Comparison of Metaraminol, Phenylephrine, and Norepinephrine Infusion for Prevention of Hypotension During Combined Spinal-Epidural Anaesthesia for Elective Caesarean Section: A Three-Arm, Randomized, Double-Blind, Non-Inferiority Trial.

BACKGROUND: A direct comparison of phenylephrine, metaraminol, and norepinephrine in preventing hypotension during spinal anaesthesia for elective caesarean section has never been made. PATIENTS AND METHODS: Seventy-five parturients scheduled for elective caesarean section were randomly assigned into the three groups. After spinal anaesthesia induction, patients received a bonus dose of vasopressor (norepinephrine 4ug, phenylephrine 50ug, or metaraminol 250ug) combined with continuous infusion (norepinephrine 8ug/mL, phenylephrine 100ug/mL, or metaraminol 500ug/mL) at a rate of 30 mL/h to prevent hypotension. The primary outcome was umbilical arterial (UA) pH and other intraoperative data were also recorded. RESULTS: The UA pH was 7.32±0.03 for metaraminol, 7.31±0.03 for phenylephrine, and 7.31±0.03 for norepinephrine. The 95% CI of MD was -0.011 to 0.026 comparing metaraminol with norepinephrine and 0.0181 to 0.0182 comparing phenylephrine with norepinephrine. Both lower bounds of the 95% CI of MD were above the predetermined lower boundary of clinical non-inferiority of -0.03, indicating both metaraminol and phenylephrine were non-inferior to norepinephrine. Moreover, the incidence of hypotension was lower in metaraminol compared with norepinephrine (P = 0.01). However, the incidence of hypertension was significantly lower in both phenylephrine and metaraminol compared with norepinephrine. CONCLUSION: Both metaraminol and phenylephrine were non-inferior to norepinephrine with respect to neonatal UA pH when used as a bolus and continuous infusion to prevent hypotension during combined spinal-epidural anaesthesia for elective caesarean section.

Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury.

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg-1min-1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg-1min-1, while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg-1min-1. CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.

A randomised double-blind trial of phenylephrine and metaraminol infusions for prevention of hypotension during spinal and combined spinal-epidural anaesthesia for elective caesarean section.

Prophylactic vasopressor administration is commonly recommended to reduce maternal hypotension during spinal anaesthesia for caesarean section. Metaraminol has undergone limited investigation in obstetric anaesthesia for this purpose, particularly in comparison with phenylephrine. In this multicentre, randomised, double-blind, non-inferiority study, we compared prophylactic phenylephrine or metaraminol infusions, started immediately after spinal anaesthesia, in 185 women who underwent elective caesarean section. Phenylephrine was initially infused at 50 µg.min-1 , and metaraminol at 250 µg.min-1 . The primary outcome was the difference in umbilical arterial pH between groups; secondary outcomes included other neonatal acid-base measures, and maternal haemodynamic changes. The mean (SD) umbilical arterial pH was 7.28 (0.06) in the phenylephrine group vs. 7.31 (0.04) in the metaraminol group (p = 0.0002). The estimated mean (95%CI) pH difference of 0.03 (0.01-0.04) was above the pre-determined lower boundary of clinical non-inferiority, and also met the criterion for superiority. Umbilical artery lactate concentration was 2.8 (1.2) mmol.l-1 in the phenylephrine group vs. 2.3 (0.7) mmol.l-1 in the metaraminol group (p = 0.0018). Apgar scores did not significantly differ between groups. There was a higher incidence of hypotension, defined as systolic arterial pressure < 90% baseline, in the phenylephrine group; there was a higher incidence of hypertension and severe hypertension (systolic arterial pressure > 110% and > 120% baseline, respectively) in the metaraminol group. There was no significant difference between groups in the incidence of nausea, vomiting or maternal bradycardia. We conclude that, when used as an infusion to prevent hypotension after spinal anaesthesia for elective caesarean section, metaraminol is at least non-inferior to phenylephrine with respect to neonatal acid-base outcomes.

Minimally invasive cardiac output monitoring: agreement of oesophageal Doppler, LiDCOrapid™ and Vigileo FloTrac™ monitors in non-cardiac surgery.

There is lack of data about the agreement of minimally invasive cardiac output monitors, which make it impossible to determine if they are interchangeable or differ objectively in tracking physiological trends. We studied three commonly used devices: the oesophageal Doppler and two arterial pressure-based devices, the Vigileo FloTrac™ and LiDCOrapid™. The aim of this study was to compare the agreement of these three monitors in adult patients undergoing elective non-cardiac surgery. Measurements were taken at baseline and after predefined clinical interventions of fluid, metaraminol or ephedrine bolus. From 24 patients, 131 events, averaging 5.2 events per patient, were analysed. The cardiac index of LiDCOrapid versus FloTrac had a mean bias of -6.0% (limits of agreement from -51% to 39%) and concordance of over 80% to the three clinical interventions. The cardiac index of Doppler versus LiDCOrapid and Doppler versus FloTrac, had an increasing negative bias at higher mean cardiac outputs and there was significantly poorer concordance to all interventions. Of the preload-responsive parameters, Doppler stroke volume index, Doppler systolic flow time and FloTrac stroke volume variation were fair at predicting fluid responsiveness while other parameters were poor. While there is reasonable agreement between the two arterial pressure-derived cardiac output devices (LiDCOrapid and Vigileo FloTrac), these two devices differ significantly to the oesophageal Doppler technology in response to common clinical intraoperative interventions, representing a limitation to how interchangeable these technologies are in measuring cardiac output.

Prewarming neurosurgical patients to minimize hypotension on induction of anesthesia: a randomized trial.

PURPOSE: Prewarming prior to surgery is effective in preventing perioperative hypothermia. There is a paucity of evidence, however, regarding the hemodynamic effects of prewarming. We hypothesized that the nadir mean arterial pressure during anesthesia induction would be higher after prewarming than after no prewarming. METHODS: We randomized 32 patients prior to elective neurosurgery to receive either one hour of forced-air convective warming at 46°C or routine care (full body blanket with convective warmer attached but not turned on). All patients had invasive blood pressure, heart rate, and core temperature monitoring before and during warming and underwent a protocolized intravenous anesthetic induction with propofol and remifentanil target-controlled infusions. The primary endpoint was the nadir mean arterial blood pressure (MAP) during induction. Hypotension was defined as systolic blood pressure (SBP) < 90 mmHg, MAP < 60 mmHg, or a reduction in either SBP or MAP > 20% from baseline values. RESULTS: No difference was found in the mean (SD) nadir MAP between the prewarmed group and the control group [64 (11) mmHg vs 68 (16) mmHg, respectively; mean difference, 5 mmHg; 95% confidence interval (CI), -6 to 15; P = 0.36]. Similarly, there was no difference between groups in the incidence of hypotension (100% of prewarmed vs 93% of control patients; relative risk, 1.07; 95% CI, 0.94 to 1.23; P = 0.32) or in the requirement for vasopressors during induction (four patients in each group required metaraminol; P = 1.00). CONCLUSION: Prewarming with convective forced air for one hour prior to intravenous anesthetic induction did not prevent hypotension during the induction period (Australian New Zealand Clinical Trials Registry [ANZCTR] ACTRN12615000431527).

Serum oxytocin concentrations in elective caesarean delivery: a randomized comparison of three infusion regimens.

BACKGROUND: The aim of this study was to determine serum oxytocin concentrations following different regimens of prophylactic oxytocin administration in women undergoing elective caesarean delivery. METHODS: Thirty healthy pregnant patients were randomized, after clamping of the umbilical cord, to receive intravenous oxytocin in one of the following groups: G1 (n=9), 10 IU of oxytocin infused over 30 min (0.33 IU/min); G2 (n=11), 10 IU of oxytocin infused over 3 min and 45 s (2.67 IU/min); and G3 (n=10), 80 IU of oxytocin infused over 30 min (2.67 IU/min). Both patient and surgeon were blinded to allocation. Uterine tone was assessed by surgical palpation. Serum oxytocin concentration was determined by enzyme immunoassay before anaesthesia (T0) and at 5 (T5), 30 (T30) and 60 (T60) min after the start of oxytocin infusion. RESULTS: Serum oxytocin concentrations (mean±standard error, ng/mL) were not significantly different in the groups at T0 (0.06±0.02, 0.04±0.02 and 0.07±0.04, respectively, P=0.76), and T60 (0.65±0.26, 0.36±0.26 and 0.69±0.26, respectively, P=0.58). G3 showed higher concentrations than G1 at T5 (3.65±0.74 versus 0.71±0.27, P=0.01) and at T30 (6.19±1.19 versus 1.17±0.37, P<0.01), and were higher than G2 at T30 (6.19±1.19 versus 0.41±0.2, P<0.01). Haemodynamic data and uterine tone were considered satisfactory and similar in all groups. No additional uterotonic agents were needed. CONCLUSION: Serum oxytocin measurements made using enzyme immunoassay in healthy pregnant women undergoing elective caesarean delivery showed that administration of 80 IU oxytocin over 30 min resulted in higher serum oxytocin levels after 5 and 30 min than the two other regimens. The concentrations did not differ between groups at 60 min.

Transient transmural ischaemia during endobronchial laser treatment: possible coronary artery embolism.

We report the case of a 51-year-old woman receiving endobronchial treatment with neodymium:yttrium garnet laser After 30 minutes of stable anaesthesia and laser treatment, sudden inferior myocardial ischaemia developed followed by haemodynamic collapse. Resuscitation with fluids, pressors, atropine and esmolol was successful, leading to rapid resolution of the ischaemia and full recovery. The sudden onset and time course of the ST segment elevation was consistent with coronary artery air embolism, as occurs occasionally during cardiac surgery. Systemic gas embolism during endobronchial laser treatment has been previously reported with poor outcomes and significant mortality. This complication can be avoided with awareness of the mechanism while appropriate monitoring may allow early detection and successful treatment.

GABA-mediated attenuation of noradrenaline release in the rat median preoptic area caused by intravenous injection of metaraminol.

Previous studies have shown that the noradrenergic system in the median preoptic nucleus (MnPO) play an important role in the control of the body fluid balance and cardiovascular function and that the release of noradrenaline in the MnPO is regulated by gamma-aminobutyric acid (GABA) receptor mechanisms. The present study was carried out to examine whether the GABAergic system is involved in the modulation of the noradrenaline release in the MnPO in response to an elevation in blood pressure using in vivo microdialysis techniques. In urethane-anaesthetised male rats, the rise in arterial pressure caused by intravenous administration of the alpha-agonist metaraminol significantly decreased dialysate noradrenaline concentration in the MnPO area. The decrease in the noradrenaline level elicited by the metaraminol administration was significantly attenuated by perfusion with either bicuculline (10 microM), a GABA(A) receptor antagonist, or phaclofen (10 microM), a GABA(B) receptor antagonist, through a microdialysis probe. The amount of the antagonist-induced attenuation was much greater in the bicuculline-treated group than in the phaclofen-treated group. These results suggest that the release of noradrenaline in the MnPO area may be modulated by neural inputs from the peripheral baroreceptors, and that the neural inputs may be mediated in part through GABA(A) receptors rather than GABA(B) receptors in the MnPO area.

Successful management of stuttering priapism using home self-injections of the alpha-agonist metaraminol

Low-flow priapism can result in impotence if treatment is delayed, yet patients with recurrent priapism often suffer delay before therapy. We describe management of recurrent priapism using self-administered injections of intracavernosal metaraminol (AramineÖ, Merck), a long-acting vasoconstricting amine that is considered safer than epinephrine. The patient injects as often as once daily using 5-10 mg of drug. Our patient reports rapid detumescence and has not required emergency room visits since starting injections. He denies complications. Treatment of priapism using metaraminol has been suggested in the hospital setting; however, this is the first report of successful home self-administration of the drug.

Successful management of stuttering priapism using home self-injections of the alpha-agonist metaraminol.

Low-flow priapism can result in impotence if treatment is delayed, yet patients with recurrent priapism often suffer delay before therapy. We describe management of recurrent priapism using self-administered injections of intracavernosal metaraminol (Aramine, Merck), a long-acting vasoconstricting amine that is considered safer than epinephrine. The patient injects as often as once daily using 5-10 mg of drug. Our patient reports rapid detumescence and has not required emergency room visits since starting injections. He denies complications. Treatment of priapism using metaraminol has been suggested in the hospital setting; however, this is the first report of successful home self-administration of the drug.

Improved stability and release control of levodopa and metaraminol using ion-exchange fibers and transdermal iontophoresis.

Achievement of controlled drug delivery and stability of drugs during storage is a problem also in transdermal drug delivery. The objective of this study was to determine, whether an easily oxidized drug, levodopa, could be stabilized during storage using pH-adjustment and ion-exchange fibers. Controlled transdermal delivery of the zwitterionic levodopa was attempted by iontophoresis and ion-exchange fiber. Ion-exchange kinetics and transdermal permeation of a cationic (presumably more stable) model drug, metaraminol, were compared to the corresponding data of levodopa. Levodopa was rapidly oxidized in the presence of water, especially at basic pH-values. At acidic pH-values the stability was improved significantly. Ion-exchange group and the pH had a clear effect on the release of both the levodopa and metaraminol from the ion-exchange fiber. The adsorption/release kinetics of metaraminol were more easily controllable than the corresponding rate and extent of levodopa adsorption/release. Iontophoretic enhancement of drug permeation across the skin was clearly more significant with the positively charged metaraminol than with the zwitterionic levodopa. Ion-exchange fibers provide a promising alternative to control drug delivery and to store drugs that are degraded easily.

Prostaglandin synthesis inhibitor improves hypotension during normothermic cardiopulmonary bypass.

Hypotension is a major systemic side effect during cardiopu monary bypass (CPB), especially at normothermia. We previously reported that prostaglandin (PG) might play a substantial role in hypotension. The purpose of this study was to clarify whether a PG synthesis inhibitor (PGSI) could improve hypotension during CPB. Thirty-six patients undergoing cardiac surgery with normothermic CPB (35-37 degrees C) were divided into two groups: a PGSI group (n = 18), whose members wer given a PGSI before and during CPB, and a control group (n = 18). In both groups, perfusion flow was sufficient and pressure was maintained at above 45 mm Hg by infusion of metaraminol, a vasoconstrictor. The mean arterial pressure throughout CPB was significantly higher in the PGSI group than in the control group (57 +/- 4 vs. 48 +/- 3 mm Hg, p < 0.01), whereas the dose of infused metaraminol was significantly lower in the PGSI group (13 +/- 7 vs. 21 +/- 6 mg, p < 0.01). The blood base excess was not significantly different (1.0 +/- 1.6 vs. 1.7 +/- 1.9 mmol/L, p = 0.28), and urine output was significantly higher in the PGSI group (503 +/- 179 vs. 354 +/- 112 ml/hr, p < 0.01). In conclusion, PGSI can improve hypotension during CPB and increase urine output without impairing peripheral circulation.

Comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section.

BACKGROUND: Although ephedrine is usually recommended as the first-line vasopressor in obstetrics, its superiority over other vasopressors has not been proven in humans. METHODS: In a double-blind study, the authors randomized women having elective cesarean section with spinal anesthesia to receive an intravenous infusion of ephedrine, starting at 5 mg/min (n = 25), or metaraminol, starting at 0.25 mg/min (n = 25), titrated to maintain systolic arterial pressure in the target range 90-100% of baseline. Umbilical cord gases, maternal hemodynamics, uterine artery puLsatility index, and Apgar scores were compared. RESULTS: Systolic arterial pressure was maintained more closely in the target range in the metaraminol group compared with the ephedrine group. In the metaraminol group, umbilical arterial pH was greater (median and interquartile range, 7.31 and 7.31-7.33 vs. 7.24 and 7.14-7.29; P < 0.0001), and umbilical venous pH was greater (7.36 and 7.35-7.38 vs. 7.33 and 7.26-7.34; P < 0.0001) compared with the ephedrine group. No patient in the metaraminol group had umbilical arterial pH less than 7.2, compared with nine patients (39%) in the ephedrine group (P = 0.0005). Apgar scores were similar between groups. Changes in uterine artery pulsatility index were similar between groups. CONCLUSIONS: When used by infusion to maintain arterial pressure during spinal anesthesia for cesarean section, metaraminol was associated with less neonatal acidosis and more closely controlled titration of arterial pressure compared with ephedrine.

Metaraminol infusion for maintenance of arterial blood pressure during spinal anesthesia for cesarean delivery: the effect of a crystalloid bolus.

We randomly allocated women having elective cesarean delivery to receive either no bolus (Control Group, n = 31) or 20 mL/kg lactated Ringer's solution (Bolus Group, n = 35) IV before spinal anesthesia. An infusion of metaraminol started at 0.25 mg/min was titrated to maintain systolic arterial blood pressure in the target range 90%-100% of baseline. The total dose of metaraminol required up to the time of uterine incision was similar between the Control Group and the Bolus Group (3.62 +/- 1.20 vs 3.27 +/- 1.39 mg, P = 0.3). However, the Control Group required more metaraminol in the first 5 min (1.29 +/- 0.60 vs 0.96 +/- 0.58 mg, P = 0.025) and a faster maximum infusion rate (0.45 +/- 0.20 vs 0.32 +/- 0.13 mg/min, P = 0.002) compared with the Bolus Group. There was no difference between groups in regards to changes in systolic arterial blood pressure or heart rate over time, or maternal or neonatal outcome. We conclude that when metaraminol is used to maintain arterial pressure during spinal anesthesia for cesarean delivery, crystalloid bolus is not essential provided that sufficient vasopressor is given in the immediate postspinal period.

A comparative study of three different methods of administering metaraminol during spinal anaesthesia in the elderly.

We compared three methods of administering metaraminol during spinal (subarachnoid) anaesthesia. Fifty-two elderly patients with fractured hips were studied. Blood pressure was maintained by either intramuscular (i.m.) metaraminol (0.1 mg x kg(-1)), intravenous (i.v.) boluses (0.01 mg x kg(-1)) or an infusion (0.05 mg x kg(-1) x h(-1)). Non-invasive blood pressure was recorded every one-minute. Spinal anaesthesia initially decreased the systolic arterial pressure by 15 (14) % compared to 35 (15) % for diastolic pressure (P<0.001). I.m. metaraminol restored the systolic arterial pressure back to baseline values (-3%), but there was significant between-subject variability resulting in a very unpredictable effect. I.v. boluses and infusion had a more predictable effect and maintained systolic arterial pressure at about 20% below baseline. Range of effect, measured by inter-quartile range and variance, was greatest in the i.m. group and least in the infusion group (P<0.003). I.m. metaraminol during spinal anaesthesia has a very unpredictable effect. Infusions of metaraminol provided the best blood pressure control. Diastolic blood pressure fell significantly after spinal anaesthesia and this merits further investigation.