Krishnan Raghavendran

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.

The evolution of isolated bilateral lung contusion from blunt chest trauma in rats : Cellular and cytokine responses

Lung contusion is the leading cause of death from blunt thoracic trauma in adults, but its mechanistic pathophysiology remains unclear. This study uses a recently developed rat model to investigate the evolution of inflammation and injury in isolated lung contusion. Bilateral lung contusion with minimal cardiac trauma was induced in 54 anesthetized rats by dropping a 0.3-kg hollow cylindrical weight onto a precordial shield (impact energy, 2.45 Joules). Arterial oxygenation, pressure-volume (P-V) mechanics, histology, and levels of erythrocytes, leukocytes, albumin, and inflammatory mediators in bronchoalveolar lavage (BAL) were assessed at 8 min, at 4, 12, 24, and 48 h, and at 7 days after injury. The role of neutrophils in the evolution of inflammatory injury was also specifically studied by depleting these cells with intravenous vinblastine before lung contusion. Arterial oxygenation was severely reduced at 8 min to 24 h postcontusion, but became almost normal by 48 h. Levels of erythrocytes, leukocytes, and albumin in BAL were increased at ≤24 h, and returned toward normal by 48 h. Deficits in P-V mechanics were most apparent at 24 h postcontusion. Levels of macrophage inflammatory polypeptide-2, cytokine-induced neutrophil chemoattractant-1, and interleukin 6 in BAL peaked at 24 h, whereas monocyte chemoattractant protein-1 and interleukin 1β peaked at 24 to 48 h postcontusion. Histology showed early hemorrhagic injury (8 min-12 h), with neutrophilic infiltration at 24 h and areas of bronchiolitis obliterans organizing pneumonia-associated fibrosis at 7 days. Vinblastine-treated neutropenic rats had significantly reduced lung injury based on total lung volume at 4 h and on BAL albumin levels at 24 h postcontusion. Inflammatory injury from isolated bilateral lung contusion in rats is most severe in the acute period (8 min-24 h) after initial blunt trauma, and includes a component of neutrophil-dependent pathology.

A rat model for isolated bilateral lung contusion from blunt chest trauma.

Lung contusion affects 17%–25% of adult blunt trauma patients, and is the leading cause of death from blunt thoracic injury. A small animal model for isolated bilateral lung contusion has not been developed. We induced lung contusion in anesthetized rats by dropping a 0.3-kg weight onto a precordial protective shield to direct the impact force away from the heart and toward the lungs. Lung injury was characterized as a function of chest impact energy (1.8–2.7 J) by measurements of arterial oxygenation, bronchoalveolar lavage (BAL) albumin and cytology, pressure-volume mechanics, and histopathology. Histology confirmed bilateral lung contusion without substantial cardiac muscle trauma. Rats receiving 2.7 J of chest impact energy had 33% mortality that exceeded prospectively defined limits for sublethal injury. Hypoxemia in rats with maximal sublethal injury (2.45 J) met criteria for acute lung injury at ≤24 h, improving by 48 h. BAL albumin levels were highest at ≤24 h, and remained elevated along with increased BAL leukocytes and decreased lung volumes at 48 h. We concluded that an impact energy of 2.45 J induces isolated, bilateral lung contusion and provides a useful model for future mechanistic pathophysiological assessments.

Surfactant dysfunction in lung contusion with and without superimposed gastric aspiration in a rat model.

This study investigates surfactant dysfunction in rats with lung contusion (LC) induced by blunt chest trauma. Rats at 24 h postcontusion had a decreased percent content of large surfactant aggregates in cell-free bronchoalveolar lavage (BAL) and altered large-aggregate composition with decreased phosphatidylcholine (PC), increased lyso-PC, and increased protein compared with uninjured controls. The surface activity of large aggregates on a pulsating bubble surfactometer was also severely impaired at 24 h postcontusion. Decreases in large surfactant aggregate content and surface activity were improved, but still apparent, at 48 and 72 h postcontusion compared with uninjured control rats and returned to normal by 96 h postcontusion. The functional importance of surfactant abnormalities in LC injury was documented in pilot studies showing that exogenous surfactant replacement at 24 h postcontusion improved inflation/deflation lung volumes. Additional experiments investigated a clinically relevant combination of LC plus gastric aspiration (combined acid and small gastric food particles) and found reductions in large surfactant aggregates in BAL similar to those for LC. However, rats given LC + combined acid and small gastric food particles versus LC had more severe surfactant dysfunction based on decreases in surface activity and alterations in large aggregate composition. Combined data for all animal groups had strong statistical correlations between surfactant dysfunction (increased minimum surface tension, decreased large aggregates in BAL, decreased aggregate PC, and increased aggregate lyso-PC) and the severity of inflammatory lung injury (increased total protein, albumin, protein/phospholipid ratio, neutrophils, and erythrocytes in BAL plus increased whole lung myeloperoxidase activity). These results show that surfactant dysfunction is important in the pathophysiology of LC with or without concurrent gastric aspiration and provides a rationale for surfactant replacement therapy in these prevalent clinical conditions.

The Role of Alveolar Macrophages in the Pathogenesis of Aspiration Pneumonitis

Rationale: A robust TNFα response is seen following aspiration of food particles, while there is only a modest response to acid. Objectives: To examine the direct effects of acid and particulate components of gastric content on local and systemic macrophages. Methods: Pathogen-free Long–Evans rats were injured with intratracheal instillation of normal saline (SHAM), low pH saline (ACID), small non-acidic particles (SNAP) or acidified particles (CASP). The alveolar (local) and the peritoneal (systemic) macrophages were harvested following the injury. Measurements: We examined the phagocytic activity and TNFα release by the alveolar and peritoneal macrophages following in vivo and in vitro exposure to acid and/or food particles. TNFα release by macrophages was examined in response to E. coli lipopolysaccaride (LPS) stimulation. Main Results: In rats injured with gastric particles, the number of the mononuclear cells was higher than those obtained from acid-injured animals. Both in vivo and in vitro exposure of the alveolar macrophages to SNAP resulted in increased production of TNFα within 8 hours. Transient exposure of the alveolar macrophages to a low pH environment suppressed LPS-induced production of this cytokine. Additionally, the phagocytic activity of the alveolar macrophages was inhibited by in vitro exposure of the macrophages to acid. Conclusions: We conclude that the two components of gastric aspiration have diverse effects on local and systemic macrophages. Although there is a synergy between acid and gastric particulate in producing an acute lung injury, the modulatory effects of these injuries on the alveolar macrophages are averse.

Statistical prediction of the type of gastric aspiration lung injury based on early cytokine/chemokine profiles

Background:Unwitnessed gastric aspiration can be a diagnostic dilemma, and early discrimination of different forms may help to identify individuals with increased risk of development of severe clinical acute lung injury or acute respiratory distress syndrome. The authors hypothesized that inflammatory mediator profiles could be used to help diagnose different types of gastric aspiration. Methods:Diagnostic modeling using a newly modified receiver operator characteristic approach was applied to recently published data from our laboratory on lavaged inflammatory mediators from rodents given intratracheal normal saline, hydrochloric acid, small nonacidified gastric particles, or a combination of acid and small gastric particles. Multiple animal groups and postaspiration times of injury were analyzed to gauge the applicability of the predictive approach: rats (6 and 24 h), C57/BL6 wild-type mice (5 and 24 h), and transgenic mice on the same background deficient in the gene for monocyte chemoattractant protein 1 (MCP-1 [−/−] mice; 5 and 24 h). Results:Overall, the four types of aspiration were correctly discriminated in 85 of 96 rats (89%), 72 of 78 wild-type mice (92%), and 59 of 73 MCP-1 (−/−) mice (81%) by models that used a maximum of only two mediators. The severe “two-hit” aspirate of the combination of acid and small gastric particles was correctly predicted in 21 of 24 rats, 23 of 23 wild-type mice, and 21 of 21 MCP-1 (−/−) mice. Specific best-fit mediators or mediator pairs varied with aspirate type, animal type, and time of injury. Cytokines and chemokines that best predicted the combination of acid and small gastric particles were cytokine-induced neutrophil chemoattractant 1 (6 h) and MCP-1 (24 h) in rats, tumor necrosis factor α/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor α/MCP-1 (24 h) in wild-type mice, and tumor necrosis factor α/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor α/keratinocyte-derived cytokine (24 h) in MCP-1 (−/−) mice. Conclusions:These results support the potential feasibility of developing predictive models that use focused measurements of inflammatory mediators to help diagnose severe clinical forms of unwitnessed gastric aspiration, such as the combination of acid and small gastric particles, that may have a high risk of progression to acute lung injury/acute respiratory distress syndrome.

Efficacy of Aminophylline for Treatment of Recurrent Symptomatic Bradycardia After Spinal Cord Injury

Cardiac dysrhythmias and cardiac arrest can occur after acute spinal cord injury (SCI). Disrupted sympathetic innervation after SCI results in unopposed parasympathetic activity leading to baseline bradycardia. Hence, vagal stimulation can result in episodes of exaggerated symptomatic bradycardia. Data supporting pharmacologic intervention for treatment of symptomatic bradycardia after SCI are limited. We describe a patient who sustained a high cervical SCI and subsequently developed episodic symptomatic bradycardia. The addition of aminophylline to the patients therapeutic regimen was associated with resolution of the bradycardia. Throughout her treatment course, the patients serum theophylline concentrations were 1.9‐3.4 mg/L. These levels were consistent with those identified in other case reports describing treatment with methylxanthines to prevent episodic bradycardia after SCI. Our understanding of drug pharmacokinetics and pharmacodynamics in patients with acute SCI is limited and provides an ideal opportunity for further study in this area.

Bullet migration within the inferior vena cava

We report the case of a patient who sustained gunshot wounds to the chest. The bullet lodged and moved freely within the inferior vena cava and its branches, but the patient had no symptoms. The bullet was retrieved from the right common femoral vein with a basket. Selective approach to bullet removal can prevent serious complications.

Posttraumatic pulmonary arteriovenous fistula: is resection the procedure of choice? A case report and review of literature.

Posttraumatic pulmonary arteriovenous fistula (PAVF) is a rare clinical entity. Most PAVFs are congenital and arise in the setting of hereditary hemorrhagic telangiectasia. Acquired PAVFs are rare and have been reported with metastatic thyroid carcinoma, cirrhosis, pulmonary schistosomiasis, actinomycosis, mitral stenosis, Fanconi’s syndrome, and trauma. We present a case of acquired PAVF presenting 1 year after a thoracic stab wound injury with a review of the previously reported cases and a discussion.

Recurrent diverticulitis after sigmoid colectomy for sigmoid colon diverticulitis.

To the Editor—We read with interest the most recent article by Thaler et al. on determinants of recurrence after sigmoid colectomy for uncomplicated diverticulitis of the sigmoid (UDS). The authors had evaluated several surgery-associated variables and used specific criteria for the diagnosis of recurrent diverticulitis (RD). They had concluded that colorectal (rather than colosigmoid) anastomosis was the single predictor of lower recurrence rates of RD. We recently had treated a 58-year female who ten years earlier had undergone sigmoid colectomy for acute diverticulitis. She was admitted to the hospital on at least two occasions seven years later with recurrent left-sided abdominal pain, nausea, vomiting, and leukocytosis. Initial computerized tomography (CT) scans showed narrowing of the lumen, thickening of the wall of the left colon, and haziness and strand-like densities in surrounding fat (Fig. 1). Colonoscopy showed a colocolic anastomosis about 25 cm proximal to the anal verge. On subsequent admission a CT scan showed an increase in inflammatory changes in the area of the left colon. At laparotomy a phlegmon involving the area of colocolic anastomosis and loops of small bowel was found adherent to left iliac fossa. There was a segment of soft sigmoid colon proximal and distal to the phlegmon. Completion sigmoid colectomy, left colectomy, and a stapled distal transverse colorectal anastomosis was performed. Pathology showed diverticulosis, diverticulitis, pericolonic abscess formation, and granulation tissue formation and fibrosis in mesenteric adipose tissue. At four-year follow-up the patient had no abdominal symptoms. The impact of colon resection on postoperative prognosis in patients with diverticulitis has been the focus of several studies, and most have reported a 25 to 30 percent rate of continued abdominal symptoms. Few patients, however, develop RD. The cause of RD is not completely understood. Possibly at least two factors may affect rates of RD, the extent of colon resection and progression of diverticulosis. As for the extent of colon resection, earlier studies had reported a RD rate of 2.7 to 8.3 percent following “conservative resection” or “resection of portion of colon bearing inflamed diverticula.” The surgery in these cases was performed as a one-stage, two-stage, or three-stage procedure or exteriorization-resection, and 4 to 40 cm of colon was resected. The resection was performed for complicated and uncomplicated diverticulitis, and the diagnosis of RD was based on “symptoms and X-ray examination.” More recent studies had reported a RD rate ranging from 2.5 to 20 percent. The surgery was performed in one or two stages, as open colon resection (OCR) or laparoscopic colon resection (LCR), and 10 cm or more of the colon was resected during these operations. The diagnosis of RD was based on the presence of left lower quadrant pain and tenderness, fever, leukocytosis, and at least one confirmatory study, CT scan, contrast enema, or laparoscopy. The extent of sigmoid resection varied. In cases where the entire proximal sigmoid colon was resected, i.e., proximal resection was placed on normal-appearing descending or more proximal colon, RD developed in 2.7 to 9.6 percent of cases. Bergamaschi and Arnaud reported a 9.6 percent recurrence rate after OCR and 2.7 percent after LCR for UDS. All recurrences had developed in patients with colosigmoidostomy. Thaler et al. reported a recurrence rate of 5 percent in patients who had undergone OCR or LCR for UDS. There was a fourfold higher risk of recurrence in patients with colosigmoidostomy as compared with coloproctostomy. In Figure 1. CT scan of the abdomen showing narrowing of the lumen and thickening of the wall of left colon (straight arrow) and haziness and strand-like densities in surrounding fat (curved arrow).