David E. Carney

Altered alveolar mechanics in the acutely injured lung.

ObjectivesAlterations in alveolar mechanics (i.e., the dynamic change in alveolar size during tidal ventilation) are thought to play a critical role in acute lung injuries such as acute respiratory distress syndrome (ARDS). In this study, we describe and quantify the dynamic changes in alveolar mechanics of individual alveoli in a porcine ARDS model by direct visualization using in vivo microscopy. DesignProspective, observational, controlled study. SettingUniversity research laboratory. SubjectsTen adult pigs. InterventionsPigs were anesthetized and placed on mechanical ventilation, underwent a left thoracotomy, and were separated into the following two groups post hoc: a control group of instrumented animals with no lung injury (n = 5), and a lung injury group in which lung injury was induced by tracheal Tween instillation, causing surfactant deactivation (n = 5). Pulmonary and systemic hemodynamics, blood gases, lung pressures, subpleural blood flow (laser Doppler), and alveolar mechanics (in vivo microscopy) were measured in both groups. Alveolar size was measured at peak inspiration (I) and end expiration (E) on individual subpleural alveoli by image analysis. Histologic sections of lung tissue were taken at necropsy from the injury group. Measurements and Main Results In the acutely injured lung, three distinct alveolar inflation-deflation patterns were observed and classified: type I alveoli (n = 37) changed size minimally (I − E&Dgr; = 367 ± 88 &mgr;m2) during tidal ventilation; type II alveoli (n = 37) changed size dramatically (I − E&Dgr; = 9326 ± 1010 &mgr;m2) with tidal ventilation but did not totally collapse at end expiration; and type III alveoli (n = 12) demonstrated an even greater size change than did type II alveoli (I − E&Dgr; = 15,418 ± 1995 &mgr;m2), and were distinguished from type II in that they totally collapsed at end expiration (atelectasis) and reinflated during inspiration. We have termed the abnormal alveolar inflation pattern of type II and III alveoli “repetitive alveolar collapse and expansion” (RACE). RACE describes all alveoli that visibly change volume with ventilation, regardless of whether these alveoli collapse totally (type III) at end expiration. Thus, the term “collapse” in RACE refers to a visibly obvious collapse of the alveolus during expiration, whether this collapse is total or partial. In the normal lung, all alveoli measured exhibited type I mechanics. Alveoli were significantly larger at peak inspiration in type II (18,266 ± 1317 &mgr;m2, n = 37) and III (15,418 ± 1995 &mgr;m2, n = 12) alveoli as compared with type I (8214 ± 655 &mgr;m2, n = 37). Tween caused a heterogenous lung injury with areas of normal alveolar mechanics adjacent to areas of abnormal alveolar mechanics. Subsequent histologic sections from normal areas exhibited no pathology, whereas lung tissue from areas with RACE mechanics demonstrated alveolar collapse, atelectasis, and leukocyte infiltration. ConclusionAlveolar mechanics are altered in the acutely injured lung as demonstrated by the development of alveolar instability (RACE) and the increase in alveolar size at peak inspiration. Alveolar instability varied from alveolus to alveolus in the same microscopic field and included alveoli that changed area greatly with tidal ventilation but remained patent at end expiration and those that totally collapsed and reexpanded with each breath. Thus, alterations in alveolar mechanics in the acutely injured lung are complex, and attempts to assess what may be occurring at the alveolar level from analysis of inflection points on the whole-lung pressure/volume curve are likely to be erroneous. We speculate that the mechanism of ventilator-induced lung injury may involve altered alveolar mechanics, specifically RACE and alveolar overdistension.

Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass.

BACKGROUND Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB. METHODS AND RESULTS Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (n=3); CPB (n=5), femoral-femoral hypothermic bypass for 1 hour; LPS (n=7), sham bypass followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1 microgram/kg); CPB+LPS (n=6), both insults; and CPB+LPS+CMT-3 (n=5), both insults plus intravenous CMT-3 dosed to obtain a 25-micromol/L blood concentration. CPB+LPS caused severe lung injury, as demonstrated by a significant fall in PaO(2) and an increase in intrapulmonary shunt compared with all groups (P<0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity. CONCLUSIONS All pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effectors.

Dynamic alveolar mechanics and ventilator-induced lung injury.

Objectives:To review the mechanism of dynamic alveolar mechanics (i.e., the dynamic change in alveolar size and shape during ventilation) in both the normal and acutely injured lung; to investigate the alteration in alveolar mechanics secondary to acute lung injury as a mechanism of ventilator-induced lung injury (VILI); and to examine the hypothesis that the reduced morbidity and mortality associated with protective strategies of mechanical ventilation is related to the normalization of alveolar mechanics. Data Extraction and Synthesis:This review is based on original published articles and review papers dealing with the mechanism of lung volume change at the alveolar level and the role of altered alveolar mechanics as a mechanism of VILI. In addition, data from our laboratory directly visualizing dynamic alveolar mechanics is reviewed and related to the literature. Conclusions:The mechanism of alveolar inflation in normal lungs is unclear. Nonetheless, normal alveoli are very stable and change size very little with ventilation. Acute lung injury causes marked destabilization of individual alveoli. Alveolar instability causes pulmonary damage and is believed to be a major component in the mechanism of VILI. Ventilator strategies that reduce alveolar instability may potentially reduce the morbidity and mortality associated with VILI.

Effect of positive end-expiratory pressure and tidal volume on lung injury induced by alveolar instability

IntroductionOne potential mechanism of ventilator-induced lung injury (VILI) is due to shear stresses associated with alveolar instability (recruitment/derecruitment). It has been postulated that the optimal combination of tidal volume (Vt) and positive end-expiratory pressure (PEEP) stabilizes alveoli, thus diminishing recruitment/derecruitment and reducing VILI. In this study we directly visualized the effect of Vt and PEEP on alveolar mechanics and correlated alveolar stability with lung injury.MethodsIn vivo microscopy was utilized in a surfactant deactivation porcine ARDS model to observe the effects of Vt and PEEP on alveolar mechanics. In phase I (n = 3), nine combinations of Vt and PEEP were evaluated to determine which combination resulted in the most and least alveolar instability. In phase II (n = 6), data from phase I were utilized to separate animals into two groups based on the combination of Vt and PEEP that caused the most alveolar stability (high Vt [15 cc/kg] plus low PEEP [5 cmH2O]) and least alveolar stability (low Vt [6 cc/kg] and plus PEEP [20 cmH2O]). The animals were ventilated for three hours following lung injury, with in vivo alveolar stability measured and VILI assessed by lung function, blood gases, morphometrically, and by changes in inflammatory mediators.ResultsHigh Vt/low PEEP resulted in the most alveolar instability and lung injury, as indicated by lung function and morphometric analysis of lung tissue. Low Vt/high PEEP stabilized alveoli, improved oxygenation, and reduced lung injury. There were no significant differences between groups in plasma or bronchoalveolar lavage cytokines or proteases.ConclusionA ventilatory strategy employing high Vt and low PEEP causes alveolar instability, and to our knowledge this is the first study to confirm this finding by direct visualization. These studies demonstrate that low Vt and high PEEP work synergistically to stabilize alveoli, although increased PEEP is more effective at stabilizing alveoli than reduced Vt. In this animal model of ARDS, alveolar instability results in lung injury (VILI) with minimal changes in plasma and bronchoalveolar lavage cytokines and proteases. This suggests that the mechanism of lung injury in the high Vt/low PEEP group was mechanical, not inflammatory in nature.

Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model.

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.

Multiple sequential insults cause post-pump syndrome

BACKGROUND We hypothesize that post-pump syndrome (PPS) following cardiopulmonary bypass (CPB) can be caused by multiple minor insults and that the mechanism of PPS is a priming and subsequent activation of polymorphonuclear (PMN) leukocytes. In this study extensive pathophysiologic and morphometric assessment was undertaken in a porcine model of sequential insult PPS. METHODS Pigs were anesthetized, placed on a ventilator, instrumented for measurements of hemodynamic function, and separated into five groups: (1) Control (n = 4)--surgery only, (2) CPB (n = 4)--placed on femoral-femoral hypothermic (28 degrees C) bypass for 1 h, (3) LPS (n = 6)--underwent sham CPB followed by infusion of low dose endotoxin [E. coli lipopolysaccharide (LPS-1 microg/kg)], (4) Heparin + protamine + LPS (HP + LPS, n = 4)--were heparinized without CPB for 1 h, following which protamine and LPS were infused and (5) CPB + LPS (n = 8)--subjected to both CPB and LPS. RESULTS Only CPB + LPS resulted in acute respiratory distress typical of PPS as indicated by a significant decrease in PaO2 and increase in intrapulmonary shunt fraction (p<0.05). CPB + LPS significantly increased tissue density and the number of sequestered monocytes and PMNs (p<0.05) above all other groups. Alveolar macrophages (AM) increased equally in all groups receiving LPS. CONCLUSIONS CPB primes the inflammatory system causing pulmonary PMN sequestration without lung injury. Exposure to an otherwise benign dose of endotoxin results in activation of the sequestered PMNs causing PPS. This study confirms that PPS can be caused by multiple minor insults.

Thyroid involvement with Langerhans cell histiocytosis in a 3‐year‐old male

We report on the thyroid involvement with Langerhans cell histiocytosis (LCH) in a 3‐year‐old male. The patient presented with goiter and primary hypothyroidism. His goiter caused life‐threatening airway obstruction. He developed locally invasive disease 4 years after his response to LCH therapy. LCH should be suspected as a cause of goiter and thyroidectomy is recommended. Pediatr Blood Cancer 2008;50:726–727.

Alveolar mechanics alter hypoxic pulmonary vasoconstriction.

ObjectivesHypoxic pulmonary vasoconstriction is the primary physiologic mechanism that maintains a proper ventilation/perfusion match, but it fails in diffuse lung injuries such as acute respiratory distress syndrome. Acute respiratory distress syndrome is associated with pulmonary surfactant loss that alters alveolar mechanics (i.e., dynamic change in alveolar size and shape during ventilation), converting normal stable alveoli into unstable alveoli. We hypothesized that alveolar instability stents open pulmonary microvessels and is the mechanism of hypoxic pulmonary vasoconstriction failure associated with acute respiratory distress syndrome. DesignProspective, randomized, controlled study. SettingUniversity research laboratory. SubjectsTen adult pigs. InterventionsAnesthetized ventilated pigs were prepared surgically for hemodynamic monitoring and were subjected to a right thoracotomy. An in vivo microscope was attached to the right lung, and the microvascular response to hypoxia (Fio2, 15%) was measured in a lung with normal stable alveoli and in a lung with unstable alveoli caused by surfactant deactivation (Tween lavage). Measurements and Main ResultsAlveolar instability, defined as the difference between alveolar area at peak inspiration and end expiration and assessed as a percentage change (I-E&Dgr;%), was significantly increased after Tween (23.9 ± 3.0, I-E&Dgr;%) compared with baseline (2.4 ± 1.0, I-E&Dgr;%). Alveolar instability was associated with the following microvascular changes: a) increased vasoconstriction (Tween, 14.9 ± 1.0%) in response to hypoxia compared with baseline (10.8 ± 1.2%, p < .05); and b) increased mean vascular diameter (Tween, 41.2 ± 1.5 &mgr;m) compared with the mean diameter at baseline (24.6 ± 1.0 &mgr;m, p < .05). ConclusionUnstable alveoli stent open pulmonary vessels, which may explain the failure of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome.

Successful treatment of earlobe keloids in the pediatric population

BACKGROUND Keloid scars present a difficult treatment challenge. Recently, intralesional steroid injection has become a common treatment modality [Akoz et al. Aesthetic Plast Surg. 2002;6:184-188; Studdiford et al. JABFM. 2008;21:149-152]. Although this has become a proven treatment technique, there is no standard injection protocol to which treating physicians commonly adhere. We hypothesize that timing of steroid injection may improve outcomes using this treatment technique in combination with lesion excision. METHODS Fifteen patients with 16 earlobe keloids were treated using a standard steroid injection protocol with Kenalog (Bristol-Myers Squibb, New York, NY), in combination with lesion excision. Strict follow-up was enforced, with repeat injections as needed at any sign of abnormal scar formation postoperatively. RESULTS Of 16 lesions, 15 (94%) were treated successfully with no sign of lesion recurrence at 6 months of follow-up. A single lesion was lost to follow-up and presented 18 months postoperatively with recurrence. This lesion was subsequently retreated successfully. CONCLUSIONS Kenalog injection in combination with excision is a well-tolerated and effective treatment of earlobe keloids in the pediatric population. We feel that timing of injection and adherence to a strict follow-up regimen is crucial to success.

Absence of Alveolar Tears in Rat Lungs with Significant Alveolar Instability

Background: Lung injury associated with the acute respiratory distress syndrome can be exacerbated by improper mechanical ventilation creating a secondary injury known as ventilator-induced lung injury (VILI). We hypothesized that VILI could be caused in part by alveolar recruitment/derecruitment resulting in gross tearing of the alveolus. Objectives: The exact mechanism of VILI has yet to be elucidated though multiple hypotheses have been proposed. In this study we tested the hypothesis that gross alveolar tearing plays a key role in the pathogenesis of VILI. Methods: Anesthetized rats were ventilated and instrumented for hemodynamic and blood gas measurements. Following baseline readings, rats were exposed to 90 min of either normal ventilation (control group: respiratory rate 35 min–1, positive end-expiratory pressure 3 cm H2O, peak inflation pressure 14 cm H2O) or injurious ventilation (VILI group: respiratory rate 20 min–1, positive end-expiratory pressure 0 cm H2O, peak inflation pressure 45 cm H2O). Parameters studied included hemodynamics, pulmonary variables, in vivovideo microscopy of alveolar mechanics (i.e. dynamic alveolar recruitment/derecruitment) and scanning electron microscopy to detect gross tears on the alveolar surface. Results: Injurious ventilation significantly increased alveolar instability after 45 min and alveoli remained unstable until the end of the study (electron microscopy after 90 min revealed that injurious ventilation did not cause gross tears in the alveolar surface). Conclusions: We demonstrated that alveolar instability induced by injurous ventilation does not cause gross alveolar tears, suggesting that the tissue injury in this animal VILI model is due to a mechanism other than gross rupture of the alveolus.