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John R Hotchkiss

Publications and source records attributed to John R Hotchkiss.

At least 19 recordsLinked to original sources
PubMed2007

Modulating cofactors of acute lung injury 2005-2006: any closer to 'prime time'?

PURPOSE OF REVIEW: Considerable progress has recently been made in understanding the modulation of acute lung injury by cofactors that are not traditionally considered 'pulmonary' in nature. We will review findings regarding some of these extrapulmonary cofactors, focusing on those most readily manipulated in the current clinical setting. RECENT FINDINGS: Recent studies have demonstrated that limiting fluid administration in the setting of acute lung injury might improve surrogate outcomes; that hypercapnea and induced hypothermia might protect against or attenuate acute lung injury; that corticosteroids can improve mechanics but not mortality in acute respiratory distress syndrome; a potential role for concomitant administration of colloid and diuretic in acute lung injury; and the potential benefits of inhaled beta agonists in acute lung injury. SUMMARY: There are a number of simple, low-cost, and rapidly deployable approaches to reducing the severity of acute lung injury that are not directly pulmonary in origin. These interventions could be rapidly implemented in any intensive care unit, once evidence for their efficacy and safety is adequate.

Acute Disease↗
PubMed2006

Contributions of vascular flow and pulmonary capillary pressure to ventilator-induced lung injury.

OBJECTIVE: To evaluate the influence of vascular flow on ventilator-induced lung injury independent of vascular pressures. DESIGN: Laboratory study. SETTING: Hospital laboratory. SUBJECTS: Thirty-two New Zealand White rabbits. INTERVENTIONS: Thirty-two isolated perfused rabbit lungs were allocated into four groups: low flow/low pulmonary capillary pressure; high flow/high pulmonary capillary pressure; low flow/high pulmonary capillary pressure, and high flow/low pulmonary capillary pressure. All lungs were ventilated with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. MEASUREMENTS AND MAIN RESULTS: Outcome measures included frequency of gross structural failure (pulmonary rupture), pulmonary hemorrhage, edema formation, changes in lung compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. Lungs exposed to high pulmonary vascular flow ruptured more frequently, displayed more hemorrhage, developed more edema, suffered larger decreases in compliance, and had larger increases in vascular resistance than lungs exposed to low vascular flows (p < .05 for each pairwise comparison between groups). CONCLUSIONS: These findings suggest that high pulmonary vascular flows might exacerbate ventilator-induced lung injury independent of their effects on pulmonary vascular pressures.

Animals↗
PubMed2006

Pathogen transmission and clinic scheduling.

We developed a model of pathogen dissemination in the outpatient clinic that incorporates key kinetic aspects of the transmission process, as well as uncertainty regarding whether or not each incident patient is contagious. Assigning appointments late in the day to patients suspected of being infectious should decrease pathogen dissemination.

Ambulatory Care Facilities↗
PubMed2005

Inhibition of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C(18)-, C(19)- and C(21)-hydroxysteroids and ketosteroids.

Epidemiologic data suggest a relationship between dietary intake of phytochemicals and a lower incidence of some cancers. Modulation of steroid hormone metabolism has been proposed as a basis for this effect. It has been shown that aromatase, 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) are inhibited by the isoflavones, genistein and daidzein, and by coumestrol. In general, the extent of inhibition has been expressed in terms of IC50-values, which do not give information as to the pattern of inhibition, i.e., competitive, non-competitive, or mixed. Less is known of the effects of these compounds on 3alpha-HSD. The human lung is known to have a high level of 17beta-HSD and 3alpha-HSD activity. During the course of studies to characterize both activities in normal and inflamed lung and lung tumors we noted that 3alpha-HSD activity with 5alpha-DHT of microsomes from normal, adult lung was particularly susceptible to inhibition by coumestrol. To clarify the pattern of inhibition, the inhibition constants Ki and K'i were evaluated from plots of 1/v versus [I] and [S]/v versus [I]. Genistein, daidzein and coumestrol gave mixed inhibition patterns versus both 5alpha-DHT and NADH. In contrast, 5alpha-androstane-3,17-dione and 5alpha-pregnane-3,20-dione were competitive with 5alpha-DHT. NAD inhibited competitively with NADH. Our findings demonstrate that phytochemicals have the potential to inhibit 5alpha-DHT metabolism and thereby affect the androgen status of the human lung. The observation of a mixed inhibition pattern suggests these compounds bind to more than one form of the enzyme within the catalytic pathway.

3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)↗
PubMed2005

An agent-based and spatially explicit model of pathogen dissemination in the intensive care unit.

OBJECTIVE: To develop and disseminate a spatially explicit model of contact transmission of pathogens in the intensive care unit. DESIGN: A model simulating the spread of a pathogen transmitted by direct contact (such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus) was constructed. The modulation of pathogen dissemination attending changes in clinically relevant pathogen- and institution-specific factors was then systematically examined. SETTING AND PATIENTS: The model was configured as a hypothetical 24-bed intensive care unit. The model can be parameterized with different pathogen transmissibilities, durations of caregiver and/or patient contamination, and caregiver allocation and flow patterns. INTERVENTIONS: Pathogen- and institution-specific factors examined included pathogen transmissibility, duration of caregiver contamination, regional cohorting of contaminated or infected patients, delayed detection and isolation of newly contaminated patients, reduction of the number of caregiver visits, and alteration of caregiver allocation among patients. MEASUREMENTS AND MAIN RESULTS: The model predicts the probability that a given fraction of the population will become contaminated or infected with the pathogen of interest under specified spatial, initial prevalence, and dynamic conditions. Per-encounter pathogen acquisition risk and the duration of caregiver pathogen carriage most strongly affect dissemination. Regional cohorting and rapid detection and isolation of contaminated patients each markedly diminish the likelihood of dissemination even absent other interventions. Strategies reducing "crossover" between caregiver domains diminish the likelihood of more widespread dissemination. CONCLUSIONS: Spatially explicit discrete element models, such as the model presented, may prove useful for analyzing the transmission of pathogens within the intensive care unit.

Caregivers↗
PubMed2005

Massive brain injury enhances lung damage in an isolated lung model of ventilator-induced lung injury.

OBJECTIVE: To assess the influence of massive brain injury on pulmonary susceptibility to injury attending subsequent mechanical or ischemia/reperfusion stress. DESIGN: Prospective experimental study. SETTING: Animal research laboratory. SUBJECTS: Twenty-four anesthetized New Zealand White rabbits randomized to control (n = 12) or induced brain injury (n = 12) group. INTERVENTIONS: After randomization, brain injury was induced by inflation of an intracranial balloon-tipped catheter, and animals were ventilated with a tidal volume of 10 mL/kg and zero end-expiratory pressure for 120 mins. Following heart-lung block extraction, isolated and perfused lungs were subjected to injurious ventilation with peak airway pressure 30 cm H2O and positive end-expiratory pressure 5 cm H2O for 30 mins. MEASUREMENTS AND MAIN RESULTS: No difference was observed between groups in gas exchange, lung mechanics, or hemodynamics during the 2-hr in vivo period following induction of brain injury. However, after 30 mins of ex vivo injurious mechanical ventilation, lungs from the brain injury group showed greater change in ultrafiltration coefficient, weight gain, and alveolar hemorrhage (all p < .05). CONCLUSIONS: Massive brain injury might increase lung vulnerability to subsequent injurious mechanical or ischemia-reperfusion insults, thereby increasing the risk of clinical posttransplant graft failure.

Animals↗
PubMed2004

Effect of core body temperature on ventilator-induced lung injury.

OBJECTIVE: Ventilator-induced lung injury is a risk in patients requiring elevated ventilatory support pressures. We hypothesized that thermal stress modulates the development of ventilator-induced lung injury. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Anesthetized rabbits. INTERVENTIONS: Two experimental studies were designed to determine the role of temperature as a cofactor in ventilator-induced lung injury. In the first study, three groups of anesthetized rabbits were randomized to be ventilated for 2 hrs at core body temperatures of 33, 37, or 41 degrees C while ventilated with pressure control ventilation of 15/3 cm H2O (noninjurious settings-control) or 35/3 cm H2O (potentially injurious settings-experimental). To exclude effects arising from cardiac output fluctuations or from extrapulmonary organs, an isolated lung model was used for the second study, perfused at a fixed rate and studied at either 33 degrees C or 41 degrees C. MEASUREMENTS AND MAIN RESULTS: In the first study, the hyperthermic group compared with the hypothermic animals had significantly reduced mean PaO2 (-114 vs. + 14 mm Hg, p <.05), increased lung edema formation (mean wet weight/dry weight ratio of 8.1 vs. 5.7), and altered pressure-volume curves. The hyperthermic isolated, perfused lungs had an increased ultrafiltration coefficient, formed more edema, and experienced greater alveolar hemorrhage than hypothermic lungs. CONCLUSIONS: In two studies of ventilator-induced lung injury in rabbits, maintaining hyperthermia compared with hypothermia augmented the development of lung injury. Similar results from both the in vivo and isolated, perfused lung studies suggest that the observed effects were not due to cardiovascular factors or consequences of heating nonpulmonary organs.

Analysis of Variance↗
PubMed2004

Effects of ventilatory pattern on experimental lung injury caused by high airway pressure.

OBJECTIVE: To determine the influence of clinician-adjustable ventilator settings on the development of ventilator-induced lung injury, as assessed by changes in gas exchange (Pao2), compliance, functional residual capacity, and wet weight to dry weight ratio. DESIGN: Randomized in vivo rabbit study. SETTING: Hospital research laboratory. SUBJECTS: Forty-four anesthetized, mechanically ventilated adult rabbits. INTERVENTIONS: Ventilation for 2 hrs with pressure control ventilation at 45 cm H2O, Fio2 = 0.6, and randomization to one of five ventilatory strategies using combinations of positive end-expiratory pressure (3 or 12 cm H2O), inspiratory time (0.45, 1.0, or 2.0 secs), and frequency (9 or 23/min). MEASUREMENTS AND MAIN RESULTS: Among the ventilator strategies applied, PEEP at 12 cm H2O (elevated positive end-expiratory pressure) and inspiratory time at 0.45 secs (reduced inspiratory time) best preserved Pao2 (p <.003) and compliance (p <.035). During injury development, two consistent changes were observed: Tidal volume increased, and airway pressure waveform was transformed by extending the time to attain target pressure. CONCLUSIONS: In this preclinical model, lung injury was attenuated by decreasing inspiratory time. As lung injury occurred, tidal volume increased and airway pressure waveform changed.

Analysis of Variance↗
PubMed2004

Transient hemodynamic effects of recruitment maneuvers in three experimental models of acute lung injury.

OBJECTIVE: Elevated lung volumes and increased pleural pressures associated with recruitment maneuvers (RM) may adversely affect pulmonary vascular resistance and cardiac filling or performance. We investigated the hemodynamic consequences of three RM techniques after inducing acute lung injury. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Hospital research laboratory. SUBJECTS: Thirteen anesthetized, mechanically ventilated pigs. INTERVENTIONS: We induced three types of acute lung injury: oleic acid injury (n = 4); ventilator-induced lung injury (n = 4); and pneumonia (n = 5). All three models were designed to initiate a similar severity of oxygenation impairment. RM methods tested were sustained inflation, incremental positive end-expiratory pressure (PEEP) with a limited peak pressure, and pressure-controlled ventilation with increased PEEP and a fixed driving pressure. From a baseline PEEP of 8 cm H2O, all interventions were tested using post-RM PEEP levels of 8, 12, and 16 cm H2O. Cardiac output by thermodilution and systemic and pulmonary artery pressures were measured frequently during the RM and for 15 mins after its completion. MEASUREMENTS AND MAIN RESULTS: During the RM, cardiac output decreased to a greater extent in the pneumonia model (0.49 of baseline cardiac output) than in the oleic acid injury (0.67 of baseline) or ventilator-induced lung injury (0.79 of baseline) models. Cardiac output recovered to the baseline value by 5 mins post-RM in oleic acid injury and ventilator-induced lung injury models. However, cardiac output remained decreased 15 mins post-RM in the pneumonia model. There were no differences in hemodynamic parameters among RM methods in oleic acid injury and ventilator-induced lung injury models. In the pneumonia model, however, cardiac output decreased to a greater extent during the RM with sustained inflation (to 0.33 of baseline cardiac output) compared with pressure-controlled ventilation (to 0.68 of baseline). CONCLUSIONS: We conclude that RM transiently but profoundly depressed cardiac output in three models of acute lung injury. The results imply that a lung recruiting maneuver should be used with caution, especially when using sustained inflation in the setting of pneumonia.

Analysis of Variance↗
PubMed2004

Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.

OBJECTIVE: To compare the relative efficacy of three forms of recruitment maneuvers in diverse models of acute lung injury characterized by differing pathoanatomy. DESIGN: We compared three recruiting maneuver (RM) techniques at three levels of post-RM positive end-expiratory pressure in three distinct porcine models of acute lung injury: oleic acid injury; injury induced purely by the mechanical stress of high-tidal airway pressures; and pneumococcal pneumonia. SETTING: Laboratory in a clinical research facility. SUBJECTS: Twenty-eight anesthetized mixed-breed pigs (23.8 +/- 2.6 kg). INTERVENTIONS: The RM techniques tested were sustained inflation, extended sigh or incremental positive end-expiratory pressure, and pressure-controlled ventilation. PRIMARY MEASUREMENTS: Oxygenation and end-expiratory lung volume. MAIN RESULTS: The post-RM positive end-expiratory pressure level was the major determinant of post-maneuver PaO2, independent of the RM technique. The pressure-controlled ventilation RM caused a lasting increase of PaO2 in the ventilator-induced lung injury model, but in oleic acid injury and pneumococcal pneumonia, there were no sustained oxygenation differences for any RM technique (sustained inflation, incremental positive end-expiratory pressure, or pressure-controlled ventilation) that differed from raising positive end-expiratory pressure without RM. CONCLUSIONS: Recruitment by pressure-controlled ventilation is equivalent or superior to sustained inflation, with the same peak pressure in all tested models of acute lung injury, despite its lower mean airway pressure and reduced risk for hemodynamic compromise. Although RM may improve PaO2 in certain injury settings when traditional tidal volumes are used, sustained improvement depends on the post-RM positive end-expiratory pressure value.

Analysis of Variance↗
PubMed2003

Bench-to-bedside review: microvascular and airspace linkage in ventilator-induced lung injury.

Experimental and clinical evidence point strongly toward the potential for microvascular stresses to influence the severity and expression of ventilator associated lung injury. Intense microvascular stresses not only influence edema but predispose to structural failure of the gas-blood barrier, possibly with adverse consequences for the lung and for extrapulmonary organs. Taking measures to lower vascular stress may offer a logical, but as yet unproven, extension of a lung-protective strategy for life support in ARDS.

Animals↗
PubMed2003

Increased killing of staphylococci and streptococci by daptomycin compared with cefazolin and vancomycin in an in vitro peritoneal dialysate model.

Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.

Anti-Bacterial Agents↗
PubMed2002

Tracheal gas insufflation during late exhalation efficiently reduces PaCO(2) in experimental acute lung injury.

OBJECTIVE: Tracheal gas insufflation (TGI) reduces PaCO(2) by flushing the tracheal and mechanical deadspace, and may have its maximum benefit when TGI gas is unopposed by significant expiratory gas flow. Thus, limiting TGI to the late expiratory period may diminish tracheal exposure to TGI gas while preserving the efficacy of TGI. This study examined the gas exchange consequences of such late-expiratory TGI. DESIGN AND SETTING: Randomized controlled trial, animal study. MATERIALS: Eleven pigs. INTERVENTIONS: After stable lung injury was established using oleic acid 11 pigs were ventilated using a standardized lung protective strategy. Phasic expiratory TGI was applied for 30 min stages during the last 20%, 40%, 60%, and 100% of expiration in random sequence. PaCO(2) was continuously measured via an indwelling blood gas analysis system. MEASUREMENTS AND RESULTS: PaCO(2) at baseline was 86.1+/-4.7 mmHg, and decreased progressively with increasing TGI duration of 20%, 40%, and 60%, but not 100%, of expiration (PaCO(2)=75.7+/-5.2, 68.8+/-3.6, 65.1+/-5.3 and 65.2+/-5.2 mmHg, respectively). For all stages the reduction in PaCO(2) relative to baseline was significant. Trends of increasing PaO(2) and airway pressure with increasing TGI duration were noted and most likely associated with a TGI-induced increase in lung volume. CONCLUSIONS: Under these conditions confining TGI to the final 60% of expiration achieved effective PaCO(2) reduction, not significantly different from panexpiratory TGI, while limiting exposure of the trachea to TGI gas, and reducing the potential for TGI-induced hyperinflation. These findings suggest that TGI is most effectively applied in a phasic manner in late expiration, with its duration titrated to effect.

Animals↗
PubMed2002

Oscillations and noise: inherent instability of pressure support ventilation?

Pressure support ventilation (PSV) is almost universally employed in the management of actively breathing ventilated patients with acute respiratory failure. In this partial support mode of ventilation, a fixed pressure is applied to the airway opening, and flow delivery is monitored by the ventilator. Inspiration is terminated when measured inspiratory flow falls below a set fraction of the peak flow rate (flow cutoff); the ventilator then cycles to a lower pressure and expiration commences. We used linear and nonlinear mathematical models to investigate the dynamic behavior of pressure support ventilation and confirmed the predicted behavior using a test lung. Our mathematical and laboratory analyses indicate that pressure support ventilation in the setting of airflow obstruction can be accompanied by marked variations in tidal volume and end-expiratory alveolar pressure, even when subject effort is unvarying. Unstable behavior was observed in the simplest plausible linear mathematical model and is an inherent consequence of the underlying dynamics of this mode of ventilation. The mechanism underlying the observed instability is "feed forward" behavior mediated by oscillatory elevation in end-expiratory pressure. In both mathematical and mechanical models, unstable behavior occurred at impedance values and ventilator settings that are clinically realistic.

Adult↗