Approaching the in vitro clinical trial: engineering organs on chips.

In vitro cell culture and animal models are the most heavily relied upon tools of the pharmaceutical industry. When these tools fail, the results are costly and have at times, proven deadly. One promising new tool to enhance preclinical development of drugs is Organs on Chips (OOCs), proposed as a clinically and physiologically relevant means of modeling health and disease. Bringing the patient from bedside to bench in this form requires that the design, build, and test of OOCs be founded in clinical observations and methods. By creating OOCs as models of the patient, the industry may be better positioned to evaluate medicinal therapeutics.

Implementation of admission decision support for community-acquired pneumonia.

STUDY OBJECTIVES: Considerable variation exists in hospital admission rates for patients with community-acquired pneumonia. Logic to determine need for admission has been proposed by several authors. We compared Intermountain Health Care pneumonia guideline recommendations for inpatient vs outpatient care with actual physician decision making and clinical outcomes before vs after implementation. A secondary objective was to determine whether the pneumonia severity index predicts need for admission in this population. DESIGN: Prospective study after implementation vs historic controls. SETTING: Four ambulatory, urgent-care facilities. PATIENTS: Four hundred sixty-three immunocompetent adults with radiographically confirmed community-acquired pneumonia. INTERVENTION: A pneumonia practice guideline including decision support logic was implemented for a 12-month period. MEASUREMENTS AND RESULTS: After implementation, physicians used the pneumonia guideline form in 90% of cases. The percentage of patients admitted within 30 days decreased from 13.6% to 6.4% (p = 0.01). Only five patients before (2.5%) and three patients after (1.1%, p = 0.3) guideline implementation required subsequent hospital admission within 30 days after initial outpatient treatment. Only two deaths occurred in the study cohort, both outpatients before implementation. The positive predictive value was 14.4%, and the negative predictive value for admission was 98.8% after guideline implementation. Guideline recommendation for admission was more likely to be followed in patients with more risk factors and hypoxemia. CONCLUSIONS: Decreased admission rate was observed after implementation of admission decision support in combination with specific recommendations for outpatient antibiotic therapy. Favorable outpatient outcomes suggest that implementation of decision support was safe.

Increased mortality of older patients with acute respiratory distress syndrome.

OBJECTIVE: To examine the relationship between age and mortality in ARDS patients and evaluate the importance of factors that increase the mortality of older ARDS patients. DESIGN: Prospective inception cohort study. SETTING: Community-based referral hospital. PATIENTS: Two hundred fifty-six ARDS patients identified from May 1987 to December 1990. ARDS was defined by the following: (1) PaO2/PAO2 < or = 0.2; (2) pulmonary capillary wedge pressure < or = 15 mm Hg; (3) total static thoracic compliance < or = 50 mL/cm H2O; (4) bilateral infiltrates on chest radiograph; and (5) an appropriate clinical setting for ARDS. MAIN OUTCOME MEASURES: Comparison of organ failure, incidence of sepsis, patient demographics, arterial oxygenation, and level of support in those 55 years and younger and those older than 55 years of age. Withdrawal of support in patients who died. RESULTS: Seventy-two of 112 patients older than 55 years (64%) died vs 65 of 144 patients 55 years and younger (45%) (p = 0.002). Examination of patient groups using age identified older than 55 years as a "cutpoint" above which mortality was greater (p = 0.002). Older nonsurvivors did not differ from nonsurvivors 55 years or younger with respect to gender, smoking history, ARDS risk factors, ARDS identifying characteristics, APACHE II (acute physiology and chronic health evaluation), number of organ failures, or the incidence of sepsis. In the 48 h prior to death, nonsurvivors 55 years and younger had more organ failure (3.4 +/- 0.2 vs 2.8 +/- 0.2; p = 0.03), higher fraction of inspired oxygen (0.82 +/- 0.03 vs 0.68 +/- 0.03; p = 0.008), and higher positive end-expiratory pressure levels (13 +/- 1 vs 8 +/- 1; p = 0.001) than older nonsurvivors. Despite more severe expression of disease, only 32 (50%) nonsurvivors 55 years and younger had support withdrawn. Significantly more nonsurvivors older than 55 years (73%) had support withdrawn (p = 0.009). Even in the absence of chronic disease states, withdrawal was more likely for patients older than 55 years (21/51) than in those 55 years and younger (3/32; p < 0.001). CONCLUSIONS: Mortality is significantly higher for patients with ARDS older than 55 years. Decisions to withdraw support are made more often in ARDS patients older than 55 years. These data suggest that age bias may influence decisions to withdraw support.

Physician-guided treatment compared with a heparin protocol for deep vein thrombosis.

BACKGROUND: Effective heparin therapy, defined by therapeutic prolongation of the activated partial thromboplastin time (APTT), decreases the risk of recurrent venous thromboembolism. Achieving therapeutic prolongation of the APTT within 24 hours of the start of heparin therapy has proved difficult. We hypothesized that a protocol that delivered high initial heparin infusions to patients without identifiable risk for bleeding complications would decrease the time to achieve a therapeutic anticoagulant effect without increasing the incidence of major bleeding complications. METHODS: To test this hypothesis, we studied concurrent patient cohorts. We defined a therapeutic anticoagulant effect (APTT > 55 seconds) to be an APTT more than 1.5 times the upper limit of normal. Twenty patients with acute symptomatic deep vein thrombosis received a 5000-U heparin bolus, followed by 1680 U/h (low risk to bleed) or 1240 U/h (high risk to bleed), adjusted by protocol-directed response to APTT results. Forty-eight patients with deep vein thrombosis were treated by their physicians. The Kaplan-Meier method was used to examine the proportion of patients who achieved an APTT greater than 55 seconds as a function of time. RESULTS: The two study cohorts did not differ with respect to age, weight, or risk factors for venous thromboembolism. Analysis of Kaplan-Meier curves showed that the heparin protocol decreased the time to achieve a therapeutic anticoagulant effect (P = .025). Ten (91%) of 11 patients (95% confidence interval, 59% to 100%) without risks to bleed who were treated by the heparin protocol and 29 (60%) of 48 patients (95% confidence interval, 45% to 74%) not treated by the protocol had an initial therapeutic APTT (P = .006). CONCLUSION: A protocol that delivers higher initial heparin infusions to patients without identifiable risks for bleeding decreases the time needed to achieve therapeutic prolongation of APTT, when compared with nonprotocol physician management.

Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome.

The impact of a new therapy that includes pressure-controlled inverse ratio ventilation followed by extracorporeal CO2 removal on the survival of patients with severe ARDS was evaluated in a randomized controlled clinical trial. Computerized protocols generated around-the-clock instructions for management of arterial oxygenation to assure equivalent intensity of care for patients randomized to the new therapy limb and those randomized to the control, mechanical ventilation limb. We randomized 40 patients with severe ARDS who met the ECMO entry criteria. The main outcome measure was survival at 30 days after randomization. Survival was not significantly different in the 19 mechanical ventilation (42%) and 21 new therapy (extracorporeal) (33%) patients (p = 0.8). All deaths occurred within 30 days of randomization. Overall patient survival was 38% (15 of 40) and was about four times that expected from historical data (p = 0.0002). Extracorporeal treatment group survival was not significantly different from other published survival rates after extracorporeal CO2 removal. Mechanical ventilation patient group survival was significantly higher than the 12% derived from published data (p = 0.0001). Protocols controlled care 86% of the time. Average PaO2 was 59 mm Hg in both treatment groups. Intensity of care required to maintain arterial oxygenation was similar in both groups (2.6 and 2.6 PEEP changes/day; 4.3 and 5.0 FIO2 changes/day). We conclude that there was no significant difference in survival between the mechanical ventilation and the extracorporeal CO2 removal groups. We do not recommend extracorporeal support as a therapy for ARDS. Extracorporeal support for ARDS should be restricted to controlled clinical trials.

Predicting the presence of pulmonary function impairment in adult respiratory distress syndrome survivors.

Varying degrees of impairment in pulmonary function in survivors of adult respiratory distress syndrome (ARDS) have been reported. Physiologic indices of the severity of disease have been associated with impaired pulmonary function after ARDS, including duration of exposure to FIO2 > 0.6, AaDO2, maximal mean pulmonary artery pressure, lowest total static thoracic compliance, and peak airway pressure. Prediction of impairment following ARDS is difficult because clinical observations may reflect reversible lung injury (e.g. lung edema) and clinical features of ARDS do not predict subsequent function reliably. We developed a severity score to predict the presence of impairment of pulmonary function in 51 ARDS survivors, by examining the following clinical variables: (1) predisposing factor for ARDS; (2) age; (3) sex; (4) severity of hypoxemia; (5) smoking history; (6) number of days of positive pressure ventilation; (7) lowest total static thoracic compliance; (8) maximal mean pulmonary artery pressure, and (9) presence of barotrauma. Pulmonary function studies were performed at least 1 year after ARDS onset. The ARDSscore developed required only two variables: ARDSscorce = duration of positive pressure ventilation (days) minus lowest static thoracic compliance (ml/cm H2O). Significant correlations (p < 0.001) were found between linear regressions of percent predicted FEV1, FVC, TLC and DLCO against ARDSscore. ARDSscore > +20 predicted an 82% probability of impaired FEV1, FVC or TLC and a 100% probability of an impaired DLCO. We conclude that a score based upon duration of positive pressure ventilation and lowest static thoracic compliance predicts impaired pulmonary function more than 1 year after ARDS.

Duplex ultrasonography for the detection of deep vein thrombi after total hip or knee arthroplasty.

The usefulness of real-time duplex ultrasonography (DU) as a screening test for deep vein thrombosis (DVT) in high-risk patients remains uncertain. To determine the sensitivity and specificity of DU for the detection of DVT, the authors prospectively studied 178 consecutive patients after total hip (n = 113) or total knee (n = 66) arthroplasty. The deep veins from the inguinal ligament to the ankle were examined first by continuous wave and then by pulsed Doppler signals as needed with real-time gray-scale ultrasound imaging using the criteria of vein noncompressibility to define DVT. Ascending contrast venography was performed within twelve hours after DU studies. Venograms and DU were interpreted independently. DU was attempted on 177 lower extremities (2 patients refused) but was judged adequate for interpretation for only 145 (82%). Venography could not be performed for 28 lower extremities and was technically inadequate for 8 studies. The primary analysis included 119 examinations for which adequate DU and ascending venograms were interpreted. DU was positive in 17 of 27 lower extremities with DVT (23 calf, 4 proximal) diagnosed by venography (sensitivity = .63; 95% confidence interval [CI] = .42 to .81), and DU was negative in 85 of 92 lower extremities with normal venograms (specificity = .92; 95% CI = .85 to .97). A secondary analysis of 81 prospectively collected anatomically complete DU studies demonstrated a sensitivity of .80 (95% CI = .56 to .94) and a specificity of .90 (95% CI = .80 to .96).(ABSTRACT TRUNCATED AT 250 WORDS)

The adult respiratory distress syndrome. A report of survival and modifying factors.

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury characterized by arterial hypoxemia, reduced thoracic compliance, normal pulmonary capillary wedge pressure, and diffuse infiltrates on chest roentgenograms. Mortality remains high and has been associated with sepsis, organ failure, age, and predisposing factors. We prospectively identified 215 ARDS patients over 34 months to examine how these factors influence outcome. One hundred two (47 percent) of 215 patients survived. Age 65 years or older was associated with a survival of 34 percent, which was statistically different from the 53 percent survival of those patients younger than 65 years (p = 0.02). Aspiration pneumonia as a predisposing factor of ARDS was associated with a better survival (p = 0.04). Survivors had statistically less organ failure and sepsis than did nonsurvivors (p less than 0.05). Cause of death was determined using the criteria of Montgomery et al for irreversible organ dysfunction. Forty-five (40 percent) of our patients died of respiratory failure (not sepsis). We conclude the following: (1) survival in our ARDS patients is different from previous reports; (2) the cause of death in our ARDS patients is different from that reported by Montgomery et al in 1985; and (3) multisystem organ failure, sepsis, age, and some predisposing factors of ARDS continue to be associated with decreased survival of ARDS patients.

Prolonged paralysis after treatment with neuromuscular junction blocking agents.

OBJECTIVES: Previous reports have described prolonged paralysis after treatment with neuromuscular junction blocking agents in critically ill patients. The purpose of this study was to further describe a group of patients who developed prolonged weakness after treatment with these agents. DESIGN: Clinical information, electrodiagnostic and muscle pathology results are described in this group of patients. Clinical information includes diagnoses, dosage of neuromuscular junction blocker, other medications affecting the neuromuscular system, and neuromuscular examination and clinical course. SETTING: All patients were seen in the ICUs of three local hospitals. PATIENTS: Included were critically ill patients with a variety of diagnoses, all of whom developed severe weakness after discontinuation of neuromuscular junction blocking agents. INTERVENTIONS: Electrodiagnostic studies and muscle biopsies were performed on several of the patients. MEASUREMENTS AND MAIN RESULTS: All patients had pronounced weakness without sensory loss. Electrodiagnostic and muscle pathology findings were consistent with failed neuromuscular transmission. Although many patients had disorders or were taking medications that can injure the neuromuscular system, no disorder or medication was common to all. Recovery of strength often took several months and most patients were slow to wean from mechanical ventilator support. CONCLUSIONS: Although alternative explanations cannot be excluded with certainty, the use of neuromuscular junction blocking agents may lead to neurogenic atrophy and care must be taken when using them.

Open lung biopsy does not correlate with pulmonary function after the adult respiratory distress syndrome.

Abnormalities of pulmonary function occur following the adult respiratory distress syndrome (ARDS). To determine if open lung biopsy (OLB) during ARDS predicts late pulmonary function abnormalities, we examined nine survivors of ARDS who had OLB during ARDS. Open lung biopsy was performed within two weeks of the diagnosis of ARDS, and the following were scored by a pulmonary pathologist as to extent and severity: hyaline membranes (HM), interstitial fibrosis (IF), air space organization (AO), interstitial cellularity (IC), and type 2 cell proliferation (T2C). Pulmonary function tests performed at least one year after ARDS were also used for analysis. Percent predicted Dco, TLC, DL/VA, and FVC were regressed against extent, severity, and combined scores. No significant correlation was found despite impressive histologic abnormalities. These data suggest that the severity and extent of HM, IF, AO, T2C, or IC do not correlate with lung function following ARDS.

Increased survival of ARDS patients with severe hypoxemia (ECMO criteria).

The adult respiratory distress syndrome (ARDS) is a form of diffuse lung injury associated with multiple risk factors. Patients with severe hypoxemia who meet blood gas criteria defined by the extracorporeal membrane oxygenation trial (ECMO) of 1974 to 1977 have a reported survival of 11 percent. The reported survival has remained unchanged for 15 years despite numerous technologic advances. We prospectively studied ARDS patients who met ECMO blood gas criteria. One hundred seventy-eight ARDS patients were prospectively screened over a 30-month period. Fifty-one of these patients met ECMO blood gas criteria and 23 (45 percent) survived (p less than 0.001 vs ECMO trial). No obvious differences in etiology, APACHE II score, organ system failure, or the incidence of sepsis was found between survivors and nonsurvivors. We conclude that survival of ARDS patients who met ECMO blood gas criteria in our institution is higher than that previously reported from both other centers and our own hospital.

The role of natural killer cells in histoplasmosis.

The natural killer (NK) cell has been suggested as an early defense mechanism against Histoplasma capsulatum. Homozygous bg/bg mice, heterozygous bg/+ mice, and bg/+ mice treated with anti-asialo GM1 (ASGM1) were used to assess this postulated role. NK cell assays demonstrated that ASGM1 was effective in reduction of NK cell activity in bg/+ mice to levels comparable to bg/bg mice. To test for possible cross reaction with other immune cells and ASGM1, we evaluated lymphocyte and macrophage function. These studies included lymphocyte transformation, delayed-type hypersensitivity (DTH), and macrophage candidacidal activity. We found no evidence of any effects from ASGM1. Mice were evaluated for survival and colony counts after intravenous (i.v.) H. capsulatum challenge. We again confirmed increased susceptibility of bg/bg mice to H. capsulatum, but found no significant differences between bg/+ mice and bg/+ mice treated with ASGM1. Therefore, we conclude that NK cells play no major role in nonspecific early host defenses against H. capsulatum.

Experimental pulmonary histoplasmosis and emphysema.

Chronic pulmonary histoplasmosis often occurs in the setting of emphysema. However, it is unknown whether emphysema directly predisposes to the development of the necrotizing lesions of chronic pulmonary histoplasmosis. We evaluated this possibility using a murine model of pulmonary histoplasmosis. Using intratracheal inoculation of elastase, we induced pulmonary emphysema in Balb/c mice. When mice with emphysema were challenged intranasally with H. capsulatum (HC) yeast cells, the course of their disease was not significantly different from that of normal mice. Mice were also exposed to HC antigens by sublethal intranasal challenge with viable or heat-killed HC, or immunized with histoplasmin. Prior sublethal challenge with viable HC did not cause prolonged illness or increased mortality in the setting of emphysema. In contrast, such mice were protected against a severe rechallenge. Additional studies showed that intranasal administration of heat-killed HC or subcutaneous immunization with histoplasmal antigens had neither protective nor deleterious effects on the course of histoplasmosis. Therefore, in this murine model, we could not substantiate an interaction of underlying emphysema with acute primary or rechallenge pulmonary histoplasmosis.

Chronic Acinetobacter calcoaceticus var anitratus pneumonia.

Gram-negative bacteria most often affect the lung in an acute, suppurative process; however, these organisms may also produce chronic pneumonia. Acinetobacter calcoaceticus has not been reported previously as a cause of chronic pneumonia. We present a patient with fatal, chronic community-acquired Acinetobacter pneumonia with chest wall invasion at autopsy.