Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.

Oral adrenergic agents produced Ventricular fibrillation and QT prolongation in an elderly patient carrying an RYR2 variant.

Mutant cardiac ryanodine receptor channels (RyR2) are “leaky,” and spontaneous Ca2+ release through these channels causes delayed afterdepolarizations that can deteriorate into ventricular fibrillation (VF). RYR2 is a causative gene of type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT). Some patients carrying RYR2 mutations in CPVT exhibit QT prolongation and are initially diagnosed with long QT syndrome. However, none have been reported to cause drug-induced VF in patients with RYR2 variants. We describe the first case of an elderly woman with drug-induced QT prolongation and VF who carried a novel RYR2variant but no other mutations related to long QT syndrome.

Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction

Adrenoceptor activators and blockers are widely used clinically for the treatment of cardiovascular and pulmonary disorders. More recently, adrenergic agents have also been used to treat neurodegenerative diseases. Recent studies indicate a location of sympathetic varicosities in close proximity to neuromuscular junctions. The pressing question is whether there could be any effects of endo- or exogenous catecholamines on cholinergic neuromuscular transmission. It was shown that the pharmacological stimulation of adrenoceptors, as well as sympathectomy, can affect both acetylcholine release from motor nerve terminals and the functioning of postsynaptic acetylcholine receptors. In this review, we discuss the recent data regarding the effects of adrenergic drugs on neurotransmission at the neuromuscular junction. The elucidation of the molecular mechanisms by which the clinically relevant adrenomimetics and adrenoblockers regulate quantal acetylcholine release from the presynaptic nerve terminals and postsynaptic sensitivity may help in the design of highly effective and well-tolerated sympathomimetics for treating a number of neurodegenerative diseases accompanied by synaptic defects.

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

P140: Variability in practice patterns in the emergency department treatment of hyperkalemia

Introduction: Hyperkalemia is a common electrolyte disturbance associated with morbidity and mortality. Commonly used therapies for hyperkalemia include IV calcium, sodium bicarbonate, insulin, beta-adrenergic agents, ion-exchange resins, diuretics and hemodialysis. This study aims to evaluate which treatments are more commonly used to treat hyperkalemia and to examine factors which influence those clinical decisions. Methods: This is a retrospective chart review of all cases of hyperkalemia encountered in 2017 at a Canadian adult ED. Potassium values were classified as mild (5.5 - 6.5 mEq/L), moderate (>6.5 - 7.5 mEq/L) and severe (>7.5 mEq/L). Treatment choices were then recorded and matched to hemodynamic stability, degree of hyperkalemia and ECG findings. More statistical methods to test correlation between treatment and specific variables will be performed over the next 2 months, including logistic regression to highlight potential determinants of treatment and Chi-square tests to verify randomness and to construct 95% confidence intervals. Results: 1867 ED visits were identified, of which 479 met the inclusion criteria. 89.1% of hyperkalemia cases were mild, 8.2% were moderate, and 2.7% were severe. IV insulin was used in 22.1% of cases, followed by Kayexalate in 20.5%, sodium bicarbonate in 12.3%, IV calcium in 9.4%, frusemide in 7.3%, salbutamol in 2.7%, and dialysis in 1.9%. Moderate and severe hyperkalemia were associated with higher use of insulin (79.5% and 64.3% respectively), IV calcium (41% and 64.3% respectively), sodium bicarbonate (56.4% and 85.7% respectively). Bradycardia was associated with higher insulin and IV calcium use (46.7% and 33.3% respectively). Hypotension was associated with a similar increase in use of insulin and IV calcium (34.2% and 23.7% respectively). There were only 15 cases of cardiac arrest in which sodium bicarbonate and IV calcium were more frequently used (80% and 60% respectively). Conclusion: This study demonstrates variability in the ED management of hyperkalemia. We found that Insulin and Kayexalate were the 2 most common interventions, with degree of hyperkalemia, bradycardia and hypotension influencing rates of treatment. Overuse of kayexalate for emergent treatment of hyperkalemia is evident despite weak supporting evidence. Paradoxically, beta adrenergic agents were underutilized despite their rapid effect and safer profile. The development of a widely accepted guideline may help narrow the differences in practice and potentially improve outcomes.

SUN-925 Carcinoid: A Crisis in the Upside Down

Unrecognized carcinoid tumors can rarely present as a life-threatening condition known as carcinoid ‘crisis’ which typically presents as significant but transient hypotension if there is no appropriate preventive treatment. Somatostatin analogs such as Octreotide are agents of choice to avoid such crises. However, there is minimal literature and a lack of guidelines regarding the management of an active, labile carcinoid crisis in patients exhibiting both hypotension and hypertension, as will be presented here. Case: A 76-year-old female with end-stage renal disease, status post kidney transplant on immunosuppressants, who was initially admitted for workup of hematuria. Abdominal CT revealed a bladder mass with various features concerning for malignancy and an incidental mesenteric mass, followed by bladder biopsy suggestive of neoplasm. The patient was taken to the OR where she first underwent resection of the bladder mass with subsequent proceeding to the removal of the mesenteric mass. Within minutes of manipulation of the mass, the patient became significantly hypotensive with a mild response to fluid resuscitation, requiring vasopressors. A frozen section suggested the possibility of a neuroendocrine tumor. Given concerns of carcinoid crisis the patient was started on Octreotide infusion achieving some degree of hemodynamic stabilization but soon developed extremely labile blood pressure with rapidly alternating hypotension (SBP <60mmHg) and hypertension (SBP >200mmgHg). During hypotensive episodes, the aid of adjunctive beta-adrenergic agents was required, while the doses for the Octreotide infusion were as high as 200mcg/hr. Initial Endocrinologic workup revealed a Chromogranin A level 1,178 ng/mL (25 - 140 ng/mL), VIP <50 pg/mL (<75 pg/mL), 24 hr 5HIAA 23.5 (<=6.0 mg/24 h), Serotonin 2,334 ng/mL (56 - 244 ng/mL) consistent with carcinoid. Repeat Serotonin levels 5 days after octreotide infusion was 674 ng/mL. The patient was successfully weaned from vasopressors but required continuation of Octreotide for additional 5 days due to intermittent episodes of hypotension. Carcinoid crisis is a life-threatening condition associated with hypotension, and less commonly hypertension, from the release of vasoactive agents from tumor manipulation. Preparation with Octreotide before any manipulation or anesthesia is recommended to avoid a carcinoid crisis. However, if a crisis develops management is mainly with a continuous Octreotide infusion. The use of beta-adrenergic agents is debated, due to a possible “paradoxical effect” which could further worsen hypotension. Others argue that there is a role in preventing prolonged episodes of hypotension. In this case, it was required high doses and the infusion was needed for 5 days, probably related to the presence of ESRD which could have prolonged the bioavailability of the vasoactive agents.

Masked Hypotension due to Elevated Venous Pressure in a Patient with Complex Adult Congenital Heart Disease

An adult with surgically corrected Tetralogy of Fallot presented with profoundly elevated central venous pressure (CVP) and acute renal dysfunction thought secondary to acute on chronic right heart failure. Treatment with dopamine promoted diuresis and a stabilization of renal function. Repeated attempts to wean the patient from dopamine were associated with hypotension and worsening renal failure. Invasive hemodynamic assessment unexpectedly demonstrated high cardiac output with low systemic vascular resistance (SVR). In retrospect, the markedly elevated CVP had concealed the impact of reduced SVR on blood pressure. After reversible causes of low SVR state were excluded, the patient was successfully managed with oral alpha-adrenergic agents. While typically negligible under physiologic conditions, elevated CVP can artificially increase mean arterial pressure. We have coined the term “masked hypotension” to describe this unique pathophysiological phenomenon.