Robert Weinstein

Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina : A phase I/IIa double-blind, randomized controlled trial

Background— A growing population of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Preclinical studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium, which enhances perfusion and function. Methods and Results— Twenty-four patients (19 men and 5 women aged 48 to 84 years) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization were enrolled in a double-blind, randomized (3:1), placebo-controlled dose-escalating study. Patients received granulocyte colony-stimulating factor 5 &mgr;g · kg−1 · d−1 for 5 days with leukapheresis on the fifth day. Selection of CD34+ cells was performed with a Food and Drug Administration–approved device. Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells (versus saline). The total dose of cells was distributed in 10 intramyocardial, transendocardial injections. Patients were required to have an implantable cardioverter-defibrillator or to temporarily wear a LifeVest wearable defibrillator. No incidence was observed of myocardial infarction induced by mobilization or intramyocardial injection. The intramyocardial injection of cells or saline did not result in cardiac enzyme elevation, perforation, or pericardial effusion. No incidence of ventricular tachycardia or ventricular fibrillation occurred during the administration of granulocyte colony-stimulating factor or intramyocardial injections. One patient with a history of sudden cardiac death/ventricular tachycardia/ventricular fibrillation had catheter-induced ventricular tachycardia during mapping that required cardioversion. Serious adverse events were evenly distributed. Efficacy parameters including angina frequency, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class showed trends that favored CD34+ cell–treated patients versus control subjects given placebo. Conclusions— A randomized trial of intramyocardial injection of autologous CD34+ cells in patients with intractable angina was completed that provides evidence for feasibility, safety, and bioactivity. A larger phase IIb study is currently under way to further evaluate this therapy.

Transfusion-related acute lung injury after the infusion of IVIG

BACKGROUND: Transfusion‐related acute lung injury (TRALI) is a well‐characterized, serious complication of blood component therapy in hospitalized patients. The signs and symptoms are often attributed to other clinical aspects of a patients condition, and therefore TRALI may go unrecognized. IVIG is a pooled plasma derivative commonly used in the outpatient setting. Respiratory complications of IVIG infusion have typically been attributed to volume overload or allergic and vasomotor reactions. TRALI has never been documented to occur after IVIG infusion.

Rituximab treatment in patients with IVIg-dependent immune polyneuropathy: a prospective pilot trial.

We studied the effect of rituximab in allowing a reduction in dose of intravenous immune globulin (IVIg) in six patients with IVIg‐dependent, relapsing immune polyneuropathy. Rituximab (375 mg/m2 intravenously each week for 4 weeks) was administered in a prospective, open‐label design to two patients with chronic inflammatory demyelinating polyneuropathy (CIDP), two with multifocal motor neuropathy (MMN), one with neuropathy and anti–myelin‐associated glycoprotein (MAG) antibody neuropathy, and one with Sjögren syndrome (SS) ataxic neuropathy. The primary endpoint was a reduced cumulative IVIg dosage by at least 25% at 1 year after rituximab therapy compared to the previous year. Secondary endpoints included an improved summed strength score by at least 5 points on the Medical Research Council scale, an increased sensory score by at least 4 points, or an improved Rankin disability score by at least 1 grade. Total IVIg dosage decreased by greater than 25% in one patient with SS neuropathy and one with MMN; the dosage was unchanged in one with CIDP, slightly reduced in the patient with anti‐MAG neuropathy, and increased in one with CIDP and another with MMN. There was no improvement in secondary endpoints. No adverse events occurred. In this small prospective study, rituximab did not reduce IVIg requirements in the majority of patients with IVIg‐dependent, immune‐mediated polyneuropathies. Muscle Nerve, 2006

Prevention of citrate reactions during therapeutic plasma exchange by constant infusion of calcium gluconate with the return fluid.

We have examined the effectiveness of intravenous calcium gluconate infusion in the prevention of citrate reactions during therapeutic plasma exchange. Over 2 years, 636 procedures were performed on 90 patients, mostly for treatment of neurological disorders. Return fluid consisted of 4–5% human serum albumin in 0.9% NaCl. Anticoagulant ACD‐A was used at a starting ratio of 1:16. Whole blood flow rates were 70–80% ml/min. Treatments were divided into three groups for management of citrate reactions: Group A (360 treatments) were managed using simple measures only, including slowing the whole blood flow rate, altering the ACD:whole blood flow ratio, and oral calcium carbonate wafers; Group B (102 treatments) received small intravenous boluses of 10% calcium gluconate, up to 25 ml during the procedure; Group C (174 treatments) received constant infusion of calcium gluconate (10 ml/liter of return fluid) during the procedure. Citrate reactions occurred in 35.6% of Group A and 29.4% of Group B treatments (P = 0.3), but in only 8.6% of Group C treatments (P < 0.0001). Men with and without reactions were the same age (mean 63.3 vs. 61 years, P = 0.0823), but women with reactions were younger than women without reactions (mean 49.9 vs 57.9 years, P < 0.0001). Supplementation of the return fluid with calcium gluconate is an effective, convenient, and well‐tolerated method for prevention of citrate toxicity during therapeutic plasma exchange procedures using albumin‐based return fluid.

Treatment experience in patients with anti-myelin-associated glycoprotein neuropathy.

We report our experience with 24 consecutively treated patients (15 men and 9 women, median age 64 years) with anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy. The rates of response to plasma exchange (40%), immune globulin (16%), and cyclophosphamide‐based therapy (36%) were similar. Five (24%) responded to the first treatment modality, 32% to a second, alternative modality, and 31% to a third. Only 4 of 12 responders had sustained improvement; the others relapsed after a median of 7 months. In those 4 patients, the median immunoglobulin M (IgM) level dropped by 25% compared to an increase of 24% in the nonresponders (P = 0.04). Thus, most patients with anti‐MAG neuropathy failed to have sustained improvement after treatment, and none of the therapies emerged as superior. Disability improved transiently after therapy in approximately 50% of cases. A 25% reduction of the IgM level predicted sustained improvement, but was difficult to achieve. There were no clinical or electrodiagnostic features associated with a treatment response, nor did a reduction of the anti‐MAG antibody titer correlate with clinical improvement.

Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders

The safety and efficiency of a novel method of rapid-infusion IV immunoglobulin (IVIg) were retrospectively reviewed in 50 patients with neuromuscular disorders. There were 89 adverse events after 341 rapid infusions (26%), 3.5% of which were considered to be major (requiring hospitalization) and 66% minor. All patients recovered without sequelae, and there were no deaths. Fourteen of 17 patients (82%) receiving maintenance therapy preferred rapid IVIg infusion because of its convenience. Rapid-infusion IVIg can be given safely and conveniently in many patients with neuromuscular disorders.

Inhibition of endothelium-dependent vasorelaxation by sickle erythrocytes☆

Interactions between erythrocytes and vascular endothelium have been implicated in the pathogenesis of vaso-occlusion in sickle cell anemia. Sickle erythrocytes adhere to endothelial cells and facilitate trapping of rigid sickle cells in microvessels. Compensatory dilation of precapillary arterioles may mitigate the occlusion. The endothelium regulates vasoreactivity by elaborating endothelium-derived relaxing factor (EDRF), a small molecule that passes freely into vascular smooth muscle where it initiates vasorelaxation by activating soluble guanylate cyclase in the smooth muscle cell cytoplasm. Endothelial release of EDRF can be stimulated by agonists such as acetylcholine. It is highly sensitive to decomposition by superoxide anions and is rapidly bound and inactivated by oxyhemoglobin in solution. The purpose of this study was to determine whether sickle cell interaction with endothelium disrupts this mechanism of endothelial regulation of vasomotor tone. Transverse strips of rabbit aorta, mounted isometrically in organ baths, were contracted with norepinephrine, and relaxation responses to acetylcholine or other agonists were determined. Responses were measured under control conditions and again in the presence of oxyhemoglobin A or S, or erythrocytes or ghosts from normal control subjects or patients with homozygous sickle cell anemia. Sickle erythrocytes inhibited vasorelaxation to acetylcholine by 83%. Approximately half of the inhibition was attributable to a small amount of oxyhemoglobin S that was leaked into the buffer from the erythrocytes. Consistent with this, sickle erythrocyte ghosts inhibited vasorelaxation to acetylcholine by up to 45%. Ghosts from normal erythrocytes did not inhibit vasorelaxation to acetylcholine, and the inhibition seen with normal erythrocytes was entirely attributable to leakage of oxyhemoglobin A into the bath buffer.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures

BACKGROUND : Hereditary antithrombin (AT) deficiency is associated with a significant risk of venous thromboembolism. Patients with this disorder frequently require long‐term anticoagulation. Discontinuation of anticoagulation for childbirth or surgery may carry a substantial thrombotic risk. For this reason, replacement with AT concentrate has been used when anticoagulation is interrupted. A new recombinant human AT concentrate, produced using transgenic technology, has recently been developed.

Phytanic acid storage disease (Refsum's disease): Clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management

Phytanic acid storage disease (known also as Refsums Disease) is caused by inherited defects in the metabolic pathway for phytanic acid, a dietary branched‐chain fatty acid. Poorly metabolized phytanic acid accumulates in fatty tissues, including myelin sheaths, and in organs including the liver and kidneys. Over time, affected individuals may develop classical diagnostic features of retinitis pigmentosa, cerebellar ataxia, peripheral polyneuropathy and an elevated protein content in the cerebrospinal fluid. Liver, kidney, and heart disease may also develop. Dietary restriction of phytanic acid is useful in preventing acute attacks and arresting the progression of organ impairment, especially in the peripheral nervous system. Therapeutic plasma exchange has been shown to be particularly useful for rapidly lowering plasma phytanic acid levels during acute attacks and may play a significant role as maintenance therapy as well. J. Clin. Apheresis 14:181–184, 1999.

Treatment of high-risk, refractory acquired methemoglobinemia with automated red blood cell exchange

Ingestion of strong oxidant substances may result in acquired methemoglobinemia, a clinical condition in which the oxidized blood hemoglobin is incapable of delivering oxygen to the tissues, and the patient becomes cyanotic. Traditional first‐line therapy consists of infusion of methylene blue, whose action depends on the availability of reduced nicotinamide adenine nucleotide phosphate (NADPH) within the red blood cell (RBC). Some patients, particularly those who are deficient in glucose‐6‐phosphate dehydrogenase (G6PD), will not benefit from methylene blue. In these patients, and in some patients who have ingested very strong oxidants, methylene blue may also precipitate Heinz body hemolytic anemia. We present a case of severe, acquired methemoglobinemia in a 26‐month‐old, 9.8‐kg boy with G6PD deficiency. He was cyanotic, in respiratory failure, intubated in a pediatric intensive care unit. In typical fashion, he did not respond to methylene blue. Manual exchange of two whole blood volumes, performed over 4 hr, also failed to resolve his severe methemoglobinemia. An automated RBC exchange (1.3 RBC volume), lowered his methemoglobin content from 31.8% to 7% in a single 40‐min procedure. Thereafter his methemoglobin level continued to decrease rapidly and spontaneously. He was discharged home 2 days later, with 0.4% methemoglobin. To our knowledge, this is the first report to demonstrate the (potentially superior) effectiveness of automated RBC exchange for treatment of patients with high‐risk acquired methemoglobinemia, that is, those with G6PD deficiency or who have ingested strong oxidants. J. Clin. Apheresis 13:28–31, 1998.