Akhil Bidani

Permissive hypercapnia in acute respiratory failure.

OBJECTIVE To evaluate the potential efficacy of pressure limitation with permissive hypercapnia in the treatment of acute respiratory failure/adult respiratory distress syndrome on the basis of current theories of ventilator-induced lung injury, potential complications of systemic hypercarbia, and available human outcome studies. DATA SOURCES Articles were identified through MEDLINE, reference citations of published data, and consultation with authorities in their respective fields. STUDY SELECTION Animal model experimentation and human clinical trials were selected on the basis of whether they addressed the questions of pressure limitation with or without hypercapnia, the pathophysiologic effects of hypercapnia, or the concept of ventilator-induced parenchymal lung injury. Frequently cited references were preferentially included. DATA EXTRACTION Data were analyzed with particular emphasis on obtaining the following variables from the clinical studies: peak inspiratory pressures, tidal volumes, minute ventilation, and PCO2. Quantitative aspects of respiratory physiology were used to analyze the theoretical effects of permissive hypercapnia on ventilatory requirements in normal and injured lungs. DATA SYNTHESIS Extensive animal model data support the hypothesis that ventilator-driven alveolar overdistention can induce significant parenchymal lung injury. The heterogeneous nature of lung injury in adult respiratory distress syndrome, with its small physiologic lung volume, may render the lung susceptible to this type of injury through the use of conventional tidal volumes (10 to 15 mL/kg). Permissive hypercapnia is an approach whereby alveolar overdistention is minimized through either pressure or volume limitation, and the potential deleterious consequences of respiratory acidosis are accepted. Uncontrolled human trials of explicit or implicit permissive hypercapnia have demonstrated improved survival in comparison with models of predictive mortality. CONCLUSIONS Avoidance of alveolar overdistention through pressure or volume limitation has significant support based on animal models and computer simulation. Deleterious effects of the associated hypercarbia in severe lung injury do not appear to be a significant limiting factor in preliminary human clinical trials. Although current uncontrolled studies suggest benefit, controlled trials are urgently needed to confirm these findings before adoption of the treatment can be endorsed.

Nonlinear multiscale wavelet diffusion for speckle suppression and edge enhancement in ultrasound images

This paper introduces a novel nonlinear multiscale wavelet diffusion method for ultrasound speckle suppression and edge enhancement. This method is designed to utilize the favorable denoising properties of two frequently used techniques: the sparsity and multiresolution properties of the wavelet, and the iterative edge enhancement feature of nonlinear diffusion. With fully exploited knowledge of speckle image models, the edges of images are detected using normalized wavelet modulus. Relying on this feature, both the envelope-detected speckle image and the log-compressed ultrasonic image can be directly processed by the algorithm without need for additional preprocessing. Speckle is suppressed by employing the iterative multiscale diffusion on the wavelet coefficients. With a tuning diffusion threshold strategy, the proposed method can improve the image quality for both visualization and auto-segmentation applications. We validate our method using synthetic speckle images and real ultrasonic images. Performance improvement over other despeckling filters is quantified in terms of noise suppression and edge preservation indices.

Hyperchloremic Metabolic Acidosis Is a Predictable Consequence of Intraoperative Infusion of 0.9% Saline

Hyperchloremic Metabolic Acidosis Is a Predictable Consequence of Intraoperative Infusion of 0.9% Saline Donald Prough;Akhil Bidani; Anesthesiology

Percutaneous extracorporeal arteriovenous CO2 removal for severe respiratory failure

BACKGROUND In previous animal studies, arteriovenous CO2 removal (AVCO2R) achieved significant reduction in ventilator pressures and improvement in the Pao2 to fraction of inspired oxygen ratio during severe respiratory failure. For our initial clinical experience, 5 patients were approved for treatment of severe respiratory failure and CO2 retention to evaluate the feasibility and safety of percutaneous AVCO2R. METHODS Patients were anticoagulated with heparin (activated clotting time, 260 to 300 seconds), underwent percutaneous femoral cannulation (10F to 12F arterial and 12F to 15F venous catheters), and then were connected to a low-resistance, 2.5-m2 hollow-fiber oxygenator for 72 hours. RESULTS Mean AVCO2R flow at 24, 48, and 72 hours was 837.4+/-73.9, 873+/-83.6, and 750+/-104.5 mL/min, respectively, with no vascular complications and no significant change in heart rate or mean arterial pressure. Removal of CO2 plateaued at an AVCO2R flow of 1086 mL/min with 208 mL/min CO2 removed. Average CO2 transfer at 24 and 48 hours was 142+/-17 and 129+/-16 mL/min. Use of AVCO2R allowed a significant decrease in minute ventilation from 7.2+/-2.3 L/min at baseline to 3.4+/-0.8 L/min at 24 hours. CONCLUSIONS All patients survived the experimental period without adverse sequelae. Percutaneous AVCO2R can achieve approximately 70% CO2 removal in adults with severe respiratory failure and CO2 retention without hemodynamic compromise or instability.

Innate Host Defense of the Lung: Effects of Lung-lining Fluid pH

Lung-lining fluid (LLF) is a primary constituent of the pulmonary host defense system. It is distributed continuously throughout the respiratory tract but is heterogeneous regarding its chemistry and physiology between the conducting airways and alveoli. The conducting airways are lined with airway surface liquid (ASL), a mucus gel-aqueous sol complex that interacts functionally with epithelial cilia as the mucociliary escalator. The alveoli are lined with alveolar subphase fluid (AVSF) and pulmonary surfactant. AVSF sterility is maintained in part by the phagocytic activity of resident alveolar macrophages. Normal ASL and AVSF are both more acidic than blood plasma. However, the details of acid-base regulation differ between the two media. Appreciable transepithelial acid-base flux is possible across the airway epithelium, whereas the alveolar epithelium is relatively impermeable to transepithelial acid-base flux. Moreover, one must consider the influence of resident macrophages on AVSF pH. Resident macrophages occupy a sizable fraction of AVSF by volume and are a substantial source of metabolic H+. The buffering capacities of ASL and AVSF probably are largely due to secreted peptides (e.g., ASL mucins and AVSF surfactant proteins). Acid-base exchange between the extracellular hydrophase and intracellular buffering systems of resident macrophages represents an additional buffer pool for AVSF. The pH of ASL and AVSF can be depressed by disease or inflammation. Low pH is predicted to suppress microbe clearance from the airways and alveoli, increase pathogen survival in both regions, and alter mediator release by resident macrophages and recruited leukocytes thereby increasing the propensity for bystander cell injury. Overall, ASL/AVSF pH is expected to be a major determinant of lung host defense responses.

Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia

OBJECTIVES To determine whether changes in cardiac output, regional blood flow, and intracranial pressure during permissive hypercapnia are blood pH-dependent and can be attenuated by correction of intravascular acidemia. DESIGN Prospective, controlled study. SETTING Research laboratory. SUBJECTS Female Marino ewes. INTERVENTIONS Animals were instrumented with a pulmonary artery catheter, femoral arterial and venous catheters, a catheter in the third cerebral ventricle, and ultrasonic flow probes on the left carotid, superior mesenteric, and left renal arteries 1 wk before experimentation. At initiation of the protocol, ewes underwent endotracheal intubation and mechanical ventilation under general anesthesia. Minute ventilation was reduced to induce hypercapnia with a target PaCO2 of 80 torr (10.7 kPa). In the pH-uncorrected group (n = 6), arterial blood pH was allowed to decreased without treatment. In the pH-corrected group (n = 5), 14.4 mEq/kg of sodium bicarbonate was given intravenously as a bolus to correct arterial blood pH toward a target arterial pH of 7.40 (dose calculated by the Henderson-Hasselbalch equation). MEASUREMENTS AND MAIN RESULTS Arterial blood pH, PCO2, cardiac output, intracranial pressure, and carotid, superior mesenteric, and renal artery blood flow rates were measured at normocapnic baseline and at every hour during hypercapnia for 6 hrs. In the pH-uncorrected group, arterial blood pH decreased from 7.41 +/- 0.03 at normocapnia to 7.14 +/- 0.01 (p < .01 vs. normocapnia) as blood PCO2 increased to 81.2 +/- 1.8 torr (10.8 +/- 0.2 kPa). In the pH-corrected group, arterial blood pH was 7.42 +/- 0.02 at normocapnia and was maintained at 7.37 +/- 0.01 while PaCO2 was increased to 80.3 +/- 0.9 torr (10.7 +/- 0.1 kPa). Significant increases in cardiac output occurred with the initiation of hypercapnia for both groups (pH-uncorrected group: 4.3 +/- 0.6 L/min at normocapnia vs. 6.8 +/- 1.0 L/min at 1 hr [p < .05]; pH-corrected group: 4.1 +/- 0.4 at normocapnia vs. 5.7 +/- 0.4 L/min at 1 hr [p < .05]). However, this increase was sustained only in the uncorrected group. Changes in carotid and mesenteric artery blood flow rates, as a percent of baseline values, showed sustained significant increases in the pH-uncorrected groups (p < .05) and only transient (carotid at 1 hr) or no (superior mesenteric) significant change in the pH-corrected groups. Conversely, significant increases in renal artery blood flow were seen only in the pH-uncorrected group during the last 2 hrs of the experiment (p < .05). Organ blood flow, as a percent of cardiac output, did not change significantly in either group. Intracranial pressure increased significantly in the pH-uncorrected group (9.0 +/- 1.5 mm Hg at normocapnia vs. 26.8 +/- 5.1 at 1 hr, p < .05), and remained increased, while showing no significant change in the pH-corrected group (8.5 +/- 1.6 mm Hg at normocapnia to 7.7 +/- 4.2 at 1 hr). CONCLUSIONS Acute hypercapnia, induced within 1 hr, is associated with significant increases in cardiac output, organ blood flow, and intracranial pressure. These changes can be significantly attenuated by correction of blood pH with the administration of sodium bicarbonate, without adverse effects on hemodynamics.

A closed-loop model of the canine cardiovascular system that includes ventricular interaction

A closed-loop model of cardiopulmonary circulation has been developed for the study of right-left ventricular interaction under physiologically normal and altered conditions. The core model provides insight into the effects of ventricular interaction and pericardial mechanics on hemodynamics. The complete model contains realistic descriptions of (a) the interacting ventricular free walls and septum, (b) the atria, (c) the pericardium, and (d) the systemic and pulmonary vascular loads. The current analysis extends previous work on ventricular interaction and pericardial influence under isolated heart conditions to loading conditions imposed by a closed-loop model of the circulation. A nonlinear least-squares parameter identification method (Levenberg-Marquardt algorithm) is used, together with parameter sensitivity analysis, to estimate the values of key parameters associated with the ventricular and circulation models. Pressure measurements taken at several anatomical locations in the circulation during open-chest experiments on dogs are used as data in the identification process. The complete circulatory model, including septal and pericardial coupling, serves as a virtual testbed for assessing the global affects of localized mechanical or hemodynamic alterations. Studies of both direct and series ventricular interaction, as well as the effect of the pericardium on cardiac performance, are accomplished with this model. Alterations in model parameter values are used to predict the impact of disease and/or clinical interventions on steady-state hemodynamic performance. Additionally, a software package titled CardioPV has been developed to integrate the complete model with data acquisition tools and a sophisticated graphical user interface. The complete software package enables users to collect experimental data, use the data to estimate model parameters, and view the model outputs in an online setting.

Processing and Presentation of a Mycobacterial Antigen 85B Epitope by Murine Macrophages Is Dependent on the Phagosomal Acquisition of Vacuolar Proton ATPase and In Situ Activation of Cathepsin D

Mycobacterium tuberculosis (strain H37Rv) and bacillus Calmette-Guérin (BCG) vaccine inhibit phagosome maturation in macrophages and their effect on processing, and presentation of a secreted Ag85 complex B protein, Ag85B, by mouse macrophages was analyzed. Macrophages were infected with GFP-expressing mycobacterial strains and analyzed for in situ localization of vacuolar proton ATPase (v-ATPase) and cathepsin D (Cat D) using Western blot analysis and immunofluorescence. H37Rv and BCG phagosomes excluded the v-ATPase and maintained neutral pH while the attenuated H37Ra strain acquired v-ATPase and acidified. Mycobacterial phagosomes acquired Cat D, although strains BCG and H37Rv phagosomes contained the inactive 46-kDa form, whereas H37Ra phagosomes had the active 30-kDa form. Infected macrophages were overlaid with a T cell hybridoma specific for an Ag85B epitope complexed with MHC class II. Coincident with active Cat D, H37Ra-infected macrophages presented the epitope to T cells inducing IL-2, whereas H37Rv- and BCG-infected macrophages were less efficient in IL-2 induction. Bafilomycin inhibited the induction of macrophage-induced IL-2 from T cells indicating that v-ATPase was essential for macrophage processing of Ag85B. Furthermore, the small interfering RNA interference of Cat D synthesis resulted in a marked decrease in the levels of macrophage-induced IL-2. Thus, a v-ATPase-dependent phagosomal activation of Cat D was required for the generation of an Ag85B epitope by macrophages. Reduced processing of Ag85B by H37Rv- and BCG-infected macrophages suggests that phagosome maturation arrest interferes with the efficient processing of Ags in macrophages. Because Ag85B is immunodominant, this state may lead to a decreased ability of the wild-type as well as the BCG vaccine to induce protective immunity.

Significant reduction in minute ventilation and peak inspiratory pressures with arteriovenous CO2 removal during severe respiratory failure

OBJECTIVES To quantify CO2 removal using an extracorporeal low-resistance membrane gas exchanger placed in an arteriovenous shunt and evaluate its effects on the reduction of ventilatory volumes and airway pressures during severe respiratory failure induced by smoke inhalation injury. DESIGN Prospective study. SETTING Research laboratory. SUBJECTS Adult female sheep (n = 5). INTERVENTIONS Animals were instrumented with femoral and pulmonary arterial catheters and underwent an LD50 cotton smoke inhalation injury via a tracheostomy under halothane anesthesia. Twenty-four hours after smoke inhalation injury, the animals were reanesthetized and systemically heparinized for cannulation of the left carotid and common jugular vein to construct a simple arteriovenous shunt. A membrane gas exchanger was interposed within the arteriovenous shunt, and blood flow produced by the arteriovenous pressure gradient was unrestricted at the time of complete recovery from anesthesia. CO2 removal by the gas exchanger was measured as the product of the sweep gas flow (FIO2 of 1.0 at 2.5 to 3.0 L/min) and the exhaust CO2 content measured with an inline capnometer. CO2 removed by the animals lungs was determined by the expired gas CO2 content in a Douglas bag. We made stepwise, 20% reductions in ventilator support hourly. We first reduced the tidal volume to achieve a peak inspiratory pressure of < 30 cm H2O, and then we reduced the respiratory rate while maintaining normocapnia. PaO2 was maintained by adjusting the FIO2 and the level of positive end-expiratory pressure. MEASUREMENTS AND MAIN RESULTS Mean blood flow through the arteriovenous shunt ranged from 1154 +/- 82 mL/min (25% cardiac output) to 1277 +/- 38 mL/min (29% cardiac output) over the 6-hr study period. The pressure gradient across the gas exchanger was always < 10 mm Hg. Maximum arteriovenous CO2 removal was 102.0 +/- 9.5 mL/min (96% of total CO2 production), allowing minute ventilation to be reduced from 10.3 +/- 1.4 L/min (baseline) to 0.5 +/- 0.0 L/min at 6 hrs of arteriovenous CO2 removal while maintaining normocapnia. Similarly, peak inspiratory pressure decreased from 40.8 +/- 2.1 to 19.7 +/- 7.5 cm H2O. PaO2 was maintained at > 100 torr (> 13.3 kPa) at maximally reduced ventilator support. Mean arterial pressure and cardiac output did not change significantly as a result of arteriovenous shunting. CONCLUSIONS Extracorporeal CO2 removal using a low-resistance gas exchanger in a simple arteriovenous shunt allows significant reduction in minute ventilation and peak inspiratory pressure without hypercapnia or the complex circuitry and monitoring required for conventional extracorporeal membrane oxygenation. Arteriovenous CO2 removal can be applied as an easy and cost-effective treatment to minimize ventilator-induced barotrauma and volutrauma during severe respiratory failure.

Bactericidal activity of alveolar macrophages is suppressed by V-ATPase inhibition

Bafilomycin A1, a selective inhibitor of V-type H+-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583–1598). Therapeutic uses of the enzyme inhibitor need to consider the agents potential effects on normal (nontumor) cells. This study determined the effects of bafilomycin A1 on resident alveolar macrophages (mφ). Treatment of alveolar mφ with bafilomycin A1 (10 μM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mφ bactericidal capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular killing, bafilomycin A1 significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A1. Comparable changes in ROS generation and mφ spreading were produced by altering cytosolic pH through changes in extracellular pH (pHo) in the absence of bafilomycin A1. These findings suggest that the agents effects on ROS production and mφ spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mφ morphology, leading to the shortening of microvilli and focal loss of surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pHo. The results demonstrate that V-ATPase activity is an important determinant of mφ functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mφ.