Aligning product development and user perspectives: social-behavioural dimensions of multipurpose prevention technologies.

Multipurpose prevention technologies provide a compelling response to the multiple and reinforcing sexual and reproductive health risks faced by women globally. To ensure that this potential is realised, product-specific characteristics and their social-behavioural correlates must be considered early in the product development process. This paper provides an overview of the key user-related social and behavioural dimensions of three broad categories of multipurpose prevention technologies: 1) sustained release vaginal rings, 2) pericoital vaginal products, and 3) co-formulated or co-administered injectables. The authors build upon the broad parameters of Target Product Profiles for such products, aligning them with user perspective considerations.

Improving outcomes of renal transplant recipients with behavioral adherence contracts: a randomized controlled trial.

The objective of this randomized controlled trial was to assess the effects of a 1-year behavioral contract intervention on immunosuppressant therapy (IST) adherence and healthcare utilizations and costs among adult renal transplant recipients (RTRs). The sample included adult RTRs who were at least 1 year posttransplant, taking tacrolimus or cyclosporine and served by a specialty pharmacy. Pharmacy refill records were used to measure adherence and monthly questionnaires were used to measure healthcare utilizations. Direct medical costs were estimated using the 2009 Medicare Expenditure Panel Survey. Adherence was analyzed using the GLM procedure and the MIXED procedure of SAS. Rate ratios and 95% confidence intervals were estimated to quantify the rate of utilizing healthcare services relative to treatment assignment. One hundred fifty RTRs were enrolled in the study. Intervention group RTRs (n = 76) had higher adherence than control group RTRs (n = 74) over the study period (p < 0.01). And 76.1% of the intervention group compared with 42.7% of the control group was not hospitalized during the 1-year study period (RR = 1.785; 95% CI: 1.314, 2.425), resulting in cost savings. Thus, evidence supports using behavioral contracts as an effective adherence intervention that may improve healthcare outcomes and lower costs.

Changes in condom use during a microbicide clinical trial in Pune, India.

Researchers have raised concerns that microbicide use during clinical trials would displace condom use. We sought to understand whether condom use changed for participants in a microbicide clinical trial in Pune, India, to understand whether condom shifts were a legitimate concern. We hypothesize that women participating in a microbicide clinical trial in Pune, India, were more likely, on average, to report condom use at follow-up. We further hypothesize that men, whose female partners participated in a microbicide clinical trial were more likely, on average, to report condom use at follow-up. The outcome measure for reported condom use was a dichotomous variable to indicate whether or not the participant had used a male or female condom with a sexual partner since 2 months before enrollment or since the last survey, depending on the visit. Data are from semi-structured interviews at baseline, 2 months, 4 months, and 6 months with HPTN 059 clinical trial participants (100 women and 57 male partners). We used generalized estimating equations with a logit link function, exchangeable correlation, and a binomial family to model condom use. The odds of condom use for clinical trial women increased from baseline to 6 months by a factor of 3.7 (95% CI: 1.84-7.63) and the change in odds of condom use for clinical trial men from baseline to 6 months increased by a factor of 2.58 (95% CI: 1.37-4.85). We found concerns about microbicide use displacing condom use were not merited in this study population. The percent of participants reporting condom use declined from 4 to 6 months, suggesting that increases in condom use may only be during active study participation. Information about clinical trial factors that enabled these men and women to enact this important HIV prevention behavior is needed to develop interventions.

Serial analysis of biomarkers of acute pancreas allograft rejection.

Pancreas transplant recipients experience graft loss in spite of improvements in immunosuppressant therapies and diagnostic technologies. Therefore, a method to improve detection and management of acute rejection is needed. This longitudinal study investigated the usefulness of three biomarkers, granzyme B, perforin, and human leukocyte antigen-DR alpha (HLA-DR) measured by real-time PCR on peripheral blood mononuclear cells, for their ability to detect acute rejection and its resolution in 13 recipients of pancreas allograft. Data demonstrated that pre-transplant baseline expression of biomarkers decreased following the initiation of immunosuppression. Throughout follow-up (range 3-27 months), individuals without acute rejection episodes had little variation in their biomarker levels. Recipients with biopsy-proven rejection had a significant increase in the levels of biomarkers as early as five wk before clinical rejection diagnosis. Furthermore, all seven patients with biopsy-proven rejection demonstrated a decrease in the levels of granzyme B and perforin following the increased immunosuppression for the treatment of rejection. This is the first clinical serial measurement of biomarkers in recipients of pancreas transplants. The data demonstrate that upregulation of granzyme B, perforin, and HLA-DR in peripheral blood mononuclear cells are sensitive to changes in the immune environment and could possibly be used to identify those patients at higher risk of rejection.

Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women.

BACKGROUND: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. METHODS: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. FINDINGS: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. INTERPRETATION: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents.

Role of reactive oxygen species in reperfusion injury of the rabbit lung.

We have developed a model of reperfusion injury in Krebs buffer-perfused rabbit lungs, characterized by pulmonary vasoconstriction, microvascular injury, and marked lung edema formation. During reperfusion there was a threefold increase in lung superoxide anion (O2-) production, as measured by in vivo reduction of nitroblue tetrazolium, and a twofold increase in the release of O2- into lung perfusate, as measured by reduction of succinylated ferricytochrome c. Injury could be prevented by the xanthine oxidase inhibitor allopurinol, the O2- scavenger SOD, the hydrogen peroxide scavenger catalase, the iron chelator deferoxamine, or the thiols dimethylthiourea or N-acetylcysteine. The protective effect of SOD could be abolished by the anion channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid, indicating that SOD consumes O2- in the extracellular medium, thereby creating a concentration gradient favorable for rapid diffusion of O2- out of cells. Our results extend information about the mechanisms of reperfusion lung injury that have been assembled by studies in other organs, and offer potential strategies for improved organ preservation, for treatment of reperfusion injury after pulmonary thromboembolectomy, and for explanation and therapy of many complications of pulmonary embolism.

Predictive performance of a pharmacodynamic model for oral etoposide.

The objective of this work was to prospectively validate a pharmacodynamic model for 21-day oral etoposide. The model had been developed in 27 untreated patients with stage IIIB or IV non-small cell lung cancer. Treatment consisted of 50 mg/m2/day, p.o., etoposide for 21 days in combination with 100 mg/m2, i.v., cisplatin on day 1 every 28 days for up to 6 courses. Weekly evaluations included etoposide plasma concentrations (Ec, microgram/ml) before the daily dose and WBC and neutrophil counts (ANC, 10(3)/microliters). The relationship between Ec and the pretreatment (WBCp, ANCp) and nadir counts (WBCn, ANCn) in the first course was described as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec)) ANCn = 0.32 (1 + ANCp x e-2.47 x Ec) The same study criteria were used to enter 26 additional patients, and 21 were evaluable for pharmacodynamics (5 had incomplete data). Predicted nadir counts were not significantly different from observed nadir counts (paired t test, P > 0.4). There were 12 and 7 patients correctly predicted to be above and below, respectively, the clinically important ANCn of 0.5 x 10(3)/microliters. The model performed reliably, and therapeutic drug monitoring appears warranted in future studies.

Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer.

PURPOSE: This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC). RESULTS: Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec). CONCLUSION: Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.

Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer.

The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide. In our previous studies, etoposide trough concentrations on this schedule were related to the hematological toxicity, expressed as WBC and neutrophil counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANCn) based on the etoposide concentration (Ec) and the pretreatment count (ANCp): ANCn=0.32(1 + ANCp x e(-2.47 x Ec)). Patients were treated with 40 mg/m2/day etoposide p.o. x 21 days and 100 mg/m2 cisplatin i.v. on day 1. All patients had non-small cell lung cancer stage IIIB or IV, had a performance status of 0-2, and had a median age of 66 (range, 42-80). Etoposide was measured in the plasma on day 8 by high-performance liquid chromatography, and dosage adjustments were made for the remainder of the course. We targeted for grade 3 neutropenia (ANCn, 500 to 999/microl) and attempted to avoid grade 4 neutropenia (ANCn, <500/microl). Of 25 patients entered, 22 were evaluable for therapeutic drug monitoring in the first course. Three patients developed grade 3 neutropenia, and seven patients developed grade 4 neutropenia. Etoposide concentrations were significantly correlated with ANCn in the first course (r=-0.50, P < 0.02). For those patients whose dosages were not changed, the estimated correlation between predicted and actual ANCn was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynamic model was detected. The etoposide dosages were increased in 12 patients and were not changed in the remaining patients. The precision of the model was good in patients whose dosages were not changed but poor in patients whose dosages were increased. The actual observed ANCn was compared with the predicted ANCn based on the pharmacodynamic model. The prediction was considered accurate if the predicted and actual ANCn values were within 500/microl of each other. Using this margin, the ANCn was accurately predicted in 10 of 22 patients. Etoposide concentrations >0.3 microg/ml on this schedule were significantly correlated with combined grades 3 and 4 neutropenia (P < 0.0001). In conclusion, the pharmacodynamic model is statistically sound when applied to a population of patients. However, when applied to individual patients for therapeutic drug monitoring, the model lacks precision and accuracy.

Long chain polyunsaturated fatty acid supplementation in infancy increases length- and weight-for-age but not BMI to 6 years when controlling for effects of maternal smoking.

Long chain polyunsaturated fatty acids (LCPUFA) are added to infant formula but their effect on long-term growth of children is under studied. We evaluated the effects of feeding LCPUFA-supplemented formula (n = 54) compared to control formula (n = 15) throughout infancy on growth from birth-6 years. Growth was described using separate models developed with the MIXED procedure of SAS(®) that included maternal smoking history and gender. Compared to children fed control formula, children who consumed LCPUFA supplemented formula had higher length-/stature-/and weight-for-age percentiles but not body mass index (BMI) percentile from birth to 6 years. Maternal smoking predicted lower stature (2-6 years), higher weight-for-length (birth-18 months) and BMI percentile (2-6 years) independent of LCPUFA effects. Gender interacted with the effect of LCPUFA on stature, and the relationship between smoking and BMI, with a larger effect for boys. Energy intake did not explain growth differences. A relatively small control sample is a limitation.

Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia.

Healthy preterm infants fed formula with long-chain n-3 fatty acids (n-3 LCFAs) from marine oil have better early visual acuity but lower plasma phosphatidylcholine (PC) arachidonic acid (AA) and growth than infants fed formula containing linolenic acid (LLA) as the sole n-3 fatty acid. This randomized, double-blind trial was designed to study the effects of a different source of n-3 LCFAs and a shorter feeding interval on visual acuity (by Teller Acuity Card) and growth of preterm infants (n = 59; 747-1275 g birth wt), some of whom required long periods of supplemental oxygen and developed bronchopulmonary dysplasia (BPD). Infants were studied at 0, 2, 4, 6, 9, and 12 mo past term. Plasma PC AA, and normalized weight, length, and head circumference were not influenced by BPD or n-3 LCFAs except that n-3 LCFA-supplemented infants weighed less at 6 (P<0.05) and 9 (P<0.01) mo and had smaller head circumferences at 9 mo (P<0.05). Compared with control infants, however, those fed n-3 LCFAs had lower weight-for-length at 2, 6, 9, and 12 mo (P<0.0003, P<0.0114, P<0.0008, and P<0.006, respectively). n-3 LCFAs improved early (2-mo) but not later acuity among infants without BPD (P<0.02). Regardless of diet, infants with BPD had poorer grating acuity at 2 (P<0.0002) and 4 (P<0.04) mo but not thereafter.

Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation.

Docosahexaenoic acid (DHA; 22:6n-3) is important for normal visual development. We hypothesized that preterm infants fed formulas with marine oil as a source of DHA would have better visual acuity than infants fed formulas without marine oil, as measured by the Teller Acuity Card procedure. Marine oil (P < 0.001) and age (P < 0.0001) influenced visual acuity, by repeated-measures analysis of variance (ANOVA) corrected for the effect of subject. Marine-oil-supplemented infants had better visual acuity than those fed standard formulas at 2 and 4 mo of age, by Fishers' least-squares difference (LSD). Acuity of both dietary groups improved through 6.5 mo of age, then plateaued. Through 4 mo of age, acuity was inversely related to oxygen supplementation (log10 h) and positively related to DHA status, by general-linear-models (GLM) analysis. After 4 mo of age, birth weight and gestational age were the only variables consistently related to visual acuity by GLM. We conclude that marine-oil-supplemented formula improved visual acuity of preterm infants through 4 mo of age by improving DHA status.

Effect of vitamin A supplementation of intravenous lipids on early vitamin A intake and status of premature infants.

Preterm infants were randomly assigned to receive routine vitamin A supplementation (Regular A) or additional vitamin A in intravenous lipids (High A). Because infants with bronchopulmonary dysplasia (BPD) have poorer vitamin A status than infants who do not develop BPD, High A and Regular A infants were divided by BPD (no or yes) before determining the effects of treatment on intake and plasma concentration of retinol in the first month. Compared with infants without BPD, those with BPD received less retinol (RE.kg-1.d-1) if assigned to Regular A and more if assigned to High A (BPD by vitamin A interaction, P < 0.002). High A-BPD infants compared with Regular A-BPD infants had significantly higher plasma retinol concentrations in the first month. Retinyl palmitate appears to be an effective adjunct to routine vitamin A administration. Infants most likely to benefit from receiving vitamin A in intravenous lipids are those advanced more slowly to full enteral feeding.

Risk factors for postimplantation pancreatitis and pancreatic thrombosis in pancreas transplant recipients.

Reperfusion pancreatitis and pancreatic thrombosis are 2 complications of pancreatic transplantation that are associated with both an increased patient morbidity and a decrease in pancreas graft survival rates. These complications are thought to be related to donor factors, procurement and preservation variables, and postimplantation recipient management. We reviewed our experience with 41 consecutive pancreas transplant patients (18 females, 23 males) performed in association with kidney transplants (n = 34), whole (n = 5) and segmental (n = 2). The average cold ischemia time (CIT) was 11.5 hr. Donor and recipient variables were related to two outcomes: (1) postoperative pancreatitis (n = 9) and (2) postoperative pancreatic thrombosis (n = 6). Steroid administration to the donor resulted in significant reduction of postimplantation pancreatitis (P < 0.001). Also, postoperative pancreatitis was significantly less common (P < 0.02) in recipients given calcium channel blockers in the early postoperative period. Pancreatic thrombosis was significantly more common in male recipients (P < 0.04) and was also significantly related to CIT (P < 0.05). These data indicate that proper donor management and pretreatment with high-dose steroids, together with shortening of CIT and postoperative administration of calcium channel blockers, are protective against pancreatic thrombosis and pancreatitis.

Prediction by postrevascularization biopsies of cadaveric kidney allografts of rejection, graft loss, and preservation nephropathy.

This prospective study of postrevascularization biopsies was undertaken to determine if pathological changes might be correlated with subsequent allograft rejection and loss. Such a relationship, if identified, could be used to predict graft outcome, thus permitting earlier intervention for individuals at an increased risk for rejection or graft loss. Fifty-seven biopsies were obtained, and the number of polymorphonuclear leukocytes marginating in the glomerular loops and peritubular capillaries was documented along with risk factors associated with the recipients' immunological status and with risk factors associated with ischemic preservation injury. The presence of seven PMN leukocytes in the peritubular capillaries is related to the subsequent occurrence of cellular rejection and accurately predicted in 82% of the patients studied whether or not rejection would occur. Mean glomerular PMN leukocyte count was related to cold ischemia time and subsequent graft loss, while an elevated mean glomerular PMN leukocyte count in conjunction with an elevated peritubular PMN leukocyte count was always associated with hyperacute rejection. Focal glomerular thrombosis (less than 50%) and tubular cast formation are manifestations of preservation nephropathy and had no effect on graft outcome. These findings suggest that the peritubular capillaries are a more sensitive target for immune changes and that minor donor/recipient disparities can be detected in the peritubular capillaries while preexisting sensitization to the donor is reflected by concurrent changes in the glomerular and peritubular capillaries.

Infections and the inflammatory response in acute respiratory distress syndrome.

STUDY OBJECTIVE: Systemic inflammatory response syndrome (SIRS) and infections are frequently associated with the development and progression of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). We investigated, at onset and during the progression of ARDS, the relationships among (1) clinical variables and biological markers of SIRS, (2) infections defined by strict criteria, and (3) patient outcome. Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8-in plasma and BAL fluid. METHODS: We prospectively studied two groups of ARDS patients: 34 patients treated conventionally (group 1) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS (group 2). Individual SIRS criteria and SIRS composite score were recorded daily for all patients. Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients received mechanical ventilation. Unless contraindicated, bilateral BAL was performed on day 1, weekly, and when ventilator-associated pneumonia was suspected. Patients were closely monitored for the development of nosocomial infections (NIs). RESULTS: ICU mortality was similar among patients with and without sepsis on admission (54% vs 40%; p < 0.45). Among patients with sepsis-induced ARDS, mortality was higher in those who subsequently developed NIs (71% vs 18%; p < 0.05). At the onset of ARDS, plasma TNF-alpha, IL-1 beta, IL-6, and IL-8 levels were significantly higher (p < 0.0001) in nonsurvivors (NS) and in those with sepsis (p < 0.0001). The NS group, contrary to survivors (S), had persistently elevated plasma IC levels over time. In 17 patients, 36 definitive NIs (17 in group 1 and 19 in group 2) were diagnosed by strict criteria. No definitive or presumed NIs caused an increase in plasma IC levels above patients' preinfection baseline. Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS, were unaffected by the development of NI, and did not correlate with plasma IC levels. CONCLUSIONS: Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels. However, NIs were not associated with an increase in SIRS composite scores, individual SIRS criteria, or plasma IC levels above patients' preinfection baseline. SIRS composite scores over time were similar in S and NS. SIRS criteria, including fever, were found to be nonspecific for NI. Irrespective of etiology of ARDS, plasma IC levels, but not clinical criteria, correlated with patient outcome. These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs.

Elevation of peak expiratory flow by a "spitting" maneuver: measured with five peak flowmeters.

STUDY OBJECTIVE: To determine if peak expiratory flow (PEF) is higher using incorrect technique versus correct technique with five marketed peak flowmeters. DESIGN: Randomized, nonblinded study. SETTING: University pulmonary medicine clinic. PATIENTS: Twenty adults with clinically stable asthma. INTERVENTIONS: After inhaling 2 puffs of albuterol via a valved aerosol holding chamber (Aerochamber), patients were instructed over the next 15 min in correct and incorrect (a "spitting" action) technique when using peak flowmeters. Order of use of five peak flowmeters and correct vs incorrect technique was random. MEASUREMENTS AND RESULTS: PEF (percentage of personal best) was recorded for best of three attempts with correct and incorrect technique. Each peak flowmeter had a statistically significant elevation in PEF with incorrect technique. The range for elevation in PEF using incorrect technique was 12.4 to 68.2% above the PEF with the subject using correct technique. CONCLUSION: Each of the five marketed peak flowmeters had a significant elevation in PEF when a "spitting action" was used. Clinicians need to instruct patients carefully regarding correct technique when using peak flowmeters.

Salmeterol administration by metered-dose inhaler alone vs metered-dose inhaler plus valved holding chamber.

STUDY OBJECTIVE: To determine whether a spacer device designed as a valved holding chamber with a flow signal increases the efficacy of the long-acting beta(2)-agonist, salmeterol, in patients who use incorrect technique with metered-dose inhaler (MDI) alone. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: University hospital outpatient rooms. PATIENTS: Twenty adult outpatients with stable persistent asthma, receiving a daily anti-inflammatory drug. INTERVENTIONS: Patients were randomized to either salmeterol MDI (incorrect use: 1 s after actuating MDI, inhale rapidly) and placebo plus spacer (correct use: inhale slowly as MDI is actuated, continue to inhale slowly and deeply) or placebo MDI (incorrect use) and salmeterol plus spacer (correct use). The following week, patients received the opposite treatment. The dose was two puffs from each device on each treatment day; each puff was separated by 1 min. MEASUREMENTS AND RESULTS: After baseline peak expiratory flow (PEF), salmeterol was administered and serial PEF determined (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h). Administration of salmeterol MDI plus spacer resulted in significantly greater increases in PEF from baseline vs MDI at 4 h (44 L/min vs 10 L/min; p < 0.01) and 6 h (49 L/min vs 24 L/min; p < 0.05). Both methods of administration were equally well tolerated. CONCLUSION: We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly. Further study is needed regarding other errors in MDI technique with salmeterol.

Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome.

BACKGROUND: Inflammatory cytokines (ICs) are important modulators of injury and repair. ICs have been found to be elevated in the BAL of patients with both early and late ARDS. We tested the hypothesis that recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation observed in nonresolving ARDS is related to a persistent inflammatory response. For this purpose, we obtained serial measurements of BAL IC and correlated these levels with lung injury score (LIS), BAL indexes of endothelial permeability (albumin, total protein [TP]), and outcome. METHODS: We prospectively studied 27 consecutive patients with severe medical ARDS. Using enzyme-linked immunosorbent assay methods, levels of tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8 were measured at frequent intervals in both plasma and BAL. In 22 patients, bilateral BAL was obtained on day 1 of ARDS and at weekly intervals when possible. Right and left BALs were analyzed separately for IC levels, total cell count and differential, albumin, TP, and quantitative bacterial cultures. RESULTS: On day 1 of ARDS, the 10 nonsurvivors had significantly higher (p = 0.0002) BAL TNF-alpha, IL-1 beta, IL-6, and IL-8 levels, which remained persistently elevated over time, indicating a continuous injury process. In contrast, the 12 survivors had a lesser elevation and a rapid reduction over time. Initial BAL IL-2 and IL-4 levels were significantly higher in patients with sepsis (p = 0.006); both increased over time in survivors and nonsurvivors. BAL levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 correlated with BAL albumin and TP concentrations but not with LIS or ratio of arterial oxygen tension to inspired oxygen concentration. BAL: plasma ratios were elevated for all measured cytokines, suggesting a pulmonary origin. On day 1 of ARDS, nonsurvivors had significantly higher (p = 0.04) BAL: plasma ratios for TNF-alpha, IL-1 beta, IL-6, and IL-8. Over time, BAL:plasma ratios for TNF-alpha, IL-1 beta and IL-6 remained elevated in nonsurvivors and decreased in survivors. CONCLUSIONS: Our findings indicate that an unfavorable outcome in ARDS is associated with an initial, exaggerated, pulmonary inflammatory response that persists unabated over time. Plasma IC levels parallel changes in BAL IC levels. The BAL:plasma ratio results suggest, but do not prove, a pulmonary origin for IC production. BAL TNF-alpha, IL-1 beta, and IL-8 levels correlated with BAL indices of endothelial permeability. In survivors, reduction in BAL IC levels over time was associated with a decline in BAL albumin and TP levels, suggesting effective repair of the endothelial surface. These findings support a causal relationship between degree and duration of lung inflammation and progression of fibroproliferation in ARDS.

Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS.

BACKGROUND: In late ARDS, a persistent and exaggerated inflammatory response causes recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation. When ARDS patients fail to improve, corticosteroid (CS) rescue treatment frequently leads to rapid improvements in lung function. We tested the hypothesis that response to CS treatment is related to suppressing the inflammatory response by comparing changes in lung function to inflammatory cytokine (IC) levels in the plasma and BAL. METHODS: Blood samples were obtained on days 1, 3, 5, and 7 of ARDS, and on days -5, -3, 0 (initiation of treatment), +3, +5, +7, +10, and +14 of CS treatment. Bilateral BAL was obtained on day 1 of ARDS, before administration of CS treatment, and at weekly intervals. We analyzed changes in IC levels during CS treatment in relation to improvements in lung injury score (LIS), indices of endothelial permeability, and final outcome. We also analyzed data to identify timing to a significant reduction in plasma IC levels and predictors of response. RESULTS: Nine patients entered the study. CS treatment was initiated 15 +/- 9 days into ARDS. Improvement in LIS (> 1-point reduction) was rapid (< 7 days) in five, delayed (< 14 days) in two, and absent in two. Baseline plasma and BAL IC levels in study patients were similar to a previously reported comparison group of 12 ARDS nonsurvivors. No significant changes in plasma and BAL IC levels were observed before CS administration. Following initiation of CS treatment, significant reductions in plasma tumor necrosis factor-alpha and interleukin 6 (IL-6) levels were seen by day 7 in both rapid and delayed responders (p = 0.03). IL-1 beta was significantly reduced by day 5 (p = 0.04) in rapid responders and by day 10 (p = 0.03) in delayed responders. In responders, improvement in LIS and BAL albumin paralleled reduction in plasma and BAL IC levels. At initiation of treatment, rapid responders had significantly lower tumor necrosis factor-alpha and IL-6 levels. Nonresponders had a significantly higher plasma IL-6 level on days 1 to 3 of ARDS (p = 0.004) and lower ratio of arteriolar oxygen tension to inspired oxygen concentration at initiation of treatment (p < 0.01). CONCLUSIONS: In patients with late ARDS and a low likelihood of survival, prolonged corticosteroid rescue treatment was associated with a reduction in plasma and BAL IC levels and parallel improvements in indices of endothelial permeability and LIS.