Henry J. Schiller

Surgical Management and Outcomes of 165 Colonoscopic Perforations From a Single Institution

BACKGROUND Increasing use of colonoscopy is making iatrogenic perforations more common. We herein present our experience with operative management of colonoscopic-related perforations. DESIGN Retrospective review (1980-2006). SETTING Tertiary referral center. PATIENTS A total of 258 248 colonoscopies performed in patients, from which we identified 180 iatrogenic perforations (incidence, 0.07%). Of these, 165 perforations were managed operatively. RESULTS Patients underwent primary repair (29%), resection with primary anastomosis (33%), or fecal diversion (38%). Patients presenting within 24 hours (78%) were more likely to have minimal peritoneal contamination (64 patients [50%] vs 6 [17%]; P = .01) and to undergo primary repair or resection with anastomosis (86 [67%] patients vs 13 [36%]; P < .01). Patients presenting after 24 hours (22%) were more likely to have feculent contamination (16 patients [44%] vs 4 [11%]; P = .02) and to receive an ostomy (23 patients [64%] vs 43 [33%]; P = .02). The sigmoid colon was the most frequent site of perforation, followed by the cecum (53% and 24%, respectively; P < .001); blunt or torque injury exceeded polypectomy and thermal injuries (55% vs 27% and 18%, respectively; P < .001). Patients with blunt injuries were more likely to receive a stoma than were those with polypectomy and thermal perforations (44 patients vs 9 and 9, respectively; P = .02), as were patients with feculent peritonitis compared with those with moderate and minimal soilage (28 patients [78%] vs 28 [42%] and 6 [10%] respectively; P = .002). Operative morbidity was 36%, with a mortality rate of 7%. Multivariate analysis indicated that blunt injuries, poor bowel preparation, corticosteroid use, and being younger than 67 years were risk factors for postoperative morbidity (P <or= .01); no factors correlated with death. CONCLUSIONS Colonoscopic perforation occurs in fewer than 1 in 1000 patients and is associated with significant morbidity and mortality. Prompt diagnosis and operative therapy are critical in most cases.

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.

Eastern Association for the Surgery of Trauma practice management guidelines for hemorrhage in pelvic fracture--update and systematic review.

BACKGROUND Hemorrhage from pelvic fracture is common in victims of blunt traumatic injury. In 2001, the Eastern Association for the Surgery of Trauma (EAST) published practice management guidelines for the management of hemorrhage in pelvic trauma. Since that time there have been new practice patterns and larger experiences with older techniques. The Practice Guidelines Committee of EAST decided to replace the 2001 guidelines with an updated guideline and systematic review reflecting current practice. METHODS Building on the previous systematic literature review in the 2001 EAST guidelines, a systematic literature review was performed to include references from 1999 to 2010. Prospective and retrospective studies were included. Reviews and case reports were excluded. Of the 1,432 articles identified, 50 were selected as meeting criteria. Nine Trauma Surgeons, an Interventional Radiologist, and an Orthopedic Surgeon reviewed the articles. The EAST primer was used to grade the evidence. RESULTS Six questions regarding hemorrhage from pelvic fracture were addressed: (1) Which patients with hemodynamically unstable pelvic fractures warrant early external mechanical stabilization? (2) Which patients require emergent angiography? (3) What is the best test to exclude extrapelvic bleeding? (4) Are there radiologic findings which predict hemorrhage? (5) What is the role of noninvasive temporary external fixation devices? and (6) Which patients warrant preperitoneal packing? CONCLUSIONS Hemorrhage due to pelvic fracture remains a major cause of morbidity and mortality in the trauma patient. Strong recommendations were made regarding questions 1 to 4. Further study is needed to answer questions 5 and 6.

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.

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.

Alveolar inflation during generation of a quasi-static pressure/volume curve in the acutely injured lung.

ObjectiveLower and upper inflection points on the quasi-static curve representing a composite of pressure/volume from the whole lung are hypothesized to represent initial alveolar recruitment and overdistension, respectively, and are currently utilized to adjust mechanical ventilation in patients with acute respiratory distress syndrome. However, alveoli have never been directly observed during the generation of a pressure/volume curve to confirm this hypothesis. In this study, we visualized the inflation of individual alveoli during the generation of a pressure/volume curve by direct visualization using in vivo microscopy in a surfactant deactivation model of lung injury in pigs. DesignProspective, observational, controlled study. SettingUniversity research laboratory. SubjectsEight adult pigs. InterventionsPigs were anesthetized and administered mechanical ventilation, underwent a left thoracotomy, and were separated into two groups: control pigs (n = 3) were subjected to surgical intervention, and Tween lavage pigs (n = 5) were subjected to surgical intervention plus surfactant deactivation by Tween lavage (1.5 mL/kg 5% solution of Tween in saline). The microscope was then attached to the lung, and the size of each was alveolus quantified by measuring the alveolar area by computer image analysis. Each alveolus in the microscopic field was assigned to one of three types, based on alveolar mechanics: type I, no visible change in alveolar size during ventilation; type II, alveoli visibly change size during ventilation but do not totally collapse at end expiration; and type III, alveoli visibly change size during tidal ventilation and completely collapse at end expiration. After alveolar classification, the animals were disconnected from the ventilator and attached to a super syringe filled with 100% oxygen. The lung was inflated from 0 to 220 mL in 20-mL increments with a 10-sec pause between increments for airway pressure and alveolar confirmation to stabilize. These data were utilized to generate both quasi-static pressure/volume curves and individual alveolar pressure/area curves. Measurements and Main ResultsThe normal lung quasi-static pressure/volume curve has a single lower inflection point, whereas the curve after Tween has an inflection point at 8 mm Hg and a second at 24 mm Hg. Normal alveoli in the control group are all type I and do not change size appreciably during generation of the quasi-static pressure/volume curve. Surfactant deactivation causes a heterogenous injury, with all three alveolar types present in the same microscopic field. The inflation pattern of each alveolar type after surfactant deactivation by Tween was notably different. Type I alveoli in either the control or Tween group demonstrated minimal change in alveolar area with lung inflation. Type I alveolar area was significantly (p < .05) larger in the control as compared with the Tween group. In the Tween group, type II alveoli increased significantly in area, with lung inflation from 0 mL (9666 ± 1340 &mgr;m2) to 40 mL (12,935 ± 1725 &mgr;m2) but did not increase further (220 mL, 14,058 ± 1740 &mgr;m2) with lung inflation. Type III alveoli initially recruited with a relatively small area (20 mL lung volume, 798 ± 797 &mgr;m2) and progressively increased in area throughout lung inflation (120 mL, 7302 ± 1405 &mgr;m2; 220 mL, 11,460 ± 1078 &mgr;m2) ConclusionThe normal lung does not increase in volume by simple isotropic (balloon-like) expansion of alveoli, as evidenced by the horizontal (no change in alveolar area with increases in airway pressure) pressure/area curve. After surfactant deactivation, the alveolar inflation pattern becomes very complex, with each alveolar type (I, II, and III) displaying a distinct pattern. None of the alveolar pressure/area curves directly parallel the quasi-static lung pressure/volume curve. Of the 16, only one type III atelectatic alveolus recruited at the first inflection point and only five recruited concomitant with the second inflation point, suggesting that neither inflection point was due to massive alveolar recruitment. Thus, the components responsible for the shape of the pressure/volume curve include all of the individual alveolar pressure/area curves, plus changes in alveolar duct and airway size, and the elastic forces in the pulmonary parenchyma and the chest wall.

Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats

BACKGROUND Neutrophil activation with concomitant matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) release has been implicated in the development of sepsis-induced acute lung injury. We hypothesized that COL-3, a chemically modified tetracycline known to inhibit MMP-2 and MMP-9, would reduce lung injury and improve survival in rats following cecal ligation and puncture (CLP). METHODS Sprague-Dawley rats were separated into five groups: 1) sham CLP+ carboxymethylcellulose (CMC; vehicle for COL-3, n = 6); 2) sham CLP + COL-3 (n = 6); 3) CLP + CMC (n = 10); 4) CLP + single-dose (SD) COL-3 administered concomitant with CLP (n = 9); and 5) CLP + multiple-dose (MD) COL-3 administered concomitant with CLP and at 24 h after CLP (n = 15). Rats were sacrificed at 168 h (7 days) or immediately after death, with survival defined as hours after CLP. Histological lung assessment was made based on neutrophil infiltration, alveolar wall thickening, and intraalveolar edema fluid. Lung MMP-2 and MMP-9 levels were assessed by immunohistochemistry. MMP-2 and MMP-9 levels were correlated with survival by simple regression analysis. RESULTS The mortality of rats in the cecal ligation and puncture without treatment group (CLP + CMC) was 70% at 168 h. A single dose of COL-3 in the CLP + COL-3 (SD) group significantly reduced mortality to 54%. Furthermore, with a repeat dose of COL-3 at 24 h after CLP, mortality was significantly reduced to 33%. Pathologic lung changes seen histologically in the CLP + CMC group were significantly reduced by COL-3. A significant reduction in lung tissue levels of MMP-2 and MMP-9 was noted in both groups treated with COL-3. Reduction of MMP-2 and MMP-9 levels correlated with improved survival. CONCLUSION Inhibition of MMP-2 and MMP-9 by COL-3 in a clinically relevant model of sepsis-induced acute lung injury reduces pulmonary injury and improves survival in a dose-dependent fashion. Our results suggest that prophylactic treatment with COL-3 in high-risk patients may reduce the morbidity and mortality associated with sepsis-induced acute respiratory distress syndrome.

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.

Quantification of hypercoagulable state after blunt trauma: Microparticle and thrombin generation are increased relative to injury severity, while standard markers are not

BACKGROUND Major trauma is an independent risk factor for developing venous thromboembolism. While increases in thrombin generation and/or procoagulant microparticles have been detected in other patient groups at greater risk for venous thromboembolism, such as cancer or coronary artery disease, this association has yet to be documented in trauma patients. This pilot study was designed to characterize and quantify thrombin generation and plasma microparticles in individuals early after traumatic injury. METHODS Blood was collected in the trauma bay from 52 blunt injured patients (cases) and 19 uninjured outpatients (controls) and processed to platelet poor plasma to allow for (1) isolation of microparticles for identification and quantification by flow cytometry, and (2) in vitro thrombin generation as measured by calibrated automatic thrombography. Data collected are expressed as either mean ± standard deviation or median with interquartile range. RESULTS Among the cases, which included 39 men and 13 women (age, 40 ± 17 years), the injury severity score was 13 ± 11, the international normalized ratio was 1.0 ± 0.1, the thromboplastin time was 25 ± 3 seconds, and platelet count was 238 ± 62 (thousands). The numbers of total (cell type not specified) procoagulant microparticles, as measured by Annexin V staining, were increased compared to nontrauma controls (541 ± 139/μL and 155 ± 148/μL, respectively; P < .001). There was no significant difference in the amount of thrombin generated in trauma patients compared to controls; however, peak thrombin was correlated to injury severity (Spearman correlation coefficient R, 0.35; P = .02). CONCLUSION Patients with blunt trauma have greater numbers of circulating procoagulant microparticles and increased in vitro thrombin generation. Future studies to characterize the cell-specific profiles of microparticles and changes in thrombin generation kinetics after traumatic injury will determine whether microparticles contribute to the hypercoagulable state observed after injury.

The effects of prehospital plasma on patients with injury: a prehospital plasma resuscitation.

BACKGROUND The prehospital resuscitation of the exsanguinating patient with trauma is time and resource dependent. Rural trauma care magnifies these factors because transportation time to definitive care is increased. To address the early resuscitation needs and trauma-induced coagulopathy in the exsanguinating patient with trauma an aeromedical prehospital thawed plasma–first transfusion protocol was used. METHODS Retrospective review of trauma and flight registries between February 1, 2009, and May 31, 2011, was performed. The study population included all patients with traumatic injury transported by rotary wing aircraft who met criteria for massive transfusion protocol RESULTS A total of 59 patients identified over 28 months met criteria for initiation of aeromedical initiation of prehospital blood product resuscitation. Nine patients received thawed plasma–first protocol compared with 50 controls. The prehospital plasma group was more commonly on warfarin (22 vs. 2%, p = 0.036) and had a greater degree of coagulopathy measured by international normalized ratio at baseline (2.6 vs. 1.5, p = 0.004) and trauma center arrival (1.6 vs. 1.3, p < 0.001). The prehospital plasma group had a predicted mortality nearly three times greater than controls based on Trauma and Injury Severity Score (0.24 vs. 0.66, p = 0.005). The use of prehospital plasma resuscitation led to a plasma–red blood cell ratio that more closely approximated a 1:1 resuscitation en route (1.3:1.0 vs. not applicable, p < 0.001), at 30 minutes (1.3:1.0 vs. 0.14:1.0, p < 0.001), at 6 hours (0.95:1.0 vs. 0.42:1.0, p < 0.001), and at 24 hours (1.0:1.0 vs. 0.45:1.0, p < 0.001). An equivalent amount of packed red blood cells were transfused between the groups. Despite more significant hypotension, less crystalloid was used in the prehospital thawed plasma group, through 24 hours after injury (6.3 vs. 16.4 L, p = 0.001). CONCLUSION Use of plasma-first resuscitation in the helicopter system creates a field ready, mobile blood bank, allowing early resuscitation of the patient demonstrating need for massive transfusion. There was early treatment of trauma-induced coagulopathy. Although there was not a survival benefit demonstrated, there was resultant damage control resuscitation extending to 24 hours in the plasma-first cohort. LEVEL OF EVIDENCE Therapeutic study, level IV.