Evaluation of edrophonium as a provocative agent for vasovagal syncope during head-up tilt-table testing.

Vasovagal syncope after head-up tilting is thought to be secondary to a complex, neurally-mediated reflex with both vasodepressor and cardioinhibitory efferent components. The efficacy of edrophonium, an acetylcholinesterase inhibitor, as a provocative agent for triggering syncope during head-up tilt testing was evaluated. Forty-five consecutive patients (22 female and 23 male) with history of recurrent unexplained syncope received edrophonium (10 mg intravenous) after 30 minutes of 60 degrees head-up tilting alone. Twenty normal control subjects (9 female and 11 male) were tested with head-up tilt testing and edrophonium. Syncope was induced in 19 of 45 patients with the diagnosis of unexplained syncope. In 9 patients who developed syncope with head-up tilting alone, the predominant hemodynamic finding was marked vasodepression. In contrast, in 10 patients who developed syncope only after head-up tilting and edrophonium, the predominant hemodynamic findings were marked vasodepression and bradycardia. Syncope was induced in 1 of 20 normal subjects after head-up tilting and edrophonium. There was no long-term complication from using edrophonium. It is concluded that head-up tilt testing with edrophonium: (1) significantly increases the identification of patients with vasovagal syncope, (2) may be particularly useful when provocation with isoproterenol is undesirable, and (3) may be an effective method to help differentiate patients with a significant reflex cardioinhibitory component from those with a predominantly reflex vasodepressor component.

Hemodynamic effects of edrophonium chloride (Tensilon) infusion.

The hemodynamic effects of a 10 mg bolus of edrophonium chloride followed by a continuous infusion of 0.25 to 1.0 mg per minute, were determined in unanesthetized patients with significant myocardial disease. The effect on heart rate of the drug was negated by studying a group of nine patients with complete heart block and permanently implanted ventricular pacemakers. After the 10 mg bolus, two of the nine patients experienced dizziness, nausea and abdominal cramps associated with a mild decrease in peripheral vascular resistance. There was no significant change in cardiac index, mean blood pressure, brachial artery upstroke time, corrected ejection time, or left ventricular systolic ejection time. This study demonstrated that the continuous infusion of 0.25 to 1.0 mg per minute of edrophonium chloride following a 10 mg loading dose, had no significant effect on myocardial function.

Effect of patient characteristics on the yield of prolonged baseline head-up tilt testing and the additional yield of drug provocation.

OBJECTIVE: To define the value of tilt testing and hte additional yield of drug provocation over prolonged baseline tilt in different patient subgroups. (Many different protocols are in use for head-up tilt testing in heterogeneous groups of patients. Not all patients in reported series have recurrent syncope, and there is often a wide age range and a variable incidence of structural heart disease.) DESIGN: In a prospective study, baseline 60 degrees head-up tilt testing was undertaken for 45 minutes, initially without drug provocation. Patients who remained symptom free were given intravenous isoprenaline (isoproterenol) and further tilting or edrophonium (10 mg bolus) during tilt, in an order determined randomly before the start of the test. If they were symptom free after the first drug, they were given the other drug. A positive test was recorded when syncope or pre-syncope occurred with a rapid fall (> 30%) in blood pressure. The impact on tilt result of the type of symptoms, presence of significant structural heart disease (SHD), presence of a non-cardiovascular cause of sudden diminished consciousness (SDC), and age was then assessed by subgroup analysis. PATIENTS: 145 patients (73 female, mean age 51 (25), range 8-94) with one or more episodes of pre-syncope or syncope. RESULTS: 39 patients (27%, 21 female, age 49 (25) years) had positive tests and 106 (73%, 52 female, age 52 (25) years) negative tests. 27 (69%) had a positive test during baseline tilt at 20.5 (10.8) minutes, five (13%) with isoprenaline infusion, and seven (18%) with edrophonium bolus. Patients with recurrent syncope rather than single syncopal episodes or single or recurrent pre-syncope were more likely to have a positive tilt test (41% v 17%, P < 0.005) and patients with SHD or SDC (69/14 patients) were much less likely than patients without (16% v 42%, P < 0.0001). The yield of positive tests was similar if patients were below (26%) or above (27%) the mean age (50 years). When multiple factors were combined, the yield ranged from 0% for 21 patients under 50 years with SHD or SDC and without recurrent syncope to 73% in 11 patients over 50 years with recurrent syncope and no SHD or SDC. The additional yield in subgroups over 45 minute baseline tilt (70 (11)%) of isoprenaline (13 (10)%) was similar to that of edrophonium (17 (8)%, P = NS), but six (50% of those who were drug positive) patients required a second drug to produce a positive result (two with isoprenaline second, four with edrophonium second). CONCLUSIONS: Head-up tilt testing in a heterogeneous population has a low yield. Simple clinical characteristics define the type of patient who is likely to have a positive tilt test and the patient who is not and in whom other investigations should receive priority. The great majority of positive tests will occur during prolonged baseline testing if this is used. Isoprenaline and edrophonium produced similar additional yields of positive tests.

The complication rate of edrophonium testing for suspected myasthenia gravis.

BACKGROUND: The incidence of life-threatening complications from edrophonium chloride (Tensilon) testing for suspected myasthenia gravis is thought to be extremely low. We carried out a survey to determine the rate of serious complications from such testing. METHODS: In April 1998, 357 physicians listed in the 1998 roster of the North American Neuro-ophthalmology Society were mailed a questionnaire for anonymous completion. Questions asked included the number of years the clinician had practised neuro-ophthalmology, the estimated number of edrophonium tests performed since completion of training, the number and nature of major complications from edrophonium, and whether the clinician preferred the sleep test or ice test to edrophonium testing. RESULTS: The response rate was 56% (199/357). Of the 199 respondents, 105 (53%) had practised neuro-ophthalmology for at least 10 years. The group estimated that they had performed at least 23,111 edrophonium tests, of which 37 (0.16%) were associated with a serious complication, mostly attributed to brady-arrythmias and syncope. Respiratory failure, seizure, severe vomiting and transient ischemic attack were also reported. Thirty-one respondents (16%) preferred the sleep test or ice test to the edrophonium test; one-third of this group reported a serious complication with edrophonium. INTERPRETATION: The rate of significant complications of edrophonium testing is low, but the complications can be potentially life threatening. Clinicians should know the nature and incidence of these complications when obtaining informed consent for edrophonium testing.

[Edrophonium chloride (Tensilon) test: a safe method in diagnosing myasthenia gravis]. / Der Edrophonium-Chlorid (Tensilon)-Test: Ein sichere Methode in der Diagnostik der Myasthenia gravis.

OBJECTIVE: To evaluate the safety of edrophonium chloride in the course of the Tensilon test by measurement of hemodynamic and ECG parameters and the observation of adverse events. METHODS: 25 patients with known or suspected myasthenia gravis were included in an open, prospective study concerning the performance of the Tensilon test. Blood pressure, heart rate, continuous ECG and adverse events were recorded 10 minutes following intravenous application of Tensilon. RESULTS: Blood pressure and heart rate did not change significantly during the observation period. One patient on beta-blockers developed a grade I AV block. Self-limiting adverse events of short duration were observed in 11 patients. Serious adverse events such as syncope or hemodynamic deterioration did not occur. CONCLUSION: The Tensilon test appears to be a safe procedure. A detailed clinical cardiac history, the history of medication and twelve lead ECG recordings should be documented in all patients undergoing the Tensilon test. Patients with a history of dysrhythmia receiving digitalis, beta-blocking agents or Ca antagonist therapy should be managed with special care, as Tensilon enhances vagal effects.

Clinical implications of new neuromuscular concepts and agents: so long, neostigmine! So long, sux!

Although antiquated and long targeted for obsolescence, neostigmine and succinylcholine still serve the anesthesia community, decades after their inferior pharmacological profiles have been recognized. The need to quickly establish a good intubation condition with a relaxant that will recover rapidly is fundamental to safe anesthesia practice. So is the need to restore muscle power safely and quickly at the end of surgery, by reversing a residual neuromuscular block. Recent data have shown that sugammadex can safely and rapidly reverse profound neuromuscular block established by rocuronium and vecuronium. This allows for use of rocuronium to establish a good intubation condition, and use of sugammadex to terminate the neuromuscular block at will. The present article assesses the clinical implications of such therapeutic regimen, and provides an educated guess on how the clinical neuromuscular practice might change, if and when sugammadex becomes clinically available.

Electrophysiological signs and the prevalence of adverse effects of acetylcholinesterase inhibitors in patients with myasthenia gravis.

The aim of this prospective study was to assess whether extra discharges (EDs), sometimes following the compound muscle action potential, could be used as a neurophysiological indicator of overdose of acetylcholinesterase inhibitors (AChEIs) in patients with myasthenia gravis (MG). The characteristics and frequency of EDs were explored and the correlation of EDs with cholinergic side effects was also determined. Twenty-two MG patients (14 women, 8 men; 61 +/- 16 years of age) with daily AChEI treatment were examined. The mean disease duration was 10 years (range 2-62 years) and all patients had been treated with AChEI since MG onset. Both single and repetitive stimulation of the ulnar and accessory nerves were performed before and 60 min after oral pyridostigmine bromide (PB) administration and after additional edrophonium injection. Fatigue, side effects, and AChE activity in blood were assessed before and 60 min after PB intake. The daily dose of PB ranged from 150 to 900 mg/day. Fourteen patients (64%) experienced daily cholinergic adverse effects, and muscarinic side effects correlated with AChE activity. Eleven patients (50%) developed EDs after oral PB. Among the eight patients with daily nicotinic side effects, EDs were significantly (P < 0.05) more common. Additionally, older patients were more prone to develop cholinergic side effects and EDs. Thus, when EDs are found, patients should be asked about daily muscular symptoms, which may be related to AChEI treatment and not solely to MG.

Edrophonium-induced right ventricular outflow tract tachycardia.

Idiopathic right ventricular outflow tract-ventricular tachycardia (RVOT-VT) generally occurs when sympathetic nervous system activity is increased, though, in a few patients, it develops when parasympathetic nervous activity (PNA) is increased. Among 101 consecutive patients with RVOT-VT confirmed by endocardial catheter mapping, 5 (4.9%) presented with nocturnal RVOT-VT. Autonomic nervous balance was studied by heart rate variability (HRV) analysis from 24-hour ambulatory electrocardiogram (ECG). Standard programmed ventricular stimulation (PVS), ventricular burst pacing, and drug provocation were performed to induce RVOT-VT. In the studied five patients, the average number of mostly nocturnal ventricular premature contractions (VPCs) was 6649 +/- 4472/day. Two patients had nocturnal nonsustained RVOT-VT on 24-hour ambulatory ECG recordings. The HRV analysis revealed that a progressive increase in high-frequency power coincided with an increase in VPCs or development of RVOT-VT at night, whereas low/high frequency ratio did not change significantly during the 24-hour period. RVOT-VT could not be induced by PVS, ventricular burst pacing, or isoproterenol or adenosine triphosphate i.v. However, RVOT-VT could only be induced by edrophonium, 5 mg i.v., in all patients. An increase in PNA was observed in a few patients before the development of RVOT-VT. Edrophonium facilitated induction of RVOT-VT in such patients.

Myasthenia gravis: protective effect of ipratropiumbromide (Atrovent) on airways obstruction caused by edrophonium chloride (Tensilon).

The preventive effect of Atrovent Dosier-Aerosol on the airway flow resistance (Raw) caused by Tensilon was studied on 10 patients suffering from myasthenia gravis. Atrovent completely prevented the increase of Raw in 8 cases and considerably decreased it in 2 cases. The measure of the reaction observed may be influenced by the intensity of the cholinergic symptoms occurring on administration of Tensilon as well as by the magnitude of the initial Raw value. No side-effect which may be attributed to the administration of Atrovent could be observed, the substance did not increase the myasthenic symptoms. According to the study, Atrovent is a suitable medicine for the prevention of airway obstruction caused by Tensilon.

The Tensilon test. A safe office procedure.

Myasthenia gravis in now known to be an autoimmune disorder in which damage of acetylcholine receptors takes place at the post-synaptic membrane. This new knowledge has improved therapy and placed a premium on early diagnosis. To overcome ophthalmologic reluctance to perform Tensilon testing, side effects of Tensilon are reviewed and a survey of the frequency of these side effects is reported.

Intraesophageal balloon distention versus drug provocation in the evaluation of noncardiac chest pain.

Intraesophageal balloon distention (IEBD) has been advocated as an effective provocative test for the evaluation of chest pain and dysphagia. The normal esophageal response to intraesophageal balloon distention is to generate a sustained contraction proximal to the balloon while showing a distinctive absence of activity distal to the balloon. We evaluated intraesophageal balloon distention in 62 patients with noncardiac chest pain and compared the diagnostic results to those obtained by using a combination of acid infusion, edrophonium (80 micrograms/kg iv) and bethanechol (80 micrograms/kg sq). These 62 patients were also compared with 10 normal volunteers who underwent intraesophageal balloon distention. Abnormal distal manometric activity consistent with spasm and was seen in 38/62 (61%) patients. Distal manometric activity was not seen in any normal volunteer. Diagnostic results (symptom reproduction with manometric changes but without EKG changes) were seen in 26/62 (42%) patients, but in nine of the 62 (14%) patients with combined drug provocation (p less than 0.05). Intraesophageal balloon distention is superior to a combination of provocative drugs in evaluating noncardiac chest pain symptoms. The presence of abnormal manometric activity distal to the balloon may represent regulation of esophageal motility.

Spontaneous noncardiac chest pain: value of ambulatory esophageal pH and motility monitoring.

We performed esophageal investigations in 20 patients suffering from noncardiac chest pain in order to assess the diagnostic value of short- versus long-term manometric and pH studies. Patients had baseline esophageal manometry with two provocative tests: a Bernstein test and an intravenous injection of edrophonium. On a separate occasion they had a 24-hr ambulatory esophageal pH and motility recording. The Bernstein test provoked chest pain in two patients, while edrophonium injection did not elicit pain in any of the patients. The ambulatory pH study helped to establish the esophagus as the likely source of pain in one patient, and the ambulatory motility one in another. In our experience, ambulatory pH and motility recordings have a low diagnostic yield in the evaluation of patients with noncardiac chest pain.

Edrophonium provocative test in noncardiac chest pain. Evaluation of testing techniques.

Edrophonium chloride is used frequently as a provocative agent in the assessment of noncardiac chest pain (NCCP). However, the optimum dose and most appropriate method of interpreting test results is controversial. We studied 150 consecutive NCCP patients and 50 age-matched controls who alternately received either 80 micrograms/kg or 10 mg intravenous bolus doses of edrophonium preceded by saline placebo injections. Distal esophageal pressures were measured before and after drug injection in response to ten 5-cc wet swallows. Following 10 mg of edrophonium, 33% of patients and 4% of controls reported chest pain, while 29% of patients and no controls receiving the 80 micrograms/kg dose complained of chest pain. Amplitude changes after either dose were not significantly different for all comparisons, but the duration of response did distinguish the two doses in patients with chest pain. A significantly greater (P = 0.01) increase in distal contraction duration occurred after 10 mg (74 +/- 12%; +/- SE) compared to 80 micrograms/kg dose (43 +/- 6%). However, individual responses to the two doses overlapped considerably. If a positive test is redefined to include both chest pain and manometric changes that are significantly different from controls, the positivity rate changes drastically; 33% to 9% in the 10-mg group and 30% to 3% in the 80-micrograms/kg group. Side effects were similar between doses, but there was a significant (P = 0.02) linear relationship between intensity of side effects and the edrophonium dose per kilogram of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological effects of edrophonium in the innervated and the transplanted denervated human heart.

In order to determine the mechanism of action of edrophonium on the cardiac conduction system, we used His bundle recording and pacing techniques to examine the electrophysiological effect of edrophonium in 6 patients undergoing diagnostic evaluation for coronary artery disease and in 9 cardiac transplant recipients who were free of acute graft rejection. After control measures were made of sinus cycle length, conduction intervals, and conduction system refractory periods, edrophonium was administered by constant intravenous infusion, and all electrophysiological measurements were repeated. In the normally innervated patients, edrophonium significantly increased sinus cycle length from 778 +/- 21 ms to 883 +/- 36 ms (P less than 0.01), AH interval from 88 +/- 11 ms to 100 +/- 12 ms (P less than 0.01), and AV nodal functional refractory period from 351 +/- 44 ms to 391 +/- 36 ms (P less than 0.05). In the patients with transplanted hearts, edrophonium had no electrophysiological effect other than increasing the cycle length of the remnant recipient atrium from 722 +/- 21 ms to 798 +/- 31 ms (P less than 0.01). We conclude that the electrophysiological effects of edrophonium in man are mediated primarily through autonomic innervation of the heart.

Clinical evaluation of the enhancement of vagal tone in acute myocardial infarction by edrophonium hydrochloride: effects on ventricular arrhythmias, His bundle electrography, and left ventricular function.

Enhanced electrical stability of acutely ischemic myocardium with vagal stimulation and acetylcholinesterase inhibition has been demonstrated experimentally. To extend these findings clinically, within 24 hours of acute myocardial infarction, 11 patients underwent continuous 10 hour Holter monitoring: 2.5 hour control before and after 5 hour constant edrophonium infusion (0.25 to 2.00 mg./minute). Continuous infusion of the agent lowered heart rate 92 to 78 b.p.m. (p less than 0.01). Although mean total ventricular extrasystoles (PVC's) per 5 hours per patient (131) and PVC's per 1,000 beats (4.7) were unchanged (p greater than 0.05), potentially lethal tachyarrhythmias (malignant PVC's: multifocal, R on T, paried, greater than 5 per minute or ventricular tachycardia) were terminated in six of 10 patients by edrophonium. However, serious ventricular arrhythmias continued in three patients and appeared in four despite the agent. Ventricular fibrillation did not occur during the 10 hour period of study. In addition, the patients were evaluated hemodynamically and by His bundle electrograms before and after a 10 mg. bolus of edrophonium prior to the 10 hour constant infusion: heart rate declined (88 to 72 b.p.m., p less than 0.01), while mean arterial pressure (98 mm. Hg), left ventricular filling pressure (14 mm. Hg), cardiac index (2.4 L. per minute per square meter), and stroke work index (36 Gm.m./M.2) were unchanged (p greater than 0.05). The edrophonium bolus prolonged the A-H interval (117 to 135 msec., p less than 0.01) while the H-Q interval was unaltered (48 msec; p greater than 0.05). It is concluded that increased vagal tone with edrophonium did not reduce the over-all presence of premature ventricular contractions in the entire study group; however, the malignant nature of PVCs and ventricular tachycardia appeared to be lessened by the parasympathomimetic agent in certain patients. In addition, no adverse hemodynamic or intraventricular conduction effects were produced by edrophonium administration.