Off-label use of aprepitant for scleroderma-associated nausea and vomiting: A case report.

WHAT IS KNOWN AND OBJECTIVE: Scleroderma is a disease characterized by excessive deposition of collagen and extracellular matrix proteins in affected organ systems, which results in tissue fibrosis and organ dysfunction. It is estimated that 90% of patients with systemic sclerosis have gastrointestinal involvement, with approximately 50% being symptomatic. Clinical manifestations of gastrointestinal scleroderma manifestations relate to impaired motility and absorption and ultimately malnutrition. Treatments for these symptoms often fail and are limited. The objective of this case report is to highlight the potential use of a substance P antagonist in the treatment of scleroderma associated nausea. CASE SUMMARY: A 56-year-old woman presented with GI complications of her underlying systemic sclerosis. The majority of her stay was marked by severe nausea and vomiting, resistant to numerous therapies. Obstructive causes for her symptoms were ruled out with a gastroscopy. A motility study revealed completely absent peristalsis in her esophagus, likely due to complete fibrosis of smooth muscle fibres. For the first time, off-label use of aprepitant 80 mg once daily was trialed with success in hospital. With this medication, she was able to maintain an adequate oral intake and ultimately achieve discharge from hospital. WHAT IS NEW AND CONCLUSION: Despite the wide array of medications for gastrointestinal scleroderma, their effect is very limited. In this article, we report to the best of our knowledge the first successful use of the substance P antagonist aprepitant to treat refractory nausea and vomiting in a patient with gastrointestinal scleroderma. Not only does this medication carry promise in treating the GI symptoms of scleroderma, but it may also prove cost effective as compared to PEG insertions or TPN. This case study is congruent with recent evidence of the utility of aprepitant in other infiltrative disease conditions. This may spur interest randomized control trials for expanding the role of this medication.

Association between Lifetime Physical Activity and Cognitive Functioning in Middle-Aged and Older Community Dwelling Adults: Results from the Brain in Motion Study.

To determine if total lifetime physical activity (PA) is associated with better cognitive functioning with aging and if cerebrovascular function mediates this association. A sample of 226 (52.2% female) community dwelling middle-aged and older adults (66.5 ± 6.4 years) in the Brain in Motion Study, completed the Lifetime Total Physical Activity Questionnaire and underwent neuropsychological and cerebrovascular blood flow testing. Multiple robust linear regressions were used to model the associations between lifetime PA and global cognition after adjusting for age, sex, North American Adult Reading Test results (i.e., an estimate of premorbid intellectual ability), maximal aerobic capacity, body mass index and interactions between age, sex, and lifetime PA. Mediation analysis assessed the effect of cerebrovascular measures on the association between lifetime PA and global cognition. Post hoc analyses assessed past year PA and current fitness levels relation to global cognition and cerebrovascular measures. Better global cognitive performance was associated with higher lifetime PA (p=.045), recreational PA (p=.021), and vigorous intensity PA (p=.004), PA between the ages of 0 and 20 years (p=.036), and between the ages of 21 and 35 years (p.5), but partially mediated the relation between current fitness and global cognition. This study revealed significant associations between higher levels of PA (i.e., total lifetime, recreational, vigorous PA, and past year) and better cognitive function in later life. Current fitness levels relation to cognitive function may be partially mediated through current cerebrovascular function.

Diuretic Strategies in Acute Decompensated Heart Failure: A Narrative Review.

Background: Heart failure is a common condition with considerable associated costs, morbidity, and mortality. Patients often present to hospital with dyspnea and edema. Inadequate inpatient decongestion is an important contributor to high readmission rates. There is little evidence concerning diuresis to guide clinicians in caring for patients with acute decompensated heart failure. Contemporary diuretic strategies have been defined by expert opinion and older landmark clinical trials. Objective: To present a narrative review of contemporary recommendations, along with their underlying evidence and pharmacologic rationale, for diuretic strategies in inpatients with acute decompensated heart failure. Data Sources: PubMed, OVID, and Embase databases were searched from inception to December 22, 2022, with the following search terms: heart failure, acute heart failure, decompensated heart failure, furosemide, bumetanide, ethacrynic acid, hydrochlorothiazide, indapamide, metolazone, chlorthalidone, spironolactone, eplerenone, and acetazolamide. Study Selection: Randomized controlled trials and systematic reviews involving at least 100 adult patients (> 18 years) were included. Trials involving torsemide, chlorothiazide, and tolvaptan were excluded. Data Synthesis: Early, aggressive administration of a loop diuretic has been associated with expedited symptom resolution, shorter length of stay, and possibly reduced mortality. Guidelines make recommendations about dose and frequency but do not recommend any particular loop diuretic over another; however, furosemide is most commonly used. Guidelines recommend that the initial furosemide dose (on admission) be 2-2.5 times the patient's home dose. A satisfactory diuretic response can be defined as spot urine sodium content greater than 50-70 mmol/L at 2 hours; urine output greater than 100-150 mL/h in the first 6 hours or 3-5 L in 24 hours; or a change in weight of 0.5-1.5 kg in 24 hours. If congestion persists after the maximization of loop diuretic therapy over the first 24-48 hours, an adjunctive diuretic such as thiazide or acetazolamide should be added. If decongestion targets are not met, continuous infusion of furosemide may be considered. Conclusions: Heart failure with congestion can be managed with careful administration of high-dose loop diuretics, supported by thiazides and acetazolamide when necessary. Clinical trials are underway to further evaluate this strategy.

Contexte: L'insuffisance cardiaque est une maladie courante entraînant des coûts, une morbidité et une mortalité considérables. Les patients se présentent souvent à l'hôpital avec une dyspnée et un oedème. Une décongestion inadéquate des patients hospitalisés contribue largement aux taux élevés de réadmission. Il existe peu de données probantes concernant la diurèse pour guider les cliniciens dans la prise en charge des patients atteints d'insuffisance cardiaque aiguë décompensée. Les stratégies diurétiques contemporaines ont été définies par l'opinion d'experts et des essais cliniques de référence plus anciens. Objectif: Présenter une revue narrative des recommandations contemporaines, ainsi que leurs données probantes sous-jacentes et leur justification pharmacologique, pour les stratégies diurétiques chez les patients hospitalisés souffrant d'insuffisance cardiaque aiguë décompensée. Sources des données: Les bases de données PubMed, OVID et Embase ont été consultées depuis leur création jusqu'au 22 décembre 2022, avec les termes de recherche suivants: insuffisance cardiaque, insuffisance cardiaque aiguë, insuffisance cardiaque décompensée, furosémide, bumétanide, acide éthacrynique, hydrochlorothiazide, indapamide, métolazone, chlorthalidone, spironolactone, éplérénone et acétazolamide. Choix de l'étude: Les essais contrôlés randomisés et les revues systématiques portant sur au moins 100 patients adultes (plus de 18 ans) ont été inclus. Les essais impliquant le torsémide, le chlorothiazide et le tolvaptan ont été exclus. Synthèse des données: L'administration précoce et agressive d'un diurétique de l'anse a été associée à une résolution accélérée des symptômes, à une durée de séjour plus courte et éventuellement à une mortalité réduite. Les lignes directrices font des recommandations sur la dose et la fréquence, mais ne recommandent pas un diurétique de l'anse particulier plutôt qu'un autre; cependant, le furosémide est le plus couramment utilisé. Les lignes directrices recommandent que la dose initiale de furosémide à l'admission soit de 2 à 2,5 fois la dose à domicile du patient. Une réponse diurétique satisfaisante peut être définie comme une teneur ponctuelle en sodium dans l'urine supérieure à 50 à 70 mmol/L après 2 heures; débit urinaire supérieur à 100 à 150 mL/h au cours des 6 premières heures ou à 3 à 5 L en 24 heures; ou un changement de poids de 0,5 à 1,5 kg en 24 heures. Si la congestion persiste après la maximisation du traitement par diurétique de l'anse au cours des premières 24 à 48 heures, un diurétique d'appoint tel que le thiazidique ou l'acétazolamide doivent être ajoutés. Si les objectifs de décongestion ne sont pas atteints, une perfusion continue de furosémide peut être envisagée. Conclusions: L'insuffisance cardiaque accompagnée de congestion peut être gérée par l'administration prudente de diurétiques de l'anse à haute dose, appuyés par des thiazidiques et de l'acétazolamide si nécessaire. Des essais cliniques sont en cours pour évaluer davantage cette stratégie.

The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults.

BACKGROUND: Aging and physical inactivity are associated with declines in some cognitive domains and cerebrovascular function, as well as an elevated risk of cerebrovascular disease and other morbidities. With the increase in the number of sedentary older Canadians, promoting healthy brain aging is becoming an increasingly important population health issue. Emerging research suggests that higher levels of physical fitness at any age are associated with better cognitive functioning and this may be mediated, at least in part, by improvements in cerebrovascular reserve. We are currently conducting a study to determine: if a structured 6-month aerobic exercise program is associated with improvements or maintenance of both cerebrovascular function and cognitive abilities in older individuals; and, the extent to which any changes seen persist 6 months after the completion of the structured exercise program. METHODS/DESIGN: Two hundred and fifty men and women aged 55-80 years are being enrolled into an 18-month combined quasi-experimental and prospective cohort study. Participants are eligible for enrollment into the study if they are inactive (i.e., not participating in regular physical activity), non-smokers, have a body mass index <35.0 kg/m(2), are free of significant cognitive impairment (defined as a Montreal Cognitive Assessment score of 24 or more), and do not have clinically significant cardiovascular, cerebrovascular disease, or chronic obstructive pulmonary airway disease. Repeated measurements are done during three sequential six-month phases: 1) pre-intervention; 2) aerobic exercise intervention; and 3) post-intervention. These outcomes include: cardiorespiratory fitness, resting cerebral blood flow, cerebrovascular reserve, and cognitive function. DISCUSSION: This is the first study to our knowledge that will examine contemporaneously the effect of an exercise intervention on both cerebrovascular reserve and cognition in an older population. This study will further our understanding of whether cerebrovascular mechanisms might explain how exercise promotes healthy brain aging. In addition our study will address the potential of increasing physical activity to prevent age-associated cognitive decline.

A case of histamine fish poisoning in a young atopic woman.

Histamine fish poisoning, also known as scombroid poisoning, is a histamine toxicity syndrome that results from eating specific types of spoiled fish. Although typically a benign syndrome, characterized by self-limited flushing, headache, and gastrointestinal symptoms, we describe a case unique in its severity and as a precipitant of an asthma exacerbation. A 25-year-old woman presented to the emergency department (ED) with one hour of tongue and face swelling, an erythematous pruritic rash, and dyspnea with wheezing after consuming a tuna sandwich. She developed abdominal pain, diarrhea and hypotension in the ED requiring admission to the hospital. A diagnosis of histamine fish poisoning was made and the patient was treated supportively and discharged within 24 hours, but was readmitted within 3 hours due to an asthma exacerbation. Her course was complicated by recurrent admissions for asthma exacerbations.

The accuracy of pulse oximetry in emergency department patients with severe sepsis and septic shock: a retrospective cohort study.

BACKGROUND: Pulse oximetry is routinely used to continuously and noninvasively monitor arterial oxygen saturation (SaO2) in critically ill patients. Although pulse oximeter oxygen saturation (SpO2) has been studied in several patient populations, including the critically ill, its accuracy has never been studied in emergency department (ED) patients with severe sepsis and septic shock. Sepsis results in characteristic microcirculatory derangements that could theoretically affect pulse oximeter accuracy. The purposes of the present study were twofold: 1) to determine the accuracy of pulse oximetry relative to SaO2 obtained from ABG in ED patients with severe sepsis and septic shock, and 2) to assess the impact of specific physiologic factors on this accuracy. METHODS: This analysis consisted of a retrospective cohort of 88 consecutive ED patients with severe sepsis who had a simultaneous arterial blood gas and an SpO2 value recorded. Adult ICU patients that were admitted from any Calgary Health Region adult ED with a pre-specified, sepsis-related admission diagnosis between October 1, 2005 and September 30, 2006, were identified. Accuracy (SpO2 - SaO2) was analyzed by the method of Bland and Altman. The effects of hypoxemia, acidosis, hyperlactatemia, anemia, and the use of vasoactive drugs on bias were determined. RESULTS: The cohort consisted of 88 subjects, with a mean age of 57 years (19 - 89). The mean difference (SpO2 - SaO2) was 2.75% and the standard deviation of the differences was 3.1%. Subgroup analysis demonstrated that hypoxemia (SaO2 < 90) significantly affected pulse oximeter accuracy. The mean difference was 4.9% in hypoxemic patients and 1.89% in non-hypoxemic patients (p < 0.004). In 50% (11/22) of cases in which SpO2 was in the 90-93% range the SaO2 was <90%. Though pulse oximeter accuracy was not affected by acidoisis, hyperlactatementa, anemia or vasoactive drugs, these factors worsened precision. CONCLUSIONS: Pulse oximetry overestimates ABG-determined SaO2 by a mean of 2.75% in emergency department patients with severe sepsis and septic shock. This overestimation is exacerbated by the presence of hypoxemia. When SaO2 needs to be determined with a high degree of accuracy arterial blood gases are recommended.

The Role of Midodrine for Hypotension Outside of the Intensive Care Unit.

Midodrine is an oral, peripherally acting alpha-adrenergic agonist. After gaining Food and Drug Administration (FDA) approval in 1996 for orthostatic hypotension, its use has evolved to target vasoplegic conditions such as intradialytic hypotension in the end-stage renal disease population, refractory ascites in cirrhotic patients to support diuresis, and in hepatorenal syndrome. Upon oral ingestion, the drug undergoes enzymatic hydrolysis to an active metabolite, desglymidodrine. Its use has been well tolerated at 2.5 mg, 5 mg, and 10 mg oral doses. The most frequently occurring side effects relate directly to its sympathomimetic profile and include piloerection, scalp pruritis, generalized paresthesias, and urinary retention. The vasoplegic profile of sepsis would be a potential target for midodrine therapy. While its use to mediate recovery from septic shock has been suggested, there is a paucity of clinical data supporting its use. Such therapy may be uniquely appropriate in septic patients who are not candidates for intensive care unit (ICU) level of care.

Targeting specific interstitial glycemic parameters with high-intensity interval exercise and fasted-state exercise in type 2 diabetes.

AIMS: To compare the acute glycemic responses to a bout of high-intensity interval exercise (HIIE) and energy-matched moderate-intensity continuous exercise (MICE) performed under fasted and postprandial conditions. METHODS: A randomized, controlled, crossover design was used. Ten individuals with type 2 diabetes were each tested in five experimental conditions after an overnight fast: 1) fasted-state HIIE (HIIEfast); 2) post-breakfast HIIE (HIIEfed); 3) fasted-state MICE (MICEfast); 4) post-breakfast MICE (MICEfed); and 5) no exercise (control). MICE was performed at workload corresponding to 55% of V.V̇O2peak, whereas HIIE was composed of repetitions of three minutes at workload corresponding to 40% followed by one minute at workload corresponding to 100% V.V̇̇O2peak. Interstitial glucose was monitored by continuous glucose monitoring over 24h under standardized diet and medication. RESULTS: Fasted-state exercise attenuated postprandial glycemic increments (p<0.05) to a greater extent than post-breakfast exercise did. HIIE reduced nocturnal and fasting glycemia on the day following exercise more than MICE did (main effect: both p<0.05). Compared to the control condition, HIIEfast lowered most interstitial glycemic parameters, i.e., 24-h mean glucose (-1.5mmol·l(-1); p<0.05), fasting glucose (-1.0mmol·l(-1); p<0.05), overall postprandial glycemic increment (-257mmol·360min·l(-1); p<0.05), glycemic variability (-1.79mmol·l(-1); p<0.05), and time spent in hyperglycemia (-283min; p<0.05). CONCLUSION: This study showed that HIIE is more effective than MICE in lowering nocturnal/fasting glycemia. Exercise performed in the fasted state reduces postprandial glycemic increments to a greater extent than post-breakfast exercise does. Performing HIIE under fasted condition may be most advantageous as it lowered most aspects of glycemia.

Cardiometabolic risk factors predict cerebrovascular health in older adults: results from the Brain in Motion study.

Aging and physical inactivity are associated with an increased risk of developing metabolic syndrome (MetS). With the rising prevalence of MetS, it is important to determine the extent to which it affects cerebrovascular health. The primary purpose of this report is to examine the impact of MetS on cerebrovascular health (resting cerebral blood flow (CBF) peak velocity (V¯P), cerebrovascular conductance (CVC), and CBF responses to hypercapnia) in healthy older adults with normal cognition. A secondary goal was to examine the influence of apolipoprotein E (APOE) ε4 expression on these indices. In a sample of 258 healthy men and women older than 53 years, 29.1% met criteria for MetS. MetS, sex, and age were found to be significant predictors of CVC, and V¯P, MetS, and APOE status were significant predictors of V¯P-reactivity, and CVC-reactivity was best predicted by MetS status. After controlling for these factors, participants with MetS demonstrated lower cerebrovascular measures (CVC, V¯P, CVC-reactivity, and V¯P-reactivity) compared to participants without MetS. APOE ε4 carriers had higher V¯P-reactivity than noncarriers. These results provide evidence that cardiometabolic and vascular risk factors clustered together as the MetS predict measures of cerebrovascular health indices in older adults. Higher V¯P-reactivity in APOE ε4 carriers suggests vascular compensation for deleterious effects of this known risk allele for Alzheimer's disease and stroke.

Cerebrovascular Responsiveness to Hypercapnia Is Stable over Six Months in Older Adults.

The primary purpose of this Brain in Motion (BIM) sub-study was to determine the 6-month stability of resting blood flow velocity and cerebrovascular responsiveness to a euoxic hypercapnic challenge in a group of physically inactive community dwelling men and men aged ≥55 yrs (range 55-92 yrs). At baseline and 6 months later 88 women (65±6 yr) and 78 men (67±7 yr) completed a hypercapnic challenge (step changes from resting end-tidal PCO2 ((PETCO2) to +1, +5 and +8 mmHg above rest) while cerebral blood flow velocity was assessed using transcranial Doppler ultrasound. Peak velocity of the middle cerebral artery (MCAv) was increased (p<0.05) at the second visit during rest (51±2 vs. 52±4); however, these differences were abolished (p>0.05) when MCAv was normalized to PETCO2. During hypercapnia, MCAv tended to be increased at follow-up, but this finding was absent when MCAv/PETCO2 was compared across time. Cerebrovascular reactivity (i.e., ΔMCAv/ΔPETCO2) was similar (p>0.05) between testing occasions regardless of the approach taken (i.e., considering only the lower step [from +1 to +5 mmHg]; the upper step [+5 to +8 mmHg]; or the complete test taken together). In conclusion, this study has shown that cerebral blood flow and cerebrovascular responsiveness to acute euoxic hypercapnia are stable in older, healthy adults over a 6-month period. Modest changes in MCAv over time must be viewed in the context of underlying differences in PETCO2, an important finding with implications for future studies considering cerebral blood flow velocity.

Intravenous lipid emulsion therapy for sustained release diltiazem poisoning: a case report.

We present a case of refractory cardiogenic shock secondary to sustained release diltiazem poisoning.  Intravenous lipid emulsion therapy was initiated approximately 13 hours after ingestion. Vasopressors were weaned off hours after initiation of intravenous lipid emulsion therapy and the patient went on to make a full recovery.  This report adds to the paucity of data on intravenous lipid emulsion rescue therapy in sustained release diltiazem poisoning. We hypothesize that the intravenous lipid emulsion may have mediated its favorable hemodynamic effects via increases in myocardial calcium concentration with resultant increased inotropy.