Negative Anion Gap Research Articles

A case report of elevated bromide levels from pyridostigmine bromide for treatment of myasthenia gravis.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Elevated serum bromide levels can cause dermatological, gastrointestinal, and neurological abnormalities. As bromide and chloride are both halogens, bromide may interfere with chloride assays, causing a falsely high serum chloride concentration and a low or negative anion gap. There is a paucity of data describing bromide toxicity from high doses of pyridostigmine bromide (PB). This case report describes a patient with an elevated bromide level with neurological symptoms from a therapeutic dose of PB. A 37-year-old male with myasthenia gravis secondary to type B2 thymoma status following thymectomy presented in myasthenic crisis. He required mechanical ventilation and was managed with steroids, intravenous immune globulin, plasmapheresis, and PB. On day 9, the patient experienced acute agitation. He had an anion gap of 2 mEq/L and a chloride concentration of 109 mEq/L. The plasma creatinine concentration was 0.63 to 1.15mg/dL and urine output was 0.76 to 1.79mL/kg/h throughout his admission. All other laboratory values were normal. The daily dose of PB was 660mg on day 9, but the patient received 76mg of intravenous PB over the first few days of his admission with the largest dose in 24 hours equal to 48mg. On day 10, the patient's bromide level was 37 μg/mL. His agitation was initially managed with quetiapine, followed by PB dose reduction. To our knowledge, there are 2 cases in the literature of bromide toxicity secondary to PB. These patients experienced neurological symptoms with bromide levels of 88 to 90 μg/mL. Bromide concentrations of more than 12 μg/mL are associated with a higher risk of neuronal dysfunction demonstrated as disturbances on an electroencephalogram, and levels greater than 50 μg/mL are considered toxic. While our patient's bromide level was not as high as those previously reported, no other causes for his agitation were identified. Elevated bromide levels from therapeutic PB can occur, and monitoring of these levels should be considered.

Close the gap

Background: Serum chloride (Cl-) is measured via direct or indirect ion selective electrodes in most laboratories. There have been reports of falsely elevated Cl- concentrations and a resultant negative anion gap due to interference from drugs containing bromide, which is a negatively charged halide, similar to Cl-.1,2 Case: A 1-year-old girl with severe, treatment resistant epilepsy presented for routine bloods. Her medication history included multiple anti-epileptics including phenobarbitone, clobazam, topiramate, vigabatrin, and also potassium bromide. No abnormality was found on full blood count, thyroid functions tests, liver and kidney function tests apart from a mildly elevated GGT of 30 U/L (RI 5–20 U/L). The anion gap was negative as Cl- was repeatedly unmeasurably high (>150 mmol/L), with the remainder of the electrolytes within normal limits. Review of her medication history prompted the possibility of bromide interference. We measured Cl- and bromide via ICP-MS: Cl- was 69 mmol/L and bromide markedly elevated at 35 mmol/L. Conclusion: Bromide-containing medications can cause a negative anion gap as a result of a falsely elevated chloride concentration. When this is suspected, measurement of chloride via a method different to ISE should be considered.

Bromide intoxication in a 3‐year‐old Thoroughbred filly

Summary A 3‐year‐old Thoroughbred filly presented with a several‐month history of weight loss, polydipsia and polyuria, intermittent diarrhoea and behavioural changes and intermittently uncoordinated gait. Neurological examination revealed hyperexcitability, bilaterally reduced pupillary light reflexes and quadrilateral ataxia with proprioceptive deficits more obvious in the forelimbs than in the hindlimbs. A multifocal neurological lesion was suspected. The laboratory finding of a persistent hyperchloraemia and an apparent negative anion gap prompted measurement of serum bromide concentration and subsequently confirmed bromide intoxication. Further questioning of the trainer revealed that the filly had been administered oral potassium bromide for behavioural modification over several months. Clinical signs of bromide intoxication resolved within 20 days following the last bromide administration, without specific medical intervention. This case report describes the risk of inadvertent bromide overdosing in horses and highlights the need for control of bromide use in the equine industry.

Frequency and Clinical Significance of Negative Anion Gap Values in an Academic Medical Center Population

Abstract Anion gap is a value calculated by determining the difference between major plasma cations (sodium, sometimes additionally potassium) and anions (namely bicarbonate and chloride), with “normal” levels falling somewhere between 8 and 16 mEq/L. Elevations in anion gap are classically described in a variety of different clinical disease states, including but not limited to uremia, ketoacidoses, lactic acidosis, and a number of drug toxicities. Comparatively little is understood about the etiology of low and negative (<0) anion gap measurements; however, certain patient populations and pathologic states have been associated with negative anion gap measurements, such as multiple myeloma and hypertriglyceridemia (Kraut, 2007). We reviewed laboratory chemistries for 340,354 pediatric and adult patients over a ten-year period (2009-2018). Laboratory testing included values from basic and comprehensive metabolic panels and blood gas analyses. Chart review was performed on adult patients with anion gaps measuring less than 0 mEq/L to assess for medical trends or other explanations such as analytical interference or data errors. Additionally, blood gas analyses from patients being cared for in the neonatal intensive care unit (NICU) over the same ten-year period were also reviewed. Of the adult patients, 0.046% (157 samples) had an anion gap measuring below 0 mEq/L. Samples obtained as part of a blood gas analysis made up 52% of all negative gaps. While no definitive trends were noted, 23 samples were noted to be from patients with history of malignancy (solid tumor and hematopoietic), including multiple myeloma (4 patients).[mkrasows1] In addition to malignancy, 17 patients with hypertriglyceridemia were also found to have negative anion gaps. Negative anion gaps were rare in outpatient populations. Negative anion gaps as a result of a laboratory error were also rare, constituting only 1.3% of cases (2 patients). Negative anion gaps were comparatively more common in the NICU population, with 983 patients having a negative anion gap[mkrasows2] (0.289 %). NICU patients constituted 91% of all blood gas analyses with a negative anion gap, demonstrating that negative anion gaps are much more prevalent in this patient population than they are in other pediatric and adult populations. Negative anion gaps are relatively rare occurrences in the adult outpatient population; however, they can be seen in association with certain underlying disease states such as malignancy. By comparison, negative anion gaps are much more common in critically-ill populations, most notably NICU patients.

Pseudohyperchloremia and Negative Anion Gap – Think Salicylate!

BackgroundPseudohyperchloremia 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. MethodsThe 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. ResultsCl-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.” ConclusionsSalicylate 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.

A Negative Anion Gap with a Positive Outcome

A Negative Anion Gap with a Positive Outcome

Spurious Hyperchloremia in the Presence of Elevated Plasma Salicylate: A Cohort Study

Background: Acute metabolic acidosis is rarely associated with a reduced or negative anion gap (AG), but several case reports have described such an abnormality occurring in the setting of acute salicylate intoxication. The underlying cause of this phenomenon is unclear. Methods: In this retrospective cohort study, we reviewed our institutional database to identify all patients admitted for salicylate intoxication at Mayo Clinic (Rochester, MN, USA) from January 2010 through December 2012. Serum chloride was measured with the Cobas INTEGRA 400 plus electrode (expedited laboratory test) or Cobas 6000 (routine laboratory test). We compared blood chloride levels measured by the 2 devices in the presence of positive blood salicylate level. Results: Twelve adult patients with salicylate levels >20 mg/dL had markedly elevated chloride concentrations. The median (interquartile range) chloride level at admission was 120 (107–145) mmol/L on their initial laboratory studies, resulting in reduced or even negative AGs. None of the patients had bromide toxicity, nor did they have any other identifiable cause of hyperchloremia or decreased AG. Further testing of the same blood samples with an alternative measurement system (Roche Cobas 6000) yielded normal chloride values, indicating that falsely elevated chloride values with the initial testing led to the diminished or negative AG values. Conclusion: Circulating levels of salicylate can interfere with chloride measured by using routine techniques, resulting in spurious hyperchloremia outcomes and erroneous AG values. In patients with acute metabolic acidosis and abnormally reduced or negative AG, salicylate interference with chloride measurement should be suspected.

An Unusual Case of Negative Anion Gap in a Patient with Hypercalcemia

An Unusual Case of Negative Anion Gap in a Patient with Hypercalcemia

Spurious Hyperchloremia and Negative Anion Gap in a Child with Refractory Epilepsy.

We report a case with spurious hyperchloremia with negative anion gap in a child who was taking potassium bromide for refractory epilepsy. Blood chemistry showed a high chloride level (171 mEq/L) and a negative anion gap (−52 mEq/L). Plasma chloride concentration is measured by an ion-selective electrode method; however the presence of other anions like bromide and iodides can interfere with chloride level and largely overestimates the chloride concentration. Thus hyperchloremia with a negative anion gap is a clue to the diagnosis of halides like bromide and iodide ingestion.

Poisoning from alcohol based hand sanitizer in a hospitalized patient

Introduction: Alcohol based hand sanitizers help to decrease infection rates in hospitals. They contain isopropanol (isopropyl alcohol) or ethanol (ethyl alcohol) in high concentrations, and are easily accessible to patients and staff in health care settings. Case Report: A 31-year-old female with history of alcohol abuse, seizure disorder and depression presented with symptoms of alcohol intoxication. Initial laboratory results were normal except an ethanol level of 311 mg/dl. She was admitted to the detoxification unit for ethyl alcohol intoxication. It was noted by the staff that she was trying to drink from the wall mounted hand sanitizers and was also seen sucking on alcohol wipes intermittently. On the third day in the detoxification unit, she was found to have lethargy, disorientation, tachycardia, hypotension, and tachypnea. She was given intravenous fluids and intubated for airway protection and transferred to intensive care unit. Laboratory tests showed normal pH, negative anion gap, normal glucose, large serum ketone, measured serum osmolality 340 mOsm/kg, osmolal gap 53 mOsm/kg, ethanol 13 mg/dl. She was treated for supraventricular arrhythmia, aspiration pneumonia. She did not require hemodialysis as acute kidney injury was mild, and osmolal gap and ketones came down with supportive care. Subsequently, she was extubated and recovered completely. Conclusion: Alcohol based hand sanitizers should be used carefully under surveillance in detoxification and psychiatric units. Poisoning due to isopropanol can be managed effectively if recognized early. Elevated osmolal gap, absence of acidosis, and positive ketones are important clues which help in diagnosing isopropanol poisoning. (This page in not part of the published article.) International Journal of Case Reports and Images, Vol. 7 No. 1, January 2016. ISSN – [0976-3198] Int J Case Rep Images 2016;7(1):40–42. www.ijcasereportsandimages.com Katikaneni et al. 40 CASE REPORT OPEN ACCESS Poisoning from alcohol based hand sanitizer in a hospitalized patient Madhavi Katikaneni, Hugo Villanueva

Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives.

Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10-year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides.

A Case of Salicylate-Intoxication-Induced Pseudohyperchloremia

Despite the increasing use of alternative analgesic agents, salicylate overdose remains a not-uncommon problem. Severe poisoning is life threatening, so prompt treatment and supportive measures are required to reduce mortality. Generally, salicylate intoxication results in the development of high-anion-gap metabolic acidosis. However, outside of Korea, normal-anion-gap or negative-anion-gap metabolic acidosis with hyperchloremia is rarely reported. We report herein the case of an 83-year-old female patient with chronic aspirin intake who presented with hyperchloremia and a negative anion gap. The patient’s symptoms improved with conservative treatment and hemodialysis; notably, her chloride levels decreased as her blood salicylate concentrations decreased. Salicylate may cause hyperchloremia, demonstrating the importance of careful documentation of patient medication histories. (Korean J Med 2015;89:457-460)

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.

Bromoderma caused by over‐the‐counter analgesic mimicking pyoderma gangrenosum

A 41-year-old Japanese woman was admitted to the emergency department of our hospital due to a seizure. She had been diagnosed with pyoderma gangrenosum 11 years ago without bone marrow disease, rheumatoid arthritis, or inflammatory bowel disease. Pyoderma with painful ulcers had repeatedly appeared on the arms, legs, face, and pubic arch despite treatment with systemic prednisolone and cyclosporine. She also had frequently complained about syncopal episodes, however, there was no evidence of neurological diseases, including epilepsy and endocrine diseases. On admission, the blood test revealed a negative anion gap, hyperchloremia, and neutrophilic leukocytosis. Since one of the major causes of negative anion gaps with hyperchloremia is bromide intoxication, we measured the serum bromide level and found that it was significantly high at 21 mg/dl. Bromide is not normaly detectable in healthy indivisuals. Furthermore, 296 empty sheets of over-the-counter(O-T-C) analgesic tablets containing bromide (Naronace: O-T-C analgesic in Japan, contain bromovalerylurea 100 mg/ tablet) were found in her house, suggesting that she had bromide intoxication. Repeated syncopal episodes may have been due to this intoxication. These findings forced us to reconsider the diagnosis of pyoderma gangrenosum in this case, because bromide causes the same clinical symptoms as pyoderma. In addition, we realized neutrophilic leukocytosis and hyperchloremia had been associated with exacerbation of the clinical symptoms for 11 years. Therefore, we examined the bromide level of the serum samples collected from the past 10 years and found that the bromide level had been as high as 112.7 mg/dl. In conclusion, we diagnosed this case with bromoderma caused by O-T-C analgesic mimicking pyoderma gangrenosum. After the patient stop taking the analgesic, the pyoderma rapidly disappeared, and the white blood cell count and the serum chloride level returned to normal levels, with no recurrence, even after the discontinuation of prednisolone and cyclosporine.

What is your diagnosis? Increased total CO2 concentration and negative anion gap in a foal

What is your diagnosis? Increased total CO₂ concentration and negative anion gap in a foal

Case files of the medical toxicology fellowship at the New York City Poison Control: Bromism: Forgotten, but not gone

After an extensive literature review, this appears to be the first case documenting bromide toxicity in a patient exposed to the product called Cordial de Monell, which contains potassium bromide. We have identified this product on store shelves in areas of New York City. We believe this child suffered from excess therapeutic sedative exposure due to her size, age, and repeated exposure. Bromism is not nearly as common as it once was, but several forms of bromide are still readily available. This diagnosis should be included in the differential diagnosis of patients who present with sedative-hypnotic-type intoxication. Elevations in the reported serum chloride levels and a negative anion gap are helpful findings if present, but our case and others before confirm that the lack of these features do not rule out this poisoning. This case further illustrates the need for clinicians to be diligent in obtaining thorough medication, dietary, herbal supplement, social, occupational, and cultural histories from their patients. Aggressive hydration with chloride-containing solutions is the cornerstone of treatment, and in severe cases dialysis may be considered. Bromides are not gone, and bromism should not be forgotten.

Bromism caused by mix-formulated analgesic injectables

Bromism, chronic bromide intoxication, can be caused by a variety of medicines, but bromism due to pain-relieving injectable medications has not been reported. In this study, the methods used were internet searching on bromide-containing injectables available in Taiwan and the first case report of bromism due to mixed-formulated injectable medication. Many analgesic/antipyretic and antihistamine injections containing bromides are still being used in Taiwan. They contain sodium bromide up to 1000 mg/ampoule or calcium bromide up to 800 mg/amp. A 25-year-old female suffered from forgetfulness and unstable gait after long-term frequent injections of a preparation to relieve head and neck pain. Blood tests showed hyperchloremia (171 mEq/L) and a negative anion gap (-48.7 mEq/L). Serum bromide measured 2150 mg/L. She recovered completely in 3 days with saline treatment. Many bromide-containing injections are still being used in Taiwan. Clinicians should keep alert on this issue to avoid iatrogenic bromism or making misdiagnoses.

Lactate and the osmolar gap

Although the teaching case report in the March 27 issue on a negative anion gap and elevated osmolar gap resulting from lithium overdose[1][1] is interesting, I identified the following concern. In the third paragraph from the end of the report, the authors listed lactate as one of the potential

Negative anion gap and elevated osmolar gap due to lithium overdose

The case: A 65-year-old man was found in a state of clouded consciousness of unknown duration. At hospital his Glasgow Coma Scale score was 9. Naloxone and thiamine were administered. A CT head scan showed no acute injury. The serum anion gap was 1 mmol/L, and the osmolar gap 12.8 mOsmol/kg ([Table

Acid-Base and Potassium Disorders in Liver Disease

Acid-base and potassium disorders occur frequently in the setting of liver disease. As the liver's metabolic function worsens, particularly in the setting of renal dysfunction, hemodynamic compromise, and hepatic encephalopathy, acid-base disorders ensue. The most common acid-base disorder is respiratory alkalosis. Metabolic acidosis alone or in combination with respiratory alkalosis also is common. Acid-base disorders in patients with liver disease are complex. The urine anion gap may help to distinguish between chronic respiratory alkalosis and hyperchloremic metabolic acidosis when a blood gas is not available. A negative urine anion gap helps to rule out chronic respiratory alkalosis. In this disorder a positive urine anion gap is expected owing to suppressed urinary acidification. Distal renal tubular acidosis occurs in autoimmune liver disease such as primary biliary cirrhosis, but often is a functional defect from impaired distal sodium delivery. Potassium disorders are often the result of the therapies used to treat advanced liver disease.