John R. Hotchkiss

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.

Effects of mean airway pressure and tidal excursion on lung injury induced by mechanical ventilation in an isolated perfused rabbit lung model.

OBJECTIVE To study the relative contributions of mean airway pressure (mPaw) and tidal excursion (V(T)) to ventilator-induced lung injury under constant perfusion conditions. DESIGN Prospective, randomized study. SETTING Experimental animal laboratory. SUBJECTS Fifteen sets of isolated rabbit lungs. INTERVENTIONS Rabbit lungs were perfused (constant flow, 500 mL/min; capillary pressure, 10 mm Hg) and randomized to be ventilated at identical peak transpulmonary pressure (pressure control ventilation [30 cm H2O and frequency of 20/min]) with three different ventilatory patterns that differed from each other by either mPaw or V(T): group A (low mPaw [13.4+/-0.2 cm H2O]/large V(T) [55+/-8 mL], n = 5); group B (high mPaw [21.2+/-0.2 cm H2O]/small V(T) [18+/-1 mL], n = 5); and group C (high mPaw [21.8+/-0.5 cm H2O]/large V(T) [53+/-5 mL], n = 5). MEASUREMENTS AND MAIN RESULTS Continuous weight gain (edema formation), change in ultrafiltration coefficient (deltaKf, vascular permeability index), and histology (lung hemorrhage) were examined. In group A, deltaKf (0.08+/-0.08 g/min/cm H2O/100 g) was less than in group B (0.28+/-0.19 g/min/cm H2O/100 g) or group C (0.41+/-0.29 g/min/cm H2O/100 g) (p = .05). Group A experienced significantly less hemorrhage (histologic score, 5.4+/-2.2) than groups B (10.3+/-2.1) and C (11.1+/-3.0) (p < .05). A similar trend was observed for weight gain. In contrast to tidal excursion, mPaw was found to be a significant factor for lung hemorrhage and increased Kf (two-way analysis of variance; p < .05). Weight gain (r2 = .54, p = .04) and lung hemorrhage (r2 = .65, p = .01) correlated with the mean pulmonary artery pressure changes that resulted from the implementation of the ventilatory strategies. The difference between the changes in mPaw and mean pulmonary artery pressure linearly predicted deltaKf (p = .005 and .05, respectively, r2 = 0.73). CONCLUSIONS Under these experimental conditions, mPaw contributes more than tidal excursion to lung hemorrhage and permeability alterations induced by mechanical ventilation.

Increased Killing of Staphylococci and Streptococci by Daptomycin Compared with Cefazolin and Vancomycin in an In Vitro Peritoneal Dialysate Model

ABSTRACT 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.

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.

Noninvasive Ventilation: An Emerging Supportive Technique for the Emergency Department

Noninvasive ventilation (NIV) is the provision of ventilatory support to a spontaneously breathing patient without endotracheal intubation. In this review, we detail concerns related to endotracheal intubation and summarize the physiologic effects and clinical application of NIV. We then address the use of NIV in 5 conditions of particular interest to the practitioner of emergency medicine: exacerbated chronic obstructive lung disease, severe asthma, patients who are not candidates for endotracheal intubation, pneumonia, and pulmonary edema.

Interpreting treatment effects from clinical trials in the context of real-world risk information: end-stage renal disease prevention in older adults.

IMPORTANCE Older adults are often excluded from clinical trials. The benefit of preventive interventions tested in younger trial populations may be reduced when applied to older adults in the clinical setting if they are less likely to survive long enough to experience those outcomes targeted by the intervention. OBJECTIVE To extrapolate a treatment effect similar to those reported in major randomized clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of end-stage renal disease (ESRD) to a real-world population of older patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS Simulation study in a retrospective cohort conducted in Department of Veterans Affairs medical centers. We included 371 470 patients 70 years or older with chronic kidney disease. EXPOSURE Level of estimated glomerular filtration rate (eGFR) and proteinuria. MAIN OUTCOMES AND MEASURES Among members of this cohort, we evaluated the expected effect of a 30% reduction in relative risk on the number needed to treat (NNT) to prevent 1 case of ESRD over a 3-year period. These limits were selected to mimic the treatment effect achieved in major trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of ESRD. These trials have reported relative risk reductions of 23% to 56% during observation periods of 2.6 to 3.4 years, yielding NNTs to prevent 1 case of ESRD of 9 to 25. RESULTS The NNT to prevent 1 case of ESRD among members of this cohort ranged from 16 in patients with the highest baseline risk (eGFR of 15-29 mL/min/1.73 m(2) with a dipstick proteinuria measurement of ≥ 2+) to 2500 for those with the lowest baseline risk (eGFR of 45-59 mL/min/1.73 m(2) with negative or trace proteinuria and eGFR of ≥ 60 mL/min/1.73 m2 with dipstick proteinuria measurement of 1+). Most patients belonged to groups with an NNT of more than 100, even when the exposure time was extended over 10 years and in all sensitivity analyses. CONCLUSIONS AND RELEVANCE Differences in baseline risk and life expectancy between trial subjects and real-world populations of older adults with CKD may reduce the marginal benefit to individual patients of interventions to prevent ESRD.

Abnormal nocturnal heart rate variability response among chronic kidney disease and dialysis patients during wakefulness and sleep

BACKGROUND Dialysis patients and patients with chronic kidney disease (CKD) experience a substantial risk for abnormal autonomic function and abnormal heart rate variability (HRV). It remains unknown whether HRV changes across sleep stages in patients with different severity of CKD or dialysis dependency. We hypothesized that high-frequency (HF) HRV (vagal tone) will be attenuated from wakefulness to non-rapid eye movement (NREM) and then to rapid eye movement (REM) sleep in dialysis patients as compared to patients with CKD. METHODS In-home polysomnography was performed in 95 patients with stages 4-5 CKD or end-stage renal disease (ESRD) on haemodialysis (HD) or peritoneal dialysis (PD). HRV was measured using fast Fourier transform of interbeat intervals during wakefulness and sleep. Low-frequency (LF) and HF intervals were generated. Natural logarithm HF (LNHF) and the logarithm LF/HF ratio (sympathovagal tone) were analysed by multivariable quantile regression and generalized estimating equations. RESULTS Of the 95 patients, 63.2% (n = 60) was male, 35.8% (n = 34) was African American and 20.4% (n = 19) was diabetic. Average age was 51.6 ± 15.1 (range 19-82). HRV variables were significantly associated with diabetic status, higher periodic limb movement indices and lower bicarbonate levels. Patients with advanced CKD did not differ from dialysis patients in their inability to increase vagal tone during sleep. During wakefulness, female gender (P = 0.05) was associated with the increases in the vagal tone. CONCLUSIONS Patients with CKD/ESRD exhibit dysregulation of the autonomic nervous system tone manifesting as a failure to increase HRV during wakefulness and sleep. Different patient characteristics are associated with changes in HRV at different sleep stages.

Implications of a biphasic two-compartment model of constant flow ventilation for the clinical setting☆

PURPOSE To investigate the theoretical effects of changing frequency (f), duty cycle (D), or end-inspiratory pause length on the distribution of ventilation and compartmental pressure in a heterogeneous, two compartment pulmonary model inflated by constant flow. METHODS Differential equations governing compartmental volume changes were derived and solved. Validation was conducted in a mechanical lung analogue with two mechanically independent compartments. Model predictions were then generated over wide ranges of f, D, or end-inspiratory pause. RESULTS Disparity of compartmental end-expiratory pressure was identified as the primary mechanism by which changes in f, D, or pause alter the distribution of ventilation. Distribution of peak pressures was less sensitive to such changes. Compartmental ventilation was much less uniform than compartmental peak pressure. Ventilation could not be made entirely uniform by changes of f, D, or pause within the usual clinical range. CONCLUSIONS In a linear, two compartment model of the respiratory system, disparity of compartmental end-expiratory pressures is the primary mechanism by which changes of f, D, or pause alter the distribution of ventilation during inflation with constant flow. Ventilation is less evenly distributed than peak alveolar pressure, and there are limits to the beneficial effects on the distribution of ventilation to be gained from manipulations of machine settings.

Effects of vascular flow and PEEP in a multiple hit model of lung injury in isolated perfused rabbit lungs.

BACKGROUND High vascular flow aggravates lung damage in animal models of ventilator-induced lung injury. Positive end-expiratory pressure (PEEP) can attenuate ventilator-induced lung injury, but its continued effectiveness in the setting of antecedent lung injury is unclear. The objective of the present study was to evaluate whether the application of PEEP diminishes lung injury induced by concurrent high vascular flow and high alveolar pressures in normal lungs and in a preinjury lung model. METHODS Two series of experiments were performed. Fifteen sets of isolated rabbit lungs were randomized into three groups (n = 5): low vascular flow/low PEEP; high vascular flow/low PEEP, and high vascular flow/high PEEP. Subsequently, the same protocol was applied in an additional 15 sets of isolated rabbit lungs in which oleic acid was added to the vascular perfusate to produce mild to moderate lung injury. All lungs were ventilated with peak airway pressure of 30 cm H2O for 30 minutes. Outcome measures included frequency of gross structural failure, pulmonary hemorrhage, edema formation, changes in static compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. RESULTS In the context of high vascular flow, application of a moderate level of PEEP reduced pulmonary rupture, edema formation, and lung hemorrhage. The protective effects of PEEP were not observed in lungs concurrently injured with oleic acid. CONCLUSIONS Under these experimental conditions, PEEP attenuates lung injury in the setting of high vascular flow. The protective effect of PEEP is lost in a two-hit model of lung injury.

Dynamic analysis of peritoneal dialysis associated peritonitis

Peritoneal dialysis associated peritonitis (PDAP) has a historical incidence of approximately 0.3 to 0.5 episodes per patient per year; it represents the leading cause for hospitalization in patients on peritoneal dialysis (PD) and imposes a significant burden of morbidity. PDAP is unique in that each dialysis exchange removes a relatively large fraction of the bacteria laden free intraperitoneal fluid. The attendant removal of bacteria existing in the fluid phase (planktonic bacteria) may interact with bacterial growth to modulate the rate at which the peritoneal burden of microorganisms is reduced. We investigated the potential interactions between bacterial growth dynamics, multiphase bacterial kinetics, and mechanical clearance of microorganisms using simple mathematical analyses based upon in vitro data regarding bacterial growth kinetics in peritoneal dialysate. There are strong dynamic interactions predicted between fluid phase bacterial kinetics, dialysis prescription, and the mechanical clearance of planktonic peritoneal bacteria. There are also strong interactions between fluid phase bacterial kinetics and the kinetics of biofilm/sanctuary site formation and clearance. More frequent exchanges might significantly hasten the clearance of intraperitoneal planktonic bacteria in the absence of catheter-associated bacterial biofilm. The formation of bacteria laden biofilm raises the possibility of a “commensal state,” in which ongoing mechanical clearance limits the total peritoneal bacterial burden.