Alpha-blocking Agent Research Articles

Pharmacokinetics of Moxisylyte in Healthy Volunteers After Intravenous Infusion and Intracavernous Administration With and Without a Penile Tourniquet

The concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an alpha-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites, tmax was significantly increased after i.c. administrations and Cmax was significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 +/- 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 +/- 20.9, 61.4 +/- 12.2, and 58.7 +/- 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of approximately 25% and seemed to increase the efficacy of the drug in healthy volunteers.

Pheochromocytoma: Update on Diagnosis, Localization, and Management

Pheochromocytoma, although rare, is associated with a high degree of morbidity and mortality if not recognized. A high degree of suspicion in patients with new-onset hypertension; hypertension with sudden worsening or development of diabetes mellitus; or a family history of MEN, neuroectodermal tumors, or simple pheochromocytoma should prompt biochemical confirmation with either 24-hour urine catecholamines (norepinephrine and epinephrine) or total MET (NMET plus MET). Following confirmation of the diagnosis, radiologic studies with CT and (if needed) MIBG are employed to localize the tumor. Surgical removal is the only definitive therapy. Medical management with alpha-blocking agents, to control symptoms and prevent a hypertensive crisis, is generally advocated for 2 weeks preoperatively and intraoperatively. Occasionally, beta-blockers, employed only after adequate alpha-blockade, are necessary to control tachycardia and tachyarrhythmias. High-dose MIBG and combination chemotherapy have been used adjunctively to treat malignant pheochromocytoma, although neither modality provides lasting satisfactory results. Normal urine assays performed 2 weeks postoperatively ensure the complete removal of all tumor. Additionally, lifelong follow-up (yearly initially) is necessary to detect any signs of benign recurrence or malignancy because these have been reported to occur as long as 41 years after the initial surgical resection. Biochemical evidence of excess catecholamine production usually precedes the clinical manifestations of catecholamine excess when these tumors recur.

Improvement of urethral resistance after the administration of an alpha-adrenoceptor blocking agent, urapidil, for neuropathic voiding dysfunction.

We assessed the effect of a new alpha-blocking agent, urapidil, on neuropathic voiding dysfunction, by urodynamic studies. The residual urine volume and rate significantly decreased, whereas the average and the maximum flow rate did not increase significantly. The pressure at maximum flow and minimum urethral resistance decreased significantly. These results suggest that improvement of the voiding dysfunction in some cases could be due to the decreased micturition pressure without increasing the flow rate. The urethral resistance calculated from the pressure/flow data seemed to be a valuable index in evaluating the effects of the drug on neuropathic voiding dysfunction.

Marked splenic hyperaemia during post-haemorrhagic hypotension in the rat, rabbit and cat.

1. The regulation of the splenic perfusion during normal and pathological conditions is incompletely understood. We studied the time course of splenic blood flow during the initial (0-24 h) development of haemorrhagic anaemia in awake and anaesthetized rats, as well as in awake rabbits and cats. Another group of rats had either normovolaemic anaemia or beginning polycythaemia. 2. The microsphere method was used to measure splenic blood flow. The awake rats were rendered anaemic either by a heavy (1.5% of body weight) or a moderate (0.7% of body weight) bleeding (hypovolaemia), by haemolysis (normovolaemia) or by bleeding (1.5% of body weight) followed by transfusion of autologous plasma (normovolaemia). Polycythaemia was induced with injections of erythropoietin. The anaesthetized rats as well as the awake rabbits and cats were also bled heavily (1.5% of body weight). 3. In awake rats, splenic blood flow increased to 215% of control within the first 5 min after bleeding. The perfusion declined nearly to baseline over the next 24 h. A similar, but less prominent splenic hyperaemia was detected in the awake rabbits and cats. However, this hyperaemic response was not detected in the normovolaemic, the polycythaemic or the anaesthetized and bled rats. 4. Administration of the adrenergic beta-blocking agent propranolol prior to bleeding significantly attenuated the splenic hyperaemia in the awake rats, while the alpha-blocking agent phentolamine or the cholinergic blocking agent atropine had no effect. 5. Concomitant with the initial increase in splenic perfusion, cardiac output increased to 123% of control in the awake, heavily bled rats. In the bled, anaesthetized rats cardiac output decreased to 91% of control 5 min after bleeding. A decrease in cardiac output to 64 and 70% of control was observed in the awake rabbits and cats, respectively. 6. Immediately following the bleeding, we noticed a substantial release of platelets from the rat spleen. 7. It appears that a heavy acute blood loss in awake rats, rabbits and cats elicits a marked reduction in splenic vascular tone, perhaps mediated by beta-adrenergic receptor activity. Anaesthesia abolished this response in rats. Possibly, the induced hypovolaemia triggered an accelerated release of platelets from the rat spleen, dependent on an augmented splenic blood flow.

Detrusor sphincter dyssynergia, detrusor instability, and urethral sphincter spasticity as the urodynamic findings in the urethral syndrome: Role of treatment with a combined anticholinergic and alpha blocking agent, bladder drill, and antibiotics

The combined effect of isopropamide 5 mg plus trifluoperazine 1 mg (a combined anticholinergic and alpha-adrenergic antagonist) (Smith, Kline and French Canada Ltd, Ontario, Canada), antibiotics, and bladder drill was retrospectively assessed on 100 consecutive women, aged 16 to 47 years, presenting with the signs and symptoms of the urethral syndrome. Assessment included history, physical examination, routine bacterial and chlamydial cultures (cervical, urethral, vaginal, and urine), cystourethroscopy, and urodynamics. Urodynamic diagnoses included detrusor sphincter dyssynergia (n=84), detrusor instability (n =8), external urethral sphincter spasticity (n=4), and sensory urgency (n=1). Three patients with positive urine cultures were excluded. Urethrotrigonitis was visualized at cystourethroscopy in all patients. Only one case of chlamydial urethritis-cervicitis was identified by culture: 82% of patients had a history of prior antibiotic therapy for lower urinary tract symptoms and 21% were being treated with antibiotics at the time of their initial assessment.

糖尿病性膀胱尿道機能障害に関する研究

In order to evaluate vesicourethral dysfunction in diabetic patients, urodynamic studies, IVP and urinalysis were performed on 173 diabetic patients (male 78, female 95) and 17 nondiabetic control cases. In addition to the classical findings as increased volume at the first desire to void and decreased maximum vesical pressure, diabetic patients showed varieties of vesicourethral dysfunctions such as overactive bladder (14.5%), low compliance bladder (11.0%) and loss of detrusor-external sphincter coordination (31.7%). Vesicourethral function of diabetics was classified in following 5 types by analysing the volume at first desire to void, volume at maximum desire to void, maximum vesical pressure, residual urine volume and bladder compliance. 1. Type 1, normal vesical function, 13 cases. 2. Type 2, vesical dysfunction with minimal residual urine, 49 cases. 3. Type 3, vesical dysfunction with residual urine, 66 cases. 4. Type 4, low compliance bladder, 20 cases. 5. Type 5, overactive bladder, 25 cases. Pyuria was observed in 59.8%, hydronephrosis was found in 10.9% and ectasia of lower ureter was found in 17.8% of diabetic patients. The highest incidence of pyuria and abnormality of the upper urinary tract were noted in Type 4 and followed by Type 3 and by Type 2 in decreasing order. Extent of pyuria and ectasis of the upper urinary tract showed statistically significant correlation with residual urine volume and detrusor-external sphincter coordination. When vesicourethral function was compensated by abdominal strain, the volume of residual urine is not elevated, but when the mechanism of compensation is lost or in the absence of detrusor-external sphincter coordination results in gradual accumulation of residual urine. In cases with long standing chronic urinary tract infection may results in fibrosis of the bladder wall with low compliance bladder. Fibrotic obstruction of uretero-vesical junction can cause hydroureteronephrosis and followed by renal function impairment. As vesical damage become irreversible at this end stage, proper management during early stage is crucial for management of diabetic patients. Cholinergic agent were effective to reduce residual urine volume in Type 3. alpha-blocking agent were effective to reduce residual urine volume in Type 3 and some cases of Type 4. In cases in which medication therapy failed to reduce residual urine, the clean intermittent catheterization was successful in control of urinary tract infection and upper urinary tract ectasis. Transurethral resection of the prostate and the bladder neck is indicated in the male patients with a large amount of residual urine in Type 3 and 4.

Diagnosis and treatment of prostatic infections

The diagnosis and management of prostatitis and pelviperineal pain is a challenge to the clinician. Careful examination of the prostatic fluid and bacteriologic cultures to differentiate bacterial from nonbacterial prostatitis are essential. Antimicrobial therapy is effective in the majority of men with acute or chronic bacterial prostatitis. Nonbacterial prostatitis is the most common type of prostatitis. The etiology is unknown and treatment with repeated antimicrobial therapy is ineffective. Alpha-blocking agents may relieve symptomatology. Pelviperineal pain may be of prostatic origin but other nonprostatic causes should be sought.

Effects of Intracavernosal Trazodone Hydrochloride: Animal and Human Studies

Trazodone hydrochloride is an oral antidepressant agent which has been associated with the improvement of erections in impotent men and the development of prolonged erections or priapism in potent men. An in vivo study in animal and human subjects was performed to gain experience with the effect of intracavernosal trazodone. In the anesthetized New Zealand White rabbit, intracavernosal trazodone or its major metabolite m-chlorophenylpiperazine (m-CPP) produced full penile erection in 76% and 84% of animals studied respectively with doses ranging from one to 15mg. On the other hand, intracavernosal administration of five mg. papaverine resulted in a prolonged erection in 90% of animals studied. In 13 selected volunteer patients, intracavernosal trazodone caused tumescence but not full penile erection with corporal body pressures of 28.2 ± 5.8mm. Hg. Intracavernosal papaverine or papaverine and phentolamine in these subjects resulted in significantly higher corporal body pressures of 58 ± 18mm. Hg (p < .05). Intracavernosal administration of alpha adrenoceptor agonists but not normal saline resulted in complete detumescence of trazodone- or m-CPP-induced prolonged erection in the animal studies. Intracavernosal trazodone results in erectile activity that appears in part based on its local alpha blocking activity but like other intracavernosal alpha-blocking agents is not as effective in initiating penile erections as are intracavernosal agents that directly induce smooth muscle relaxation. (J. Urol., 144: 1277–1282, 1990)

Influence of aging and drug treatment on the bioenergetics of hypoxic brain

Synaptosomes isolated from the forebrain of rats of different ages (20, 60 and 100 weeks of age) were incubated in Krebs-Henseleit-Hepes (pH 7.4) buffer, for 10 min at 24 degrees C. The energetic state was defined by the redox state of the intramitochondrial NAD-couple (delta Gox-red) and the phosphorylation state of adenine nucleotide system (delta GATP). The biological energy "lost" by the system during the coupled reactions was estimated by the delta delta G = delta Gox-red - delta GATP. The animals were submitted for 10 min to different degrees of in vivo hypoxia. To elucidate the mechanism of action, the effect of the pretreatment with drugs acting on oxygen availability (almitrine) or on microcirculation and metabolism (delta-yohimbine) was tested. In synaptosomes isolated from the forebrain of animals submitted to moderate degree of hypoxia (oxygen arterial partial pressure ranging between 32 and 29 mmHg) the efficiency of the system was quite similar to that observed in normoxia, with the exception of the older rats. In synaptosomes isolated from the forebrain of rats submitted to severe degree of hypoxia (oxygen arterial partial pressure ranging between 20 and 18 mmHg) the efficiency of the system was markedly altered as a function of both aging and severity of hypoxemia. The pretreatment with the agent increasing the oxygen availability partially modified the efficiency of the system, the alpha-blocking agent being less important. The drug action was markedly related to both the age and the degree of hypoxia.

Bladder-neck opening test in spinal cord injury patients using a new i.v. alpha-blocking agent, alfuzosin

A bladder-neck opening test using alfuzosin, a new alpha-adrenoceptor blocking agent, was carried out in 21 patients with spinal cord injury. The efficacy of alfuzosin was assessed with 4 simple urodynamic parameters: micturition, residual urine, posterior urethral pressure and diameter. Both mean urethral pressure and diameter were significantly affected after the administration of 5 mg i.v. alfuzosin. The test was clinically positive in 18 patients: 11 out of 13 patients using intermittent catheterisation or continuous drainage urinated and 6 out of 8 patients already tapping had reduced residual urine volumes. A decrease in posterior urethral pressure was also observed in 2 out of 3 patients who did not respond clinically to alfuzosin. Alfuzosin was well tolerated during this test. Oral alfuzosin should therefore be investigated in patients who gave a satisfactory response to such a test.

Hypothalamic cyclic AMP after the injection of ovarian steroids into ovariectomized rats

The effect of ovarian steroids on the concentration of adenosine 3',5'-cyclic monophosphate (cAMP) in the hypothalamus was studied in ovariectomized rats. Ovariectomized rats exhibited a lower cAMP concentration than intact rats. The administration of a single dose of estradiol benzoate (50 micrograms/kg body weight) resulted 3 days later in a rise of cAMP values, but levels did not reach those observed in estrous rats. Progesterone (2 mg/rat) injected 3 days after the priming dose of estradiol benzoate produced 4 h later no further changes in hypothalamic cAMP. The changes in hypothalamic cAMP concentration induced by estrogen treatment depend, at least in part, on noradrenergic inputs, since they were prevented by the injection of the norepinephrine synthesis inhibitor, diethyldithiocarbamate. In addition, administration of the beta-blocking agent, propranolol, to estradiol- and estradiol-progesterone-treated rats lowered the concentration of cAMP in the hypothalamus in a dose-dependent manner. In contrast, the administration of an alpha-blocking agent, phenoxybenzamine, had no effect at the tested concentration. The results of this study indicate that estrogen increases cAMP concentration in the hypothalamus by a noradrenergic mechanism involving beta-receptors. Moreover, the findings suggest that estrogen induces an increase in the number of beta-receptor sites, whereas progesterone increases the apparent propranolol sensitivity for these receptor sites.

Severe arterial insufficiency in impotence confirmed with an improved angiographic technique: the impact of smoking and some other etiologic factors.

Arteriography of the penile arteries in patients with pharmacologic erection has been performed by our group since 1983. Pathological Doppler findings and weak response to locally administered papaverine or alpha-blocking agents in these impotent men led to pharmacoangiography in 17 of 372 patients with erectile dysfunction; of these 372 patients 130 (35%) had subnormal penile blood flow according to Doppler ultrasonography. Only one had a proximal lesion (occlusion of the right common iliac artery) while the rest had distal lesions. Three patients were nonsmokers and the remaining 14 patients (82%) were smokers or had smoked previously. Only 2 of the 14 had other predisposing diseases.

Protection against cyclosporine-induced impairment of renal microcirculation by verapamil in mice.

Fluorescence microscopy was used to examine the effect of cyclosporine (CsA) infusion on renal subcapsular (cortical) blood flow in 53 living mice, using FITC-dextran (MW: 156,000) as a fluorescent marker. CsA (8-19 mg/kg body weight) given i.v. for 1 min induced complete inhibition of blood flow. A complete standstill of flow was also obtained during a continuous infusion with a rate of 0.8-2 mg/kg/min. With lower infusion rates (0.15-0.23 mg/kg/min), blood flow was partially impaired. In all experiments, the decrease in flow occurred after a 15-25 min delay, suggesting a CsA metabolite or exhaustion of a protective mechanism as the causative agent. Pretreatment with an alpha-blocking agent, phentolamine (1.0 mg/kg), did not prevent the CsA-induced inhibition of blood flow. In contrast, pretreatment with a calcium antagonist, verapamil (0.3-0.4 mg/kg), prevented the impairment of blood flow at low (0.15-0.23 mg/kg/min), and partially at higher (0.8-2.4 mg/kg/min) rates of CsA infusion. Clinical studies are warranted to explore the role of calcium antagonists in the prevention of posttransplant acute cyclosporine-induced nephrotoxicity.

Hypertension and diabetes. Clinical problems.

The choice of an appropriate antihypertensive agent and the hazards of postural hypotension are common problems faced in the treatment of diabetic hypertensive patients. The results of 3 studies addressing these problems are described in this report. In the first study, indoramin, an alpha-blocking agent, was administered to patients with non-insulin-dependent diabetes and mild to moderate hypertension. Blood pressure control was achieved in 57% of patients with mild, and in none with moderate hypertension. The blood glucose and insulin responses to an oral 50g glucose loading, as well as the blood concentrations of HbA1 did not change during therapy. Seven patients were excluded because of side effects. In 4 of them postural hypotension was observed. In the second study, the effects of angiotensin-converting enzyme (ACE) inhibitors, administered to patients with non-insulin-dependent diabetes and mild to moderate hypertension, were evaluated. Blood pressure control was achieved in 78% of the patients on captopril (n = 14) and in 74% of patients on enalapril therapy (n = 23). Symptomatic postural hypotension (n = 2) and hyperkalaemia (n = 2) were observed with both drugs. Significant reductions in 24-hour urinary protein or albumin excretion were detected in 12 patients on enalapril therapy. No changes in 2-hour postprandial blood glucose and HbA1 levels were observed during therapy with ACE inhibitors. In the third study, dopaminergic antagonist agents were evaluated in diabetic patients with orthostatic hypotension. In 7 patients metoclopramide (20mg intravenously) reduced the fall in mean arterial pressure induced by upright tilt.(ABSTRACT TRUNCATED AT 250 WORDS)

Polymorphous ventricular tachycardia due to alpha-blockade

We report a case of polymorphous ventricular tachycardia caused by treatment with the post-synaptic alpha-blocking agent indoramin. This has not been reported with indoramin previously, nor to our knowledge with any other alpha-blocker. This pro-arrhythmic effect appears to be related to its class 3 anti-arrhythmic properties (QT interval prolongation) which is dose dependent, occurring only at large doses.

Issues in the pharmacologic management of primary hypertension in adolescence

Hypertension may occur in as many as 12% of adolescents and is usually of primary origin. There is an age-related increase of the blood pressure, making it difficult to define the limits of normal. True hypertension can be defined as blood pressure exceeding 140 90 mmHg regardless of age. Borderline blood pressure is said to exist when the blood pressure is above the 90th percentile for age. Blood pressure can be lowered with a wide variety of drugs, and adolescents are most often prescribed adult doses. There are specific concerns about the drugs' side effects in adolescents, particularly effects on growth and development, cognitive function, and metabolism. Diuretics are not the best first choice for therapy because of their metabolic effects. Cardiac hypertrophy and the morbidity of sustained hypertension are reduced by sympathetic inhibitors. Beta-blockers are the best currently available choice, although newer alpha-blocking agents may have some advantages. Even borderline pressure has been associated with evidence of cardiac hypertrophy, and there is substantial evidence that the adolescents with the highest blood pressures, even if still within normal limits, have the highest likelihood of developing sustained hypertension as adults. Yet there is no data establishing a beneficial effect on long-term risk of early treatment with drugs. For these reasons, nonpharmacologic intervention and close follow up are preferred as treatment for borderline blood pressure.

Studies on the Mode of Vasodilating Action of Carvedilol

Investigations were performed on isolated rat aortic strips and in pithed rats in order to elucidate the mechanism of vasorelaxation or the acute blood pressure lowering effect induced by carvedilol. In particular, the possible role of the beta-receptor-stimulating activities or alpha-blocking properties has been investigated. beta 2-stimulation can be ruled out, since preincubation of isolated vessels with the beta 2-receptor blocker ICI 118.551 does not influence the vasorelaxing activity of carvedilol. Additionally, its optical enantiomers also induce the same vasorelaxing effect in vitro. In contrast to the standard alpha-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of alpha-receptor agonists at hypotensive doses, but inhibition of the effects of alpha-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential alpha-blocking activity of carvedilol. For example, the dose required for a specific inhibitory effect on norepinephrine responses observed in pithed rats is at least 20 times higher than that required for a decrease in blood pressure in spontaneously hypertensive rats. Furthermore, the alpha-blocking activity is at least 20 times lower than the beta-blocking activity, whereas hypotension and beta-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the alpha-blocking activity does not contribute substantially to the decrease in blood pressure at doses normally used. It is suggested that a not yet defined postreceptor mechanism is involved in the vasorelaxing and acute blood pressure lowering activity of carvedilol.

Alpha-adrenergic system in the modulation of pancreatic A and B cell function in normal rats

The role of the alpha-adrenergic system in the control of pancreatic A and B cell function was investigated in an isolated perfused rat pancreas model. Two experimental procedures were performed. In the first one we evaluated the effects of two distinct concentrations (10(-8) M and 10(-7) M) of five adrenergic substances, with varying degrees of potency on the alpha-adrenergic presynaptic receptor, on insulin (IRI) and glucagon (IRG) release induced by arginine (20 mM) plus glucose (6.6 mM). In the second procedure we studied the effects of the two alpha-blocking agents yohimbine (alpha 2-blocker) and prazosin (alpha 1-blocker) at 10(-7) M on epinephrine-modulated IRI and IRG response to the same combined metabolic stimulus. The inhibitory activity on basal and metabolically induced IRI secretion of the agonists was superimposable on their potency on the presynaptic alpha 2-adrenergic receptors. Similarly, the alpha 1-blocking agent prazosin was less effective than the alpha 2-blocker yohimbine in counteracting the inhibitory effects of epinephrine on basal and arginine plus glucose-induced insulin release. The alpha-cell activity was clearly stimulated by epinephrine, whereas selective alpha-adrenergic drugs showed no significant action on IRG secretion. Both alpha-blockers were ineffective on basal IRG release, while they had some potentiating effect on the epinephrine-induced glucagon release in basal state and during the metabolic stimulus, without a significant difference between the two drugs. We conclude that, at least in the isolated perfused rat pancreas, alpha 2-adrenergic receptors are involved in the inhibition of IRI release induced by catecholamines. On the contrary, the alpha-adrenergic system does not seem to play an essential role in the regulation of IRG secretion; the potentiation of the epinephrine-induced stimulation of A cell function by the alpha-adrenergic blockade could be accounted for by a greater availability of the catecholamine at the beta-receptor binding sites.

腎機能低下を示す高血圧患者に対するＢＫＵ反復投与時の薬物動態

The pharmacokinetics of the alpha-blocking agent urapidil have been elucidated only in subjects with normal renal function. In the present study, BKU-15 (sustained-release capsules containing 15mg of urapidil) was administered for 7 consecutive days to 7 hypertensive patients with mild to moderate impairment of renal function. Treated were 3 males and 4 females between the ages of 24 to 74 years, and the dosing regimen was BKU-15 s. i. d. at 8: 00 a. m. on days 1 and 7, and b. i. d. at 8: 00 a. m. and 5: 00 p.m. on days 2 to 6.The minimum plasma concentration of urapidil determined at 8: 00 a. m. stabilized by day 5, measuring 74.0±19.8ng/ml on day 7. The pharmacokinetic parameters calculated after administration on day 7 were as follows: Cmax 205.5±31.0ng/ml; Tmax 4.3±0.3hrs; kel 0.1±0.02/hr; t1/2 8.4±1.5hrs. The absorption rate constant, minimum plasma concentration, and Cmax of urapidil were comparable to the corresponding values in healthy subjects given a 2-fold dose (Ebihara et al.), whereas elimination was delayed by a factor of two.A decrease in blood pressure was observed at 2 to 10 hours after administration of BKU-15. There was no significant change in heart rate. Two patients complained of hot flushes and throbbing in the temporal region, which might be related to the pharmacological effects of the drug. Severe nausea was noted in another patient.It is thus considered that BKU-15 b. i. d, may be adequate as the initial dosage in treating hypertensive patients with impaired renal function.

Manipulation of the micro-circulation for free flap surgery

Small vessel vasospasm during microvascular surgery imposes technical difficulties during microanastomosis which may compromise free flap transfer. Factors which tend to promote vasospasm are surgical manipulation, hypothermia, a reduced cardiac output and acid-base disturbance. Various anaesthetic regimes have been described to try to overcome these problems. Active and passive warming techniques to prevent hypothermia with consequent vasoconstriction are mandatory. In addition, specific techniques have been advocated to promote small vessel dilatation and flow which include epidural blockade, colloid infusion and the administration of alpha-blocking agents. Our experience has shown that these measures are not always successful in avoiding the vasospasm caused by local factors such as surgical manipulation or produced by the general factors which diminish tissue perfusion during long surgical procedures. A logical approach seeking to overcome the problems of vasospasm during free flap transfer, employing the directly-acting vasodilator, sodium nitroprusside (SNP) combined with intravenous fluid augmentation is used to reduce the haematocrit whilst increasing the cardiac output. In this context, unlike techniques that are designed to reduce operative haemorrhage, vasodilation with fluid augmentation leads to an increase in recipient site perfusion. The resultant increase in tissue flow provides good conditions for micro-surgical anastomosis. The use of SNP is logical as, unlike epidural blockade or many vasodilators previously tried, its action is independent of a non-functioning autonomic nervous system, a condition of the free flap. Its vascular smooth muscle relaxant properties also diminish vasospasm. Other factors influencing peripheral flow, such as temperature, acid-base disturbance, oedema and blood viscosity are strictly controlled.