Phenylephrine Infusion Research Articles

Inorganic Nitrate Supplementation Blunts Vasoconstrictor Responsiveness During Exercise in Patients with Type 2 Diabetes

Patients with type 2 diabetes (T2D) have exaggerated α1‐ and α2‐vasoconstrictor responsiveness during exercise indicating reduced functional sympatholysis. Nitric oxide (NO) is purported to offset α‐mediated vasoconstriction during exercise (i.e., is sympatholytic). Given T2D have attenuated NO bioavailability, supplementation with inorganic nitrate (an exogenous source of NO) may reduce α1‐ and/or α2‐vasoconstrictor responsiveness during exercise in T2D. Thus, we examined if 8wks of inorganic nitrate supplementation (250mg daily, NO3 group) reduced vasoconstrictor responsiveness to intra‐arterial infusions of phenylephrine (PE, α1‐agonist) and/or dexmedetomidine (DEX, α2‐agonist) during handgrip exercise in T2D relative to a placebo (PL group). Handgrip exercise trials lasted for 6min at 20% maximum grip strength. Steady‐state (SS) blood flow was achieved during the first 3min with either PE or DEX infused during the latter 3min. Forearm blood flow (FBF, ml/min) was calculated using brachial artery diameter and blood velocity measured via Doppler ultrasound. Forearm vascular conductance (FVC, ml/min/100mmHg), a surrogate of vasodilation, was calculated using FBF and mean arterial pressure (MAP). Both FBF and FVC were calculated from data averaged over the final 30sec of rest and SS exercise. Vasoconstrictor responsiveness for all trials was quantified as: ((SS FVCwith drug − SS FVCpre‐drug)/SS FVCpre‐drug)x100%. The magnitude of sympatholysis was calculated as the difference in %vasoconstriction at rest and exercise for both α‐agonists. After baseline assessments, T2D were randomly assigned to the NO3 (n=17, 13M/4F, 58±9yrs, 31.8±5.2kg/m2) or PL (n=17, 12M/5F, 58±9yrs, 32.3±5.3kg/m2) supplementation groups. Following supplementation, there were no differences in resting α1‐ or α2‐vasoconstrictor responsiveness observed between groups (group‐by‐time p=0.86 and 0.15, respectively). The NO3 group had greater increases in FBF (164±68 to 185±70ml/min, p<0.05) and FVC (136±53 to 164±61ml/min/100mmHg, p<0.05) responses to exercise (Δ from rest) relative to the PL group (149±66 to 149±65ml/min and 129±64 to 133±60ml/min/100mmHg, p=0.93 and 0.59, respectively). No between‐group differences were observed for α1‐mediated vasoconstrictor responsiveness during exercise or the corresponding magnitude of sympatholysis (group‐by‐time p=0.41 and 0.90, respectively). However, the NO3 group had reduced α2‐mediated vasoconstrictor responsiveness during exercise (−23.4±6.9 to −20.2±5.6% vs. −24.0±7.9 to −26.5±10.5%) with concomitant improvement in the magnitude of sympatholysis (−26.1±12.9 to −38.1±19.4 vs. −25.1±15.9 to −24.7±15.6) compared to the PL cohort, respectively (p<0.05 for both). Principally, we found 8wks of inorganic nitrate supplementation augments the hyperemic (FBF) and vasodilatory (FVC) responses to exercise in T2D. Additionally, these beneficial effects could be attributable to decreased α2‐mediated vasoconstrictor responsiveness in contracting skeletal muscle (i.e., improved functional sympatholysis).Support or Funding InformationAmerican Diabetes Association 1‐16‐1CTA‐015.

Alpha adrenergic receptor regulation of blood flow during passive leg movement: The impact of age.

Passive leg movement (PLM) evokes a robust and transient increase in limb blood flow (LBF). The magnitude of this response is attenuated with aging and this reduction has been largely attributed to diminished nitric oxide (NO) bioavailability. Importantly, aging is also associated with heightened sympathetic activity and altered vasomotor tone, which may contribute to the age‐related reduction in PLM. Therefore, this study sought to determine the contribution of α‐adrenergic signaling to the PLM‐induced LBF response in aging. The central hypothesis is that aging is associated with sympathetically‐mediated restraint of the LBF during PLM. Following intravenous infusion of the β‐blocker propranolol, five young (24±6 yr) and five old (68±4 yr) healthy male subjects underwent PLM during intra‐arterial infusion of saline (CON; control), phenylephrine (PE; α1‐adrenergic receptor agonist) and phentolamine (PHEN; nonspecific α‐adrenergic receptor antagonist). LBF through the common femoral artery was determined second‐by‐second by Doppler ultrasound. Compared with CON, PE did not reduce baseline LBF in the young (CON: 251±11; PE: 193±18 ml/min, p=0.23) or old (CON: 265±18; PE: 239±36 ml/min, p=0.74); however, PHEN increased baseline LBF in both the young (PHEN: 725 ± 63 ml/min, p<0.01 vs. CON) and the old (PHEN: 680 ± 122 ml/min, p<0.01 vs. CON). During PLM in the young, PE reduced the peak change in LBF (ΔPeakLBF) (CON: 595±67; PE: 393±46 ml/min, p=0.038) while PHEN increased the ΔPeakLBF (827 ± 89 ml/min, p=0.02 vs. CON). In contrast, in the old, no changes in ΔPeakLBF in response to PE or PHEN were evident (CON: 342±17; PE: 311±22, PHEN: 378±65 ml/min, p=0.37 for the treatment effect). The magnitude of α‐adrenergic receptor contribution (PHEN ΔPeakLBF – PE ΔPeakLBF) was different between young and old (young: 434±97; old: 67±75 ml/min, p=0.02). The overall hyperemic response, assessed by the LBF area under the curve (LBFAUC) during PLM, was not different when comparing CON (127 ± 23 ml/min) to PE (67 ± 19 ml/min, p=0.22) nor PHEN (210 ± 31 ml/min, p=0.095) in the young; however, LBFAUC was significantly different between PE and PHEN (p=0.02). Neither PE nor PHEN altered the LBFAUC in the old (CON: 82 ± 17, PE: 65 ± 9, PHEN: 127 ± 32 ml/min, p=0.29 for the treatment effect). Although both groups exhibited robust increases in baseline LBF after adrenergic receptor inhibition, only the young demonstrated alterations to the PLM response following stimulation and inhibition of adrenergic receptors. In line with previous findings, we observed sympathetic restraint of resting LBF in both young and old individuals. However, the age related reduction in ΔPeakLBF and LBFAUC during PLM in old individuals does not appear to be associated with augmented sympathetic regulation of vasomotor tone.

Determinants of Diastolic Dysfunction in Swine with HFpEF Arising From Transient Repetitive Left Ventricular Pressure Overload

ObjectiveWe recently demonstrated that swine subjected to 2‐weeks of repetitive pressure overload (RPO) exhibit adaptive myocardial remodeling in the absence of left ventricular (LV) hypertrophy. This remodeling is similar to that arising in many patients with heart failure and a preserved ejection fraction (HFpEF). While LV compliance is markedly reduced, the relative contribution of altered myocardial relaxation vs. passive myocardial properties to this is unclear. Accordingly, the objective of the present study was to determine how RPO affects passive myocardial stiffness and active myocardial relaxation, two key components of LV diastolic function.MethodsSwine (n=14) were subjected to 2‐weeks of RPO via daily infusions of phenylephrine (300 ug/min, 2 hours/day). Invasive measurements of LV performance were collected before and after RPO at rest and during alterations in loading conditions elicited by transient manipulation of venous return. To assess reversibility, a subset of animals (n=6) underwent repeat studies 2‐weeks after cessation of RPO. After the final study, myocardial tissue was collected from the LV free wall for post‐mortem assessment of calcium handling protein expression (western blot; n=8), passive myocardial stiffness (uniaxial tensile testing; n=3), and quantification of interstitial fibrosis (picrosirius red staining).ResultsCompared with baseline measurements, 2‐weeks of RPO did not significantly affect the LV relaxation time constant (Tau) or the rate of LV pressure change during isovolumic relaxation (dP/dtmin; Table ). Consistent with this observation, myocardial expression of calcium handling proteins SERCA (from 0.58±0.24 to 0.52±0.25, p=0.62), ryanodine receptor (from 0.37±0.17 to 0.36±0.14, p=0.99), and phospholamban (from 0.46±0.21 to 0.33±0.15, p=0.17) was not different following RPO vs. normal controls (n=8). However, assessment of LV performance under altered loading conditions revealed a significant increase in the LV stiffness coefficient (β) during IVC occlusion as well as the ΔEDP/ΔEDV ratio during rapid saline loading. These functional changes persisted for 2‐weeks following cessation of RPO and were accompanied by a significant increase in passive myocardial stiffness and interstitial fibrosis.ConclusionsThese results demonstrate that the reduction in LV compliance arising after RPO is not related to delayed active myocardial relaxation at rest or altered expression of sarcoplasmic reticulum calcium handling proteins. However, RPO elicits a persistent increase in passive myocardial stiffness that is likely mediated by interstitial collagen deposition. These passive diastolic properties may explain exercise intolerance in HFpEF patients despite normal resting hemodynamics and the absence of anatomic LV hypertrophy.Support or Funding InformationFunding Sources: The National Heart Lung and Blood Institute (HL‐061610), the American Heart Association (17SDG33660200), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), the Community Foundation for Greater Buffalo, and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine. Baseline/Control RPO Cessation of RPO Tau (ms) 36.5 ± 1.6 35.9 ± 1.6 34.3 ± 1.7 dP/dtmin (mmHg/s) −2116 ± 369 −2301 ± 133 −2464 ± 272 Diastolic Stiffness Coefficient (β) 0.025 ± 0.003 0.054 ± 0.007 * 0.043 ± 0.009 * ΔEDP/ΔEDV During Saline Loading (mmHg/mL) 0.09 ± 0.02 0.21 ± 0.04 * 0.23 ± 0.03 * Ex Vivo Passive Stiffness (kPa) 77.8 ± 11.0 ‐‐‐ 131.0 ± 6.1 * Interstitial Fibrosis (%) 6.6 ± 0.7 12.9 ± 1.8 * 16.3 ± 1.1 * Values are mean ± SEM. *p<0.05 vs. Baseline/Control

Angiotensin II Type I Receptor Agonistic Autoantibody Blockade Improves Cerebral Blood Flow Autoregulation, Blood Brain Barrier Permeability, and Hypertension in the Pre‐Clinical Rat Model of Preeclampsia

BackgroundPreeclampsia (PE) is a pregnancy disorder that is characterized by an increase in blood pressure, angiotensin II type1 receptor agonistic autoantibodies (AT1‐AA), and neurological complications. The pre‐clinical RUPP (reduced uterine perfusion pressure) rat model of PE displays many of the clinical pathologies associated with PE, such as increased blood pressure, AT1‐AAs, blood brain barrier (BBB) permeability, and impaired cerebral blood flow (CBF) autoregulation.HypothesisWe hypothesized that specific inhibition of AT1‐AA, using the epitope binding 7 amino acid peptide sequence (7AA), will improve blood pressure, BBB integrity, and CBF autoregulation in RUPP rats.MethodsSprague Dawley rats, were divided into 3 groups: normal pregnant (NP) (n=19), RUPP (n=19), and RUPP+AT1‐AA inhibition (7AA) (n=21). RUPP surgery was performed on gestational day (GD) 14 and 7AA (2μg/μl) was administered via osmotic minipumps. GD 19, mean arterial pressure (MAP) was determined and BBB permeability was assessed using the in‐vivo imaging system (IVIS). CBF was measured by laser Doppler flowmetry through a 4 mm x 4 mm cranial window under anesthesia. MAP was elevated step‐wise from 100–190 mmHg by infusion of phenylephrine to determine changes in CBF.ResultsMAP was increased in RUPP vs NP (124±3 vs 100±1 mmHg, p<0.05) and decreased in RUPP+7AA vs RUPP (105±2 vs 124±3 mmHg, p<0.05) rats. Using IVIS, Texas Red/FITC green fluorescent imaging was decreased in RUPP+7AA vs RUPP (0.2±0.001 vs 0.6±0.001, p<0.05), indicating improvement in BBB permeability with AT1‐AA inhibition. CBF autoregulation was impaired in RUPP vs NP rats at 140 mmHg (142±7 vs 119±4%, p<0.05) and 160 mmHg (157±10 vs 129±6%, p<0.05) (both pressures are within the normal CBF autoregulatory range). AT1‐AA inhibition prevented impaired CBF at 140mmHg (125±5 RUPP+7AA vs 142±7% RUPP, p<0.05) and 160 mmHg (125±9 RUPP+7AA vs 157±10% RUPP, p<0.05). Furthermore, the increases in CBF at pressures above the autoregulatory range, 180 mmHg (122±10 vs 198±17%, p<0.05) and 190 mmHg (123±11 vs 208±19%, p<0.05), was prevented in RUPP+7AA vs RUPP, respectively.ConclusionAT1‐AA inhibition improved blood pressure, BBB permeability, and CBF autoregulation in the pre‐clinical RUPP rat model of PE, indicating that AT1‐AA inhibition may be a potential therapy used to improve neurological complications during PE.Support or Funding InformationSupported: AHA18CDA34110264

The Effect of Phenylephrine Infusion on Maternal Hemodynamic Changes During Spinal Anesthesia for Cesarean Delivery.

BackgroundSpinal anesthesia is used as a common anesthetic technique in many routine and outpatient surgeries.ObjectivesThe aim of this study was to determine the effect of phenylephrine on maternal hemodynamic changes during spinal anesthesia for cesarean delivery.MethodsThis double-blind randomized controlled trial was conducted on 116 pregnant women candidate for the elective cesarean section through spinal anesthesia in the Shahid Akbarabadi Hospital, Tehran in 2019. The eligible women were randomly divided into the intervention (phenylephrine; n = 58) and control (normal saline; n = 58) groups. The data collection tool was a checklist, including the demographic and clinical variables, such as age, height, weight, body mass index, gravid, gestational age, Apgar score of 1 and 5, systolic blood pressure, diastolic blood pressure, heart rate, mean arterial pressure, SPO2, PH of the umbilical cord, PCO2, HCO3, base excess, nausea, and vomiting. Data were analyzed using SPSS 24 software and P value < 0.05 was considered as significant.ResultsThe intervention and control groups showed a significant difference in terms of the PH of the umbilical cord, PCO2, and nausea and vomiting (P value < 0.05). The results of the repeated measure ANOVA test showed a significant statistical difference between the intervention and control groups at different time points in terms of arterial pressure, systolic and diastolic blood pressures (P value < 0.05).ConclusionsPhenylephrine is effective in the prevention of some complications, like reducing mean arterial pressure, systolic and diastolic blood pressures, nausea, and vomiting during spinal anesthesia for cesarean delivery. Therefore, these drugs can be used based on maternal hemodynamic status during spinal anesthesia for cesarean delivery.

Augmented blood pressure variability following continuous infusion of noradrenaline in rats.

Augmented blood pressure (BP) variability has been shown to be associated with cardiovascular diseases. Activity of the sympathetic nervous system is an important determinant factor of the 24-h profile of BP variability, although it is unknown whether persistent adrenergic activation causes augmented BP variability or not. Here we report that continuous infusion of noradrenalin augments 24-h BP variability in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 μg/h noradrenalin, 150 μg/h of the α1-adrenergic agonist phenylephrine, or 30 μg/h of the β-agonist isoproterenol, for 14 days. Noradrenalin-infused rats were also administered either oral 5 mg/day prazosin or 50 mg/day atenolol during the infusion period. BP variability was evaluated before and after 7 and 14 days of the infusion, using a coefficient of variation of BP recorded every 15 min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. Continuous infusion of noradrenalin significantly increased 24-h BP variability at 7 and 14 days, slightly elevating BP levels, while this increase in BP variability was partially attenuated by prazosin, but not by atenolol. Continuous infusion of phenylephrine augmented BP variability, but isoproterenol had no effect on the variability. Continuous infusion of noradrenalin augmented 24-h BP variability partly through an α1-adrenergic receptor-mediated mechanism in rats, suggesting that the noradrenalin-infused rat is an animal model of augmented BP variability induced by persistent adrenergic activation.

Effects of anaesthesia-induced hypotension and phenylephrine on plasma volume expansion by hydroxyethyl starch: A randomised controlled study.

Changes in blood haemoglobin concentration indicate plasma volume expansion following hydroxyethyl starch (HES) infusion, but may be affected by vascular tone and HES-induced shedding of the endothelial surface layer (ESL). We hypothesised that anaesthesia-induced hypotension enhances changes in plasma volume as assessed by blood haemoglobin concentration (ΔPVHb , %) following HES infusion. Fifty-two patients undergoing abdominal surgery were randomised to receive a continuous infusion of saline (S group) or phenylephrine to restore vascular tone (P group) (n=26 each). Both groups received an infusion of 8mL/kg 6% HES solution after induction of general anaesthesia. We compared ΔPVHb at the end of fluid infusion (15minutes) and 15minutes later (30minutes) between the two groups. We assessed changes in ESL structure by measuring plasma concentrations of hyaluronate and syndecan-1. P<.05 was considered statistically significant. Mean arterial blood pressure was lower in the S group approximately by 30-40% compared to the P group (P<.001). ΔPVHb was larger in the S group compared to the P group at 15minutes (24.9 [5.2] % vs 19.0 [5.2] %; P<.001) and 30minutes (26.5 [5.9] % vs 16.9 [6.6] %; P<.001). There were no clinically significant differences in plasma concentrations of hyaluronate and syndecan-1 with time and between the groups. Increased volume expansion of circulating plasma following HES infusion in anaesthesia-induced hypotension compared to when blood pressure is restored by phenylephrine may result from an attenuation of transcapillary fluid filtration, rather than ESL shedding. UMIN Clinical Trial Registration Number: UMIN000017394 (http://www.umin.ac.jp/ctr/index.htm).

End-Expiratory Occlusion Test During Increase of Vasomotor Tone in a Rabbit Model of Hemorrhage

End-expiratory occlusion test (EEOT) has been proposed as a preload responsiveness test that overcomes several limitations of pulse pressure (PPV) and stroke volume (SVV) variations. We compared the ability of EEOT versus SVV and PPV to predict fluid responsiveness during the increase of the vasomotor tone in a rabbit model of hemorrhage. Ten rabbits were anesthetized, paralyzed, and mechanically ventilated during basal load (BL), after progressive blood withdrawal (BW), and after volume replacement. Other two sets of data were obtained during vasomotor increase by phenylephrine (PHE) infusion in BL and BW. We estimated the change of stroke volume (∆SVEEOT) and aortic flow (∆AoFEEOT) during the EEOT. PPV and SVV were obtained by the variation of beat-to-beat PP and SV, respectively. Baseline PPV, SVV, ∆SVEEOT, and ∆AoFEEOT increased significantly after BW, with a decrease of aortic flow (P < 0.05). PHE induced a significant decrease of PPV and SVV, but without affecting ∆SVEEOT, and ∆AoFEEOT. We conclude that ∆SV and ∆AoF during EEOT kept the ability to predict fluid responsiveness during PHE infusion in a rabbit hemorrhage model. This result may suggest the advantage of EEOT with respect to SVV and PPV in predicting fluid responsiveness during vasomotor tone increase.

Dose-Response Study of 4 Weight-Based Phenylephrine Infusion Regimens for Preventing Hypotension During Cesarean Delivery Under Combined Spinal-Epidural Anesthesia.

Prophylactic IV infusion of phenylephrine has been recommended to prevent hypotension during spinal anesthesia for cesarean delivery. However, the optimal infusion dose is unknown. This study aimed to determine the infusion dose of phenylephrine that would be effective in preventing hypotension in 50% (ED50) and 90% (ED90) of patients when administered as a prophylactic infusion at a fixed rate based on the individual body weight. Eighty parturients scheduled for elective cesarean delivery were randomly allocated to receive IV infusion of prophylactic phenylephrine at 0.25, 0.375, 0.5, or 0.625 µg/kg/min (n = 20 per group) started immediately after intrathecal injection of 10 mg hyperbaric bupivacaine and 5 µg sufentanil using a combined spinal-epidural technique. An effective dose was defined by the occurrence of no hypotension (defined as a decrease in systolic blood pressure by ≥20% below baseline and to <90 mm Hg) during the interval from the initiation of spinal anesthesia to delivery of the infant. Values for ED50 and ED90 of prophylactic phenylephrine were calculated using probit analysis. Hypotension occurred in 13/20, 8/20, 2/20, and 1/20 patients in the groups that received phenylephrine infusion at 0.25, 0.375, 0.5, or 0.625 µg/kg/min, respectively. The calculated values for ED50 and ED90 were 0.31 (95% CI, 0.24-0.36) and 0.54 (95% CI, 0.46-0.76) µg/kg/min, respectively. No difference was found in the incidence of adverse effects and neonatal outcomes among groups. Under the conditions of this study, when phenylephrine was given as a fixed-rate prophylactic infusion during spinal anesthesia for cesarean delivery to prevent hypotension, the values for ED50 and ED90 were 0.31 (95% CI, 0.24-0.36) and 0.54 (95% CI, 0.46-0.76) µg/kg/min, respectively.

P121 Pressure overload-induced functional and metabolic impairments in type 2 diabetic hearts are ameliorated by inhibition of xanthine oxidase

Abstract Funding Acknowledgements SANWA KAGAKU KENKYUSHO Co., Ltd. Background We have recently demonstrated that AMP deaminase (AMPD) is upregulated in OLETF, obese type 2 diabetic (T2DM) rats, and that the upregulated AMPD contributes to depletion of myocardial ATP at the time of pressure overload, leading to diastolic dysfunction. On the other hand, AMPD promotes the formation of IMP from AMP, and IMP is in turn further converted to hypoxanthine and xanthine, substrates of xanthine oxidase (XO), which produces uric acid with ROS as a byproduct. Based on these findings, we tested the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction in T2DM rats. Methods and results Metabolomic analyses of the left ventricular myocardium revealed that levels of myocardial hypoxanthine and xanthine were significantly higher by 30% and 28%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of pressure overloading (200-230 mmHg) induced by phenylephrine infusion. Myocardial XO activity in OLETF was 57.9% higher than that in LETO, and the activity was significantly attenuated by oral administration of topiroxostat, an XO inhibitor, at 0.1-0.5 mg/kg/day for 14 days in a dose-dependent manner. Pressure volume loop analyses showed that the pressure overloading induced by phenylephrine infusion resulted in significantly higher LVEDP in OLETF than in LETO (18.3 ± 1.5 vs. 12.2 ± 1.3 mmHg, p &amp;lt; 0.05, n = 7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6 ± 0.4 vs. 4.7 ± 0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3 ± 1.5 vs. 11.3 ± 1.1 mmHg, p &amp;lt; 0.05) but not in LETO. Tau, the time constant of LV pressure decay, was significantly prolonged to 14.7 ± 0.7 ms (p &amp;lt; 0.05) by pressure overloading in OLETF but not in LETO, though baseline Tau values were similar in LETO and OLETF (6.1 ± 0.2 vs. 8.0 ± 0.4 ms). The prolongation of Tau by pressure overloading in OLETF was significantly attenuated by treatment with topiroxostat. Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3 ± 0.3 vs. 1.6 ± 0.3, p &amp;lt; 0.05) under the condition of pressure overloading, and it was also improved by topiroxostat in OLETF (1.2 ± 0.2, p &amp;lt; 0.05). Myocardial ATP content was lower in OLETF than in LETO under the condition of pressure overloading (2966 ± 400 vs. 1818 ± 171 nmol/g wet tissue, p &amp;lt; 0.05), but treatment with topiroxostat significantly restored the ATP level (2629 ± 307 nmo/g wet tissue). Conclusion: In T2DM hearts, not only XO activity but also XO substrates are upregulated and upregulated AMPD may be involved in the upregulation. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling most likely through augmented ATP preservation.

Clinical comparison of prophylactic phenylephrine infusion vs. bolus regimens on maternal hemodynamics and neonatal outcomes during cesarean section

Background and Objective: Phenylephrine bolus or infusion is used to maintain arterial blood pressure during the subarachnoid block (SAB) for cesarean section. The objective was to assess the clinical efficacy of prophylactic phenylephrine infusion or bolus doses for maternal hemodynamics maintenance and its effect on fetal outcomes. Materials and Methods: Sixty parturients were randomized to receive either a continuous prophylactic IV infusion of phenylephrine (n = 30, group A) at a dose of 0.50 μg.kg−1.min−1 or phenylephrine (n = 30, Group B) 50 μg bolus dose after the systolic blood pressure (SBP) fell by 20% from the baseline. The changes in hemodynamics, ill effects, neonatal APGAR scores, and fetal acidosis were recorded at different time intervals. Results: SBP was significantly higher over time in group A. Group A showed a significant fall in heart rate from baseline after giving SAB and remained significantly low throughout the intraoperative period (P 20% from the baseline; however, hypotension was observed in 21 patients in group B (P 20% of baseline value, were noted in 3 out of 30 patients in the Group A. There was also a statistically nonsignificant trend toward a less frequent incidence of nausea and vomiting in the group A (P

93 A hemodynamic challenge in assessment of echocardiographic mitral regurgitation severity

Abstract Mitral regurgitation severity is, in accordance to current recommendations, typically evaluated by echocardiography. Several hemodynamic factors may influence this evaluation, especially systemic arterial blood pressure at the time of echocardiographic evaluation. A 71-year-old woman was admitted in our Cardiology ward with acute decompensated heart failure. She had been previously admitted about 3 months earlier by acute decompensated heart failure, and at that time, admission transthoracic echocardiography (TTE) demonstrated mitral regurgitation, which was evaluated as severe. Systolic systemic arterial blood pressure at the time of that TTE was registered as 135mmHg. For further evaluation of mitral regurgitation mechanism, the patient underwent transoesophageal echocardiography (TEE), and in that exam mitral regurgitation was assessed as only moderate. For that exam, patient was sedated with 5mg of intravenous Midazolam, a drug with known secondary hypotensive effect. Although systemic arterial blood pressure was not described in the TEE report, retrospective analysis of nursery blood pressure records showed that patient was hypotensive during exam with systolic arterial blood pressure of 80-90mmHg. Patients was discharged, and in actual admission, concern was raised that mitral regurgitation could have been underestimated in previous TEE due to reduced afterload caused by the hypotensive effect of sedation. It was then decided to repeat TEE, and, in order to counterpose the hypotensive effect of Midazolam, TEE was performed under intravenous continuous infusion of Phenylephrine, a selective α-1 receptor antagonist with a significant vasopressor effect and minimal effect on cardiac contractility. Systolic systemic arterial blood pressure during this exam was recorded as 135-140mmHg. In this exam mitral regurgitation was confirmed as severe and patient was patient was oriented for mitral valve surgery. DIscussion This case illustrates the importance of assessment of hemodynamic status of the patient during echocardiographic evaluation of mitral regurgitation severity, and presents a pharmacological strategy to compensate hypotensive effects of sedative agents used during TEE.

Prophylactic phenylephrine and fluid co-administration to reduce spinal hypotension during elective caesarean section in a resource-limited setting: a prospective alternating intervention study.

Spinal hypotension is a common and clinically important problem during caesarean section. Current consensus recommendations for resource-rich settings suggest the use of a titrated phenylephrine infusion, in combination with fluid coloading, for prevention of maternal hypotension. In resource-limited settings, where syringe drivers are unavailable, these recommendations advise the addition of 500μg phenylephrine to the first 1l of intravenous fluid given after initiation of spinal anaesthesia, with additional vasopressor boluses as required. This prospective, alternating intervention study compared the use of a conventional phenylephrine rescue bolus strategy for prevention of hypotension, defined as systolic arterial pressure <90mmHg, with a phenylephrine infusion given according to the consensus recommendation. We studied 300 women having elective caesarean section. There were 77 (51%) women who developed hypotension in the bolus group vs. 55 (37%) in the phenylephrine infusion group (p=0.011). This represented a 29% reduction in hypotension, with a number needed to treat of 6.8. The six highest systolic arterial pressure readings occurred in the phenylephrine infusion group (range 166-188mmHg), and there were four instances of bradycardia (heart rate <50 beats.min-1 ) with preserved systolic arterial pressure in each group. There were no adverse clinical sequelae, and no differences in neonatal Apgar scores in either group. The consensus recommendation for phenylephrine and fluid co-administration in resource-limited settings appears effective in preventing maternal hypotension, but at the cost of sporadic systolic hypertension.

A Prospective Observational Study of the Change in Regional Cerebral Oxygen Saturation During Cesarean Delivery in Women Receiving Phenylephrine Prophylaxis for Spinal Hypotension

(Int J Obstet Anesth. 2019;37:29–35) During cesarean delivery (CD) performed under spinal anesthesia, the incidence of hypotension has been reported to be as high as 70% to 80%. Previous studies have shown that this spinal-induced hypotension leads to decreased regional cerebral oxygen saturation (ScO2), and treatment with ephedrine has returned ScO2 to baseline levels. In current practice, though, a prophylactic phenylephrine infusion is frequently used to prevent spinal hypotension during CD. There has been limited research on the effect of phenylephrine on ScO2. This prospective, observational cohort study was performed to investigate the change in ScO2 using near infrared spectroscopy in women receiving a prophylactic phenylephrine infusion during CD under spinal anesthesia.

Safety and Feasibility of Phenylephrine Administration Through a Peripheral Intravenous Catheter in a Neurocritical Care Unit.

Blood pressure optimization and maintenance of cerebral and spinal perfusion pressure are mainstays in the treatment of a neurocritically ill patient. Traditionally, central venous access has been required for vasopressor administration, with risk of inherent complications. The authors have previously reported pilot data on the safety of peripheral administration of phenylephrine in a neurocritical care unit. In this follow-up, we report the safety, feasibility, and potential efficacy of peripheral administration of low-concentration phenylephrine in a more robust cohort. A retrospective chart review was conducted on all consecutive patients who received peripheral phenylephrine in a tertiary care hospital neurocritical care unit. A cohort of 125 patients were identified and included in the final analysis. The average age was 59.3 years, with an average intensive care unit (ICU) length of stay of 7.61 days. The most common indication for phenylephrine use was spinal perfusion (both with/without neurogenic shock) in 38.4% of cases, followed by postsurgical/anesthesia resuscitation in 16.8% of cases; 25.6% of patients in our cohort required escalation to central venous access (central venous catheter + peripherally inserted central catheter). A total of 2880 patient-hours were recorded with peripheral phenylephrine infusion, of which 73.9% were at goal blood pressure (either systolic or mean arterial pressure). Only one major complication of thrombophlebitis and 8 minor complications were recorded. Protocol-driven peripheral administration of lower concentration phenylephrine in an ICU setting is safe and feasible. This strategy is potentially effective at achieving hemodynamic targets in the majority of patients avoiding the need for central venous access.

The influence of the infusion of ephedrine and phenylephrine on the hemodynamic stability after subarachnoid anesthesia in senior adults - a controlled randomized trial

BackgroundWe studied the influence of ephedrine or phenylephrine infusion administered immediately after spinal anesthesia (SA) on hemodynamics in elderly orthopedic patients.MethodsA prospective, randomized, double-blind, placebo-controlled study.After a subarachnoid injection of 15 mg of levobupivacaine, the participants received an infusion of either ephedrine 20 mg (E group), phenylephrine 250 mcg (P group) or saline (C group) within 30 min. We measured blood pressure, cardiac index (CI) and heart rate (HR) from 15 min before to 30 min after SA.ResultsSeventy patients were included in the final analysis. At the end of measurements, mean arterial pressure (MAP) decreased significantly after SA in comparison to the baseline value in the C group but was maintained in the P and E group, with no significant differences between the groups. CI decreased after SA in the C group, was maintained in the P group, and increased significantly in the E group with significant differences between the C and E group (p = 0.049) also between the P and E (p = 0.01) group at the end of measurements. HR decreased significantly after SA in the C and P group but was maintained in the E group, with significant differences between the P and E group (p = 0.033) at the end of measurements.ConclusionsHemodynamic changes after SA in elderly orthopedic patients can be prevented by an immediate infusion of phenylephrine or ephedrine. In addition to maintaining blood pressure, the ephedrine infusion also maintains HR and increases CI after SA.Trial registrationISRCTN registry with registration number ISRCTN44377602, retrospectively registered on 15 June 2017.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Variable versus fixed-rate infusion of phenylephrine during cesarean delivery: a randomized controlled trial

BackgroundPhenylephrine is the most commonly used vasopressor for prophylaxis against maternal hypotension during cesarean delivery; however, the best regimen for its administration is not well established. Although variable infusion protocols had been suggested for phenylephrine infusion, evidence-based evaluation of variable infusion regimens are lacking. The aim of this work is to compare variable infusion, fixed on-and-off infusion, and intermittent boluses of phenylephrine for prophylaxis against maternal hypotension during cesarean delivery.MethodsA randomized controlled study was conducted, including full-term pregnant women scheduled for elective cesarean delivery. Participants were divided into three groups which received phenylephrine by either intermittent boluses (1.5 mcg/Kg phenylephrine), fixed on-and-off infusion (with a dose of 0.75 mcg/Kg/min), or variable infusion (with a starting dose of 0.75 mcg/Kg/min). The three groups were compared with regard to frequency of: maternal hypotension (primary outcome), second episode hypotension, reactive hypertension, and bradycardia. Other outcomes included heart rate, systolic blood pressure, physician interventions, and neonatal outcomes.ResultsTwo-hundred and seventeen mothers were available for final analysis. The 2 infusion groups showed less incidence of maternal hypotension {26/70 (37%), 22/71 (31%), and (51/76 (67%)} and higher incidence of reactive hypertension compared to the intermittent boluses group without significant differences between the two former groups. The number of physician interventions was highest in the variable infusion group compared to the other two groups. The intermittent boluses group showed lower systolic blood pressure and higher heart rate compared to the two infusion groups; whilst the two later groups were comparable.ConclusionBoth phenylephrine infusion regimens equally prevented maternal hypotension during cesarean delivery compared to intermittent boluses regimen. Due to higher number of physician interventions in the variable infusion regimen, the current recommendations which favor this regimen over fixed infusion regimen might need re-evaluation.

Intraoperative Phenylephrine Infusion to Reduce Postoperative Shivering in Lower Segment Caesarean Section

Intraoperative Phenylephrine Infusion to Reduce Postoperative Shivering in Lower Segment Caesarean Section

P: 18 Impaired Cerebral Oxygenation, but Preserved Cerebrovascular reactivity, in an Animal Model of Hepatic Encephalopathy

BACKGROUND: We have recently obtained evidence of energy deficiency, in the form of impaired lactate release, in the brains of cirrhotic animals with hepatic encephalopathy (HE). Previous reports of cerebral hypoperfusion in patients with HE indicated that cerebral oxygen supply could also be compromised (Dam et al., 2013). Decreased lactate and reduced oxygen supply may lead to CNS energy deficiency and have important neurological consequences, particularly in patients with advanced cirrhosis. In this study we assessed cerebral tissue oxygen tension and CO2 cerebrovascular reactivity in an animal model of HE. METHODS: HE was induced by bile duct ligation (BDL) and after 4 weeks rats were anesthetized with α-chloralose (100 mg·kg−1), instrumented for arterial blood pressure recording and artificially ventilated. 7 BDL and 6 sham-operated animals were treated daily for one week with an ammonia lowering treatment, ornithine phenylacetate (OP) in order to investigate the role of ammonia on brain oxygenation. Blood gas tensions and pH were maintained within physiological ranges in all animal groups. Cerebral tissue PO2 was monitored by fluorescence method (Oxylite™). After a small craniotomy, optical sensors were placed in the somatosensory cortex and sealed. PO2 at baseline and in response to systemic hypercapnia (10% CO2, 5 min) was recorded. RESULTS: BDL resulted in high plasma ammonia concentrations which was lowered with OP treatment. At similar levels of blood PO2 and PCO2, BDL rats had a significantly lower brain PO2 (15.3 ± 2 mm Hg; n = 10) compared to sham controls (26 ± 2 mm Hg; n = 6; P = 0.001). BDL rats treated with OP showed a significant improvement in cerebral PO2 (22 ± 1 mm Hg, n = 6, P = 1), increasing the oxygen tension to levels similar to that recorded in OP treated sham rats (27 ± 2 mm Hg, n = 7), when blood PO2 and PCO2 were constant. Systemic hypercapnia resulted in similar increases in cerebral PO2 in BDL and sham-operated animals (ΔPO2 21 ± 2 vs. 24 ± 2 mm Hg; P = 0.6). Additionally, under anaesthesia, the mean systemic arterial blood pressure was found to be significantly lower in BDL animals (60 ± 3 vs. 84 ± 8 mm Hg; P = 0.04). Cerebral oxygenation did not recover when the blood pressure was normalised via infusion of phenylephrine, but it significantly improved with infusion of acetazolamide which increases cerebral blood flow. CONCLUSIONS: In the BDL model of HE, cerebral tissue oxygen tension is compromised but cerebrovascular reactivity to CO2 appears to be preserved. The cause of the low basal PO2 remains unknown however; high ammonia concentrations and hypoperfusion could be contributing factors.