Victor J. Cardenas

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.

Partial liquid ventilation in adult patients with ARDS: A multicenter phase I-II trial

OBJECTIVE: To evaluate the safety and efficacy of partial liquid ventilation (PLV) in adult patients with the acute respiratory distress syndrome (ARDS). SUMMARY BACKGROUND DATA: Previous studies have evaluated gas exchange and the safety of PLV in adult patients with severe respiratory failure whose gas exchange was partially provided by extracorporeal life support (ECLS). This is the first experience with adult patients who were not on ECLS. METHODS: Intratracheal perflubron in a total dose of 30.1 +/- 7.1 ml/kg was administered over a period of 45 +/- 9 hours to nine adult patients with mean age = 49 +/- 4 years and mean PaO2/FiO2 ratio = 128 +/- 7 as part of a prospective, multicenter, phase I-II noncontrolled trial. RESULTS: Significant decreases in mean (A-a)DO2 (baseline = 430 +/- 47, 48 hour = 229 +/- 17, p = 0.0127 by ANOVA) and FiO2 (baseline = 0.82 +/- 0.08, 48 hour = 0.54 +/- 0.06, p = 0.025), along with an increase in mean SvO2 (baseline = 75 +/- 3, 48 hour = 85 +/- 2, p = 0.018 by ANOVA) were observed. No significant changes in pulmonary compliance or hemodynamic variables were noted. Seven of the nine patients in this study survived beyond 28 days after initiation of partial liquid ventilation whereas 5 patients survived to discharge. Three adverse events [hypoxia (2) and hyperbilirubinemia (1)] were determined to be severe in nature. CONCLUSIONS: These data suggest that PLV may be performed safely with few related severe adverse effects. Improvement in gas exchange was observed in this series of adult patients over the 48 hours after initiation of PLV.

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.

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.

Total Arteriovenous CO2 Removal: Simplifying Extracorporeal Support for Respiratory Failure

BACKGROUND To reduce the complexity, complications, and cost of conventional extracorporeal membrane oxygenation, we have developed a technique of simplified arteriovenous extracorporeal CO2 removal (AVCO2R) with a low-resistance membrane gas exchanger for total CO2 removal to provide lung rest in the setting of severe respiratory failure. METHODS We initially used AVCO2R in healthy animals to quantify the gas exchange capabilities of the system and establish ventilator management protocols for the subsequent studies of AVCO2R in a large animal model of respiratory failure secondary to a severe smoke inhalation injury. RESULTS In healthy sheep the maximum spontaneous arteriovenous flow ranged from 1,350 to 1,500 mL/min, whereas CO2 removal plateaued at a blood flow of approximately 1,000 mL/min in which 112 +/- 3 mL/min CO2 was removed, allowing an 84% reduction in the minute ventilation of from 6.9 +/- 0.8 L/min to 1.1 +/- 0.4 L/min (p < 0.01) without triggering hypercapnia. A subsequent reduction in extracorporeal flow at a reduced minute volume led to the development of hypercapnia only if it decreased to less than 500 mL/min. We also applied AVCO2R in mechanically ventilated sheep with a severe smoke inhalation injury and removed 95% (111 +/- 4 mL/min) of the total CO2 production. This allowed the minute ventilation to be reduced by 95% and the peak inspiratory pressures by 52% (both p < 0.05) over 6 hours and produced no adverse hemodynamic effects. The partial pressure of arterial oxygen was maintained above 100 mm Hg at a maximally reduced minute volume. The mean AVCO2R flow was 1,213 +/- 29 mL/min, averaging 27% +/- 1% of the cardiac output. CONCLUSIONS We conclude that AVCO2R in a simple arteriovenous shunt is a less complicated technique than extracorporeal membrane oxygenation and is capable of total CO2 removal that allows a significant reduction in the minute ventilation and peak airway pressure during severe respiratory failure.

Rapid Response Team in an Academic Institution: Does It Make a Difference?

BACKGROUND Although data remain contradictory, rapid response systems are implemented across US hospitals. We aimed to determine whether implementation of a rapid response team (RRT) in a tertiary academic hospital improved outcomes. METHODS Our hospital is a tertiary academic medical center with 24-h in-house resident coverage. We conducted a retrospective cohort study comparing 27 months after implementation of the RRT (April 1, 2006, to June 31, 2008) and 9 months before (January 1, 2005, to September 31, 2005). Outcomes included incidence of codes (cardiac and/or respiratory arrests), outcome of the codes, and overall hospital mortality. RESULTS We analyzed 16,244 nonobstetrics hospital admissions and 70,208 patient days in the control period and 45,145 nonobstetrics hospital admissions and 161,097 patient days after the RRT was implemented. The RRT was activated 1,206 times (7.7 calls per 1,000 patient days). There was no difference in the code rate (0.83 vs 0.98 per 1,000 patient days, P = .3). There was a modest but nonsustained improvement in nonobstetrics hospital mortality during the study period (2.40% vs 2.15%; P = .05), which could not be explained by the RRT effect on code rates. The mortality was 2.40% in the control group and 2.06%, 1.94%, and 2.46%, respectively, during the next three consecutive 9-month intervals. CONCLUSIONS In our single-institution study involving an academic hospital with 24-h in-house coverage, we found that RRT implementation did not reduce code rates in the 27 months after intervention. Although there was a decrease in overall hospital mortality, this decrease was small, nonsustained, and not explained by the RRT effect on code rates.

Venovenous carbon dioxide removal in chronic obstructive pulmonary disease: experience in one patient.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. Acute exacerbations of COPD account for up to 84% of the total economic cost of this disease. The altered mechanics of the COPD patient represent a unique challenge to the clinician instituting assisted ventilation in this population. We developed an alternative mode of limited extracorporeal support termed Venovenous carbon dioxide removal (VVCO2R). We report our first case using VVCO2R, a 42-year-old white woman with a history of COPD and asthma, who was a heavy smoker at the time of admission. We utilized a compact, low flow pediatric extracorporeal circuit interposed with a low resistance gas exchange device. Venovenous carbon dioxide removal allowed for a reduction in the patients minute ventilation to 30% of baseline with improved arterial blood gases (ABGs), a reduction in peak airway pressures and improvement in her hyperinflation. Our experience demonstrates that this system can effectively remove CO2 safely in a single cannula venous configuration while maintaining minimal anticoagulation. We believe this system could potentially be utilized in any medical or surgical intensive care unit.

Acute Respiratory Distress Syndrome From Chlorine Inhalation During a Swimming Pool Accident: A Case Report and Review of the Literature

Chlorine inhalation can result in significant morbidity and mortality. The most common clinical ramification is mucosal irritation. Rarely, depending upon the degree of exposure, patients can develop acute respiratory distress syndrome. Management is usually supportive with an unproven role for inhaled or systemic corticosteroids. A case of a young woman who developed respiratory failure secondary to acute respiratory distress syndrome from accidental exposure to chlorine fumes at a community swimming pool is described. The patient suffered a prolonged hospitalization with the need for mechanical ventilation. Despite limited data to support the decision, the patient was started on treatment with corticosteroids. She recovered completely from her illness and was discharged home without supplemental oxygen. A concise discussion of chlorine inhalation injury and a literature review on the utility of inhaled and/or systemic corticosteroids for this clinical entity is presented.

Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and are Susceptible to Innate Inflammation

Background: NEIL2 (Nei-like 2) is a mammalian oxidized base-specific DNA glycosylase. Results: Neil2-null mice accumulate oxidative damage in transcribed genes and are susceptible to inflammatory agents. Conclusion: In long-lived species, NEIL2 plays a critical role in maintaining genomic integrity and tissue homeostasis. Significance: We provide in vivo evidence for NEIL2s role in preferential repair of oxidized bases in active genes in mammals. Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2s role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans.

FcγRIIb Inhibits Allergic Lung Inflammation in a Murine Model of Allergic Asthma

Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcγRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcγRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcγRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcγRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcγRIIb in the lungs. Disruption of IFN-γ gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcγRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcγRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcγRIIb in the lungs by IFN-γ- and Th1-dependent mechanisms. RWE challenge upregulated FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcγRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcγRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-γ dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcγRIIb may be a therapeutic strategy in allergic airway disorders.