Michael A. Norman

Hypotensive Resuscitation Strategy Reduces Transfusion Requirements and Severe Postoperative Coagulopathy in Trauma Patients With Hemorrhagic Shock: Preliminary Results of a Randomized Controlled Trial

BACKGROUND Trauma is a leading cause of death worldwide and is thus a major public health concern. Previous studies have shown that limiting the amount of fluids given by following a strategy of permissive hypotension during the initial resuscitation period may improve trauma outcomes. This study examines the clinical outcomes from the first 90 patients enrolled in a prospective, randomized controlled trial of hypotensive resuscitation, with the primary aim of assessing the effects of a limited transfusion and intravenous (IV) fluid strategy on 30-day morbidity and mortality. METHODS Patients in hemorrhagic shock who required emergent surgery were randomized to one of the two arms of the study for intraoperative resuscitation. Those in the experimental (low mean arterial pressure [LMAP]) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure (MAP) was 50 mm Hg. Those in the control (high MAP [HMAP]) arm were managed with standard fluid resuscitation to a target MAP of 65 mm Hg. Patients were followed up for 30 days. Intraoperative fluid requirements, mortality, postoperative complications, and other clinical data were prospectively gathered and analyzed. RESULTS Patients in the LMAP group received a significantly less blood products and total i.v. fluids during intraoperative resuscitation than those in the HMAP group. They had significantly lower mortality in the early postoperative period and a nonsignificant trend for lower mortality at 30 days. Patients in the LMAP group were significantly less likely to develop immediate postoperative coagulopathy and less likely to die from postoperatively bleeding associated with coagulopathy. Among those who developed coagulopathy in both groups, patients in the LMAP group had significantly lower international normalized ratio than those in the HMAP group, indicating a less severe coagulopathy. CONCLUSIONS Hypotensive resuscitation is a safe strategy for use in the trauma population and results in a significant reduction in blood product transfusions and overall IV fluid administration. Specifically, resuscitating patients with the intent of maintaining a target minimum MAP of 50 mm Hg, rather than 65 mm Hg, significantly decreases postoperative coagulopathy and lowers the risk of early postoperative death and coagulopathy. These preliminary results provide convincing evidence that support the continued investigation and use of hypotensive resuscitation in the trauma setting.

TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients.

BACKGROUND For nearly a decade, our center performed thromboelastograms (TEGs) to analyze coagulation profiles, allowing rapid data-driven blood component therapy. After consensus recommendations for massive transfusion protocols (MTPs), we implemented an MTP in October 2009 with 1:1:1 ratio of blood (red blood cells [RBC]), plasma (fresh-frozen plasma [FFP]), and platelets. We hypothesized that TEG-directed resuscitation is equivalent to MTP resuscitation. METHODS All patients receiving 6 units (U) or more of RBC in the first 24 hours for 21 months before and after MTP initiation in an urban Level I trauma center were examined. Demographics, mechanism of injury (MOI), Injury Severity Score (ISS), 24-hour volume of RBC, FFP, platelets, crystalloid, and 30-day mortality were compared, excluding patients with traumatic brain injuries. Variables were analyzed using Student’s t-test and &khgr;2 or Fisher’s exact test. RESULTS For the preMTP group, there were 165 patients. In the MTP group, there were 124 patients. There were no significant differences in ISS, age, or sex. PreMTP patients with 6U or more RBC had significantly more penetrating MOI (p = 0.017), whereas preMTP patients with 10U or more RBC had similar MOIs. All patients received less crystalloid after MTP adoption (p < 0.001). There was no difference in volume of blood products or mortality in patients receiving 6U or more RBC. Blunt trauma MTP patients who received 10U or more RBC received more FFP (p = 0.02), with no change in mortality. Penetrating trauma patients who received 10U or more RBC received a similar volume of FFP; however, mortality increased from 54.1% for MTP versus 33.3% preMTP (p = 0.04). CONCLUSION TEG-directed resuscitation is equivalent to standardized MTP for patients receiving 6U or more RBC and for blunt MOI patients receiving 10U or more RBC. MTP therapy worsened mortality in penetrating MOI patients receiving 10U or more RBC, indicating a continued need for TEG-directed therapy. A 1:1:1 strategy may not be adequate in all patients. LEVEL OF EVIDENCE Therapeutic study, level IV.

Modern management of traumatic subclavian artery injuries: a single institution's experience in the evolution of endovascular repair

BACKGROUND Subclavian artery injuries traditionally require morbid surgical procedures. Repair by way of an endovascular approach can potentially decrease the morbidity and mortality associated with these injuries. METHODS A 2-year retrospective review of trauma patients with subclavian artery injuries was performed at our institution. Relevant data were extracted from patient records and analyzed. These results were then used to develop an algorithm for the management of trauma patients with subclavian artery injuries. RESULTS Fifteen patients with subclavian artery injuries were identified. Five patients died in the emergency room. Of the 10 surviving patients, 8 had their diagnosis made at arteriogram. Six patients underwent endovascular repair, and 4 of these repairs were successful. Three patients were managed by way of open repair. Two deaths occurred in the endovascular group, and 1 death occurred in the open group. CONCLUSIONS Our findings suggest that endovascular management of subclavian artery injuries is an acceptable technique in appropriate candidates and compares favorably with open repair. However, as with open repair, the associated morbidity and mortality remains quite high. We propose an algorithm whereby hemodynamically stable patients with hard signs of vascular injury proceed directly to angiography, whereas open repair is reserved for those patients who are unstable or in whom a catheter-based approach has previously failed.

SSTR5 ablation in islet results in alterations in glucose homeostasis in mice.

Somatostatin (SST) peptide is a potent inhibitor of insulin secretion and its effect is mediated via somatostatin receptor 5 (SSTR5) in the endocrine pancreas. To investigate the consequences of gene ablation of SSTR5 in the mouse pancreas, we have generated a mouse model in which the SSTR5 gene was specifically knocked down in the pancreatic beta cells (βSSTR5Kd) using the Cre‐lox system. Immunohistochemistry analysis showed that SSTR5 gene expression was absent in beta cells at three months of age. At the time of gene ablation, βSSTR5Kd mice demonstrated glucose intolerance with lack of insulin response and significantly reduced serum insulin levels. Insulin tolerance test demonstrated a significant increase of insulin clearance in vivo at the same age. In vitro studies demonstrated an absence of response to SST‐28 stimulation in the βSSTR5Kd mouse islet, which was associated with a significantly reduced SST expression level in βSSTR5Kd mice pancreata. In addition, βSSTR5Kd mice had significantly reduced serum glucose levels and increased serum insulin levels at 12 months of age. Glucose tolerance test at an older age also indicated a persistently higher insulin level in βSSTR5Kd mice. Further studies of βSSTR5Kd mice had revealed elevated serum C‐peptide levels at both 3 and 12 months of age, suggesting that these mice are capable of producing and releasing insulin to the periphery. These results support the hypothesis that SSTR5 plays a pivotal role in the regulation of insulin secretion in the mouse pancreas.

Deficiency of somatostatin (SST) receptor type 5 (SSTR5) is associated with sexually dimorphic changes in the expression of SST and SST receptors in brain and pancreas

The actions of somatostatin (SST) are mediated through five somatostatin receptor subtypes, termed SSTR1-5. Although SSTRs commonly display an overlapping pattern of tissue distribution, subtype-selective responses have been shown to occur in the same tissue. In the present study, we have investigated the changes in SSTR subtypes at the cellular and molecular level in both the brain and the pancreatic islets of mice deficient in SSTR5 (SSTR5KO). Expression levels of insulin and glucagon were also determined in the pancreas of these mice. Semi-quantitative RT-PCR and Western blot analysis showed significant increases in the expression of SSTR2 and 3 with a corresponding reduction in SSTR4 in the brains of female SSTR5KOs, while no changes were observed in male KOs. Strikingly, SST mRNA and SST-like immunoreactivity (SST-LI) were reduced in the brain of male KO animals but not in their female counterparts. In male SSTR5KO islets, there was an increase in the number of cells immunoreactive for SSTR1-3, whereas in female islets only SSTR3 expression was increased. Pancreatic SST-LI and SST mRNA, as well as immunoreactivity for insulin were reduced in male but not in female KO mice. These data indicate that deficiency of SSTR5 leads to subtype-selective sexually dimorphic changes in the expression of both brain and pancreatic SSTRs.

PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a “drugable” target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNAPDX-1, was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNAhumanPDX-1 lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNAmousePDX-1 lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNAmousePDX-1 lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.

Alterations in glucose homeostasis in SSTR1 gene-ablated mice.

SSTR1 is found on the majority of human pancreatic beta cells, however, its role in insulin secretion has yet to be elucidated. In this study, we used the SSTR1 knockout mouse model to examine the role of SSTR1 in insulin secretion and glucose homeostasis in mice. Despite the reported effect of SSTR1 in inhibiting growth hormone secretion, SSTR1-/- mice had significantly reduced body weight with growth retardation. Perfusion of isolated mouse pancreata at 3 months of age demonstrated a significant increase in insulin secretion in SSTR1-/- mice compared with that of WT controls. We also found that at 3 months of age, SSTR1-/- mice had significantly decreased levels of systemic insulin secretion and were glucose intolerant. However, SSTR1 gene-ablated mice had a much higher rate of insulin clearance compared to WT mice at the same age. When challenged at 12 months of age, we found SSTR1-/- mice had increased glucose tolerance with exaggerated increase of insulin levels at the end of the experiment. Immunochemical analysis showed that the pancreatic islets of SSTR1-/- mice had significantly decreased levels of somatostatin staining and a significant decrease of SSTR5 expression. These results demonstrate that SSTR1 plays an important role in the regulation of insulin secretion in the endocrine pancreas in mice.

Sulfonylurea receptor knockout causes glucose intolerance in mice that is not alleviated by concomitant somatostatin subtype receptor 5 knockout

ObjectiveTo examine the long-term effects of Sur KO, SSTR5 KO, and double Sur/SSTR5 KO on insulin secretion and glucose regulation. Summary Background DataThe sulfonylurea receptor (Sur) and somatostatin receptor type 5 (SSTR5) play an integral role in the regulatory pathways of the endocrine pancreas. Sur knockout (KO) and SSTR5 KO mice were generated in the authors’ laboratories and crossbred to generate Sur/SSTR5 KO mice. All mice were genotyped by Southern blotting and polymerase chain reaction analysis. MethodsOne-year-old Sur KO, Sur/SSTR5 KO, SSTR5 KO, and age-matched wild-type control mice underwent single-pass perfusion of isolated pancreata with low and high glucose concentration (n = 4–6/group). Another group of mice also underwent intraperitoneal glucose tolerance tests with 1.2 g glucose/kg body weight (n = 4/group per time point). ResultsSur1 KO and Sur/SSTR5 KO mice had profoundly decreased insulin secretion in vitro, whereas SSTR5 KO had increased insulin secretion compared with wild-type mice. Sur1 KO and Sur/SSTR5 mice had increased glucose response in vivo compared with wild-type mice. Sur1 KO and Sur/SSTR5 KO mice exhibit glucose intolerance and SSTR5 KO mice show increased insulin response in vitro. ConclusionsSur1 KO causes glucose intolerance and SSTR5 KO causes increased insulin secretion. However, Sur/SSTR5 double ablation does not alleviate the diabetic state of the Sur1 KO.

Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington's Disease Transgenic Mice

Background Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntingtons disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5). Methods and Findings To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2). Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5−/− and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice. Conclusions This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntingtons disease.

Intraoperative hypotensive resuscitation for patients undergoing laparotomy or thoracotomy for trauma: Early termination of a randomized prospective clinical trial.

Background Hemorrhagic shock is responsible for one third of trauma related deaths. We hypothesized that intraoperative hypotensive resuscitation would improve survival for patients undergoing operative control of hemorrhage following penetrating trauma. Methods Between July 1, 2007, and March 28, 2013, penetrating trauma patients aged 14 years to 45 years with a systolic blood pressure of 90 mm Hg or lower requiring laparotomy or thoracotomy for control of hemorrhage were randomized 1:1 based on a target minimum mean arterial pressure (MAP) of 50 mm Hg (experimental arm, LMAP) or 65 mm Hg (control arm, HMAP). Patients were followed up 30 days postoperatively. The primary outcome of mortality; secondary outcomes including stroke, myocardial infarction, renal failure, coagulopathy, and infection; and other clinical data were analyzed between study arms using univariate and Kaplan-Meier analyses. Results The trial enrolled 168 patients (86 LMAP, 82 HMAP patients) before early termination, in part because of clinical equipoise and futility. Injuries resulted from gunshot wounds (76%) and stab wounds (24%); 90% of the patients were male, and the median age was 31 years. Baseline vitals, laboratory results, and injury severity were similar between groups. Intraoperative MAP was 65.5 ± 11.6 mm Hg in the LMAP group and 69.1 ± 13.8 mm Hg in the HMAP group (p = 0.07). No significant survival advantage existed for the LMAP group at 30 days (p = 0.48) or 24 hours (p = 0.27). Secondary outcomes were similar for the LMAP and HMAP groups: acute myocardial infarction (1% vs. 2%), stroke (0% vs. 3%), any renal failure (15% vs. 12%), coagulopathy (28% vs. 29%), and infection (59% vs. 58%) (p > 0.05 for all). Acute renal injury occurred less often in the LMAP than in HMAP group (13% vs. 30%, p = 0.01). Conclusion This study was unable to demonstrate that hypotensive resuscitation at a target MAP of 50 mm Hg could significantly improve 30-day mortality. Further study is necessary to fully realize the benefits of hypotensive resuscitation. LEVEL OF EVIDENCE Therapeutic study, level II.