The use of vasopressors during spinal anaesthesia for caesarean section.

PURPOSE OF REVIEW: Hypotension remains one of the most researched subjects in obstetric anaesthesia. The purpose of this study is to review the most recent published articles on the use of vasopressors during spinal anaesthesia for caesarean section. RECENT FINDINGS: Despite continued research indicating advantages of phenylephrine over ephedrine, practitioners in some countries continue to favour ephedrine. Recent research has continued to compare the two drugs with some work emerging on high-risk patients. Concern about reflexive bradycardia during phenylephrine use has led to consideration of alternatives. Norepinephrine which has mild ß-adrenergic activity has been shown to have equivalent pressor activity but with less depressant effect on heart rate and cardiac output versus phenylephrine. Research continues to focus on methods of vasopressor administration. Prophylactic infusions of phenylephrine have been shown to be effective and may require less physician intervention compared with intermittent boluses. Automated computer-controlled systems have been further investigated using multiple agents and continuous noninvasive blood pressure monitoring. SUMMARY: Evidence continues to support phenylephrine as the first-line vasopressor in obstetrics. However, recent research is emerging to suggest that low-dose norepinephrine may be a better alternative. Prophylactic infusions are effective and automated systems have potential for the future.

Libertas: a phase II placebo-controlled study of NRL001 in patients with faecal incontinence showed an unexpected and sustained placebo response.

PURPOSE: Faecal incontinence (FI) is distressing, significantly reduces quality of life (QoL) and has few pharmacological treatments. The α1-adrenoceptor agonist NRL001 (1R,2S-methoxamine hydrochloride) improves anal sphincter tone. NRL001 efficacy was evaluated by changes in Wexner scores at week 4 vs. baseline in NRL001-treated patients compared with placebo. Impact of NRL001 on QoL and safety were also assessed. METHODS: Four hundred sixty-six patients received NRL001 (5, 7.5 or 10 mg) or placebo as suppository, once daily over 8 weeks. Wexner score, Vaizey score and QoL were analysed at baseline, week 4 and week 8. FI episodes and adverse events were recorded in diaries. RESULTS: At week 4, mean reductions in Wexner scores were -3.0, -2.6, -2.6 and -2.4 for NRL001 5, 7.5, 10 mg and placebo, respectively. All reduced further by week 8. As placebo responses also improved, there was no significant treatment effect at week 4 (p = 0.6867) or week 8 (p = 0.5005). FI episode frequency improved for all patients, but not significantly compared with placebo (week 4: p = 0.2619, week 8: p = 0.5278). All patients' QoL improved, but not significantly for all parameters (p > 0.05) except depression/self-perception at week 4 (p = 0.0102) and week 8 (p = 0.0069), compared with placebo. Most adverse events were mild and judged probably or possibly related to NRL001. CONCLUSIONS: All groups demonstrated improvement in efficacy and QoL compared with baseline. NRL001 was well-tolerated without serious safety concerns. Despite the improvement in all groups, there was no statistically significant treatment effect, underlining the importance of relating results to a placebo arm.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

AIMS: The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). METHODS: Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. RESULTS: Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. CONCLUSIONS: Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect.

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

AIMS: Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. METHODS: Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. DISCUSSION: This is the first randomised controlled study to investigate the efficacy and safety of a selective α1 -adrenoceptor agonist for the treatment of faecal incontinence. Furthermore, this is the first time the impact of NRL001 on assessments of QoL, health outcomes and patient satisfaction will be assessed. Innovative strategies were developed to meet the challenge of recruiting patients for this study, for example, media advertising, posters and mailshots as allowed by each study centre.

Motor deficits and recovery in rats with unilateral spinal cord hemisection mimic the Brown-Sequard syndrome.

Cervical incomplete spinal cord injuries often lead to severe and persistent impairments of sensorimotor functions and are clinically the most frequent type of spinal cord injury. Understanding the motor impairments and the possible functional recovery of upper and lower extremities is of great importance. Animal models investigating motor dysfunction following cervical spinal cord injury are rare. We analysed the differential spontaneous recovery of fore- and hindlimb locomotion by detailed kinematic analysis in adult rats with unilateral C4/C5 hemisection, a lesion that leads to the Brown-Séquard syndrome in humans. The results showed disproportionately better performance of hindlimb compared with forelimb locomotion; hindlimb locomotion showed substantial recovery, whereas the ipsilesional forelimb remained in a very poor functional state. Such a differential motor recovery pattern is also known to occur in monkeys and in humans after similar spinal cord lesions. On the lesioned side, cortico-, rubro-, vestibulo- and reticulospinal tracts and the important modulatory serotonergic, dopaminergic and noradrenergic fibre systems were interrupted by the lesion. In an attempt to facilitate locomotion, different monoaminergic agonists were injected intrathecally. Injections of specific serotonergic and noradrenergic agonists in the chronic phase after the spinal cord lesion revealed remarkable, although mostly functionally negative, modulations of particular parameters of hindlimb locomotion. In contrast, forelimb locomotion was mostly unresponsive to these agonists. These results, therefore, show fundamental differences between fore- and hindlimb spinal motor circuitries and their functional dependence on remaining descending inputs and exogenous spinal excitation. Understanding these differences may help to develop future therapeutic strategies to improve upper and lower limb function in patients with incomplete cervical spinal cord injuries.

Analysis of baroreflex sensitivity during undulation pump ventricular assist device support.

The aim of this study was to examine the baroreflex sensitivity (BRS), which involves the autonomic nervous system, in a goat with a chronically implanted undulation pump ventricular assist device (UPVAD). The UPVAD involved transforming the rotation of a brushless DC motor into an undulating motion by a disc attached via a special linking mechanism, and a jellyfish valve in the outflow cannula to prevent diastolic backflow. The pump was implanted into the thoracic cavity of a goat by a left thoracotomy, and the inflow and outflow cannulae were sutured to the apex of the left ventricle and to the descending aorta, respectively. The driving cable was wired percutaneously to an external controller. Electrocardiogram and hemodynamic waveforms were recorded at a sampling frequency of 1 kHz. BRS was determined when awake by the slope of the linear regression of R-R interval against mean arterial pressure changes, which were induced by the administration of methoxamine hydrochloride, both with continuous driving of the UPVAD as well as without assistance. BRS values during the UPVAD support and without assistance were 1.60 +/- 0.30 msec/mm Hg and 0.98 +/- 0.22 msec/mm Hg (n = 5, P < 0.05), respectively. BRS was significantly improved during left ventricular assistance. Therefore, UPVAD support might decrease sympathetic nerve activity and increase parasympathetic nerve activity to improve both microcirculation and organ function.

Chronic inhibition of inducible nitric oxide synthase ameliorates cardiovascular abnormalities in streptozotocin diabetic rats.

Previous studies from our lab have demonstrated cardiovascular abnormalities such as depressed mean arterial blood pressure and heart rate, endothelial dysfunction and attenuated pressor responses to vasoactive agents in streptozotocin diabetic rats. We investigated whether these abnormalities are due to diabetes-associated chronic activation of inducible nitric oxide synthase (iNOS). Control and streptozotocin (60 mg/kg, iv) diabetic rats were treated with either vehicle or N6-(1-Iminoethyl)-L-lysine dihydrochloride (L-NIL, 3 mg/kg/day, p.o), a specific inhibitor of iNOS for 8 weeks. At the end of treatment, the mean arterial blood pressure and heart rate were measured in freely moving conscious rats. Further, pressor responses to bolus doses of methoxamine were determined. Endothelial nitric oxide synthase (eNOS) and iNOS expression as well as nitrotyrosine (NT) levels were assessed in the heart and superior mesenteric arteries by western blot and immunohistochemistry. Untreated diabetic rats showed depressed mean arterial blood pressure and heart rate and exhibited vascular hyporeactivity that were significantly improved by treatment with L-NIL. Further, decreased eNOS expression and increased iNOS expression and activity were associated with increased NT levels in the heart and superior mesenteric arteries of untreated diabetic rats. L-NIL treatment of diabetic rats normalized the expression of eNOS and NT levels without any effect on iNOS expression in the heart and superior mesenteric arteries. The results of our study suggest that induction of iNOS in cardiovascular tissues contributes significantly to the depressed mean arterial blood pressure, heart rate and pressor responses to vasoactive agents. Chronic inhibition of iNOS in diabetes may prove beneficial in the treatment of cardiovascular abnormalities.

High-flow priapism as a complication of a veno-occlusive priapism: two case reports.

The presentation of two cases of veno-occlusive priapism, in patients of 36 and 58 years, in whom the different medical and surgical techniques employed, failed. The suspicion that high-flow priapism had been provoked by said surgical intervention was confirmed by bilateral arteriographs of the pudendal artery. The treatment, selective embolisation of the affected cavernosal artery with reabsorbable material, led to a rapid return of penile detumescence.

Successful treatment of retrograde ejaculation with the alpha1-adrenergic agonist methoxamine: case study.

We treated two patients affected by retrograde ejaculation (RE) with the pure alpha1-adrenergic agonist methoxamine; the drug was self-administered intramuscularly by the patients 30 min prior to intercourse or masturbation. A previous trial with oral imipramine had been ineffective in both patients. Sperm count increased substantially, particularly in the first patient who had insulin-dependent diabetes and was seeking fertility. In this patient, total ejaculated sperm increased from 22 millions to 488 and 419.5 millions on two different occasions, with good motility; two clinical pregnancies were obtained in the partner of this patient after 3 and 4 months of treatment, respectively. The second patient did not desire fertility. In both patients, no side effects were seen except for slight piloerection; blood pressure values increased slightly, and heart rate was unchanged. We conclude that self-administered methoxamine can be a useful, noninvasive and inexpensive treatment of RE, when oral agents are ineffective.

Idiopathic long QT syndrome with early afterdepolarization induced by epinephrine. Acase report.

A patient with idiopathic long QT syndrome had repeated syncopal episodes. The QTc interval on the electrocardiogram at rest was 530 ms and was prolonged by exercise up to 740 ms with T wave alternation. Intravenous epinephrine (0.1 microg/kg weight per min), but not isoproterenol (0.7 microg/min), produced early after depolarization of the monophasic action potential recorded at the right ventricular apex. Epinephrine prolonged the QTc interval to 710 ms. After the addition of propranolol to the epinephrine, the QTc (580 ms) was longer than at baseline. Methoxamine also prolonged the QTc to 580 ms. The QT interval in long QT syndrome is generally considered to be prolonged by a beta-adrenergic effect, but in the present case alpha-adrenergic stimulation had an additional effect on the prolongation of the QT interval.

[Role of heat shock protein 90 in hyperdynamic circulation of portal hypertensive rats].

OBJECTIVE: To study the role of heat shock protein 90 (HSP 90) in the formation of hyperdynamic circulation of portal hypertensive rats. METHODS: Animal model of portal hypertension was established by partial ligation of the portal vein among 20 SD rats (group P). Ten rats underwent sham operation (group S) Four weeks after the operation, the rats were killed and their mesenteric arteries and portal veins were obtained. The expression of HSP 90 in the portal veins and part of the superior mesenteric arteries was detected by Western blotting. Another mesenteric arteries underwent continuous perfusion with methoxamine (MTX, 30 and 100 micro mol/L) or acetylcholine (Ach). The perfusion pressure was monitored by a sensor. The concentration-response curves were examined in response to MTX and Ach infusion respectively. Then geldanamycin (GA) was infused; responses to MTX and ACh were repeated as described above. The endothelia of these arteries was denuded. After endothelial denudation was achieved, response to sodium nitroprusside (SNP) was examined. RESULTS: The expression of HSP 90 was much stronger in the group P than in the group S. The perfusion pressure of the mesenteric artery of the group P was 13.32 mm Hg +/- 0.55 mm Hg, significantly lower than that of the group S (17.33 mm Hg +/- 0.57 mm Hg, n = 10, P < 0.001). After the addition of MTX, the perfusion pressure of the mesenteric artery of the group P was 141.9 mm Hg +/- 7.6 mm Hg, significantly lower than that of the group S (181.1 mm Hg +/- 16.2 mm Hg, n = 8, P < 0.001). GA and 30 micro mol/L or 100 micro mol/L MTX were added successively into the perfusion fluid for the mesenteric superior artery of the group P, then the perfusion pressure became 106.7 mm Hg +/- 7.5 mm Hg or 124.9 mm Hg +/- 5.5 mm Hg, significantly higher than those of the mesenteric superior artery of the group P without addition of GA (60.9 mm Hg +/- 4.3 mm Hg, n = 5, P < 0.05 and 98.7 mm Hg +/- 4.7 mm Hg, n = 5, P < 0.05). GA and 100 micro mol/L MTX were added successively into the perfusion fluid for the mesenteric superior artery of the group S, the perfusion pressure became 151.2 mm Hg +/- 7.1 mm Hg, not significantly different from that of the mesenteric superior artery of the group S without addition of GA (149.8 mm Hg +/- 5.6 mm Hg, P > 0.05). With the addition of GA in advance, the ACh-dependent vasorelaxation of the isolated perfused rat mesenteric artery was significantly attenuated in comparison with the mesenteric artery without addition of GA into whose perfusion fluid (P < 0.05). However, GA did not affect the vasodilation of the ensothelium-neduded mesenteric artery in response to SNP. CONCLUSION: HSP90 is responsible for the hyperdynamic circulation in the portal hypertensive rats.

[Priapism secondary to chronic myeloid leukemia: value of initial treatment with cavernous lavage plus adjuvant methoxamine]. / Priapismo secundario a leucemia mieloide crónica: valor del tratamiento inicial con lavado cavernoso más metoxamina adyuvante.

OBJECTIVE: To report a case of priapism secondary to leukemia, with special reference to the initial treatment in the emergency services. METHODS: A 53-year-old male with chronic myeloid leukemia presented with prolonged involuntary painful erection of 12 hours' duration. The physical examination and particularly the cavernosal blood gas study, indicated low flow priapism. Punction-lavage of the corpora cavernosa was performed. Because complete response was not achieved with this procedure, adjuvant intracavernous methoxamine was administered. RESULTS: Complete detumescence was achieved after the third dose of methoxamine. There was no recurrence and erectile function was preserved. CONCLUSIONS: We underscore the utility of combined cavernous lavage + adjuvant alpha-1 adrenergic agonist as initial therapy in priapism with this special etiology.

Use of methoxamine in the resuscitation of epinephrine-resistant electromechanical dissociation.

We describe three cases of electromechanical dissociation under anaesthesia that were unresponsive to doses of intravenous epinephrine given according to current Advanced Life Support guidelines, but which responded immediately to the intravenous administration of the pure alpha agonist, methoxamine. We suggest a possible mechanism to explain this finding and review the literature on vasopressor drugs used for cardiopulmonary resuscitation during electromechanical dissociation. An intravenous alpha agonist, such as methoxamine 20 mg, should be considered for any case of cardiac arrest secondary to electromechanical dissociation which is unresponsive to epinephrine given according to current guidelines.

Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study.

The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous methoxamine or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. Methoxamine evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects.

Prevention of spinal anaesthesia-induced hypotension in the elderly: i.m. methoxamine or combined hetastarch and crystalloid.

We have compared two methods of reducing hypotension during spinal anaesthesia in elderly patients, 6% hetastarch and crystalloid or methoxamine 10 mg i.m., in terms of haemodynamic stability and requirements for additional vasopressors. Sixty-two patients (aged 60-97 yr) undergoing surgical fixation of fractured neck of femur were allocated randomly to receive 6% hetastarch (Hespan) 500 ml followed by Hartmann's solution 500 ml (group HS, n = 32) or a bolus injection of methoxamine 10 mg i.m. (group MX, n = 30), 10 min before induction of spinal anaesthesia with 0.5% hyperbaric bupivacaine 2.25-3.0 ml. Arterial pressure was measured non-invasively by an oscillotonometer at 2-min intervals from 0 to 40 min and at 5-min intervals thereafter. Methoxamine 2 mg i.v. was given if systolic arterial pressure (SAP) decreased to < 100 mm Hg. Hypotension was defined as a 25% decrease from baseline SAP or mean arterial pressure (MAP). Patient data, sensory level and blood loss were similar in the two groups. SAP and MAP increased initially from baseline until induction of spinal anaesthesia and then decreased for 30 min in both groups, but remained higher in group MX (P < 0.05). Heart rate (HR) decreased from baseline in group MX (P < 0.05) and was less than in group HS at all times from 2 to 60 min (P < 0.01). The incidence of SAP hypotension (47% vs 75%; P = 0.03, odds ratio (OR) = 3.43) and MAP hypotension (47% vs 67%; P = 0.09, OR = 2.51) was less in group MX than in group HS. Requirements for rescue methoxamine i.v. (27% vs 53%, P = 0.04, OR = 3.11) was less in group MX than in group HS but the dose of rescue methoxamine given (mean 6.3 (95% confidence intervals 3.0-9.6) vs 8.9 (5.6-12.2) mg) and time to onset of hypotension (20.7 (14.5-26.7) vs 17.3 (11.4-23.1) min) were similar in groups MX and HS, respectively. We conclude that methoxamine 10 mg i.m., given 10 min before induction of spinal anaesthesia in normovolaemic elderly patients, reduced subsequent SAP and MAP hypotension, HR and requirements for rescue vasopressor therapy compared with a combination of 6% hetastarch 500 ml and crystalloid 500 ml. The previously reported benefit of such volume administration may not extend to the elderly.

Intracavernous methoxamine in the treatment of priapism.

Methoxamine is an alpha-adrenergic drug, its unique pharmacokinetics and mechanism of action on alpha-1 receptors lead to consider it, similarly to phenylephrine, as a first-choice drug for treating drug-induced or veno-occlusive priapism. The experience obtained with its use in the management of three cases of priapism lasting over 7 h and one case of sustained rigid erection caused during anesthetic induction are reported.

Lack of delayed effects of amphetamine, methoxamine, and prazosin (adrenergic drugs) on behavioral outcome after lateral fluid percussion brain injury in the rat.

This study examined the delayed effects of the administration of d-amphetamine, methoxamine (an alpha1-adrenergic receptor agonist), and prazosin (an alpha1-adrenergic receptor antagonist) on the behavioral outcome of lateral fluid-percussion (FP) brain injury. Rats trained to perform a beam-walking task were subjected to brain injury of moderate severity (2.1 to 2.2 atm). Twenty-four hours after injury, rats were treated with amphetamine, methoxamine, or prazosin at two or three different dose levels. Amphetamine-treated animals displayed no significant improvement in beam-walking ability either during or after drug intoxication (from days 3 to 5 after brain injury). Similarly, neither methoxamine nor prazosin significantly affected beam-walking ability during or after drug intoxication. Neither amphetamine treatment at three different doses nor treatment with methoxamine or prazosin at two different doses affected the spatial learning disabilities of brain-injured animals. These results suggest that (1) unlike amphetamine administration after sensorimotor cortex (SMC) ablation or contusion brain injury models, amphetamine administration at 24 h after concussive FP brain injury does not improve beam-walking performance; (2) unlike amphetamine administration 10 min after concussive FP brain injury amphetamine administration 24 h after injury does not improve cognitive function; and (3) unlike prazosin administration after SMC ablation brain injury, prazosin administration 24 h after concussive FP brain injury does not effect beam-walking performance.