Inconsequential role for chemerin-like receptor 1 in the manifestation of ozone-induced lung pathophysiology in male mice.

We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a Gi/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-ß-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone.

Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O3), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3-exposed IL-11Rα1-deficient as compared with O3-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3-exposed mice. However, airway responsiveness to acetyl-ß-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.

Chest compression by two-thumb encircling method generates higher carotid artery blood flow in swine infant model of cardiac arrest.

OBJECTIVE: Two-Thumb(TT) technique provides superior quality chest compressions compared with Two-Finger(TF) in an instrumented infant manikin. Whether this translates to differences in blood flow, such as carotid arterial blood flow(CABF), has not been evaluated. We hypothesized that TT-CPR generates higher CABF and Coronary Perfusion Pressure(CPP) compared with TF-CPR in a neonatal swine cardiac arrest model. METHODS: Twelve anesthetized & ventilated piglets were randomized after 3 min of untreated VF to receive either TT-CPR or TF-CPR by PALS certified rescuers delivering a compression rate of 100/min. The primary outcome, CABF, was measured using an ultrasound transonic flow probe placed on the left carotid artery. CPP was calculated and end-tidal CO2(ETCO2) was measured during CPR. Data(mean ± SD) were analyzed and p-value ≤0.05 was considered statistically significant. RESULTS: Carotid artery blood flow (% of baseline) was higher in TT-CPR (66.2 ± 35.4%) than in the TF-CPR (27.5 ± 10.6%) group, p = 0.013. Mean CPP (mm Hg) during three minutes of chest compression for TT-CPR was 12.5 ± 15.8 vs. 6.5 ± 6.7 in TF-CPR, p = 0.41 and ETCO2 (mm Hg) was 29.0 ± 7.4 in TT-CPR vs. 20.7 ± 5.8 in TF-CPR group, p = 0.055. CONCLUSION: TT-CPR achieved more than twice the CABF compared with TF-CPR in a piglet cardiac arrest model. Although CPP and ETCO2 were higher during TT-CPR, these parameters did not reach statistical significance. This study provides direct evidence of increased blood flow in infant swine using TT-CPR and further supports that TT chest compression is the preferred method for CPR in infants.

Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone.

Inhalation of ozone (O3), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O3 Furthermore, each of these aforementioned cells express chemokine (C-C motif) receptor-like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O3-induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O3, we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O3 To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl-ß-methylcholine chloride (respiratory system resistance) in wild-type and mice genetically deficient in Ccrl2 (Ccrl2-deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O3 In air-exposed mice, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased BALF chemerin in mice of both genotypes, yet following O3 exposure, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O3-induced lung pathology.

Ventricular Fibrillation-Induced Cardiac Arrest Results in Regional Cardiac Injury Preferentially in Left Anterior Descending Coronary Artery Territory in Piglet Model.

Objective. Decreased cardiac function after resuscitation from cardiac arrest (CA) results from global ischemia of the myocardium. In the evolution of postarrest myocardial dysfunction, preferential involvement of any coronary arterial territory is not known. We hypothesized that there is no preferential involvement of any coronary artery during electrical induced ventricular fibrillation (VF) in piglet model. Design. Prospective, randomized controlled study. Methods. 12 piglets were randomized to baseline and electrical induced VF. After 5 min, the animals were resuscitated according to AHA PALS guidelines. After return of spontaneous circulation (ROSC), animals were observed for an additional 4 hours prior to cardiac MRI. Data (mean ± SD) was analyzed using unpaired t-test; p value ≤ 0.05 was considered statistically significant. Results. Segmental wall motion (mm; baseline versus postarrest group) in segment 7 (left anterior descending (LAD)) was 4.68 ± 0.54 versus 3.31 ± 0.64, p = 0.0026. In segment 13, it was 3.82 ± 0.96 versus 2.58 ± 0.82, p = 0.02. In segment 14, it was 2.42 ± 0.44 versus 1.29 ± 0.99, p = 0.028. Conclusion. Postarrest myocardial dysfunction resulted in segmental wall motion defects in the LAD territory. There were no perfusion defects in the involved segments.

Plasminogen activator inhibitor-1 does not contribute to the pulmonary pathology induced by acute exposure to ozone.

Expression of plasminogen activator inhibitor (PAI)-1, the major physiological inhibitor of fibrinolysis, is increased in the lung following inhalation of ozone (O3), a gaseous air pollutant. PAI-1 regulates expression of interleukin (IL)-6, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)-2, which are cytokines that promote lung injury, pulmonary inflammation, and/or airway hyperresponsiveness following acute exposure to O3 Given these observations, we hypothesized that PAI-1 contributes to the severity of the aforementioned sequelae by regulating expression of IL-6, KC, and MIP-2 following acute exposure to O3 To test our hypothesis, wild-type mice and mice genetically deficient in PAI-1 (PAI-1-deficient mice) were acutely exposed to either filtered room air or O3 (2 ppm) for 3 h. Four and/or twenty-four hours following cessation of exposure, indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells], pulmonary inflammation (BALF IL-6, KC, MIP-2, macrophages, and neutrophils), and airway responsiveness to aerosolized acetyl-ß-methylcholine chloride (respiratory system resistance) were measured in wild-type and PAI-1-deficient mice. O3 significantly increased indices of lung injury, pulmonary inflammation, and airway responsiveness in wild-type and PAI-1-deficient mice. With the exception of MIP-2, which was significantly lower in PAI-1-deficient as compared to wild-type mice 24 h following cessation of exposure to O3, no other genotype-related differences occurred subsequent to O3 exposure. Thus, following acute exposure to O3, PAI-1 neither regulates pulmonary expression of IL-6 and KC nor functionally contributes to any of the pulmonary pathological sequelae that arise from the noxious effects of inhaled O3.

Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure.

Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines-including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1ß)-promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1ß, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-ß-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology.

Effect of antigen sensitization and challenge on oscillatory mechanics of the lung and pulmonary inflammation in obese carboxypeptidase E-deficient mice.

Atopic, obese asthmatics exhibit airway obstruction with variable degrees of eosinophilic airway inflammation. We previously reported that mice obese as a result of a genetic deficiency in either leptin (ob/ob mice) or the long isoform of the leptin receptor (db/db mice) exhibit enhanced airway obstruction in the presence of decreased numbers of bronchoalveolar lavage fluid (BALF) eosinophils compared with lean, wild-type mice following antigen (ovalbumin; OVA) sensitization and challenge. To determine whether the genetic modality of obesity induction influences the development of OVA-induced airway obstruction and OVA-induced pulmonary inflammation, we examined indices of these sequelae in mice obese as a result of a genetic deficiency in carboxypeptidase E, an enzyme that processes prohormones and proneuropeptides involved in satiety and energy expenditure (Cpe(fat) mice). Accordingly, Cpe(fat) and lean, wild-type (C57BL/6) mice were sensitized to OVA and then challenged with either aerosolized PBS or OVA. Compared with genotype-matched, OVA-sensitized and PBS-challenged mice, OVA sensitization and challenge elicited airway obstruction and increased BALF eosinophils, macrophages, neutrophils, IL-4, IL-13, IL-18, and chemerin. However, OVA challenge enhanced airway obstruction and pulmonary inflammation in Cpe(fat) compared with wild-type mice. These results demonstrate that OVA sensitization and challenge enhance airway obstruction in obese mice regardless of the genetic basis of obesity, whereas the degree of OVA-induced pulmonary inflammation is dependent on the genetic modality of obesity induction. These results have important implications for animal models of asthma, as modeling the pulmonary phenotypes for subpopulations of atopic, obese asthmatics critically depends on selecting the appropriate mouse model.

Use of impedance threshold device in conjunction with our novel adhesive glove device for ACD-CPR does not result in additional chest decompression.

OBJECTIVE: To evaluate the hemodynamic effects of using an adhesive glove device (AGD) to perform active compression-decompression CPR (AGD-CPR) in conjunction with an impedance threshold device (ITD) in a pediatric cardiac arrest model. DESIGN: Controlled, randomized animal study. METHODS: In this study, 18 piglets were anesthetized, ventilated, and continuously monitored. After 3min of untreated ventricular fibrillation, animals were randomized (6/group) to receive either standard CPR (S-CPR), active compression-decompression CPR via adhesive glove device (AGD-CPR) or AGD-CPR along with an ITD (AGD-CPR+ITD) for 2min at 100-120compressions/min. AGD is delivered using a fingerless leather glove with a Velcro patch on the palmer aspect and the counter Velcro patch adhered to the pig's chest. Data (mean±SD) were analyzed using one-way ANOVA with pair wise multiple comparisons to assess differences between groups. p-Value≤0.05 was considered significant. RESULTS: Both AGD-CPR and AGD-CPR+ITD groups produced lower intrathoracic pressure (IttP, mmHg) during decompression phase (-13.4±6.7, p=0.01 and -11.9±6.5, p=0.01, respectively) in comparison to S-CPR (-0.3±4.2). Carotid blood flow (CBF, % of baseline mL/min) was higher in AGD-CPR and AGD-CPR+ITD (respectively 64.3±47.3%, p=0.03 and 67.5±33.1%, p=0.04) as compared with S-CPR (29.1±12.5%). Coronary perfusion pressure (CPP, mmHg) was higher in AGD-CPR and AGD-CPR+ITD (respectively 19.7±4.6, p=0.04 and 25.6±12.1, p=0.02) when compared to S-CPR (9.6±9.1). There was no statistically significant difference between AGD-CPR and AGD-CPR+ITD groups with reference to intra-thoracic pressure, carotid blood flow and coronary perfusion pressure. CONCLUSION: Active compression decompression delivered by this simple and inexpensive adhesive glove device resulted in improved cerebral blood flow and coronary perfusion pressure. There was no statistically significant added effect of ITD use along with AGD-CPR on the decompression of the chest.

Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine.

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-ß-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.

Novel adhesive glove device (AGD) for active compression-decompression (ACD) CPR results in improved carotid blood flow and coronary perfusion pressure in piglet model of cardiac arrest.

OBJECTIVE: ACD-CPR improves coronary and cerebral perfusion. We developed an adhesive glove device (AGD) and hypothesized that ACD-CPR using an AGD provides better chest decompression resulting in improved carotid blood flow as compared to standard (S)-CPR. DESIGN: Prospective, randomized and controlled animal study. METHODS: Sixteen anesthetized and ventilated piglets were randomized after 3 min of untreated VF to receive either S-CPR or AGD-ACD-CPR by a PALS certified single rescuer with compressions of 100 min(-1) and C:V ratio of 30:2. AGD consisted of a modified leather glove exposing the fingers and thumb. A wide Velcro patch was sewn to the palmer aspect of the glove and the counter Velcro patch was adhered to the pig's chest wall. Carotid blood flow was measured using ultrasound. Data (mean±SD) was analyzed using one way ANOVA and unpaired t-test; p-value ≤ 0.05 was considered statistically significant. RESULTS: Right atrial pressure (mmHg) during the decompression phase was lower during AGD-ACD-CPR (-3.32±2.0) when compared to S-CPR (0.86±1.8, p=0.0007). Mean carotid blood flow was 53.2±27.1 (% of baseline blood flow in ml/min) in AGD vs. 19.1±12.5% in S-CPR, p=0.006. Coronary perfusion pressure (CPP, mmHg) was 29.9±5.8 in AGD vs. 22.7±6.9 in S-CPR, p=0.04. There was no significant difference in time to ROSC and number of epinephrine doses. CONCLUSION: Active chest decompression during CPR using this simple and inexpensive adhesive glove device resulted in significantly better carotid blood flow during the first 2 min of CPR.

Two-thumb technique is superior to two-finger technique during lone rescuer infant manikin CPR.

OBJECTIVE: Infant CPR guidelines recommend two-finger chest compression with a lone rescuer and two-thumb with two rescuers. Two-thumb provides better chest compression but is perceived to be associated with increased ventilation hands-off time. We hypothesized that lone rescuer two-thumb CPR is associated with increased ventilation cycle time, decreased ventilation quality and fewer chest compressions compared to two-finger CPR in an infant manikin model. DESIGN: Crossover observational study randomizing 34 healthcare providers to perform 2 min CPR at a compression rate of 100 min(-1) using a 30:2 compression:ventilation ratio comparing two-thumb vs. two-finger techniques. METHODS: A Laerdal Baby ALS Trainer manikin was modified to digitally record compression rate, compression depth and compression pressure and ventilation cycle time (two mouth-to-mouth breaths). Manikin chest rise with breaths was video recorded and later reviewed by two blinded CPR instructors for percent effective breaths. Data (mean+/-SD) were analyzed using a two-tailed paired t-test. Significance was defined qualitatively as p< or =0.05. RESULT: Mean % effective breaths were 90+/-18.6% in two-thumb and 88.9+/-21.1% in two-finger, p=0.65. Mean time (s) to deliver two mouth-to-mouth breaths was 7.6+/-1.6 in two-thumb and 7.0+/-1.5 in two-finger, p<0.0001. Mean delivered compressions per minute were 87+/-11 in two-thumb and 92+/-12 in two-finger, p=0.0005. Two-thumb resulted in significantly higher compression depth and compression pressure compared to the two-finger technique. CONCLUSION: Healthcare providers required 0.6s longer time to deliver two breaths during two-thumb lone rescuer infant CPR, but there was no significant difference in percent effective breaths delivered between the two techniques. Two-thumb CPR had 4 fewer delivered compressions per minute, which may be offset by far more effective compression depth and compression pressure compared to two-finger technique.

Improved chest recoil using an adhesive glove device for active compression-decompression CPR in a pediatric manikin model.

OBJECTIVE: We developed an adhesive glove device (AGD) to perform ACD-CPR in pediatric manikins, hypothesizing that AGD-ACD-CPR provides better chest decompression compared to standard (S)-CPR. DESIGN: Split-plot design randomizing 16 subjects to test four manikin-technique models in a crossover fashion to AGD-ACD-CPR vs. S-CPR. Healthcare providers performed 5min of CPR with 30:2 compression:ventilation ratio in the four manikin models: (1) adolescent; (2) child two-hand; (3) child one-hand; and (4) infant two-thumb. METHODS: Modified manikins recorded compression pressure (CP), compression depth (CD) and decompression depth (DD). The AGD consisted of a modified oven mitt with an adjustable strap; a Velcro patch was sewn to the palmer aspect. The counter Velcro patch was bonded to the anterior chest wall. For infant CPR, the thumbs of two oven mitts were stitched together with Velcro. Subjects were asked to actively pull up during decompression. Subjects' heart rate (HR), respiratory rate (RR) and recovery time (RT) for HR/RR to return to baseline were recorded. Subjects were blinded to data recordings. Data (mean+/-SEM) were analyzed using a two-tailed paired t-test. Significance was defined qualitatively as P< or =0.05. RESULTS: Mean decompression depth difference was significantly greater with AGD-ACD-CPR compared to S-CPR; 38-75% of subjects achieved chest decompression to or beyond baseline. AGD-ACD-CPR provided 6-12% fewer chest compressions/minute than S-CPR group. There was no significant difference in CD, CP, HR, RR and RT within each group comparing both techniques. CONCLUSION: A simple, inexpensive glove device for ACD-CPR improved chest decompression with emphasis on active pull in manikins without excessive rescuer fatigue. The clinical implication of fewer compressions/minute in the AGD group needs to be evaluated.

Effect of alternative chest compression techniques in infant and child on rescuer performance.

OBJECTIVE: Current chest compression (CC) guidelines for an infant recommend a two-finger (TF) technique with lone rescuer and a two- thumb (TT) technique with two rescuers, and for a child either an one hand (OH) or a two hand (TH) technique with one or two rescuers. The effect of a 30:2 compression:ventilation ratio using these techniques on CC quality and rescuer fatigue is unknown. We hypothesized that during lone rescuer CC, TT technique, in infant and TH in child achieve better compression depth (CD) without additional rescuer fatigue compared with TF and OH, respectively. DESIGN: Randomized observational study. SETTING: University-affiliated pediatric hospital. SUBJECTS: Adult healthcare providers certified in basic life support or pediatric advanced life support. INTERVENTIONS: Laerdal baby advanced life support trainer and Resusci junior manikin were modified to digitally record CD, compression pressure (CP) and compression rate. Sixteen subjects were randomized to each of the four techniques to perform 5 minutes of lone rescuer 30:2 compression:ventilation cardiopulmonary resuscitation. Rescuer heart rate (HR) and respiratory rate were recorded continuously and the recovery time interval for HR/respiratory rate to return to baseline was determined. Subjects were blinded to data recording. Groups were compared using two-sample, two-sided Student's t tests. MEASUREMENTS AND MAIN RESULTS: Two-thumb technique generated significantly higher CD and peak CP compared with TF (p < 0.001); there was no significant difference between OH vs. TH. TF showed decay of CD and CP over time compared with TT. Compression rate (per minute) and actual compressions delivered were not significantly different between groups. No significant differences in fatigue and recovery time were observed, except the TT group had greater increase in the rescuer's HR (bpm) from baseline compared with TF group (p = 0.04). CONCLUSIONS: Two-thumb compression provides higher CD and CP compared with TF without any evidence of decay in quality and additional rescuer fatigue over 5 minutes. There was no significant difference in child CC quality or rescuer fatigue between OH and TH. Two-thumb technique is preferred for infant CC and our data support the current guidelines for child CC.

Outcome following cardiopulmonary arrest.

This article summarizes the current state of outcomes and outcome predictors following pediatric cardiopulmonary arrest with special emphasis on neurologic outcome. The authors briefly describe the factors associated with outcome and review clinical signs, electrophysiology, neuroimaging, and biomarkers used to predict outcome after cardiopulmonary arrest. Although clinical signs, imaging, and somatosensory evoked potentials are best associated with outcome, there are limited data to guide clinicians. Combinations of these predictors will most likely improve outcome prediction, but large-scale outcome studies are needed to better define these predictors.

Chest compression quality and rescuer fatigue with increased compression to ventilation ratio during single rescuer pediatric CPR.

OBJECTIVE: The effects of the recommended 30:2 compression:ventilation (C:V) ratio on chest compression rate (CR), compression depth (CD), compression pressure (CP) and rescuer fatigue is unknown during pediatric CPR. We hypothesized that a 30:2 C:V ratio will decrease compression depth and compression pressure and increase rescuer fatigue compared with a 15:2 ratio. DESIGN: Randomized crossover observational study. METHODS: Adolescent, child and infant manikins were modified to digitally record compression rate, compression depth, compression pressure and total compression cycles (CC). BLS or PALS certified volunteers were randomized to five CPR groups: adolescent (AD), child 1-hand (OH), child 2-hand (TH), infant two-finger (TF) and infant two-thumb (TT). Each rescuer performed each ratio for 5 min with the order randomized. Rescuer heart rate (HR) and respiratory rate (RR) were recorded continuously during CPR and used to determine the recovery time (RT) for HR/RR to return to baseline. Data (mean+/-S.D.) were contrasted by paired differences for quantitative data and the sign rank test for ordinal data. RESULTS: Eighty subjects (16 per group) were randomized. The peak compression pressure and compression rate were not different within any group, but total compression cycle were higher in all 30:2 groups. Compression depth (mm) was not significantly different within any group. The rescuer's HR (bpm) increased significantly during 30:2 CPR in AD and OH group with no significant differences in RR and recovery time. Subjects reported that 15:2 CPR was easier to perform (P<0.001). CONCLUSION: During single rescuer pediatric BLS, more compression cycles were achieved with 30:2 C:V ratio without effect on compression depth, pressure and rate. Increased HR with 30:2 C:V ratio was noted during larger manikin CPR without subjective difference of reported fatigue. Most rescuers in AD and TF group did not achieve recommended compression depth regardless of C:V ratio.

Analysis of the evidence for the lower limit of systolic and mean arterial pressure in children.

OBJECTIVE: Systolic blood pressure (SBP) and mean arterial pressure (MAP) are essential evaluation elements in ill children, but there is wide variation among different sources defining systolic hypotension in children, and there are no normal reference values for MAP. Our goal was to calculate the 5th percentile SBP and MAP values in children from recently updated data published by the task force working group of the National High Blood Pressure Education Program and compare these values with the lowest limit of acceptable SBP and MAP defined by different sources. DESIGN: Mathematical analysis of clinical database. METHODS: The 50th and 95th percentile SBP values from task force data were used to derive the 5th percentile value for children from 1 to 17 yrs of age stratified by height percentiles. MAP values were calculated using a standard mathematical formula. Calculated SBP values were compared with systolic hypotension definitions from other sources. Linear regression analysis was applied to create simple formulas to estimate 5th percentile SBP and 5th and 50th percentile MAP for different age groups at the 50th height percentile. RESULTS: A 9-21% range in both SBP and MAP values was noted for different height percentiles in the same age groups. The 5th percentile SBP values used to define hypotension by different sources are higher than our calculated values in children but are lower than our calculated values in adolescents. Clinical formulas for calculation of SBP and MAP (mm Hg) in normal children are as follows: SBP (5th percentile at 50th height percentile) = 2 x age in years + 65, MAP (5th percentile at 50th height percentile) = 1.5 x age in years + 40, and MAP (50th percentile at 50th height percentile) = 1.5 x age in years + 55. CONCLUSION: We developed new estimates for values of 5th percentile SBP and created a table of normal MAP values for reference. SBP is significantly affected by height, which has not been considered previously. Although the estimated lower limits of SBP are lower than currently used to define hypotension, these values are derived from normal healthy children and are likely not appropriate for critically ill children. Our data suggest that the current values for hypotension are not evidence-based and may need to be adjusted for patient height and, most important, for clinical condition. Specifically, we suggest that the definition of hypotension derived from normal children should not be used to define the SBP goal; a higher target SBP is likely appropriate in many critically ill and injured children. Further studies are needed to evaluate the appropriate threshold values of SBP for determining hypotension.

Pediatric critical care community survey of knowledge and attitudes toward therapeutic hypothermia in comatose children after cardiac arrest.

OBJECTIVE: Therapeutic hypothermia improves neurologic outcome and survival after adult out-of-hospital cardiac arrest. To help us design a prospective hypothermia trial in children, we developed a survey to assess current knowledge and attitude of pediatric critical care providers regarding therapeutic hypothermia and potential impediments to implementing a prospective study. DESIGN: Anonymous survey. SETTING: Internet-based survey of pediatric critical care community. INTERVENTIONS: None. RESULTS: A total of 159 responders completed the survey. Most respondents (92%) were fellowship-trained in pediatric critical care, with 9.9 +/- 6.5 yrs of experience. Many (85%) worked in the United States; 89% were in large tertiary care centers with residency or fellowship training programs. Most (65%) were aware of the adult randomized trials of therapeutic hypothermia, but only 9% (always) or 38% (sometimes) utilize this therapy. The most common reason to use hypothermia was likelihood of patient recovery, absence of life-limiting disease, and presence of coma for >/=1 hr after resuscitation. The majority of responders using therapeutic hypothermia cool their patients to 33-35 degrees C for a duration ranging from as short as 12 hrs to as long as 96 hrs; 91% do not actively rewarm the patient. A majority (81%) agree that a randomized, controlled trial of therapeutic hypothermia in children is ethical, and 95% would be willing to randomize their patients. Finally, 81% thought that therapeutic hypothermia should be studied in other ischemic insults and not just cardiac arrest. CONCLUSIONS: Despite widespread awareness of therapeutic hypothermia's beneficial effects after arrest, it is not widely used by pediatric critical care clinicians sampled in our survey. Among those using hypothermia, there is wide variation in methodology and end points of therapy. This seems to result from a lack of evidence, difficulty with the technique, and unavailability of explicit protocols. Pediatric studies are needed to assess the safety, feasibility, and effectiveness of therapeutic hypothermia after cardiac arrest and other causes of brain injury.

Intravascular infusion of acid promotes intrapulmonary inducible nitric oxide synthase activity and impairs blood oxygenation in rats.

OBJECTIVE: To test the hypothesis that intravascular acid infusion promotes intrapulmonary nitric oxide formation by promoting inducible nitric oxide synthase (iNOS) and inhibiting endothelial nitric oxide synthase (eNOS) expression in rats. DESIGN: Prospective, placebo controlled, randomized laboratory study. SETTING: University laboratory. SUBJECTS: Twelve male Sprague-Dawley rats weighing 317 +/- 30 g served as study subjects. All animals were anesthetized, paralyzed, and mechanically ventilated throughout the experiment. INTERVENTIONS: The animals were randomized to receive either 0.1 N hydrochloric acid or 0.9% saline intravenously. The infusions were initially given at a rate of 11 mL/kg/hr for 15 mins and then at a rate of 0.95 mL/kg/hr for the remainder of the experiment. Exhaled nitric oxide concentrations and hemodynamic measurements were monitored throughout the experiment. Lung tissues were harvested for Western blot analysis and immunostaining 4 hrs after starting the intravascular infusion. MEASUREMENT AND MAIN RESULTS: At the end of the experiment, we found more than a four-fold higher concentration of exhaled nitric oxide in the acid-treated animals than in the saline-treated animals (p <.001). Western blot analysis revealed that the acid infusion increased intrapulmonary iNOS concentrations (p <.001), yet it decreased intrapulmonary eNOS concentrations (p =.009). Acid-related lung injury manifested as a decrease in blood oxygen tensions (p =.045) and as an increase in lung homogenate interleukin-6 concentrations (p =.003). CONCLUSIONS: Our results reveal that hydrochloric acid infusion stimulates intrapulmonary nitric oxide formation at least in part by promoting the expression of iNOS. Our findings suggest that correcting acidosis should attenuate iNOS formation. Our data also support the idea that metabolic acidosis itself can lead to impaired intrapulmonary gas exchange and increased expression of pro-inflammatory cytokines such as interleukin-6. Whether the induction of intrapulmonary nitric oxide formation mediates or simply indicates lung injury warrants further investigation.

Dexamethasone suppresses iNOS yet induces GTPCH and CAT-2 mRNA expression in rat lungs.

The in vivo mechanisms by which glucocorticoids inhibit nitric oxide expression await detailed investigation. In cell culture experiments, glucocorticoids have been shown to inhibit inducible nitric oxide synthase (iNOS) formation and activity. Glucocorticoids can inhibit iNOS activity in cultured cells by blocking arginine transport and inhibiting tetrahydrobiopterin biosynthesis. We recently reported that changes in intrapulmonary formation of nitric oxide in endotoxemic rats correspond with changes in transcription of the predominant arginine transporter cationic amino acid transporter (CAT)-2. Realizing that hemorrhagic shock induces nitric oxide overproduction in intact animals, we sought to explore whether glucocorticoids attenuate hemorrhagic shock-induced increases in intrapulmonary nitric oxide formation and whether they might do so by inhibiting the formation of tetrahydrobiopterin, iNOS protein, and CAT-2. We randomly assigned 10 male Sprague-Dawley rats to receive dexamethasone or normal saline. Bleeding the animals to a mean systemic blood pressure of between 40 and 45 mmHg created the hemorrhagic shock. Dexamethasone abrogated the increase in exhaled nitric oxide concentrations caused by hemorrhagic shock. At the end of the experiment, plasma nitrate/nitrite values were lower in the dexamethasone group than in the control group. The iNOS protein concentrations were also lower in the dexamethasone group than in the control group. Dexamethasone decreased the intrapulmonary iNOS mRNA concentrations yet increased both guanosine triphosphate cyclohydrolase I mRNA and CAT-2 mRNA. Our results support the idea that dexamethasone inhibits nitric oxide formation in a manner that is independent of tetrahydrobiopterin and arginine transport yet dependent on downregulation of iNOS mRNA expression.