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Chest Nov 2023This review discusses the rationale for vasopressin use, summarizes the results of clinical trials evaluating vasopressin, and focuses on the timing of vasopressin... (Review)
Review
TOPIC IMPORTANCE
This review discusses the rationale for vasopressin use, summarizes the results of clinical trials evaluating vasopressin, and focuses on the timing of vasopressin initiation to provide clinicians guidance for optimal adjunctive vasopressin initiation in patients with septic shock.
REVIEW FINDINGS
Patients with septic shock require vasoactive agents to restore adequate tissue perfusion. After norepinephrine, vasopressin is the suggested second-line adjunctive agent in patients with persistent inadequate mean arterial pressure. Vasopressin use in practice is heterogeneous likely because of inconsistent clinical trial findings, the lack of specific recommendations for when it should be used, and the high drug acquisition cost. Despite these limitations, vasopressin has demonstrated price inelastic demand, and its use in the United States has continued to increase. However, questions remain regarding optimal vasopressin use in patients with septic shock, particularly regarding patient selection and the timing of vasopressin initiation.
SUMMARY
Experimental studies evaluating the initiation timing of vasopressin in patients with septic shock are limited, and recent observational studies have revealed an association between vasopressin initiation at lower norepinephrine-equivalent doses or lower lactate concentrations and lower mortality.
Topics: Humans; United States; Vasoconstrictor Agents; Shock, Septic; Vasopressins; Norepinephrine; Arterial Pressure
PubMed: 37479058
DOI: 10.1016/j.chest.2023.07.009 -
Gastroenterology Jan 2024Cirrhosis is a major cause of morbidity and mortality in the United States and worldwide. It consists of compensated, decompensated, and further decompensated stages;... (Review)
Review
DESCRIPTION
Cirrhosis is a major cause of morbidity and mortality in the United States and worldwide. It consists of compensated, decompensated, and further decompensated stages; median survival is more than 15 years, 2 years, and 9 months for each stage, respectively. With each stage, there is progressive worsening of portal hypertension and the vasodilatory-hyperdynamic circulatory state, resulting in a progressive decrease in effective arterial blood volume and renal perfusion. Vasoconstrictors reduce portal pressure via splanchnic vasoconstriction and are used in the management of variceal hemorrhage. Intravenous (IV) albumin increases effective arterial blood volume and is used in the prevention of acute kidney injury (AKI) and death after large-volume paracentesis and in patients with spontaneous bacterial peritonitis (SBP). The combination of vasoconstrictors and albumin is used in the reversal of hepatorenal syndrome (HRS-AKI), the most lethal complication of cirrhosis. Because a potent vasoconstrictor, terlipressin, was recently approved by the US Food and Drug Administration, and because recent trials have explored use of IV albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and IV albumin in the following 3 specific scenarios: variceal hemorrhage, ascites and SBP, and HRS.
METHODS
This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. It underwent internal peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Some of the statements are unchanged from published guidelines because of lack of new evidence in the literature. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality and evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Vasoactive drugs should be initiated as soon as the diagnosis of variceal hemorrhage is suspected or confirmed, preferably before diagnostic and/or therapeutic endoscopy. BEST PRACTICE ADVICE 2: After initial endoscopic hemostasis, vasoactive drugs should be continued for 2-5 days to prevent early rebleeding. BEST PRACTICE ADVICE 3: Octreotide is the vasoactive drug of choice in the management of variceal hemorrhage based on its safety profile. BEST PRACTICE ADVICE 4: IV albumin should be administered at the time of large-volume (>5 L) paracentesis. BEST PRACTICE ADVICE 5: IV albumin may be considered in patients with SBP. BEST PRACTICE ADVICE 6: Albumin should not be used in patients (hospitalized or not) with cirrhosis and uncomplicated ascites. BEST PRACTICE ADVICE 7: Vasoconstrictors should not be used in the management of uncomplicated ascites, after large-volume paracentesis or in patients with SBP. BEST PRACTICE ADVICE 8: IV albumin is the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with AKI. BEST PRACTICE ADVICE 9: Vasoactive drugs (eg, terlipressin, norepinephrine, and combination of octreotide and midodrine) should be used in the treatment of HRS-AKI, but not in other forms of AKI in cirrhosis. BEST PRACTICE ADVICE 10: Terlipressin is the vasoactive drug of choice in the treatment of HRS-AKI and use of concurrent albumin can be considered when accounting for patient's volume status. BEST PRACTICE ADVICE 11: Terlipressin treatment does not require intensive care unit monitoring and can be administered intravenously through a peripheral line. BEST PRACTICE ADVICE 12: Terlipressin use is contraindicated in patients with hypoxemia and in patients with ongoing coronary, peripheral, or mesenteric ischemia, and should be used with caution in patients with acute-on-chronic liver failure grade 3. The benefits may not outweigh the risks in patients with serum creatinine >5 mg/dL and in patients listed for transplantation with a Model for End-stage Liver Disease ≥35.
Topics: Humans; Terlipressin; Pharmaceutical Preparations; Octreotide; Esophageal and Gastric Varices; Ascites; End Stage Liver Disease; Gastrointestinal Hemorrhage; Severity of Illness Index; Vasoconstrictor Agents; Liver Cirrhosis; Hepatorenal Syndrome; Acute Kidney Injury; Albumins
PubMed: 37978969
DOI: 10.1053/j.gastro.2023.10.016 -
Pediatrics Jan 2024Sepsis and septic shock are major causes of morbidity, mortality, and health care costs for children worldwide, including >3 million deaths annually and, among...
Sepsis and septic shock are major causes of morbidity, mortality, and health care costs for children worldwide, including >3 million deaths annually and, among survivors, risk for new or worsening functional impairments, including reduced quality of life, new respiratory, nutritional, or technological assistance, and recurrent severe infections. Advances in understanding sepsis pathophysiology highlight a need to update the definition and diagnostic criteria for pediatric sepsis and septic shock, whereas new data support an increasing role for automated screening algorithms and biomarker combinations to assist earlier recognition. Once sepsis or septic shock is suspected, attention to prompt initiation of broad-spectrum empiric antimicrobial therapy, fluid resuscitation, and vasoactive medications remain key components to initial management with several new and ongoing studies offering new insights into how to optimize this approach. Ultimately, a key goal is for screening to encompass as many children as possible at risk for sepsis and trigger early treatment without increasing unnecessary broad-spectrum antibiotics and preventable hospitalizations. Although the role for adjunctive treatment with corticosteroids and other metabolic therapies remains incompletely defined, ongoing studies will soon offer updated guidance for optimal use. Finally, we are increasingly moving toward an era in which precision therapeutics will bring novel strategies to improve outcomes, especially for the subset of children with sepsis-induced multiple organ dysfunction syndrome and sepsis subphenotypes for whom antibiotics, fluid, vasoactive medications, and supportive care remain insufficient.
Topics: Child; Humans; Shock, Septic; Quality of Life; Sepsis; Anti-Bacterial Agents; Phenotype
PubMed: 38084084
DOI: 10.1542/peds.2023-062967 -
Archives of Disease in Childhood. Fetal... Feb 2024The management of low blood flow states in premature neonates is fraught with many challenges. We remain over-reliant on regimented stepwise protocols that use mean... (Review)
Review
The management of low blood flow states in premature neonates is fraught with many challenges. We remain over-reliant on regimented stepwise protocols that use mean blood pressure as a threshold for intervention to guide treatment, without giving due consideration to the underlying pathophysiology. The current available evidence does not reflect the need to concentrate on the unique pathophysiology of the preterm infant and thus leads to widespread misuse of vasoactive agents that often do not provide the desired clinical effect. Therefore, understanding the underlying pathophysiological underpinnings of haemodynamic compromise may better guide choice of agent and assess physiological response to the selected intervention.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Hypotension; Hemodynamics; Infant, Newborn, Diseases; Intensive Care Units, Neonatal
PubMed: 37173119
DOI: 10.1136/archdischild-2022-324935 -
Nature Communications Jul 2023Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis...
Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.
Topics: Animals; Mice; Humans; Neurogenic Inflammation; Whole Genome Sequencing; Mutation; Genetic Predisposition to Disease; Rosacea; Nerve Tissue Proteins
PubMed: 37402769
DOI: 10.1038/s41467-023-39761-2 -
Shock (Augusta, Ga.) Dec 2023Background: Septic shock is a distributive shock with decreased systemic vascular resistance and MAP. Septic shock contributes to the most common causes of death in the... (Meta-Analysis)
Meta-Analysis
Background: Septic shock is a distributive shock with decreased systemic vascular resistance and MAP. Septic shock contributes to the most common causes of death in the intensive care unit (ICU). Current guidelines recommend the use of norepinephrine as the first-line vasopressor, whereas adrenergic agonists and vasopressin analogs are also commonly used by physicians. To date, very few studies have synthetically compared the effects of multiple types of vasoactive medications. The aim of this study was to systemically evaluate the efficacy of vasoactive agents both individually and in combination to treat septic shock. Methods: The PubMed, MEDLINE, Embase, Web of Science, and Cochrane Central Register for Controlled Trials (CENTRAL) were searched up to May 12, 2022, to identify relevant randomized controlled trials. A network meta-analysis was performed to evaluate the effect of different types of vasopressors. The primary outcome was 28-day all-cause mortality. The secondary outcome was the ICU length of stay. Adverse events are defined as any undesirable outcomes, including myocardial infarction, cardiac arrhythmia, peripheral ischemia, or stroke and cerebrovascular events. Findings: Thirty-three randomized controlled trials comprising 4,966 patients and assessing 8 types of vasoactive treatments were included in the network meta-analysis. The surface under the cumulative ranking curve provided a ranking of vasoactive medications in terms of 28-day all-cause mortality from most effective to least effective: norepinephrine plus dobutamine, epinephrine, vasopressin, terlipressin, norepinephrine, norepinephrine plus vasopressin, dopamine, and dobutamine. Dopamine was associated with a significantly shorter ICU stay than norepinephrine, terlipressin, and vasopressin, whereas other vasoactive medications showed no definite difference in ICU length of stay. Regarding adverse events, norepinephrine was associated with the highest incidences of myocardial infarction and peripheral ischemia. Dopamine was associated with the highest incidence of cardiac arrhythmia. Epinephrine and terlipressin were associated with the highest incidences of myocardial infarction and peripheral ischemia. Interpretation: The results of this network meta-analysis suggest that norepinephrine plus dobutamine is associated with a lower risk of 28-day mortality in septic shock patients than other vasoactive medications, and the use of dopamine is associated with a higher risk of 28-day mortality due to septic shock than norepinephrine, terlipressin, and vasopressin.
Topics: Humans; Shock, Septic; Dopamine; Terlipressin; Dobutamine; Network Meta-Analysis; Vasoconstrictor Agents; Epinephrine; Norepinephrine; Vasopressins; Arrhythmias, Cardiac; Ischemia; Myocardial Infarction
PubMed: 37548686
DOI: 10.1097/SHK.0000000000002193 -
The Journal of Clinical Investigation Jul 2023Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that...
Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
Topics: Humans; Mice; Animals; Acriflavine; Diabetes Mellitus, Experimental; Retina; Retinal Neovascularization; Diabetic Retinopathy; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37227777
DOI: 10.1172/JCI163290