Rheumatoid arthritis and cardiovascular complications during delivery: a United States inpatient analysis.

BACKGROUND AND AIMS: Persons with rheumatoid arthritis (RA) have an increased risk of obstetric-associated complications, as well as long-term cardiovascular (CV) risk. Hence, the aim was to evaluate the association of RA with acute CV complications during delivery admissions. METHODS: Data from the National Inpatient Sample (2004-2019) were queried utilizing ICD-9 or ICD-10 codes to identify delivery hospitalizations and a diagnosis of RA. RESULTS: A total of 12 789 722 delivery hospitalizations were identified, of which 0.1% were among persons with RA (n = 11 979). Individuals with RA, vs. those without, were older (median 31 vs. 28 years, P < .01) and had a higher prevalence of chronic hypertension, chronic diabetes, gestational diabetes mellitus, obesity, and dyslipidaemia (P < .01). After adjustment for age, race/ethnicity, comorbidities, insurance, and income, RA remained an independent risk factor for peripartum CV complications including preeclampsia [adjusted odds ratio (aOR) 1.37 (95% confidence interval 1.27-1.47)], peripartum cardiomyopathy [aOR 2.10 (1.11-3.99)], and arrhythmias [aOR 2.00 (1.68-2.38)] compared with no RA. Likewise, the risk of acute kidney injury and venous thromboembolism was higher with RA. An overall increasing trend of obesity, gestational diabetes mellitus, and acute CV complications was also observed among individuals with RA from 2004-2019. For resource utilization, length of stay and cost of hospitalization were higher for deliveries among persons with RA. CONCLUSIONS: Pregnant persons with RA had higher risk of preeclampsia, peripartum cardiomyopathy, arrhythmias, acute kidney injury, and venous thromboembolism during delivery hospitalizations. Furthermore, cardiometabolic risk factors among pregnant individuals with RA rose over this 15-year period.

Real-World Experience of Tixagevimab and Cilgavimab (Evusheld) in Rheumatologic Patients on Rituximab.

BACKGROUND/OBJECTIVE: Although vaccination is the primary strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), rheumatologic patients on B-cell depleting agent rituximab may have a suboptimal response. Tixagevimab and cilgavimab (Evusheld) could be administered under Food and Drug Administration emergency use authorization as pre-exposure prophylaxis. METHODS: A cohort study of rheumatologic patients on rituximab therapy who received Evusheld was followed longitudinally. Adverse events were monitored. RESULTS: Forty-three patients received Evusheld, with diagnoses including rheumatoid arthritis, ANCA vasculitis, immune-mediated myositis, Sjögren disease, and systemic lupus erythematosus. Average time to follow-up was 100 ± 33 days. One patient experienced symptomatic infection with SARS-CoV-2 confirmed by home antigen test twice. A total of 97.8% of patients during follow-up did not contract acute SARS-CoV-2 infection. At the same time, 32,074 new local cases were reported with a local cumulative SARS-CoV-2 incidence rate of 4.32%. Adverse events included myalgia, flu-like symptoms, fevers, injection site pain, or headache. No serious adverse events, anaphylaxis, or cardiac events occurred. CONCLUSIONS: Evusheld demonstrated effectiveness in preventing symptomatic SARS-CoV-2 infection in a real-world cohort of rheumatologic patients on rituximab therapy. Administration of Evusheld may be considered as part of a multilayered approach to risk mitigation in this high-risk population as pre-exposure prophylaxis.

A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome.

POTS (postural tachycardia syndrome) is a chronic form of OI (orthostatic intolerance). Neuropathic POTS is characterized by decreased adrenergic vasoconstriction, whereas hyperadrenergic POTS exhibits increased adrenergic vasoconstriction. We hypothesized that midodrine, an α1-adrenergic receptor agonist, would increase CVR (calf vascular resistance), decrease C(v) (calf venous capacitance) and decrease orthostatic tachycardia in neuropathic POTS, but not alter haemodynamics in hyperadrenergic POTS. A total of 20 POTS patients (12 neuropathic and eight hyperadrenergic), ages 12-20 years, participated in this randomized placebo-controlled double-blind cross-over study. Of these subjects, 15 were female. POTS subjects received 2 weeks of treatment with midodrine or placebo, with increased dosing from 2.5 to 10 mg three times daily. Following a 7-day drug-washout period, subjects received the cross-over treatment. HR (heart rate), MAP (mean arterial pressure), Q(calf) (calf blood flow) and CVR were measured supine and during 35° HUT (head-up tilt). C(v) was measured supine. In neuropathic POTS, midodrine decreased supine HR, Q(calf) and C(v), while increasing MAP and CVR compared with placebo. During HUT, in neuropathic POTS, midodrine decreased HR, Q(calf) and C(v), while increasing MAP and CVR. In hyperadrenergic POTS, placebo and midodrine both decreased upright HR and increased supine CVR. Placebo also increased supine C(v), compared with midodrine in hyperadrenergic POTS. Therefore midodrine improved postural tachycardia in neuropathic POTS by increasing CVR and decreasing Q(calf) and C(v), whereas these effects were not seen in hyperadrenergic POTS patients who experienced a placebo effect. This suggests that midodrine is probably an effective treatment for neuropathic POTS, but not for hyperadrenergic POTS.

Secondary Immunodeficiency and Vaccine Response in Rheumatoid and Psoriatic Arthritis on Immunosuppressive Medicines.

Background Rheumatoid arthritis and psoriatic arthritis patients have dysregulated immune system parameters that may increase infection risk at baseline. In addition, treatment of these conditions with immunosuppressive medications may lead to the development of secondary immunodeficiency (SID). Our objective was to assess SID in a cohort on immunosuppressive medications. We hypothesized that SID is clinically detectable by assessing immune parameters and polysaccharide and protein-based vaccination responses. Methodology A prospective cohort study of 42 subjects on immunosuppressive medications was assessed. Analysis included immunoglobulin levels, lymphocyte subsets, and two-step response to diphtheria, tetanus, and 23-valent Streptococcus pneumoniae vaccinations. Exclusions included primary immunodeficiency, malignancy, pregnancy, neutropenia, immunoglobulin replacement, prior B-cell-depleting medication or chemotherapy, use of non-immunosuppressive medication, or recent use of glucocorticoids. Suboptimal vaccine response was defined as an abnormal response based on standard criteria for each vaccine. Results Low IgM levels (below 50 mg/dL) occurred in seven (17%) subjects and IgG (below 650 mg/dL) in three (7%) subjects. Impaired lymphocyte subsets were uncommon. In total, 33 (78%) subjects completed the two-step vaccination assessment. Overall, 29 of 33 (88%) subjects demonstrated suboptimal response to pneumococcal vaccination, 10 (30%) demonstrated suboptimal response to diphtheria, and four (12%) to tetanus. Two (6%) subjects demonstrated suboptimal response to all vaccinations. Finally, 31 (94%) subjects demonstrated suboptimal response to at least one vaccination. Conclusions SID may develop, is clinically detectable, and most notably demonstrated in suboptimal responses to polysaccharide vaccinations, especially against S. pneumoniae.

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome.

Neurocognition is impaired in chronic fatigue syndrome (CFS). We propose that the impairment relates to postural cerebral hemodynamics. Twenty-five CFS subjects and twenty control subjects underwent incremental upright tilt at 0, 15, 30, 45, 60, and 75° with continuous measurement of arterial blood pressure and cerebral blood flow velocity (CBFV). We used an n-back task with n ranging from 0 to 4 (increased n = increased task difficulty) to test working memory and information processing. We measured n-back outcomes by the number of correct answers and by reaction time. We measured CBFV, critical closing pressure (CCP), and CBFV altered by neuronal activity (activated CBFV) during each n value and every tilt angle using transcranial Doppler ultrasound. N-back outcome in control subjects decreased with n valve but was independent of tilt angle. N-back outcome in CFS subjects decreased with n value but deteriorated as orthostasis progressed. Absolute mean CBFV was slightly less than in control subjects in CFS subject at each angle. Activated CBFV in control subjects was independent of tilt angle and increased with n value. In contrast, activated CBFV averaged 0 in CFS subjects, decreased with angle, and was less than in control subjects. CCP was increased in CFS subjects, suggesting increased vasomotor tone and decreased metabolic control of CBFV. CCP did not change with orthostasis in CFS subjects but decreased monotonically in control subjects, consistent with vasodilation as compensation for the orthostatic reduction of cerebral perfusion pressure. Increasing orthostatic stress impairs neurocognition in CFS subjects. CBFV activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased CCP and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.

Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome.

CFS (chronic fatigue syndrome) is commonly co-morbid with POTS (postural tachycardia syndrome). Individuals with CFS/POTS experience unrelenting fatigue, tachycardia during orthostatic stress and ill-defined neurocognitive impairment, often described as 'mental fog'. We hypothesized that orthostatic stress causes neurocognitive impairment in CFS/POTS related to decreased CBFV (cerebral blood flow velocity). A total of 16 CFS/POTS and 20 control subjects underwent graded tilt table testing (at 0, 15, 30, 45, 60 and 75°) with continuous cardiovascular, cerebrovascular, and respiratory monitoring and neurocognitive testing using an n-back task at each angle. The n-back task tests working memory, concentration, attention and information processing. The n-back task imposes increasing cognitive challenge with escalating (0-, 1-, 2-, 3- and 4-back) difficulty levels. Subject dropout due to orthostatic presyncope at each angle was similar between groups. There were no n-back accuracy or RT (reaction time) differences between groups while supine. CFS/POTS subjects responded less correctly during the n-back task test and had greater nRT (normalized RT) at 45, 60 and 75°. Furthermore, at 75° CFS/POTS subjects responded less correctly and had greater nRT than controls during the 2-, 3- and 4-back tests. Changes in CBFV were not different between the groups and were not associated with n-back task test scores. Thus we conclude that increasing orthostatic stress combined with a cognitive challenge impairs the neurocognitive abilities of working memory, accuracy and information processing in CFS/POTS, but that this is not related to changes in CBFV. Individuals with CFS/POTS should be aware that orthostatic stress may impair their neurocognitive abilities.

A 15-year-old female with amenorrhea, abdominal distention, and elevated human chorionic gonadotropin: pregnancy, right? Not so fast .

Nongestational choriocarcinoma, a rare ovarian tumor, may present in young women with amenorrhea, abdominal distention, and elevated urine human chorionic gonadotropin (hCG), all of which may be mistaken for pregnancy. A 15-year-old Hispanic female, who reported no sexual activity, presented with 6 months of amenorrhea, abdominal pain, and progressive abdominal distension. Initially, suspicion of pregnancy was considered. Physical examination was significant for abdominal distension, but no uterine fundus or fetal anatomy could be palpated, and auscultation did not reveal any fetal heart sounds or bruits. Laboratory values showed elevated urine hCG, cancer antigen 125, and cancer antigen 19.9 levels but normal serum hCG level and was inconsistent with pregnancy. Computed tomographic scans revealed a large abdominal heterogeneous mass and pleural effusions. Salpingo-oophorectomy with total omentectomy and inversion appendectomy removed a 21 × 20.5 × 16.5-cm tumor. Pathological testing determined it to be a nongestational choriocarcinoma. This rare tumor is more common in the pediatric adolescent population than in adults. Surgical resection and chemotherapy often result in a positive prognosis. In female adolescent patients presenting with elevated hCG level, amenorrhea, and abdominal distention, choriocarcinoma should be considered, especially in those with no history of sexual activity or before menarche.

Real-World Effectiveness of Tixagevimab and Cilgavimab (Evusheld) in Patients With Hematological Malignancies.

Background: Immunocompromised individuals with hematological malignancy have increased risk for poor outcomes and death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This special population may mount a suboptimal response to vaccination. We assessed the effectiveness of tixagevimab and cilgavimab (Evusheld), a monoclonal antibody combination against SARS-CoV-2, in conjunction with standard preventative measures, at preventing symptomatic incident infection. Methods: Patients aged 18 years and older with hematological malignancy consented to receive Evusheld. Patients were followed longitudinally for development of symptomatic incident SARS-CoV-2 infections. Adverse events were monitored. Results: Two hundred and three patients (94 female) with hematological malignancies and mean age 72 ± 10 years were included. Of the patients, 99.5% had received at least one mRNA vaccination against SARS-CoV-2. Average time of follow-up was 151 ± 50 days. Nineteen patients (9.3%) developed incident symptomatic SARS-CoV-2 infection, with only one (0.5%) requiring hospitalization. During the same follow-up period, local incident rate of infection was 84,123 cases (11.3% of population). Of those, 3,386 cases (4%) of SARS-CoV-2 required hospital admission. The incidence rate ratio was 0.79. No serious adverse events occurred following administration of Evusheld. Conclusion: Patients with hematological malignancy who received Evusheld infrequently developed symptomatic infections or require hospitalization. The high-risk cohort incidence was at least as comparable to the average risk general population. Evusheld appears effective and is well tolerated, and may be administered in conjunction with vaccination and standard prevention measures, at decreasing incident SARS-Co-V2 cases in this high-risk population.

Respiration drives phase synchronization between blood pressure and RR interval following loss of cardiovagal baroreflex during vasovagal syncope.

Loss of the cardiovagal baroreflex (CVB), thoracic hypovolemia, and hyperpnea contribute to the nonlinear time-dependent hemodynamic instability of vasovagal syncope. We used a nonlinear phase synchronization index (PhSI) to describe the extent of coupling between cardiorespiratory parameters, systolic blood pressure (SBP) or arterial pressure (AP), RR interval (RR), and ventilation, and a directional index (DI) measuring the direction of coupling. We also examined phase differences directly. We hypothesized that AP-RR interval PhSI would be normal during early upright tilt, indicating intact CVB, but would progressively decrease as faint approached and CVB failed. Continuous measurements of AP, RR interval, respiratory plethysomography, and end-tidal CO2 were recorded supine and during 70-degree head-up tilt in 15 control subjects and 15 fainters. Data were evaluated during five distinct times: baseline, early tilt, late tilt, faint, and recovery. During late tilt to faint, fainters exhibited a biphasic change in SBP-RR interval PhSI. Initially in fainters during late tilt, SBP-RR interval PhSI decreased (fainters, from 0.65±0.04 to 0.24±0.03 vs. control subjects, from 0.51±0.03 to 0.48±0.03; P<0.01) but then increased at the time of faint (fainters=0.80±0.03 vs. control subjects=0.42±0.04; P<0.001) coinciding with a change in phase difference from positive to negative. Starting in late tilt and continuing through faint, fainters exhibited increasing phase coupling between respiration and AP PhSI (fainters=0.54±0.06 vs. control subjects=0.27±0.03; P<0.001) and between respiration and RR interval (fainters=0.54±0.05 vs. control subjects=0.37±0.04; P<0.01). DI indicated respiratory driven AP (fainters=0.84±0.04 vs. control subjects=0.39±0.09; P<0.01) and RR interval (fainters=0.73±0.10 vs. control subjects=0.23±0.11; P<0.001) in fainters. The initial drop in the SBP-RR interval PhSI and directional change of phase difference at late tilt indicates loss of cardiovagal baroreflex. The subsequent increase in SBP-RR interval PhSI is due to a respiratory synchronization and drive on both AP and RR interval. Cardiovagal baroreflex is lost before syncope and supplanted by respiratory reflexes, producing hypotension and bradycardia.

Ascorbate improves circulation in postural tachycardia syndrome.

Low flow postural tachycardia syndrome (LFP) is associated with vasoconstriction, reduced cardiac output, increased plasma angiotensin II, reduced bioavailable nitric oxide (NO), and oxidative stress. We tested whether ascorbate would improve cutaneous NO and reduce vasoconstriction when delivered systemically. We used local cutaneous heating to 42°C and laser Doppler flowmetry to assess NO-dependent conductance (%CVC(max)) to sodium ascorbate and the systemic hemodynamic response to ascorbic acid in 11 LFP patients and in 8 control subjects (aged 23 ± 2 yr). We perfused intradermal microdialysis catheters with sodium ascorbate (10 mM) or Ringer solution. Predrug heat response was reduced in LFP, particularly the NO-dependent plateau phase (56 ± 6 vs. 88 ± 7%CVC(max)). Ascorbate increased baseline skin flow in LFP and control subjects and increased the LFP plateau response (82 ± 6 vs. 92 ± 6 control). Systemic infusion experiments used Finometer and ModelFlow to estimate relative cardiac index (CI) and forearm and calf venous occlusion plethysmography to estimate blood flows, peripheral arterial and venous resistances, and capacitance before and after infusing ascorbic acid. CI increased 40% after ascorbate as did peripheral flows. Peripheral resistances were increased (nearly double control) and decreased by nearly 50% after ascorbate. Calf capacitance and venous resistance were decreased compared with control but normalized with ascorbate. These data provide experimental support for the concept that oxidative stress and reduced NO possibly contribute to vasoconstriction and venoconstriction of LFP.

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity.

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.

Cutaneous constitutive nitric oxide synthase activation in postural tachycardia syndrome with splanchnic hyperemia.

Models of microgravity are linked to excessive constitutive nitric oxide (NO) synthase (NOS), splanchnic vasodilation, and orthostatic intolerance. Normal-flow postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance associated with splanchnic hyperemia. To test the hypothesis that there is excessive constitutive NOS in POTS, we determined whether cutaneous microvascular neuronal NO and endothelial NO are increased. We performed two sets of experiments in POTS and control subjects aged 21.4 ± 2 yr. We used laser-Doppler flowmetry to measure the cutaneous response to local heating as an indicator of bioavailable neuronal NO. To test for bioavailable endothelial NO, we infused intradermal acetylcholine through intradermal microdialysis catheters and used the selective neuronal NOS inhibitor l-N(ω)-nitroarginine-2,4-L-diamino-butyric amide (N(ω), 10 mM), the selective inducible NOS inhibitor aminoguanidine (10 mM), the nonspecific NOS inhibitor nitro-l-arginine (NLA, 10 mM), or Ringer solution. The acetylcholine dose response and the NO-dependent plateau of the local heating response were increased in POTS compared with those in control subjects. The local heating plateau was significantly higher, 98 ± 1%maximum cutaneous vascular conductance (%CVC(max)) in POTS compared with 88 ± 2%CVC(max) in control subjects but decreased to the same level with N(ω) (46 ± 5%CVC(max) in POTS compared with 49 ± 4%CVC(max) in control) or with NLA (45 ± 3%CVC(max) in POTS compared with 47 ± 4%CVC(max) in control). Only NLA blunted the acetylcholine dose response, indicating that NO produced by endothelial NOS was released by acetylcholine. Aminoguanidine was without effect. This is consistent with increased endothelial and neuronal NOS activity in normal-flow POTS.

Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation.

Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18-26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V(E)), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V(E) increased from 8.8 ± 1.3 l/min in room air to 14.6 ± 0.8 l/min during hypoxia and to 20.1 ± 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V(E) doubled during SNP. CO increased from 4.9 ± .3 l/min in room air to 6.1 ± .6 l/min during hypoxia and 6.4 ± .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V(E) versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia.

Increased pulsatile cerebral blood flow, cerebral vasodilation, and postsyncopal headache in adolescents.

OBJECTIVE: We hypothesize that, after a sudden decrease in cerebral blood flow velocity (CBFV) in adolescents, a faint, rapid hyperemic pulsatile CBFV occurs upon the patient's return to the supine position and is associated with postsyncopal headache. STUDY DESIGN: This case-control study involved 16 adolescent subjects with a history of fainting and headaches. We induced fainting during 70° tilt-table testing and measured mean arterial pressure, heart rate, end-tidal CO(2), and CBFV. Fifteen control subjects were similarly evaluated with a tilt but did not faint, and comparisons with fainters were made at equivalent defined time points. RESULTS: Baseline values were similar between the groups. Upon fainting, mean arterial pressure decreased 49% in the patients who fainted vs 6% in controls (P < .001). The heart rate decreased 15% in fainters and increased 35% in controls (P < .001). In patients who fainted, cerebrovascular critical closing pressure increased markedly, which resulted in reduced diastolic (-66%) and mean CBFV (-46%) at faint; systolic CBFV was similar to controls. Pulsatile CBFV (systolic-diastolic CBFV) increased 38% in fainters, which caused flow-mediated dilatation of cerebral vessels. When the fainters returned to the supine position, CBFV exhibited increased systolic and decreased diastolic flows compared with controls (P < .02). CONCLUSION: Increased pulsatile CBFV during and after faint may cause postsyncopal cerebral vasodilation and headache.

Initial orthostatic hypotension in the young is attenuated by static handgrip.

Initial orthostatic hypotension is common in children. Isometric handgrip increases arterial pressure, central blood volume, cardiac output, and total peripheral resistance. We show that in 14 subjects with initial orthostatic hypotension, isometric handgrip coupled with standing abolished symptoms of initial orthostatic hypotension and minimized decreases in blood pressure and cardiac output with standing.

Postural change alters autonomic responses to breath-holding.

OBJECTIVE: We used breath-holding during inspiration as a model to study the effect of pulmonary stretch on sympathetic nerve activity. METHODS: Twelve healthy subjects (7 females, 5 males; 19-27 years) were tested while they performed an inspiratory breath-hold, both supine and during a 60 degrees head-up tilt (HUT 60). Heart rate (HR), mean arterial blood pressure (MAP), respiration, muscle sympathetic nerve activity (MSNA), oxygen saturation (SaO(2)) and end tidal carbon dioxide (ETCO(2)) were recorded. Cardiac output (CO) and total peripheral resistance (TPR) were calculated. RESULTS: While breath-holding, ETCO(2) increased significantly from 41 +/- 2 to 60 +/- 2 Torr during supine (p < 0.05) and 38 +/- 2 Torr to 58 +/- 2 during HUT60 (p < 0.05); SaO(2) decreased from 98 +/- 1.5% to 95 +/- 1.4% supine, and from 97 +/- 1.5% to 94 +/- 1.7% during HUT60 (p = NS). MSNA showed three distinctive phases, a quiescent phase due to pulmonary stretch associated with decreased MAP, HR, CO, and TPR; a second phase of baroreflex-mediated elevated MSNA which was associated with recovery of MAP and HR only during HUT60; CO and peripheral resistance returned to baseline while supine and HUT60; a third phase of further increased MSNA activity related to hypercapnia and associated with increased TPR. INTERPRETATION: Breath-holding results in initial reductions of MSNA, MAP, and HR by the pulmonary stretch reflex followed by increased sympathetic activity related to the arterial baroreflex and chemoreflex.

Decreased upright cerebral blood flow and cerebral autoregulation in normocapnic postural tachycardia syndrome.

Postural tachycardia syndrome (POTS), a chronic form of orthostatic intolerance, has signs and symptoms of lightheadedness, loss of vision, headache, fatigue, and neurocognitive deficits consistent with reductions in cerebrovascular perfusion. We hypothesized that young, normocapnic POTS patients exhibit abnormal cerebral autoregulation (CA) that results in decreased static and dynamic cerebral blood flow (CBF) autoregulation. All subjects had continuous recordings of mean arterial pressure (MAP) and CBF velocity (CBFV) using transcranial Doppler sonography in both the supine supine position and during a 70 degrees head-up tilt. During tilt, POTS patients (n = 9) demonstrated a higher heart rate than controls (n = 7) (109 +/- 6 vs. 80 +/- 2 beats/min, P < 0.05), whereas controls demonstrated a higher MAP than POTS (87 +/- 2 vs. 77 +/- 3 mmHg, P < 0.05). Also during tilt, mean CBFV decreased 19.5 +/- 2.6% in POTS patients versus 10.3 +/- 2.0% in controls (P < 0.05). We then used a transfer function analysis of MAP and CFBV in the frequency domain to quantify these changes. The low-frequency (LF; 0.04-0.15 Hz) component of CBFV variability increased during tilt in POTS patients (supine: 3 +/- 0.9 vs. tilt: 9 +/- 2, P < 0.02). In POTS patients, there was an increase in LF and high-frequency coherence between MAP and CBFV, an increase in LF gain, and a lack of significant change in phase. Static CA may be less effective in POTS patients compared with controls, since immediately after tilt CBFV decreased more in POTS patients and was highly oscillatory and autoregulation did not restore CBFV to baseline values until the subjects became supine. Dynamic CA may be less effective in POTS patients because MAP and CBFV during tilt became almost perfectly synchronous. We conclude that dynamic and static autoregulation of CBF are less effective in POTS patients compared with control subjects during orthostatic challenge.

Increased phase synchronization and decreased cerebral autoregulation during fainting in the young.

Vasovagal syncope may be due to a transient cerebral hypoperfusion that accompanies frequency entrainment between arterial pressure (AP) and cerebral blood flow velocity (CBFV). We hypothesized that cerebral autoregulation fails during fainting; a phase synchronization index (PhSI) between AP and CBFV was used as a nonlinear, nonstationary, time-dependent measurement of cerebral autoregulation. Twelve healthy control subjects and twelve subjects with a history of vasovagal syncope underwent 10-min tilt table testing with the continuous measurement of AP, CBFV, heart rate (HR), end-tidal CO2 (ETCO2), and respiratory frequency. Time intervals were defined to compare physiologically equivalent periods in fainters and control subjects. A PhSI value of 0 corresponds to an absence of phase synchronization and efficient cerebral autoregulation, whereas a PhSI value of 1 corresponds to complete phase synchronization and inefficient cerebral autoregulation. During supine baseline conditions, both control and syncope groups demonstrated similar oscillatory changes in phase, with mean PhSI values of 0.58+/-0.04 and 0.54+/-0.02, respectively. Throughout tilt, control subjects demonstrated similar PhSI values compared with supine conditions. Approximately 2 min before fainting, syncopal subjects demonstrated a sharp decrease in PhSI (0.23+/-0.06), representing efficient cerebral autoregulation. Immediately after this period, PhSI increased sharply, suggesting inefficient cerebral autoregulation, and remained elevated at the time of faint (0.92+/-0.02) and during the early recovery period (0.79+/-0.04) immediately after the return to the supine position. Our data demonstrate rapid, biphasic changes in cerebral autoregulation, which are temporally related to vasovagal syncope. Thus, a sudden period of highly efficient cerebral autoregulation precedes the virtual loss of autoregulation, which continued during and after the faint.

Severe cholestatic hyperbilirubinaemia secondary to thyrotoxicosis complicated with bile cast nephropathy treated with plasma exchange and haemodialysis.

Thyrotoxicosis rarely presents as cholestatic hyperbilirubinaemia, and severe bilirubin elevation may lead to bile cast nephropathy. We present a case of a young woman with newly diagnosed Graves' disease with thyrotoxicosis who developed severe hyperbilirubinaemia and bile cast nephropathy. Serial plasma exchange and temporary haemodialysis led to full renal recovery. After treatment of her thyrotoxicosis with antithyroid medication and radioactive iodine ablation, her bilirubin normalised.