Norepinephrine versus phenylephrine infusion for preventing postspinal hypotension during cesarean section for twin pregnancy: a double-blinded randomized controlled clinical trial.

BACKGROUND: Compared with singleton pregnancy, twin gestation is featured by a greater increase in cardiac output. Therefore, norepinephrine might be more suitable than phenylephrine for maintaining blood pressure during cesarean section for twins, as phenylephrine causes reflex bradycardia and a resultant decrease in cardiac output. This study was to determine whether norepinephrine was superior to phenylephrine in maintaining maternal hemodynamics during cesarean section for twins. METHODS: Informed consent was obtained from all the patients before enrollment. In this double-blinded, randomized clinical trial, 100 parturients with twin gestation undergoing cesarean section with spinal anesthesia were randomized to receive prophylactic norepinephrine (3.2 µg/min) or phenylephrine infusion (40 µg/min). The primary outcome was the change of heart rate and blood pressure during the study period. The secondary outcomes were to compare maternal complications, neonatal outcomes, Apgar scores and umbilical blood acid-base status between the two vasopressors. RESULTS: There was no significant difference observed for the change of heart rate between two vasopressors. The mean standardized area under the curve of heart rate was 78 ± 12 with norepinephrine vs. 74 ± 11 beats/min with phenylephrine (mean difference 4.4, 95%CI - 0.1 to 9.0; P = .0567). The mean standardized area under the curve of systolic blood pressure (SBP) was significantly lower in parturients with norepinephrine, as the mean of differences in standardized AUC of SBP was 6 mmHg, with a 95% CI from 2 to 9 mmHg (P = .0013). However, requirements of physician interventions for correcting maternal hemodynamical abnormalities (temporary cessation of vasopressor infusion for reactive hypertension, rescuing vasopressor bolus for hypotension and atropine for heart rate less < 50 beats/min) and neonatal outcomes were also not significantly different between two vasopressors. CONCLUSION: Infusion of norepinephrine was not associated with less overall decrease in heart rate during cesarean section for twins, compared with phenylephrine. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR1900021281 ).

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.

A hydrophilic interaction liquid chromatography - Tandem mass spectrometry method for the determination of phenylephrine in dried blood spots from preterm infants.

A sensitive and accurate hydrophilic interaction liquid chromatography - tandem mass spectrometry method (HILIC-MS/MS) was developed and validated for the determination of phenylephrine concentration in Dried Blood Spot (DBS) samples from preterm infants, after ocular administration of an ophthalmic solution with phenylephrine. Sample preparation involved the extraction of the analyte from an 85 µL DBS sample with methanol - acetonitrile (50:50, v/v). Chromatographic separation was achieved on an ACQUITY UPLC BEH AMIDE column, under isocratic conditions within a 5 min run. Detection was achieved with a triple quadrupole MS applying electrospray ionization in positive mode. The method was fully validated and proved precise and accurate with in a linear range of 0.59-3.53 ng/ml in blood. The method was developed to provide insights on the level of exposure of infant population to phenylephrine after ocular administration.

Comparison of push-dose phenylephrine and epinephrine in the emergency department.

BACKGROUND: There is limited evidence to support the efficacy and safety of push-dose vasopressor (PDP) use outside of the operating room (OR). Specifically, there are few head-to-head comparisons of different PDP in these settings. The purpose of this study was to compare the efficacy and safety of push-dose phenylephrine (PDP-PE) and epinephrine (PDP-E) in the Emergency Department (ED). METHODS: This retrospective, single-center study evaluated adults given PDP-PE or PDP-E in the ED from May 2017 to November 2020. The primary outcome was a change in heart rate (HR). Secondary outcomes included changes in blood pressure, adverse effects, dosing errors, fluid and vasopressor requirements, ICU and hospital lengths of stay (LOS), and in-hospital mortality. RESULTS: Ninety-six patients were included in the PDP-PE group and 39 patients in the PDP-E group. Median changes in HR were 0 [-7, 6] and - 2 [-15, 5] beats per minute (BPM) for PDP-PE and PDP-E, respectively (p = 0.138). PDP-E patients had a greater median increase in systolic blood pressure (SBP) (33 [24, 53] vs. 26 [8, 51] mmHg; p = 0.049). Dosing errors occurred more frequently in patients that received PDP-E (5/39 [12.8%] vs. 2/96 [2.1%]; p = 0.021). PDP-E patients more frequently received continuous epinephrine infusions before and after receiving PDP-E. There were no differences in adverse effects, fluid requirements, LOS, or mortality. CONCLUSION: PDP-E provided a greater increase in SBP compared to PDP-PE. However, dosing errors occurred more frequently in those receiving PDP-E. Larger head-to-head studies are necessary to further evaluate the efficacy and safety of PDP-E and PDP-PE.

Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes.

Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects. Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests. Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine. Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Determination of the 90% Effective Dose of Phenylephrine Boluses to Treat Spinal Anesthesia-Induced Hypotension in Patients with Severe Preeclampsia during Cesarean Delivery: A Pilot Study.

PURPOSE: Treatment of spinal anesthesia-induced hypotension in patients with severe preeclampsia assumes special concern as hypotension may further reduce placental perfusion. Phenylephrine is still the first-line vasopressor for treating spinal anesthesia-induced hypotension. However, the optimal dose of phenylephrine used as intravenous (IV) boluses in patients with severe preeclampsia has not been clearly determined. We aim to calculate the 90% effective dose (ED90) of phenylephrine as IV boluses for treating spinal anesthesia-induced hypotension in patients with severe preeclampsia undergoing cesarean delivery. PATIENTS AND METHODS: Forty patients with severe preeclampsia were enrolled in this prospective sequential allocation dose-finding trial. Using the biased coin up-and-down (BCUD) method, all patients in our study received an IV bolus phenylephrine of either 40, 50, 60, 70, or 80 µg when the mean arterial pressure (MAP) decreased to less than 80% of the baseline level and the ED90 was determined. The primary outcome was the success of the assigned phenylephrine bolus to maintain the MAP at or above 80% of baseline value between the induction of spinal anesthesia and delivery of the fetus. Secondary outcomes included hypertension, nausea, vomiting, bradycardia, upper sensory level of anesthesia, umbilical blood gases, and Apgar score. Estimating of the ED90 with 95% confidence interval (CI) was achieved by isotonic regression method. RESULTS: The ED90 of phenylephrine was estimated as 62.00 µg (95% CI=50.00-67.40 µg) using the isotonic regression method. No patients enrolled in our study experienced bradycardia and those patients who developed hypertension were all observed at the dose level 70 µg. CONCLUSION: For clinical practice, we recommend that phenylephrine 60 µg may be both effective and safe for treatment of spinal anesthesia-induced hypotension in severe preeclampsia during cesarean delivery.

Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors.

Postprandial orthostasis activates mechanisms of cardiovascular homeostasis to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (60°-head-up-tilt for 20 min) on splanchnic and systemic hemodynamics before and after ingesting an 800-kcal composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed noninvasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 mL of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction. Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation to maintain a normal BP during orthostasis.NEW & NOTEWORTHY A unique integrated investigation on the effect of meal on neurohumoral mechanisms and blood flow redistribution of the mesenteric circulation during orthostasis was investigated. Food ingestion results in cardiovascular hyperdynamism, reduction in cardiac vagal tone, and baroreflex sensitivity and causes a decrease in α1-adrenoceptor responsiveness only in the venous intrahepatic sinusoids. About 500-mL blood shifts from the mesenteric to the systemic circulation during orthostasis. Accordingly, the orthostatic homeostatic mechanisms are better understood.

Systemic adverse events after screening of retinopathy of prematurity with mydriatic.

PURPOSE: To evaluate systemic adverse events after screening for retinopathy of prematurity (ROP) performed with mydriatic. METHODS: This was a retrospective case series study. Medical records of consecutive patients who underwent screening for ROP with 0.5% phenylephrine and 0.5% tropicamide eyedrops were retrospectively reviewed. The score of abdominal distention (0-5), volume of milk sucked and volume of stool, along with systemic details (pulse and respiration rates, blood pressure and number of periods of apnea) were collected at 1 week and 1 day before ROP examination, and at 1 day after examination. Results were compared between the days before and after examination. Correlation between body weight at the time of examination and the score of abdominal distention was examined. The numbers of infants with abdominal and/or systemic adverse events were compared between pre- and post-examination periods. RESULTS: Eighty-six infants met the inclusion criteria. The score of abdominal distention increased from 2.0 at 1 day before examination to 2.3 at 1 day after examination (p = 0.005), and the number of infants who had worsened abdominal distension increased after examination (p = 0.01). Infants with lower body weight had a higher score of abdominal distention (p < 0.0001, r = -0.57). The number of infants with reduced milk consumption increased after examination (p = 0.0001), as did the number of infants with decreased pulse rate (p = 0.0008). CONCLUSIONS: Screening for ROP with mydriatic may have adverse effects on systemic conditions. Infants should be carefully monitored after ROP screening with mydriatic.

Acute Ischemic Priapism: An AUA/SMSNA Guideline.

PURPOSE: Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation and results in a prolonged and uncontrolled erection. Given its time-dependent and progressive nature, priapism is a situation that both urologists and emergency medicine practitioners must be familiar with and comfortable managing. Acute ischemic priapism, characterized by little or no cavernous blood flow and abnormal cavernous blood gases (ie, hypoxic, hypercarbic, acidotic) represents a medical emergency and may lead to cavernosal fibrosis and subsequent erectile dysfunction. MATERIALS AND METHODS: A comprehensive search of the literature was performed by Emergency Care Research Institute for articles published between January 1, 1960 and May 1, 2020. Searches identified 2948 potentially relevant articles, and 2516 of these were excluded at the title or abstract level for not meeting inclusion criteria for any key question. Full texts for the remaining 432 articles were reviewed, and ultimately 137 unique articles were included in the report. RESULTS: This Guideline was developed to inform clinicians on the proper diagnosis and surgical and non-surgical treatment of patients with acute ischemic priapism. This Guideline addresses the role of imaging, adjunctive laboratory testing, early involvement of urologists when presenting to the emergency room, discussion of conservative therapies, enhanced data for patient counseling on risks of erectile dysfunction and surgical complications, specific recommendations on intracavernosal phenylephrine with or without irrigation, the inclusion of novel surgical techniques (eg, tunneling), and early penile prosthesis placement. CONCLUSIONS: All patients with priapism should be evaluated emergently to identify the sub-type of priapism (acute ischemic versus non-ischemic) and those with an acute ischemic event should be provided early intervention. Treatment of the acute ischemic patient must be based on patient objectives, available resources, and clinician experience. As such, a single pathway for managing the condition is oversimplified and no longer appropriate. Using a diversified approach, some men may be treated with intracavernosal injections of phenylephrine alone, others with aspiration/irrigation or distal shunting, and some may undergo non-emergent placement of a penile prosthesis.

The use of electrical impedance tomography (EIT) to evaluate pulse rate in anaesthetised horses.

Electrical impedance tomography (EIT) provides clinically useful lung images; however, it would be an advantage to extract additional cardiovascular information from the data. The aim of this study was to evaluate if cardiac-related changes measured by EIT can be used to measure pulse rate (PR) under physiological as well as high and low blood pressure states in anaesthetised horses. Electrical impedance tomography data and PR from seven horses anaesthetised in dorsal recumbency were recorded over 1 min during mechanical ventilation and 1 min of apnoea. Data were collected at four measurement time points; before and during intravenous administration of nitroprusside and phenylephrine, respectively. Nine pixels, estimated to represent the heart, were chosen from the EIT image. A novel algorithm detected peaks of impedance change for these pixels over 10 s intervals. Concurrent PR measured using an invasive blood pressure trace, was recorded every 10 s. EIT- and pulse-rate data were compared using Bland-Altman assessment for multiple measurements on each horse. Overall, 288 paired datasets from six of seven horses were available for analysis. There was excellent agreement for baseline measurements, as well as during hypertension and hypotension, with a bias of -0.26 and lower and upper limit of agreement at -2.22 (95% confidence intervals [CI], -2.89 to -1.86) and 1.69 (95% CI, 1.34-2.36) beats per min, respectively. EIT can be used to evaluate PR using cardiac-related impedance changes. More work is required to determine bias that might occur in anaesthetised horses in other recumbencies or clinical situations.

PEX5 prevents cardiomyocyte hypertrophy via suppressing the redox-sensitive signaling pathways MAPKs and STAT3.

Peroxisomal biogenesis factor 5 (PEX5) is a member of peroxisome biogenesis protein family which serves as a shuttle receptor for the import of peroxisome matrix protein. The function of PEX5 on cardiomyocyte hypertrophy remained to be elucidated. Our study demonstrated that the protein expression level of PEX5 was declined in primary neonatal rat cardiomyocytes treated with phenylephrine (PE) and hearts from cardiac hypertrophic rats induced by abdominal aortic constriction (AAC). Overexpression of PEX5 alleviated cardiomyocyte hypertrophy induced by PE, while silencing of PEX5 exacerbated cardiomyocyte hypertrophy. PEX5 improved redox imbalance by decreasing cellular reactive oxygen species level and preserving peroxisomal catalase. Moreover, PEX5 knockdown aggravated PE-induced activation of redox-sensitive signaling pathways, including mitogen-activated protein kinase (MAPK) pathway and signal transducer and activator of transcription 3 (STAT3); whereas PEX5 overexpression suppressed activation of MAPK and STAT3. But PEX5 did not affect PE-induced phosphorylation of mammalian target of rapamycin (mTOR). In conclusion, the present study suggests that PEX5 protects cardiomyocyte against hypertrophy via regulating redox homeostasis and inhibiting redox-sensitive signaling pathways MAPK and STAT3.

Factors Associated With Corporoglandular Shunting for Patients With First-time Ischemic Priapism.

OBJECTIVE: To establish predictive factors of patients who failed intra-cavernosal injection therapy and ultimately required corporoglandular shunting during first-time ischemic priapism episodes. METHODS: A retrospective review was performed of all patients over the age of 18 who presented to our institution with first-time episode of ischemic priapism from 2009 to 2019. Variables assessed included: body mass index, diabetes, hypertension, race, insurance-type, hypertension, etiology, age, duration of erection prior to evaluation, total amount of phenylephrine injected, and use of corporal irrigation. A receiver operating characteristic (ROC) curve was performed utilizing duration of erection and amount of phenylephrine. RESULTS: One-hundred and forty-seven patients met inclusion criteria of which 24 patients required surgical intervention. There were differences associated with mean total phenylephrine used, duration of erection between shunted patients and non-shunted patients with regards to age (P = .38) or etiology (P = .81). Multivariable analysis revealed differences between duration of erection and BMI greater than 25 kg/m2. ROC curve analyses revealed total amount of phenylephrine injected and duration of erection were acceptable and excellent predictors of need for shunt procedures with area under the curves of 0.72 and 0.90, respectively. Optimal cut-off values for each were found to be 950 mcg and 15.5 hours. CONCLUSION: Our study suggests that patients who require greater than 950 mcg of total phenylephrine or present with erections lasting greater than 15.5 hours are significantly more likely to require corporoglandular shunting and should be counseled appropriately as such.

Assessing the Clinical Requirement of 2.5% Phenylephrine for Diagnostic Pupil Examination.

Purpose: To evaluate whether the standard dilating drop regimen consisting of phenylephrine, tropicamide, and proparacaine produces clinically significant improvement in pupil size compared to tropicamide and proparacaine during diagnostic eye examination. Methods: Sixty-three adult patients at Washington University School of Medicine Eye Clinic were enrolled in this prospective, randomized trial. Each patient received one of two dilating drop regimens: phenylephrine + tropicamide + proparacaine (PE+T+PP), which is considered the standard therapy, or tropicamide + proparacaine (T+PP). Main outcome measures were the proportion of pupils able to achieve successful clinical examination without need for additional dilating drops and change in predilation to postdilation pupil size. Comparisons were made using McNemar's test, repeated measures analysis of variance, and Fisher's test to determine whether PE is a necessary component of the standard eye examination. Results: There were no statistically significant differences between the PE+T+PP and T+PE treatment groups in predilation to postdilation changes in average resting pupil size (1.58 ± 0.66 and 2.61 ± 0.79; P = 0.57) or constricted pupil size (2.52 ± 0.93 and 3.56 ± 0.96; P = 0.15). There was no statistically significant difference between patients who obtained a successful dilated pupil examination between those receiving PE+T+PP and those receiving T+PP as determined by the examining physicians (Fisher's, P = 0.67). Conclusion: The addition of phenylephrine to tropicamide and proparacaine did not improve pupillary dilation size or ability to conduct a clinical examination. A single dilating agent using tropicamide should be considered in clinical practice.

Phentolamine Eye Drops Reverse Pharmacologically Induced Mydriasis in a Randomized Phase 2b Trial.

SIGNIFICANCE: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations. PURPOSE: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication. METHODS: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points. RESULTS: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours. CONCLUSIONS: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile.

Use of lidocaine with phenylephrine (Co-phenylcaine) spray for anaesthesia of the external auditory canal.

OBJECTIVE: A method is described for topical local anaesthesia of the tympanic membrane and ear canal using lidocaine and phenylephrine (Co-phenylcaine) spray and soaked micropatties. DISCUSSION: The advantages of this method are discussed in comparison to existing methods.

Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study.

BACKGROUND: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the ß-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through ß-adrenergic affinity. METHODS: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and ß-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 µg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 µg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.). RESULTS: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with ß-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03). CONCLUSIONS: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the ß-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. CLINICAL TRIAL REGISTRATION: NCT02675868 (Clinicaltrials.gov).

Effect of Phenylephrine Push Before Continuous Infusion Norepinephrine in Patients With Septic Shock.

BACKGROUND: IV pushes of phenylephrine may be used for patients with septic shock with the intent of rapidly achieving mean arterial pressure (MAP) goals. However, the clinical effectiveness and safety of this approach are unclear. RESEARCH QUESTION: In patients with septic shock, is administration of a phenylephrine push before norepinephrine initiation associated with a higher incidence of hemodynamic stability? METHODS: This retrospective, multicenter cohort study included adult patients with septic shock initiated on norepinephrine. Propensity scores for initial phenylephrine push receipt were generated, and patients receiving an initial phenylephrine push were propensity score-matched 1:2 to those not receiving an initial phenylephrine push. The primary outcome was achievement of hemodynamic stability (defined as maintaining MAP of ≥ 65 mm Hg for at least 6 h without an increase in continuous infusion vasoactive agent dosage) within 3 and 12 h of norepinephrine initiation. RESULTS: Of 1,317 included patients, 181 received an initial phenylephrine push; 141 phenylephrine push patients were matched to 282 patients not receiving a phenylephrine push. More patients who received a phenylephrine push achieved hemodynamic stability at hour 3 than those who did not receive a phenylephrine push (28.4% vs 18.8%; risk difference, 10%; 95% CI, 0.9%-18%). Phenylephrine push receipt was associated independently with hemodynamic stability within 3 h (adjusted OR, 1.8; 95% CI, 1.09-2.97), but not at 12 h (adjusted OR, 1.42; 95% CI, 0.93-2.16). Phenylephrine push receipt was associated independently with higher ICU mortality (adjusted OR, 1.88; 95% CI, 1.1-3.21). INTERPRETATION: Phenylephrine pushes were associated with a higher incidence of early, but not sustained, hemodynamic stability and were associated independently with higher ICU mortality. Caution is warranted when clinicians are considering the use of phenylephrine pushes in patients with septic shock.

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

BACKGROUND/OBJECTIVE: 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. METHODS: A retrospective chart review was conducted on all consecutive patients who received peripheral phenylephrine in a tertiary care hospital neurocritical care unit. RESULTS: 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. CONCLUSIONS: 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.

Randomised controlled pilot trial comparing low dose and very low- dose microdrop administration of phenylephrine and cyclopentolate for retinopathy of prematurity eye examinations in neonates.

AIMS: To determine ifVery low dose mydriatic eye microdrop regimen sufficiently dilates the pupil (above 4.1 mm) compared with the currently used low dose mydriatic eye microdrop regimen.Cardiovascular, gastrointestinal and respiratory adverse effects occur following eye drop instillation. METHODS: Seventeen premature infants were recruited into this prospective, randomised controlled pilot trial in January 2017 to November 2018. Data were collected from the single-centre Neonatal Intensive Care Unit, Dunedin Hospital, New Zealand. The inclusion criteria were birth weight less than 1500 g or gestational age less than 31 weeks, or any premature infant requiring red reflex testing. Infants were randomised to receive either phenylephrine 1% or 0.5% and cyclopentolate 0.2% or 0.1%, 1 microdrop in both eyes. Efficacy outcome measures were pupil size at retinopathy of prematurity eye examination (ROPEE) and ophthalmologist rating of ease of screen. RESULTS: All participants had sufficient pupillary dilation for a successful ROPEE. Ophthalmologists rated the ROPEE as easy for 90% of all examinations. Pupil dilation measurements at the time of examination, mean±SD, 4.8±0.2 (95% CI 4.5 to 5.2) mm for treatment A and 5±0.2 (95%CI 4.6 to 5.4) mm for treatment B (p=0.61). There were no statistically significant differences between the groups for safety data. CONCLUSIONS: Very low dose microdrop administration of phenylephrine and cyclopentolate appears to be effective at sufficiently dilating the neonatal pupil for ROPEEs. Low dose and very low dose microdrop mydriatic regimens may also reduce the risk of unwanted adverse effects associated with these medicines. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (reference ACTRN12616001266459p).