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.

Alternative to ganglionic blockade with anticholinergic and alpha-2 receptor agents.

The ganglionic blocking agent trimethaphan (TMP) is no longer produced. Therefore, a need exists for alternative pharmacological approaches to investigate baroreflex control of the circulation. The aim of the present study was to examine baroreflex-mediated cardiovascular responses during the administration of a muscarinic receptor antagonist (glycopyrrolate; GLY: ) and a selective alpha-2 receptor agonist (dexmedetomidine; DEX: ) and to compare responses to ganglionic blockade with TMP. We hypothesized that combined GLY-: DEX: would inhibit the baroreflex similar to TMP. Ten volunteers participated in two study days and were instrumented with pulse oximeter, nasal cannula, ECG, continuous blood pressure monitoring (Finapres), and I.V. catheter for drug infusions. Each study day consisted of a control condition followed by either combined GLY: -DEX: or TMP on alternating days. A Valsalva maneuver was performed under each condition with every subject and six subjects received bolus phenylephrine (25 mug) during GLY: -DEX: and TMP. Combined GLY: -DEX: increased (P < 0.05) blood pressure (99 +/- 4 mmHg) and heart rate (99 +/- 3 bpm) relative to control condition (BP: 90 +/- 2 mmHg; HR: 64 +/- 3 bpm) and TMP infusion decreased (P < 0.05) blood pressure (79 +/- 3 mmHg) while increasing heart rate (88 +/- 3 bpm). Valsalva maneuver elicited a persistent drop in arterial pressure (no phase IIb recovery) with the absence of a phase IV overshoot during both GLY: -DEX: and TMP conditions. Phenylephrine increased systolic pressure 34 +/- 4 mmHg under GLY: -DEX: and 23 +/- 3 mmHg with TMP (P < 0.05). Heart rate only decreased 1 +/- 2 bpm during GLY: -DEX: and 1 +/- 1 bpm with TMP. Taken together, our results suggest that GLY: -DEX: is a reasonable alternative to TMP for baroreflex inhibition.

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.

Emergência hipertensiva / Hypertensive emergencies

A emergência hipertensiva é uma condiçäo de risco iminente de vida caracterizada por elevaçäo súbita da pressäo arterial e comprometimento de órgäo-alvo. O cérebro, coraçäo, rins, retina e aorta säo alvos frequentes. Säo importantes a presteza diagnóstica e o tratamento precoce. Dá-se escolha aos anti-hipertensivos parenterais de açäo rápida e de curta duraçäo, evitando-se, porém, quedas pressóricas que comprometam a perfusäo de órgäos ou sistemas. O objetivo desta revisäo é mostrar como se diagnostica e se trata precocemente a emergência hipertensiva.

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.

Systemic hypertension induced by aortic cross-clamping: detrimental effects of direct smooth muscle relaxation compared with ganglionic blockade.

PURPOSE: Infrarenal aortic cross-clamping performed during vascular reconstructive procedures is often accompanied by systemic supraclamp hypertension. Much of the disease and death that attend aortic cross-clamping centers around hypertension. Many different strategies have been developed to attenuate intraoperative hypertension, and a host of pharmacologic agents are regularly used to lessen the heart-related, cerebral, and systemic effects of clamp-induced hypertension. This study was performed to evaluate two such strategies; the intravenous administration of either trimethaphan camsylate or nitroprusside. METHODS: We used a highly controllable and reproducible model of aortic cross-clamping in which we have previously shown the hypertension associated with clamping to be an active process mediated by means of a reflex arc. Ten dogs, five treated with nitroprusside (NP group) and five treated with trimethaphan camsylate (TC group), underwent 90 minutes of aortic cross-clamping. During this 90-minute period each group received 30 minutes of antihypertensive therapy. RESULTS: Control mean arterial pressure +/- SEM was 80 +/- 5 mm Hg for both groups and increased to 140 +/- 5 mm Hg with clamp application. With antihypertensive treatment the elevation in mean arterial pressure produced by cross-clamping was reduced to preclamp levels in the TC group and only partially (52%) in the NP group, despite very high doses of nitroprusside. Cardiac output (CO) increased in the NP group by 115% and decreased by 36% in the TC group. This increase in CO translates into a large (101%) increase in cardiac minute work for the NP group. CONCLUSIONS: The attenuation of clamp-induced hypertension by nitroprusside is associated with a dramatic increase in CO and cardiac work whereas the use of trimethaphan camsylate is not. The use of this ganglionic blocker may be more appropriate in this setting.

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.

Treatment of stress response during balanced anesthesia. Comparative effects of isoflurane, alfentanil, and trimethaphan.

Acute hypertensive responses during nitrous oxide-opioid-relaxant anesthesia are a common clinical problem. In adult men undergoing radical prostatectomy procedures and anesthetized with a standardized technique, we evaluated the effectiveness of alfentanil, isoflurane, and trimethaphan in treating acute hemodynamic and stress hormone responses to surgical stimulation. Stress hormone concentrations were measured 1 min before skin incision, after the onset of an acute hypertensive response, and after returning the mean arterial pressure to within 10% of the preincision values with one of the three treatment modalities. Pretreatment plasma alfentanil concentrations (151 +/- 47 to 156 +/- 47 ng.ml-1) and end-tidal nitrous oxide concentrations (66 +/- 2 to 68 +/- 2%) were similar in all three groups. Acute hypertensive events were associated with significantly increased concentrations of catecholamines and vasopressin (antidiuretic hormone [ADH]). Whereas intravenous alfentanil returned all hormone concentrations to preincision values, norepinephrine and glucose concentrations were significantly increased after adjunctive isoflurane administration. Although trimethaphan decreased the norepinephrine concentration, the epinephrine, beta-endorphin, cortisol, ADH, and glucose concentrations were significantly increased compared to preincision values. However, the persistent elevation in the posttreatment ADH concentration in the trimethaphan group was the only significant difference between the three groups. Mean (+/- standard deviation) times to awakening (2.8 +/- 3.3 to 3.8 +/- 4.2 min), extubation (8.1 +/- 4.8 to 10.3 +/- 8.5 min), and orientation (19.6 +/- 20.4 to 24.6 +/- 19.1 min) were similar in all three groups. Naloxone was required more frequently in patients in the alfentanil (35%) and isoflurane (24%) groups than in the trimethaphan group (4%).(ABSTRACT TRUNCATED AT 250 WORDS)

[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)

Preservation of platelet function during trimethaphan infusion.

The effect of trimethaphan (Arfonad) infusion on platelet function was prospectively evaluated in 38 (n = 38) patients (28 patients receiving trimethaphan, ten control patients) undergoing elective cardiac surgery. Any patient with a positive history for the ingestion of medication known to interfere with platelet function was excluded from the study. Following induction of anesthesia with fentanyl (and prior to cardiopulmonary bypass) 28 patients (n = 28) received trimethaphan as clinically indicated to maintain a mean blood pressure of 80 mmHg. The infusion rate and total dose of trimethaphan delivered was recorded for each patient. The evaluation of platelet function was performed via adenosine diphosphate (ADP) and epinephrine-induced platelet aggregation tests. The administration of trimethaphan failed to result in any detrimental effect on platelet function as assessed via these aggregation studies. Template bleeding times were also performed on all study patients. Bleeding time measurements performed in patients following trimethaphan administration were unchanged from baseline values. Platelet aggregation studies and bleeding time performed in control group following the administration of fentanyl (30 micrograms/kg) plus enflurane (inspired concentration 0.5-1%) did not reveal any deviation from baseline values. These results are in contrast to a previous study that demonstrated a negative effect upon platelet function following sodium nitroprusside administration (at clinically acceptable doses). These data demonstrate that trimethaphan provides control of arterial pressure with preservation of platelet function.

Effects of circulating endogenous catecholamines on plasma glucose, potassium and magnesium.

1. To examine the metabolic effects of increases in circulating endogenous plasma catecholamines, we measured plasma glucose, potassium and magnesium in 14 patients undergoing elective coronary artery bypass grafting. The patients were randomized into two groups and received either sodium nitroprusside (a direct-acting vasodilator) or trimetaphan camsylate (a ganglion-blocking agent) for routine control of blood pressure during the operation. 2. There were significant differences between the two groups in the levels of all three metabolic variables studied. Plasma glucose levels rose in both groups, but were significantly higher in the sodium nitroprusside group [peak levels 9.14 (SEM 0.72)mmol/l compared with 6.71 (0.88) mmol/l, P less than 0.001, analysis of variance]. The cardioplegia solution caused a large increase in plasma magnesium in both groups but in the sodium nitroprusside group the level rose higher [to 1.59 (0.12)mmol/l compared with 1.34 (0.06)mmol/l] and fell faster (P less than 0.05, analysis of variance). In the group receiving sodium nitroprusside, plasma potassium fell, by a mean of 0.34mmol/l, as plasma catecholamine levels rose; no such fall was seen in the group receiving trimetaphan camsylate (P less than 0.05, analysis of variance). 3. It is concluded that the sympathoadrenal system is important in causing metabolic changes during cardiopulmonary bypass and may be relevant in other conditions such as acute myocardial infarction.