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1.  A rapid analysis of plasma/serum ethylene and propylene glycol by headspace gas chromatography 
SpringerPlus  2013;2:203.
A rapid headspace-gas chromatography (HS-GC) method was developed for the analysis of ethylene glycol and propylene glycol in plasma and serum specimens using 1,3-propanediol as the internal standard. The method employed a single-step derivitization using phenylboronic acid, was linear to 200 mg/dL and had a lower limit of quantitation of 1 mg/dL suitable for clinical analyses. The analytical method described allows for laboratories with HS-GC instrumentation to analyze ethanol, methanol, isopropanol, ethylene glycol, and propylene glycol on a single instrument with rapid switch-over from alcohols to glycols analysis. In addition to the novel HS-GC method, a retrospective analysis of patient specimens containing ethylene glycol and propylene glycol was also described. A total of 36 patients ingested ethylene glycol, including 3 patients who presented with two separate admissions for ethylene glycol toxicity. Laboratory studies on presentation to hospital for these patients showed both osmolal and anion gap in 13 patients, osmolal but not anion gap in 13 patients, anion but not osmolal gap in 8 patients, and 1 patient with neither an osmolal nor anion gap. Acidosis on arterial blood gas was present in 13 cases. Only one fatality was seen; this was a patient with initial serum ethylene glycol concentration of 1282 mg/dL who died on third day of hospitalization. Propylene glycol was common in patients being managed for toxic ingestions, and was often attributed to iatrogenic administration of propylene glycol-containing medications such as activated charcoal and intravenous lorazepam. In six patients, propylene glycol contributed to an abnormally high osmolal gap. The common presence of propylene glycol in hospitalized patients emphasizes the importance of being able to identify both ethylene glycol and propylene glycol by chromatographic methods.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-2-203) contains supplementary material, which is available to authorized users.
PMCID: PMC3667371  PMID: 23741644
Ethylene glycol; Glycols; Gas chromatography; Propylene glycol; Toxicology
2.  An evaluation of the osmole gap as a screening test for toxic alcohol poisoning 
The osmole gap is used routinely as a screening test for the presence of exogenous osmotically active substances, such as the toxic alcohols ethylene glycol and methanol, particularly when the ability to measure serum concentrations of the substances is not available. The objectives of this study were: 1) to measure the diagnostic accuracy of the osmole gap for screening for ethylene glycol and methanol exposure, and 2) to identify whether a recently proposed modification of the ethanol coefficient affects the diagnostic accuracy.
Electronic laboratory records from two tertiary-care hospitals were searched to identify all patients for whom a serum ethylene glycol and methanol measurement was ordered between January 1, 1996 and March 31, 2002. Cases were eligible for analysis if serum sodium, blood urea nitrogen, glucose, ethanol, ethylene glycol, methanol, and osmolality were measured simultaneously. Serum molarity was calculated using the Smithline and Gardner equation and ethanol coefficients of 1 and 1.25 mOsm/mM. The diagnostic accuracy of the osmole gap was evaluated for identifying patients with toxic alcohol levels above the recommended threshold for antidotal therapy and hemodialysis using receiver-operator characteristic curves, likelihood ratios, and positive and negative predictive values.
One hundred and thirty-one patients were included in the analysis, 20 of whom had ethylene glycol or methanol serum concentrations above the threshold for antidotal therapy. The use of an ethanol coefficient of 1.25 mOsm/mM yielded higher specificities and positive predictive values, without affecting sensitivity and negative predictive values. Employing an osmole gap threshold of 10 for the identification of patients requiring antidotal therapy resulted in a sensitivity of 0.9 and 0.85, and a specificity of 0.22 and 0. 5, with equations 1 and 2 respectively. The sensitivity increased to 1 for both equations for the identification of patients requiring dialysis.
In this sample, an osmole gap threshold of 10 has a sensitivity and negative predictive value of 1 for identifying patients for whom hemodialysis is recommended, independent of the ethanol coefficient applied. In patients potentially requiring antidotal therapy, applying an ethanol coefficient of 1.25 resulted in a higher specificity and positive predictive value without compromising the sensitivity.
PMCID: PMC2390580  PMID: 18442409
3.  Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap 
Journal of Nephropathology  2013;2(2):139-143.
Background: Ethylene glycol ingestion can lead to acute kidney injury from tubular deposition of oxalate crystals.  The diagnosis of ethylene glycol intoxication is based on a history of ingestion, clinical examination, high anion gap metabolic acidosis, high osmolal gap, and a measured serum level of ethylene glycol.  However, depending on the delay in time from ingestion to arrival to a hospital, the osmolal gap may become normal, thereby creating a confusing clinic picture for the treating clinician.
Case: A 71 year-old man with a history of alcohol abuse had been unconscious for an unknown period of time.  Upon hospitalization, he was found to have a high anion gap metabolic acidosis but a normal serum osmolal gap and subsequently developed acute kidney injury.  The serum lactic acid and glucose levels were unremarkable, and there were no ketones in the serum. Urine analysis showed numerous red blood cells and calcium oxalate crystals.  The renal biopsy showed multiple oxalate crystals in the renal tubules demonstrating birefringence under polarized light. Given the history of alcohol abuse, the clinical presentation, the unexplained high anion gap metabolic acidosis, and the biopsy findings, ethylene glycol intoxication was deemed the most likely diagnosis.
Conclusions: In cases of ethylene glycol intoxication, a high serum osmolal gap is supportive of ethylene glycol intoxication, but a normal serum osmolal gap does not exclude the diagnosis, especially when the time of ingestion is unknown. Physicians should be aware of potentially normal serum osmolal gap values in cases of ethylene glycol intoxication.
PMCID: PMC3891144  PMID: 24475441
Acute Kidney Injury; Oxalate Nephropathy; Ethylene Glycol; Normal Serum Osmolal Gap
4.  Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis—a single-centre experience 
Clinical Kidney Journal  2012;5(2):120-123.
Intoxication with ethylene glycol happen all around the world and without rapid recognition and early treatment, mortality from this is high.
In our study, we retrospectively analysed six cases of ethylene glycol intoxication in our department. We measured ethylene glycol or glycolate levels, lactate levels and calculated the osmolal and anion gap.
Data from six patients admitted to the nephrology department between 1999 and 2011 with ethylene glycol poisoning are reported. All patients were men. The mean pH on admission was 7.15 ± 0.20 and the anion and osmolal gap were elevated in five of six patients. Four patients had an acute kidney injury and one patient had an acute-on-chronic kidney injury. All patients survived and after being discharged, two patients required chronic intermittent haemodialysis. Interestingly, at the time of admission, all patients had elevated lactate levels but there was no linear regression between toxic levels and lactate levels and no linear correlation was found between initial lactate levels and anion gap and osmolal gap.
The initial diagnosis of ethylene glycol poisoning is difficult and poisoning with ethylene glycol is rare but life threatening and needs rapid recognition and early treatment. Therefore, intoxication with ethylene glycol should not be misdiagnosed as lactic acidosis in patients with metabolic acidosis and elevated lactate levels.
PMCID: PMC4235595  PMID: 25503773
acute kidney injury; ethylene glycol poisoning; lactate levels
5.  Osmol gap method for the detection of diethylene glycol in human serum 
Measurement of the osmol gap (OG) is a technique that is used frequently in toxic alcohol poisonings (ethylene glycol (EG) and methanol) as a rapid means to estimate exposure, and can be performed in virtually all hospital laboratories. The value of the OG has not been previously evaluated for diethylene glycol (DEG) exposures. The primary objective of this study was to evaluate the utility of the OG in estimating DEG serum concentrations using the most common formula that is currently used for estimating methanol, ethanol, and ethylene glycol concentrations.
This was a controlled laboratory investigation using serum samples individually spiked with a known quantity of toxic alcohol compared to no toxic alcohol. Test samples were spiked with ethanol, DEG, EG, and methanol. Serum chemistries and osmolality and osmolarity were determined, and the OG was determined for each specimen.
The percent error of estimating DEG concentrations of 26.3% was similar to the mean percent error for estimating other alcohol concentrations, 30.5%±5.6% (P>0.05, 95% confidence interval 16.7%-44.3%).
The severity of metabolic effects associated with DEG and the need to appropriately determine rescue treatments mandate early detection of significant exposures for effective triage and patient management. Our results indicate that the percent error of the osmol gap method for estimating DEG concentration is similar to that of other toxic alcohols; this simple technique could be a valuable clinical tool, since quantitative DEG analysis is rarely available.
PMCID: PMC4129750  PMID: 25214950
Diethylene glycol; Osmol gap; Metabolic acidosis
6.  Accuracy of prediction equations for serum osmolarity in frail older people with and without diabetes1234 
Background: Serum osmolality is an accurate indicator of hydration status in older adults. Glucose, urea, and electrolyte concentrations are used to calculate serum osmolarity, which is an indirect estimate of serum osmolality, but which serum osmolarity equations best predict serum osmolality in the elderly is unclear.
Objective: We assessed the agreement of measured serum osmolality with calculated serum osmolarity equations in older people.
Design: Serum osmolality was measured by using freezing point depression in a cross-sectional study. Plasma glucose, urea, and electrolytes were analyzed and entered into 38 serum osmolarity-prediction equations. The Bland-Altman method was used to evaluate the agreement and differential bias between measured osmolality and calculated osmolarity. The sensitivity and specificity of the most-promising equations were examined against serum osmolality (reference standard).
Results: A total of 186 people living in UK residential care took part in the Dehydration Recognition In our Elders study (66% women; mean ± SD age: 85.8 ± 7.9 y; with a range of cognitive and physical impairments) and were included in analyses. Forty-six percent of participants had impending or current dehydration (serum osmolality ≥295 mmol/kg). Participants with diabetes (n = 33; 18%) had higher glucose (P < 0.001) and serum osmolality (P < 0.01). Of 38 predictive equations used to calculate osmolarity, 4 equations showed reasonable agreement with measured osmolality. One [calculated osmolarity = 1.86 × (Na+ + K+) + 1.15 × glucose + urea +14; all in mmol/L] was characterized by narrower limits of agreement and the capacity to predict serum osmolality within 2% in >80% of participants, regardless of diabetes or hydration status. The equation's sensitivity (79%) and specificity (89%) for impending dehydration (≥295 mmol/kg) and current dehydration (>300 mmol/kg) (69% and 93%, respectively) were reasonable.
Conclusions: The assessment of a panel of equations for the prediction of serum osmolarity led to identification of one formula with a greater diagnostic performance. This equation may be used to predict hydration status in frail older people (as a first-stage screening) or to estimate hydration status in population studies. This trial was registered at the Research Register for Social Care ( as 122273.
PMCID: PMC4135495  PMID: 25030781
7.  “Essential” hypernatremia due to ineffective osmotic and intact volume regulation of vasopressin secretion 
A physiological explanation for sustained hyperosmolality was sought in a patient with histiocytosis. During 23 days of observation with only sodium intake regulated at 100 mEq daily, elevation (mean 310 mOsm/kg of water) and fluctuation (range 298-323) of the fasting plasma osmolality were recorded. The presence of endogenous vasopressin was indicated by the patient's ability to concentrate the urine to as high as 710 mOsm/kg of water with a creatinine clearance of 84 cc/min, and by dilution of the urine in response to alcohol. The failure of increasing fluid intake to as high as 6.2 liters daily to lower the plasma osmolality indicated that deficient fluid intake was not solely responsible for the elevated plasma osmolality. Hypertonic saline infusion during water diuresis resulted in the excretion of an increased volume of dilute urine. The water diuresis continued despite a rise in plasma osmolality from 287 to 339. An isotonic saline infusion initiated during hydropenia resulted in a water diuresis which continued despite a rise in the plasma osmolality from 303 to 320. Stable water diuresis induced during recumbency by either oral ingestion of water or intravenous infusion of normal saline was terminated by orthostasis and resumed with the return to the recumbent position. Antecedent alcohol ingestion blocked the antidiuresis of orthostasis. The data are interpreted as indicating impairment of the osmoreceptor mechanism as the primary cause of the hyperosmolar syndrome. They also indicate that vasopressin secretion was regulated primarily by changes in effective blood volume. Chlorpropamide was found to be an effective treatment for the syndrome.
PMCID: PMC291897  PMID: 5101300
8.  Predictors of Ethylene Glycol Ingestion Cases Called into a Regional Poison Center 
Journal of Medical Toxicology  2012;8(2):130-134.
Poison center consultations for potential toxic alcohol poisonings are challenging because blood levels are typically not immediately available. The primary objective of this study was to determine whether readily obtainable laboratory values can be used to accurately and rapidly diagnose these poisonings. Over a 15-month period, patients with a history of toxic alcohol ingestion or a metabolic acidemia (pH ≤ 7.30 or serum bicarbonate ≤ 18 mEq/L) that prompted a poison center consultation were enrolled. A predictive logistic regression model was used to assess the combined ability of serum pH, calcium, osmolar gap, and anion gap levels to predict a final diagnosis of toxic alcohol poisoning. There were 102 subjects included in the analysis. A total of 44% (45/102) patients had a final diagnosis of ethylene glycol (EG) poisoning. Higher levels of calcium, osmolar gap, and anion gap were independently associated with statistically significant or marginally significant increases in the odds of a final diagnosis of EG poisoning. The c-index was estimated at 0.81, indicating that the model showed a reasonable ability to discriminate EG cases from others. The final model had a sensitivity and specificity of 78% and 89%, respectively, and positive and negative predictive values of 84% and 83% respectively. The combination of elevated calcium, osmolar gap, and anion gap is associated with a high likelihood of EG poisoning, but clinician gestalt is still essential for its diagnosis. Further refinement of the model is needed.
PMCID: PMC3550235  PMID: 22231275
Toxic Alcohol; Ethylene Glycol; Poison Center
9.  Uncoventional Views on Certain Aspects of Toxin-Induced Metabolic Acidosis 
This discussion will highlight the following 9 specific points that related to metabolic acidosis caused by various toxins. The current recommendation suggests that alcohol dehydrogenase inhibitor fomepizole is preferred to ethanol in treatment of methanol and ethylene glycol poisoning, but analysis of the enzyme kinetics indicates that ethanol is a better alternative. In the presence of a modest increase in serum osmolal gap (<30 mOsm/L), the starting dose of ethanol should be far less than the usual recommended dose. One can take advantage of the high vapor pressure of methanol in the treatment of methanol poisoning when hemodialysis is not readily available. Profuse sweating with increased water ingestion can be highly effective in reducing methanol levels. Impaired production of ammonia by the proximal tubule of the kidney plays a major role in the development of metabolic acidosis in pyroglutamic acidosis. Glycine, not oxalate, is the main final end product of ethylene glycol metabolism. Metabolism of ethylene glycol to oxalate, albeit important clinically, represents less than 1% of ethylene glycol disposal. Urine osmolal gap would be useful in the diagnosis of ethylene glycol poisoning, but not in methanol poisoning. Hemodialysis is important in the treatment of methanol poisoning and ethylene glycol poisoning with renal impairment, with or without fomepizole or ethanol treatment. Severe leucocytosis is a highly sensitive indicator of ethylene glycol poisoning. Uncoupling of oxidative phosphorylation by salicylate can explain most of the manifestations of salicylate poisoning.
PMCID: PMC3041497  PMID: 21468195
metabolic acidosis; toxin; ethylene glycol; methanol; poisoning; urine osmolal gap
10.  Osmolar relation between cerebrospinal fluid and serum in hyperosmolar hypernatraemic dehydration. 
Archives of Disease in Childhood  1976;51(9):660-666.
The relation between cerebrospinal fluid (CSF) and serum osmolality was studied in 16 patients with hyperosmolar hypernatraemic dehydration before treatment. After correcting shock and acidosis, 0-45% saline in 2-5 or 5% dextrose was infused in each patient over a 48- to 72-hour period. During rehydration, serum osmolality, electrolyte concentrations, urea nitrogen, and blood pH were measured sequentially. Five patients developed severe neurological abnormalities within 48 hours of addmission (convulsions 2, convulsions with hemiplegia 2, hemiplegia 1). Of these, 3 had residual defects on follow-up at least one year later. This group was indistinguishable from the 11 without significant neurological abnormality, both on clinical grounds before rehydration, and after analysis of admission and subsequent serum biochemical variables. A significant osmolar gap (greater than 4 mmol/kg H2O) between serum and CSF was found in 13 patients. Severe neurological disturbance only occurred when CSF osmolality exceeded that of serum by 7 or more mmol/kg H2O. Discriminant analysis of the paired osmolar data showed that D = -117+1-74 X(CSF osmolality) -1-41 X (serum osmolality), and that severe neurological abnormality was predicted when D was positive.
PMCID: PMC1546236  PMID: 11753
11.  The Role of Blood Osmolality and Volume in Regulating Vasopressin Secretion in the Rat 
Journal of Clinical Investigation  1973;52(12):3212-3219.
A sensitive and specific radioimmunoassay for plasma arginine vasopressin (AVP) has been used to study the effects of blood osmolality and volume in regulating AVP secretion in unanesthetized rats. Under basal conditions, plasma AVP and osmolality were relatively constant, averaging 2.3±0.9 (SD) pg/ml and 294±1.4 mosmol/kg, respectively. Fluid restriction, which increased osmolality and decreased volume, resulted in a progressive rise in plasma AVP to about 10 times basal levels after 96 h. A 2-3-fold increase in plasma AVP occurred as early as 12 h, when osmolality and volume had each changed by less than 2%. Intraperitoneal injections of hypertonic saline, which had no effect on blood volume, also produced a rise in plasma AVP that was linearly correlated with the rise in osmolality (r > 0.9) and quantitatively similar to that found during fluid restriction (plasma AVP increased 2-4-fold with each 1% increase in osmolality). Intraperitoneal injection of polyethylene glycol, which decreased blood volume without altering osmolality, also increased plasma AVP but this response followed an exponential pattern and did not become significant until volume had decreased by 8% or more. At these levels of hypovolemia, the osmoregulatory system continued to function but showed a lower threshold and increase sensitivity to osmotic stimulation. We conclude that AVP secretion is regulated principally by blood osmolality but that the responsiveness of this mechanism may be significantly altered by modest changes in blood volume.
PMCID: PMC302597  PMID: 4750450
12.  Cerebral depression due to propylene glycol in a patient with chronic epilepsy--the value of the plasma osmolal gap in diagnosis. 
Postgraduate Medical Journal  1988;64(754):610-613.
A case of propylene glycol poisoning is described in a 39 year old woman which resulted in her admission to hospital in status epilepticus. She had had a long-standing history of uncontrollable epilepsy. The diagnosis of propylene glycol poisoning resulted directly from the finding of a high plasma osmolal gap on admission. This finding would have been missed if later samples only had been analysed. Plasma osmolality and the osmolal gap should be considered first line investigations in patients presenting with metabolic acidosis and cerebral signs and symptoms. Since her discharge from hospital a year ago the patient has had no further seizures.
PMCID: PMC2428931  PMID: 3249707
13.  Ethylene glycol ingestion treated only with fomepizole 
Journal of Medical Toxicology  2007;3(3):125-128.
Ethylene glycol is a widely used chemical that is capable of causing significant injury if ingested. Treatment for ethylene glycol poisoning typically includes basic supportive care, alcohol dehydrogenase inhibition, and hemodialysis. Recent data have suggested that hemodialysis may not be necessary for cases of ethylene glycol poisoning that can be treated with fomepizole as blocking therapy before acidosis or renal dysfunction develops.
Case Report
A 33-year-old man presented to the emergency department 1 hour after drinking approximately 1/2 gallon of ethylene glycol antifreeze and an unknown quantity of beer. On arrival he was mildly inebriated but otherwise displayed no other features of ethylene glycol poisoning. Fomepizole therapy was initiated and initial laboratory studies later revealed an osmol gap of 157 mOsm and an ethylene glycol concentration of 706 mg/dL. Nephrology and toxicology services were consulted. Over the next 3 days, fomepizole therapy was continued while the patient’s acid-base status and renal function were closely monitored. No evidence of acid-base abnormalities or renal impairment was ever observed and the patient was discharged to psychiatric care on the fourth hospital day.
This report describes the case of a patient who presented soon after a massive ingestion of ethylene glycol with very high serum concentrations. He was successfully treated using fomepizole and basic supportive care. Our patient developed neither renal insufficiency nor metabolic acidosis. His concomitant ethanol consumption, early presentation, and treatment likely contributed to his favorable outcome. This case report underscores the effectiveness of supportive care and fomepizole in the treatment of ethylene glycol poisoning.
PMCID: PMC3550067  PMID: 18072148
ethylene glycol; ingestion; fomepizole; poisoning; hemodialysis
14.  Halotolerance in Methanosarcina spp.: Role of N(sup(epsilon))-Acetyl-(beta)-Lysine, (alpha)-Glutamate, Glycine Betaine, and K(sup+) as Compatible Solutes for Osmotic Adaptation 
Applied and Environmental Microbiology  1995;61(12):4382-4388.
The methanogenic Archaea, like the Bacteria and Eucarya, possess several osmoregulatory strategies that enable them to adapt to osmotic changes in their environment. The physiological responses of Methanosarcina species to different osmotic pressures were studied in extracellular osmolalities ranging from 0.3 to 2.0 osmol/kg. Regardless of the isolation source, the maximum rate of growth for species from freshwater, sewage, and marine sources occurred in extracellular osmolalities between 0.62 and 1.0 osmol/kg and decreased to minimal detectable growth as the solute concentration approached 2.0 osmol/kg. The steady-state water-accessible volume of Methanosarcina thermophila showed a disproportionate decrease of 30% between 0.3 and 0.6 osmol/kg and then a linear decrease of 22% as the solute concentration in the media increased from 0.6 to 2.0 osmol/kg. The total intracellular K(sup+) ion concentration in M. thermophila increased from 0.12 to 0.5 mol/kg as the medium osmolality was raised from 0.3 to 1.0 osmol/kg and then remained above 0.4 mol/kg as extracellular osmolality was increased to 2.0 osmol/kg. Concurrent with K(sup+) accumulation, M. thermophila synthesized and accumulated (alpha)-glutamate as the predominant intracellular osmoprotectant in media containing up to 1.0 osmol of solute per kg. At medium osmolalities greater than 1.0 osmol/kg, the (alpha)-glutamate concentration leveled off and the zwitterionic (beta)-amino acid N(sup(epsilon))-acetyl-(beta)-lysine was synthesized, accumulating to an intracellular concentration exceeding 1.1 osmol/kg at an osmolality of 2.0 osmol/kg. When glycine betaine was added to culture medium, it caused partial repression of de novo (alpha)-glutamate and N(sup(epsilon))-acetyl-(beta)-lysine synthesis and was accumulated by the cell as the predominant compatible solute. The distribution and concentration of compatible solutes in eight strains representing five Methanosarcina spp. were similar to those found in M. thermophila grown in extracellular osmolalities of 0.3 and 2.0 osmol/kg. Results of this study demonstrate that the mechanism of halotolerance in Methanosarcina spp. involves the regulation of K(sup+), (alpha)-glutamate, N(sup(epsilon))-acetyl-(beta)-lysine, and glycine betaine accumulation in response to the osmotic effects of extracellular solute.
PMCID: PMC1388658  PMID: 16535193
15.  Role of antidiuretic hormone in the abnormal water diuresis of anterior hypopituitarism in man 
Journal of Clinical Investigation  1971;50(7):1478-1489.
To evaluate the role of antidiuretic hormone (ADH) in the defect in water excretion which is characteristic of glucocorticoid deficiency, the effects of hydrocortisone and ethanol upon urinary dilution during a sustained water load were studied in patients with anterior hypopituitarism. A spectrum of defects in urinary dilution was found in the seven patients with anterior hypopituitarism, and the subjects were separable into two groups. Four patients were unable to excrete a urine hypotonic to plasma (group I) while three diluted the urine (group II). In two of the group II patients, despite maintenance of hydration, urinary osmolality later rose to hypertonicity. Physiological doses of hydrocortisone improved urinary dilution in all patients. Submaximal doses of oral hydrocortisone, when given to the group I patients, converted their response to hydration to one characteristic of the group II patients, i.e., an initial hypotonic urine followed by a secondary rise to hypertonicity. Ethanol, a known inhibitor of ADH secretion, had no effect in the group I patients. When two of these patients were pretreated with sub-maximal doses of hydrocortisone, however, so that they were able to transiently dilute the urine, ethanol prevented the secondary rise in urine osmolality. Similarly, the administration of ethanol to the untreated group II patients, when the urine was hypotonic, improved diluting ability as characterized by a lowering of urinary osmolality and an increased excretion of solute-free water in all three patients. Hydrocortisone did not improve urinary dilution in three patients with complete hypophyseal diabetes insipidus and one with both anterior and posterior insufficiency receiving constant infusions of vasopressin. These data suggest, therefore, that inappropriately elevated levels of ADH play a major role in the defect in water excretion of anterior hypopituitarism. Glucocorticoids appear to be necessary for a normal neurohypophyseal response to inhibitory stimuli.
PMCID: PMC292088  PMID: 5090063
16.  Persistent lactic acidosis after chronic topical application of silver sulfadiazine in a pediatric burn patient: a review of the literature 
A 3-year old male who sustained 2nd and 3rd degree burns that covered approximately 60% TBSA presented to a large adult and pediatric verified burn center. On hospital day (HD) 26 of his stay, Candida fungemia was identified by blood culture, delaying operative management until HD 47. On HD 47, after his first operative intervention, the patient developed a persistent metabolic and lactic acidosis. On HD 66, a search for a cause of his osmol gap of 56 mOsm/kg revealed a potential source-propylene glycol. Previous studies have implicated the propylene glycol emulsifier in the silver sulfadiazine that was being applied to his skin as a rare cause of lactic acidosis in severely burned patients. Within 24 hours of stopping the silver sulfadiazine therapy, his lactic acidosis and osmol gap resolved; within 72 hours his metabolic acidosis resolved. Silver sulfadiazine is commonly used adjunct therapy in the treatment of 2nd and 3rd degree burns and generally has few adverse reactions. The absorption of propylene glycol systemically can rarely occur when applied to extensive burns, presumably due to the disruption of the skin barrier; the half-life of PG is 10 hours and can be prolonged with renal disease because ~50% of the sulfadiazine is excreted in the urine unchanged. When propylene glycol is present systemically, it is metabolized to lactic acid in the liver, which can cause a lactic acidosis. Several commonly used drugs also use propylene glycol as an emulsifier, including IV preparations of lorazepam, pentobarbital, phenobarbital, and phenytoin. In all of these clinical scenarios, including severe burn patients that are being treated with silver sulfadiazine, both lactic acid and propylene glycol levels should be measured to monitor for this rare, potentially serious co-morbidity.
PMCID: PMC3560485  PMID: 23386980
Burn; propylene glycol; silver sulfadiazine; metabolic acidosis; hyperosmolality
17.  Plasma osmolality predicts clinical outcome in patients with acute coronary syndrome undergoing percutaneous coronary intervention 
The impact of plasma osmolality on clinical outcome in acute coronary syndrome (ACS) patients has not been investigated so far.
In a retrospective analysis, we included 985 patients with ACS undergoing percutaneous coronary intervention (PCI). Plasma osmolality was calculated using concentrations of sodium, plasma glucose, and blood urea nitrogen at admission. Patients were stratified by quartiles (Q) of admission osmolality, clinical outcome was compared between those groups. The primary endpoints were in-hospital, 30-day, and 1-year mortality.
Univariate analysis in the Cox proportional-hazards model revealed significantly higher rates of in-hospital death for patients with osmolality in Q4, as compared to patients with osmolality in Q1–3 (HR 5.4, 95% CI 3.3–9.0, p<0.01). After adjustment for confounding baseline variables, osmolality in Q4 was associated with 2.8-fold hazard of in-hospital death (HR 2.75, 95% CI 1.35–5.61, p=0.005). Upon multivariate analysis, admission osmolality in Q4 vs. Q1–3 was associated with higher mortality rates after 30 days (HR 2.53, 95% CI 1.23–5.21, p=0.012) and 1 year (HR 1.73, 95% CI 1.02–2.91, p=0.04). Moreover, we performed landmark analysis in order to exclude critically ill patients, which revealed similar adjusted rates of death beyond 30 days to 1 year (HR 1.21, 95% CI 0.55–2.66, p=0.642).
Using the 4th quartile of plasma osmolality at admission as a natural cut-off point, osmolality in Q4, as compared to Q1–3, was significantly predictive of short term but not long-term outcome in ACS patients undergoing coronary stenting. Our data suggest osmolality to be an independent, feasible, and cost-effective tool for rapid risk stratification in ACS patients.
PMCID: PMC3932780  PMID: 24337920
Acute coronary syndrome; osmolality; risk stratification
18.  Qualitative and/or quantitative drinking water recommendations for pediatric obesity treatment 
The qualitative recommendation to ‘drink water instead of caloric beverages’ may facilitate pediatric obesity treatment by lowering total energy intake. The quantitative recommendation to ‘drink enough water to dilute urine’ might further facilitate weight loss by increasing fat oxidation via cell hydration-mediated changes in insulin.
This 8 week randomized intervention tested whether both qualitative-plus-quantitative (QQ) drinking water recommendations result in more weight loss than the qualitative recommendation alone (Q) in 25 children (9–12y) with body mass index at or above the 85th Percentile, given a reduced glycemic diet and usual physical activity. Random urine osmolality, saliva insulin, and body weight were assessed weekly. Mixed models explored if insulin mediated an effect of urine osmolality on weight loss.
In intention-to-treat analyses, QQ and Q participants did not differ significantly with respect to level of urine osmolality, saliva insulin, or weight loss. Only 4 out of 16 QQ participants complied with instruction to drink enough water to dilute urine, however. In completers analyses, the compliant QQ participants, who diluted urine osmolality from 910 ± 161 mmol/kg at baseline to below 500 mmol/kg over time (8 week mean±SE: 450 ± 67 mmol/kg), had significantly lower saliva insulin over time (8 week mean±SE: 13 ± 8 pmol/l vs. 22 ± 4 pmol/l) and greater weight loss (mean ± SE: −3.3 ± 0.7kg vs. −2.0 ± 0.5 kg) than compliant Q participants (7 out of 9 participants) who maintained elevated urine osmolality over time (8- week mean±SE: 888 ± 41 mmol/kg). Urine osmolality below 500 mmol/kg was significantly associated with weight loss. Change in saliva insulin partially explained the association.
QQ recommendations may increase weight loss for those able to dilute urine. Work is warranted to pursue cell hydration effects of drinking water for pediatric obesity treatment.
PMCID: PMC4306278  PMID: 25632375
Drinking water; Urine osmolality; Weight loss; Saliva insulin; Children; Adolescents
19.  Hypernatraemia due to a reset osmostat for vasopressin release and thirst, complicated by nephrogenic diabetes insipidus. 
Postgraduate Medical Journal  1987;63(745):979-982.
We describe a patient with chronic hypernatraemia (plasma sodium 148-155 mmol/l) and partial nephrogenic diabetes insipidus who had received prolonged lithium treatment. Despite stopping the drug for one year the abnormalities remained. Infusion of hypertonic saline (NaCl 855 mmol/l) allowed the characterization of osmoregulation of thirst and vasopressin secretion. Linear regression analysis of plasma vasopressin and osmolality defined the function, pAVP = 0.27 (pOsm - 301), and analysis of thirst measured by a visual analogue scale and plasma osmolality, the function, thirst = 0.16 (pOsm - 302) where pAVP and pOsm represent plasma arginine vasopressin and osmolality respectively. The slopes of the regression lines which describe the sensitivity of the osmoreceptors were within the normal range, but both abscissal intercepts, which define the thresholds for vasopressin release and thirst, were markedly elevated in comparison to normal (upper limit less than 290 mOsm/kg). Other investigations of electrolytes, anterior pituitary function and high definition computed tomographic scanning of hypothalamo-pituitary region were all normal. We conclude that this patient's chronic hypernatraemia was due to resetting of the osmostats for both vasopressin release and thirst, a rarely described mechanism to account for hypernatraemia. Although it is probable that the partial nephrogenic diabetes insipidus was related to prolonged lithium therapy, the cause of the reset osmostats remains unclear.
PMCID: PMC2428725  PMID: 3451225
20.  Plasma osmolality, sodium, and urea in healthy breast-fed and bottle-fed infants in Newcastle upon Tyne. 
Archives of Disease in Childhood  1975;50(9):731-734.
Dale, G., Goldfinch, M. E., Sibert, J. R., and Webb, J. K. G. (1975). Archives of Disease in childhood, 50, 731. Plasma osmolality, sodium, and urea in healthy breast-fed and bottle-fed infants in Newcastle upon Tyne. Plasma osmolality, sodium, and urea were measured on samples from 50 healthy infants, aged between 18 and 125 days, attending child health clinics in Newcastle upon Tyne. 3 infants had osmolalities greater than 300 mOsm/kg, a lower incidence of hyperosmolality than that previously reported. There was a difference (P less than 0-001) between the plasma urea levels of breast-fed and bottle-fed infants, but not between the osmolalities of these groups. The mean plasma urea of bottle-fed babies was 53 mg/100 ml (SD 12-47), 50-1 mg/100 ml (SD 10-9) if additional solids were being given, and 18-4 mg/100 ml (SD 7-81) for breast-fed babies. There was little difference between the plasma sodium levels of each group. The mean plasma sodium for all groups combined was 135-2 mmol/1 (SD 2-3); no plasma sodium exceeded 140 mmol/1.
PMCID: PMC1545619  PMID: 1190823
21.  CSF sub-compartments in relation to plasma osmolality in healthy controls and in patients with first episode schizophrenia 
Psychiatry Research  2007;155(1):57-66.
Preliminary evidence suggests that plasma Na+ level/osmolality may have effects on brain morphology; thus we investigated the link between plasma osmolality and ventricle size in healthy controls and patients with first episode schizophrenia. A total of 16 patients and 28 healthy controls were examined with magnetic resonance imaging (MRI) and gave blood samples. High-resolution 3D SPGR images were obtained on a 1.5 Tesla scanner. Scalp-edited MRI volumes were used for estimates of intracranial gray, white matter and CSF. Regional changes in CSF concentration and ventricular morphology were measured. The groups did not differ in plasma osmolality, but patients had higher plasma Na+. There were no differences in ventricle size. Controlling for plasma osmolality did not change the results. A mixed model procedure indicated a significant group effect and a significant osmolality by group interaction in ventricle measures. Healthy control group showed a significant relationship between osmolality and ventricle measures; this relationship was absent in the patients. Significant correlations between osmolality and lateral ventricle surface deformations were observed along the superior horn of the lateral ventricles in the healthy controls. These results suggest that plasma osmolality is related to ventricle size in healthy volunteers and that this physiological link is impaired in patients with first episode schizophrenia.
PMCID: PMC3299193  PMID: 17398079
MRI; Osmolality; Lateral ventricle; Healthy control; Schizophrenia
22.  Urine Concentrating Ability in Infants with Sickle Cell Disease: Baseline Data from the Phase III Trial of Hydroxyurea (BABY HUG) 
Pediatric blood & cancer  2010;54(2):265-268.
A urine concentrating defect is quite common in sickle cell anemia, has its onset in early childhood, and may be reversible with transfusion. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is a double-blind, placebo-controlled trial to assess efficacy of hydroxyurea in preventing organ damage in young children with sickle cell anemia.
Enrolled infants were subjected to parent-supervised fluid deprivation and urine and serum osmolality were determined.
Of 185 infants age 7.5 – 17.9 months (mean 13.0+/-2.7) and fluid-deprived 7.4+/-2.4 hours (range 4-13), 178 had concurrent determinations of urine and serum osmolality. Mean serum osmolality was 286+/-6 mOsm/kg H2O (range 275-312) and independent of age, height, weight, or duration of fluid deprivation. Urine osmolality (mean 407+/-151, range 58-794 mOsm/ kg H2O) was greater than serum (p<0.0001) and correlated with duration of fluid deprivation (p=0.001). Of 142 (77.2%) who concentrated urine, 54 (29.4%) had urine osmolality > 500 mOsm/kg H2O. Urine osmolality correlated with 99mTc-DTPA clearance (p=0.02) and serum urea nitrogen (p<0.0001), but not with serum osmolality, gender, age, height, weight or serum creatinine. Infants able to produce urine with osmolality > 500 mOsm/kg H2O had higher mean fetal hemoglobin concentrations than did those who could not (p=0.014).
Even with often limited fluid deprivation, 77.2 percent of young infants with sickle cell anemia were able to concentrate urine. Preservation of concentrating ability was associated with higher fetal hemoglobin concentration. Assessment will be repeated after two years of hydroxyurea or placebo treatment. ( number, NCT00006400.)
PMCID: PMC2795020  PMID: 19621454
nephropathy; urine osmolality; isosthenuria; hyposthenuria
23.  Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone—A Viable Therapeutic Option 
Journal of Medical Toxicology  2010;6(2):131-134.
Fomepizole is used to treat and prevent toxicity from ethylene glycol poisoning. Treatment with fomepizole without hemodialysis in massive ethylene glycol ingestion has been rarely reported in the literature; however, published literature and practice guidelines recommend considering dialysis for ethylene glycol levels >50 mg/dL. We report a case of massive ethylene glycol ingestion resulting in the highest serum ethylene glycol concentration in a patient without ethanol co-ingestion who was treated with fomepizole and was not hemodialyzed. A 48-year-old male presented to the emergency department after reportedly ingesting >1liter of antifreeze in an attempt at self-harm. He denied concomitant ethanol consumption. His initial presenting serum ethylene glycol level was 700 mg/dL, with normal renal function, and a metabolic acidosis with a high anion gap. One hour after presentation, he was started on intravenous fomepizole. Treatment with fomepizole continued until the patient's plasma ethylene glycol concentration was 16 mg/dL. His metabolic acidosis quickly resolved, he had no adverse reactions to the treatment, and his renal function remained normal. Ultimately, he was discharged to a psychiatric unit without sequelae. Published literature and practice guidelines suggests considering hemodialysis initiation in patients with an ethylene glycol level >50 mg/dL. This recommendation is anecdotally, rather than evidence, based. With the potential risks inherent in hemodialysis, our case provides evidence that treatment with fomepizole without hemodialysis appears to be a viable alternative option in patients with even extremely high plasma ethylene glycol concentrations as long as their renal function is intact.
PMCID: PMC3550287  PMID: 20422336
Ethylene glycol; Fomepizole; Hemodialysis; Overdose
24.  The hyponatremic patient: a systematic approach to laboratory diagnosis 
HYPONATREMIA (SERUM SODIUM LEVEL LESS THAN 134 MMOL/L) is a common electrolyte disturbance. Its high prevalence and potential neurologic sequelae make a logical and rigorous differential diagnosis mandatory before any therapeutic intervention. A history of concurrent illness and medication use as well as the assessment of extracellular volume status on physical examination may provide useful clues as to the pathogenesis of hyponatremia. Measurement of the effective serum tonicity (serum osmolality less serum urea level) is the first step in the laboratory evaluation. In patients with normal or elevated effective serum osmolality (280 mOsm/kg or greater), pseudohyponatremia should be excluded. In the hypo-osmolar state (serum osmolality less than 280 mOsm/kg), urine osmolality is used to determine whether water excretion is normal or impaired. A urine osmolality value of less than 100 mOsm/kg indicates complete and appropriate suppression of antidiuretic hormone secretion. A urine sodium level less than 20 mmol/L is indicative of hypovolemia, whereas a level greater than 40 mmol/L is suggestive of the syndrome of inappropriate antidiuretic hormone secretion. Levels of hormones (thyroid-stimulating hormone and cortisol) and arterial blood gases should be determined in difficult cases of hyponatremia.
PMCID: PMC100882  PMID: 12002984
25.  Changes in Drug Utilization during a Gap in Insurance Coverage: An Examination of the Medicare Part D Coverage Gap 
PLoS Medicine  2011;8(8):e1001075.
Jennifer Polinski and colleagues estimated the effect of the "coverage gap" during which US Medicare beneficiaries are fully responsible for drug costs and found that the gap was associated with a doubling in discontinuing essential medications.
Nations are struggling to expand access to essential medications while curbing rising health and drug spending. While the US government's Medicare Part D drug insurance benefit expanded elderly citizens' access to drugs, it also includes a controversial period called the “coverage gap” during which beneficiaries are fully responsible for drug costs. We examined the impact of entering the coverage gap on drug discontinuation, switching to another drug for the same indication, and drug adherence. While increased discontinuation of and adherence to essential medications is a regrettable response, increased switching to less expensive but therapeutically interchangeable medications is a positive response to minimize costs.
Methods and Findings
We followed 663,850 Medicare beneficiaries enrolled in Part D or retiree drug plans with prescription and health claims in 2006 and/or 2007 to determine who reached the gap spending threshold, n = 217,131 (33%). In multivariate Cox proportional hazards models, we compared drug discontinuation and switching rates in selected drug classes after reaching the threshold between all 1,993 who had no financial assistance during the coverage gap (exposed) versus 9,965 multivariate propensity score-matched comparators with financial assistance (unexposed). Multivariate logistic regressions compared drug adherence (≤80% versus >80% of days covered). Beneficiaries reached the gap spending threshold on average 222 d ±79. At the drug level, exposed beneficiaries were twice as likely to discontinue (hazard ratio [HR]  = 2.00, 95% confidence interval [CI] 1.64–2.43) but less likely to switch a drug (HR  = 0.60, 0.46–0.78) after reaching the threshold. Gap-exposed beneficiaries were slightly more likely to have reduced adherence (OR  = 1.07, 0.98–1.18).
A lack of financial assistance after reaching the gap spending threshold was associated with a doubling in discontinuing essential medications but not switching drugs in 2006 and 2007. Blunt cost-containment features such as the coverage gap have an adverse impact on drug utilization that may conceivably affect health outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, more effective drugs for more diseases become available. But the availability of so many drugs poses a problem. How can governments provide their citizens with access to essential medications but control drug costs? Many different approaches have been tried, among them the “coverage gap” or “donut hole” approach that the US government has incorporated into its Medicare program. Medicare is the US government's health insurance program for people aged 65 or older and for younger people with specific conditions. Nearly 50 million US citizens are enrolled in Medicare. In 2006, the government introduced a prescription drug insurance benefit called Medicare Part D to help patients pay for their drugs. Until recently, beneficiaries of this scheme had to pay all their drug costs after their drug spending reached an initial threshold in any calendar year ($2,830 in 2010). Beneficiaries remained in this coverage gap (although people on low incomes received subsidies to help them pay for their drugs) until their out-of-pocket spending reached a catastrophic coverage spending threshold ($4,550 in 2010) or a new year started, after which the Part D benefit paid for most drug costs. Importantly, the 2010 US health reforms have mandated a gradual reduction in the amount that Medicare Part D enrollees have to pay for their prescriptions when they reach the coverage gap.
Why Was This Study Done?
Three to four million Medicare Part D beneficiaries reach the coverage gap every year (nearly 15% of all Part D beneficiaries). Supporters of the coverage gap concept argue that withdrawal of benefits increases beneficiaries' awareness of medication costs and encourages switching to cost-effective therapeutic options. However, critics argue that the coverage gap is likely to lead to decreased drug utilization, increased use of health services, and adverse outcomes. In this study, the researchers examine the impact of entering the coverage gap on drug discontinuation, switching to another drug for the same indication, and drug adherence (whether patients take their prescribed drugs regularly).
What Did the Researchers Do and Find?
The researchers studied 663,850 Medicare beneficiaries enrolled in Part D or in retiree drug plans (which provide coverage under a employer's group health plan after retirement; the retiree drug plans included in this study did not have coverage gaps) who made prescription claims in 2006 and/or 2007. A third of these individuals reached the gap spending threshold. The researchers used detailed statistical analyses to compare the drug discontinuation, switching, and adherence rates of 1,993 beneficiaries who had no financial assistance during the coverage gap (exposed beneficiaries) with those of 9,965 matched beneficiaries who had financial assistance during the coverage gap (unexposed). On average, beneficiaries reached the gap spending threshold 222 days into the year (mid August). In a drug-level analysis, exposed beneficiaries were twice as likely to discontinue a drug and slightly more likely to have reduced drug adherence than unexposed beneficiaries but 40% less likely to switch a drug after reaching the threshold. Similar results were obtained in a beneficiary-level analysis in which discontinuation, switching, and adherence rates were considered in terms of the complete drug regimen of individual beneficiaries.
What Do These Findings Mean?
These findings show that, among the Medicare beneficiaries investigated, a lack of financial assistance to pay for drugs after reaching the coverage gap spending threshold led to a doubling in the rate of drug discontinuation and a slight reduction in drug adherence. Surprisingly, lack of financial assistance resulted in a decrease in drug switching even though the Centers for Medicare and Medicaid Services advise patients to consider switching to generic or low-cost drugs. Importantly, the researchers estimate that, for the whole Medicare population, the lack of financial assistance to pay for drugs could result in an additional 18,000 patients discontinuing one or more prescription drug per year. Although this study did not directly investigate the effect of the coverage gap on patient outcomes, these findings suggest that this and other blunt cost-containment approaches could adversely affect health outcomes through their effects on drug utilization. Thus, insurance strategies that specifically promote the use of drugs with high benefit but low cost might be a better approach for governments seeking to improve the health of their citizens while reining in drug costs.
Additional Information
Please access these websites via the online version of this summary at
The US Department of Health and Human Services Centers for Medicare and Medicaid provides information on all aspects of Medicare, including general advice on bridging the coverage gap and an information sheet on bridging the coverage gap in 2011, the official US government website for Medicare, provides information on all aspects of Medicare (in English and Spanish), including a description of Part D prescription drug coverage
An information sheet from the Kaiser Family Foundation explains the key changes to the Medicare Part D drug benefit coverage gap that were introduced in the 2010 health care reforms
MedlinePlus provides links to further information about Medicare (in English and Spanish)
PMCID: PMC3156689  PMID: 21857811

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