Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension.

Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction.

To estimate the ultimate extent of myocardial damage during evolving myocardial infarction in conscious dogs and patients, we analyzed early serum creatine phosphokinase (CPK) changes with nonlinear curve-fitting techniques. In experiments with dogs, serial serum CPK changes were fit to a log-normal function by the least squares method; the extent of the completed infarct was calculated by analysis of observed serum CPK changes and verified by measurement of myocardial CPK depletion 24 h after coronary occlusion. Early prediction of myocardial damage was based on projected serum CPK values from best fit curves based on data obtained during the first 5 h after initial elevation of enzyme activity. The correlation between predicted and observed values was close (r > 0.96, n = 11). In 11 additional conscious animals subjected to coronary occlusion, isoproterenol was administered continuously as soon as damage had been estimated from projected serum CPK values. The extent of the completed infarct was assessed by analysis of all serial serum CPK values and verified by analysis of myocardial CPK depletion 24 h after coronary occlusion. In each experiment the calculated completed infarct size exceeded infarct size projected before administration of isoproterenol (average increase = 44+/-10 [SE]%). When similar calculations were applied in experiments with eight dogs treated with propranolol, myocardial salvage was detected in 50% of the animals. In 30 patients with uncomplicated acute myocardial infarction the extent of the completed infarct, measured by analysis of CPK activity in serum samples obtained every 2 h, was compared with damage estimated from CPK values projected by the best fit log-normal curve derived from data obtained during the first 7 h after the initial serum CPK elevation. The estimate of damage based on early data correlated closely with the extent of infarction calculated from all available serial serum CPK values (r = 0.93, n = 30). Thus, the extent of the completed infarct could be estimated accurately during the early evolution of infarction. In patients with spontaneous extension of infarction manifested by chest pain and electrocardiographic changes, the calculated extent of the completed infarct exceeded that predicted. Conversely, salvage of myocardium, after reduction of myocardial oxygen requirements by administration of trimethaphan, was reflected by reduction of the extent of the calculated completed infarct with respect to that predicted from early serum CPK changes.

Hypertensive encephalopathy: recognition and management.

Hypertensive encephalopathy is a dramatic syndrome characterized by severe elevation of blood pressure, headache, visual disturbances, altered mental status, and convulsions. Although the syndrome is uncommon, to recognize and treat it promptly is important or the condition may prove to be fatal. Hypertensive encephalopathy should be distinguished from other cerebral complications of severe hypertension by obtaining careful history and performing thorough physical examination. The only definitive criterion for the diagnosis of this syndrome is its prompt response to therapy. If the patient's condition does not improve with hypotensive therapy, the physician should immediately search for alternate diagnoses. Potent drugs are available for prompt reduction of blood pressure. There are few medical emergencies in which the objective response to therapy is so strikingly apparent as in hypertensive encephalopathy.

Respiratory paralysis during treatment of hypertension with trimethaphan camsylate.

Four cases are reported in which respiratory arrest occured coincident with the intravenous administration of large doses of trimethaphan camsylate (Arfonad) to control hypertension. The mechanism of the respiratory depression is unknown, but it may have been related to a direct effect of trimethaphan on the respiratory center or to a curare-like effect of the drug. Close monitoring of ventilatory capacity should be maintained in all patients treated with trimethaphan.

Menetrier's disease. Effect of medical and surgical vagotomy.

A 62-year-old woman with incapacitating atherosclerotic vascular occlusive disease was found to have severe hypoproteinemia as a result of Menetrier's disease. That diagnosis was suspected on roentgenographic and gastroscopic examinations and confirmed by examination of full-thickness surgical gastric biopsy specimens. The protein loss from the stomach was significantly decreased by treatment with trimethaphan and atropine and led us to perform proximal gastric vagotomy at the time of endarterectomy. Subsequent protein turnover studies suggest that there has been a significant decrease in protein loss by the stomach. Further evaluation of the possible role of medical and surgical vagotomy in this disease seems warranted.

The diagnosis and management of hypertensive crises.

Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.

Effects of central and peripheral nicotinic blockade on human nicotine discrimination.

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Control of acute aortic dissection.

An experimental model of acute aortic dissection has been designed in an effort to examine myocardial contractility and systolic arterial pressure as factors influencing the progression of dissection. Thirty mongrel dogs divided into three experimental groups underwent left thoracotomy and construction of a standard intimal tear in the proximal descending aorta. Nine of ten animals in the control group showed progression of the aortic dissection a mean of 81.5 percent of the distance from the aortotomy to the celiac axis. Group II consisted of ten dogs pretreated with propranolol. The myocardial contractility (dp/dt) was significantly depressed in this group without change in systolic pressure. However, progression of dissection occurred in nine of ten animals as in the control group. In Group III, ten dogs were pretreated with trimethaphan lowering the systolic blood pressure to 90 mm. Hg and depressing the dp/dt to levels equal to those of Group II. There was no progression of aortic dissection in any of the animals in this group. The results indicate that, under these experimental conditions, depression of myocardial contractility alone has no inhibitory effect on the progression of dissection. When controlled hypotension is added to myocardial depression, aortic dissection is inhibited completely.

Epidural blood flow during prostaglandin E1 or trimethaphan induced hypotension.

To evaluate the effect of prostaglandin E1 (PGE1) or trimethaphan (TMP) induced hypotension on epidural blood flow (EBF) during spinal surgery, EBF was measured using the heat clearance method in 30 patients who underwent postero-lateral interbody fusion under isoflurane anaesthesia. An initial dose of 0.1 microgram.kg-1.min-1 of PGE1 (15 patients), or 10 micrograms.kg-1.min-1 of TMP (15 patients) was administered intravenously after the dural opening and the dose was adjusted to maintain the mean arterial blood pressure (MAP) at about 60 mmHg. The hypotensive drug was discontinued at the completion of the operative procedure. After starting PGE1 or TMP, MAP and rate pressure product (RPP) decreased significantly compared with preinfusion values (P < 0.01), and the degree of hypotension due to PGE1 remained constant until 60 min after its discontinuation. Heart rate (HR) did not change in either group. EBF did not change during PGE1 infusion whereas in the TMP group, EBF decreased significantly at 30 min and 60 min after the start of TMP (preinfusion: 45.9 +/- 13.9 ml/100 g/min. 30 min: 32.3 +/- 9.9 ml/100 g/min (P < 0.05). 60 min: 30 +/- 7.5 ml/100 g/min (P < 0.05). These results suggest that PGE1 may be preferable to TMP for hypotensive anaesthesia in spinal surgery because TMP decreased EBF.

Epidural blood flow during prostaglandin E1 or trimethaphan induced hypotension.

To evaluate the effect of prostaglandin E1 (PGE1) or trimethaphan (TMP) induced hypotension on epidural blood flow (EBF) during spinal surgery, EBF was measured using the heat clearance method in 30 patients who underwent postero-lateral interbody fusion under isoflurane anaesthesia. An initial dose of 0.1 microgram.kg-1.min-1 of PGE1 (15 patients), or 10 micrograms.kg-1.min-1 of TMP (15 patients) was administered intravenously after the dural opening and the dose was adjusted to maintain the mean arterial blood pressure (MAP) at about 60 mmHg. The hypotensive drug was discontinued at the completion of the operative procedure. After starting PGE1 or TMP, MAP and rate pressure product (RPP) decreased significantly compared with preinfusion values (P < 0.01), and the degree of hypotension due to PGE1 remained constant until 60 min after its discontinuation. Heart rate (HR) did not change in either group. EBFF did not change during PGE1 infusion whereas in the TMP group, EBF decreased significantly at 30 and 60 min after the start of TMP (preinfusion: 45.9 +/- 13.9 ml/100g/min. 30 min: 32.3 +/- 9.9 ml/100 g/min (P < 0.05). 60 min: 30 +/- 7.5 ml/100 g/min (P < 0.05)). These results suggest that PGE1 may be preferable to TMP for hypotensive anaesthesia in spinal surgery because TMP decreased EBF.

Management of acute aortic dissection.

The therapy for acute dissecting aneurysm of the aorta remains a difficult problem for thoracic surgeons. Because of an excessive operative mortality in patients with acute dissection who were operated on within 24 hours of hospital admission, we have utilized intensive medical management to delay surgical intervention. Even patients with acute aortic insufficiency can be supported medically, allowing their operations to be delayed at least 3 weeks or longer. Since this policy has been implemented, there has been no operative mortality in our last 13 patients with acute dissection. Medical therapy as the definitive treatment is now reserved solely for Type III dissections or for patients who cannot be operated on for other reasons. This report outlines our rationale for therapy and our current method of managing acute dissection.

Hypertensive emergencies.

The clinical syndrome of accelerated hypertension is a relatively rare complication of hypertensive disease. The syndrome is recognized by high blood pressures, progressive neurologic and visual symptoms, acute renal damage, cardiac failure, and microangiopathic hemolytic anemia. When diagnosed, it must be recognized as an acute medical emergency. The patient should be admitted to an intensive care unit, arterial lines should be placed, and the blood pressure lowered as soon as possible. Once blood pressure has been controlled, oral medications should be begun. Long-term results in the treatment of hypertensive emergencies are gratifying. It is anticipated that with more experience gained in the use of medications in this situation, an even better prognosis will be achieved.

Preoperative estimation of cerebral blood flow autoregulation curve for control of cerebral circulation after cerebral revascularization.

In this report, the anesthetic management for cerebral revascularization in 3 patients with ischemic cerebral vascular disease was presented. Arterial pressure was maintained above their ordinary level before revascularization. To prevent cerebral hemorrhage or edema due to the breakthrough phenomenon, the arterial pressure was reduced to the lower limit pressure of cerebral blood flow (CBF) autoregulation which was measured preoperatively. The patients did not show any new neurological deficit after the operations.

Acute aortic dissection.

Acute aortic dissection is the most lethal complication affecting the aorta. The use of two-dimensional echocardiography and computed tomography has greatly expanded the physician's ability to establish this diagnosis through noninvasive techniques. Surgery is the definitive treatment for type I and II dissection, whereas medical management with drugs that reduce cardiac output remains the treatment of choice in type III dissection. With improvements in surgical techniques, including cardiopulmonary bypass and composite grafting, immediate and long-term morbidity and mortality have been significantly reduced.

Hypertensive crisis.

Although uncommon, hypertensive crisis must be recognized properly and quickly so that immediate treatment can be instituted to prevent serious and irreversible complications. It is important to bear in mind that it is not necessarily the absolute level of hypertension that signals impending danger but the function of an affected target organ such as the heart or kidneys that allows the physician to make the diagnosis of hypertensive crisis. There are a variety of potent antihypertensive drugs that can lower the blood pressure promptly, but the choice must be based on careful clinical and hemodynamic assessment of the patient. The goal is to lower the blood pressure and to stabilize or improve the target organ function without causing underperfusion.

Changes in cerebral blood flow accompanied with reduction of blood pressure treatment in patients with hypertensive intracerebral hemorrhages.

Blood pressure usually is reduced in patients with hypertensive intracerebral hemorrhage for the prevention of the expansion of the hematoma and recurrent hemorrhage in acute stage. However, disturbed autoregulation of cerebral circulation is expected, and decreased cerebral blood flow (CBF) caused by excessive hypotension has been pointed out. There are different mechanisms of action in hypotensives, thereby the influence of hypotension on CBF in patients with the thalamic hemorrhage was investigated using nitroglycerin (TNG), diltiazem hydrochloride (DH) and trimethaphan camsilate (TC). Average CBF in a hemisphere on the hematoma side, the hemisphere without hematoma, and around the hematoma showed a slight decline after administration of TNG or DH. However, CBF declined more, after TC than DH. DH and TNG are preferable in descending order to control blood pressure of patients with intracerebral hemorrhage in the acute stages in view of a smaller decline in CBF.

Intravenous trimethaphan during epidural plus general anesthesia decreases the direct radial artery pressure lower than the brachial artery pressure.

STUDY OBJECTIVE: To determine whether vasodilators such as sodium nitroprusside (SNP) and trimethaphan (TMP) produce a pressure difference between the radial artery and the brachial artery during epidural plus general anesthesia or simple general anesthesia. DESIGN: Randomized study and prospective study. SETTING: Operating rooms of two hospitals. PATIENTS: 36 and 6 adult patients in the first and second studies, respectively, who received spherical acetabular osteotomy with induced hypotensive anesthesia. INTERVENTIONS: In the first study, 18 patients received epidural plus general anesthesia (epidural group) and 18 patients received general anesthesia alone (general group). All patients received the hypotensive drugs for more than 50 minutes each. In the second study, 6 patients received TMP-induced hypotension for 20 minutes under epidural plus general anesthesia. MEASUREMENTS AND MAIN RESULTS: In the first study, radial intra-arterial blood pressure (RIBP) and tonometric blood pressure (TBP) calibrated with oscillometric blood pressure of the arm were compared. In the second study, RIBP and the brachial intra-arterial blood pressure (BIBP) were compared. In the first study, the bias between RIBP and TBP for systolic, mean and diastolic blood pressure were significantly less during TMP-induced hypotension in the epidural group (-11.5 +/- 2.5 (mean +/- SD), -6.0 +/- 3.1, and -2.8 +/- 3.7 mmHg, respectively] than during SNP-induced hypotension in the epidural group and SNP- and TMP-induced hypotension in the general group (p < 0.01). The precision of systolic and mean pressures were significantly greater during TMP-induced hypotension in the epidural group (11.8 +/- 2.3 and 7.1 +/- 1.9 mmHg, respectively) than the other three hypotension groups (p < 0.01). In the second study, the bias between RIBP and BIBP for systolic, mean, and diastolic pressures were significantly less (p < 0.01), and precision was significantly greater during hypotension than during normotension (p < 0.01). CONCLUSIONS: Our results demonstrate that TMP decreases the direct radial artery systolic and mean pressures to levels below the brachial artery systolic and mean pressures in patients who received epidural plus general anesthesia.

Trimethaphan (Arfonad) control of hypertension and tachycardia during electroconvulsive therapy: a double-blind study.

STUDY OBJECTIVE: To ascertain the optimal dose of trimethaphan camsylate administered by intravenous (i.v.) bolus injection for the control of hypertension and tachycardia during electroconvulsive therapy (ECT). DESIGN: Prospective, double blind, within-subject study. SETTING: Treating room of the psychiatric unit of the University Hospital at Stony Brook, NY. SUBJECTS: Patients undergoing ECT for major psychiatric illnesses. MEASUREMENTS AND MAIN RESULTS: Fifteen ASA status I or II patients received in a random sequence placebo, or 5, 10, or 15 mg boluses of trimethaphan during their second to fifth treatments. Blood pressure (BP) and heart rate (HR) were recorded every 30 seconds by automated oscillometric recorder. Recordings taken before administration, during seizure, 5, and 20 minutes after seizure were examined. All doses ameliorated BP (systolic, diastolic, and mean), HR, and rate pressure product (RPP) increases during the seizure, compared with placebo. The group that received 15 mg exhibited smaller increases in RPP, i.e., 67.7% increase compared with 155.4%, 110.9%, and 98.7% increases for the placebo, 5, and 10 mg, respectively. The 10 mg and 15 mg doses caused a faster return to baseline than did the 5 mg dose or placebo. No rebound hypertension, prolonged hypotension, arrhythmias, or other side effects were noted. Trimethaphan did not alter seizure duration. CONCLUSIONS: Trimethaphan is safe, practical, and effective in the management of the hyperdynamic response to ECT. An i.v. bolus injection of 15 mg is more effective than 10 mg or 5 mg.

Study on peroperative bleeding in ear, nose and throat surgery.

Some interventions in ENT surgery are very difficult or are even impossible if the slightest bleeding occurs. Microsurgery of the ear is the best example. For this reason we choose this particular intervention to test different anesthesia techniques. Bleeding in the surgical field is followed, while simultaneously respiratory, venous and arterial pressure tracings are recorded. These parameters are followed and changes can be attributed directly to observations by microscope of the surgical field. Successively neuroleptanalgesia in its pure form or with help of several drugs (trimetaphan, furosemide, enflurane) is studied. One conclusion can probably be made of the analysis of our series: an anesthesia with "light" analgesia gives better results than an anesthesia protecting completely the patient.

[Hemodynamic studies on the vertebral artery system during the vertebral arterial surgery].

Few hemodynamic studies on the vertebral artery system in the human can be seen. The authors measured the vertebral arterial blood flow (VAF) with an electromagnetic flow meter in 45 patients who obtained vertebral arterial surgeries. The patients showing vertebrobasilar insufficiency such as vertigo and drop attack had serious kinking and stenosis at the first portion of the vertebral artery. The effects of induced hypotension by trimethaphan camsilate, induced hypertension by phenylephrine, cervical epidural anesthesia and induced hypertension under epidural anesthesia on the VAF were investigated. During the control state, mean systemic arterial blood pressure (SABP), mean VAF were 97 mmHg and 54 ml/min, respectively. The effects of varied SPBP were analyzed by (delta mean VAF/mean VAF)/(delta mean SABP/mean SABP), (delta V/delta S). The delta mean VAF and delta mean SABP indicated varied mean values of VAF and SABP, respectively. Mean SABP was varied significantly by about 25% in each method. The delta V/delta S in induced hypotension, induced hypertension, epidural anesthesia and induced hypertension under epidural anesthesia were -0.05, 0.07, 0.90 and 0.61, respectively, on the average. Induced hypotension by epidural anesthesia and induced hypertension under epidural anesthesia presented significant changes in mean VAF.(ABSTRACT TRUNCATED AT 250 WORDS)