Mark E. Wylam

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Effect of 24-hour mandatory versus on-demand critical care specialist presence on quality of care and family and provider satisfaction in the intensive care unit of a teaching hospital*

Objective:The benefit of continuous on-site presence by a staff academic critical care specialist in the intensive care unit of a teaching hospital is not known. We compared the quality of care and patient/family and provider satisfaction before and after changing the staffing model from on-demand to continuous 24-hr critical care specialist presence in the intensive care unit. Design:Two-year prospective cohort study of patient outcomes, processes of care, and family and provider survey of satisfaction, organization, and culture in the intensive care unit. Setting:Intensive care unit of a teaching hospital. Patients:Consecutive critically ill patients, their families, and their caregivers. Interventions:Introduction of night-shift coverage to provide continuous 24-hr on-site, as opposed to on-demand, critical care specialist presence. Measurements and Main Results:Of 2,622 patients included in the study, 1,301 were admitted before and 1,321 after the staffing model change. Baseline characteristics and adjusted intensive care unit and hospital mortality were similar between the two groups. The nonadherence to evidence-based care processes improved from 24% to 16% per patient-day after the staffing change (p = .002). The rate of intensive care unit complications decreased from 11% to 7% per patient-day (p = .023). When adjusted for predicted hospital length of stay, admission source, and do-not-resuscitate status, hospital length of stay significantly decreased during the second period (adjusted mean difference −1.4, 95% confidence interval −0.3 to −2.5 days, p = .017). The new model was considered optimal for patient care by the majority of the providers (78% vs. 38% before the intervention, p < .001). Family satisfaction was excellent during both study periods (mean score 5.87 ± 1.7 vs. 5.95 ± 2.0, p = .777). Conclusions:The introduction of continuous (24-hr) on-site presence by a staff academic critical care specialist was associated with improved processes of care and staff satisfaction and decreased intensive care unit complication rate and hospital length of stay.

Divergent differentiation paths in airway smooth muscle culture: induction of functionally contractile myocytes

We tested the hypothesis that prolonged serum deprivation would allow a subset of cultured airway myocytes to reacquire the abundant contractile protein content, marked shortening capacity, and elongated morphology characteristic of contractile cells within intact tissue. Passage 1 or 2 canine tracheal smooth muscle (SM) cells were grown to confluence, then serum deprived for up to 19 days. During serum deprivation, two differentiation pathways emerged. One-sixth of the cells developed an elongated morphology and aligned into bundles. Elongated myocytes contained cables of contractile myofilaments, dense bodies, gap junctions, and membrane caveoli, ultrastructural features of contractile SM in tissue. These cells immunostained intensely for SM alpha-actin, SM myosin heavy chain (MHC), and SM22 (an SM-specific actin-binding protein), and Western analysis of culture lysates disclosed 1.8 (SM alpha-actin)-, 7.7 (SM MHC)-, and 5.8 (SM22)-fold protein increases during serum deprivation. Immunoreactive M3 muscarinic receptors were present in dense foci distributed throughout elongated, SM MHC-positive myocytes. ACh (10(-3) M) induced a marked shortening (59.7 +/- 14.4% of original length) in 62% of elongated myocytes made semiadherent by gentle proteolytic digestion, and membrane bleb formation (a consequence of contraction) occurred in all stimulated cells that remained adherent and so did not shorten. Cultured airway myocytes that did not elongate during serum deprivation instead became short and flattened, lost immunoreactivity for contractile proteins, lacked the M3 muscarinic-receptor expression pattern seen in elongated cells, and exhibited no contractile response to ACh. Thus we demonstrate that prolonged serum deprivation induces distinct differentiation pathways in confluent cultured tracheal myocytes and that one subpopulation acquires an unequivocally functional contractile phenotype in which structure and function resemble contractile myocytes from intact tissue.

Inhaled helium-oxygen revisited: Effect of inhaled helium-oxygen during the treatment of status asthmaticus in children

OBJECTIVES To assess the effects of breathing a low-density gas mixture on dyspnea and the pulsus paradoxus in children with status asthmaticus. DESIGN In an urban academic tertiary referral center, 18 patients, aged 16 months to 16 years, who were being treated for status asthmaticus with continuously inhaled beta-agonist and intravenously administered methylprednisolone and had a pulsus paradoxus of greater than 15 mm Hg received either an 80%:20% helium-oxygen gas mixture (HELIOX patients) or room air (control patients) at 10 L/min by nonrebreathing face mask in a double-blind, randomized, controlled trial. In all patients, baseline data, including pulsus paradoxus (determined by sphygmomanometer or arterial catheter blood pressure readings), respiratory rate, heart rate, investigator-scored dyspnea index, and oxygen saturation, were compared with values obtained 15 minutes during and after intervention. In a subset of patients, peak flows before and after breathing HELIOX or room air were measured. When clinically indicated, arterial blood gases were obtained. RESULTS The pulsus paradoxus (in millimeters of mercury) fell significantly from an initial mean value of 23.3 +/- 6.8 to 10.6 +/- 2.8 with HELIOX breathing (p < 0.001) and increased again to 18.5 +/- 7.3 after cessation of HELIOX. Peak flow increased 69.4% +/- 12.8% during HELIOX breathing (p < 0.05). The dyspnea index decreased from an initial mean value of 5.7 +/- 1.3 to 1.9 +/- 1.7 with HELIOX breathing (p < 0.0002) and increased again to 4.0 +/- 0.5 after cessation of HELIOX breathing. In control patients, there was no significant difference in pulsus paradoxus or dyspnea index at any time during the study period. Mechanical ventilation was averted in three patients in whom dyspnea lessened dramatically during breathing of HELIOX. CONCLUSION During acute status asthmaticus, inhaled HELIOX significantly lowered the pulsus paradoxus, increased peak flow, and lessened the dyspnea index. Moreover, HELIOX spared three patients a planned intubation and caused no apparent side effects. Thus HELIOX reduces the work of breathing and may forestall respiratory failure in children with status asthmaticus, thus preventing the need for mechanical ventilation.

Nitric oxide and septic vascular dysfunction.

S eptic shock is characterized by a systemic inflammatory response syndrome, hypotension with vasopressor-resistant systemic vasodilation, and development of multiple organ hypoperfusion and dysfunction (1). Organ failure in sepsis is thought to be mediated by a combination of direct parenchymal cytotoxicity and locally ineffective delivery or use of oxygen and nutrients (2). Sepsis is the leading cause of death in noncoronary intensive care units (1), while infectious disease, in general, is the third leading cause of death (after cardiovascular disease and cancer) in the United States (3). The mortality of patients with septic shock is approximately 50% (4,5), and it is an important cause of early (, 3 days) death in patients with severe sepsis (5). Sepsis leads to elaboration of a self-amplifying cascade of proor antiinflammatory cytokines and mediators, including a number of vasoactive substances (prostaglandins, nitric oxide [NO], endothelins, platelet activating factor [PAF], leukotrienes) (1). NO appears to be an important mediator of impaired vascular responsiveness to vasoconstrictor agents in sepsis. Inhibition of NO synthesis improves vasopressor-responsiveness and increases blood pressure (BP) in most septic animal models and in humans; however, animal studies reveal numerous adverse effects of NO synthase (NOS) inhibition (6–10). This article reviews the role of NO in the pathogenesis of septic vascular dysfunction, focusing on the physiologic role of endothelial NO production in regulating blood flow distribution and tissue perfusion and the adverse effects of sepsis and of NOS inhibitors on endothelial function. Contributions of NO to the physiologic regulation of renal function are reviewed, and the renal effects of sepsis and NOS inhibition are discussed in detail. The effects of sepsis and NOS inhibition in the pulmonary and splanchnic circulations are likewise reviewed. We discuss promising data suggesting that selective inhibition of the inducible NOS (iNOS) isoform favorably affects global and regional hemodynamics in animal experiments and improves short-term survival when compared with either standard (catecholamine) or isoform-nonselective NOS inhibitor support. Finally, we conclude that the balance between beneficial and deleterious effects of NO in human sepsis will ultimately determine whether NOS inhibitors become standard components of septic shock therapy.

Acute eosinophilic pneumonia: A cause of reversible, severe, noninfectious respiratory failure

We report a case of acute eosinophilic pneumonia associated with adult respiratory distress syndrome in an adolescent. This entity should be considered in the differential diagnosis in previously well children and adolescents who are seen with unexplained respiratory failure and who have many eosinophils in bronchoalveolar lavage fluid. Prompt recognition of this rapidly reversible noninfectious disorder and institution of corticosteroids may be lifesaving.

Eosinophils, major basic protein, and polycationic peptides augment bovine airway myocyte Ca2+mobilization

Previous studies in vivo or in isolated airway preparations have suggested that eosinophil-derived polycationic proteins enhance airway smooth muscle tone in an epithelium-dependent manner. We assessed the direct effects of activated human eosinophil supernatant, major basic protein (MBP), and polycationic polypeptides on basal and agonist-stimulated intracellular Ca2+ concentrations ([Ca2+]i) in cultured bovine tracheal smooth muscle (TSM) cells. A 1-h incubation of myocytes with activated eosinophil buffer resulted in a doubling of basal [Ca2+]i and increased responsivity to histamine compared with myocytes that were exposed to sham-activated eosinophil buffer. In addition, concentration-dependent acute transient increases and subsequent 1-h sustained elevations of basal [Ca2+]i were observed immediately after addition of MBP and model polycationic proteins. Finally, both peak and plateau [Ca2+]i responses to bradykinin addition were augmented significantly in cultured myocytes that had been exposed to low concentrations of MBP or model polycationic proteins but were inhibited at greater concentrations. This elevated [Ca2+]i to polycationic proteins was manifest in epithelium-denuded bovine TSM strips as concentration-dependent increased basal tone. We conclude that activated eosinophil supernatant, MBP, and other polycationic proteins have a direct effect on both basal and subsequent agonist-elicited Ca2+ mobilization in cultured TSM cells; TSM strips in vitro demonstrated, respectively, augmented and diminished responses to the contractile agonist acetylcholine. It is possible that alteration in myocyte Ca2+ mobilization induced by these substances may influence clinical states of altered airway tone, such as asthma.

Paradoxical use of tumor necrosis factor in treating pulmonary edema

Most recently, in a scientific collaboration effort between APEPTICO, the Vascular Biology Center of the Georgia Regents University (Prof. Dr. Rudolf Lucas, USA), and the Institute of Pharmacology and Toxicology of the University of Vienna (Prof. Dr. Rosa Lemmens-Gruber, Austria), the detailed mechanism has been discovered how APEPTICO’s clinically stage “AP301-peptide” (identical to the lectin-like domain of native TNF-alpha) activates the specific pulmonary ion channel “ENaC” to result in “Activation of Lung Oedema Clearance”.

USE OF INHALED NITRIC OXIDE IN THE ADULT RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH MILIARY TUBERCULOSIS. 246

USE OF INHALED NITRIC OXIDE IN THE ADULT RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH MILIARY TUBERCULOSIS. 246