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The Journal of Clinical Endocrinology... Jul 2020Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
OBJECTIVE
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
DESIGN
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898).
SETTING
Multicenter study including 9 centers in The Netherlands.
PATIENTS
134 patients with nonmetastatic PPGL.
INTERVENTION
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
MAIN OUTCOME MEASURES
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
RESULTS
Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
CONCLUSIONS
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Blood Pressure; Doxazosin; Female; Humans; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Treatment Outcome
PubMed: 31714582
DOI: 10.1210/clinem/dgz188 -
European Journal of Translational... Jan 2022This article was not intended to be a complete review of the electromyography of pathological muscle states, but it was written to illustrate how the "Coletti Method of...
This article was not intended to be a complete review of the electromyography of pathological muscle states, but it was written to illustrate how the "Coletti Method of EMG ChemoDenervation" (CMECD®) protocol for the treatment of chronic pain resulting from chronic muscle spasm was developed and established. That process led to an unexpected understanding of the underlying pathophysiology of chronic muscle spasm, which represents a paradigm shift in our understanding and ultimately in our treatment of muscle spasm-induced chronic pain. Other investigators had brought to light the presence of spontaneous electrical activity (SEA) in states of muscle spasm. Those findings were all but ignored by standard EMG/Nerve conduction studies in clinical practice. Starting with a simple EMG device I experimented with various medications to treat patients with chronic pain associated with chronic muscle spasm. Suppression of SEA with long-acting medications resolved both the chronic spasm and chronic pain. A successful protocol using phenoxybenzamine was established and clinical outcomes were followed. More than 200 patients were successfully treated during last 12 years. Correlating known exercise muscle physiology with the development of the pathological state of chronic muscle spasm as seen by electromyography led to the postulation of the ischemic model of chronic muscle spasm. Light microscopy pathophysiologic supportive findings are presented and discussed. Predictions from this model to various aspects of treatment were supportive. Implications regarding treatment by the CMECD procedure, as well as other standard therapies, are discussed. Application of the ischemic model to other pain conditions was explored with implications of therapeutic modification. Recommendations for changes in rehabilitation therapy are discussed.
PubMed: 35044134
DOI: 10.4081/ejtm.2022.10323 -
Cureus Nov 2022Pheochromocytomas are rare tumors located in the adrenal medulla, that derives from the chromaffin cells and produce catecholamines. They are an uncommon cause of...
Pheochromocytomas are rare tumors located in the adrenal medulla, that derives from the chromaffin cells and produce catecholamines. They are an uncommon cause of hypertension, and only 50% of the patients present symptoms compatible with this pathology. Here we describe the case of a 70-year-old woman with a history of anxiety, hypertension and palpitation, who had an unspecified nodule in the right adrenal gland. Laboratory studies revealed an elevated urinary metanephrines secretion. A diagnosis of pheochromocytoma was made and an adrenalectomy was performed. Our aim is to highlight the diagnosis of this rare tumor and how its early management can prevent morbidity and mortality.
PubMed: 36523722
DOI: 10.7759/cureus.31409 -
Frontiers in Pediatrics 2017Pheochromocytoma (PCC) and paraganglioma (PGL) are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors.... (Review)
Review
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors. Although a rare cause of secondary hypertension in pediatrics, the presentation of hypertension in these patients is characteristic, and treatment is definitive. The gold standard for diagnosis is measurement of plasma free metanephrines, with imaging studies performed for localization, identification of metastatic lesions and for surgical resection. Preoperative therapy with alpha-blocking agents, beta blockers, and potentially tyrosine hydroxylase inhibitors aid in a safe pre-, intra- and postoperative course. PCC and PGL are inherited in as much as 80% of pediatric cases, and all patients with mutations should be followed closely given the risk of recurrence and malignancy. While the presentation of chromaffin cell tumors has been well described with multiple endocrine neoplasia, NF1, and Von Hippel-Lindau syndromes, the identification of new gene mutations leading to chromaffin cell tumors at a young age is changing the landscape of how clinicians approach such cases. The paraganglioma-pheochromocytoma syndromes (SDHx) comprise familial gene mutations, of which the SDHB gene mutation carries a high rate of malignancy. Since the inheritance rate of such tumors is higher than previously described, genetic screening is recommended in all patients, and lifelong follow-up for recurrent tumors is a must. A multidisciplinary team approach allows for optimal health-care delivery in such children. This review serves to provide an overview of pediatric PCC and PGL, including updates on the preferred methods of imaging, guidelines on gene testing as well as management of hypertension in such patients.
PubMed: 28752085
DOI: 10.3389/fped.2017.00155 -
Journal of Neuroengineering and... May 2018Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural...
BACKGROUND
Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural pathways of electrical vasoconstriction in-vivo.
METHODS
Charge-balanced, asymmetric pulses were delivered through a pair of metal disc electrodes. Vasoconstriction was assessed by measuring the diameter of rat saphenous vessels stimulated with low-voltage (20 V, 1 ms) and high-voltage (150 V, 10 μs) stimuli at 10 Hz for 5 min. Activation pathways were explored by topical application of a specific neural agonist (phenylephrine, alpha-1 receptor), a non-specific agonist (KCl) and neural inhibitors (phenoxybenzamine, 25 mg/ml; guanethidine, 1 mg/ml). Acute tissue damage was assessed with a membrane permeability (live-dead) fluorescent assay. The Joule heating in tissue was estimated using COMSOL Multiphysics modeling.
RESULTS
During stimulation, arteries constricted to 41 ± 8% and 37 ± 6% of their pre-stimulus diameter with low- and high-voltage stimuli, while veins constricted to 80 ± 18% and 40 ± 11%, respectively. In arteries, despite similar extent of constriction, the recovery time was very different: about 30 s for low-voltage and 10 min for high-voltage stimuli. Neural inhibitors significantly reduced low-voltage arterial constriction, but did not affect high-voltage arterial or venous constriction, indicating that high-voltage stimuli activate non-neural vasoconstriction pathways. Adrenergic pathways predominantly controlled low-voltage arterial but not venous constriction, which may involve a purinergic pathway. Viability staining confirmed that stimuli were below the electroporation threshold. Modeling indicates that heating of the blood vessels during stimulation (< 0.2 °C) is too low to cause vasoconstriction.
CONCLUSIONS
We demonstrate that low-voltage stimuli induce reversible vasoconstriction through neural pathways, while high-voltage stimuli activate non-neural pathways, likely in addition to neural stimulation. Different stimuli providing precise control over the extent of arterial and venous constriction as well as relaxation rate could be used to control bleeding, perfusion or blood pressure.
Topics: Animals; Electric Stimulation; Male; Rats; Rats, Long-Evans; Saphenous Vein; Vasoconstriction
PubMed: 29843762
DOI: 10.1186/s12984-018-0390-y -
Endocrine Practice : Official Journal... Sep 2022Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive...
OBJECTIVE
Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine.
METHODS
We conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs.
RESULTS
Twenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin.
CONCLUSION
Phenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.
Topics: Adrenal Gland Neoplasms; Adrenergic alpha-Antagonists; Case-Control Studies; Doxazosin; Humans; Phenoxybenzamine; Phenylephrine; Pheochromocytoma; Prospective Studies
PubMed: 35809774
DOI: 10.1016/j.eprac.2022.06.013 -
Frontiers in Endocrinology 2023Resection of pheochromocytoma and paraganglioma (PPGL) carries risks with perioperative hemodynamic instability. Phenoxybenzamine (PXB) is a commonly used α-blockade to...
Influence of duration of preoperative treatment with phenoxybenzamine and secretory phenotypes on perioperative hemodynamics and postoperative outcomes in pheochromocytoma and paraganglioma.
OBJECTIVES
Resection of pheochromocytoma and paraganglioma (PPGL) carries risks with perioperative hemodynamic instability. Phenoxybenzamine (PXB) is a commonly used α-blockade to prevent it. It is unclear whether lengthening the preoperative duration of PXB is better for hemodynamic stability and postoperative outcomes. Furthermore, different types of catecholamines have varying effects on perioperative hemodynamics. Thus, our study aimed to investigate the impact of the duration of preoperative preparation with PXB and secretory phenotypes of the patients on intraoperative hemodynamic stability and postoperative complications in PPGL.
METHODS
Between Dec 2014 and Jan 2022, 166 patients with PPGL were operated on by the same team at Sun Yat-sen Memorial Hospital. They were divided into group A(1-14d), Group B(15-21d), and Group C(>21d) based on the duration of management with PXB and into the adrenergic and the noradrenergic phenotype group based on secretory profiles. Data on intraoperative hemodynamics and postoperative outcomes were collected and compared among groups.
RESULTS
A total of 96 patients occurred intraoperative hemodynamic instability, and 24 patients had 29 postoperative complications related to the surgery. Among the 145 patients treated with PXB, no significant differences were found in the cumulative time outside the target blood pressure(6.67%[0-17.16%] 5.97%[0-23.08%] 1.22%[0-17.27%], =0.736) or in the median total HI-score(42.00[30.00-91.00] 89.00[30.00-113.00] 49.00[30.00-93.00], =0.150) among group A(n=45), B(n=51) and C(n=49). Multivariate analysis demonstrated that the level of plasma-free metanephrine(MN) was an independent risk factor for intraoperative hemodynamic instability. And the median cumulative time outside of the target blood pressure in the adrenergic phenotype group was significantly greater than that in the noradrenergic phenotype group(8.17%[0-26.22%] 1.86%[0-11.74%], =0.029). However, the median total HI-score(99.50[85.00-113.25] 90.00[78.00-105.00], =0.570) and postoperative outcomes showed no differences between the two groups.
CONCLUSIONS
A preoperative duration of nearly 14 days with PXB is sufficient for ensuring intraoperative hemodynamic stability in PPGL. And lengthening the preparation duration may not provide additional benefits in the era of widespread application and advanced techniques of laparoscopic surgery. Additionally, patients with the adrenergic phenotype are more prone to intraoperative hemodynamic instability than the noradrenergic phenotype. Thus, more attention should be given to the adrenergic phenotype during surgery.
Topics: Humans; Phenoxybenzamine; Pheochromocytoma; Paraganglioma; Hemodynamics; Metanephrine; Postoperative Complications; Norepinephrine; Adrenal Gland Neoplasms; Adrenergic Agents
PubMed: 37152936
DOI: 10.3389/fendo.2023.1139015 -
Scientific Reports May 2022Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for...
Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for LUAD. To analyze the differences in tumor immune microenvironment between distinct risk groups of LUAD based on the model classification. The CMap database was also used to screen potential therapeutic compounds for LUAD based on the differential genes between distinct risk groups. he data from the Cancer Genome Atlas (TCGA) database. We divided the transcriptome data into a mRNA subset and a lncRNA subset, and use multiple methods to extract mRNAs and lncRNAs associated with immunity and prognosis. We further integrated the mRNA and lncRNA subsets and the corresponding clinical information, randomly divided them into training and test set according to the ratio of 5:5. Then, we performed the Cox risk proportional analysis and cross-validation on the training set to construct a LUAD risk scoring model. Based on the risk scoring model, patients were divided into distinct risk group. Moreover, we evaluate the prognostic performance of the model from the aspects of Area Under Curve (AUC) analysis, survival difference analysis, and independent prognostic analysis. We analyzed the differences in the expression of immune cells between the distinct risk groups, and also discuss the connection between immune cells and patient survival. Finally, we screened the potential therapeutic compounds of LUAD in the Connectivity Map (CMap) database based on differential gene expression profiles, and verified the compound activity by cytostatic assays. We extracted 26 mRNAs and 74 lncRNAs related to prognosis and immunity by using different screening methods. Two mRNAs (i.e., KLRC3 and RAET1E) and two lncRNAs (i.e., AL590226.1 and LINC00941) and their risk coefficients were finally used to construct the PRS-model. The risk score positions of the training and test set were 1.01056590 and 1.00925190, respectively. The expression of mRNAs involved in model construction differed significantly between the distinct risk population. The one-year ROC areas on the training and test sets were 0.735 and 0.681. There was a significant difference in the survival rate of the two groups of patients. The PRS-model had independent predictive capabilities in both training and test sets. Among them, in the group with low expression of M1 macrophages and resting NK cells, LUAD patients survived longer. In contrast, the monocyte expression up-regulated group survived longer. In the CMap drug screening, three LUAD therapeutic compounds, such as resveratrol, methotrexate, and phenoxybenzamine, scored the highest. In addition, these compounds had significant inhibitory effects on the LUAD A549 cell lines. The LUAD risk score model constructed using the expression of KLRC3, RAET1E, AL590226.1, LINC00941 and their risk coefficients had a good independent prognostic power. The optimal LUAD therapeutic compounds screened in the CMap database: resveratrol, methotrexate and phenoxybenzamine, all showed significant inhibitory effects on LUAD A549 cell lines.
Topics: Adenocarcinoma; Carrier Proteins; Histocompatibility Antigens Class I; Humans; Lung; Lung Neoplasms; Male; Membrane Proteins; Methotrexate; Phenoxybenzamine; RNA, Long Noncoding; RNA, Messenger; Resveratrol; Tumor Microenvironment
PubMed: 35504892
DOI: 10.1038/s41598-022-11052-8