Intentional Hydroxychloroquine Overdose Treated with High-Dose Diazepam: an Increasing Concern in the COVID-19 Pandemic.

INTRODUCTION: Recent attention on the possible use of hydroxychloroquine and chloroquine to treat COVID-19 disease has potentially triggered a number of overdoses from hydroxychloroquine. Toxicity from hydroxychloroquine manifests with cardiac conduction abnormalities, seizure activity, and muscle weakness. Recognizing this toxidrome and unique management of this toxicity is important in the COVID-19 pandemic. CASE REPORT: A 27-year-old man with a history of rheumatoid arthritis presented to the emergency department 7 hours after an intentional overdose of hydroxychloroquine. Initial presentation demonstrated proximal muscle weakness. The patient was found to have a QRS complex of 134 ms and QTc of 710 ms. He was treated with early orotracheal intubation and intravenous diazepam boluses. Due to difficulties formulating continuous diazepam infusions, we opted to utilize an intermitted intravenous bolus strategy that achieved similar effects that a continuous infusion would. The patient recovered without residual side effects. DISCUSSION: Hydroxychloroquine toxicity is rare but projected to increase in frequency given its selection as a potential modality to treat COVID-19 disease. It is important for clinicians to recognize the unique effects of hydroxychloroquine poisoning and initiate appropriate emergency maneuvers to improve the outcomes in these patients.

A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban.

Platelet inhibition is central to the efficacy of glycoprotein (GP) IIb-IIIa antagonist therapy, but is not routinely measured during percutaneous coronary intervention (PCI). Data directly comparing the antiplatelet effects of these agents are also limited. Therefore, we compared ex vivo platelet function by standard light transmission aggregometry (LTA) and two automated bedside platelet function assays in 36 patients undergoing PCI with GP IIb-IIIa inhibitors. At baseline and 10 min following clinically recommended bolus and infusion of abciximab (0.25 mg/kg, 0.125 microg/kg/min), eptifibatide (180 microg/kg, 2 microg/kg/min), or tirofiban (10 microg/kg, 0.1 microg/kg/min), we measured 20 microM ADP- and 1.9 mg/mL collagen-induced platelet aggregation using LTA. Platelet function was also assessed using the bedside Accumetrics Ultegra-Rapid Platelet Function Assay (RPFA) and the Xylum Clot Signature Analyzer (CSA). The degree of platelet inhibition, as assessed by LTA, varied significantly between the clinically recommended doses of these GP IIb-IIIa antagonists. RPFA measurements agreed closely with LTA for abciximab, but tended to overestimate the degree of platelet inhibition for small molecules. CSA demonstrated profoundly inhibited shear-induced platelet function, but lacked sensitivity to discriminate between agents. These findings may have implications for the results of trials comparing the efficacy of these agents in patients undergoing PCI.

Predictors of non-Q-wave acute myocardial infarction in patients with acute ischemic syndromes: an analysis from the Thrombolysis in Myocardial Ischemia (TIMI) III trials.

Among patients with acute ischemic syndromes, patients with non-Q-wave acute myocardial infarction (AMI) are known to be at higher risk for death, reinfarction, and other morbidity than those with unstable angina. The aim of this study was to develop a clinically useful prediction rule to assist in distinguishing, at the time of presentation, patients with non-Q-wave AMI from those with unstable angina. The TIMI IIIB trial enrolled 1,473 patients presenting with ischemic pain at rest within 24 hours who had either electrocardiographic changes or documented coronary artery disease. Non-Q-wave AMI on presentation was documented by elevation of creatine kinase-MB in 33% of patients. Fifty clinical and electrocardiographic variables were compared between the patients with non-Q-wave AMI and unstable angina. After performing logistic regression, 4 baseline characteristics independently predicted non-Q-wave myocardial AMI: the absence of prior coronary angioplasty (odds ratio [OR] = 3.3, p < 0.001), duration of pain > or = 60 minutes (OR = 2.9, p < 0.001), ST-segment deviation on the qualifying electrocardiogram (OR = 2.0, p < 0.001), and recent-onset angina (OR = 1.7, p = 0.002). Using these 4 characteristics, a prediction rule for non-Q-wave AMI was developed. For the entire cohort of patients in TIMI III, the percentages of patients with non-Q-wave AMI when 0, 1, 2, 3, and 4 risk factors were present were 7.0%, 19.6%, 24.4%, 49.9%, and 70.6%, respectively (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.

OBJECTIVES: The aim of our study was to determine a superior thrombolytic regimen from three: anistreplase (APSAC), front-loaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy. BACKGROUND: Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolytic-antithrombotic regimens could improve the outcome achieved with standard regimens. METHODS: To address this issue, 382 patients with acute myocardial infarction were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point "unsatisfactory outcome" was a composite clinical end point assessed through hospital discharge. RESULTS: Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]). CONCLUSIONS: Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome.

Clot-selective coronary thrombolysis with low-dose synergistic combinations of single-chain urokinase-type plasminogen activator and recombinant tissue-type plasminogen activator. The Pro-Urokinase for Myocardial Infarction Study Group.

The effect of simultaneous infusions of low-dose recombinant tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, pro-urokinase) on coronary arterial thrombolysis was investigated in 23 patients treated within 6 hours (mean 2.6 +/- 1.1, range 1.2 to 5.9) of symptoms of an acute myocardial infarction. Infarct artery patency at 90 minutes was achieved in 16 (70%, 95% confidence limits of 0.47 to 0.87) of 23 patients after a 1-hour intravenous infusion of 20 and 16.3 mg of t-PA and scu-PA, respectively. At 90 minutes, the fibrinogen concentration decreased from 369 +/- 207 to 316 +/- 192 mg/dl (p = not significant), while plasminogen decreased to 69 +/- 24% (p = 0.001) and alpha-2-antiplasmin to 77 +/- 24% (p = 0.001) of pretreatment values. Although no bleeding requiring termination of drug infusion or transfusion occurred, 1 patient with cerebrovascular amyloidosis had a fatal intracerebral hemorrhage. These findings suggest that combination therapy may allow substantial reductions in total thrombolytic doses while still achieving effective fibrin-specific coronary thrombolysis.

Lovastatin therapy for hypercholesterolemia in cardiac transplant recipients.

Hypercholesterolemia (type II hyperlipidemia) after cardiac transplantation is common and may play a role in the accelerated rate of coronary atherosclerosis seen following the procedure. However, conventional cholesterol-lowering drugs are either ineffective or contraindicated for use in transplant recipients. The presence of type II hyperlipidemia was identified in 11 cardiac transplant recipients during a mean follow-up period of 15 months (range 3 to 41) after transplantation. Lovastatin, at an initial dosage of 20 mg/day, was administered for a period of 1 year. The maximal dosage of lovastatin was 60 mg/day. All patients received maintenance dosages of immunosuppressive agents, including cyclosporine-A, prednisone and, in some instances, azathioprine. Lipid profiles, hepatic transaminases, serum creatinine, creatine kinase and cyclosporine-A serum trough levels were measured quarterly. Total cholesterol decreased by 27% (354 +/- 50 vs 258 +/- 36 mg/dl, p less than 0.01) after 3 months and remained stable thereafter. Similarly, low density lipoprotein cholesterol decreased by 34% (221 +/- 51 vs 146 +/- 40 mg/dl, p less than 0.01) after 3 months and remained constant. Triglycerides, high density lipoprotein, hepatic transaminases, creatinine, creatine kinase and trough cyclosporine-A levels remained stable during the 1-year follow-up period. Lovastatin was uniformly well tolerated in this study group. When given in modest dosages, lovastatin appears to be a safe, effective and well-tolerated therapy for hypercholesterolemia in cardiac transplant recipients.

Nonthrombolytic intervention in acute myocardial infarction.

Alternative interventions are available for patients in whom thrombolytic therapy is inappropriate after an acute myocardial infarction. Administration of a beta blocker within the first 24 hours of the patient's admission to the coronary care unit can reduce overall morbidity and mortality within the first 7 days by about 15%. Maintenance therapy with an oral beta blocker can reduce mortality within the succeeding 3 years by about 25%. Esmolol, a unique cardioselective beta 1-adrenergic receptor blocker with a half-life of 9 minutes, can enable some patients with relative contraindications to beta blockers to nevertheless benefit from early beta-blocking therapy. It also is useful in screening patients for subsequent therapy with beta blockers. Those who tolerate the esmolol infusion can be given a long-acting beta blocker. For patients who exhibit intolerance to esmolol, the infusion can be terminated with rapid return to baseline hemodynamics.

Clot-selective coronary thrombolysis with pro-urokinase.

Recognition that myocardial infarction is caused by coronary thrombosis has stimulated a search for a safe, rapidly acting, and effective thrombolytic regimen. Tissue plasminogen activator (t-PA) can provide relatively clot-selective thrombolysis, but one quarter of patients fail to achieve reperfusion, lysis speed is not optimal, and higher doses have been associated with an increased incidence of hemorrhagic stroke. We report the results of a multicenter study of pro-urokinase, a second naturally occurring plasminogen activator that has structural similarities to t-PA but has a different mechanism of action. Pro-urokinase was administered 3.9 +/- 1.1 hours after the onset of chest pain to 40 patients with acute myocardial infarction with angiographically confirmed complete coronary occlusion (TIMI grade 0). After a 90-minute intravenous infusion of pro-urokinase (4.7-9 million units, 36-69 mg) 51% (20 of 39) of the patients demonstrated reperfusion (TIMI grade 2 or 3) occurring 64.8 +/- 22.3 minutes after initiation of therapy. Fibrinogen levels fell only 10 +/- 17% from baseline, confirming the fibrin specificity of pro-urokinase. As with t-PA, however, this specificity was only relative. alpha 2-Antiplasmin decreased to 39% and plasminogen decreased to 64% of initial values. Fibrinogen degradation products increased 63% and the fibrin-specific D-dimer increased 8.7-fold. Thus, pro-urokinase produces relatively clot-selective coronary thrombolysis similar to that produced by t-PA, but the use of either pro-urokinase or t-PA alone in higher doses would be likely to produce more nonspecific effects.

Left ventricular tamponade: echocardiographic and hemodynamic manifestations.

A patient with progressive systemic sclerosis was evaluated for dyspnea. Echocardiography revealed enlarged right heart chambers, a moderate pericardial effusion, and diastolic collapse of the left ventricle. Hemodynamic studies before and after removal of pericardial fluid were consistent with compromise of left, but not right, heart filling by the pericardial fluid.

Use of an ultrashort-acting beta-receptor blocker (esmolol) in patients with acute myocardial ischemia and relative contraindications to beta-blockade therapy.

The hemodynamic responses to esmolol, an ultrashort-acting (t1/2 = 9 min) beta 1-adrenergic receptor antagonist, were examined in 16 patients with myocardial ischemia and compromised left ventricular function as evidenced by a mean pulmonary capillary wedge pressure of 15 to 25 mm Hg. Esmolol was infused intravenously to a maximal dose of 300 micrograms/kg body weight per min for less than or equal to 48 h in 16 patients: 9 with acute myocardial infarction, 6 with periinfarction angina and 1 with acute unstable angina. The sinus rate and systolic arterial pressure declined rapidly in all patients from baseline values of 99 +/- 12 beats/min and 126 +/- 19 mm Hg to 80 +/- 14 beats/min (p less than 0.05) and 107 +/- 20 mm Hg (p less than or equal to 0.05) during esmolol treatment. Rate-pressure product decreased by 33% and cardiac index by 14% during esmolol treatment, but pulmonary capillary wedge pressure was not significantly altered by drug infusion (19 +/- 3 mm Hg at baseline versus 19 +/- 5 during treatment, p = NS). In all patients there was a rapid return toward baseline hemodynamic measurements within 15 min of stopping administration of esmolol, and virtually complete resolution of drug effect was evident within approximately 30 min. During infusion of esmolol, four of nine patients receiving intravenous nitroglycerin required downward adjustment of nitroglycerin infusion rate to maintain systolic blood pressure greater than 90 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Streptokinase-induced, antibody-mediated platelet aggregation: a potential cause of clot propagation in vivo.

The administration of intracoronary streptokinase to a patient with a prior history of rheumatic fever was associated with the retrograde propagation of thrombus from the left anterior descending coronary artery into the left main coronary artery with near catastrophic consequences. The addition of streptokinase to platelet-rich plasma from the patient initiated platelet aggregation and secretion in vitro. Platelet aggregation was also seen in 1 of 15 control subjects after the addition of streptokinase, and the addition of plasma or immunoglobulin G (IgG) from the index patient supported platelet aggregation in the presence of streptokinase in all of the previously nonreactive control subjects. This in vitro platelet aggregation was specific for streptokinase and not initiated by either urokinase or tissue plasminogen activator. Streptokinase-induced platelet aggregation was not inhibited by aprotinin, but was completely attenuated by the addition of an excess of antihuman IgG Fab. These findings suggest that streptokinase can initiate specific antibody-mediated platelet aggregation in vitro and may be more than coincidentally related to clot propagation or thromboembolism in vivo.

Cutaneous pseudo abscesses: an unusual presentation of severe pancreatitis.

In this report, we present a 53-yr-old man with extensive subcutaneous fat necrosis due to acute pancreatitis presenting as fluctuant collections resembling large multiple abscesses. The diagnosis was suggested by examination of the wound aspirate. Findings included absence of organisms on the gram stain, presence of fat globules on wet mount, and an elevated amylase in the wound aspirate. This dramatic presentation preceded any symptoms or signs of overt pancreatitis.

Responses of coronary arteries of cardiac transplant patients to acetylcholine.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation.

Most patients with severe congestive heart failure have secondary pulmonary hypertension (PHT). Elevation of pulmonary vascular resistance (PVR) to greater than 480 dynes.sec.cm-5 (6 Wood units) is currently the principle hemodynamic contraindication to orthotopic cardiac transplantation. We performed serial two-dimensional Doppler echocardiographic examinations and right heart catheterizations in 24 recipients (21 men, 14-58 years old) of orthotopic cardiac transplants to determine the time course of resolution of PHT and the concomitant remodeling of the donor right ventricle. Right and left heart filling pressures declined in parallel and reached the upper normal range at 2 weeks after the transplant procedure and remained unchanged at 1 year follow-up. Mean pulmonary arterial pressure (mm Hg) decreased from 38 +/- 9 preoperatively to 22 +/- 5 at 2 weeks and was 19 +/- 5 at 1 year after the transplantation procedure. At 1 year after surgery, PVR had decreased from 202 +/- 89 dynes.sec.cm-5 preoperatively to 99 +/- 36 dynes.sec.cm-5 (p less than .001), while cardiac output increased from 3.7 +/- 1.2 to 6.3 +/- 1.5 liters/min (p less than .001). Echocardiographic analysis showed that transplant recipients had an enlarged right ventricle on day 1 after surgery, and a volume overload contraction pattern and tricuspid regurgitation was present in the majority. This increase in right ventricular size was maintained at 1 year follow-up while the incidence of tricuspid regurgitation decreased. We conclude that there is rapid resolution of moderately elevated pulmonary arterial pressures after cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Myopericarditis as an initial presentation of meningococcemia. Unusual manifestation of infection with serotype W135.

Acute meningococcemia is a dramatic clinical syndrome from infection with the gram-negative diplococcus, Neisseria meningitidis. Although pericarditis may complicate the course of meningococcemia, it is distinctly unusual as a presenting sign. A case of disseminated meningococcemia presenting as acute myopericarditis is reported. The serotype isolated, type W135, was a sporadic cause of N. meningitidis in the Boston area. Although the patient had meningitis, bacteremia, and myopericarditis, his course was uncomplicated with early institution of antibiotic therapy.

Value of the intracoronary electrocardiogram to monitor myocardial ischemia during percutaneous transluminal coronary angioplasty.

To enhance detection of ischemia during percutaneous transluminal coronary angioplasty (PTCA), unipolar intracoronary electrocardiograms (ECGs) were recorded during PTCA in 25 patients from the tips of guidewires positioned distal to stenoses being dilated. Surface electrocardiographic leads chosen to reflect likely areas of reversible ischemia during PTCA were recorded simultaneously. In 21 of 29 stenoses dilated (72%), ST segment elevation and/or T wave peaking in intracoronary ECG appeared during balloon inflation and disappeared after deflation, accompanied by transient angina on 19 occasions. Two patients had transient ST segment elevation in intracoronary ECGs during PTCA without associated angina. ST changes in the surface ECG during PTCA were seen on only nine occasions (31%), always accompanied by ST segment elevation in the intracoronary ECG that appeared earlier and was of much greater magnitude. Five patients with prior myocardial infarction and aneurysm formation had fixed ST segment elevation in the intracoronary ECG unrelated to balloon inflation. Myocardial ischemia during PTCA can be detected easily with intracoronary ECGs and with greater sensitivity than that of the surface ECG. Furthermore, intracoronary ECGs may help to clarify the nature of chest pain during balloon inflation or during suspected complications.