Reuven Rabinovici

Is It Safe to Delay Appendectomy in Adults With Acute Appendicitis

Objective:To examine whether delayed surgical intervention in adult patients with acute appendicitis is safe by correlating the interval from onset of symptoms to operation (total interval) with the degree of pathology and incidence of postoperative complications. Summary Background Data:Prompt appendectomy has long been the standard of care for acute appendicitis because of the risk of progression to advanced pathology. This time-honored practice has been recently challenged by studies in pediatric patients, which suggested that acute appendicitis can be managed in an elective manner once antibiotic therapy is initiated. No such data are available in adult patients with acute appendicitis. Methods:A retrospective review of 1081 patients who underwent an appendectomy for acute appendicitis between 1998 and 2004 was conducted. The following parameters were monitored and correlated: demographics, time from onset of symptoms to arrival at the emergency room (patient interval) and from arrival to the emergency room to the operating room (hospital interval), physical, computed tomography (CT scan) and pathologic findings, complications, length of stay, and length of antibiotic treatment. Pathologic state was graded 1 (G1) for acute appendicitis, 2 (G2) for gangrenous acute appendicitis, 3 (G3) for perforation or phlegmon, and 4 (G4) for a periappendicular abscess. Results:The risk of advanced pathology, defined as a higher pathology grade, increased with the total interval. When this interval was <12 hours, the risk of developing G1, G2, G3, and G4, was 94%, 0%, 3%, and 3%, respectively. These values changed to 60%, 7%, 27%, and 6%, respectively, when the total interval was 48 to 71 hours and to 54%, 7%, 26%, and 13% for longer than 71 hours. The odds for progressive pathology was 13 times higher for the total interval >71 hours group compared with total interval<12 hours (95% confidence interval = 4.7–37.1). Although both prolonged patient and hospital intervals were associated with advanced pathology, prehospital delays were more profoundly related to worsening pathology compared with in-hospital delays (P < 0.001). Advanced pathology was associated with tenderness to palpation beyond the right lower quadrant (P < 0.001), guarding (P < 0.001), rebound (P < 0.001), and CT scan findings of peritoneal fluid (P = 0.01), fecalith (P = 0.01), dilation of the appendix (P < 0.001), and perforation (P < 0.001). Increased length of hospital stay (P < 0.001) and antibiotic treatment (P < 0.001) as well as postoperative complications (P < 0.001) also correlated with progressive pathology. Conclusion:In adult patients with acute appendicitis, the risk of developing advanced pathology and postoperative complications increases with time; therefore, delayed appendectomy is unsafe. As delays in seeking medical help are difficult to control, prompt appendectomy is mandatory. Because these conclusions are derived from retrospective data, a prospective study is required to confirm their validity.

Characterization of a murine model of endotoxin-induced acute lung injury.

Endotoxin-induced microvascular lung injury in mice is a commonly used experimental model of the acute respiratory distress syndrome (ARDS). The present paper aimed to characterize this popular model in a comprehensive and systematic fashion. Male C57bl/6 mice (n = 5) were administered an LD55 dose of E. coli endotoxin (15 mg/kg, i.p.), and lungs were harvested at several time points and evaluated for injury as well as for expression of a variety of inflammatory mediators. Endotoxin induced many features characteristic of acute microvascular lung injury. These included early (1-2 h) expression of inflammatory mediators (IL-1&agr;, IL-1&bgr;, IL-4, IL-6, IL-10, TNF-&agr;, interferon-&agr;, interferon-&ggr;, and MCP-1) and leukocyte accumulation in lung tissue (lung myeloperoxidase activity 18.5 ± 7.8 U/g tissue, P < 0.05), followed by pulmonary edema (lung water content index 17.4% ± 2.5%, P < 0.05) and mortality. Histopathological evaluation of lung tissue was compatible with these findings. The characterization of this murine model of endotoxin-induced microvascular injury will facilitate its utilization in ARDS research.

Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation

Adenosine‐to‐inosine (A‐to‐I) RNA editing is a post‐transcriptional modification of pre‐mRNA catalysed by an RNA‐specific adenosine deaminase (ADAR). A‐to‐I RNA editing has been previously reported in the pre‐mRNAs of brain glutamate and serotonin receptors and in lung tissue during inflammation. Here we report that systemic inflammation markedly induces inosine‐containing mRNA to approximately 5% of adenosine in total mRNA. Induction was the result of up‐regulation of A‐to‐I RNA editing as both dsRNA editing activity and ADAR1 expression were increased in the spleen, thymus and peripheral lymphocytes from endotoxin‐treated mice. Up‐regulation of ADAR1 was confirmed in vitro in T lymphocytes and macrophages stimulated with a variety of inflammatory mediators including tumour necrosis factor‐α and interferon‐γ. A late induction of RNA editing was detected in concanavalin A‐activated splenocytes stimulated with interleukin‐2 in vitro. Taken together, these data suggest that a large number of inosine‐containing mRNAs are produced during acute inflammation via up‐regulation of ADAR1‐mediated RNA editing. These events may affect the inflammatory and immune response through modulation of protein production.

Modified rapid deployment hemostat bandage reduces blood loss and mortality in coagulopathic pigs with severe liver injury.

BACKGROUND Hemostasis can be difficult to achieve after blunt abdominal trauma, especially if the patient is coagulopathic. The U.S. Food and Drug Administration has recently approved a hemostatic dressing for treating bleeding after extremity trauma (RDH bandage; Marine Polymer Technologies, Cambridge, MA). It has not been evaluated for internal bleeding after trauma. We redesigned this dressing for internal use, and then tested whether this modified bandage (Miami-modified Rapid Deployment Hemostat) could achieve hemostasis when used as an adjunct to standard laparotomy pad packing in a pig model of severe liver injury with coagulopathy. METHODS Anesthetized swine (35-45 kg) received an isovolemic 45% blood volume replacement with refrigerated Hextend (6% hetastarch). Core body temperature was maintained at 33-34 degrees C with intra-abdominal ice packs. A coagulopathic condition was documented by thromboelastography. At this point a severe liver injury was induced by the avulsion of the left lateral hepatic lobe, then the pigs were randomized to treatment with either standard abdominal packing (control) or packing plus Miami-modified Rapid Deployment Hemostat. Two series of experiments were conducted. In series one (n = 14), the abdomen was closed and the animals were observed with no resuscitation. After one hour, the abdomen was opened, the packing was removed and the presence of bleeding was noted. In series two (n = 10), the abdomen was closed and the animal resuscitated with one unit of blood plus as much lactated Ringers intravenous fluid (IVF) as required to maintain a mean arterial pressure (MAP) > 70 mm Hg. After one hour, the packing was removed, the abdomen closed, and data were collected for an additional two hours. RESULTS Series one: 6/7 animals in the control group had continued bleeding at one hour; 1/7 animals in the treatment group had active bleeding (p = 0.0291). Series two: With control vs. Miami-modified Rapid Deployment Hemostat, the three-hour survival was zero vs. 80% (p = 0.0476). The total blood loss was 1.2 +/- 0.1 vs. 0.3 +/- 0.1 mL/kg/min (p = 0.001) and the IVF requirement was 1.6 +/- 0.3 vs. 0.6 +/- 0.3 mL/kg/min (p = 0.026). CONCLUSIONS The Miami-modified Rapid Deployment Hemostat bandage significantly reduced mortality, blood loss, and fluid requirements when used as an adjunct to standard abdominal packing following severe liver injury in coagulopathic pigs [corrected].

Aortic intimal injuries from blunt trauma: resolution profile in nonoperative management.

OBJECTIVE To provide preliminary data on the resolution profile of aortic intimal injuries treated nonoperatively and on the safety of nonoperative management of these injuries. METHODS Five blunt trauma patients diagnosed by transesophageal echocardiography (TEE) with traumatic intimal injury of the aorta were assigned to nonoperative management. This included beta-blockade to maintain systolic blood pressure between 80 and 90 mm Hg and heart rate between 60 and 80 beats/min, serial TEE studies, and invasive monitoring in the intensive care unit. The evolution of injury, the effectiveness of nonoperative treatment, and the potential need for an operative intervention were monitored. RESULTS The patients had a mean Injury Severity Score of 32 and sustained multiple associated thoracic and extrathoracic injuries. Aortic injuries were located at the level of the ligamentum arteriosum and in the descending aorta adjacent to the diaphragm in three and two patients, respectively. The mean size of injury was 12.5 mm (range, 5-20 mm) and a thrombus attached to the endothelium was present in three of the five patients. Complete resolution of injury occurred within 9.4 +/- 6.6 days (range, 3-19 days). All patients remained hemodynamically stable and adequately perfused. All demonstrated progressive resolution of their aortic intimal injuries. No complications related to the aortic injuries were identified during a mean follow-up of 16.8 months. CONCLUSION This small series suggests that aortic intimal injuries smaller than 20 mm in hemodynamically stable patients treated with beta-blockade resolve within several days. This approach appears safe when monitored by serial TEE studies performed by experienced experts, and continuous invasive hemodynamic monitoring.

Platelet-activating factor (PAF) in experimental and clinical sepsis.

Despite considerable progress in understanding the pathogenic mechanisms of Gram-negative sepsis, the outcome of septic patients has not significantly improved. There are ample data that support a role for inflammatory mediators in sepsis that act in synergy with infectious agents to initiate and propagate the disease process. One such mediator is the glycerophospholipid platelet-activating factor (PAF). The objective of the present review is to summarize experimental and clinical evidence implicating PAF as a mediator in the pathomechanism of sepsis. This review is timely because many potent and selective PAF antagonists have matured for clinical development and a careful analysis of the data that support or refute the merit of clinical trials with such compounds may be important for both academic and pharmaceutical applications.

Serum tumor necrosis factor-alpha profile in trauma patients.

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in several late consequences of trauma such as sepsis, multiple organ failure, and ischemia-reperfusion injury. However, no data are available to indicate whether TNF-alpha is involved in the initial pathophysiologic response to trauma. To address this issue, serum TNF-alpha was determined (by ELISA) longitudinally (first blood sample on admission) in 100 randomly selected trauma patients admitted to the emergency department and trauma division at Jefferson Medical Center, Philadelphia. The TNF-alpha levels were detectable at one or more time points in 35 patients. Mean values tended to be elevated (50.3 +/- 11.5 pg/mL) during the first 5 days, but this trend did not differ statistically from that in healthy controls (n = 12) and did not correlate with the severity of injury (Injury Severity Score and Glasgow Coma Scale score). The TNF-alpha response was not dependent on the mechanism and site of injury, the presence of shock (systolic blood pressure < 90 mm Hg), and the need for emergent surgery. Also, serum TNF-alpha levels were not significantly elevated in patients who subsequently developed multiple organ failure (n = 4), septic shock (n = 5), or both (n = 3). Taken together, these data do not support a role for circulating TNF-alpha in the initial acute inflammatory response to trauma.

The initial response to the Boston marathon bombing: lessons learned to prepare for the next disaster.

Objective:We discuss the strengths of the medical response to the Boston Marathon bombings that led to the excellent outcomes. Potential shortcomings were recognized, and lessons learned will provide a foundation for further improvements applicable to all institutions. Background:Multiple casualty incidents from natural or man-made incidents remain a constant global threat. Adequate preparation and the appropriate alignment of resources with immediate needs remain the key to optimal outcomes. Methods:A collaborative effort among Bostons trauma centers (2 level I adult, 3 combined level I adult/pediatric, 1 freestanding level I pediatric) examined the details and outcomes of the initial response. Each center entered its respective data into a central database (REDCap), and the data were analyzed to determine various prehospital and early in-hospital clinical and logistical parameters that collectively define the citywide medical response to the terrorist attack. Results:A total of 281 people were injured, and 127 patients received care at the participating trauma centers on that day. There were 3 (1%) immediate fatalities at the scene and no in-hospital mortality. A majority of the patients admitted (66.6%) suffered lower extremity soft tissue and bony injuries, and 31 had evidence for exsanguinating hemorrhage, with field tourniquets in place in 26 patients. Of the 75 patients admitted, 54 underwent urgent surgical intervention and 12 (22%) underwent amputation of a lower extremity. Conclusions:Adequate preparation, rapid logistical response, short transport times, immediate access to operating rooms, methodical multidisciplinary care delivery, and good fortune contributed to excellent outcomes.

Chest Tube Removal: End-inspiration or End-expiration?

BACKGROUND Recurrent pneumothorax is the most significant complication after discontinuation of thoracostomy tubes. The primary objective of the present study was to determine which method of tube removal, at the end of inspiration or at the end of expiration, is associated with a lesser risk of developing a recurrent pneumothorax. A secondary objective was to identify potential risk factors for developing recurrence. METHODS A prospective study of 102 chest tubes in 69 trauma patients (1.5 tubes per patient) randomly assigned to removal at the end of inspiration (n = 52) or the end of expiration (n = 50). RESULTS Recurrent pneumothorax or enlargement of a small but stable pneumothorax was observed after the removal of four chest tubes in the end-inspiration group (8%) and after discontinuation of three chest tubes (6%) in the end-expiration group (p = 1.0). Of those, only two tubes in the end-inspiration group and 1 tube in the end-expiration group required repeat closed thoracostomy. Multiple factors were analyzed that did not adversely affect outcome. These included patient age, Injury Severity Score, Revised Trauma Score, mechanism of injury, hemothorax, thoracotomy, thoracostomy, previous lung disease, chest tube duration, the presence of more than one thoracostomy tube in the same hemithorax, or a small (but stable) pneumothorax at the time of tube removal. CONCLUSIONS Discontinuation of chest tubes at the end of inspiration or at the end of expiration has a similar rate of post-removal pneumothorax. Both methods are equally safe.

Priming by platelet-activating factor of endotoxin-induced lung injury and cardiovascular shock.

Platelet-activating factor (PAF) is a glycerophospholipid known for its unusual potent vasoactive and proinflammatory activities. The present study examined whether PAF might serve as a priming factor in endotoxin-induced tumor necrosis factor-alpha (TNF alpha) synthesis, cardiovascular shock, and lung injury in anesthetized rats. Intravenous infusion of PAF (1 pmol/kg/min for 60 minutes, n = 5) alone or endotoxin (0.1 micrograms/kg i.v. bolus, n = 5) failed to alter blood pressure, serum TNF alpha and thromboxane B2, platelet and leukocyte count, and hematocrit, nor was lung histology, myeloperoxidase activity, and water content changed. In contrast, the combined administration of PAF and endotoxin markedly elevated serum TNF alpha (1,359 +/- 362 pg/ml, n = 5, p less than 0.01) and thromboxane B2 (43 +/- 5 pg/100 microliters, n = 8, p less than 0.01) along with hypotension, hemoconcentration, leukopenia, and thrombocytopenia. Most notably, the combined regimen caused neutrophil aggregation, adhesion, and accumulation into the lung parenchyma along with platelet-fibrin deposits in postcapillary venules, pulmonary edema, and increased lung myeloperoxidase activity. The role of PAF in this process was confirmed by 1) the prevention of the priming effect by pretreatment with the PAF antagonist BN 50739 (n = 5), and 2) the failure of lyso-PAF, the cardinal nonactive PAF-metabolite, to prime for endotoxin-induced production of TNF alpha (n = 4). These data suggest that PAF could serve as a key mediator in priming for endotoxin-induced tissue injury, especially the typical pulmonary pathophysiology of adult respiratory distress syndrome, a severe pathological outcome of septic shock, burns, and multiple organ injury.