lower (p less than 0.001) in the patients whereas low density cholesterol was higher (p less than 0.001). In conclusion, this study highlights the need for constant biochemical evaluation on hypertensives on antihypertensive therapy as part of management of hypertensive patients.     

Lack of effect of piretanide (a potassium-stable diuretic) on serum magnesium

Serum magnesium and potassium concentrations were determined in 188 patients undergoing diuretic treatment for mild to moderate hypertension in four controlled clinical trials (eleven treatment groups). Measurements were made before and after 12 weeks of treatment with piretanide monosubstance (including the retarded form) in the range 3 to 12 mg daily, with triamterene as monosubstance and in fixed dose combination with piretanide, and with amiloride in combination with hydrochlorothiazide. Eumagnesaemia and eupotassaemia were preserved at all dosage of the piretanide monosubstance. Mean serum potassium concentrations were significantly increased following treatment with the potassium-sparing agents triamterene (with and without piretanide) and amiloride in combination with hydrochlorothiazide. These changes were not accompanied by changes in mean serum magnesium levels, that is, a magnesium-sparing effect was not demonstrated. Individual values of changes in serum magnesium levels before and after diuretic therapy did not correlate with the corresponding changes in serum potassium levels in any of the eleven groups of patients. This result is in contrast to the findings of other authors, which suggested that serum magnesium and potassium levels were correlated. Long-term treatment with diuretics can lead to hypomagnesaemia and hypokalaemia, and, if in combination with a potassium-sparer, to hyperkalaemia. The results of this analysis show that piretanide, in addition to its smooth and effective antihypertensive action, is also able to preserve serum magnesium and potassium homeostasis when administered in the range of 3 to 12 mg for 12 weeks.     

Effect of a scorpion (Leiurus quinquestriatus H and E) venom on blood gases and acid-base balance in the rat

Leiurus quinquestriatus crude venom caused metabolic alkalosis which was partially compensated by respiratory acidosis. Fraction 1 of the venom caused metabolic and respiratory acidosis. The other fractions caused metabolic alkalosis with various degrees of compensation by respiratory acidosis. Fraction 1 caused a marked decrease in blood pH. Hypoxia seemed to be an important contributing factor for this change. Sodium levels decreased while potassium levels increased in the plasma.     

Effect of acute paracetamol overdose on changes in serum and urine electrolytes

What is already known about this subject

• Paracetamol causes renal failure in overdose. Experimental studies have shown that paracetamol can inhibit COX II systemically in a manner similar to selective COX-II inhibitors.
• In overdose nonsteroidal anti-inflammatory drugs such as ibuprofen, cause dose-dependent increase in urinary potassium excretion (FeK) and sodium retention, probably due to vasoconstriction.

What this study adds

• Paracetamol overdose is associated with dose-related hypokalaemia and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose.
• This effect seems likely to be via cyclo-oxygenase inhibition and may be separate from the nephrotoxic effects of paracetamol.

Aims

To investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man.

Methods

Two studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study.

Results

There was a significant dose-dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure.

Conclusions

Paracetamol overdose is associated with dose-related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.     

Use of a bioassay in healthy men to evaluate diuretic-spironolactone combinations.

The plasma potassium responses to 1 week's treatment with metolazone 0.625 mg, 1.25 mg and 2.5 mg in combination with spironolactone 50 mg, and metolazone 2.5 alone were examined in a double-blind, crossover study in twelve healthy subjects. Spironolactone attenuated the hypokalaemia induced by metolazone--addition of spironolactone 50 mg to metolazone 2.5 mg raised plasma potassium by 0.18 mmol/l (P less than 0.025). In the presence of spironolactone, a linear log metolazone dose-plasma potassium response relationship (P less than 0.01) was demonstrated. Spironolactone was unable to compensate fully for metolazone's hypokalaemic effect although in combination with metolazone 0.625 mg and 1.25 mg, plasma potassium concentration was maintained close to pretreatment levels. The human bioassay employed provided conveniently quantitative information which allows the rational development of a fixed dose diuretic-spironolactone combination tablet.     

Effect of indapamide on the renin-aldosterone system, and urinary excretion of potassium and calcium in essential hypertension

The effect of indapamide, 2.5 mg daily, on blood pressure, electrolyte balance and the renin-aldosterone system was studied in 11 patients with essential hypertension. During indapamide treatment blood pressure decreased and the renin-aldosterone system was stimulated. A moderate hypokalaemia seen during indapamide treatment was not correlated to changes in plasma aldosterone concentration. Fractional excretion of potassium was unchanged during treatment, while renal calcium excretion was reduced. No effect on calcium in serum was observed.     

Effectiveness of Sodium Polystyrene Sulfonate for Short-Term Treatment of Hyperkalemia

Background:Sodium polystyrene sulfonate (SPS) is a potassium-binding resin that is commonly used to treat mild hyperkalemia. However, there is limited evidence supporting its effectiveness in the short-term management of hyperkalemia.Objective:To determine whether SPS is effective in reducing serum potassium in general medical patients after a single oral dose.Methods:A retrospective observational study was conducted for patients admitted to the internal medicine service of a tertiary care hospital between January 2011 and May 2012 with documentation of a serum potassium level between 5.0 and 5.9 mmol/L during the hospital stay. Patients eligible for inclusion were adults without chronic or acute renal failure or recent changes in medication or diet that would affect serum potassium level. Propensity score matching was performed to minimize differences between the control group (no treatment) and the treatment group (treatment with oral SPS). Follow-up serum potassium levels (at 6–24 h) were compared with index potassium levels.Results:A total of 138 patients met the inclusion criteria, 72 in the control group and 66 in the treatment group. For most patients in the treatment group, the dose was 15 or 30 g of SPS orally. The difference between the control and treatment groups in terms of mean change in serum potassium at 6 to 24 h after the index potassium measurement was statistically significant (by paired t test) in both an unmatched analysis (−0.41 ± 0.50 and −0.58 ± 0.39 mmol/L, respectively; p = 0.039) and a matched analysis (−0.44 ± 0.29 and −0.58 ± 0.39 mmol/L, respectively; p = 0.026). No difference was observed in terms of mean change in serum potassium between patients who received 15 and 30 g of SPS (−0.51 ± 0.38 and −0.66 ± 0.40 mmol/L, respectively; p = 0.13).Conclusions:In patients with mild hyperkalemia, oral SPS therapy reduced serum potassium by 0.14 mmol/L more than control. Although this difference was statistically significant, the small treatment effect observed in this study may not be clinically important. Furthermore, the cost and potential adverse effects of treatment suggest that routine use of SPS may be inappropriate for patients with mild hyperkalemia. Prospective randomized controlled trials would help in further evaluating the effectiveness and safety of SPS.