Alexander C. White

Glutathione deficiency in human disease

Abstract Glutathione has multiple metabolic actions that are essential for cellular homeostasis. In spite of this important role in cellular physiology, disease states due to glutathione deficiency are not common. The participation of both tissue and circulating glutathione deficiency in disease pathogenesis is likely to be subtle and not easily defined. Despite these difficulties, a number of inherited conditions of glutathione deficiency are known, and acquired ones are being identified. Examples of the acquired deficiency state include idiopathic pulmonary fibrosis, human immunodeficiency virus-related disease, and respiratory distress syndrome. Much of our current understanding of the utility of glutathione supplementation in states of tissue injury is derived from biochemical, animal, and cell culture studies. In this article we will review what is known about glutathione deficiency states and explore strategies by which tissue glutathione levels might be maintained or increased to prevent tissue injury and disease.

An Update on Pulmonary Complications of Hematopoietic Stem Cell Transplantation

The indications for hematopoietic stem cell transplantation (HSCT) continue to expand. However, the risk for pulmonary complications post-HSCT continues to be high. Early recognition and treatment of pulmonary complications may improve outcomes. This is an overview of diagnosis, manifestations, and treatment of the most common infectious and noninfectious pulmonary complications post-HSCT. Knowing the patients timeframe post-HSCT (preengraftment, postengraftment, late), type of HSCT (allogeneic vs autologous), radiographic findings, and clinical presentation can help to differentiate between the many pulmonary complications. This article will also address pretransplantation evaluation and infectious and noninfectious complications in the patient post-HSCT. While mortality post-HSCT continues to improve, respiratory failure continues to be the leading cause of ICU admissions for patients who have undergone HSCT. Mechanical ventilation is a predictor of poor outcomes in these patients, and further research is needed regarding their critical care management, treatment options for noninfectious pulmonary complications, and mortality prediction models posttransplantation.

Modulation of transforming growth factor-beta 1 antiproliferative effects on endothelial cells by cysteine, cystine, and N-acetylcysteine.

Early passaged bovine pulmonary artery endothelial cells exposed to 0.1-2.0 ng/ml transforming growth factor-beta 1 (TGF-beta 1) showed concentration-dependent growth inhibition, as assessed by [3H]thymidine labeling and cell counts, over a 96-h interval. Most of the inhibition of [3H]thymidine labeling measured at 96 h persisted when the medium was replaced with TGF-beta 1-free medium after 24 h, but the inhibition of labeling was prevented by the presence of anti-TGF-beta 1 antibody in the replacement medium. Additions of 2 mM cysteine, 1 mM cystine, or 2 mM N-acetylcysteine at the time of the initial addition of TGF-beta 1 blocked the inhibitory effect of TGF-beta 1 on [3H]-thymidine labeling when this was assessed after 72-96 h, but not at earlier times. Prevention of the inhibitory effect on cellular proliferation produced by cysteine, cystine and N-acetylcysteine was associated with elevation of cellular glutathione that was present at 48-96 h. There was no evidence for direct inactivation of TGF-beta 1 by the thiol-amino acids. Conditioned medium from TGF-beta 1-treated endothelial cells inhibited proliferation of mink lung carcinoma (CCL64) cells, supporting a previously reported concept of autocrine production of TGF-beta 1 by the endothelial cells. The inhibitory action of the conditioned medium was partially prevented when 1 mM cysteine was added during conditioning. Thus, TGF-beta 1 treatment of endothelial cells appears to set off autocrine production by these cells of TGF-beta 1 that perpetuates the inhibition of cellular proliferation. Replenishment of cellular glutathione with thiol-amino acids counteracts the growth-inhibitory effect of TGF-beta 1 through a currently undefined mechanism.

Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation

We performed a retrospective analysis of muscle strength testing obtained following sibling or unrelated donor hematopoietic stem cell transplant (HSCT) between 1 January 1999 and 31 December 2003 in a cohort of 44 subjects at Tufts-New England Medical Center. Maximal inspiratory pressure (PImax) was ⩽80% predicted in 52% of subjects and ⩽60% predicted in 20% of subjects; maximal expiratory pressure (PEmax) was ⩽80% predicted in 88% of subjects and ⩽60% predicted in 74% of subjects. Patients with a PImax ⩽60% predicted spent significantly longer time in hospital following HSCT compared with subjects with PImax 60% predicted. Grip strength (n=32) was reduced to ⩽80% predicted in 75% of subjects and ⩽60% predicted in 47% of subjects following HSCT. Analysis of paired measurements obtained before and after HSCT in 20 of the 44 subjects (45%) showed significant reduction in both PImax and PEmax between the two measures. Respiratory and skeletal muscle weakness is present in a significant percentage of subjects undergoing pulmonary function testing in the post-HSCT period, and may contribute to pulmonary morbidity in subjects with pulmonary complications of HSCT.

Chronic graft-versus-host disease-related polymyositis as a cause of respiratory failure following allogeneic bone marrow transplant.

An unusual case of respiratory failure and dropped head syndrome as a complication of severe chronic graft-versus-host disease (GVHD)-related polymyositis is described. The patient required tracheostomy and mechanical ventilation but recovered following treatment with aggressive immunosuppression and intensive rehabilitation. The differential diagnoses of muscle weakness in the bone marrow transplant (BMT) patient and the dropped head syndrome are both discussed. To our knowledge, this is the first reported case of respiratory failure requiring mechanical ventilation occurring as a complication of GVHD-related polymyositis. Bone Marrow Transplantation (2000) 26, 1117–1120.

Prolonged Mechanical Ventilation: Review of Care Settings and an Update on Professional Reimbursement

The goal of this article is to provide an update on recent changes to current procedural terminology codes used for billing physician services for mechanical ventilation in chronic care facilities. In addition to billing information, background data relevant to prolonged mechanical ventilation are reviewed. Topics covered include a description of the settings in which patients receive prolonged mechanical ventilation; home mechanical ventilation; the role of physician extenders; documentation of ventilator services; and reporting and coding ventilator management.

Long-Term Mechanical Ventilation: Management Strategies

This paper reviews management strategies for patients undergoing prolonged mechanical ventilation (PMV). Topics covered include how to identify and correct barriers to weaning, the systematic approach to weaning trials, when to cease weaning trials and proceed with life-long support, managing the tracheostomy tube during PMV, and, finally, how to select a suitable mechanical ventilator for PMV.

Dialysis disequilibrium syndrome : an unusual cause of respiratory failure in the medical intensive care unit

Abstract We describe a case of the dialysis disequilibrium syndrome (DDS) that was marked by the rapid onset of cerebral edema and the subsequent development of acute respiratory failure. The patient was treated successfully with a combination of mechanical hyperventilation and mannitol. The clinical presentation, pathogenesis, prevention and treatment of the entity are discussed.

Decannulation Following Tracheostomy for Prolonged Mechanical Ventilation

Background: We examined the process of decannulation following tracheostomy in patients transferred to a long-term acute care (LTAC) hospital for weaning from prolonged mechanical ventilation (PMV). Methods: A retrospective chart review of 135 patients. Results: Decannulation was successful in 35% of patients a median of 45 days (IQR, 32-76) following tracheostomy. Patients who failed decannulation had a tracheostomy tube placed earlier (14 days; IQR 11-18 vs. 18 days; IQR 14-30, P = .04) and had a shorter length of stay at the acute facility (20 days; IQR, 16-23 vs. 31 days; IQR, 24-45, P = .003) compared with patients who were decannulated. Length of stay and cost of care at the LTAC did not differ with decannulation status. At 3.5 years, 35% (47/135) of all patients and 62% (29/47) of decannulated patients were alive. Conclusions: Decannulation was achieved in 35% of patients transferred to an LTAC for weaning from prolonged mechanical ventilation.

Terminal withdrawal of mechanical ventilation at a long-term acute care hospital: comparison with a medical ICU.

BACKGROUND Failure to wean from prolonged mechanical ventilation (MV) is common in long-term acute care hospitals (LTACHs), but the process of terminal withdrawal of MV in LTACHs is not well described. We compared terminal withdrawal of MV at an LTACH with that in a medical ICU (MICU). METHODS A retrospective medical chart review was done of all patients undergoing terminal withdrawal of MV in an LTACH (n = 30) and in a MICU (n = 74) over a 2-year period. RESULTS The decision to withdraw MV was more likely initiated by patient or family in the LTACH and by medical staff in the MICU (p < 0.0001). Social workers, pastoral care, and hospital administration were more likely to participate in the withdrawal process at the LTACH compared with the MICU (p < 0.05). Time from initiation of MV to orders for do not resuscitate, comfort measures only, or withdrawal of MV was significantly greater in the LTACH (weeks) compared with the MICU (days) (p < 0.05). The dose of benzodiazepines given during the final 24 h of life was greater in the MICU as compared with the LTACH (p < 0.05). Narcotic and benzodiazepine use in the hour before or after withdrawal of MV did not differ between the two groups. COPD and pneumonia were the most common causes of death among patients undergoing withdrawal of MV at the LTACH, as opposed to septic shock in the MICU (p < 0.05). CONCLUSIONS Terminal withdrawal of MV in the LTACH differs from that in the MICU with regard to decision making, benzodiazepine use, and cause of death.