History Of Orthostatic Hypotension Research Articles

Phase 1 Study of BXCL701, a Dipeptidyl Peptidase Inhibitor, in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Background and Significance: BXCL701 is an oral small molecule inhibitor of dipeptidyl peptidases (DPP)-primarily DPP8/9-that has been extensively studied in humans with metastatic castration-resistant prostate cancer (both small cell neuroendocrine and adenocarcinoma), non-small cell lung cancer, melanoma, non-Hodgkin's lymphoma, and GI malignancies. Inhibition of DPP8/9 triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß, bridging innate and adaptive immunity. Preclinical studies have demonstrated that BXCL701 may have direct induction of apoptosis in AML cells through activation of CARD8 and subsequent activation of inflammatory cytokines and Gasdermin D. Mouse model studies demonstrated a reduction in AML blasts and AML tumor size when treated with BXCL701. We hypothesize that BXCL701 can be safe and effective in patients with relapsed/refractory AML or patients with relapsed/refractory MDS with blasts ≥ 10%. Study Design and Methods: This is a Phase 1 single center investigator-initiated trial of BXCL701 in patients with relapsed/refractory AML or relapsed/refractory MDS with blasts ≥10% (ClinicalTrials.gov Identifier: NCT05703542). In the lead-in stage, we will use a 3 + 3 design with 4 dose levels of BXCL701 (0.2 mg, 0.4 mg, 0.6 mg and 0.8 mg). Doses of BXCL701 will be given on Days 1-3, Days 8-10, Days 15-17, and Days 22-24 on a 28-day cycle. The primary objective is to evaluate the safety of BXCL701 in the AML or MDS with ≥ 10% blasts. Secondary objectives include determining the maximum tolerated dose or recommended phase 2 dose, pharmacokinetics, and to estimate response, duration of response and overall survival. Exploratory endpoints include: pharmacodynamic profiling, T-cell response, inhibitory effect on DPP8/9, and evaluation of potential biomarkers such as Copy Number Variants and mRNA levels of DPP8, DPP9, FAP, Caspase-1, Pro-caspase-1, NLRP1, and CARD8. Major eligibility criteria include: ≥18 years of age, relapsed or refractory AML or relapsed or refractory MDS with ≥10%.refractory to at least 4 cycles of hypomethylating agent, ECOG performance status ≤2, adequate renal function (CrCl ≥30 mL/min), adequate liver function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN), WBC <25,000/µL on Day 1 Cycle 1 (hydroxyurea permitted), no symptomatic CNS disease, no active viral or bacterial infections, and >100 days from allogeneic bone marrow transplant with no active graft versus host disease. Patients on gliptin therapy are not permitted on the study due to drug interaction; patients are also excluded if they have a history of orthostatic hypotension or uncontrolled hypertension. There will be a second phase of the study that will evaluate BXCL701 in combination with a hypomethylating agent (decitabine or azacytidine) and venetoclax. Dose selection of BXCL701 in the combination stage will be based on the data from the single agent study. Conclusion: The trial is currently open and continuing to enroll.

P186 Disseminated Histoplasmosis in an immunocompetent patient in a tertiary care center in North India

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM ObjectivesHistoplasmosis is a geographically restricted dimorphic fungi that causes disseminated infection in immune-competent as well as immunocompromised patients. Adrenal involvement is seen in disseminated disease but sometimes it may be the only site where then infection can be demonstrated. Early diagnosis and treatment are needed to save the patient from fatal adrenal insufficiency. We present a case of bilateral adrenal histoplasmosis in immunocompetent patient.MethodsA 63-year-old male presented to our hospital with a history of insidious onset of decreased appetite and unintentional weight loss for the last 6 months associated with generalized weakness. Patient had a history of mild to moderate intensity epigastric pain and discomfort which was intermittent in nature. Patient originally belongs to Azamgarh, Uttar Pradesh, but he was residing in Kolkata for the last 8 months.Patient had no history of fever, cough, hemoptysis, jaundice, chronic diarrhea, and steatorrhea. No history of orthostatic hypotension, salt craving, hyperpigmentation, headache, visual field disturbances, polyuria, behavioral changes, episodic headache, palpitation, diaphoresis, systemic hypertension with episodic all four-limb weakness. There was no history of abdominal striae, easy bruisability, difficulty in standing from squatting position. There was no history of tuberculosis among family members. On detailed history, it was revealed that he fed pigeons every day in the slum house where he lived in Kolkata.On the CECT abdomen it was found that there is an ill-defined hypodense enhancing lesion (72 × 52 × 77 mm) in right suprarenal region and bulky, necrosed 25 × 26 × 19 mm lesion in left suprarenal gland associated with multiple nonnecrotic paraaortic and aortic caval lymphadenopathy. He also received empirical anti-tubercular therapy for 15 days in the form of ethambutol and levofloxacin.ResultsIn all, 10% KOH wet mount of crushed smear of adrenal biopsy samples showed tissue debris and small narrow neck budding yeasts. Giemsa stain shows few small budding yeasts. Culture was put in SDA at 25°C and 37°C and incubated. On day 12, growth of colony in 25°C appears as white cottony growth with yellowish white reverse. On day 24, colony appears as buff brown with yellowish brown reverse. LPCB was done from the colony showing presence of characteristic tuberculate macroconidia (8–14) μm in diameter formed on short, hyaline, undifferentiated conidiophores and production of plenty round to pyriform microconidia (2–4 μm) in diameter, occurring on short branches and directly on the sides of the hyphae. Based on the direct microscopy and culture characteristics a diagnosis of Histoplasma capsulatum was given.ConclusionSystemic histoplasmosis is typically acquired through inhalation of microconidia or small hyphal elements in soil contaminated with bird and bat droppings leading to primary infection. This patient only manifested bilateral adrenal involvement with nonspecific symptoms.

Over 5 years follow-up of three cases of autoimmune autonomic ganglionopathy

We report the clinical course of three cases of anti-ganglionic acetylcholine receptor (gAChR) antibody positive auto-immune autonomic ganglionopathy (AAG) that have been followed for over 5 years. In all three cases, the symptoms improved by acute treatment, but ultimately relapsed. The first case was a female in her 20s who had a chronic history of photophobia, constipation and amenorrhea. The symptoms almost disappeared by plasma exchange, and menstruation resumed. During the course, it relapsed once after a cold. There was no recurrence of AAG during the two pregnancies. The second case was a male in his 60s who visited a hospital for the acute onset of orthostatic hypotension (OH) and psychological symptoms (infantilization and psychogenic pseudosyncope). Although IVIg was effective, it recurred frequently and was difficult to treat. However, all the symptoms disappeared eight years after the onset without any particular reasons. The third case was a female in her 80s who had a chronic history of OH. Acute treatment was effective, but AAG recurred repeatedly. Additionally, it was difficult to judge relapse because of the residual sequelae. During the course, cerebral hemorrhage due to supine hypertension or short-time blood pressure variability and femoral neck fracture caused by OH occurred. She eventually became a wheelchair. This report is clinically important because there are few reports of long-term follow-up of AAG.

Orthostatic hypotension: the last 20 years

In the second article of the new Neurocardiology series, Helen Cowan looks at the history of orthostatic hypotension

Risk of orthostatic hypotension associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials.

Objective:The aim of this study was to assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of orthostatic hypotension (OH) in patients with type 2 diabetes mellitus (T2DM).Method:A systematic literature retrieval was performed using PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception up to 16 October 2019. Data for study characteristics and outcomes of interest were extracted from each eligible study. Pooled risk ratios (RRs) with 95% confidence intervals (CI) for OH were calculated using a random-effects model.Result:A total of 16 studies (n = 12,749) were included in our meta-analysis, with a result of 44 incident OH cases (29 in the SGLT2 inhibitor group, and 15 in the control group). The pooled RR was 1.17 (95% CI: 0.65–2.09). There was no evidence that receiving SGLT2 inhibitors increased the risk of OH, when stratified by age, duration of T2DM, or placebo-control or active-control and baseline blood pressure.Conclusion:This meta-analysis suggested that, in general, SGLPT2 inhibitors did not increase the risk of OH in patients with T2DM. The possibility of OH should be, therefore, considered on an individual basis, especially in patients with a history of OH, long duration of T2DM, or comorbidities.

Orthostatic hypotension: the last 20 years

In the second article of the new Neurocardiology series, Helen Cowan looks at the history of orthostatic hypotension

Going Beyond the Guidelines in Individualising the Use of Antihypertensive Drugs in Older Patients.

Hypertension is commonly diagnosed in older patients, with increasing cardiovascular (CV) risk as systolic blood pressure (BP) increases. Maximising CV risk reduction must be reconciled with minimising the risk of treatment-related harms and burden, especially among frail, multi-morbid and older old patients who have been excluded from most randomised trials. Contemporary clinical guidelines, based on such trials, differ in their recommendations as to threshold levels warranting treatment with antihypertensive drugs (AHDs) and target levels that should be achieved. In optimising AHD prescribing in older patients, we propose the following decision framework: decide therapeutic goals in accordance with patient characteristics and preferences; estimate absolute CV risk; measure and profile BP accurately in ways that account for lability in BP levels and minimise error in BP measurement; determine threshold and target BP levels likely to confer net benefit, taking into account age, co-morbidities, frailty and cognitive function; and consider situations that warrant AHD deprescribing on the basis of potential current or future harm. In applying this framework to older persons, and based on a review of relevant randomised trials and observational studies, individuals most likely to benefit from treating systolic BP to no less than 130mmHg are those of any age who are fit and have high baseline systolic BP (≥160mmHg); high CV risk, i.e. established CV disease or risk of CV events exceeding 20% at 10years; previous stroke or transient ischaemic attack; heart failure; and stage 3-4 chronic kidney disease with proteinuria. Individuals most likely to be harmed from treating BP to target systolic <140mmHg are those who have no CV disease and aged over 80years; moderate to severe frailty, cognitive impairment or functional limitations; labile BP and/or history of orthostatic hypotension, syncope and falls; or life expectancy < 12months. Treatment should never be so intense as to reduce diastolic BP to < 60mmHg in any older person. At a time when guidelines are calling for less conservative management of hypertension in all age groups, we contend that a more temperate approach, such as that offered here and based on the totality of available evidence, may assist in maximising net benefit in older patients.

Abstract P343: Utility of Autonomic Testing for the Diagnosis of Neurogenic Orthostatic Hypotension and Subsequent Management With Droxidopa

A 62-year-old man with a history of Hodgkin lymphoma, lupus, type 2 diabetes mellitus, neuropathy, hypercholesterolemia, hypothyroidism, and orthostatic hypotension who was taking gabapentin, saxagliptin, pravastatin, levothyroxine sodium, omeprazole, prednisone, midodrine, and fludrocortisone was evaluated for syncope, collapse, and fluctuating blood pressure (BP). He reported a 2-year history of syncope, with progressive worsening over a 3-month period. Initially, his episodes of syncope were preceded by dizziness and nausea, but began to occur without warning. He also reported a 5-year history of orthostatic hypotension, with supine BP of 100/60 mmHg and standing BP of 50-60/40 mmHg. Treatment with midodrine (10 mg three times daily) and fludrocortisone (0.1 mg twice daily [BID]) did not relieve his symptoms. Initial cardiac evaluation revealed a systolic murmur, but was otherwise unremarkable. Autonomic function tests, including continuous electrocardiography, BP and heart rate monitoring at 2-min intervals, and transcranial Doppler, were performed in the supine and 80° head-up tilt positions. A BP drop from 112/68 mmHg to 76/60 mmHg occurred within 2 min of tilt, accompanied by dizziness and presyncope. Heart rate with deep breathing revealed a depressed baseline autonomic tone, and a Valsalva maneuver test showed a depressed Valsalva response (Valsalva ratio: 1.15). Taken together, these results indicated a diagnosis of neurogenic orthostatic hypotension (nOH). Treatment with droxidopa (100 mg BID) was initiated; this dose was titrated to 100 mg once daily due to hypertension, for which, a nitroglycerin patch (0.2 mg nightly) was prescribed. All other medications were continued. Treatment with droxidopa significantly improved his symptoms; he no longer loses consciousness upon positional change, but still experiences some symptoms of presyncope (eg, slight lightheadedness, dizziness). This has allowed greater integration into activities of daily living and a less strenuous routine for the patient and his caretakers . In conclusion, autonomic function testing in this patient effectively led to a timely diagnosis of nOH which, in turn, allowed for implementation of appropriate pharmacologic intervention to manage symptoms.

Laryngeal dystonia in the course of multiple system atrophy: a cause of postoperative respiratory insufficiency

Multiple system atrophy (MSA) is an adult onset, incurable neurodegenerative disease, characterized by symptoms of nervous system failure. Occurrence of laryngeal dystonia indicates increased risk of sudden death caused by airway occlusion. We present the case report of 63-year-old patient with history of orthostatic hypotension, parkinsonism, progressive adynamia, and stridor. The patient was admitted to the hospital for diagnosis of orthostatic hypotension. A diagnosis of possible MSA was made. Because of patient’s complaints, an X-ray of the hip joint was taken. It revealed femoral neck fracture. Endoprosthesis insertion under general anesthesia was performed. Two days later the patient presented progressive adynamy and respiratory insufficiency. Endotracheal intubation and respiratory support were required followed by extubation and one more intubation. After second extubation, stridor and acute respiratory insufficiency occurred. Urgent tracheostomy was performed. After 13 days in ICU, the patient was discharged to the rehabilitation center.

Disappearance of “phantom limb” and amputated arm usage during dreaming in REM sleep behaviour disorder

Limb amputation is followed, in approximately 90% of patients, by “phantom limb” sensations during wakefulness. When amputated patients dream, however, the phantom limb may be present all the time, part...

Mutual control of breathing and blood pressure: case report

Trial outcome. To demonstrate the relationship between circulation and breathing with orthostasis in a tetraplegic man. A long-term care unit at a Veterans Administration Hospital, USA. A tetraplegic patient with a history of orthostatic hypotension was monitored for blood flow at the level of the supraorbital artery, for breathing by nasal air flow, and for pulse oxymetry on a tilt table at 0, 45 and 0 degrees of head elevation. Tilting up caused a coincidental reduction in blood flow and enhanced breathing. These effects were coincidentally reversed by tilting down. Oxyhemoglobin concentration and pulse rates increased with orthostasis and returned to baseline on tilting down. A reciprocal relationship between breathing and circulation has been demonstrated in a tetraplegic patient challenged by orthostasis.

Too hot to handle: heat stroke in multiple system atrophy

Too hot to handle: heat stroke in multiple system atrophy

Vasopressin administration facilitates fluid removal during hemodialysis

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal. To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase. We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed. Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription. We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024). Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01). Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid. Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

Refractory hyponatremia

Refractory hyponatremia

Treatment of post-dialytic orthostatic hypotension with an inflatable abdominal band in hemodialysis patients

The purpose of this study was to ascertain whether abdominal compression with an inflatable abdominal band, a device we developed, improved post-dialytic orthostatic hypotension (OH) in hemodialysis (HD) patients. Twenty-five chronic HD patients with intractable post-dialytic OH were recruited. Post-HD changes in systolic blood pressure (DeltaSBP) in the supine and standing positions were compared in the patients, measured with or without the use of the band. The study showed DeltaSBP after HD without the band was significantly greater than that measured before HD (-36.1+/-18.2 vs -13.1+/-16.8 mm Hg; P<0.0001). DeltaSBP after HD with the band was reduced significantly in comparison to DeltaSBP after HD without the band (-19.4+/-21.2 vs -36.1+/-18.2 mm Hg; P<0.002). Use of the band did not cause an elevation in SBP in the supine position (149.0+/-29.6 vs 155.4+/-25.7 mm Hg); however, it did increase SBP upon standing (129.6+/-27.3 vs 117.2+/-22.6 mm Hg; P<0.05). Eight patients in whom an increase in SBP of 25 mm Hg or more was achieved with the band were classified as responders. Ejection fraction was significantly higher (76.4+/-11.1 vs 61.9+/-13.6%; P<0.02) and atrial natriuretic peptide concentration significantly lower (27.9+/-22.0 vs 68.9+/-47.5 pg/ml; P<0.02) in responders than in non-responders. We conclude that the abdominal band was effective for overcoming post-dialytic OH, without elevating supine SBP in some patients.

Slow-transit constipation: solitary symptom of a systemic gastrointestinal disease.

Autonomic neuropathy is thought to play a role in the pathogenesis of slow-transit constipation, but other gastrointestinal organs may also be involved, even if they are symptom-free. We investigated whether motility in gastrointestinal organs other than the colon was impaired in patients with slow-transit constipation and whether the autonomic nervous system was involved. Twenty-one consecutive patients (18 females; median age, 46 years) with severe chronic constipation (< or = 2 defecations/week and delayed colonic transit time) were studied. Autonomic neuropathy function was tested with esophageal manometry, gastric and gallbladder emptying (fasting and postprandial motility) by ultrasonography, orocecal transit time (H2-breath test), colonic transit time (radiopaque markers), and anorectal volumetric manometry. The integrity of the autonomic nervous system was assessed by a quantitative sweat-spot test for preganglionic and postganglionic fibers, tilt-table test, and Valsalva electrocardiogram R-R ratio. Esophageal manometry showed gastroesophageal reflux or absence of peristalsis in five of the seven patients examined. Gallbladder dysmotility (i.e., increased fasting, postprandial residual volume, or both) was observed in 6 of 14 (43 percent) patients. Gastric emptying was decreased in 13 of 17 (76 percent) patients. Orocecal transit time was delayed in 18 of 20 (90 percent) patients; median transit time was 160 (range, 90-200) minutes. Median colonic transit time was 97 (range, 64-140) hours. Anorectal function showed abnormal rectoanal inhibitory reflex and decreased rectal sensitivity in 11 of 19 (58 percent) patients. Signs of autonomic neuropathy of the sympathetic cholinergic system were found in 14 of 18 (78 percent) patients. Only one of nine patients had vagal abnormalities detected with the Valsalva test and four of five patients with a history of orthostatic hypotension had a positive tilt-table test. Slow-transit constipation may be associated with impaired function of other gastrointestinal organs. More than 70 percent of patients with slow-transit constipation present some degree of autonomic neuropathy. Severe constipation may be the main complaint in patients with a systemic disease involving several organs and possibly involving the autonomic nervous system. This should be considered in the management of such cases.

Orthostatic vital signs: Variation with age, specificity, and sensitivity in detecting a 450-mL blood loss

The authors conducted this study to: (1) determine the effect of age on orthostatic vital signs; and (2) to define the sensitivity and specificity of alternative definitions of “abnormal” orthostatic vital signs in blood donors sustaining an acute 450-mL blood loss. The population studied were 100 healthy adult volunteer blood donors and 100 self-sufficient ambulatory citizens attending a senior citizens daytime activity center. Subjects with a history of orthostatic hypotension were excluded. Subjects were first placed in the recumbent position and their rate pulse and blood pressure were determined after 1 minute; these same parameters were measured in the same arm beginning 30 seconds after standing. In blood donors measurement of orthostatic vital signs was repeated immediately after blood donation. Blood donors served as their own controls in the determination of sensitivities and specificities. Mean orthostatic vital sign changes were as follows: pulse rate, 2 ± 7 beats per minute; systolic blood pressure, −3 ± 9 mm Hg; and diastolic blood pressure, 1 ± 7 mm Hg. There was no clinically meaningful variance in orthostatic blood pressure changes with age. For a given specificity, pulse rate increase was the most sensitive of the orthostatic vital signs used alone; a pulse rise of >20 beats per minute had a sensitivity of 9% with a specificity of 98%. The addition of diastolic blood pressure change improved sensitivity with little loss in specificity. A pulse rise of greater than 20 beats per minute or a diastolic blood pressure fall of more than 10 mm Hg resulted in a sensitivity of 17% and a specificity of 98%. The addition of systolic blood pressure change did not result in improved sensitivity for a given specificity. The authors concluded there was no clinically important difference in orthostatic vital sign changes with age in adults. No combination of orthostatic vital sign changes with a specificity of 95% or higher was sensitive enough to reliably detect an acute 450-mL blood loss.