Spectrophotometric analysis of purple urine secondary to methylene blue and hydroxocobalamin co-administration.

BACKGROUND: The development of purple urine after methylene blue (methylthioninium chloride) and hydroxocobalamin co-administration is a rare clinical entity that has not been fully elucidated. A 47-year-old male presented to the emergency department with hypotension, cyanosis, and depressed mental status. The patient was noted to have profound peripheral and central cyanosis, as well as chocolate-colored arterial blood. He was treated with both methylene blue and hydroxocobalamin and developed purple urine for approximately 1 week. METHODS: Color chromatography was performed by placing the patient's urine directly onto absorbent filter paper. Urine spectrophotometry was performed utilizing the NanoDrop One/One C UV-Vis Spectrophotometer. RESULTS: Color chromatography of the urine was demonstrated clear separation of distinct red and blue phases. Urine spectrophotometry demonstrated near perfect overlap between the methylene blue + hydroxocobalamin absorbance spectrum and the patient's purple urine absorbance spectrum. CONCLUSION: Purple urine secondary to methylene blue and hydroxocobalamin co-administration is due to combined urinary excretion of methylene blue (blue) and hydroxocobalamin (red), and not a novel purple metabolite. We anticipate that this is going to be an increasingly common clinical entity as the roles of both hydroxocobalamin and methylene blue expand from toxicologic antidotes to adjunct therapies for vasoplegia, poor cardiac output, and sepsis.

Impacts of United States Medical Licensing Examination Step 1 Scoring Change on Emergency Medicine Applicant Screening.

BACKGROUND: The U.S. Medical Licensing Examination (USMLE) Step 1 has been used as a screening tool for residency selection. In February 2020, Step 1 numerical scoring changed to pass/fail. OBJECTIVE: Our aim was to survey emergency medicine (EM) residency program attitudes towards the new Step 1 scoring change and to identify important applicant screening factors. METHODS: A 16-question survey was distributed through the Council of Residency Directors in Emergency Medicine listserv from November 11 through December 31, 2020. Given the Step 1 scoring change, the survey questioned the importance of EM rotation grades, composite standardized letters of evaluation (cSLOEs), and individual standardized letters of evaluation, using a Likert scale. Descriptive statistics of demographic characteristics and selection factors were performed along with a regression analysis. RESULTS: Of the 107 respondents, 48% were program directors, 28% were assistant or associate program directors, 14% were clerkship directors, and 10% were in other roles. Sixty (55.6%) disagreed with pass/fail Step 1 scoring change and, of those, 82% believed that numerical scoring was a good screening tool. The cSLOEs, EM rotation grades, and interview were the most important selection factors. Residencies with 50 or more residents had 5.25 odds (95% CI 1.25-22.1; p = 0.0018) of agreeing with pass/fail scoring and those who ranked cSLOEs as the most important selection factor had 4.90 odds (95% CI 1.125-21.37; p = 0.0343) of agreeing with pass/fail scoring. CONCLUSIONS: Most EM programs disagree with pass/fail scoring of Step 1 and will most likely use Step 2 score as a screening tool. The cSLOEs, EM rotation grades, and interview are considered the most important selection factors.

Severe alcohol withdrawal in an adolescent male.

Ethanol remains one of the most frequently abused agents by adolescents, exceeding all others except for vaping nicotine, and use is rising. With increased ethanol use comes a greater risk for dependence and potential for alcohol withdrawal syndromes (AWS). Pediatric AWS is extremely rare and poorly characterized in the literature. Pediatric acute care practitioners may have limited exposure to AWS. We report the case of a 16-year-old male with a history of polysubstance abuse who presented with mild AWS and progressed rapidly to delirium tremens. His withdrawal was initially refractory to high dose benzodiazepine therapy but responded well to phenobarbital. This case highlights how rapidly and dangerously AWS can progress if not aggressively treated. Given the rise in adolescent alcohol use and potential for life threatening symptoms, practitioners, especially in acute care specialties such as emergency medicine, critical care, and hospital medicine, would benefit from additional familiarity with AWS diagnoses and management strategies.

The impact of particulate electron paramagnetic resonance oxygen sensors on fluorodeoxyglucose imaging characteristics detected via positron emission tomography.

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation.

Phenytoin Toxicity After Transjugular Intrahepatic Portosystemic Shunt (TIPS).

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) alters portal blood flow and may impact drug metabolism and bioavailability. However, little evidence has been published to provide guidance on medication alterations after TIPS procedures. CASE REPORT: We report a patient who developed phenytoin toxicity requiring a prolonged readmission after a TIPS procedure. It is likely that the TIPS procedure altered phenytoin metabolism and led to toxicity in this patient. Phenytoin is an antiepileptic drug that is primarily eliminated by hepatic metabolism. It is possible that phenytoin toxicity may occur after TIPS, and that decreased dose requirements may be a durable effect of the procedure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: TIPS is now the most common portal hypertension decompressive procedure performed by interventional radiologists and has become the primary portosystemic shunt (surgical or percutaneous) performed in the United States. Patients with a history of TIPS procedures commonly present to tertiary- and quaternary-care emergency departments with complex clinical presentations. Greater familiarity with the potential effects of TIPS on drug metabolism may help emergency physicians prevent adverse drug effects and optimize clinical outcomes.

Combined endogenous MR biomarkers to assess changes in tumor oxygenation induced by an allosteric effector of hemoglobin.

Hypoxia is a crucial factor in cancer therapy, determining prognosis and the effectiveness of treatment. Although efforts are being made to develop methods for assessing tumor hypoxia, no markers of hypoxia are currently used in routine clinical practice. Recently, we showed that the combined endogenous MR biomarkers, R1 and R2 *, which are sensitive to [dissolved O2 ] and [dHb], respectively, were able to detect changes in tumor oxygenation induced by a hyperoxic breathing challenge. In this study, we further validated the ability of the combined MR biomarkers to assess the change in tumor oxygenation induced by an allosteric effector of hemoglobin, myo-inositol trispyrophosphate (ITPP), on rat tumor models. ITPP induced an increase in tumor pO2 , as observed using L-band electron paramagnetic resonance oximetry, as well as an increase in both R1 and R2 * MR parameters. The increase in R1 indicated an increase in [O2 ], whereas the increase in R2 * resulted from an increase in O2 release from blood, inducing an increase in [dHb]. The impact of ITPP was then evaluated on factors that can influence tumor oxygenation, including tumor perfusion, saturation rate of hemoglobin, blood pH and oxygen consumption rate (OCR). ITPP decreased blood [HbO2 ] and significantly increased blood acidity, which is also a factor that right-shifts the oxygen dissociation curve. No change in tumor perfusion was observed after ITPP treatment. Interestingly, ITPP decreased OCR in both tumor cell lines. In conclusion, ITPP increased tumor pO2 via a combined mechanism involving a decrease in OCR and an allosteric effect on hemoglobin that was further enhanced by a decrease in blood pH. MR biomarkers could assess the change in tumor oxygenation induced by ITPP. At the intra-tumoral level, a majority of tumor voxels were responsive to ITPP treatment in both of the models studied.

Characterization of a clinically used charcoal suspension for in vivo EPR oximetry.

OBJECTIVES: Electron paramagnetic resonance (EPR) oximetry using particulate materials allows repeatable measurements of oxygen in tissues. However, the materials identified so far are not medical devices, thus precluding their immediate use in clinical studies. The aim of this study was to assess the magnetic properties of Carbo-Rep®, a charcoal suspension used as a liquid marker for preoperative tumor localization. MATERIALS AND METHODS: Calibration curves (EPR linewidth as a function of pO2) were built using 9-GHz EPR spectrometry. The feasibility of performing oxygen measurements was examined in vivo by using a low-frequency (1 GHz) EPR spectrometer and by inducing ischemia in the gastrocnemius muscle of mice or by submitting rats bearing tumors to different oxygen-breathing challenges. RESULTS: Paramagnetic centers presenting a high oxygen sensitivity were identified in Carbo-Rep®. At 1 GHz, the EPR linewidth varied from 98 to 426 µT in L-band in nitrogen and air, respectively. The sensor allowed repeated measurements of oxygen over 6 months in muscles of mice. Subtle variations of tumor oxygenation were monitored in rats when switching gas breathing from air to carbogen. DISCUSSION: The magnetic properties of Carbo-Rep® are promising for its future use as oxygen sensor in clinical EPR oximetry.

Impact of myo-inositol trispyrophosphate (ITPP) on tumour oxygenation and response to irradiation in rodent tumour models.

Tumour hypoxia is a well-established factor of resistance in radiation therapy (RT). Myo-inositol trispyrophosphate (ITPP) is an allosteric effector that reduces the oxygen-binding affinity of haemoglobin and facilitates the release of oxygen by red blood cells. We investigated herein the oxygenation effect of ITPP in six tumour models and its radiosensitizing effect in two of these models. The evolution of tumour pO2 upon ITPP administration was monitored on six models using 1.2 GHz Electron Paramagnetic Resonance (EPR) oximetry. The effect of ITPP on tumour perfusion was assessed by Hoechst staining and the oxygen consumption rate (OCR) in vitro was measured using 9.5 GHz EPR. The therapeutic effect of ITPP with and without RT was evaluated on rhabdomyosarcoma and 9L-glioma rat models. ITPP enhanced tumour oxygenation in six models. The administration of 2 g/kg ITPP once daily for 2 days led to a tumour reoxygenation for at least 4 days. ITPP reduced the OCR in six cell lines but had no effect on tumour perfusion when tested on 9L-gliomas. ITPP plus RT did not improve the outcome in rhabdomyosarcomas. In 9L-gliomas, some of tumours receiving the combined treatment were cured while other tumours did not benefit from the treatment. ITPP increased oxygenation in six tumour models. A decrease in OCR could contribute to the decrease in tumour hypoxia. The association of RT with ITPP was beneficial for a few 9L-gliomas but was absent in the rhabdomyosarcomas.

A Case of Acute Pericarditis Following Intravenous Injection of Crushed Morphine Tablets.

A 37-year-old male presented with sharp, severe chest pain following seven days of intravenous injection of crushed morphine tablets. The chest pain was positional and pleuritic in nature and resolved with leaning forward. Work-up was notable for an ECG with inferior and anterolateral PR depressions as well as a CT chest with diffuse centrilobular nodules. Per radiology, the CT findings along with the patient's history were concerning for pulmonary granulomatosis from deposition of talc or some other foreign body. Cardiology was consulted and diagnosed the patient with acute pericarditis, given his typical symptoms and ECG changes. On review of the literature, pulmonary granulomatosis following intravenous injection of foreign bodies is well documented. There are numerous studies documenting foreign body deposition and granulomatosis in organs other than the lungs on post-mortem analyses of individuals with a history of IV injection of crushed tablets. We are suggesting that intravenous injection of crushed morphine tablets can cause pericardial irritation and a syndrome of acuter pericarditis. To our knowledge, there has not been a previous report of acute pericarditis secondary to intravenous injection of crushed tablets.

Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study.

PURPOSE: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R1, water R1, lipids R1, and R2*. R1 is sensitive to dissolved molecular oxygen, whereas R2* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R1, water R1, lipids R1, and R2* with pO2 assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). METHODS AND MATERIALS: R1, R2*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O2, 5% CO2). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. RESULTS: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO2. Global and lipids R1 were found to be correlated to pO2 in the rhabdomyosarcoma model, whereas R2* was found to be inversely correlated to pO2 in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R2* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. (18)F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. CONCLUSION: This work illustrates the sensitivity of oxygen-sensitive R1 and R2* parameters to changes in tumor oxygenation. However, R1 parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R2* was found to be correlated with the outcome in the responsive model.

DW-MRI and (18) F-FLT PET for early assessment of response to radiation therapy associated with hypoxia-driven interventions. Preclinical studies using manipulation of oxygenation and/or dose escalation.

Early markers of treatment response may help in the management of patients by predicting the outcome of a specific therapeutic intervention. Here, we studied the potential value of diffusion-weighted MRI (DW-MRI) and (18)F-fluorothymidine ((18)F-FLT), markers of cell death and cell proliferation respectively, to predict the response to irradiation. In addition, dose escalation and/or carbogen breathing were used to modulate the response to irradiation. The studies were performed on two hypoxic rat tumor models: rhabdomyosarcoma and 9L-glioma. The rats were imaged using MRI and PET before and two days after the treatment. In both tumor models, changes in ADC (apparent diffusion coefficient) and (18)F-FLT SUV (standardized uptake value) were significantly correlated with the tumor growth delay. For both tumor models, the ADC values increased in all irradiated groups two days after the treatment while they decreased in the untreated groups. At the same time, the uptake of (18)F-FLT increased in the untreated groups and decreased in all treated groups. Yet, ADC values were not sensitive enough to predict the added value of dose escalation or carbogen breathing in either model. Change in (18)F-FLT uptake was able to predict the higher tumor response when using increased dose of irradiation, but not when using a carbogen breathing challenge. Our results also emphasize that the magnitude of change in (18)F-FLT uptake was strongly dependent on the tumor model.

Internet-purchased ibogaine toxicity confirmed with serum, urine, and product content levels.

UNLABELLED: Ibogaine, a psychotropic indole alkaloid, is gaining popularity among medical subcultures for its purported anti addictive properties. Its use has been associated with altered mental status, ataxia, gastrointestinal distress, ventricular arrhythmias, and sudden and unexplained deaths.Its pharmacokinetics in toxic states is not well understood. Case report:A 33-year-old man overdosed on ibogaine in an attempt to quit his use of heroin. He developed altered state of consciousness, tremor, ataxia,nausea, vomiting, and transient QT interval prolongation, which all remitted as he cleared the substance. Ibogaine was confirmed in his urine and serum with a peak serum concentration of 377 ng/mL. Nonlinear elimination kinetics and a formula match to its active metabolite noriobgaine were observed as well. CONCLUSION: This case presents the unique description of serial serum concentrations as well as urine and product-confirmed ibogaine toxicity with transient toxin-related QT interval prolongation.

Predictive value of (18)F-FAZA PET imaging for guiding the association of radiotherapy with nimorazole: a preclinical study.

PURPOSE: To assess the predictive value of hypoxia imaging by (18)F-FAZA PET in identifying tumors that may benefit from radiotherapy combined with nimorazole, a hypoxic radiosensitizer. MATERIAL AND METHODS: Rats of two tumor models (Rhabdomyosarcoma and 9L-glioma) were divided into two treated groups: radiotherapy (RT) alone or RT plus nimorazole. (18)F-FAZA PET images were obtained to evaluate tumor hypoxia before the treatment. Treatment outcome was assessed through the tumor growth time assay, defined as the time required for tumor to grow to 1.5 times its size before irradiation. RESULTS: For rhabdomyosarcomas, the benefit of adding nimorazole to RT was not significant when considering all tumors. When stratifying into more and less hypoxic tumors according to the median (18)F-FAZA T/B ratio, we found that the combined treatment significantly improved the response of the "more hypoxic" subgroup, while there was no significant difference in the tumor growth time between the two treatment modalities for the "less hypoxic" subgroup. For 9L-gliomas, a clear benefit was demonstrated for the group receiving RT+nimorazole. However, the individual responses within the RT+nimorazole group were highly variable and independent of the (18)F-FAZA uptake. CONCLUSIONS: (18)F-FAZA PET may be useful to guide hypoxia-directed RT using nimorazole as radiosensitizer. It identified a subgroup of more hypoxic tumors (displaying T/B ratio>2.72) that would benefit from this combined treatment. Nevertheless, the predictive power was limited to rhabdomyosarcomas and ineffective for 9L-gliomas.

Orbeez: the magic water absorbing bead--risk of pediatric bowel obstruction?

OBJECTIVES: In December 2012, the U.S. Consumer Product Safety Commission recalled the water-absorbing toy WaterBalz after reports of small intestine obstruction after ingestion by children. Orbeez, another water-absorbing bead, remains available and is marketed as a children's toy. We sought to determine the extent to which Orbeez enlarge in various liquid media and the potential risk for bowel obstruction. METHODS: Three Orbeez beads were added to 210 mL of the following liquid media: room temperature tap water, whole milk, simulated gastric fluid, GoLytely (polyethelyelene glycol, 3350 and electrolytes), and vodka (40% ethanol by volume). Diameters before exposure to media were measured using a caliper to the nearest 0.1 mm and again at 1, 2, 4, 6, 12, and 24 hours. Ten beads were then added to the beads already immersed in simulated gastric fluid and water and observed for an additional 72 hours (96 hours total) for clumping or increase in diameter. Clumping was defined as two or more beads remaining persistently adherent to one another despite gentle circular movement (swirling) of the liquid. RESULTS: Growth in each of the media was observed. Growth in simulated gastric fluid was minimal, whereas the beads were observed to be the largest after 24 hours in vodka. Clumping of the beads was not observed to occur. CONCLUSIONS: Orbeez beads enlarge to a different extent in different liquid media. It is unlikely that Orbeez beads would expand to sizes or demonstrate clumping that would be concerning for intestinal obstruction.