Surgical applications of organ preconditioning.

In 1986, Murry et al. reported that brief periods of antecedent ischemia in dogs paradoxically reduced (rather than exacerbated) the size of myocardial infarcts created by subsequent prolonged ischemia. This fortuitous discovery, now termed "preconditioning", stimulated further investigation of the inherent adaptive mechanisms present in a variety of tissues and organs. In addition to ischemia, it is now recognized that a protective response can be initiated by multiple means including lipopolysaccharide, heat stress, exercise, adrenergic drugs and even noise. Furthermore, preconditioning protects not only against cell death but also against postischemic contractile dysfunction, stunning and arrhythmias. Despite the preponderance of animal studies demonstrating the benefits of preconditioning, its clinical application has been hampered by clinicians' hesitancy to intentionally subject patients to a noxious stress prior to a planned intervention. However, many of the intracellular signals responsible for the protective effect of preconditioning have been delineated, and pharmacologic manipulation of these signals can accomplish the same benefits. The existence of preconditioning in humans has been demonstrated in vitro and in small clinical trials, and targeted strategies that exploit this endogenous protective mechanism promise to broaden the therapeutic potential of organ preconditioning.

Organ preconditioning.

The initial discovery of cardiac preconditioning has evolved into an exciting series of practical surgical applications. An enormous amount of evidence demonstrating both the safety and efficacy of ischemic preconditioning is available from animal studies. The challenging premise of intentionally subjecting patients and their organs to transient ischemia has acted as a formidable psychological and ethical impediment to the widespread clinical application of organ preconditioning. A more palatable alternative to ischemic preconditioning now involves approved medications designed to manipulate the cellular machinery mediating ischemic preconditioning. Pharmacologically induced preconditioning seems to confer equal organ protection. The relatively brief (but surgically relevant) window of protection provided by strategies such as ischemic preconditioning or adenosine agonists and potassium-adenosine triphosphate channel openers may, in the future, be extended. We have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes with subsequent protection against sepsis-induced dysfunction. Targeted strategies will ultimately broaden the therapeutic potential of organ preconditioning.

TNF receptor I mediates chemokine production and neutrophil accumulation in the lung following systemic lipopolysaccharide.

BACKGROUND: Tumor necrosis factor (TNF)-alpha is a critical effector of lipopolysaccharide (LPS)-induced acute lung injury, and its effects are mediated by two structurally related receptors, RI and RII. Cellular adhesion molecules and C-X-C chemokines (Keratinocyte chemoattractant (KC) and macrophage inflammatory protein [MIP]-2) regulate tissue neutrophil polymorphonuclear neutrophil (PMN) accumulation in a multitude of inflammatory states. We hypothesized that TNFRI signaling dictates PMN accumulation in the lung via regulation of chemokine molecule production. Therefore, the purposes of this study were to (1) delineate LPS-induced lung TNF-alpha production and (2) characterize the contribution of both TNF receptors to lung chemokine production and neutrophil influx following systemic LPS. METHODS: Wild-type or TNFRI and TNFRII knockout (KO) mice were injected with vehicle (saline) or LPS (Escherichia coli 0.5 mg/kg intraperitoneally). After 2, 4, 6, or 24 h, lungs were analyzed for TNF-alpha and chemokine (KC and MIP-2) protein expression (enzyme-linked immunosorbent assay) and PMN accumulation (myeloperoxidase assay). RESULTS: There was an increase in total lung TNF-alpha (vehicle, 5.0 +/- 1.2 pg/mg total protein vs LPS, 950 +/- 318; P < 0.05) after LPS. Lung chemokine production and PMN accumulation were also increased compared to vehicle-injected mice. Lung chemokine production and PMN accumulation were significantly lower in TNFRI KO, but not TNFRII KO, mice, despite no difference in TNF-alpha production (TNFRI KO, 925 +/- 301 vs TNFRII KO, 837 +/- 267, P = 0.82). CONCLUSIONS: Acute lung injury following systemic LPS administration is characterized by increased lung (1) TNF-alpha production, (2) C-X-C chemokine production, and (3) neutrophil accumulation. The maximal effect of LPS-induced lung neutrophil accumulation appears to be dependent upon the TNFRI receptor but not the TNFRII receptor. .

A low level of TNF-alpha mediates hemorrhage-induced acute lung injury via p55 TNF receptor.

Acute lung injury after hemorrhagic shock (HS) is associated with the expression of tumor necrosis factor (TNF)-alpha in the lung. However, the role of TNF-alpha and its receptors in this pulmonary disorder remains obscure. This study examined the temporal relationship of pulmonary TNF-alpha production to neutrophil accumulation during HS and determined the role of TNF-alpha in neutrophil accumulation and lung leak. HS was induced in mice by removal of 30% of total blood volume. Lung TNF-alpha was measured by ELISA. Neutrophil accumulation was detected by immunofluorescent staining, and microvascular permeability was assessed using Evans blue dye. Although HS induced a slight and transient increase in lung TNF-alpha, neutrophil accumulation preceded the increase in TNF-alpha. However, lung neutrophil accumulation and lung leak were abrogated in TNF-alpha knockout mice, and both were restored by administration of recombinant TNF-alpha to TNF-alpha knockout mice before HS. Neutrophil accumulation and lung leak were abrogated in mice lacking the p55 TNF-alpha receptor, but neither was influenced by p75 TNF-alpha receptor knockout. This study demonstrates that a low level of pulmonary TNF-alpha is sufficient to mediate HS-induced acute lung injury during HS and that the p55 TNF-alpha receptor plays a dominant role in regulating the pulmonary inflammatory response to HS.

Vascular cell adhesion molecule--1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.

BACKGROUND: Sepsis-induced cardiac dysfunction occurs commonly in critically ill patients and is associated with high mortality rates. Neutrophils play a central role in sepsis-induced lung and liver injury; however, the mechanism of sepsis-induced cardiac dysfunction remains unclear. Vascular cell adhesion molecule-1 (VCAM-1) has been implicated in neutrophil-mediated liver injury during endotoxemia and is also expressed in myocardium. The purposes of this study were to examine the temporal relationship of myocardial VCAM-1 expression with neutrophil accumulation during endotoxemia and to determine whether VCAM-1 mediates neutrophil accumulation and cardiac dysfunction during endotoxemia. METHODS: Mice were subjected to lipopolysaccharide (LPS; 0.5 mg/kg, intraperitoneally). Myocardial VCAM-1 expression and neutrophil accumulation were determined by immunofluorescence staining. Cardiac performance with or without VCAM-1 blocking antibody (5 mg/kg, intravenously) was determined by the Langendorff technique. RESULTS: LPS caused a time-dependent increase in both myocardial VCAM-1 expression and neutrophil accumulation. At 6 hours after LPS, the immunofluorescent intensity for VCAM-1 increased from 2.5 +/- 0.6 x 10(6) in saline solution controls to 19.9 +/- 3.5 x 10(6) (P <.05, analysis of variance), and neutrophil count increased from 2.4 +/- 1.7/mm(2) in saline solution controls to 13.0 +/- 2.5/mm(2) (P <.05). Left ventricular developed pressure was decreased maximally at 6 hours after LPS compared with saline solution controls (29.1 +/- 1.1 mm Hg vs 53.1 +/- 3.9 mm Hg; P <.05). Treatment with VCAM-1 monoclonal antibody abrogated both myocardial neutrophil accumulation and cardiac dysfunction during endotoxemia. CONCLUSIONS: LPS-induced myocardial dysfunction is associated with increased expression of VCAM-1 and with neutrophil accumulation. Blockade of VCAM-1 abrogates myocardial neutrophil accumulation and preserves cardiac function during endotoxemia, which supports a role for VCAM-1 as a therapeutic target for myocardial protection during sepsis.

Clinical applications of cardiovascular angiogenesis.

Angiogenesis is fundamental to both normal physiologic (wound healing) and pathologic (cancer) processes. Manipulation of divergent angiogenic signals promises effective therapy of atherosclerotic cardiovascular disease. Positive proangiogenic strategies promise collateral circulation to ischemic territories, while negative antiangiogenic strategies starve the fibromuscular proliferation within the atherosclerotic lesion. Indeed, recent phase 1 trials suggest that delivering DNA or recombinant protein to the site of vascular occlusion may stimulate physiologically significant collateral circulation in chronically ischemic myocardium. While symptomatic and functional improvement has been documented, toxicity profiles and effects on long-term patient survival are still unclear. The purposes of this article are as follows: (1) to review the pathophysiologic basis for pro- and antiangiogenic strategies in the treatment of cardiovascular disease, (2) to examine the clinical trials of proangiogenic gene or recombinant protein delivery into ischemic beds, and conversely, (3) to explore antiangiogenic strategies in the prevention and treatment of intimal neovascularization and smooth muscle proliferation within the vessel wall.

Differential cardiopulmonary recruitment of neutrophils during hemorrhagic shock: a role for ICAM-1?

Hemorrhagic shock and subsequent resuscitation can result in acute lung injury and cardiac dysfunction. Previous studies have demonstrated that tissue neutrophil accumulation contributes to cardiopulmonary injury associated with trauma. Thus, suppression of tissue neutrophil recruitment in an early therapeutic window after hemorrhagic shock may protect the cardiopulmonary system. It is unclear whether hemorrhagic shock induces cardiopulmonary recruitment of neutrophils before resuscitation. Intercellular adhesion molecule-1 (ICAM-1) is one of the important factors that mediate tissue neutrophil recruitment. The physiologic significance of ICAM-1 expression after hemorrhage before resuscitation is not well delineated. The present study examined the role of ICAM-1 in neutrophil accumulation in the heart and lung after severe hemorrhage without resuscitation. Mice were subjected to hemorrhagic shock by removal of 30% of total blood volume. Lung neutrophil number as determined by immunofluorescent staining increased by 1 h after hemorrhage and was maximal at 4 h whereas myocardial neutrophil number was not changed. Lung neutrophil accumulation was not associated with an up-regulation of ICAM-1 expression or an alteration in ICAM-1 subcellular distribution. Surprisingly, deletion of the ICAM-1 gene enhanced hemorrhagic shock-induced lung neutrophil accumulation. These results suggest that hemorrhagic shock induces preferential neutrophil accumulation to the lung that appears to occur independent of ICAM-1-expression.

The abdominal compartment syndrome is a morbid complication of postinjury damage control surgery.

BACKGROUND: The abdominal compartment syndrome (ACS) is a recognized complication of damage control surgery (DCS). The purposes of this study were to (1) determine the effect of ACS on outcome after DCS, (2) identify patients at high risk for the development of ACS, and (3) determine whether ACS can be prevented by preemptive intravenous bag closure during DCS. METHODS: Patients requiring postinjury DCS at our institution from January 1996 to June 2000 were divided into groups depending on whether or not they developed ACS. ACS was defined as an intra-abdominal pressure (IAP) greater than 20 mm Hg in association with increased airway pressure or impaired renal function. RESULTS: ACS developed in 36% of the 77 patients who underwent DCS with a mean IAP prior to decompression of 26 +/- 1 mm Hg. The ACS versus non-ACS groups were not significantly different in patient demographics, Injury Severity Score, emergency department vital signs, or intensive care unit admission indices (blood pressure, temperature, base deficit, cardiac index, lactate, international normalized ratio, partial thromboplastin time, and 24-hour fluid). The initial peak airway pressure after DCS was higher in those patients who went on to develop ACS. The development of ACS after DCS was associated with increased ICU stays, days of ventilation, complications, multiorgan failure, and mortality. CONCLUSIONS: ACS after postinjury DCS worsens outcome. With the exception of early elevation in peak airway pressure, we could not identify patients at higher risk for ACS; moreover, preemptive abdominal bag closure during initial DCS did not prevent this highly morbid complication.

Laparoscopic approach to adrenal and endocrine pancreatic tumors.

Laparoscopic adrenalectomy quickly has become the procedure of choice for benign adrenal lesions because it results in less pain, shorter hospital stay, comparable safety, and more patient satisfaction overall. The laparoscopic approach requires advanced laparoscopic surgical skills. Surgeons should be familiar with these techniques and the open approaches before attempting this procedure. When first learning the technique, small left-sided lesions are likely the easiest, and a more experienced surgeon should be present for the initial few cases; however, at this point, the laparoscopic approach to pancreatic endocrine tumors does not have a clear benefit, and it should be considered primarily investigational without clearly established benefits.

Percutaneous tracheostomy: a cost-effective alternative to standard open tracheostomy.

Percutaneous tracheostomy was initiated as an alternative to open tracheostomy at our institution in December 1993. To assess safety, operative time, and cost, a comparative analysis of percutaneous and open tracheostomies was performed. A retrospective evaluation of all patients who underwent percutaneous tracheostomy (P) from December 1993 to March 1996 was completed. Patients were evaluated for indications for tracheostomy, length of operation, morbidity, and cost. The results were compared with patients who underwent open tracheostomy (O) during the 12 months prior to introduction of the percutaneous technique. Tracheostomy was performed percutaneously in 74 patients and by a standard open technique in 109 patients. Indications for tracheostomy included: chronic ventilator dependence (P, 49 vs O, 58); airway protection (P, 19 vs O, 42); laryngeal dysfunction (P, 2 vs O, 7); and facial trauma (P 6 vs O, 2). The length of operation was 21 +/- 6 minutes and 46 +/- 21 minutes for percutaneous and open tracheostomy, respectively (P < 0.05). Perioperative morbidity occurred in 2 patients (3%) following percutaneous tracheostomy compared to 10 patients (9%) following open tracheostomy (P > 0.05). The mean operating room costs per patient were $1093 and $1370 for percutaneous and open tracheostomy, respectively. Percutaneous tracheostomy is a safe procedure that can be performed in less time and at a lower cost than standard open tracheostomy.