Phenylephrine Infusion Research Articles

Spinal decompression surgery may alleviate vasopressor-induced spinal hemorrhage and extravasation during acute cervical spinal cord injury in rats

BACKGROUNDCervical spinal injury often disrupts the supraspinal vasomotor pathways projecting to the thoracic sympathetic preganglionic neurons, leading to cardiovascular dysfunction. The current guideline is to maintain the mean arterial blood pressure at 85 to 90 mmHg using a vasopressor during the first week of the injury. Some studies have demonstrated that this treatment might be beneficial to alleviate secondary injury and improve neurological outcomes; however, elevation of blood pressure may exacerbate spinal hemorrhage, extravasation, and edema, exacerbating the initial injury. PURPOSEThe present study was designed to (1) examine whether vasopressor administration exacerbates spinal hemorrhage and extravasation; (2) evaluate whether spinal decompression surgery relieves vasopressor-induced spinal hemorrhage and extravasation. STUDY DESIGNIn vivo animal study. METHODSAnimals received a saline solution or a vasopressor (phenylephrine hydrochloride, 500 or 1000 μg/kg, 7 mL/kg/h) after mid-cervical contusion with or without spinal decompression (ie, incision of the dura and arachnoid mater). Spinal cord hemorrhage and extravasation were examined by expression of Evans blue within the spinal cord section. RESULTSThe results demonstrated that cervical spinal contusion significantly reduced the mean arterial blood pressure and induced spinal hemorrhage and extravasation. Phenylephrine infusion significantly elevated the mean arterial blood pressure to the preinjury level within 15 to 60 minutes postcontusion; however, spinal hemorrhage and extravasation were more extensive in animals that received phenylephrine than in those that received saline. Notably, spinal decompression mitigated spinal hemorrhage and extravasation in contused rats who received phenylephrine. CONCLUSIONSThese data indicate that, although phenylephrine can prevent hypotension after cervical spinal injury, it also causes excess spinal hemorrhage and extravasation. CLINICAL SIGNIFICANCESpinal decompressive surgery seemed to minimize the side effect of phenylephrine as vasopressor treatment during acute spinal cord injury.

Hyoscine butyl-bromide versus ondansetron for nausea and vomiting during caesarean delivery under spinal anaesthesia. A randomized clinical trial

ABSTRACT Background The unopposed vagal activity with sympathetic block and maternal bradycardia that is likely to occur with phenylephrine infusion might be some causes of intraoperative nausea and vomiting (IONV) during spinal anaesthesia. We aimed at comparing hyoscine butyl-bromide (HBB) and ondansetron in reduction of intraoperative bradycardia and thus IONV in women undergoing caesarean delivery (CD). Methods In a randomized, double-blind, placebo-controlled trial, women undergoing elective CD were randomly assigned to administer either IV HBB 20 mg, ondansetron 8 mg, or the same volume of 0.9% saline right before spinal anaesthesia. The primary endpoint was the incidence of IONV. Secondary endpoints included intraoperative maternal bradycardia and hypotension and postoperative nausea and vomiting (PONV). Results 55 subjects in each group received the assigned intervention. During the intraoperative period, HBB decreased only the incidence of emesis when compared to the control group (P = 0.046) while ondansetron statistically decreased the incidence of IONV when compared to the control group (P = 0.034). HBB statistically decreased the incidence of intraoperative maternal bradycardia when compared to the controls (1.8% vs 14.5%; OR = 0.1, 95% CI = [0.01, 0.90]; P < 0.039). Compared to the control group, ondansetron was superior to HBB in reducing PONV (P = 0.001 & 0.57), respectively. Conclusions In women scheduled for CD with spinal anaesthesia, prophylactic HBB was as effective as ondansetron in reducing intraoperative emesis, with the added benefit of the less incidence of intraoperative bradycardia than ondansetron. Meanwhile, Ondansetron reduced the incidence of PONV significantly.

Abstract P3067: Emerging Immune Checkpoint Therapies Reshape The Cardiac Immune Landscape And Promote Myocardial Vulnerability

Immune checkpoint therapies have shown remarkable efficacy across multiple tumor types by amplifying cancer-immunity and boosting T-cell immune response against tumors. As an increasing number of immune checkpoint molecules have been identified, numerous combination therapeutic strategies are under clinical investigation. For instance, the combination of an OX40 (TNFRSF4) agonist and PD-1 (Programmed cell death protein 1) inhibitor has been shown to have promising anti-tumor effects in pre-clinical studies and early clinical trials. Despite remarkable therapeutic benefit, it has become evident with increasing clinical usage that these agents elevate the risk of immune-related adverse events (irAEs), especially cardiovascular sequelae. Mitigating irAEs is critical for the establishment of efficacious and safe interventions. Currently, little is understood regarding the cardiac effects of combined OX40 activation and PD-1 inhibition. In this study, we observed that PD-1 deletion upregulated OX40 expression on cardiac T-cells. Combined PD1 inhibition (Pdcd1 -/- or PD-1 blocking antibody) and OX40 activation (OX40 agonistic antibody) increased the frequency of splenic and cardiac effector memory CD4 + and CD8 + T-cells, inflammatory monocyte and macrophage infiltration into the heart, and enhanced myocardial expression of numerous chemokines and cytokines in both naïve and tumor bearing mice. Intriguingly, persistent increases in cardiac effector memory CD4 + and CD8 + T-cells and inflammatory macrophages was observed at chronic time points suggesting long term effects on the cardiac immune landscape. Furthermore, OX40 activation aggravates angiotensin II and phenylephrine (AngII/PE) infusion induced cardiac hypertrophy, fibrosis and inflammation in Pdcd1 -/- mice suggesting that the reshaped T-cell and macrophage landscape imparts myocardial vulnerability. This study will also uncover mechanism-based therapeutic targets to prevent or treat cardiac adverse events elicited by combined OX40 activation and PD-1 inhibition.

Comparative study of norepinephrine and phenylephrine infusion for prophylaxis against post-spinal hypotension in patients undergoing elective cesarean section

Comparative study of norepinephrine and phenylephrine infusion for prophylaxis against post-spinal hypotension in patients undergoing elective cesarean section

Comparing the Effect of Phenylephrine Bolus and Phenylephrine Infusion for Maintaining Arterial Blood Pressure During Cesarean Delivery Under Spinal Anesthesia: A Randomized Prospective Study.

Maternal hypotension is a common complication of spinal anesthesia in cesarean section and requires immediate intervention. Phenylephrine is most commonly used as a vasopressor agent for the treatment of hypotension due to subarachnoid block.Our aim was to compare the bolus dose of 50 µg of phenylephrine with a fixed infusion at 50 µg.min-1 of phenylephrine for maintaining arterial blood pressure during cesarean delivery. This was a prospective, randomized comparative study. One hundred normotensive pregnant females aged 18-35 years, body mass index 18-29kg.m2, American Society of Anesthesiologists (ASA) physical status classificationIIscheduled to undergo cesarean section (elective/emergency) under spinal anesthesia were randomly divided into two groups of 50 each. Group PB received a bolus dose of phenylephrine 50 µg after they developed hypotension i.e., a decrease in systolic blood pressure (SBP) ≥ 20% from the baseline. Similarly, patients in Group PI were administered prophylactic infusion using a syringe pump of phenylephrine 50 µg.min-1, started just after the administration of subarachnoid block. The phenylephrine infusion was continued either till the delivery of the baby or when SBP rises >20% above the baseline. Parameters like blood pressure, heart rate, and peripheral oxygen saturation were recorded.After the delivery of the baby, theneonatal APGAR score was assessed at one minute and five minutes. Demographic data were comparable in terms of demographic profile, duration of surgery, and ASA physical status classificationbetween the groups. The heart rate was higher in Group PB compared to Group PI throughout the monitoring period (P<0.001). The fall in mean blood pressure was more in Group PB compared to Group PI till 18 minutes of surgery and was statistically significant (P<0.05). After 18 minutes of surgery, mean blood pressure stabilized and was comparable between the groups. Other variables like APGAR score at one minute and five minutes were comparable between the groups.Bradycardia and hypertension were more common in Group PI whereas hypotension, nausea, and vomiting were more common in group PB. We concluded that during cesarean section under spinal anesthesia, phenylephrine infusion provides better hemodynamic stability and APGAR score during the perioperative period.

A Prospective Single-Center Brazilian Study Investigating the Efficacy and Safety of Prophylactic Phenylephrine Infusion for the Management of Hypotension During Cesarean Section Under Spinal Anesthesia.

Background Maternal hypotension occurs in up to 80% of parturients during cesarean section (CS) under spinal anesthesia. Phenylephrine, a direct-acting α-1 agonist, has been widely recommended for the prevention of hypotension. We evaluated the efficacy and safety of phenylephrine infusion to prevent hypotension in obese and non-obese patients during cesarean section. Methods One hundred forty-one patients were included in this single-arm study. Patients received prophylactic phenylephrine infusion at a rate of 50 μg/min-1 immediately after spinal local anesthetic injection until delivery.Hypotension was defined as a systolic blood pressure <100 mmHg or <20% of baseline. The primary outcome was the incidence of hypotension. Results The incidence of hypotension was 17%. The median and interquartile range (IQR) of the number of hypotensive episodes was 0 (0-0). It was observed that 79.1% of the patients had hypotension in the first six minutes. Reactive hypertension and bradycardia occurred in 20.5 and 12.7% of the patients, respectively. In addition, there was a higher incidence of bradycardia in pregnant women with a body index mass of < 30 kg/m-2.Patients with baseline systolic blood pressure <120 mmHg had a threefold increased risk of hypotension. The incidence of nausea and vomiting was 13.4 and 2.8%, respectively. The incidence of an Apgar score <7 at the first minute was 2.8%, and no neonates presented an Apgar score <7 at the fifth minute. A pH of <7.2 occurred in 6.3% of the neonates.All neonates had no sequelae and were discharged together with their mothers. Conclusion The prophylactic infusion of phenylephrine 50 μg/min-1 is safe and demonstrates efficacy in reducing maternal hypotension providing adequate maternal hemodynamic stability during CS under spinal anesthesia.

C-fos expression in the solitary nucleus medial region and reaction to acute hemorrhage in streptozotocin-stimulated diabetic rats

Examination of circulatory dynamics and autonomic nerve activity in acute hemorrhage in diabetic (DM) rats revealed that despite decreased receptor sensitivity to arterial blood pressure, the DM rats experienced a decline in the heart rate and acceleration of the parasympathetic nerve activity at the sympathoinhibitory phase in response to bleeding (Bezold–Jarisch [B–J] reflex). To elucidate the involvement of the B–J reflex as a reaction to acute hemorrhage in DM rats by assessing c-Fos-positive cell (c-Fos) expression in the nucleus of the solitary tract (SolM), the primary relay nucleus of the baroreflex, Streptozotocin-induced DM and non-DM rats underwent controlled-graded bleeding or continuous phenylephrine infusion under conscious state. Changes in hemodynamics and autonomous nervous system caused by acute hemorrhage and continuous phenylephrine infusion were examined by analyzing blood pressure–heart rate variability. Furthermore, effects of hemorrhage and phenylephrine infusion on the expression of c-Fos in SolM were examined. DM rats showed increased c-Fos expression in response to acute blood loss in the SolM. Non-DM rats showed the same phenomenon in response to continuous phenylephrine infusion in the SolM. Significant interactions between DM and Non-DM rats were observed among hemodynamic and autonomic response to acute hemorrhage and continuous phenylephrine infusion. DM rats were sensitive to acute blood loss, and the circulatory system easily collapsed with accelerating parasympathetic activity in the form of the B–J reflex.

Agreement of cardiac output measurements by esophageal Doppler and transesophageal echocardiography with intermittent pulmonary artery thermodilution during pharmacologic manipulation of hemodynamics in anesthetized dogs.

To compare cardiac output (CO) measurements by transesophageal echocardiography (TEECO) and esophageal Doppler monitor (EDMCO) with pulmonary artery thermodilution (PATDCO) in anesthetized dogs subjected to pharmacological interventions. The effect of treatments on EDM-derived indexes was also investigated. 6 healthy male dogs (10.8 ± 0.7 kg). Dogs were anesthetized with propofol and isoflurane, mechanically ventilated, and monitored with invasive mean arterial pressure (MAP), end-tidal isoflurane concentration (ETISO), PATDCO, TEECO, EDMCO, and EDM-derived indexes. Four treatments were administered to all dogs by randomization. Baseline data were collected before each treatment: (1) dobutamine infusion; (2) esmolol infusion; (3) phenylephrine infusion; and (4) ETISO > 3%. Data were collected after 10-minute stabilization and after 30 minutes of washout between treatments. Statistical tests were pairwise t test, Bland-Altman analysis, Lin's concordance correlation (ρc), and polar plot analysis with P < .05 set as significance. The mean ± SD relative bias (limits of agreement) for TEECO was 0.35 ± 25.2% (-49.1% to 49.8%) and for EDMCO was -27.2 ± 22.5% (-71.4% to 17%) versus PATDCO. The percent error for TEECO and EDMCO was 27.6% and 44.1%, respectively. The ρc value was 0.82 for TEECO and 0.66 for EDMCO. TEECO and EDMCO showed good trending ability. EDM-derived indexes displayed significant changes specific to the drug administered (P < .001). For minimally invasive CO monitoring, TEE may provide more favorable performance than EDM in clinical settings; however, EDM-derived indexes yield valuable hemodynamic information that reliably follows trends in CO, thus supporting critical decision-making in canine patients.

Prophylactic Fixed-Rate Phenylephrine Versus Norepinephrine Infusion in the Prevention of Post-spinal Anesthesia Hypotension During Cesarean Delivery.

Background Maternal hypotension following spinal anesthesia can be actively countered by the use of vasopressors. Prophylactic infusion of vasopressors with a rescue bolus dosing was observed to be more effective for hemodynamic stability when compared to administering a bolus dose alone. Although phenylephrine is the recommended drug to treat spinal hypotension, many recent studies have focussed on the role of norepinephrine infusions during cesarean section. In this study, we compared prophylactic fixed-rate intravenous infusions of phenylephrine and norepinephrine during cesarean delivery under spinal anesthesia and the requirement of intraoperative provider-administered rescue bolus of phenylephrine needed to overcome post-spinal anesthesia hypotension. Methodology A total of 208 patients undergoing elective cesarean section under spinal anesthesia were randomly assigned to two groups (group P and group N). Group N included 104 patients who received norepinephrine infusion at a rate of 2.5 μg/minute (0.04 μg/kg/minute), and group P included 104 patients who received phenylephrine infusion at a rate of 50 μg/minute (0.8 μg/kg/minute)to treat spinal hypotension. The primary outcome of our study was to compare the reduction in the number and total dose of intraoperative provider-administered rescue bolus of phenylephrine needed to maintain systolic blood pressure. The secondary outcome of our study was to compare the neonatal outcome using umbilical venous blood gas sampling and Apgar score at one and five minutes. Results The total number of phenylephrine rescue bolus required to treat hypotension was significantly lower in group N (p = 0.0005) compared to group P. The neonatal outcome was similar between the two groups. Conclusions Prophylactic norepinephrine infusion when compared to prophylactic phenylephrine infusion is associated with a lesser requirement of rescue phenylephrine boluses.

Randomized Clinical Study to Compare the Efficacy of Phenylephrine Bolus and Infusion for Maternal Hypotension and Neonatal Outcome during Lower Segment Cesarean Section under Spinal Anesthesia

Randomized Clinical Study to Compare the Efficacy of Phenylephrine Bolus and Infusion for Maternal Hypotension and Neonatal Outcome during Lower Segment Cesarean Section under Spinal Anesthesia

Comparison of Prophylactic Infusion of Phenylephrine Versus Norepinephrine for the Prevention of Post Spinal Hypotension in Parturients Undergoing Elective Caesarean Section-a Randomized, Double-Blinded, Non-Inferiority Trial.

Postspinal hypotension occurs in nearly 50% of women undergoing cesarean section (CS). Although phenylephrine (PE) is currently the vasopressor of choice, severe maternal bradycardia may adversely affect the fetal status due to the reduction in the maternal cardiac output. Norepinephrine (NE) is not associated with bradycardia and is now being evaluated for the treatment of post-spinal hypotension in obstetric patients. The hypothesis of this study was that the prophylactic NE infusion was non-inferior to PE infusion when used for the prevention of postspinal hypotension. This was a randomized, double-blinded controlled study conducted in 130 parturients scheduled for CS. The participants received either prophylactic NE (5 μg min-1) or PE (25 μg min-1) infusion beginning at the time of spinal injection. The primary outcome was the incidence of hypotension in both groups. Maternal bradycardia, reactive hypertension, nausea and vomiting, requirement of rescue boluses of vasopressor and/or atropine, and neonatal acid base status were also recorded. The incidence of hypotension was 33.80% (22 of 65) in Group PE and 26.10% (17 of 65) in Group NE (P=0.85). The absolute risk difference [90% confidence interval (CI)] in the incidence of hypotension between the groups was -7.7% (-20.9, 5.4). The upper limit of the CI was less than the non-inferiority margin of 20%, indicating that the NE infusion was non-inferior to PE. Prophylactic infusion of NE is not inferior to prophylactic PE infusion in the prevention of postspinal hypotension in patients undergoing CS.

A survey in the West Midlands of the United Kingdom of current practice in managing hypotension in lower segment caesarean section under spinal anaesthesia

BackgroundSpinal anaesthesia, the most common form of anaesthesia for caesarean section, leads to sympathetic blockade and profound maternal hypotension resulting in adverse maternal and neonatal outcomes. Hypotension, nausea and vomiting remain common but until the publication of the National Institute of Health and Care Excellence (NICE) 2021 guidance, no national guideline existed on how best to manage maternal hypotension following spinal anaesthesia for caesarean section. A 2017 international consensus statement recommended prophylactic vasopressor administration to maintain a systolic blood pressure of >90% of an accurate pre-spinal value, and to avoid a drop to <80% of this value.This survey aimed to assess regional adherence to these recommendations, the presence of local guidelines for management of hypotension during caesarean section under spinal anaesthesia, and the individual clinician’s treatment thresholds for maternal hypotension and tachycardia. MethodsThe West Midlands Trainee-led Research in Anaesthesia and Intensive Care Network co-ordinated surveys of obstetric anaesthetic departments and consultant obstetric anaesthetists across 11 National Health Service Trusts in the Midlands, England. ResultsOne-hundred-and-two consultant obstetric anaesthetists returned the survey and 73% of sites had a policy for vasopressor use; 91% used phenylephrine as the first-line drug but a wide range of recommended delivery methods was noted and target blood pressure was only listed in 50% of policies. Significant variation existed in both vasopressor delivery methods and target blood pressures. ConclusionsAlthough NICE has since recommended prophylactic phenylephrine infusion and a target blood pressure, the previous international consensus statement was not adhered to routinely.

A randomized controlled study to compare the dose requirement of oxytocin for management of uterine atony in patients receiving prophylactic phenylephrine during caesarean delivery

Background &amp; Aims: Most common side effect of subarachnoid block during caesarean delivery is postspinal hypotension which can lead to increased maternal and neonatal morbidity and mortality. Phenylephrine has been shown to be effective in preventing commonly encountered hypotension associated with spinal anesthesia (60% to 70%) in obstetric patients and has become the vasopressor of choice. The following study was conducted to compare the dose requirement of intravenous oxytocin between patients receiving an infusion of prophylactic intravenous phenylephrine to those receiving a saline control infusion under spinal anesthesia in patients undergoing caesarean delivery. Material &amp; Methods: It was a double-blinded, randomized controlled study having 48 subjects in test and control arm each. Results: The mean oxytocin dose administered was higher in the phenylephrine group than in the control group (6.1 ± 2.7 (IU) vs. 5.2 ± 2.3 IU, respectively). The proportion of patients who required a secondary uterotonic agent was higher in the phenylephrine intervention group (22% vs. 8%, respectively). Conclusion: Obstetricians and anesthesiologists must pay close attention to uterine tone for patients receiving a phenylephrine infusion for the prevention of postspinal hypotension and the increased dose requirement of oxytocin. Future multicentric studies are required to further establish the effects of continuous infusion as found in our study.

Arterial baroreflex control of heart rate in young and older adults and in patients with heart failure with preserved ejection fraction

Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p&lt;0.05), with no difference between the older controls and patients with HFpEF (p=0.718). During BP falls, cardiac baroreflex gain was not different between groups (p=0.06), but was qualitatively lower in patients with HFpEF (0.6±1.5 ms/mmHg) compared to young (5.3±5.5 ms/mmHg) and older controls (5.2±1.9 ms/mmHg). During BP rises, cardiac baroreflex gain was not different between older controls (2.6±0.8 ms/mmHg) and patients with HFpEF (2.3±2.0 ms/mmHg) (p&gt;0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p&lt;0.05). Conclusion: These findings suggest an age-related attenuation in the overall ARB control of HR that does not appear to be further exacerbated in patients with HFpEF. However, patients with HFpEF may exhibit a selective attenuation in ABR-mediated tachycardia in response to acute reductions in BP that may pose an increased risk of hypotension and frank syncope. This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The haemodynamic effects of phenylephrine after cardiac surgery.

Phenylephrine increases systemic- and pulmonary resistances and therefore may increase blood pressures at the expense of blood flow. Cardio-pulmonary bypass alters vasoreactivity and many patients exhibit chronotropic insufficiency after cardiac surgery. We aimed to describe the haemodynamic effects of phenylephrine infusion after cardiac surgery. Patients in steady state after low-risk cardiac surgery received incremental infusion rates of phenylephrine up to 1.0 μg/kg/min with the aim of increasing systemic mean arterial blood pressure 20 mmHg. Invasive haemodynamic parameters, including pulmonary wedge pressures, were captured along with echocardiographic measures of biventricular function before, during phenylephrine infusion at target systemic blood pressure, and 20 min after phenylephrine discontinuation. Thirty patients were included. Phenylephrine increased mean arterial pressure increased from 78 (±9) mmHg to 98 (±10) mmHg with phenylephrine infusion. Also, pulmonary blood pressure as well as systemic- and pulmonary resistances increased. The ratio between systemic- and pulmonary artery resistances did not change statistically significantly (p = .59). Median cardiac output was 4.35 (interquartile range [IQR] 3.6-5.4) L/min at baseline and increased significantly with phenylephrine infusion (median Δcardiac output was 0.25 [IQR 0.1-0.6] L/min) (p = .012). Pulmonary artery wedge pressure increased from 10.2 (±3.0) mmHg to 11.9 (±3.4) mmHg (p < .001). This was accompanied by significant increases in central venous pressure. Phenylephrine infusion increased left ventricular end-diastolic volume from 105 (±46) mL to 119 (±44) mL (p < .001). All results of phenylephrine infusion were reversed with discontinuation. In haemodynamically stable patients after cardiac surgery, phenylephrine increased PVR and SVR, but did not change the PVR/SVR ratio. Phenylephrine increased biventricular filling pressures and left ventricular end-diastolic area. Consequently, CO increased as ejection fraction was maintained. These findings do not discourage the use of phenylephrine after low-risk cardiac surgery. clinicaltrial.gov (identifier NCT04419662).

Ultrasound dilution cardiac output and echocardiography findings in anesthetized mature alpacas (Vicugna pacos) during normotension, hypotension and hypertension.

Alpacas (Vicugna pacos) have physiologic adaptations to live at high altitude. These adaptations may result in unexpected responses to changes in cardiac performance and blood pressure during general anesthesia. There are few studies evaluating cardiovascular variables in anesthetized alpacas. The purpose of this study was to report cardiovascular performance in anesthetized mature alpacas during normotension, hypotension, and hypertension using ultrasound dilution and echocardiography. Six adult alpacas, 3 females and 3 castrated males, weighing 62.6 to 88.7 kg were anesthetized and maintained with isoflurane and placed in right lateral recumbency. Each alpaca underwent ultrasound dilution and echocardiography measurements during three cardiovascular phases, normotension, hypotension via increased isoflurane concentration, and hypertension via phenylephrine infusion. Variables were analyzed with a Friedman test and a post hoc Dunn's test when significant. A p < 0.05 was used for significance. Cardiac output, cardiac index, systemic vascular resistance, stroke volume, total ejection fraction, left ventricular internal diameter during diastole, and total stroke volume indexed to body weight were greater for hypertension compared to hypotension. Total ejection fraction, stroke volume, and left ventricular ejection time were greater for hypertions compared to normotension. There was no difference between ultrasound dilution and echocardiography determined cardiac output measurements within each cardiovascular phase. Phenylephrine appeared to have increased ventricular performance and/or increased preload in anesthetized, mature alpacas. For detecting change in cardiovascular status in anesthetized alpacas, ultrasound dilution and echocardiography may be useful.

Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial

BackgroundIntraoperative hypotension is associated with postoperative complications. The use of vasopressors is often required to correct hypotension but the best vasopressor is unknown. MethodsA multicentre, cluster-randomised, crossover, feasibility and pilot trial was conducted across five hospitals in California. Phenylephrine (PE) vs norepinephrine (NE) infusion as the first-line vasopressor in patients under general anaesthesia alternated monthly at each hospital for 6 months. The primary endpoint was first-line vasopressor administration compliance of 80% or higher. Secondary endpoints were acute kidney injury (AKI), 30-day mortality, myocardial injury after noncardiac surgery (MINS), hospital length of stay, and rehospitalisation within 30 days. ResultsA total of 3626 patients were enrolled over 6 months; 1809 patients were randomised in the NE group, 1817 in the PE group. Overall, 88.2% received the assigned first-line vasopressor. No drug infiltrations requiring treatment were reported in either group. Patients were median 63 yr old, 50% female, and 58% white. Randomisation in the NE group vs PE group did not reduce readmission within 30 days (adjusted odds ratio=0.92; 95% confidence interval, 0.6–1.39), 30-day mortality (1.01; 0.48–2.09), AKI (1.1; 0.92–1.31), or MINS (1.63; 0.84–3.16). ConclusionsA large and diverse population undergoing major surgery under general anaesthesia was successfully enrolled and randomised to receive NE or PE infusion. This pilot and feasibility trial was not powered for adverse postoperative outcomes and a follow-up multicentre effectiveness trial is planned. Clinical trial registrationNCT04789330 (ClinicalTrials.gov).

Comparison of Carbetocin as a Bolus or Infusion With Prophylactic Phenylephrine on Maternal Heart Rate During Cesarean Delivery Under Spinal Anesthesia: A Double-Blinded Randomized Controlled Trial

(Can J Anesth/J Can Anesth. 2022:69:715–725) Carbetocin is used in elective cesarean deliveries to reduce the risk of postpartum hemorrhage, and the current practice is to administer the drug as a bolus injection. Side effects of carbetocin include low blood pressure and elevated or irregular heart rate. For some patients, this may lead to hemodynamic alterations and raises the question of potential benefits to heart rate and other hemodynamic factors by administering carbetocin via a 10-minute infusion. This study compared a bolus injection to a 10-minute infusion, both with a prophylactic infusion of phenylephrine, to understand if there are significant and clinically applicable differences in heart rate. This study primarily examined variation in heart rate within 20 minutes of drug administration, but also examined other hemodynamic factors such as blood pressure and stroke volume.

Central role for BRAF in cardiac hypertrophy: rethinking the pathological-physiological divide.

The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.

Adrenergic control of skeletal muscle blood flow during chronic hypoxia in healthy males.

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during 1) incremental intra-arterial infusion of phenylephrine to assess α1-adrenergic receptor responsiveness and 2) combined intra-arterial infusion of β-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-β-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; +3 ± 18%; P < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; P = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; P = 0.041) doses. Blockade of β-adrenergic receptors alone had no effect on resting FVC (P = 0.500) and combined α-β-blockade induced a similar vasodilatory response at SL and HA (P = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA (P = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-β-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-β-blockade: +19 ± 23%; P = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-β-blockade: -23 ± 11%; P = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α1-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.