Nifedipine outperforms labetalol: A comparative analysis of hypertension management in black pregnancies.

BACKGROUND: Nifedipine has previously exhibited superior efficacy to labetalol in managing hypertension in the non-pregnant Black population, establishing itself as a first-line treatment option. However, the unique challenges of hypertension during pregnancy, especially prevalent in Black individuals, remain underexplored in terms of effective medication choices. This gap highlights the need for targeted research on antihypertensive efficacy specifically within this population. OBJECTIVE: This study aims to evaluate the effectiveness of nifedipine versus labetalol in managing blood pressure in Black pregnancies. The primary measure is the mean systolic and diastolic blood pressure trajectories throughout pregnancy, determining the superiority of nifedipine in this context. STUDY DESIGN: A retrospective cohort study was conducted at a multi-center institution in the metropolitan Detroit area, encompassing data from 1,235 Black pregnancies affected by chronic hypertension between 2015 and 2022. Mean blood pressure trajectories during pregnancy were fit by linear mixed effects model with a random intercept and time effect. RESULTS: Patients on nifedipine had an estimated 2.08 mmHg lower mean systolic and 1.60 mmHg lower mean diastolic blood pressure compared to those on labetalol, with significant p-values of 0.040 and 0.028. Additionally, nifedipine users were less likely to need increased doses, with an odds ratio of 0.28 (95 % CI: 0.19-0.40, p < 0.001) compared to labetalol users. CONCLUSION: This study provides compelling evidence that nifedipine outperforms labetalol in managing blood pressure during Black pregnancies. These findings suggest that the initiation of nifedipine should be considered in the management of chronic hypertension among Black pregnant individuals, offering a potentially more effective treatment option.

Pregnancy Outcomes of Nifedipine Compared With Labetalol for Oral Treatment of Mild Chronic Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Lipid Emulsions Inhibit Labetalol-Induced Vasodilation in the Isolated Rat Aorta.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.

Effect of low-molecular-weight heparin calcium combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function and pregnancy outcome in early-onset severe preeclampsia.

OBJECTIVE: This paper was aimed at unveiling the effect of low-molecular-weight heparin calcium (LMWH) combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function, and pregnancy outcome in early-onset severe preeclampsia (EOSP). METHODS: Pregnant women with EOSP were divided into the control group and the study group, each with 62 cases. Patients in the control group were treated with labetalol and magnesium sulfate, and those in the study group were treated with LMWH in combination with the control grou Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), 24-h urine protein, coagulation indices [D-dimer (D-D), plasma fibrinogen (Fg), prothrombin time (PT), activated partial thromboplastin time (APTT), and prothrombin time (TT)], endothelial function [endothelin (ET-1) and nitric oxide (NO)], oxidative stress indices [oxidized low-density lipoproteins (ox-LDL), lipid peroxidation (LPO), superoxide dismutase (SOD), and malondialdehyde (MDA)], pregnancy outcome, and adverse effects occurred in the two groups were compared. RESULTS: After treatment, lower SBP, DBP, and 24-h urine protein levels; lower Fg and D-D levels; higher PT, APPT, and TT levels; higher NO levels; lower ET-1 levels; lower ox-LDL, MDA, and LPO levels; higher SOD levels; and lower incidence of adverse pregnancy and adverse reactions were noted in the study group in contrast to the control group. CONCLUSION: EOSP patients given with LMWH combined with magnesium sulfate and labetalol can effectively reduce the patient's blood pressure and urinary protein level; improve coagulation function, oxidative stress, and vascular endothelial function indices; reduce the adverse pregnancy outcomes; and improve the safety of treatment.

The "Preeclampsia and Hypertension Target Treatment" study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings.

BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.

Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Anti-hypertensive therapy for preeclampsia: a network meta-analysis and systematic review.

BACKGROUND: Preeclampsia (PE) is a pregnancy disorder that represents a major cause of maternal and perinatal morbidity and mortality. METHODS: This network meta-analysis was registered with PROSPERO. We searched the PubMed, ClinicalTrials.gov. and Embase databases for studies published from inception to the 31st of March 2023. RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis (DMA) statistical analysis. Funnel maps, network meta-analysis (NMA), the surface under the cumulative ranking curve (SUCRA) to rank the different interventions and publication bias were generated by STATA 17.0 software. RESULTS: We included eight randomized controlled trials (RCTs) involving a total of 1192 women with PE; two studies were of high quality and six were of moderate quality. Eight interventions were addressed in the NMA. In the DMA, we found that blood pressure in the Ketanserin group were significantly higher than those in the Nicardipine group. NMA showed that blood pressure in the Dihydralazine group was significantly higher than that in the Methyldopa, Labetalol, Nicardipine and Diltiazem groups. And the blood pressure in the Labetalol group was significantly lower than that in the Nicardipine group. SUCRA values showed that Diltiazem was more effective in lowering blood pressure than other drugs looked at in this study. CONCLUSION: According to the eight RCTs included in this study, Diltiazem was the most effective in reducing blood pressure in PE patients; Labetalol and Nicardipine also had good effects. Diltiazem is preferred for the treatment of patients with severe PE and high blood pressure.

Comparison of labetalol and lidocaine in induction of controlled hypotension in tympanoplasty: a randomized clinical trial.

OBJECTIVES: This study aimed to compare the efficacy of labetalol and lidocaine in tympanoplasty surgery, specifically evaluating their impact on hemodynamic changes and perioperative outcomes. METHODS: A randomized controlled trial was conducted with 64 patients scheduled for tympanoplasty. Patients were randomly assigned to receive either 0.5-2 mg/min labetalol or 1.5 mg/kg/h lidocaine 1% to achieve controlled hypotension during surgery. The efficacy of the drugs was assessed by comparing the Mean Arterial Pressure (MAP), surgeon's satisfaction, time to target MAP, bleeding volume, postoperative pain scores, the need for analgesic medication in recovery, sedation, and other additional parameters. RESULTS: The hemodynamic parameters showed a similar trend over time in both the labetalol and lidocaine groups. The median bleeding volume in the labetalol group (10 cc) was lower than that in the lidocaine group (30 cc), although this difference was not statistically significant (p = 0.11). Similarly, surgeon's satisfaction level, pain intensity, and sedation level in the recovery room did not show statistically significant differences between the two groups (p > 0.05). The duration of surgery, recovery stay, and extubation time also did not significantly differ between the groups. Both medications took approximately the same time (20 min) to reach the target MAP and exhibited comparable hemodynamic responses (p > 0.05). CONCLUSION: Both labetalol and lidocaine effectively achieved controlled hypotension during tympanoplasty surgery, thereby improving surgical conditions. The choice of medication should be based on individual patient characteristics and the anesthesiologist's judgment. LEVEL OF EVIDENCE: II.

Clinical Trials That Have Changed Obstetric Practice: The Chronic Hypertension and Pregnancy (CHAP) Trial.

We describe the evolution of treatment recommendations for chronic hypertension (CHTN) in pregnancy, the CHTN and pregnancy (CHAP) trial, and its impact on obstetric practice. The US multicenter CHAP trial showed that antihypertensive treatment for mild CHTN in pregnancy [blood pressures (BP)<160/105 mm Hg] to goal<140/90 mm Hg, primarily with labetalol or nifedipine compared with no treatment unless BP were severe reduced the composite risk of superimposed severe preeclampsia, indicated preterm birth <35 weeks, placental abruption, and fetal/neonatal death. As a result of this trial, professional societies in the United States recommended treatment of patients with CHTN in pregnancy to BP goal<140/90 mm Hg.

Effects of intravenous nicardipine followed by oral labetalol in combination with nifedipine controlled-release tablet on severe peripartum hypertension.

OBJECTIVES: To investigate the effects of intravenous nicardipine as initial therapy and oral labetalol combined with nifedipine controlled-release tablet as subsequent treatment of severe peripartum hypertension. MATERIAL AND METHODS: Intravenous nicardipine was delivered as the initial treatment, after the target blood pressure (BP) had been achieved, oral labetalol was used to maintain the target BP. If oral labetalol failed to maintain the target BP, oral labetalol combined with nifedipine controlled-release tablet was used. RESULTS: A total number of 131 patients were enrolled. The target BP (BP < 140/90 mmHg) was achieved in all patients within 60 minutes by intravenous nicardipine. After receiving labetalol orally, the target BP was maintained in nine patients. However, in 104 patients, we had to combine oral labetalol and nifedipine controlled-release tablet due to re-elevation of their systolic BP to 140-159 mmHg. In 18 patients, we restarted intravenous nicardipine because their systolic BP re-elevated above 160 mm Hg. Among the 104 patients who received oral labetalol and nifedipine controlled-release tablet, the target BP was achieved and maintained in 96 patients, and eight patients had to restart nicardipine. Of the total number of 26 patients in whom intravenous nicardipine was resumed, the target BP was successfully maintained in 22 patients with oral labetalol combined with nifedipine controlled-release tablet. CONCLUSIONS: Intravenous nicardipine rapidly and safely lowered severe peripartum hypertension. As subsequent therapy, oral labetalol combined with nifedipine controlled-release tablet protocol may be applied to effectively maintain a target BP.

Labetalol Ameliorates Experimental Colitis in Rat Possibly Through its Effect on Proinflammatory Mediators and Oxidative Stress.

BACKGROUND: Members of beta blockers drugs possess significant antioxidant activities. The current research is to assess the effect of the labetalol on acetic acid (AA-induced) colitis in rat model. METHODS: Forty adult Wistar rats were separated into 4 groups, including the negative control group, AA group, AA + sulfasalazine (100 mg/kg/day) group, and AA + labetalol (300 mg/kg/day) group. Colitis was induced in rats by the interrectal installation of 2 mL of 4% (v/v) AA. Sulfasalazine and labetalol were administered orally for 7 days after 2 hours of induction. The following parameters were measured: disease activity index (DAI), histopa-thological changes and colon tissue homogenate concentrations of proinflammatory mediators IL-1ß, adhesion molecules ICAM-1, and oxidative stress marker myeloperoxidase (MPO). RESULTS: The treatment with labetalol significantly reduced DAI and histopathological changes induced by AA. Also, labetalol markedly decreased the concentrations of IL-1ß, ICAM-1, and MPO in colonic tissue that were increased by AA. The effects of labetalol were significantly lower than that produced by sulfasalazine as standard drug. CONCLUSIONS: Labetalol exerts ameliorative effects on disease activity and histopathological features of AA-induced colitis in rats possibly through antioxidant effects and inhibition of inflammatory mediators.

An audit of postoperative haemodynamic stability after intraoperative labetalol administration in non-cardiac surgery patients.

Anaesthesiologists commonly use intravenous labetalol to adjust patient haemodynamics during surgical procedures. Cases of profound hypotension after continuous labetalol infusions have been reported; however, there is limited evidence regarding the safety of intraoperative labetalol boluses. This audit examined the frequency of postoperative hypotension and bradycardia in 292 adult non-cardiac surgery patients treated with intraoperative labetalol boluses. Blood pressure and heart rate data were collected from the post-anaesthesia care unit and on the floor units for 24 hours after surgery. The median total intraoperative labetalol dose was 10mg. A total of 30/292 patients had all-cause postoperative hypotension within 24 hours of surgery, 26 of which had other medical or surgical precipitants. Fifteen patients developed bradycardia. There were no deaths or intensive care unit admissions attributed to labetalol. This audit demonstrates a low risk of all-cause postoperative hypotension (10%) and bradycardia (5%) after the use of small IV doses of intraoperative labetalol.

Risk of postpartum readmission after hypertensive disorder of pregnancy and variation by discharge antihypertensive medication prescription.

BACKGROUND: Patients with hypertensive disorders of pregnancy have a high rate of postpartum readmission. OBJECTIVE: This study aimed to evaluate whether the type of antihypertensive medication prescribed at discharge was associated with postpartum readmission after a hypertensive disorder of pregnancy. STUDY DESIGN: This was a retrospective cohort study of 57,254 pregnancies complicated by hypertensive disorders of pregnancy between 2012 and 2018 in the electronic obstetrical database of Kaiser Permanente Northern California. Postpartum readmissions occurred within 6 weeks after discharge from delivery hospitalization. Cox regression models were used to evaluate the association between the type of antihypertensive medication prescription at discharge (none, labetalol only, nifedipine only, or 2 or more antihypertensive medications) and postpartum readmission, adjusted for type of hypertensive disorder of pregnancy, final inpatient systolic and diastolic blood pressures, age, body mass index, mode of delivery, insurance status, race and ethnicity, delivery facility, comorbidity score, smoking, preterm delivery, parity, and Neighborhood Deprivation Index. RESULTS: Among eligible patients with a hypertensive disorder of pregnancy, 1696 (3.0%) were readmitted within 6 weeks. Approximately 86% of patients were discharged without a prescription for antihypertensive medication; among those discharged with a prescription for antihypertensive medication, most were prescribed either labetalol only (54%) or nifedipine only (30%). The unadjusted readmission risk was the highest for patients discharged with a prescription for labetalol only (7.6%), lower for those discharged with a prescription for nifedipine only (3.6%) or 2 or more antihypertensive medications (3.2%), and the lowest for those discharged without a prescription for antihypertensive medication (2.5%). In the adjusted models, compared with discharge without a prescription for antihypertensive medication, discharge with a prescription for labetalol only was associated with a 63% (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) greater incidence of postpartum readmission, and discharge with a prescription for nifedipine only and discharge with a prescription for 2 or more antihypertensive medications were associated with 26% (hazard ratio, 0.74; 95% confidence interval, 0.59-0.93) and 47% (hazard ratio, 0.53; 95% confidence interval, 0.38-0.74) lower incidence of postpartum readmission, respectively. There was no strong evidence to suggest that the effect of the type of antihypertensive medication at discharge on the incidence of readmission varied by race and ethnicity (interaction P=.88). The results indicating an elevated risk associated with labetalol use were consistent in models that excluded patients with prepregnancy hypertension. CONCLUSION: Discharge with a prescription for nifedipine alone or multiple antihypertensive medications (vs no medication) was associated with a lower incidence of readmission, whereas discharge with a prescription for labetalol alone was associated with an elevated readmission incidence. A large-scale, prospective research to compare the effectiveness of commonly prescribed hypertension medications at discharge is warranted.

Physiologic Treatment of Severe Hypertension in Pregnancy and Postpartum.

We aimed to evaluate physiologic treatment of severe hypertension. This was a retrospective cohort study of pregnant and postpartum patients with severe hypertension (systolic blood pressure [BP] 160 mm Hg or higher or diastolic BP 110 mm Hg or higher) treated with intravenous labetalol or hydralazine at a single tertiary care center between 2013 and 2018. Patients were classified as having physiologic treatment if they had hyperdynamic physiology (pulse pressure 65 mm Hg or higher) and received labetalol or had vasoconstrictive physiology (diastolic BP 100 mm Hg or higher) and received hydralazine. The primary outcome was number of antihypertensive doses to achieve nonsevere BP. Of 1,120 patients included in the analysis, 653 had physiologic treatment and 467 had nonphysiologic treatment, with 16 (1.4%) excluded for inability to classify physiology. Physiologic treatment was associated with fewer antihypertensive doses (1.4±0.9 doses vs 1.6±1.4 doses; adjusted ß -0.28, 95% CI, -0.42 to -0.14) and lower odds of medication conversion (2.5% vs 4.7%; adjusted odds ratio 0.48, 95% CI, 0.24-0.93) but no difference in time to nonsevere BP (31 minutes [interquartile range 16-66 minutes] vs 34 minutes [interquartile range 15-76 minutes]; adjusted hazard ratio 1.0, 95% CI, 0.9-1.2). Physiologic treatment of severe hypertension warrants further evaluation.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Buffalo yogurt fermented with commercial starter and Lactobacillus plantarum originating from breast milk lowered blood pressure in pregnant hypertensive rats.

Nutritional therapy, which may have advantages over medication, is being investigated as a novel treatment for pregnancy-induced hypertension. Several studies have shown that probiotic yogurt supplementation during pregnancy has beneficial effects on maternal and fetal health. In this study, fermented buffalo milk was produced with yogurt culture and Lactobacillus plantarum B, a probiotic isolated from healthy breast milk with high angiotensin-converting enzyme inhibitory activity. The fermentation conditions under which the angiotensin-converting enzyme (ACE) inhibitory activity reached 84.51% were optimized by the response surface method as follows: 2 × 106 cfu/mL of L. plantarum B, yogurt culture 2.5 × 105 cfu/mL, and 8 h at 37°C. The distribution of ACE inhibitory peptides from fermented buffalo milk and fermented cow milk were further analyzed by liquid chromatography-mass spectrometry. By searching according to the structural features of ACE inhibitory peptides, 29 and 11 peptides containing ACE inhibitory peptide features were found in fermented buffalo milk and fermented cow milk, respectively. To investigate the in vivo antihypertensive activity of fermented buffalo milk, 18 pregnant rats were divided into 3 groups (n = 6 in each group) and administered 10 mL of normal saline, yogurt (20 mg/kg), or labetalol hydrochloride (4 mg/kg) daily from the beginning of pregnancy to parturition. To induce hypertension, methyl nitrosoarginine (125 mg/kg) was injected subcutaneously every day from d 15 of pregnancy to the day of delivery. Blood pressure was not significantly changed in the yogurt and labetalol groups after induction of hypertension and was lower compared with the normal saline group, but there was no difference between the yogurt and labetalol groups. This implied that the buffalo yogurt had a preventive and antihypertensive effect in the pregnancy-induced hypertensive rat model. Further studies to determine the mechanism of action, as well as a randomized control trial, are warranted.

Pharmacogenomics of Preeclampsia therapies: Current evidence and future challenges for clinical implementation.

Preeclampsia is a pregnancy-specific disorder, and it is a leading cause of maternal and perinatal morbidity and mortality. The application of pharmacogenetics to antihypertensive agents and dose selection in women with preeclampsia is still in its infancy. No current prescribing guidelines from the clinical pharmacogenetics implementation consortium (CPIC) exist for preeclampsia. Although more studies on pharmacogenomics are underway, there is some evidence for the pharmacogenomics of preeclampsia therapies, considering both the pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs used in preeclampsia. It has been revealed that the CYP2D6*10 variant is significantly higher in women with preeclampsia who are non-responsive to labetalol compared to those who are in the responsive group. Various genetic variants of PD targets, i.e., NOS3, MMP9, MMP2, TIMP1, TIMP3, VEGF, and NAMPT, have been investigated to assess the responsiveness of antihypertensive therapies in preeclampsia management, and they indicated that certain genetic variants of MMP9, TIMP1, and NAMPT are more frequently observed in those who are non-responsive to anti-hypertensive therapies compared to those who are responsive. Further, gene-gene interactions have revealed that NAMPT, TIMP1, and MMP2 genotypes are associated with an increased risk of preeclampsia, and they are more frequently observed in the non-responsive subgroup of women with preeclampsia. The current evidence is not rigorous enough for clinical implementation; however, an institutional or regional-based retrospective analysis of audited data may help close the knowledge gap during the transitional period from a traditional approach (a "one-size-fits-all" strategy) to the pharmacogenomics of preeclampsia therapies.

Haemodynamic effects of labetalol in isoflurane-anaesthetized dogs that received dexmedetomidine: A randomized clinical trial.

OBJECTIVE: To test whether labetalol improved cardiovascular function in anaesthetized dogs injected with dexmedetomidine. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A group of 20 healthy client-owned dogs undergoing ovariohysterectomy. METHODS: Each dog received dexmedetomidine (5 µg kg-1) and methadone (0.2 mg kg-1) intramuscularly. General anaesthesia was induced with propofol and maintained with isoflurane in oxygen. All dogs were mechanically ventilated, and epidural anaesthesia with lidocaine was performed. Standard anaesthetic monitoring, invasive blood pressure, oesophageal Doppler and near-infrared tissue perfusion/oxygenation were applied. Peak velocity (PV), mean acceleration and stroke distance (SD) from the oesophageal Doppler were recorded. Arterial elastance (Ea) was calculated. Tissue oxygenation (rStO2) was also recorded. Prior to surgery, animals received either 0.1 mg kg-1 of labetalol intravenously (IV) over 60 seconds or the equivalent volume of saline. Data were recorded for 20 minutes. Age, weight and propofol dose were compared with a Wilcoxon rank-sum test. The effects of time, treatment and their interaction with haemodynamic and perfusion variables were analysed with mixed-effect models and Tukey's post hoc tests. RESULTS: Significant effects of the interaction between treatment and time were observed whereby heart rate (HR) was higher in dogs given labetalol (p = 0.01), whereas arterial blood pressure and Ea were lower (p < 0.01). Similarly, PV, SD and rStO2 were higher in the labetalol group, and significant effects were detected for the interaction between treatment and time (p < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Labetalol at a dose of 0.1 mg kg-1 IV in dogs under general anaesthesia and administered a pre-anaesthetic medication of dexmedetomidine produced mild vasodilation (reduction of Ea), resulting in an increase in HR and left ventricular outflow. Although labetalol could be an effective option to achieve haemodynamic optimization after dexmedetomidine-induced vasoconstriction, future studies are needed to assess long-term effects.

Comparison of outcomes following intravenous magnesium compared with intravenous labetalol and oral nifedipine in 355 pregnant Han Chinese women with preeclampsia.

As per the American College of Obstetricians and Gynecologists in 2013, magnesium sulfate is the gold standard for the management of preeclampsia, but it has a short action time that does not provide stable maintenance of blood pressure. Labetalol is currently recommended as first-line treatment by the national UK guidance. This study included 355 pregnant Han Chinese women with preeclampsia and aimed to compare outcomes following intravenous magnesium compared with intravenous labetalol and oral nifedipine. Women received 4 g intravenous magnesium sulfate followed by the maintenance dose of 1 g/h intravenous magnesium sulfate (MS cohort, n = 104) or intravenous labetalol (LB cohort, n = 115), or oral nifedipine (NF cohort, n = 136). Therapy success: systolic blood pressure ~140 mm Hg and diastolic blood pressure ~90 mm Hg, therapy failure: persistent systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 110 mm Hg after maximum dosage of therapy (EL). Women of all cohorts successfully decreased systolic and diastolic blood pressures at EL as compared to them before therapy conditions (P < .001, for all). At EL, systolic and diastolic blood pressures of women of the LB cohort decreased more than those of women of the MS and NF cohorts (P < .05, for all). Therapy was more successful in women of the LB cohort than those of the NF cohort (107 [93%] vs 112 [82%], P = .0132). More numbers of women were reduced blood pressure after 1 day of therapy from the LB cohort than those of the NF (75 [65%] vs 21 [15%]) and MS (75 [65%] vs 35 [34%]) cohorts (P < .0001 for both). Labetalol-induced tachycardia, bradycardia, and intracranial hemorrhage in pregnant women and respiratory distress syndrome and hypoglycemia in neonates. Intravenous labetalol provides proper reduction of blood pressure in Han Chinese women with preeclampsia but has the risk of undesirable maternal and neonatal adverse effects (Level of Evidence: IV; Technical Efficacy: Stage 4).