Outcome of adult umbilical cord blood transplant patients admitted to a medical intensive care unit.

Umbilical cord blood transplant (UCBT) has emerged as an alternate source of stem cells for transplantation in patients with hematologic malignancies. However, outcomes of adult UCBT patients requiring ICU admission remain unknown. In order to identify predictors of ICU transfer and mortality in UCBT patients, the course and outcome of all adult (> or = 16 years old) patients who underwent UCBT between 1 January 1998 and 31 December 2003 at University Hospitals of Cleveland were analyzed. Forty-four patients underwent UCBT during the study period and 25 (57%) required ICU transfer. Use of a myeloablative preparative regimen was a significant predictor of ICU transfer (P = 0.03). An infusion of higher numbers of nucleated cells was protective from ICU transfer (P = 0.05). For those patients transferred to the ICU, mortality was 72%. The univariate predictors of mortality, at the time of ICU admission were a high APACHE III score (P = 0.0004), use of vasopressors (P = 0.03), and a low platelet count (P = 0.03). We conclude that transfer of UCBT patients to an ICU may be predicted by their preparative regimen, while ICU mortality may be predicted by physiologic parameters upon admission.

Differential activation of MAP kinase signaling pathways and nuclear factor-kappaB in bronchoalveolar cells of smokers and nonsmokers.

BACKGROUND: Prolonged exposure of alveolar macrophages (AM) to components of tobacco smoke, including nicotine and aromatic hydrocarbons, may lead to alterations in activation of cellular signaling pathways. In this study, we compared the spontaneous and LPS-stimulated activation of MAP kinases and NF-kappaB in bronchoalveolar cells (BAC) from smokers and nonsmokers. MATERIAL AND METHODS: BAC, which were predominantly comprised of AM, were obtained by bronchoalveolar lavage of healthy volunteering adult smokers and nonsmokers. Nuclear and cytoplasmic extracts were prepared from cell lysates. Activation of NF-kappaB was assessed by electrophoretic mobility shift assay. Degradation of the inhibitor of NF-kappaB (IkappaB) and total MAP kinases were assessed by Western blot analysis. Activation of MAP kinases, ERK, SAPK/JNK, and p38 were assessed by immunoprecipitation of cell lysates and kinase assays. RESULTS: LPS induced the activation of NF-kappaB in a dose-dependent manner, but BAC from smokers were approximately 10 times more sensitive, and showed faster kinetics of activation of NF-kappaB than BAC from nonsmokers. All three classes of MAP kinase-ERK, SAPK, and p38-were simultaneously activated by LPS in BAC from smokers and nonsmokers. However, the individual MAP kinases exhibited differential kinetics of activation. Activation of p38 was more rapid in BAC from smokers, whereas the activation of ERK and SAPK was similar in both groups. CONCLUSION: The differences in activation of NF-kappaB and MAP kinases in BAC from smokers and nonsmokers may relate to the differences in their microenvironment in situ as affected by chronic exposure to cigarette smoke. These differences may contribute to the increased susceptibility of smokers to infections, including infection with HIV-1, and lung disease.

Dysregulation of beta-chemokines in the lungs of HIV-1-infected patients.

The beta-chemokines, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, monocyte chemotactic protein (MCP)-1 and regulated-on-activation normal T cell, expressed and secreted (RANTES) are not only chemotactic for mononuclear cells but may be important in suppression of HIV-1 replication through competitive binding to the chemokine receptor, CCR5, which is critical to viral entry. In this study, bronchoalveolar cells (BACs) and autologous peripheral blood mononuclear cells (PBMCs) were obtained from HIV-1-infected participants who did not manifest clinical signs of lung disease with peripheral CD4 T-cell count >200/mm(3) (n = 7, group with high CD4 count), or CD4 T-cell count <200/mm(3) (n = 12, group with low CD4 count), and from healthy study subjects (n = 5). The capacity to express beta-chemokines and CCR5 was assessed. Induction of MIP-1 alpha by lipopolysaccharide (LPS) in BAC of HIV-1-infected study subjects from the low CD4 group was less than BAC from healthy study subjects (p <.001), and also was less than in BACs from the group with a high CD4 group (p <.001). Moreover, the intracellular expression of MIP-1 alpha in LPS-induced monocytes of HIV-1-infected patients was significantly less than that from healthy study subjects (p <.01). In addition, spontaneous expression of mRNAs for CCR5 and MIP-1 alpha in BAC was significantly lower in HIV-1-infected patients compared with in healthy study subjects (p <.03 and p <.02, respectively). In contrast to the findings with MIP-1 alpha, LPS stimulated MCP-1 in BAC from the group of HIV-1-infected patients with high CD4 count was significantly higher than healthy study subjects (p <.001). These dysregulations in the ability to express beta-chemokines by BAC may be important in the progression of HIV-1 infection in the lung.

Tracheobronchomalacia: dynamic airway evaluation with multidetector CT.

OBJECTIVE. The objective of our study was to evaluate the role of dynamic inspiratory-expiratory imaging with multidetector CT in patients with suspected tracheobronchomalacia. CONCLUSION. Multidetector CT with inspiratory-expiratory imaging is a promising method in the evaluation of patients with dynamic airway collapse. In our study, the degree of dynamic collapse correlated well with bronchoscopic results. Dynamic expiratory multidetector CT may offer a feasible alternative to bronchoscopy in patients with suspected tracheobronchomalacia.

The pathobiology of acute asthma.

Acute bronchial asthma is a common problem with immense medical and economic impacts. It is estimated that this disease affects 12 to 14 million people in the United States with costs in excess of $6 billion per year. Most of the morbidity and all of the mortality of asthma tends to be associated with acute exacerbations, and treatment of these events accounts for the majority of expenditures in money and health care resources. Unfortunately, the factors that contribute to the destabilization of asthma are rarely studied and much of the pathogenesis and pathobiology of acute asthma remains unknown. This article examines these issues and suggests treatment for acute asthma.

Integrated response of the upper and lower respiratory tract of asthmatic subjects to frigid air.

To evaluate the influence of cold air hyperpnea on integrated upper and lower airway behavior, 22 asthmatic volunteers hyperventilated through their mouths (OHV) and noses (NHV) while pulmonary and nasal function were determined individually and in combination. In the isolated studies, OHV at a minute ventilation of 65 +/- 3 l/min lowered the 1-s forced expiratory volume (FEV(1)) 24 +/- 2% (P < 0. 001) and NHV (40 l/min) induced a 31 +/- 9% (P < 0.001) increase in nasal resistance (NR). In the combined studies, oral hyperpnea reduced the FEV(1) (DeltaFEV(1) 26 +/- 2%, P < 0.001) and evoked a significant rise in NR (DeltaNR 26 +/- 9%, P = 0.01). In contrast, NHV only affected the upper airway. NR rose 33 +/- 9% (P = 0.01), but airway caliber did not change (DeltaFEV(1) 2%, P = 0.27). The results of this investigation demonstrate that increasing the transfer of heat and water in the lower respiratory tract alters bronchial and nasal function in a linked fashion. Forcing the nose to augment its heat-exchanging activity, however, reduces nasal caliber but has no effect on the intrathoracic airways.

Lack of interaction of hyperpnoea with methacholine and histamine in asthma.

1. The thermal precipitants of asthma (exercise and hyperventilation) appear to have a unique pathogenesis that does not alter bronchial responsiveness. In the present work, we tested whether hyperpnoea interacts with other constrictor stimuli.2. To provide data on this issue, we exposed 17 subjects with asthma to isocapnic hyperventilation of frigid air (HV), methacholine (METH) and histamine (HIS) alone and in combination.3. With HV (mean ventilation=55.6+/-7.7 litres/min), METH (2.20+/-0.7 mmol/l) and HIS (10.35+/-5.04 mmol/l) alone, the decrements in forced expiratory volume in 1 s (FEV1) from baseline were 27.4+/-3.4, 27.4+/-3.8 and 32.4+/-3% respectively (n=9). Giving the agonists simultaneously did not produce additive effects (Delta FEV1 HV+METH=32.8+/-3.6%; HV+HIS=28.7+/-5.1%). None of the individual or combined responses was significantly different from each other. Changing the sequence of the experiments and giving METH at the height of the HV-induced bronchial narrowing, instead of during hyperpnoea, did not alter the findings (n=8). The maximum fall in FEV1 after both bronchoconstrictors in this experiment (Delta FEV1=32.3+/-4.3%) was not significantly different from either alone (HV=22.8+/-1.0%; METH=27.3+/-1.9%). When METH and HIS were administered together, however (n=5), a positive interaction ensued (METH=1.53+/-0.56 mmol/l, Delta FEV1=15.6+/-4.6%; HIS=4.77+/-2.07 mmol/l, Delta FEV1=18. 8+/-3.1%; METH+HIS Delta FEV1=33.4+/-5.2%; P<0.001 compared with the individual effects).4. These results indicate that HV does not interact with stimuli that directly or indirectly modulate airway calibre. It is unclear if this effect represents protection conferred from increased bronchial blood flow or derives from differences in effector mechanisms between the thermal and pharmacological agonists.

Comparison of two dosage regimens of albuterol in acute asthma.

BACKGROUND: The standard therapy for acute episodes of asthma in the United States consists of three 2.5-mg doses of aerosolized albuterol given every 20 minutes. Whether this approach represents optimum therapy has never been tested. METHODS: This study employed a prospective, sequential design in which the effects of two doses of 5.0 mg of aerosolized albuterol administered during 40 minutes (high dose) were contrasted with the standard dose (three 2.5-mg doses). Improvements in pulmonary function, clinical resolution of the asthma attacks, and admission rates were used as primary endpoints. Both regimens were part of an overall care plan that involved objective, pretested decision algorithms. RESULTS: In an emergency department, 160 patients who presented with acute exacerbations of asthma received either standard (n = 80) or high-dose (n = 80) albuterol treatment. There were no significant baseline differences in gender, racial composition, clinical signs and symptoms, medication use, or peak expiratory flow (PEF) between the groups. Both treatment schedules were effective, but the high-dose regimen increased lung function more rapidly and to a greater extent than standard-dose therapy. It also resulted in lower charges to third party payers. More subjects attained the discharge criteria quicker and left the emergency department with peak expiratory flows closer to normal. Fewer patients in the high-dose group were admitted, but this trend did not quite reach statistical significance. CONCLUSIONS: Two 5.0-mg treatments of aerosolized albuterol at a 40-minute interval provide effective therapy for acute exacerbations of asthma. This combination of dose and frequency promotes maximum bronchodilatation, increases efficiency, and reduces the risks of undertreatment.

Observations on the effects of aerosolized albuterol in acute asthma.

To determine the dose of albuterol required to terminate acute episodes of asthma, 92 acutely ill subjects received three doses of 2.5 mg each by nebulization every 20 min. Peak expiratory flow rates (PEFR) and signs and symptoms were serially monitored. A dose-response increase in pulmonary function was found, but only 66% of the subjects improved sufficiently to be sent home. Of these, 56% required < or = 5.0 mg of drug to reach the discharge threshold, whereas the remainder needed 7.5 mg. In 34% of participants, albuterol was ineffectual. These individuals were characterized by more severe obstruction at presentation, and after three doses of medication their PEFR still did not exceed 40% of the expected value. Further treatment in the emergency department (ED) or hospital was not immediately helpful, and these patients ultimately required 3.8 +/- 0.4 d of inpatient care to become asymptomatic. There were no discernible differences between responders and nonresponders in the type or quantity of medications used. However, the nonresponders had more severe disease as measured by recurrent hospitalizations and ED visits. This study demonstrates that, in emergency situations, albuterol does not relieve acute airway obstruction in all asthmatic individuals with equal efficacy. Two-thirds of patients are sensitive, and in these patients 5 to 7.5 mg of albuterol provides optimal treatment. In the remainder, albuterol, even in high doses, has little effect for days.

Effect of hypoxia on reflex responses of tracheal submucosal glands.

The effects of moderate sustained normocapnic hypoxia on tracheal submucosal gland reflex responses were studied. Experiments were performed in anesthetized, paralyzed, and mechanically ventilated dogs. The changes in the number of secreting glands and volume of secreted fluid in the subsequent period of time were recorded after 15-30 min of controlled ventilation with room air [arterial PO2 (PaO2) 86 +/- 3 Torr], hypoxic gas mixture (PaO2 49 +/- 4 Torr), or 100% O2 (PaO2 339 +/- 39 Torr), under isocapnic and isohydric conditions. The hillocks method was used to quantify the changes in submucosal gland secretion. The changes in secretion 30 s after stimulation of pulmonary C-fiber receptors by right atrial injection of capsaicin (10 micrograms/kg; n = 10) were markedly lower during moderate hypoxia than in normoxia or hyperoxia. Differences in the number of liquid droplets and the volume of secreted fluid were statistically significant (P < 0.05 and P < 0.001, respectively). Stimulation of airway rapidly adapting receptors by lung deflation increased airway secretion; the number of "hillocks" and the volume of secreted fluid were lower in hypoxic than in hyperoxic state. Differences between response curves for the number of glands activated and secreted volume were statistically significant (P < 0.05 and P < 0.001). The number of glands activated by substance P given locally by arterial infusion was not affected by the state of oxygenation, but the calculated volume of secreted fluid was lower during the hypoxic state than under hyperoxic condition (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pathways and mechanisms involved in neural control of laryngeal submucosal gland secretion.

The purpose of this study was to define the pathways and mechanisms involved in the neural regulation of laryngeal mucosal gland functions. In anesthetized, paralyzed, and artificially ventilated dogs, the responses of laryngeal submucosal glands to stimulation of laryngeal mechanoreceptors and peripheral chemoreceptors were examined by measuring the number of hillocks and volume of secreted fluid before and after activation of sensory nerve endings. Compared with a control period, the number of hillocks and volume of secreted fluid significantly increased (P < 0.05) with mechanical stimulation of the vocal folds (n = 13) and with chemical activation of peripheral chemoreceptors by systemic administration of sodium cyanide (100 micrograms/kg; n = 11). The reflex responses induced by vocal fold stimulation and activation of peripheral chemoreceptors were slightly decreased by interrupting transmission in the recurrent laryngeal nerves (P > 0.05) and were abolished by subsequent sectioning of superior laryngeal nerves or prior intravenous administration of atropine methylnitrate (P < 0.05). In denervated animals, topical application of nicotine on laryngeal epithelium caused significant activation of submucosal glands (P < 0.05). We conclude that laryngeal secretion can be significantly altered reflexly by stimulation of laryngeal sensory nerve endings and peripheral chemoreceptors, that both superior and recurrent laryngeal nerves convey cholinergic outflow to laryngeal submucosal glands, and that nicotine acting locally activates laryngeal submucosal glands.