Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/microliters (range 23,000-790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenectomized, lasting 3-4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2-10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gamma-globulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.     

Clinical responses following nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma are associated with expansion of CD8+ IFN-gamma-producing T cells

Nonmyeloablative allogeneic stem cell transplantation (NST) is thought to be an immunologic therapy in which donor T cells mediate a graft-versus-tumor effect. We recently reported the clinical outcome of a phase II trial of NST in metastatic renal cell carcinoma (RCC). However, the immune response correlates of clinical activity remain unknown. We now describe the analysis of T-cell subsets and T-cell cytokine-producing potential for those patients evaluable for immune monitoring. The incidence of graft-versus-host disease (GVHD) correlated with clinical outcome, with all responders exhibiting chronic GVHD. Following initial tapering of immunosuppression, an increase in the total numbers of CD8+ T cells but not CD4+ T cells was observed among responders compared to nonresponders. In addition, a greater ratio of CD8+ to CD4+ T cells producing IFN-gamma and IL-2 was seen in clinical responders at the time when clinical responses were first detected (day 180 after transplantation). Our results support the hypothesis that the antitumor effects of NST may be mediated by IFN-gamma-producing CD8+ T cells, and indicate that isolation of putative tumor antigen-specific T cells, ideally, should be pursued around day +180.     

Thrombosis at venous insertion sites after inferior vena caval filter placement

Color Doppler flow imaging or compression ultrasound (US) was used to prospectively determine frequency of thrombosis at 54 venous insertion sites (47 in common femoral veins, seven in right internal jugular veins) after percutaneous placement of Greenfield filters for interruption of the inferior vena cava. Fifty-one filters were successfully placed in 51 patients with a dilator set or a balloon angioplasty catheter. Nine focal thrombi were detected in the common femoral vein (19%) and one in the right internal jugular vein (14%). Use of dilators induced eight thrombi (24%), compared with two (10%) from balloon catheters. The left common femoral vein had a high frequency of thrombosis, regardless of dilation technique (five of nine). Of nine patients with acute common femoral vein thrombosis, four became symptomatic within 10 days after the procedure. Patients may remain asymptomatic or have delayed symptoms; thus, US is valuable for determining patients at risk of thrombosis of the common femoral vein.     

Intra-articular Botulinum Toxin Type A: A new approach to treat arthritis joint pain

There is a growing need for novel treatments of refractory arthritis joint pain as the aging population is expanding with many patients who are unable to undergo joint replacement surgery. We are studying the efficacy and safety of intra-articular injection of Botulinum Toxin Type A (IA-BoNT/A) into joints with arthritis pain. In several small open label studies, initial effects for IA-BoNT/A were encouraging because two thirds of the patients had more than 50% reduction in joint pain severity that was associated with a significant improvement in function. Importantly no serious adverse effects of IA-BoN/A were noted. Based on these initial results, we have completed two pilot randomized controlled trials in painful shoulder joints and painful knee joints. In the shoulder study, IA-BoNT/A produced a significant decrease in shoulder pain severity at one month (6.8-4.4 on VAS, p = .002) that was also significantly better than the non-significant change after IA-Saline placebo (1.6 unit difference favoring IA-BoNT/A, p = .014). In the knee study IA-BoNT/A produced a significant 48% decrease in McGill Total Pain Score at one month (p = .01 1) that was still significant at 3 mo after injection (p = .002). There was a strong placebo response in one third of those but the decrease in pain severity was not significant. We are currently conducting a RCT of IA-BoNT/A for painful prosthetic knee joints. Based on these initial studies of IA-BoNT/A we have gone ‘back to the bench’ to standardize a menu of pain behaviors for mice with acute inflammatory arthritis pain and chronic inflammatory arthritis pain. IA-BoNT/A significantly reduced arthritis joint tenderness (evoked pain score) in acute and chronic inflammatory arthritis and normalized impaired spontaneous wheel running in mice with chronic inflammatory arthritis but not in those with acute inflammatory arthritis. With these models of arthritis and pain behavior methods we will be able to screen potential intra-articular analgesics, define dose response curves and injection schedule, and study the relationships of articular pain and loss of function.     

Injurious sleep behavior disorders (parasomnias) affecting patients on intensive care units

There are no previous reports on parasomnias (sleep behavior disorders) affecting patients on intensive care units (ICUs). During 8 years of clinical practice, we evaluated over 200 adults with complaints of injurious, sleep-related behaviors, 20 of whom had ICU admissions while their parasomnias had been active and generally undiagnosed/untreated. Mean age during ICU confinement was 62.8 (±SD 13.1) years; 85,0% (17/20) were males. Patients underwent comprehensive clinical examinations along with extensive polysomnographic and audiovisual monitoring (electrooculogram, 9 channel EEG with paper speeds of 15 and 30 mm/sec, electromyogram [submental and 4 limbs], EKG, airflow). The polysomnographic studies were diagnostic for the REM sleep behavior disorder (vigorous dream-enactment during rapid eye movement [REM] sleep) in 85.0% (17/20) of patients, and for night terrors/sleepwalking in 15.0% (3/20). Three groups of parasomnia-ICU relationships were identified: i) Parasomnias originating in ICUs, stroke-induced (n=3); ii) Admission to ICUs resulting from parasomnia-induced injuries: C2 odontoid process fracture and C3 spinous process fracture with severe concussion (n=2); iii) Parasomnias in patients admitted to ICUs for various other medical problems (n=15). Physicians should be thus alerted about the possibility of injurious, but usually treatable, parasomnias in ICU patients.     

Acute care research: is it ethical?

BACKGROUND: Research in acute care is a troubling area for Institutional Review Board (IRB) approval and informed consent. Confusion about ethical and legal requirements has hampered research efforts and subsequent patient benefits. ANALYSIS: Acute care patients are the relatively few critical care patients who have suffered unexpected events that carry a high probability of mortality or severe morbidity unless immediate medical intervention is provided. We argue that acute care research is justified if the usual ethical requirements for research are modified to reflect the uniqueness of the situation. CONCLUSIONS: Our recommendations are to: a) use an explicit definition of acute care as distinct from other modes of critical care; b) eliminate the requirement for informed consent (as it is usually understood); and c) require stringent IRB oversight, regarding the unique ethical problems raised by this area of research. We further suggest that IRB oversight includes review of the protocol by a panel of individuals who represent possible enrollees in the proposed study.