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Cureus Jul 2023Maternal hypotension is a common complication of spinal anesthesia in cesarean section and requires immediate intervention. Phenylephrine is most commonly used as a...
Comparing the Effect of Phenylephrine Bolus and Phenylephrine Infusion for Maintaining Arterial Blood Pressure During Cesarean Delivery Under Spinal Anesthesia: A Randomized Prospective Study.
INTRODUCTION
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 of phenylephrine for maintaining arterial blood pressure during cesarean delivery.
MATERIALS AND METHOD
This was a prospective, randomized comparative study. One hundred normotensive pregnant females aged 18-35 years, body mass index 18-29kg.m, American Society of Anesthesiologists (ASA) physical status classification II scheduled 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, 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, the neonatal APGAR score was assessed at one minute and five minutes.
RESULTS
Demographic data were comparable in terms of demographic profile, duration of surgery, and ASA physical status classification between 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.
CONCLUSION
We concluded that during cesarean section under spinal anesthesia, phenylephrine infusion provides better hemodynamic stability and APGAR score during the perioperative period.
PubMed: 37654965
DOI: 10.7759/cureus.42713 -
Journal of Cardiothoracic and Vascular... Oct 2023To investigate the effects of remimazolam on postoperative cognitive function, intraoperative hemodynamics, and oxygenation in older patients undergoing lobectomy. (Randomized Controlled Trial)
Randomized Controlled Trial
Propofol Versus Remimazolam on Cognitive Function, Hemodynamics, and Oxygenation During One-Lung Ventilation in Older Patients Undergoing Pulmonary Lobectomy: A Randomized Controlled Trial.
OBJECTIVES
To investigate the effects of remimazolam on postoperative cognitive function, intraoperative hemodynamics, and oxygenation in older patients undergoing lobectomy.
DESIGN
A prospective, double-blind, randomized, controlled study.
SETTING
A university hospital.
PARTICIPANTS
Eighty-four older patients with lung cancer who underwent lobectomy, aged ≥65 years.
INTERVENTIONS
Patients were divided randomly into the remimazolam (group R) and propofol (group P) groups. Group R underwent remimazolam anesthesia induction and maintenance, whereas group P underwent propofol anesthesia induction and maintenance. Cognitive function was assessed with neuropsychological tests 1 day before surgery and 7 days after surgery. The Clock Drawing Test, Verbal Fluency Test (VFT), Digit Symbol Switching Test (DSST), and Auditory Verbal Learning Test-Huashan (AVLT-H) assessed visuospatial ability, language function, attention, and memory, respectively. The systolic blood pressure (SBP), heart rate, mean arterial pressure (MAP), and cardiac index were recorded 5 minutes before induction of anesthesia (T0), 2 minutes after sedation (T1), 5 minutes after intubation with two-lung ventilation (T2), 30 minutes after one-lung ventilation (OLV) (T3), 60 minutes after OLV (T4), and at the end of surgery (T5), and the incidences of hypotension and bradycardia were recorded. The PaO, oxygenation index (OI), and intrapulmonary shunt (Qs/Qt) were assessed at T0, T2, T3, T4, and T5. The levels of S-100β and interleukin 6 were measured by enzyme-linked immunosorbent assay at T0, T5, 24 hours after surgery (T6), and on day 7 after surgery (T7).
MEASUREMENTS AND MAIN RESULTS
The VFT, DSST, immediate recall AVLT-H, and short-delayed recall AVLT-H scores were significantly higher in group R than in group P on day 7 after surgery (p < 0.05). The SBP and MAP at T2 to T5 were significantly higher in group R than in group P, the incidence of hypotension was significantly lower in group R (9.5%) than in group P (35.7%) (p = 0.004), and remimazolam significantly reduced the dose of phenylephrine used (p < 0.05). The PaO and OI at T4 were significantly higher in group R than in group P, and Qs/Qt was significantly lower in group R than in group P. The levels of S-100β at T5 were significantly lower in group R than in group P (p < 0.05).
CONCLUSION
The results showed that remimazolam (versus propofol) may lessen the degree of short-term postoperative cognitive dysfunction measured by standard neuropsychological tests, better optimize intraoperative hemodynamics, and lead to improved oxygenation during OLV.
Topics: Humans; Aged; Propofol; One-Lung Ventilation; Prospective Studies; S100 Calcium Binding Protein beta Subunit; Lung; Hemodynamics; Anesthesia, General; Cognition
PubMed: 37422336
DOI: 10.1053/j.jvca.2023.06.027 -
American Journal of Veterinary Research Nov 2023To elucidate the cardiovascular effects of escalating doses of phenylephrine and norepinephrine in dogs receiving acepromazine and isoflurane.
OBJECTIVE
To elucidate the cardiovascular effects of escalating doses of phenylephrine and norepinephrine in dogs receiving acepromazine and isoflurane.
ANIMALS
8 beagles aged 1 to 2 years (7.4 to 11.2 kg).
METHODS
All dogs received acepromazine 0.01 mg/kg, propofol 4 to 5 mg/kg, and isoflurane and were mechanically ventilated. Mean arterial pressure (MAP) from a femoral artery catheter and continuous electrocardiogram were recorded. Cardiac output (CO) was measured with transpulmonary thermodilution. Systemic vascular resistance (SVR), global end-diastolic volume (GEDV), and global ejection fraction (GEF) were subsequently calculated. Phenylephrine and norepinephrine were infused in random order at 0.07, 0.3, 0.7, and 1.0 μg/kg/min. All variables were measured after 15 minutes of each infusion rate. The effects of dose, agent, and their interaction on the change of each variable were evaluated with mixed-effect models. A P < .05 was used for significance.
RESULTS
Atrial premature complexes occurred in 3 dogs during norepinephrine infusion at doses of 0.3, 0.7, and 1 μg/kg/min; no dysrhythmias were seen with phenylephrine administration. MAP increased during dose escalation (P < .0001) within each agent and did not differ between agents (P = .6). The decrease in HR was greater for phenylephrine (P < .0001). Phenylephrine decreased CO and GEF and increased GEDV and SVR (all P < .03). Norepinephrine decreased the SVR and increased CO, GEDV, and GEF (all P < .03).
CLINICAL RELEVANCE
Our results confirm that phenylephrine increases arterial pressures mainly through vasoconstriction in acepromazine-premedicated dogs while norepinephrine, historically considered a vasopressor, does so primarily through an increase in inotropism.
Topics: Animals; Dogs; Acepromazine; Isoflurane; Norepinephrine; Phenylephrine; Blood Pressure
PubMed: 37657733
DOI: 10.2460/ajvr.23.06.0147 -
Journal of the American Heart... Sep 2023Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis...
Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation-induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA-seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine-treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B-dependent manner. Conclusions Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.
Topics: Mice; Animals; Rats; Proto-Oncogene Proteins c-akt; TNF Receptor-Associated Factor 4; Heart Failure; Phenylephrine; Cardiomegaly
PubMed: 37642020
DOI: 10.1161/JAHA.122.028185 -
Circulation Apr 2024Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce....
BACKGROUND
Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear.
METHODS
Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF.
RESULTS
METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury.
CONCLUSIONS
Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.
PubMed: 38686562
DOI: 10.1161/CIRCULATIONAHA.123.068358 -
The American Journal of Emergency... Dec 2023Hypotension is a common problem in the emergency department (ED) and intensive care unit (ICU) and can increase risk for poor outcomes. Many EDs/ICUs utilize epinephrine...
BACKGROUND
Hypotension is a common problem in the emergency department (ED) and intensive care unit (ICU) and can increase risk for poor outcomes. Many EDs/ICUs utilize epinephrine and phenylephrine to treat hypotension and these medications are most often administered as a continuous infusion (CI). Push-dose (PD) is the administration of small medication doses as intermittent intravenous pushes (IVPs). There is limited information comparing the time required to prepare and administer PD versus CI and errors have been reported when preparing and administering these medications at bedside. This simulation study sought to estimate preparation and administration times and preparation and errors with PD and CI epinephrine and phenylephrine when prepared by an ED/ICU pharmacist.
METHODS
This crossover simulation study took place in a simulation center at an academic medical center and utilized a multi-venous intravenous training arm kit equip with an 18-gauge intravenous line, an extension tubing set, and a luer-lock adapter. The primary outcome was total preparation and administration time in seconds. The secondary outcome was major preparation and administration errors, defined as errors causing a five-fold or greater overdose.
RESULTS
In total, 16 pharmacists participated, including nine ED and seven ICU pharmacists. PD had faster total preparation and administration time and administration time, but not preparation time; PD showed an approximate 70 s decrease in total preparation and administration time versus CI. PD had more major preparation and administration errors and six PD preparations (18.8%, 6/32) had at least one major preparation and administration error. CI, on the other hand, had no major preparation and administration errors.
DISCUSSION
This simulation found faster total preparation and administration time with PD versus CI epinephrine and phenylephrine, but also found that PD had more major preparation and administration errors. Dilutional errors during medication preparation were the cause of 83.3% (5/6) of our overdoses.
CONCLUSION
This simulation study showed that ED/ICU pharmacists had faster median total preparation and administration times for PD epinephrine and phenylephrine versus CI, but PD also had more preparation and administration errors.
Topics: Humans; Phenylephrine; Medication Errors; Epinephrine; Infusions, Intravenous; Hypotension
PubMed: 37832396
DOI: 10.1016/j.ajem.2023.10.002 -
Journal of Cellular and Molecular... Sep 2023Previous studies have reported that visfatin can regulate macrophage polarisation, which has been demonstrated to participate in cardiac remodelling. The aims of this...
Previous studies have reported that visfatin can regulate macrophage polarisation, which has been demonstrated to participate in cardiac remodelling. The aims of this study were to investigate whether visfatin participates in transverse aortic constriction (TAC)-induced cardiac remodelling by regulating macrophage polarisation. First, TAC surgery and angiotensin II (Ang II) infusion were used to establish a mouse cardiac remodelling model, visfatin expression was measured, and the results showed that TAC surgery or Ang II infusion increased visfatin expression in the serum and heart in mice, and phenylephrine or hydrogen peroxide promoted the release of visfatin from macrophages in vitro. All these effects were dose-dependently reduced by superoxide dismutase. Second, visfatin was administered to TAC mice to observe the effects of visfatin on cardiac remodelling. We found that visfatin increased the cross-sectional area of cardiomyocytes, aggravated cardiac fibrosis, exacerbated cardiac dysfunction, further regulated macrophage polarisation and aggravated oxidative stress in TAC mice. Finally, macrophages were depleted in TAC mice to investigate whether macrophages mediate the regulatory effect of visfatin on cardiac remodelling, and the results showed that the aggravating effects of visfatin on oxidative stress and cardiac remodelling were abrogated. Our study suggests that visfatin enhances cardiac remodelling by promoting macrophage polarisation and enhancing oxidative stress. Visfatin may be a potential target for the prevention and treatment of clinical cardiac remodelling.
Topics: Mice; Animals; Ventricular Remodeling; Nicotinamide Phosphoribosyltransferase; Constriction; Myocytes, Cardiac; Aortic Valve Stenosis; Macrophages; Oxidative Stress; Angiotensin II; Mice, Inbred C57BL; Fibrosis; Cardiomegaly
PubMed: 37584247
DOI: 10.1111/jcmm.17854 -
International Journal of Molecular... Sep 2023Our previous studies revealed the protection of stachydrine hydrochloride (STA) against cardiopathological remodeling. One of the underlying mechanisms involves the...
Our previous studies revealed the protection of stachydrine hydrochloride (STA) against cardiopathological remodeling. One of the underlying mechanisms involves the calcium/calmodulin-dependent protein kinase Ⅱ (CaMKII). However, the way STA influences CaMKII needs to be further investigated. The nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-coupled reactive oxygen species (ROS) overproduction putatively induces the oxidative activation of CaMKII, resulting in the occurrence of pathological cardiac remodeling and dysfunction in experimental models of mice. Thus, in this study, we assessed the role of the NOX2-ROS signal axis in STA cardioprotection. The transverse aortic constriction (TAC)-induced heart failure model of mice, the phenylephrine-induced hypertrophic model of neonatal rat primary cardiomyocytes, and the HO-induced oxidative stress models of adult mouse primary cardiomyocytes and H9c2 cells were employed. The echocardiography and histological staining were applied to assess the cardiac effect of STA (6 mg/kg/d or 12 mg/kg/d), which was given by gavage. NOX2, ROS, and excitation-contraction (EC) coupling were detected by Western blotting, immunofluorescence, and calcium transient-contraction synchronous recordings. ROS and ROS-dependent cardiac fibrosis were alleviated in STA-treated TAC mice, demonstrating improved left ventricular ejection fraction and hypertrophy. In the heart failure model of mice and the hypertrophic model of cardiomyocytes, STA depressed NOX2 protein expression and activation, as shown by inhibited translocation of its phosphorylation, p67phox and p47phox, from the cytoplasm to the cell membrane. Furthermore, in cardiomyocytes under oxidative stress, STA suppressed NOX2-related cytosolic Ca overload, enhanced cell contractility, and decreased Ca-dependent regulatory protein expression, including CaMKⅡ and Ryanodine receptor calcium release channels. Cardioprotection of STA against pressure overload-induced pathological cardiac remodeling correlates with the NOX2-coupled ROS signaling cascade.
Topics: Animals; Rats; Reactive Oxygen Species; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Hydrogen Peroxide; Stroke Volume; Ventricular Remodeling; Ventricular Function, Left; Heart Failure; Hypertrophy; Myocytes, Cardiac; Aortic Valve Stenosis; Calcium, Dietary
PubMed: 37762672
DOI: 10.3390/ijms241814369 -
Biochemical Pharmacology Feb 2024Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II... (Review)
Review
Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II (Ang II), although the renin-angiotensin-aldosterone system (RAAS) is upregulated. Preeclampsia (PE) is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg), and dysregulation of angiotensin biosynthesis and signaling have been implicated. Ang II activates vascular Ang II type-1 receptor (ATR) and Ang II type-2 receptor (ATR), while angiotensin-(1-7) promotes Ang-(1-7)/MasR signaling. The role of ATR in vasoconstriction and the activated cellular mechanisms are well-characterized. The sensitivity of vascular ATR to Ang II and consequent activation of vasoconstrictor mechanisms decrease during Norm-Preg, but dramatically increase in HTN-Preg. Placental ischemia in late pregnancy could also initiate the release of ATR agonistic autoantibodies (ATAA) with significant impact on endothelial dysfunction and activation of contraction pathways in vascular smooth muscle including [Ca] and protein kinase C. On the other hand, the role of ATR and Ang-(1-7)/MasR in vascular relaxation, particularly during Norm-Preg and PE, is less clear. During Norm-Preg, increases in the expression/activity of vascular ATR and Ang-(1-7)/MasR promote the production of endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor leading to generalized vasodilation. Aortic segments of Preg rats show prominent endothelial ATR staining and increased relaxation and NO production in response to ATR agonist CGP42112A, and treatment with ATR antagonist PD123319 enhances phenylephrine-induced contraction. Decreased vascular ATR and Ang-(1-7)/MasR expression and receptor-mediated mechanisms of vascular relaxation have been suggested in HTN-Preg animal models, but their role in human PE needs further testing. Changes in angiotensin-converting enzyme-2 (ACE2) have been observed in COVID-19 patients, and whether ACE2 influences the course of COVID-19 viral infection/immunity in Norm-Preg and PE is an intriguing area for research.
Topics: Animals; Female; Humans; Pregnancy; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Biological Factors; COVID-19; Hypertension; Peptide Fragments; Placenta; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Vasoconstrictor Agents
PubMed: 38061417
DOI: 10.1016/j.bcp.2023.115963 -
European Journal of Pharmacology Jul 2023A role for mitochondrial fission in vascular contraction has been proposed based on the vasorelaxant activity of the dynamin (and mitochondrial fission) inhibitors...
A role for mitochondrial fission in vascular contraction has been proposed based on the vasorelaxant activity of the dynamin (and mitochondrial fission) inhibitors mdivi-1 and dynasore. However, mdivi-1 is capable to inhibit Ba currents through Ca1.2 channels (I), stimulate K1.1 channel currents (I), and modulate pathways key to the maintenance of vessel active tone in a dynamin-independent manner. Using a multidisciplinary approach, the present study demonstrates that dynasore, like mdivi-1, is a bi-functional vasodilator, blocking I and stimulating I in rat tail artery myocytes, as well as promoting relaxation of rat aorta rings pre-contracted by either high K or phenylephrine. Conversely, its analogue dyngo-4a, though inhibiting mitochondrial fission triggered by phenylephrine and stimulating I, did not affect I but potentiated both high K- and phenylephrine-induced contractions. Docking and molecular dynamics simulations identified the molecular basis supporting the different activity of dynasore and dyngo-4a at Ca1.2 and K1.1 channels. Mito-tempol only partially counteracted the effects of dynasore and dyngo-4a on phenylephrine-induced tone. In conclusion, the present data, along with previous observations (Ahmed et al., 2022) rise caution for the use of dynasore, mdivi-1, and dyngo-4a as tools to investigate the role of mitochondrial fission in vascular contraction: to this end, a selective dynamin inhibitor and/or a different experimental approach are needed.
Topics: Rats; Animals; Mitochondrial Dynamics; Dynamins; Niacinamide; Phenylephrine
PubMed: 37179045
DOI: 10.1016/j.ejphar.2023.175786