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Pharmacotherapy Apr 2023Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk... (Review)
Review
Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline.
Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk factors. Although peripheral administration of vesicants may increase the risk of extravasation injuries, the time and resources required for central venous catheter placement may delay administration of time-sensitive therapies. Recent literature gathered from the growing use of peripheral vasopressors and hypertonic sodium suggests low risk of harm for initiating these emergent therapies peripherally, which may prevent delays and improve patient outcomes. Physiochemical causes of tissue injury include vasoconstriction, pH-mediated, osmolar-mediated, and cytotoxic mechanisms of extravasation injuries. Acidic agents, such as promethazine, amiodarone, and vancomycin, may cause edema, sloughing, and necrosis secondary to cellular desiccation. Alternatively, basic agents, such as phenytoin and acyclovir, may be more caustic due to deeper tissue penetration of the dissociated hydroxide ions. Osmotically active agents cause cellular damage as a result of osmotic shifts across cellular membranes in addition to agent-specific toxicities, such as calcium-induced vasoconstriction and calcifications or arginine-induced leakage of potassium causing apoptosis. A new category has been proposed to identify absorption-refractory mechanisms of injury in which agents such as propofol and lipids may persist in the extravasated space and cause necrosis or compartment syndrome. Pharmacological antidotes may be useful in select extravasations but requires prompt recognition and frequently complex administration strategies. Historically, intradermal phentolamine has been the preferred agent for vasopressor extravasations, but frequent supply shortages have led to the emergence of terbutaline, a β -agonist, as an acceptable alternative treatment option. For hyperosmolar and pH-related mechanisms of injuries, hyaluronidase is most commonly used to facilitate absorption and dispersion of injected agents. However, extravasation management is largely supportive and requires a protocolized multidisciplinary approach for early detection, treatment, and timely surgical referral when required to minimize adverse events.
Topics: Vasoconstrictor Agents; Saline Solution, Hypertonic; Extravasation of Diagnostic and Therapeutic Materials; Risk Factors; Drug-Related Side Effects and Adverse Reactions; Vasoconstriction; Humans
PubMed: 36938775
DOI: 10.1002/phar.2794 -
Frontiers in Veterinary Science 2021Fluid overload (FO) is characterized by hypervolemia, edema, or both. In clinical practice it is usually suspected when a patient shows evidence of pulmonary edema,... (Review)
Review
Fluid overload (FO) is characterized by hypervolemia, edema, or both. In clinical practice it is usually suspected when a patient shows evidence of pulmonary edema, peripheral edema, or body cavity effusion. FO may be a consequence of spontaneous disease, or may be a complication of intravenous fluid therapy. Most clinical studies of the association of FO with fluid therapy and risk of harm define it in terms of an increase in body weight of at least 5-10%, or a positive fluid balance of the same magnitude when fluid intake and urine output are measured. Numerous observational clinical studies in humans have demonstrated an association between FO, adverse events, and mortality, as have two retrospective observational studies in dogs and cats. The risk of FO may be minimized by limiting resuscitation fluid to the smallest amount needed to optimize cardiac output and then limiting maintenance fluid to the amount needed to replace ongoing normal and pathological losses of water and sodium.
PubMed: 34268347
DOI: 10.3389/fvets.2021.668688 -
American Family Physician Nov 2022Edema is a common clinical sign that may indicate numerous pathologies. As a sequela of imbalanced capillary hemodynamics, edema is an accumulation of fluid in the...
Edema is a common clinical sign that may indicate numerous pathologies. As a sequela of imbalanced capillary hemodynamics, edema is an accumulation of fluid in the interstitial compartment. The chronicity and laterality of the edema guide evaluation. Medications (e.g., antihypertensives, anti-inflammatory drugs, hormones) can contribute to edema. Evaluation should begin with obtaining a basic metabolic panel, liver function tests, thyroid function testing, brain natriuretic peptide levels, and a urine protein/creatinine ratio. Validated decision rules, such as the Wells and STOP-Bang (snoring, tired, observed, pressure, body mass index, age, neck size, gender) criteria, can guide decision-making regarding the possibility of venous thromboembolic disease and obstructive sleep apnea, respectively. Acute unilateral lower-extremity edema warrants immediate evaluation for deep venous thrombosis with a d-dimer test or compression ultrasonography. For patients with chronic bilateral lower-extremity edema, duplex ultrasonography with reflux can help diagnose chronic venous insufficiency. Patients with pulmonary edema or elevated brain natriuretic peptide levels should undergo echocardiography to assess for heart failure. Lymphedema is often a clinical diagnosis; lymphoscintigraphy can be performed if the diagnosis is unclear. Treatment of edema is specific to the etiology. Diuretics are effective but should be used only for systemic causes of edema. Ruscus extract and horse chestnut seed demonstrate moderate-quality evidence to improve edema from chronic venous insufficiency. Compression therapy is effective for most causes of edema.
Topics: Humans; Natriuretic Peptide, Brain; Edema; Venous Insufficiency; Lymphedema; Primary Health Care
PubMed: 36379502
DOI: No ID Found -
The New England Journal of Medicine Sep 2020Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective...
BACKGROUND
Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.
METHODS
We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.
RESULTS
A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.
CONCLUSIONS
Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Edema; Exons; Female; Gene Dosage; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Nausea; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Triazines
PubMed: 32877583
DOI: 10.1056/NEJMoa2002787 -
Frontiers in Cardiovascular Medicine 2022Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced... (Review)
Review
Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.
PubMed: 36237903
DOI: 10.3389/fcvm.2022.933215 -
Advances in Kidney Disease and Health Mar 2023The development of peripheral edema can often pose a significant diagnostic and therapeutic challenge for practitioners due to its association with a wide variety of... (Review)
Review
The development of peripheral edema can often pose a significant diagnostic and therapeutic challenge for practitioners due to its association with a wide variety of underlying disorders ranging in severity. Updates to the original Starling's principle have provided new mechanistic insights into edema formation. Additionally, contemporary data highlighting the role of hypochloremia in the development of diuretic resistance provide a possible new therapeutic target. This article reviews the pathophysiology of edema formation and discusses implications for treatment.
Topics: Humans; Causality; Acid-Base Imbalance; Diuretics; Edema
PubMed: 36868727
DOI: 10.1053/j.akdh.2022.12.002 -
Critical Care (London, England) May 2023Fluid normally exchanges freely between the plasma and interstitial space and is returned primarily via the lymphatic system. This balance can be disturbed by diseases... (Review)
Review
Fluid normally exchanges freely between the plasma and interstitial space and is returned primarily via the lymphatic system. This balance can be disturbed by diseases and medications. In inflammatory disease states, such as sepsis, the return flow of fluid from the interstitial space to the plasma seems to be very slow, which promotes the well-known triad of hypovolemia, hypoalbuminemia, and peripheral edema. Similarly, general anesthesia, for example, even without mechanical ventilation, increases accumulation of infused crystalloid fluid in a slowly equilibrating fraction of the extravascular compartment. Herein, we have combined data from fluid kinetic trials with previously unconnected mechanisms of inflammation, interstitial fluid physiology and lymphatic pathology to synthesize a novel explanation for common and clinically relevant examples of circulatory dysregulation. Experimental studies suggest that two key mechanisms contribute to the combination of hypovolemia, hypoalbuminemia and edema; (1) acute lowering of the interstitial pressure by inflammatory mediators such as TNFα, IL-1β, and IL-6 and, (2) nitric oxide-induced inhibition of intrinsic lymphatic pumping.
Topics: Humans; Hypovolemia; Hypoalbuminemia; Edema; Respiration, Artificial; Crystalloid Solutions
PubMed: 37245039
DOI: 10.1186/s13054-023-04496-5 -
The New England Journal of Medicine Sep 2020A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC)....
BACKGROUND
A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.
METHODS
In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.
RESULTS
As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.
CONCLUSIONS
Among patients with advanced NSCLC with a confirmed exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Edema; Exons; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines
PubMed: 32469185
DOI: 10.1056/NEJMoa2004407 -
British Journal of Clinical Pharmacology Aug 2021Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca... (Review)
Review
Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.
Topics: Edema; Heart Failure; Humans; Lymphedema; Pharmaceutical Preparations; Vasodilation
PubMed: 33506982
DOI: 10.1111/bcp.14752