Mortality rates of severe traumatic brain injury patients: impact of direct versus nondirect transfers.

BACKGROUND: Direct transport of patients with severe traumatic brain injury (sTBI) to trauma centers (TCs) that can provide definitive care results in lower mortality rates. This study investigated the impact of direct versus nondirect transfers on the mortality rates of patients with sTBI. METHODS: Data on patients with TBI admitted between January 1, 2012, and December 31, 2013, to our Level I TC were obtained from the trauma registry. Data included patient age, sex, mechanism, and type of injury, comorbidities, Glasgow Coma Scale, Injury Severity scores, prehospital time, time to request and to transfer, time to initiation of multimodality monitoring and goal-directed therapy protocol, dwell time in the emergency department (EDT), and mortality. Data, reported in means ± standard deviation, were analyzed with the Student t-test and chi-square. Statistical significance was accepted at a P value < 0.05. RESULTS: sTBI direct transfer to TC versus transfer from non-TCs (NTC): Of the 1187 patients with TBI admitted to our TC, 768 (64.7%) were admitted directly from the scene, whereas 419 (35.3%) were admitted after secondary transfer. One hundred seventy-one (22.2%) of the direct transfers had Glasgow Coma Scale < 8 (sTBI) and 92 (21.9%) of the secondary transfers had sTBI. The transfer time: Time from scene to arrival to the EDT was significantly shorter for TC versus NTCs 43 ± 14 versus 77 ± 26 min, respectively (P < 0.05). EDT dwell time before transfer and time from injury to arrival to TC were 4.2 ± 2.1 and 6.2 ± 8.3 h, respectively. Mortality: There was a statistically significant lower mortality for patients with sTBI transferred directly from the scene to TCs as opposed to patients secondarily transferred, 33/171 (19.3%) versus 33/92 (35.8%), respectively (P < 0.05). CONCLUSIONS: To decrease TBI-related mortality, patients with suspected sTBI should be taken directly to a Level I or II TC unless they require life-saving stabilization at NTCs.

Pancreatic trauma: Management and literature review. / Traumatismos de páncreas: manejo y revisión de la literatura.

Pancreatic injury is an uncommon event often difficult to diagnose at an early stage. After abdominal trauma, the surgeon must always be aware of the possibility of pancreatic trauma due to the complications associated with missed pancreatic injuries. Due to its retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extra abdominal injuries explain the high morbidity and mortality. The aim of this study is to present a concise description of the incidence of these injuries, lesional mechanisms, recommended diagnostic methods, therapeutic indications including nonoperative management, endoscopy and surgery, and an analysis of pancreas-specific complications and mortality rates in these patients based on a 60-year review of the literature, encompassing 6,364 patients. Due to pancreatic retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extraaabdominal injuries explain the high morbidity and mortality of these patients.

Treatment of complex perineal trauma. A review of the literature. / Tratamiento del trauma perineal complejo. Revisión de la literatura.

Perineal injuries are uncommon, but not rare. They may present a wide variety of injury patterns which demand an accurate diagnostic assessment and treatment. Perineal injuries may occur as isolated injuries to the soft tissues or may be associated with pelvic organ, abdominal or even lower extremity injury. Hence the importance to know in depth not only the anatomy of the perineum and its organs, but also the implications of the patient's hemodynamic stability on the decision making process when treating these injuries using established trauma guidelines. The purpose of this review is to describe the current epidemiology and clinical presentation of perineal injuries in order to provide specific guidelines for the diagnosis and treatment of both stable and unstable patients.

Duodenal injuries due to trauma: Review of the literature.

Duodenal injuries constitute a challenge to the Trauma Surgeon, mainly due to their retroperitoneal location. When identified, they present associated with other abdominal injuries. Consequently, they have an increased morbidity and mortality. At best estimates, duodenal lesions occur in 4.3% of all patients with abdominal injuries, ranging from 3.7% to 5%, and because of their anatomical proximity to other organs, they are rarely an isolated injury. The aim of this paper is to present a concise description of the anatomy, diagnosis, surgical management and treatment of complications of duodenal trauma, and an analysis of complications and mortality rates of duodenal injuries based on a 46-year review of the literature.

Retrospective observational study correlating traumatic pelvic fractures and their associated injuries according to the Tile classification.

INTRODUCTION: Pelvic fractures due to high energy trauma present a high risk of associated injuries that compromise the functional and vital prognosis of the patients. The objective of this study was to analyze the relationship between traumatic pelvic fractures and their associated injuries according to the Tile classification. METHODS: Retrospective observational study of patients who suffered traumatic pelvic fractures (Type A, B or C of the Tile classification) with concomitant associated injuries, analyzing hemoglobin levels, between 6/2013 and 1/2016. RESULTS: A total of 42 patients were included; of those 69% (n = 29) were males, mean age was 48 years. 45% (n = 19) suffered traffic accidents and 26.2% (n = 11) falls. There was a different proportion in pelvic injuries: Tile A (n = 15, 35.7%), B (n = 20, 47.6%), and C (n = 7, 16.6%) of cases. 54.8% (n = 23) underwent surgery, 21.4% (n = 9) needed temporary or definitive external fixation. Significant differences were found between Tile A type and scapula fractures (P = .032), and Tile B with sacral fractures (P = .033) and visceral injuries (P = .049), while there is a tendency without a statistical significal between Tile C and costal fractures. 61.9% (n = 26) needed blood transfusion; 9.5% (n = 4) presented hypovolemic shock. CONCLUSIONS: Tile A pelvic fractures were associated with scapular fractures, and Tile B with transforaminal fractures of the sacrum and with visceral injuries (lungs, liver and genitourinary). The small number of Tile C prevent us to confirm an association with any pathology, although they are the ones which presnt more hemodynamically instability and thoracic injuries.

A prospective comparative study of the functional results associated with the use of Björk flap tracheostomy versus standard tracheostomy.

BACKGROUND: Placement of a tracheostomy for patients requiring prolonged mechanical ventilation (PMV) improves patients' comfort, decreases dead space ventilation, allows superior airway hygiene, and reduces the incidence of ventilator-associated pneumonia. Controversy still exists regarding the role of standard tracheostomy (ST) as opposed to the less frequently done Björk flap tracheostomy (BFT). This study compares the functional outcomes of these two techniques. STUDY DESIGN: Seventy-nine patients receiving tracheostomy in a 12-month period: 38 BFT vs. 41 ST. Data included demographics, indications for PMV, ventilator days before tracheostomy, time to and a number of patients who passed the fiberoptic endoscopic evaluation of swallowing (FEES), time to and a number of patients decannulated. RESULTS: Indications in both groups were PMV from trauma (18/38 vs 15/41), pneumonia (13/38 vs 13/41), and ARDS (7/38 vs 11/4), respectively (p > 0.05). Patients in both groups did not differ with regard to age, sex, GCS, duration of PMV before tracheostomy, the time to and a number of patients who passed the 1st FEES. However, the number of days and the number of FEES required before the next successful FEES in the 20 BFT and 21 ST patients who failed the 1st was 9 (4) vs. 16 (5), and 2 (1) vs. 4 (1), respectively (p < 0.05). Additionally, the number of intraoperative complications in aggregate were 0/38 in the BFT as opposed to 6/41 in the ST group (p < 0.05). CONCLUSION: We conclude that BFT may be associated with an overall shorter time to restoration of normal swallowing when compared to ST.

Bleeding risk secondary to deep vein thrombosis prophylaxis in patients with lower gastrointestinal bleeding.

INTRODUCTION: Deep vein thrombosis (DVT) and pulmonary embolism (PE) continue to pose a major burden on the health care system in the United States. The precise timing of anticoagulation initiation in critically ill patients with recent or active lower gastrointestinal bleeding (LGIB) is not well defined. We set out to study the safety and efficacy of early heparin administration for DVT prophylaxis in these patients. METHODS: A review of all patients admitted to the ICU with a diagnosis of LGIB over a 13-year period was performed. A total of 60 patients received subcutaneous heparin along with mechanical prophylaxis, whereas 59 patients had intermittent pneumatic compression devices alone. RESULTS: There was no difference in morbidity or mortality between the groups who received heparin and the nonheparin cohort. Neither of the groups developed a DVT or PE during the study period. Patients who received heparin had a median ICU LOS of 3 days, when compared with 2 days for patients who did not receive heparin (P < .0118). There was a significant association between units of blood received during the first 24 hours in the ICU and heparin usage (P < .0229). Those administered heparin received more units (median 3) than those who did not receive heparin (median 2). CONCLUSIONS: Administration of subcutaneous heparin increases the transfusion requirements and LOS in ICU patients with LGIB. After 24 hours, however, the blood transfusion requirements are equivalent. DVT prophylaxis in patients with a diagnosis of LGIB should be initiated after 24 hours of ICU admission.

Correlation of brain flow variables and metabolic crisis: a prospective study in patients with severe traumatic brain injury.

INTRODUCTION: Current treatment guidelines for patients with severe TBI (sTBI) are aimed at preventing secondary brain injury targeting specific endpoints of intracranial physiology to avoid the development of metabolic crisis. We sought to identify factors contributing to development of metabolic crisis in the setting of a Multi-modality Monitoring and Goal-Directed Therapy (MM&GDTP) approach to patients with severe TBI. METHODS: Prospective monitoring of sTBI patients was performed, with retrospective data analysis. MM&GDTP was targeted to intracranial pressure (ICP) ≤ 20 mmHg, cerebral perfusion pressure (CPP) ≥ 60 mmHg, brain tissue oxygen pressure (PbtO2) ≥ 20 mmHg, and cerebral oxygen extraction measured by bi-frontal Near infrared Spectroscopy (NIRS) > 55%. Brain flow abnormality was defined by one of the following combinations: CPP < 60 mmHg with NIRS < 55% (Type 1), CPP < 60 mmHg with PbtO2 < 20 mmHg (Type 2), or PbtO2 < 20 mmHg with NIRS < 55% (Type 3). Cerebral micro-dialysate was analyzed hourly for glucose, lactate, pyruvate, glutamate, glycerol, and lactate/pyruvate ratio (LPR). Statistical analysis was performed with student t-test, chi-square and Pearson's tests as applicable. RESULTS: A total of 109,474 consecutive minutes of recorded multimodality monitoring was available for analysis. There was a significant difference in the number of minutes of brain flow abnormalities between survivors and non-survivors: 0.8% (875) versus 7.49% (8,199), respectively (p < 0.05). The duration of Type 1-3 flow abnormality per patient was higher in non-survivors (5.7 ± 2.5 h) compared to survivors (0.7 ± 0.6 h) as well as the duration of metabolic crisis, namely, 5.2 ± 2.2 versus 0.6 ± 1.0 h per patient. The occurrence of severe metabolic crisis was associated with a Type 2 flow abnormality (CPP < 60 mmHg and PbtO2 < 20 mmHg), r = 0.97, p < 0.001, but not with Type 1 and 3. CONCLUSIONS: Metabolic crisis can occur despite a MM&GDTP approach aimed at optimizing cerebral blood flow. Severe metabolic crisis is associated to failure to maintain CPP and PbtO2 above 60 and 20 mmHg, respectively. The occurrence of severe metabolic crisis portends a poor prognosis in patients with sTBI.

Incidence and effects of deep vein thrombosis on the outcome of patients with coronavirus disease 2019 infection.

BACKGROUND: Deep vein thrombosis (DVT) has been reported to occur at different rates in patients with coronavirus disease 2019 (COVID-19). Limited data exist regarding comparisons with non-COVID-19 patients with similar characteristics. Our objective was to compare the rates of DVT in patients with and without COVID-19 and to determine the effect of DVT on the outcomes. METHODS: We performed a retrospective, observational cohort study at a single-institution, level 1 trauma center comparing patients with and without COVID-19. The 573 non-COVID-19 patients (age, 61 ± 17 years; 44.9% male) had been treated from March 20, 2019 to June 30, 2019, and the 213 COVID-19 patients (age, 61 ± 16 years; 61.0% male) had been treated during the same interval in 2020. Standard prophylactic anticoagulation therapy consisted of 5000 U of heparin three times daily for the medical patients without COVID-19 who were not in the intensive care unit (ICU). The ICU, surgical, and trauma patients without COVID-19 had received 40 mg of enoxaparin daily (not adjusted to weight). The patients with COVID-19 had also received enoxaparin 40 mg daily (also not adjusted to weight), regardless of whether treated in the ICU. The two primary outcomes were the rate of deep vein thrombosis (DVT) in the COVID-19 group vs that in the historic control and the effect of DVT on mortality. The subgroup analyses included patients with adult respiratory distress syndrome (ARDS), pulmonary embolism (PE), and intensive care unit patients (ICU). RESULTS: The rate of DVT and PE for the non-COVID-19 patients was 12.4% (71 of 573) and 3.3% (19 of 573) compared with 33.8% (72 of 213) and 7.0% (15 of 213) for the COVID-19 patients, respectively. Unprovoked PE had developed in 10 of 15 COVID-19 patients (66.7%) compared with 8 of 497 non-COVID-19 patients (1.6%). The 60 COVID-19 patients with ARDS had had an incidence of DVT of 46.7% (n = 28). In contrast, the incidence of DVT for the 153 non-COVID-19 patients with ARDS was 28.8% (n = 44; P = .01). The COVID-19 patients requiring the ICU had had an increased rate of DVT (39 of 90; 43.3%) compared with the non-COVID-19 patients (33 of 123; 33.3%; P = .01). The risk factors for mortality included age, DVT, multiple organ failure syndrome, and prolonged ventilatory support with the following odd ratios: 1.030 (95% confidence interval [CI], 1.002-1.058), 2.847 (95% CI, 1.356-5.5979), 4.438 (95% CI, 1.973-9.985), and 5.321 (95% CI, 1.973-14.082), respectively. CONCLUSIONS: The incidence of DVT for COVID-19 patients receiving standard-dose prophylactic anticoagulation that was not weight adjusted was high, especially for ICU patients. DVT is one of the factors contributing to increased mortality. These results suggest a reevaluation is necessary of the present standard-dose thromboprophylaxis for patients with COVID-19.

Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion.

RATIONALE: Milk fat globule epidermal growth factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. It attenuates chronic and acute inflammation such as autoimmune glomerulonephritis and bacterial sepsis by enhancing apoptotic cell clearance. Ischemia-reperfusion (I/R) injury of the gut results in severe inflammation, apoptosis, and remote organ damage, including acute lung injury (ALI). OBJECTIVES: To determine whether MFG-E8 attenuates intestinal and pulmonary inflammation after gut I/R. METHODS: Wild-type (WT) and MFG-E8(-/-) mice underwent superior mesenteric artery occlusion for 90 minutes, followed by reperfusion for 4 hours. A group of WT mice was treated with 0.4 microg/20 g recombinant murine MFG-E8 (rmMFG-E8) at the beginning of reperfusion. Four hours after reperfusion, MFG-E8, cytokines, myeloperoxidase activity, apoptosis, and histopathology were assessed. A 24-hour survival study was conducted in rmMFG-E8- and vehicle-treated WT mice. MEASUREMENTS AND MAIN RESULTS: Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, including the lungs. MFG-E8 levels decreased in the spleen and lungs by 50 to 60%, suggesting impaired apoptotic cell clearance. Treatment with rmMFG-E8 significantly suppressed inflammation (TNF-alpha, IL-6, IL-1beta, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment with rmMFG-E8 significantly improved the survival in WT mice. CONCLUSIONS: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.

Predictive Factors for Surgical Site Infections in Patients Undergoing Surgery for Breast Carcinoma.

INTRODUCTION: Operative interventions for breast cancer are generally classified as clean surgeries. Surgical site infections (SSIs), while rare, do occur. This study sought to identify risk factors for SSI, using the National Surgical Quality Improvement Program (NSQIP). METHODS: NSQIP's participant use data files (PUF) between 2012 and 2015 were examined. Female patients with invasive breast cancer who underwent surgery were identified through CPT and ICD9 codes. Non-SSI and SSI groups were compared and the statistical differences were addressed through propensity score weighting. Multivariate logistic regression testing was used to identify predictors of SSI. RESULTS: This study examined 30 544 lumpectomies and 23 494 mastectomies. SSI rate was 1126/54 038 patients (2.1%). In the weighted dataset, mastectomy, diabetes, smoking, COPD, ASA class-severe, BMI >35 kg/m2, and length of stay (LOS) >1 day were associated with an increased odds ratio (OR) of SSI. The OR for SSI was highest after mastectomy with reconstruction (OR 2.626, P < .001; 95% CI 2.073-3.325). Postoperative variables associated with an increased OR of SSIs included systemic infection, unplanned reoperation wound dehiscence, and renal failure. CONCLUSION: Mastectomy, diabetes, smoking, COPD, ASA class-severe, BMI >35 kg/m2, length of stay (LOS) >1 day are associated with an increased OR for SSIs following breast surgery.

An analysis of 979 patients with pelvic fractures stratified by the presence or absence of solid organ injury.

BACKGROUND: Pelvic fractures (PF) require high force mechanism and their severity have been linked with an increase in the incidence of associated injuries within the abdomen and chest. Our goal is to assess the impact of solid organ injury (SOI) on the outcome of patients with PF and to identify risk factors predictive of morbidity and mortality among these patients. STUDY DESIGN: We conducted a single-center retrospective review of medical records of patients 16 years or older admitted to our level 1 trauma center with pelvic fracture with and without OI associated from blunt trauma between 1/1/2010-7/31/2015. RESULTS: 979 patients with PF were identified. 261/979 (26.7%) had at least one associated SOI. The grade of the SOI ranged from I to III in 246 patients, grade IV in five patients and grade V in 10 patients with SOI sustained a higher pelvic AIS grade and required a statistically significant greater amount of blood products (BP). Thoracic and urogenital injuries were also more common. The mortality of patients with PF was not affected by the presence of SOI. Increasing age, Injury Severity Score, Glasgow Coma Scale, hypothermia and the amount of BP transfused were predictive of mortality. CONCLUSIONS: The presence of SOI did not affect the outcome of patients with pelvic fracture, although our results may be linked to the limited number of patients with high grade SOI. The degree of pelvic AIS is predictive of associated injuries within the abdomen and chest.

Factors associated with severity of accidental hypothermia: A cohort retrospective multi-institutional study.

BACKGROUND: Frequently it is difficult to determine illness severity in hypothermic patients. Our goal was to determine if there are factors associated with illness severity of hypothermic emergency department (ED) patients. METHODS: Multi-hospital retrospective cohort. Consecutive patients in 24 EDs (1-1-2012 to 4-30-2015). Hypothermic patients (≤35 °C) were identified using ICD codes. We used hospital admission as marker of illness severity. Student's t-test was used for differences between mean age and temperature for admitted and discharged patients. We calculated the percent of patients admitted by factor, the difference from overall admission rate and 95% confidence interval (CI) of difference. RESULTS: There were 2094 visits with hypothermia ICD code. Of these, 132 patients had initial rectal temperatures ≤35 °C. Females comprised 42%; the mean age was 55 ± 23 years, and overall admission rate was 62%. The percent of patients with alcohol, trauma and found indoors were 39%, 27% and 27%, respectively. For admitted and discharged patients the mean ages were 60 and 48 years, respectively (p = 0.01), and initial mean temperature 32.3 °C vs. 33 °C, respectively (p = 0.07). Found indoors was associated with an 86% admission rate, a 22% increase (95% CI, 3%-34%) compared to overall admission rate. There was no statistically significant difference in admission rates from overall admission rate based on gender, alcohol or trauma. CONCLUSIONS: For hypothermic ED patients increased severity of illness was associated with older age and found indoors but not associated with initial temperature, gender, alcohol or trauma. These findings may assist physicians in treatment and disposition decisions.

Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein.

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12-48 microg/kg body weight) was administered in combination with human AMBP-1 (40-160 microg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%-80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.

Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis.

In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. The purpose of this study is to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI) and, if so, the potential mechanism responsible for the benefit. To study this, adult male rats were exposed to 5-Gy whole body irradiation followed by cecal ligation and puncture (CLP, a model of sepsis) 48 h thereafter. Human ghrelin (30 nmol/rat) or vehicle (saline) was infused intravenously via an osmotic minipump immediately after radiation exposure. Blood and tissue samples were collected at 20 h after RCI (68 h after irradiation or 20 h after CLP) for various measurements. To determine the longterm effect of human ghrelin after RCI, the gangrenous cecum was removed at 5 h after CLP and 10-d survival was recorded. In addition, vagotomy or sham vagotomy was performed in sham and RCI animals immediately prior to ghrelin administration, and various measurements were performed at 20 h after RCI. Our results showed that serum levels of ghrelin and its gene expression in the stomach were decreased markedly at 20 h after RCI. Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems.

Human adrenomedullin and its binding protein attenuate organ injury and reduce mortality after hepatic ischemia-reperfusion.

OBJECTIVE: To determine whether administration of a vasoactive peptide, human adrenomedullin (AM), in combination with its binding protein (ie, AMBP-1), prevents or minimizes hepatic ischemia-reperfusion (I/R) injury. SUMMARY BACKGROUND DATA: Hepatic I/R injury results from tissue hypoxia and subsequent inflammatory responses. Even though numerous pharmacological modalities and substances have been studied to reduce I/R-induced mortality, none have been entirely successful. We have shown that administration of AM/AMBP-1 produces significant beneficial effects under various pathophysiological conditions. However, it remains unknown if human AM/AMBP-1 has any protective effects on hepatic I/R-induced tissue damage and mortality. METHODS: Seventy percent hepatic ischemia was induced in male adult rats by placing a microvascular clip across the hilum of the left and median lobes for 90 minutes. After removing the clip, human AM alone, human AMBP-1 alone, human AM in combination with human AMBP-1 or vehicle was administered intravenously over a period of 30 minutes. Blood and tissue samples were collected 4 hours after reperfusion for various measurements. In additional groups of animals, the nonischemic liver lobes were resected at the end of 90-minute ischemia. The animals were monitored for 7 days and survival was recorded. RESULTS: After hepatic I/R, plasma levels of AM were significantly increased, whereas AMBP-1 levels were markedly decreased. Likewise, gene expression of AM in the liver was increased significantly, whereas AMBP-1 expression was markedly decreased. Administration of AM in combination with AMBP-1 immediately after the onset of reperfusion down-regulated inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. On the other hand, administration of human AM alone or human AMBP-1 alone after hepatic I/R failed to produce significant protection. CONCLUSIONS: Human AM/AMBP-1 may be a novel treatment to attenuate tissue injury after an episode of hepatic ischemia.

Ghrelin hyporesponsiveness contributes to age-related hyperinflammation in septic shock.

OBJECTIVE: To test the hypothesis that hyporesponsiveness to ghrelin due to reduced growth hormone (GH) contributes to the aging-related hyperinflammatory state in sepsis. SUMMARY BACKGROUND DATA: Sepsis and septic shock are a serious problem, particularly in the geriatric population. Ghrelin is an endogenous ligand for the GH secretagogue receptor 1a (GHSR1a, ie, ghrelin receptor). The decline in GH with age is directly associated with many adverse changes that occur with aging. However, the role of GH, ghrelin, and GHSR1a in the age-associated vulnerability to sepsis remains unknown. METHODS: Male Fischer 344 rats (young: 3 months; aged: 24 months) were used. Plasma GH levels, ghrelin receptor expression, and neuronal activity in the parasympathostimulatory nuclei of the brain stem in normal young and aged animals were measured. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS, 15 mg/kg BW). RESULTS: While LPS-induced release of proinflammatory cytokines from macrophages isolated from aged rats decreased, LPS injection resulted in an in vivo hyperinflammatory state. GH levels were lower in aged rats, which was associated with lower expression of GHSR1a in the dorsal vagal complex and a decrease in parasympathostimulatory neuronal activity. GHSR1a antagonist elevated LPS-induced cytokine release in young rats. GH increased GHSR-1a expression in the dorsal vagal complex in aged rats. Coadministration of ghrelin and GH, but not ghrelin alone or GH alone, markedly reduced cytokine levels and organ injury after endotoxemia in aged rats, which was associated with significantly elevated parasympathostimulatory neuronal activity. CONCLUSIONS: These findings suggest that the reduced central (brain) responsiveness to ghrelin due to the decreased GH, plays a major role in producing the hyperinflammatory state, resulting in severe organ injuries and high mortality after endotoxemia in aged animals. Ghrelin and GH can be developed as a novel therapy for sepsis in the geriatric population.

Human vasoactive hormone adrenomedullin and its binding protein rescue experimental animals from shock.

We recently discovered that vascular responsiveness to adrenomedullin (AM), a vasoactive hormone, decreases after hemorrhage, which is markedly improved by the addition of its binding protein AMBP-1. One obstacle hampering the development of AM/AMBP-1 as resuscitation agents in trauma victims is the potential immunogenicity of rat proteins in humans. Although less potent than rat AM, human AM has been shown to increase organ perfusion in rats. We therefore hypothesized that administration of human AM/AMBP-1 improves organ function and survival after severe blood loss in rats. To test this, male Sprague-Dawley rats were bled to and maintained at an MAP of 40 mmHg for 90 min. They were then resuscitated with an equal volume of shed blood in the form of Ringer's lactate (i.e., low-volume resuscitation) over 60 min. At 15 min after the beginning of resuscitation, human AM/AMBP-1 (12/40 or 48/160 microg/kg BW) were administered intravenously over 45 min. Various pathophysiological parameters were measured 4h after resuscitation. In additional groups of animals, a 12-day survival study was conducted. Our result showed that tissue injury as evidenced by increased levels of transaminases, lactate, and creatinine, was present at 4h after hemorrhage and resuscitation. Moreover, pro-inflammatory cytokines TNF-alpha and IL-6 were also significantly elevated. Administration of AM/AMBP-1 markedly attenuated tissue injury, reduced cytokine levels, and improved the survival rate from 29% (vehicle) to 62% (low-dose) or 70% (high-dose). However, neither human AM alone nor human AMBP-1 alone prevented the significant increase in ALT, AST, lactate and creatinine at 4h after the completion of hemorrhage and resuscitation. Moreover, the half-life of human AM and human AMBP-1 in rats was 35.8 min and 1.68 h, respectively. Thus, administration of human AM/AMBP-1 may be a useful approach for attenuating organ injury, and reducing mortality after hemorrhagic shock.

Comparison between thromboelastography and conventional coagulation test: Should we abandon conventional coagulation tests in polytrauma patients? / Comparación entre tromboelastografía y test de coagulación convencionales: ¿deberíamos abandonar los test de coagulación convencional en el paciente politraumatizado?

INTRODUCTION: TEG provides an in-vivo assessment of viscoelastic clot strength in whole blood compared with CCT, which may not reflect the influence of platelets. The aim of this study was to compare TEG vs. CCT in trauma patients stratified by mechanism of injury (MOI) and pre-existing coagulation status. METHODS: A retrospective, observational study of 230 polytrauma patients admitted to a University Hospital Level 1 Trauma Center, with TEG and CCT on admission stratified by MOI: multiple trauma (MT), isolated traumatic brain injury (TBI) or MT+TBI. Statistical analysis included correlation between TEG and CCT in all groups and a subgroup analysis of anticoagulated patients. Data were analyzed with ANOVA, Spearman and lineal regression when appropriate. Statistical significance was accepted at P<0.05. RESULTS: TEG was normal in 28.7%, hypercoagulable in 68.3%, hypocoagulable in 7%. There was no difference in TEG status among the groups. The coagulation status was not affected by age, ISS or shock. The CCT were abnormal in 63.6% of patients with normal TEG. Normal or hypercoagulable-TEG was found in 21/23 patients on Coumadin who had elevated INR and in 10/11 patients on NOAC. An analysis of the 23 patients on Coumadin stratified by INR showed a normal or hypercoagulable-TEG in 21/23 patients. Only 2 patients had a hypocoagulable-TEG. Mortality was 5.2% (58.3% severe TBI). CONCLUSIONS: TEG is more useful than CCT in polytrauma patients, including patients on anticoagulants. TBI could increase the incidence of hypercoagulability in trauma. CCT are not useful from the standpoint of treatment.

Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion.

BACKGROUND: Ischemic bowel remains a critical problem, resulting in up to 80% mortality. Acute lung injury, a common complication after intestinal ischemia/reperfusion (I/R), might be responsible for such a high mortality rate. Our previous studies have shown that administration of a novel vasoactive peptide adrenomedullin (AM) and its binding protein (AMBP-1) reduces the systemic inflammatory response in rat models of both hemorrhage and sepsis. It remains unknown whether administration of AM/AMBP-1 has any protective effects on intestinal I/R-induced acute lung injury. We hypothesized that administration of AM/AMBP-1 after intestinal I/R prevents acute lung injury through downregulation of proinflammatory cytokines. STUDY DESIGN: Intestinal I/R was induced by placing a microvascular clip across superior mesenteric artery (SMA) for 90 minutes in adult male Sprague-Dawley rats (275 to 325 g). On release of the SMA clamp, the animals were treated with either AM (12 mug/kg body weight) in combination with AMBP-1 (40 microg/kg body weight) or vehicle (1 mL normal saline) during a period of 30 minutes through a femoral vein catheter. Lung samples were collected at 4 hours after treatment or sham operation. Lung injury was assessed by examining lung water content, morphologic changes, and granulocyte myeloperoxidase activity. Tumor necrosis factor-alpha and interleukin-6 gene expression and their protein levels in the lungs were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In additional groups of animals, AM/AMBP-1 or vehicle was administered at 1 hour after onset of reperfusion. Lung histology was examined at 3 hours after treatment. RESULTS: Intestinal I/R induced considerable lung injury, as characterized by lung edema, histopathologic changes, increased myeloperoxidase activity, and proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) levels in the lungs. Administration of AM/AMBP-1 after ischemia mitigated lung injury and dramatically downregulated proinflammatory cytokines. Lung injury was also ameliorated by delayed AM/AMBP-1 treatment as evidenced by improvement in lung histology. CONCLUSIONS: AM/AMBP-1 can be developed as a novel treatment to attenuate acute lung injury after an episode of gut ischemia. The protective effect of AM/AMBP-1 appears to be mediated through downregulation of proinflammatory cytokines.