Meta-analysis of prognostic factors for amputation following surgical repair of lower extremity vascular trauma.

BACKGROUND: Lower extremity vascular trauma (LEVT) is a major cause of amputation. A clear understanding of prognostic factors for amputation is important to inform surgical decision-making, patient counselling and risk stratification. The aim was to develop an understanding of prognostic factors for amputation following surgical repair of LEVT. METHODS: A systematic review was conducted to identify potential prognostic factors. Bayesian meta-analysis was used to calculate an absolute (pooled proportion) and relative (pooled odds ratio, OR) measure of the amputation risk for each factor. RESULTS: Forty-five studies, totalling 3187 discrete LEVT repairs, were included. The overall amputation rate was 10·0 (95 per cent credible interval 7·4 to 13·1) per cent. Significant prognostic factors for secondary amputation included: associated major soft tissue injury (26 versus 8 per cent for no soft tissue injury; OR 5·80), compartment syndrome (28 versus 6 per cent; OR 5·11), multiple arterial injuries (18 versus 9 per cent; OR 4·85), duration of ischaemia exceeding 6 h (24 versus 5 per cent; OR 4·40), associated fracture (14 versus 2 per cent; OR 4·30), mechanism of injury (blast 19 per cent, blunt 16 per cent, penetrating 5 per cent), anatomical site of injury (iliac 18 per cent, popliteal 14 per cent, tibial 10 per cent, femoral 4 per cent), age over 55 years (16 versus 9 per cent; OR 3·03) and sex (men 7 per cent versus women 8 per cent; OR 0·64). Shock and nerve or venous injuries were not significant prognostic factors for secondary amputation. CONCLUSION: A significant proportion of patients who undergo lower extremity vascular trauma repair will require secondary amputation. This meta-analysis describes significant prognostic factors needed to inform surgical judgement, risk assessment and patient counselling.

Reperfusion strategies in the management of extremity vascular injury with ischaemia.

BACKGROUND: Extremity injury with ischaemia is the most common pattern of vascular trauma and is a challenge for surgeons who must make decisions about the timing and mechanism of limb reperfusion. In modern military conflicts, effective use of limb tourniquets and rapid transport of the injured have increased the number of casualties who reach a medical service with potentially survivable vascular trauma. This report provides a review of extremity ischaemia and reperfusion following vascular trauma. METHODS: A review was undertaken of extremity vascular injury with ischaemia, including a focus on adjuncts aimed at reducing reperfusion injury and improving neuromuscular recovery and limb salvage. RESULTS: Findings from basic and clinical research support the need to restore perfusion to an ischaemic limb as soon as possible in order to achieve optimal neuromuscular recovery. Large-animal studies demonstrate that haemorrhagic shock worsens the impact of ischaemia on the neuromuscular structures of the limb and reduces the ischaemic threshold to as little as 1 h. Surgical adjuncts such as vascular shunts, fasciotomy, regional limb cooling and ischaemic conditioning may reduce the severity of ischaemic injury. Medical therapies have also been described including hypertonic saline, statins and ethyl pyruvate, which reduce the inflammatory response following limb reperfusion. CONCLUSION: Contemporary translational research refutes a casual approach to extremity vascular injury with ischaemia, instead emphasizing expedited reperfusion. Surgical and medical adjuncts exist to expedite reperfusion and mitigate reperfusion injury. Additional research and development of these adjuncts is necessary to improve quality or functional limb salvage after vascular trauma.

Stable vesicles composed of monocarboxylic or dicarboxylic fatty acids and trimethylammonium amphiphiles.

The self-assembly of cationic and anionic amphiphile mixtures into vesicles in aqueous media was studied using two different systems: (i) decanoic acid and trimethyldecylammonium bromide and (ii) hexadecanedioic acid (a simple bola-amphiphile) and trimethyldecylammonium bromide. The resulting vesicles with varying amphiphile ratios were characterized using parameters such as the critical vesicle concentration, pH sensitivity, and encapsulation efficiency. We also produced and observed giant vesicles from these mixtures using the electroformation method and confocal microscopy. The mixed catanionic vesicles were shown to be more stable than those formed by pure fatty acids. Those containing bola-amphiphile even showed the encapsulation of a small hydrophilic solute (8-hydroxypyrene-1,3,6-trisulfonic-acid), suggesting a denser packing of the amphiphiles. Compression and kinetics analysis of monolayers composed of these amphiphiles mixtures at the air/water interface suggests that the stabilization of the structures can be attributed to two main interactions between headgroups, predominantly the formation of hydrogen bonds between protonated and deprotonated acids and the additional electrostatic interactions between ammonium and acid headgroups.

Migration of Aortic Occlusion Balloons in an in vitro model of the human circulation.

BACKGROUND: Aortic Occlusion Balloons (AOB) are used for hemorrhage control in hemodynamically unstable patients. Stability of an AOB is essential for reliable aortic occlusion. The primary aim of this study is to determine whether different types of AOB migrate after total, intermittent or partial occlusion in a porcine aorta positioned in an in vitro model. MATERIALS AND METHODS: A porcine thoracic aortic section was positioned in a model of the human circulation. Primary and secondary migration was tested in Cook Coda™ 2-9.0-35-120-32 and 2-10-35-140-46, Cook Medical, USA; Rescue balloon™ Tokai RB-167080-E, Tokai Medical Products, Japan; Reliant™ AB46, Medtronic, USA; Russian prototype AOB; ER-REBOA™, Prytime Medical Devices, USA; LeMaitre™ 28 and 45 Aortic Occlusion Catheter, LeMaitre Vascular, USA. These AOB were tested in hypotensive, normotensive and hypertensive scenarios. Migration in total occlusion, intermittent occlusion and partial occlusion was recorded for all AOB. RESULTS: Limited primary migration occurred in all AOB after total occlusion. The Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration in 1 test cycle. No migration occurred during intermittent occlusion. Kinking occurs in various degrees but does not seem to prevent a successful occlusion of the aorta. No migration occurred during partial occlusion except in the Russian prototype AOB. In a partial occlusion scenario, distal perfusion occurred only with 5 ml remaining in all balloon types. CONCLUSIONS: All AOB were successful in full aortic occlusion. Limited primary migration occurred in all AOB after total occlusion only the Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration once. No migration occurred during intermittent occlusion, during partial occlusion only the Russian prototype AOB migrated. Stiffness and size of the catheter are important factors in preventing migration and kinking.

Fibrinolysis in trauma: a review.

Fibrinolytic dysregulation is an important mechanism in traumatic coagulopathy. It is an incompletely understood process that consists of a spectrum ranging from excessive breakdown (hyperfibrinolysis) and the shutdown of fibrinolysis. Both hyperfibrinolysis and shutdown are associated with excess mortality and post-traumatic organ failure. The pathophysiology appears to relate to endothelial injury and hypoperfusion, with several molecular markers identified in playing a role. Although there are no universally accepted diagnostic tests, viscoelastic studies appear to offer the greatest potential for timely identification of patients presenting with fibrinolytic dysregulation. Treatment is multimodal, involving prompt hemorrhage control and resuscitation, with controversy surrounding the use of antifibrinolytic drug therapy. This review presents the current evidence on the pathophysiology, diagnostic challenges, as well as the management of this hemostatic dysfunction. LEVEL OF EVIDENCE: Level III.

The complete amino acid sequence of human placental oxytocinase.

The complete amino acid sequence of human placental oxytocinase (placental leucine aminopeptidase) has been determined by cDNA cloning and sequencing. Oxytocinase is a type II integral membrane protein of 1025 amino acid residues, consisting of an acidic intracellular region of 110 amino acids followed by a hydrophobic transmembrane segment of 22 residues and 893 extracellular residues containing the characteristic Zn2+ coordination sequence element His-Glu-Xaa-Xaa-His-(18 residues)-Glu found in gluzincins. Two sets of cDNA clones with different 5'-ends were isolated and suggested to represent different spliced products of 3.6 kb (mature mRNA) and 12 kb, respectively. Oxytocinase mRNA is present in large amounts in placenta, heart and skeletal muscle and in small amounts in brain, kidney, liver and pancreas. A conserved sequence element, the GAMEN motif, which distinguishes the aminopeptidase family among gluzincins from other gluzincins, has been identified.

Endovascular therapy in trauma.

The practice of medicine has experienced a revolution in the use of catheter-based or endovascular techniques to manage age-related vascular disease over the past 15 years. In many scenarios the less invasive, endovascular method is associated with reduced morbidity and mortality than the traditional open surgical approach. Although somewhat delayed, the use of endovascular approaches in the management of certain trauma scenarios has also increased dramatically. With improvements in catheter-based and imaging technologies and a broader acceptance of the value of the endovascular approach, this trend is likely to continue to the benefit of patients. The use of endovascular techniques in trauma can be considered in three broad categories: (1) large-vessel repair (e.g. covered stent repair), (2) mid- to small-vessel hemostasis (e.g. coils, plugs, and hemostatic agents), and (3) large-vessel balloon occlusion for resuscitation (e.g. resuscitative endovascular balloon occlusion of the aorta). While not exclusive, these categories provide a framework from which to consider establishing a trauma-specific endovascular inventory and performance of these techniques in the setting of severe injury. The aim of this review is to use this framework to provide a current appraisal of endovascular techniques to manage various forms: vascular injury, bleeding, and shock; including injury patterns in which an endovascular approach is established and scenarios in which it is nascent and evolving.

Inflammatory aortic aneurysms. A clinical review with new perspectives in pathogenesis.

OBJECTIVE: The authors present a review of abdominal aortic aneurysms (AAAs) and to examine the literature on the diagnosis, operative management, and long-term survival of patients with inflammatory AAAs. Furthermore, to review current theories on the cause of inflammatory AAAs and present recent studies that provoke new thought on the cause of these aneurysms. BACKGROUND DATA: Inflammatory AAAs represent 3% to 10% of all AAAs and present the surgical team with a unique challenge. Progress has occurred in the technical approach to these aneurysms, and operative morbidity and mortality have been reduced. However, the pathogenesis remains an enigma. Recent studies raise questions regarding the influence of tobacco and genetic factors that accentuate an antigen-driven inflammatory response. METHODS: The authors conduct a review of the literature on both noninflammatory and inflammatory AAAs. RESULTS: Review of the literature of inflammatory AAAs reveals advancement in the definition, diagnosis, management, and long-term survival of patients with inflammatory AAAs. This review found an evolution in thought regarding the cause of inflammatory AAAs. In contrast to initial reports describing a distinct clinical entity, recent evidence suggests that inflammatory AAAs arise from the same causal stimulus responsible for noninflammatory AAAs. Finally, recent studies show an influence of tobacco and genetic factors on the pathogenesis. CONCLUSIONS: The literature supports the theory that inflammatory AAAs arise from the same or similar antigenic stimulus which is responsible for the noninflammatory AAA. Genetic and chemical factors such as tobacco use predispose certain persons to the development of noninflammatory AAAs and others to develop the extreme end of an inflammatory spectrum, the inflammatory AAA. Furthermore, inflammatory AAAs can be managed with the same operative morbidity, mortality, and long-term survival as noninflammatory AAAs.

Laparoscopic repair of colonoscopic perforations of the colon.

Acute colonic perforation is an uncommon but distressing complication of colonoscopic procedures. We describe the successful management of 3 such cases using laparoscopic techniques.

Structure of the human beta2-glycoprotein I (apolipoprotein H) gene.

The gene encoding the human plasma protein beta2-glycoprotein I or apolipoprotein H was cloned and its structure determined. The gene which consists of eight exons was shown to span 18 kb and was localized to chromosome 17q23-24. The transcriptional initiation site was assigned to a position 31 bp upstream of the start codon. Several consensus sequence elements relevant for regulation of transcription in liver were seen in the 5'-upstream region of the gene. Exon 1 contains the 5'-UTR together with the signal peptide coding sequences. Short consensus repeats (SCRs) 1, 3, 4, and 5 are encoded by single exons each while SCR2 is encoded by two exons. Exon 8 comprises the region encoding the C-terminal end of beta2-glycoprotein I (from His-310), the stop codon and the 3'-UTR.

Cardiovascular actions of ET-B activation in vivo and modulation by receptor antagonism.

The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and participates in vasodilatation and vasoconstriction. Controversy exists regarding the role of the ET-B receptor as a mediator of systemic, pulmonary, and renal vasoconstriction in states of marked ET-1 activation. Moreover, the potential activation of endogenous ET-1 with secondary stimulation of the ET-A receptor in response to sarafotoxin S6c (S6c) remains unclear. This study was designed to assess the cardiovascular actions of ET-B activation with S6c in the presence and absence of selective ET-A antagonism with FR-139317 and dual ET-A/ET-B antagonism with SB-209670 in the anesthetized dog. Compared with time control (n = 5), S6c increased from baseline systemic vascular resistance (SVR) [28 +/- 7 vs. 14 +/- 3 resistance units (RU), P < 0.05] and pulmonary vascular resistance (PVR) (3.2 +/- 0.7 vs. 0.9 +/- 0.3 RU, P < 0.05) and decreased cardiac output (CO) (-1.7 +/- 0.3 vs. -0.5 +/- 0.1 l/min, P < 0.05), with no differences in renal vascular resistance in association with increases in plasma ET-1. S6c also decreased mixed venous oxygen saturation (SVO2) (56 +/- 6 vs. 76 +/- 5%, P < 0.05). Selective ET-A receptor antagonism did not affect the actions of S6c, with the exception that ET-A receptor antagonism blocked the increase in SVR to high-dose S6c. Dual ET-A/ET-B receptor antagonism attenuated the increase from baseline in SVR (7 +/- 1 vs. 28 +/- 7 RU, P < 0.05) and PVR (0.7 +/- 0.2 vs. 3.2 +/- 0.7 RU, P < 0.05) and decrease from baseline in CO (-0.9 +/- 0.1 vs. -1.7 +/- 0.3 l/min, P < 0.05) and SVO2 (-7 +/- 3 vs. -20 +/- 3%, P < 0.05) observed with S6c alone. In summary, this study demonstrates an important role of ET-B receptor activation in vivo, which results in increases in plasma ET-1 and systemic and pulmonary vasoconstriction and reductions in CO and SVO2. This study also supports a modest role for the ET-A receptor in mediating the systemic vasoconstrictor response to high-dose S6c.

Structure of the human oxytocinase/insulin-regulated aminopeptidase gene and localization to chromosome 5q21.

The human oxytocinase/insulin-regulated aminopeptidase (OTase/IRAP) is a 1024 amino acid type II integral membrane protein that is expressed mainly in fat, muscle and placenta tissues. It has been thought to be involved mainly in the control of onset of labour but recently rat OTase/IRAP was shown to participate in the regulation of glucose transporter isoform 4 vesicle trafficking in adipocytes as well. To approach an understanding of OTase/IRAP gene regulation the organization of the human gene was determined. Accordingly, three overlapping genomic clones were isolated and characterized. The human OTase/IRAP gene (OTASE) was found to span approximately 75 kb containing 18 exons and 17 introns. The gluzincin aminopeptidase motif: GAMEN-(31 amino acids)-HELAH-(18 amino acids)-E associated with Zn2+-binding, substrate binding and catalysis is encoded by exons 6 and 7. A major and a minor transcriptional initiation site in OTASE were identified by primer extension 514 bp and 551 bp, respectively, upstream of the translation start codon. Chloroamphenicol acetyltransferase-reporter assays revealed a functional CpG-rich promoter/enhancer region located between nucleotide -621 and the major transcriptional initiation site. Human OTASE was assigned to chromosome 5 by hybridization to genomic DNA from characterized somatic cell hybrids. Finally, the OTASE and the human aminopeptidase A gene were subchromosomally localized to 5q21 and 4q25, respectively, by in situ hybridization.

Renal role of the endogenous natriuretic peptide system in acute congestive heart failure.

BACKGROUND: Atrial and brain natriuretic peptides exert renal and cardiovascular actions through binding to the natriuretic peptide-A receptor, while C-type natriuretic peptide mediates actions that occur through binding to the natriuretic peptide-B receptor, with subsequent generation of cyclic guanosine monophosphate. This study determined responses of circulating atrial natriuretic peptides in experimental acute heart failure and addressed the hypothesis that elevated circulating atrial natriuretic peptides serve a homeostatic role in regulating sodium excretion and that this action is localized to the glomerulus and distal nephron, sites rich in natriuretic peptide-A receptors. METHODS AND RESULTS: Studies were performed in the absence and presence of HS-142-1, an inhibitor of the natriuretic peptide receptors. Two groups of anesthetized dogs underwent induction of acute heart failure by rapid ventricular pacing, as characterized by decreases in cardiac output and increases in filling pressures with associated elevation of endogenous atrial natriuretic peptides secondary to increases in atrial stretch. In group 1 (n = 5, vehicle intrarenal bolus), despite acute heart failure-mediated decreases in cardiac output, sodium excretion was preserved with maintenance of the glomerular filtration rate and distal fractional sodium reabsorption. In group 2 (n = 5), in response to the natriuretic peptide receptor antagonist, HS-142-1 (0.5 mg/kg intrarenal bolus), sodium excretion (17.0 +/- 4.4 to 5.9 +/- 3.2 microEq/min; P < .05) and glomerular filtration rate decreased (33.0 +/- 3.6 to 21.0 +/- 3.9 mL/min; P < .05) and distal fractional sodium reabsorption increased (98.0 +/- 0.63 to 99.3 +/- 0.25%; P < .05), in association with a decrease in plasma cyclic guanosine monophosphate (13.0 +/- 3.5 to 6.6 +/- 2.9 pmol/mL; P < .05) and renal cyclic guanosine monophosphate generation (1,216 +/- 421 to 466 +/- 208 pmol/min; P < .05). CONCLUSIONS: This study supports a functionally significant role for the endogenous natriuretic peptide system in preserving sodium homeostasis and glomerular filtration rate in acute heart failure.

Genetic similarity in inflammatory and degenerative abdominal aortic aneurysms: a study of human leukocyte antigen class II disease risk genes.

PURPOSE: Clinically, abdominal aortic aneurysms (AAAs) display a spectrum of inflammation that extends from apparently noninflamed (degenerative) AAAs to the classic inflammatory variant. Genes encoded in the human leukocyte antigen (HLA) region are important in the development of both variants of AAA; however, their role in progression to the inflammatory variant is unknown. The purpose of this study was to compare HLA class II genes in patients with degenerative versus classic inflammatory AAAs and to quantify their impact as disease risk factors. METHODS: Genotypes of the 12 major alleles of the HLA-DR B1 locus were determined in patients with degenerative (102) and inflammatory (40) AAAs who were compared with controls (118). Univariate and multivariate logistic regression analyses were used to determine allele distributions and to quantify disease risk. RESULTS: Distribution of the HLA-DR B1 alleles was nonrandom and similar in both degenerative and inflammatory AAA groups compared with controls. The B1*02 and B1*04 alleles were enhanced in both degenerative (39.2% vs. 25.4%, P =.03; and 35.3% vs. 24.6%, P =.08 respectively) and inflammatory (47.5% vs. 25.4%, P =.01; and 32.5% vs. 24.6%, P =.09, respectively) AAAs compared with controls. The B1*02 and B1*04 alleles were associated with risk for both degenerative (odds ratio [OR] 2.2; 95% CI, 1.2-4.0; and OR 2.0; 95% CI, 1.1-3.7, respectively) and inflammatory AAAs (OR 3.7; 95% CI, 1.8-8.6; and OR 2.5; 95% CI, 1.1-6.1). CONCLUSION: This study demonstrates that identical HLA alleles function as genetic risk factors for both inflammatory and degenerative AAAs. These results support the concept of a common, immune-mediated pathogenesis for AAAs that may be modulated by HLA-independent factors.

Genetic risk factors in inflammatory abdominal aortic aneurysms: polymorphic residue 70 in the HLA-DR B1 gene as a key genetic element.

PURPOSE: Evidence of a genetic predisposition to the development of inflammatory abdominal aortic aneurysms (AAAs) exists as a positive family history in 17% of patients. Familial clustering and other similarities between inflammatory AAAs and giant cell arteritis (GCA), which possesses a genetic risk determinant mapped to the HLA-DR molecule, suggest a role of genetic risk factors in inflammatory AAAs. The purpose of this study was to explore whether patients with inflammatory AAAs express disease-relevant genes associated with the HLA-DR region on the short arm of chromosome 6. METHODS: Thirty-seven patients with histomorphologic findings of inflammatory AAA at operation were genotyped for the polymorphism of the HLA-DR B1 and HLA DQ B1 alleles and compared to ethnically matched, healthy control subjects (n = 90). RESULTS: Distribution of HLA-DR B1 alleles was nonrandom in patients with inflammatory AAAs versus control subjects. The HLA-DR B1 alleles B1*15 and B1*0404 were enriched in patients with inflammatory AAAs compared with control subjects (47% versus 27%, and 14% versus 3%; p < 0.05, respectively). Analysis of functionally relevant amino acid polymorphisms encoded by the HLA-DR B1 gene showed relevance at amino acid position 70. HLA-DR B1 alleles overrepresented in patients with inflammatory AAAs express a glutamine substitution at position 70, whereas alleles disfavored in the patient cohort express a negatively charged aspartic acid. Distribution of HLA-DQ B1 alleles were indistinguishable in patients and control subjects. CONCLUSION: These data indicate that a genetic risk determinant can be mapped to the HLA-DR B1 locus in patients with inflammatory AAAs. This association suggests a critical contribution of antigen binding in the pathogenesis of this disease.

Temporary arterial shunts to maintain limb perfusion after arterial injury: an animal study.

BACKGROUND: Temporary shunt placement can quickly restore perfusion after extremity arterial injury. This study examined the adequacy of limb blood flow with shunt use, non-heparin-bonded shunt patency over prolonged periods, and the safety of this technique. METHODS: Common iliac arteries were divided and 4.0-mm Silastic Sundt shunts placed in 16 anesthetized pigs. Eight (group I) had shunts placed immediately; eight others (group II) were shunted after an hour of limb ischemia and hemorrhagic shock. Physiologic parameters and femoral artery blood flow in both hindlimbs were continuously monitored. Limb lactic acid generation, oxygen utilization, and hematologic and metabolic effects were serially evaluated for 24 hours. RESULTS: Shunts remained patent in 13 of 16 pigs. Shunts thrombosed in two group I animals because of technical errors, but functioned well after thrombectomy and repositioning. Patency could not be maintained in one animal that died from shock. Flow in group I shunted limbs was 57 (+/-11 SD) % of control. For group II animals in shock, shunted limb flow initially averaged 46 +/- 15% of control, but 4 hours after shunt placement, the mean limb blood flow was the same as in group I. Increased oxygen extraction compensated for the lower flow. Lactic acid production was not increased in comparison to control limbs. CONCLUSION: Shunts provided adequate flow in this model of extremity trauma. Correctly placed shunts stayed patent for 24 hours, without anticoagulation, if shunt placement followed resuscitation.