Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial.

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Crystalloid resuscitation in trauma patients: deleterious effect of 5L or more in the first 24h.

BACKGROUND: Over-aggressive intravenous fluid therapy with crystalloids has adverse effects in trauma patients. We assessed the role of large-volume (≥5l) administration of crystalloids within 24h of injury as an independent risk-factor for mortality, in-hospital complications, and prolonged mechanical ventilation. METHODS: A retrospective cohort analysis of adult trauma patients admitted to a level 1-trauma center between December 2011 and December 2012. Patient demographics, clinical and laboratory values, and total resuscitation fluid administered within the first 24h of injury were obtained. Outcomes included mortality, in-hospital complications and ventilator-days. Multivariable logistic regression and Poisson regression analyses were performed to investigate any association between the administration of ≥5L crystalloids with the aforementioned outcomes while controlling for selected clinical variables. RESULTS: A total of 970 patients were included in the analysis. 264 (27%) received ≥5L of crystalloids in the first 24h of injury. 118 (12%) had in-hospital complications and 337 (35%) required mechanical ventilation. The median age was 46 years (interquartile range (IQR) 27-65) years and 73% (n = 708) were males. The median injury severity score (ISS) was 17 (IQR 9-25). Overall mortality rate was 7% (n = 67). Multivariable logistic regression analysis showed several variables independently associated with mortality (p < 0.05), including resuscitation with ≥5L crystalloid in the first 24h (adjusted odds ratio (aOR) 2.55), older age (aOR 1.03), higher ISS (aOR 1.09), and lower temperature (aOR 0.68). The variables independently associated with in-hospital complications (p < 0.05) were older age, longer ICU stay, and platelet transfusion within 24h of the injury. Need for mechanical ventilation was more common in patients who received ≥5L crystalloids (RR 2.31) had higher ISS (RR 1.02), developed in-hospital complications (RR 1.91) and had lower presenting temperature (RR 0.87). CONCLUSION: Large-volume crystalloid resuscitation is associated with increased mortality and longer time ventilated, but not with in-hospital complications such as pneumonia and sepsis. Based on this data, we recommend judicious use of crystalloids in the resuscitation of trauma patients.

Using rotational thromboelastometry clot firmness at 5 minutes (ROTEM® EXTEM A5) to predict massive transfusion and in-hospital mortality in trauma: a retrospective analysis of 1146 patients.

Viscoelastic assays such as TEG® and ROTEM® are increasingly used to guide transfusion of blood products. The EXTEM assay maximum clot firmness (MCF) is a ROTEM measure available after 25-29 min used to guide early decisions. EXTEM A10, the clot firmness at 10 min, is an accepted early surrogate, but investigators differ on whether A5, the clot firmness at 5 min, is acceptable. We re-examined this in a retrospective observational analysis of 1146 trauma patients in one centre who had ROTEM data recorded. A5 and A10 both correlated well with maximum clot firmness, with Pearson coefficients of r = 0.92 and r = 0.96, respectively. The correlations of A5, A10 and maximum clot firmness with requirement for massive transfusion were all similarly high, with c-stats of 0.87, 0.89 and 0.90, respectively. The correlations with mortality were also similar but weaker, with c-stats of 0.67, 0.69 and 0.69, respectively. Using a previously validated cut-off of A5 < 35 mm to predict massive transfusion gave a sensitivity of 95%, specificity 83%, positive predictive value 9.3% and negative predictive value 100%. Using a value of A5 < 29 mm, for a pragmatic positive predictive value of 20%, gave a sensitivity of 67%, specificity 95% and negative predictive value 99%. Whether aiming for a high sensitivity or a strong predictive value, A5 was non-inferior to A10 and actually missed fewer cases needing massive transfusion. A5 has similar utility to both A10 and maximum clot firmness as an early measure of clot firmness, and a low A5 value is strongly predictive of the need for massive transfusion.

Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial.

BACKGROUND: Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS: Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS: Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS: Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.

[Early viscoelasticity-based coagulation therapy for severely injured bleeding patients: Report of the consensus group on the consensus conference 2014 for formulation of S2k guidelines]. / Frühe viskoelastizitätsbasierte Gerinnungstherapie bei blutenden Schwerverletzten: Bericht der Konsensusgruppe über die Konsensuskonferenz 2014 zur Erarbeitung einer S2k-Leitlinie.

Although there is increasing interest in the use of a viscoelastic test procedure (ROTEM/TEG) for diagnostics and therapy guidance of severely injured and bleeding patients, currently no uniformly accepted guidelines exist for how this technology should be integrated into clinical treatment. In September 2014 an international multidisciplinary group of opinion leaders in the field of trauma-induced coagulopathy and other disciplines involved in the treatment of severely injured patients were assembled for a 2-day consensus conference in Philadelphia (USA). This panel included trauma/accident surgeons, general/abdominal surgeons, vascular surgeons, emergency/intensive care surgeons, hematologists, transfusion specialists, anesthesiologists, laboratory physicians, pathobiologists/pathophysiologists and the lay public. A total of nine questions regarding the impact of viscoelastic testing in the early treatment of trauma patients were developed prior to the conference by a panel consensus. Early use was defined as baseline viscoelastic test result thresholds obtained within the first minutes of hospital arrival, when conventional laboratory results are not yet available. The available data for each question were then reviewed in person using standardized presentations by the expert panel. A consensus summary document was then developed and reviewed by the panel in an open forum. Finally, a 2-round Delphi poll was administered to the panel of experts regarding viscoelastic thresholds for triggering the initiation of specific treatments including fibrinogen (concentrates), platelet concentrates, blood plasma products and prothrombin complex concentrates (PCC). This report summarizes the findings and recommendations of this consensus conference, which correspond to a S2k guideline according to the system of the Association of the Scientific Medical Societies in Germany (AWMF) and taking formal consensus findings including Delphi methods into consideration.

Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate.

BACKGROUND: We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level. METHODS: A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCS(amount)) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCS(amount) would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCS(level)) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents. RESULTS: Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source. CONCLUSIONS: We successfully developed two theoretical tools answering the questions: 'How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?' and 'What would be the resultant fibrinogen level for a specified amount of haemostatic agent?' The current tools are not intended for clinical application, but they are potentially useful for educational purposes.

Selective non-operative management of penetrating abdominal injury in Great Britain and Ireland: survey of practice.

BACKGROUND: The selective non-operative management of penetrating abdominal injury is gaining increasing acceptance. In Great Britain and Ireland, the management of trauma remains the responsibility of general surgeons. This study appraises the acceptance and utilisation of selective non-operative management strategies by British and Irish general surgeons, compared with trauma surgeons in the United States of America. METHODS: Electronic questionnaire survey of British and Irish consultant general surgeons and trauma surgeons in the United States of America. RESULTS: 139 British and Irish general surgeons and 75 US trauma surgeons completed the survey. 84.3% of British and Irish general surgeons and 94.4% of US trauma surgeons practise selective non-operative management of abdominal stab wounds, and 14.0% and 74.3% practise selective non-operative management of abdominal gunshot wounds. The management of those British and Irish surgeons who do practise selective non-operative management is broadly similar to that of US trauma surgeons, with the exception of the use of laparoscopy to examine the left hemidiaphragm following thoracoabdominal injuries, which is employed by fewer British and Irish general surgeons than US trauma surgeons. CONCLUSIONS: The selective non-operative management of abdominal stab wounds is generally accepted by British and Irish general surgeons. In contrast, few British and Irish surgeons are comfortable with non-operatively managing patients with abdominal gunshot wounds, reflecting both the rarity of this type of injury, and surgeons' training and experience. This proportion is unlikely to change until the management of torso trauma is recognised as a specialty, and services are concentrated in regional centres.

Cryoprecipitate transfusion: assessing appropriateness and dosing in trauma.

BACKGROUND: Originally developed for patients with congenital factor VIII deficiency, cryoprecipitate is currently largely used for acquired hypofibrinogenemia in the context of bleeding. However, scant evidence supports this indication and cryoprecipitate is commonly used outside guidelines. In trauma, the appropriate cryoprecipitate dose and its impact on plasma fibrinogen levels are unclear. OBJECTIVES: The aims were to evaluate (i) the appropriateness of cryoprecipitate transfusion in trauma and (ii) the plasma fibrinogen response to cryoprecipitate transfusion during massive transfusion in trauma. METHODS: Retrospective review (January 1998-June 2008) of indications, dose and plasma fibrinogen response to cryoprecipitate transfusion at a large teaching hospital. A fibrinogen of <1.0 g L(-1) within 2 and 6 h of transfusion was used for evaluating appropriateness. RESULTS: Ten thousand five hundred and forty cryoprecipitate units were transfused in 1004 patients. Thirty-seven percent and 31% were used in cardiac surgery and trauma, respectively. In 394 events in trauma, 238 (60%) and 259 (66%) were considered appropriate using the 2- and 6-h cut-off criteria, respectively. In patients who did not receive plasma components 2 h prior to cryoprecipitate, a dose of 8.7 (± 1.7) units caused a mean increase in fibrinogen levels of 0.55 (± 0.24) g L(-1), or 0.06 g L(-1) per unit. CONCLUSIONS: In our hospital, where transfusion guidelines are overseen by transfusion medicine specialists and technologists, and policies for rapid blood component and laboratory turnaround times exist, it is possible to achieve high rates of appropriateness for cryoprecipitate transfusion in trauma. The current recommended dose causes a modest increase in fibrinogen levels (0.55 g L(-1) ).

Rabbit model of uncontrolled hemorrhagic shock and hypotensive resuscitation

Clinically relevant animal models capable of simulating traumatic hemorrhagic shock are needed. We developed a hemorrhagic shock model with male New Zealand rabbits (2200-2800 g, 60-70 days old) that simulates the pre-hospital and acute care of a penetrating trauma victim in an urban scenario using current resuscitation strategies. A laparotomy was performed to reproduce tissue trauma and an aortic injury was created using a standardized single puncture to the left side of the infrarenal aorta to induce hemorrhagic shock similar to a penetrating mechanism. A 15-min interval was used to simulate the arrival of pre-hospital care. Fluid resuscitation was then applied using two regimens: normotensive resuscitation to achieve baseline mean arterial blood pressure (MAP, 10 animals) and hypotensive resuscitation at 60 percent of baseline MAP (10 animals). Another 10 animals were sham operated. The total time of the experiment was 85 min, reproducing scene, transport and emergency room times. Intra-abdominal blood loss was significantly greater in animals that underwent normotensive resuscitation compared to hypotensive resuscitation (17.1 ± 2.0 vs 8.0 ± 1.5 mL/kg). Antithrombin levels decreased significantly in normotensive resuscitated animals compared to baseline (102 ± 2.0 vs 59 ± 4.1 percent), sham (95 ± 2.8 vs 59 ± 4.1 percent), and hypotensive resuscitated animals (98 ± 7.8 vs 59 ± 4.1 percent). Evidence of re-bleeding was also noted in the normotensive resuscitation group. A hypotensive resuscitation regimen resulted in decreased blood loss in a clinically relevant small animal model capable of reproducing hemorrhagic shock caused by a penetrating mechanism.

Rabbit model of uncontrolled hemorrhagic shock and hypotensive resuscitation.

Clinically relevant animal models capable of simulating traumatic hemorrhagic shock are needed. We developed a hemorrhagic shock model with male New Zealand rabbits (2200-2800 g, 60-70 days old) that simulates the pre-hospital and acute care of a penetrating trauma victim in an urban scenario using current resuscitation strategies. A laparotomy was performed to reproduce tissue trauma and an aortic injury was created using a standardized single puncture to the left side of the infrarenal aorta to induce hemorrhagic shock similar to a penetrating mechanism. A 15-min interval was used to simulate the arrival of pre-hospital care. Fluid resuscitation was then applied using two regimens: normotensive resuscitation to achieve baseline mean arterial blood pressure (MAP, 10 animals) and hypotensive resuscitation at 60% of baseline MAP (10 animals). Another 10 animals were sham operated. The total time of the experiment was 85 min, reproducing scene, transport and emergency room times. Intra-abdominal blood loss was significantly greater in animals that underwent normotensive resuscitation compared to hypotensive resuscitation (17.1 ± 2.0 vs 8.0 ± 1.5 mL/kg). Antithrombin levels decreased significantly in normotensive resuscitated animals compared to baseline (102 ± 2.0 vs 59 ± 4.1%), sham (95 ± 2.8 vs 59 ± 4.1%), and hypotensive resuscitated animals (98 ± 7.8 vs 59 ± 4.1%). Evidence of re-bleeding was also noted in the normotensive resuscitation group. A hypotensive resuscitation regimen resulted in decreased blood loss in a clinically relevant small animal model capable of reproducing hemorrhagic shock caused by a penetrating mechanism.

Occult pneumomediastinum in blunt chest trauma: clinical significance.

INTRODUCTION: Thoracic injuries are potentially responsible for 25% of all trauma deaths. Chest X-ray is commonly used to screen patients with chest injury. However, the use of computed tomography (CT) scan for primary screening is increasing, particularly for blunt trauma. CT scans are more sensitive than chest X-ray in detecting intra-thoracic abnormalities such as pneumothoraces and pneumomediastinums. Pneumomediastinum detected by chest X-ray or "overt pneumomediastinum", raises the concern of possible aerodigestive tract injuries. In contrast, there is scarce information on the clinical significance of pneumomediastinum diagnosed by CT scan only or "occult pneumomediastinum". Therefore we investigated the clinical consequences of occult pneumomediastinum in our blunt trauma population. METHODS: A 2-year retrospective chart review of all blunt chest trauma patients with initial chest CT scan admitted to a level I trauma centre. Data extracted from the medical records include; demographics, occult, overt, or no pneumomediastinum, the presence of intra-thoracic aerodigestive tract injuries (trachea, bronchus, and/or esophagus), mechanism and severity of injury, endotracheal intubation, chest thoracostomy, operations and radiological reports by an attending radiologist. All patients with intra-thoracic aerodigestive tract injuries from 1994 to 2004 were also investigated. RESULTS: Of 897 patients who met the inclusion criteria 839 (93.5%) had no pneumomediastinum. Five patients (0.6%) had overt pneumomediastinum and 53 patients (5.9%) had occult pneumomediastinum. Patients with occult pneumomediastinum had significantly higher ISS and AIS chest (p<0.0001) than patients with no pneumomediastinum. A chest thoracostomy tube was more common (p<0.0001) in patients with occult pneumomediastinum (47.2%) than patients with no pneumomediastinum (10.4%), as well as occult pneumothorax. None of the patients with occult pneumomediastinum had aerodigestive tract injuries (95%CI 0-0.06). Follow up CT scan of patients with occult pneumomediastinum showed complete resolution in all cases, in average 3 h after the initial exam. CONCLUSION: Occult pneumomediastinum occurred in approximately 6% of all trauma patients with blunt chest injuries in our institution. Patients who had occult pneumomediastinum were more severely injured than those who without. However, none of the patients with occult pneumomediastinum had aerodigestive tract injuries and follow up chest CT scans demonstrated their complete and spontaneous resolution.

Normal range values for thromboelastography in healthy adult volunteers

Thromboelastography (TEG®) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG® parameters analyzed were R, K, á, MA, LY30, and coagulation index. All volunteers outside the manufacturer’s normal range underwent extensive coagulation investigations. Reference ranges for 95 percent for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, á: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77 percent, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81 percent specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer’s normal values for citrated blood-kaolin had a specificity of 81 percent and would incorrectly identify 8.5 percent of the healthy volunteers as coagulopathic. This study supports the manufacturer’s recommendation that each institution should determine its own normal values before adopting TEG®, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG®.

Normal range values for thromboelastography in healthy adult volunteers.

Thromboelastography (TEG) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG parameters analyzed were R, K, alpha, MA, LY30, and coagulation index. All volunteers outside the manufacturer's normal range underwent extensive coagulation investigations. Reference ranges for 95% for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, alpha: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77%, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81% specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer's normal values for citrated blood-kaolin had a specificity of 81% and would incorrectly identify 8.5% of the healthy volunteers as coagulopathic. This study supports the manufacturer's recommendation that each institution should determine its own normal values before adopting TEG, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG.

The evidence for the use of recombinant factor VIIa in massive bleeding: development of a transfusion policy framework.

A review of the recent randomized control trial evidence of the use of recombinant factor VIIa (rFVIIa) in massive bleeding. rFVIIa is a recombinant genetically engineered clotting factor that has been used for the management of haemophilia patients with inhibitors. There has been increasing use in patients with massive bleeding, even when there is no underlying coagulation disorder present. In November 2006, the Canadian National Advisory Committee on Blood and Blood Products engaged in a consultation and review process with several leading Canadian experts to review and discuss the current evidence up to November 2006. There is little evidence to support the routine use of rFVIIa in massive bleeding on review of 13 randomized controlled trials. rFVIIa should only be considered as part of a transfusion policy framework for massive bleeding after all other transfusion and supportive measures are considered. An example of a policy framework is presented.

Blunt hasson trocar injury: long intra-abdominal trocar and lean patient--a dangerous combination.

Injury at the time of trocar placement with the Hasson approach is rare. The cone of the Hasson cannula is wedged into the skin for an air seal, and, using fascial sutures, fastened under tension to flanges of the cannula. The shorter the fascial securing suture, the greater the tension and the more secure the air seal. Flanges for securing the fascial suture were attached to the external cannula in early Hasson cannula models. With these, much of the trocar needs to be intra-abdominal in order to shorten the suture. For lean patients, with very little distance between the anterior and posterior abdominal walls, the force required to fasten the sutures to the flanges may allow an intra-abdominal trocar to damage intervening organs. Later versions of the cannula had the flanges attached to the cone, allowing for short suture without need for intra-abdominal cannula. These models avoid the possibility of such injury. An unusually lean patient underwent laparoscopic cholecystectomy using an older Hasson cannula with flanges for the fascial securing suture attached to the cannula. Postoperative changes in vital signs and hemoglobin led to a diagnosis of intra-abdominal bleeding, and laparotomy revealed a transsected branch of the middle colic artery. Earlier Hasson cannulas, where the flanges are attached to the cannula, should be replaced with those with flanges attached to the cone.

Advances in fluid resuscitation of hemorrhagic shock.

The optimal fluid for resuscitation in hemorrhagic shock would combine the volume expansion and oxygen-carrying capacity of blood without the need for cross-matching or the risk of disease transmission. Although the ideal fluid has yet to be discovered, current options are discussed in this review, including crystalloids, colloids, blood and blood substitutes. The future role of blood substitutes is not yet defined, but the potential advantages in trauma or elective surgery may prove to be enormous.

In vivo and in vitro modulation of intercellular adhesion molecule (ICAM)-1 expression by hypertonicity.

Hepatic ischemia-reperfusion (I/R) is an important cause of organ dysfunction in the critically ill. With reperfusion, Kupffer cells release pro-inflammatory cytokines that promote endothelial cell (EC) expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, facilitating neutrophil (PMN) infiltration. Studies suggest hypertonic saline (HTS) might exert beneficial effects on development of organ injury following shock on the basis of reduced PMN-EC interactions. We hypothesized that HTS alters expression of EC ICAM-1 and thus minimizes PMN-mediated injury. To test our hypothesis, we used an in vivo model of hepatic I/R and an in vitro model of activated EC. Rats underwent 30 min of hepatic ischemia after pretreatment with HTS (7.5% NaCl, 4cc/kg ia) or normal saline (NS). At 4 h reperfusion, plasma was taken for aspartate aminotransferase (AST) and liver tissue was harvested for assessment of hepatic ICAM-1 mRNA by Northern blot analysis. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) and exposed to hypertonic medium (350-500 mOsM). HUVEC ICAM-1 protein was measured by cell ELISA and ICAM-1 mRNA by Northern blot analysis. HTS prevented hepatic I/R injury as measured by AST. AST of shams was 282.6+/-38.1 IU/L. I/R following NS pretreatment caused significant injury (AST 973.8+/-110.9 IU/L) compared to sham (SM) (P < 0.001). Pretreatment with HTS exerted significant protection following I/R with an AST of 450.9+/-56.3 IU/L (P < 0.05). There was no significant difference in AST levels between SM and HTS groups. Reduced hepatic injury after HTS and I/R was accompanied by inhibition of I/R-induced hepatic ICAM-1 mRNA expression compared to NS treated animals (P < 0.01). Similarly, hypertonicity inhibited HUVEC LPS-induced ICAM-1 protein (LPS: 1.86+/-0.19 absorbance units; 400 mOsM +/- LPS: 1.45+/-0.14 absorbance units; 450 mOsM + LPS: 1.02+/-0.19 absorbance units, P < 0.001) and mRNA expression. Thus, hypertonicity modulates endothelial ICAM-1 expression as one possible protective mechanism against I/R injury.

Hypertonic inhibition of exocytosis in neutrophils: central role for osmotic actin skeleton remodeling.

Hypertonicity suppresses neutrophil functions by unknown mechanisms. We investigated whether osmotically induced cytoskeletal changes might be related to the hypertonic inhibition of exocytosis. Hyperosmolarity abrogated the mobilization of all four granule types induced by diverse stimuli, suggesting that it blocks the process of exocytosis itself rather than individual signaling pathways. Concomitantly, osmotic stress provoked a twofold increase in F-actin, induced the formation of a submembranous F-actin ring, and abolished depolymerization that normally follows agonist-induced actin assembly. Several observations suggest a causal relationship between actin polymerization and inhibition of exocytosis: 1) prestimulus actin levels were inversely proportional to the stimulus-induced degranulation, 2) latrunculin B (LB) prevented the osmotic actin response and restored exocytosis, and 3) actin polymerization induced by jasplakinolide inhibited exocytosis under isotonic conditions. The shrinkage-induced tyrosine phosphorylation and the activation of the Na(+)/H(+) exchanger were not affected by LB. Inhibition of osmosensitive kinases failed to prevent the F-actin change, suggesting that the osmotic tyrosine phosphorylation and actin polymerization are independent phenomena. Thus cytoskeletal remodeling appears to be a key component in the neutrophil-suppressive, anti-inflammatory effects of hypertonicity.

Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor.

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.