The classic triad of findings in rhabdomyolysis is muscle pain, weakness, and dark urine. Patients with rhabdomyolysis usually have some combination of highly elevated creatine kinase, myoglobinuria, hyperkalemia, hyperphosphatemia, acute kidney injury, hypocalcemia, and metabolic acidosis with or without an anion gap.In this patient’s case, there was no clear inciting event, and her symptoms were episodic with spontaneous resolution. Additionally, she did not complain of focal pain or weakness as would be expected in compartment syndrome. Although she did have an elevated creatine kinase, the elevation was not significant and the expected laboratory findings of hyperkalemia and hyperphosphatemia were not present. I felt that compartment syndrome and rhabdomyolysis were unlikely. In this young adult patient with episodic weakness and hypokalemia, hypokalemic periodic paralysis was immediately considered as part of the differential diagnosis. This condition is characterized by attacks of weakness with a normal neurologic exam in between, as seen in this patient. Primary hypokalemic periodic paralysis follows an autosomal dominant inheritance pattern, and notably this patient had no known family history of the same. Bulbar and respiratory functions are preserved and between attacks, patients will also present with normal plasma potassium. Triggers include stress, exercise, and carbohydrates. The condition also presents with arrhythmias.There are, however, other conditions that can cause non-familial hypokalemic paralysis, including RTA.All three sub-types of RTA are characterized by an inability to acidify the urine. As a result of this, RTAs present with an increased urine anion gap, but this information was not provided in the case history. In distal or type 1 RTA,pipp grow racks there is impaired hydrogen ion secretion in the distal tubule of the nephron. In proximal or type 2 RTA, there is impaired bicarbonate reabsorption in the proximal tubule of the nephron. In type 4 RTA, there is decreased aldosterone secretion or aldosterone resistance.
As a result of this, type 4 RTA is associated with serum hyperkalemia while the other two types of RTA result in hypokalemia.8 Due to the serum potassium levels, which were not suggestive of aldosterone resistance, I eliminated type 4 RTA from my list of possibilities. The types of hypokalemic RTAs are differentiated by examining the potential of hydrogen of the patient’s urine. In type 2 RTA, urine pH is initially high, then decreases to < 5.5. The urine pH remains above 5.5 in type 1 RTA.This patient had a urine pH of 7.0, suggesting either a type 1 RTA or an early type 2 RTA. Type 1 RTA can be hereditary or be caused by autoimmune diseases such as Sjögren’s syndrome, or as a complication of chemotherapy or toluene use. The causes of type 2 RTA include genetic abnormalities, Fanconi syndrome, monoclonal gammopathy, and carbonic anhydrase inhibitor use.There was no mention of chemotherapy or carbonic anhydrase inhibitors with the patient’s presentation. The patient had no family history of similar issues, and it would stand to reason that a genetic abnormality would have come to light before age 19 years. As such, I feel type 1 RTA is more likely than type 2 RTA. The Agency for Toxic Substances and Disease Registry notes that toluene is a solvent found in paints, nail polish, paint thinners, and adhesives, among other substances. It can have toxic effects if ingested or inhaled.The findings of acute toluene use include a hypokalemic paralysis and a metabolic acidosis. Patients are also often found to have liver injury and rhabdomyolysis, and may present with altered mentation, renal failure, and acidemia.This patient’s presentation is most consistent with type 1 RTA due to toluene use. She denied any illicit drug use but did admit to a history of alcohol ingestion and marijuana use, raising the question of whether there could be toxic alcohols or other coingestions. Unfortunately, there is no diagnostic test for toluene use. However, proximal and distal RTA can be differentiated by calculating the urinary ammonium ion concentration from the measured urine anion gap and osmolar gap. Therefore, my test of choice would be a urine electrolyte panel to calculate the anion gap and osmolar gap.
Additionally, I would consult nephrology to assist in management of this patient.The patient developed bigeminy while in the ED but remained hemodynamically stable and did not have a change in her mental status. Her electrolytes were replaced with oral and intravenous potassium, with improvement of her arrythmia and symptoms. She declined central line placement for more rapid replacement. The patient was admitted to the pediatric intensive care unit for further management and evaluation. Nephrology was consulted because these results demonstrated an elevated urine anion gap suggestive of RTA. The patient’s symptoms completely resolved once her electrolytes were repleted. She was found to have positive antinuclear and anti–Sjögren’s-syndrome-related antigen A autoantibodies, leading to the diagnosis of Sjögren’s syndrome, despite a lack of phenotypic features. The patient’s urine anion gap was indeterminate for the etiology of her non-anion gap metabolic acidosis; however, her urine osmolar gap of less than 150 milliosmoles per kilogram suggested type 1 or type 4 RTA as the etiology. This coupled with laboratory findings suggestive of autoimmune disease led to the diagnosis of type 1 RTA. Her RTA was treated with potassium supplementation and alkali therapy to achieve a normal serum bicarbonate concentration. Unfortunately, the patient has not been compliant with her home therapy and has required multiple hospitalizations since her original presentation. Her presentation and urine anion gap strongly suggest toluene toxicity, but the patient repeatedly denied insufflating glue and there is no diagnostic test for toluene.Hyperchloremic, hypokalemic metabolic acidosis is a condition all emergency providers should be prepared to diagnose and manage. In this case, the patient presented with a cardiac arrhythmia due to severe hypokalemia. The underlying etiology of the hypokalemia should be sought while simultaneously treating the condition. The initial ED evaluation includes obtaining a basic metabolic panel and a urinalysis. Once it is determined that the patient does not have a serum anion gap, the clinician should consider three broad categories of non-anion gap acidosis and their etiologies: increased acid production; loss of bicarbonate; and decreased renal excretion of acid .
Type 1 or distal RTA is a primary problem of urine acidification due to impaired hydrogen ion secretion in the distal convoluted tubules. The underlying etiology in adults is usually autoimmune diseases such as Sjögren’s syndrome or rheumatoid arthritis.In pediatrics, the cause is usually a hereditary gene mutation for either the basolateral chloridebicarbonate exchanger or the apical hydrogenadenosine triphosphatase gene. Lastly, a distal RTA can be iatrogenic due to ifosfamide, a chemotherapeutic analog of cyclophosphamide.Type 2 or proximal RTA is a primary problem of impaired bicarbonate reabsorption leading to increased bicarbonate loss.In adults, the underlying etiology is most commonly proximal tubular toxicity from increased exertion of monoclonal immunoglobulin light chains as seen in multiple myeloma.Type 2 RTAs are seen in Fanconi syndrome , and in patients prescribed carbonic anhydrase inhibitors .In pediatric patients, type 2 RTAs are usually idiopathic, but they can be due to a complication from chemotherapy, cystinosis , or inherited mutations in the KCNJ15 and SLC4A4 genes.The term “type 3 RTA” is rarely used as it is now considered a combination of types 1 and 2. Type 4 RTA is beyond the scope of this discussion. The test of choice when evaluating for a RTA is urine electrolytes so that the clinician can calculate how much ammonium is being excreted.18 Ammonium excretion will be decreased in a true RTA and normal/increased if the acidosis is due to toluene use or chronic diarrhea. Unfortunately, ammonium excretion is rarely measured directly. Urine ammonium excretion can be estimated by using the urine anion gap or urine osmolar gap.20The misuse of opiates is a serious problem worldwide, is increasing in young adults, and has substantial individual and societal consequences. In 2014 in the United States alone, approximately 1.9 million people had an opiate use disorder, including 586,000 heroin users. Neuroimaging in opiate dependence indicates both altered brain structure, particularly in the anterior cingulate cortex , and brain function involving dorsolateral prefrontal cortex and ACC. Magnetic resonance spectroscopy allows the non-invasive quantitation of brain metabolites that provide information on the neurophysiologic integrity of brain tissue. The few 1H MRS studies in opiate dependence to date revealed lower concentration of N-acetylaspartate , a marker of neuronal integrity, in the medial frontal cortex, including the ACC, as well as lower glutamate , a primary excitatory neurotransmitter,motel grow racks or glutamate+glutamine concentration in some but not all studies. The discrepant MRS findings may relate to differences among study participants regarding the prevalence and severity of comorbid substance use , the type, dose and duration of replacement therapy for heroin users , and/or participant age.
The ACC, DLPFC and orbitofrontal cortex are important components of the brain reward/executive oversight system, a neural network critically involved in the development and maintenance of addictive disorders. Structural brain imaging in opiate dependence revealed generally lower gray matter volume or density in frontal regions, including the DLPFC, with thinner frontal cortices related to longer duration of opiate misuse. Functional MR imaging showed that the DLPFC, OFC and ACC are involved in decision making, and in opiate dependent individuals, lower task-based fMRI activity in the ACC related to compromised behavioural control of cognitive interference. Furthermore, smaller frontal gray matter volume in opiate dependence related to higher impulsivity on the Barratt Impulsivity Scale . Correspondingly, opiate dependence is associated with cognitive deficits, primarily in executive functioning and self-regulation . Thus, the neuroimaging literature in opiate dependence suggests altered frontal brain structure as well as compromised neuronal integrity and glutamatergic metabolism. Few if any studies however investigated their relationships to opioid and other substance use behaviour or cognition. Further research into specific regional brain effects and their potential cognitive and behavioural correlates may inform better targeted treatment of individuals with opioid use disorders. We measured in opiate dependent individuals’ metabolite concentrations from the ACC and previously unexplored DLPFC and OFC and related them to quantitative measures of neurocognition, self-regulation, and substance use. Specifically, we compared opiate dependent individuals on buprenorphine maintenance to controls . We also included another control group, a substance-dependent ‘control’ group of 3 week abstinent alcohol dependent individuals , a commonly investigated treatment-seeking group to differentiate opiate dependence from not only control individuals but also individuals with a substance dependence . Our primary hypotheses were that: OD have lower NAA and Glu concentrations than CON in ACC, DLPFC, and OFC, these frontal cortical NAA and Glu deficits are associated with the level of opiate use and cigarette-smoking severity, the frontal NAA and Glu deficits in OD relate to higher impulsivity, poorer executive function, and lower decision making skills, and OD have more pronounced metabolite concentration deficits than ALC. The results of this study will contribute to a better understanding of the neurobiology and neuropsychology in OD, helping to identify novel targets for the treatment of opiate dependence. All participants provided informed consent according to the Declaration of Helsinki and underwent procedures approved by the University of California, San Francisco and San Francisco VA Medical Center 00000068. Twenty-one chronic cigarette smoking OD, stable on buprenorphine maintenance therapy for at least 3 months, met DSM-IV criteria for dependence on opiates; they were allowed to meet DSMIV criteria for current abuse or dependence on cocaine, amphetamines, and/or cannabis, but dependence on alcohol or benzodiazepines was exclusionary. OD was part of a buprenorphine treatment program focusing on smoking cessation and they were studied before smoking cessation. For group comparisons of metabolite concentrations specifically in the ACC, DLPFC, and POC and when correlated with neuropsychological variables, there were data from thirty-five cigarette smoking ALC recruited from local treatment programs of the VA and Kaiser Permanente and 28 cigarette smoking CON recruited from the community. The ALC group met DSM-IV criteria for alcohol dependence and was abstinent from alcohol for 21 ± 11 days at time of study. For group comparisons of metabolite concentrations in the OFC and when correlated with neuropsychological variables , smokers and non-smokers were included in the ALC and CON groups: 21 ALC and 19 CON due to a lack of sufficient data in smokers. All participants were studied with structural MRI, 1H MRS, and neuropsychological testing, all were fluent in English and they were allowed to smoke ad libitum before assessment and during breaks. Table 1 contains demographics, tobacco and alcohol use variables, mood measures, and laboratory variables for the three groups.