Long-term effects of pharmacological therapy for vasovagal syncope on the basis of reproducibility during head-up tilt testing

The purpose of this study was to determine the efficacy of long-term pharmacological therapy selected on the basis of a head-up tilt test (HUT) in patients in whom reproducibility of the HUT response was demonstrable in the initial study. The HUT (80 degrees upright) was performed for 15 min with or without an infusion of isoproterenol (0.01-0.03 microgram/kg per min) in 54 patients with recurrent unexplained syncope. When vasovagal syncope was induced (positive response), the HUT was repeated to examine the test reproducibility. Vasovagal syncope was induced in 24 patients during HUT alone, and in 30 patients during the HUT with isoproterenol. Acute reproducibility was observed in 49/54 (91%) patients. In the tilt-positive patients, HUT was repeated after an intravenous administration of propranolol (0.1 mg/kg) or disopyramide (1 mg/kg) (acute test). Propranolol proved effective in 21 (80%) of 26 patients, and disopyramide in 13 (56%) of 23 patients. Thereafter, evaluation was done on the long-term clinical follow-up of the pharmacological intervention selected on the basis of the acute test in the 34 patients in whom the HUT could not induce vasovagal syncope after the oral administration of the pharmacological agent (propranolol 60 mg/day, disopyramide 300 mg/day). Thirty-two of 34 patients (94%) did not develop syncopal attacks during a 44 +/- 12-month period. Thus, in patients with unexplained syncope, HUT appears to have a high degree of acute reproducibility, and the acute drug response guided by HUT may be used to develop an effective long-term pharmacological therapy.     

Response and mechanism of vasovagal syncope induced by tilt table test]

Although the benefits of relaxation are widely recognized, clinicians need to remain cognizant of its possible adverse effects. Equally, some people with mental illness may experience an exacerbation of their symptoms with the injudicious use of relaxation techniques that use imagery. This paper explores two conditions where vivid, often emotionally charged, images are problematic: (i) post traumatic stress disorder; and (ii) hallucinoses. Individuals who have these disorders may have difficulty controlling shifts between these internal and external events, or difficulty even recognising events as internal rather than external. Employing a relaxation technique that encourages imagery is likely to produce a stronger reaction because the impact of the imagery is increased by relaxation. This would result in an increase in arousal, the antithesis of relaxation. This paper suggests that relaxation techniques that avoid imagery or consider the patient's experience would be less likely to provoke unwanted reactions.     

Response to head-up tilt testing in patients with situational syncope

The results of head-up tilt testing were compared between 24 patients with situational syncope and 44 age-matched patients with typical vasovagal syncope. Patients with situational syncope showed poor positive responses, especially in the passive tilt results (8.3% vs. 39%, p = 0.0078).     

Role of endogenous opioids in syncope induced by head-up tilt test and its relationship with isoproterenol-dependent and isoproterenol-independent neurally-mediated syncope

Pleural dissemination in lung cancer was prospectively evaluated by helical computed tomography (CT), and the usefulness of thick-section CT (10-mm collimation; pitch 1) and thin-section CT (2-mm collimation; pitch 1) were compared. The study included 54 patients with pulmonary adenocarcinoma in whom plain chest radiographs showed no evidence of pleural effusion and in whom the primary lesion was seen to be contiguous with the pleural surface on thick-section CT. Thin-section CT was performed for evaluation of the costal, mediastinal, interlobar, and diaphragmatic pleural surfaces. Pathologic examination revealed pleural dissemination in 20 patients (8 resected, 12 nonresected). Pleural dissemination was diagnosed in 12 patients on thick-section CT, and in 20 patients on thin-section CT. False negatives occurred in ten and two patients, respectively. The same two patients were false positives by both methods. Accuracy was 78% for thick-section CT and 93% for thin-section CT, and sensitivity was 50% and 90%, respectively. Thin-section CT provided more useful information than thick-section CT for the evaluation of pleural dissemination in lung cancer.     

Worsening of head-up tilt test response during chronic beta-blocker therapy in patients treated for neurally mediated syncope

The prognosis of patients with neurally mediated syncope and asystolic response at tilt test is controversial and there is no consensus regarding their management. Many patients seem to benefit from beta-blockers and their effectiveness has been assessed with repeated tilt tests in asystolic patients as well. However, little is known about the long-term effects of beta-blockers. Preliminary data and isolated reports suggest that in some cases, these agents may actually worsen the clinical outcome or the tilt test response. Three patients are described who experienced worsening of tilt test response with prolonged asystole (19.9, 9 and 5.5 sec respectively) during chronic treatment with beta-blockers in the absence of spontaneous symptoms. At discharge, one patient received a dual-chamber pace-maker combined with metoprolol, another one continued to take metoprolol and enalapril. The third patient refused any further medication. During follow-up (8, 11, 13 months respectively), they were symptom-free. The clinical and prognostic significance of this response is not clear and needs further investigation.     

Usefulness of intravenous metoprolol to prevent syncope induced by head-up tilt

Intravenous metoprolol was found to be significantly more effective than placebo in preventing head-up tilt-table induced neurally mediated syncope. The reproducibility of acute tilt-table testing is only 63% and suggests caution in the interpretation of acute drug testing during tilt-table studies.     

Usefulness of plasma catecholamines during head-up tilt as a measure of sympathetic activation in vasovagal patients

We purified and characterized a thermophilic beta-galactosidase from Thermus sp. A4 isolated from the Atagawa hot spring (Shizuoka, Japan). The enzyme was monomeric, and its molecular mass was estimated to be 75 kDa by SDS-polyacrylamide gel electrophoresis. The enzyme was extremely thermostable and retained its full activity after incubation at 70 degrees C for 20 h. The Km observed were 5.9 mM for ortho-nitrophenyl beta-D-galactopyranoside and 19 mM for lactose. We cloned and analyzed the complete sequence of the gene encoding this enzyme. It was found to consist of 645 amino acid residues. We propose that this enzyme and seven other unclassified beta-galactosidases are new members of family 42 of the glycosyl hydrolases.     

Present trends in the pathogenesis, diagnosis and therapy of vasovagal syncope

Vasovagal syncope is the most frequent cause of syncopal conditions. In its pathogenesis autonomic nervous, neurohumoral, cerebrovascular and other mechanisms participate. The gold standard in the diagnosis of vasovagal syncope is in recent years the head up tilt test. In treatment pharmacotherapy, cardiac pacing or their combination can be used.     

The specific bronchial provocation test in the diagnosis of occupational asthma

Specific bronchial challenge (SBC) testing is a key technique for diagnosing the origin of occupational asthma (OA). SBC is indicated in specific circumstances, including whenever several agents present in the work environment may be the cause of OA, when new or unusual occupational agents need to be identified, when evidence for legal action is required, or when research is conducted. SBC procedures are not standardized, because of the great diversity of occupational agents and the variety of physical and chemical properties involved. Thus, SBC testing with agents found in fumes, gases or vapors can be administered in special cabins or in closed circuits with continuous monitoring of sub-irritant concentrations. Agents found in dust, most but not all of which have high molecular weights, may be appropriate for routine SBC testing in an allergy laboratory. This paper will treat only these cases. SBC must be formed in specialized centers by experienced personnel, as it is a sophisticated and potentially dangerous technique. We describe a series of 20 patients diagnosed of OA in our unit over the past two years in whom SBC provided an etiologic diagnosis. All were exposed to dust or aerosols at work. The cause was a substance of high molecular weight in 17 cases, and low molecular weight in 3. The procedure used is described and models of bronchial response are discussed.     

Hemodynamic mechanism of vasovagal syncope

Vasovagal syncope is a common clinical problem, however the hemodynamic mechanism is not clearly understood. The aim of the present study was to investigate the circulatory control mechanism of vasovagal syncope provoked by the head-up tilt test. Thirty two patients with recurrent unexplained syncope were studied using a head-up (60 degrees) tilt test. The electrocardiogram, arterial blood pressure, pulmonary arterial pressure and central venous pressure were monitored continuously, and the cardiac output was measured by the thermodilution method. Twenty patients (62.5%) had positive tilt test responses, of which 12 developed typical vasovagal syncope with marked hypotension and bradycardia; the others developed hypotension without bradycardia. There were five women and seven men with a mean age (+/- SD) of 53.3 +/- 15 years. The effect of head-up tilt resembled that of hypovolemia. The central venous pressure, pulmonary capillary wedge pressure and cardiac output declined with an increase of heart rate and systemic vascular resistance. However the mean blood pressure was maintained. During vasovagal syncope, the heart rate and blood pressure fell precipitously and significantly, the cardiac index was reduced from 2.22 +/- 0.43 to 1.51 +/- 0.32 liters/min/m2 (p value < 0.05) and the systemic vascular resistance index decreased from 3,689 +/- 859 to 1,999 +/- 543.9 dynes s cm5/m2 (p value < 0.05). The results of our study showed that both reduction of cardiac output and withdrawal of sympathetic vasoconstriction tone contribute to the development of hypotension in vasovagal syncope.     

Autonomic control of asystolic vasovagal syncope

A 30 year old woman with a lifelong history of severe, recurrent, vasovagal syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up tilt. During early tilt, sympathetic activity, heart rate, left ventricular contractility, and cardiac output increased. Mean blood pressure was initially maintained. Presyncope was associated with maximal contractility and bradycardia despite sustained sympathetic activity. Subsequently, asystole occurred associated with complete withdrawal of muscle nerve sympathetic activity. In asystolic vasovagal reactions, presyncope may be triggered by increased left ventricular contractility and is associated with increased levels of parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation may be caused by sudden and complete withdrawal of the increased sympathetic activity.     

Prediction of head-up tilt test result by analysis of early heart rate variations

BACKGROUND: Head-up tilt testing is a useful test for investigating vasovagal syncope. The determination of early, accurate, predictive criteria for a negative result would permit a reduction in the duration of the tilt test. METHODS AND RESULTS: Patients with no drug use and no illnesses other than recurrent unexplained syncope were recruited. In an initial study (110 consecutive patients), we aimed to determine a predictive criterion based on heart rate variations during the first minutes of upright tilting that could distinguish between patients with positive and negative tilt tests (patients with an early continual decrease in heart rate or blood pressure were excluded). Then we tested the predictive value of the established criterion in a second independent sample of patients with unexplained syncope (109 consecutive patients). An early sustained increase in heart rate < or = 18 bpm during the first 6 minutes of upright tilting at a 60 degree angle allowed us to predict negative tilt tests with 100% specificity, 100% positive predictive value, and 88.6% sensitivity. This criterion was validated in the second, prospective arm of the study (96.4% specificity, 98.4% positive predictive value, and 87.3% sensitivity), even with subsequent use of isoproterenol in low doses. CONCLUSIONS: In patients with no drug use and no illnesses other than recurrent unexplained syncope, a simple clinical criterion identifies patients who will not develop syncope during a prolonged upright tilt.     

Cerebral circulation dysfunction and hemodynamic abnormalities in syncope during upright tilt test

OBJECTIVE: To assess the hemodynamic features, including monitoring of cerebral circulation, blood pressure and heart rate, in syncope patients during upright tilt test. DESIGN: Nonrandomized sequential patients with history of syncope of uncertain etiology compared with healthy subjects. SETTING: Noninvasive hemodynamic laboratory of a tertiary referral centre. PATIENTS: Twenty patients with history of syncope and 10 controls without syncope. PROCEDURES: Transcranial Doppler measurement or middle cerebral artery flow velocity, noninvasive and invasive blood pressure monitoring, electrocardiography and pulse oximetry monitoring during upright tilt testing. Measurements were taken in patients at the height of symptoms in supine and upright posture. MAIN RESULTS: Ten patients, while still normotensive, had a drop of 53 +/- 10% (mean +/- SD) in cerebral bloodflow velocity (P = 0.0001) and an increase in heart rate by 58 +/- 35%. The remaining 10 patients had a 58 +/- 15% reduction in cerebral bloodflow velocity (P = 0.0001), a drop in blood pressure of 33 +/- 8% (P = 0.0001) and no change in heart rate. The controls showed no significant changes in cerebral bloodflow velocity and a 25 +/- 12% increase in heart rate (P = 0.0002). CONCLUSIONS: Transcranial Doppler monitoring of cerebral bloodflow velocity during upright tilt testing may improve insight into the complex physiology of syncope.     

A clinical study of multistage isoproterenol tilt table test for patients with unexplained syncope]

The present study examined whether eliprodil (SL 82.0715), an N-methyl-D-aspartate (NMDA) receptor antagonist acting on the polyamine sites induced expression of the 70 kDa heat shock protein (HSP70) in the rat brain. Whereas the NMDA channel blocker MK801 consistently induced HSP70 in posterior cingulate and retrosplenial cortices, eliprodil had no such effects even at the highest dose (50 mg/kg, intraperitoneally), supporting the idea that injury to the cerebrocortical neurones by NMDA receptor antagonists is probably related to specific sites of the receptor. Furthermore, eliprodil, given immediately after injection of MK801, blocked the effects of MK801 on HSP70. The result is discussed in terms of high affinity of eliprodil for the sigma receptor.     

Changes in plasma epinephrine concentration and in heart rate during head-up tilt testing in patients with neurocardiogenic syncope: correlation with successful therapy with beta-receptor antagonists

OBJECTIVE: To develop, implement and evaluate an effective and efficient heparin nomogram. DESIGN: Retrospective and prospective data collection. SETTING: Coronary care unit (CCU) of a university-affiliated hospital. PATIENTS: Patients with acute coronary ischemic syndromes requiring intravenous (i.v.) heparin who were not receiving thrombolytic and/or warfarin therapy. INTERVENTIONS: A retrospective chart review of 52 CCU patients receiving iv heparin provided the historical control group. The effectiveness of a heparin nomogram (5000 U bolus followed by an initial weight-based infusion of 15 U/kg/h with subsequent rate adjustments according to activated partial thromboplastin time [aPTT] results) was then prospectively assessed in a further 56 consecutive patients. MAIN RESULTS: The historical control and nomogram groups did not significantly differ with respect to age, weight, duration of therapy or total number of aPTTs drawn. Approximately 79% and 84% of patients in the control and nomogram groups, respectively, achieved an aPTT within the therapeutic range (60 to 90 s, P > 0.05), whereas 89% and 100% of control and nomogram patients, respectively, surpassed the therapeutic threshold (longer than 60 s) at some point during treatment (P = 0.009). Compared with empiric dose adjustment, the nomogram more effectively avoided periods of inadequate anticoagulation. Similarly, the time to achieve the therapeutic threshold was significantly longer in the control than in the nomogram group (8.2 +/- 5.9 versus 6.7 +/- 3.7 h, P = 0.026). No adverse bleeding events were noted in either group. CONCLUSIONS: Compared with conventional approaches, the heparin nomogram successfully achieved and maintained adequate anticoagulation in a greater proportion of patients with acute cardiovascular diseases without the need for additional aPTT measurements.     

Complex demodulation of cardiorespiratory dynamics preceding vasovagal syncope

BACKGROUND: The dynamic autonomic processes leading to vasovagal syncope are poorly understood. METHODS AND RESULTS: We used complex demodulation to continuously assess changes in respiration, R-R interval, and arterial pressure (blood pressure) variability during 60 degree head-up tilt in 25 healthy subjects with tilt-induced vasovagal syncope and 25 age-matched nonsyncopal control subjects. Coherence and transfer function analyses were used to examine the relation between respiration and R-R interval variability before syncope. Baseline blood pressure, R-R, and ventilation were similar between syncope subjects and control subjects. Syncope subjects experienced an increase in tidal volume and decrease in BP beginning 3 minutes before impending syncope (systolic blood pressure <80 mm Hg) necessitated termination of tilt. Approximately 90 seconds before syncope there was a sudden prolongation of R-R interval and increase in amplitude of high and low frequency R-R interval variability, indicating an abrupt enhancement of vagal tone. The increase in respiratory amplitude between 180 and 90 seconds before syncope was not accompanied by changes in R-R interval or R-R variability, suggesting a dissociation between respiration and the respiratory sinus arrhythmia. The coherence analysis showed fewer syncope subjects with coherence between respiratory and R-R interval variabilities and lower transfer magnitudes in syncope subjects compared with control subjects. Nonsyncopal subjects had no change in respiratory, R-R interval, or blood pressure dynamics during matched time periods before the time of syncope. CONCLUSIONS: Vasovagal syncope is preceded by a period of hyperpnea and cardiorespiratory decoupling followed by an abrupt increase in cardiovagal tone. Respiratory pumping without inspiratory cardiac slowing may partially counteract preload reduction until sudden bradycardia precipitates syncope.     

Tilt test in the etiological diagnosis of syncope unexplained by electrophysiological study

In order to determine the role of tilt testing in the aetiological diagnosis of syncope unexplained by electrophysiological investigation, the authors retrospectively studied the results of this test in 275 patients with a mean age of 64 +/- 16 years. These 275 patients were divided into two groups: group I: 43 patients with a mean age of 50 +/- 19 years presenting with vagal syncopes, group II: 232 patients with unexplained syncope, probably vagal: group IIa (120 patients, mean age: 67 +/- 15 years), sudden syncope: group IIb (112 patients, mean age: 67 +/- 13 years). The electrophysiological investigation was inconclusive in every case. In group II, 50% of tilt tests were positive (19% under basal conditions, 31% after isoproterenol), with 61% of positive tests in group IIa, including 31% on the basal test, and 38% of positive tests in group IIb, including 11% on the basal test. In group I, 84% of tests were positive (33% on the basal test, 51% after isoproterenol), indicating a sensitivity of the test of 84%. In 96 patients with a doubtful electrophysiological investigation, the tilt test was positive in 70% of cases, allowing specific treatment or a pacemaker to be avoided in the majority of cases. 84% of vasovagal syncopes were therefore confirmed by tilt testing; 50% of syncopes unexplained by electrophysiological investigation were demonstrated to be of vasovagal origin. The author emphasize the value of tilt testing in certain discordant situations in which the clinical context is disturbing and/or electrophysiological investigation is not completely reassuring.