Improved survival with early fluid resuscitation following hemorrhagic shock.

Recent studies have questioned the benefits of early fluid resuscitation in hemorrhagic shock. The purpose of the current study is to evaluate the effects of early fluid resuscitation (HSE) (15 minutes), delayed fluid resuscitation (HSD) (60 minutes), and no fluid resuscitation (HSU) on cytokine levels, hepatic resting membrane potential (Em), renal function, and mortality. Eighty male Sprague-Dawley rats (350-450 g) were hemorrhaged 35% of their total blood volume and then received 40, 80, or 100 ml of crystalloid per kilogram as intravenous fluids (IVFs). The implementation of HSE resulted in stabilization of the Em (-29 mV), which was significantly different from that seen with HSD or HSU (-24 and -29 mV, respectively). The timing of resuscitation did not affect the elevation of tumor necrosis factor (TNFalpha) levels. The interleukin-6 (IL-6) levels for the HSE group were 81, 101, and 274 pg/ml for 40, 80, and 100 ml/kg, respectively. In contrast, HSD group IL-6 levels were 440, 566, and 632 pg/ml for 40, 80, and 100 ml/kg (p < 0.0001). IL-6 levels for the HSU group was 427 pg/ml, which was significantly different from that of the HSE group (p < 0.05). Urine output was present in 58% of the HSE rats but only 24% in the HSD rats and 0% of the HSU rats. Mortality was 11% for HSE, 58% for HSD, and 50% for HSU rats. Despite the recent studies questioning the benefits of early fluid resuscitation, these data show marked improvement in hepatic stability, the presence of urine output, decreased IL-6 levels, and significantly lower mortality when IVFs were given early after hemorrhagic shock. Furthermore, excessive fluid resuscitation (100 ml/kg) resulted in an increased inflammatory cytokine level and mortality and may account for the controversy.

Matrix metalloproteinase inhibition protects hepatic integrity in hemorrhagic shock.

Hemorrhagic shock increases cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), and compromises hepatic function and integrity. The production of TNF-alpha involves a cascade reaction regulated by the enzyme TNF-alpha convertase. The purpose of this study was to examine the effects of matrix metalloproteinase inhibitor (MMPI) (British Biotech 1101) in vivo on hepatic integrity in a rat model of hemorrhagic shock. Sprague-Dawley rats (n = 26) were divided as follows: hemorrhagic shock (group 1) and hemorrhagic shock plus MMPI (group 2). TNF-alpha, IL-6, and hepatic membrane potentials (Em) were obtained. The administration of MMPI significantly decreased TNF-alpha levels (P <0.001) and stabilized the membrane potential at -30 mV as compared to the depolarized membrane potential at -20 mV for hemorrhagic shock without MMPI. IL-6 levels were not affected by the MMPI. This study demonstrates that MMPI decreases TNF-alpha levels and protects hepatic integrity in hemorrhagic shock, as evidenced by the stabilization of the membrane potential, independent of the mean arterial pressure. The hepatic protection is closely related to the decrease in TNF-alpha levels seen in the portal circulation.

Hepatic integrity dependent on matrix metalloproteinase inhibition, not tumor necrosis factor alpha or different bleeding rates.

Discrepancies in the levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) following hemorrhagic shock (HS) may be due to the inconsistent rates of bleeding. The purpose of this study was to investigate the effects of rapid versus slow bleeding rates on TNF-alpha levels and if inhibition of TNF-alpha convertase by a matrix metalloproteinase inhibitor (MMPI) affects hepatic integrity in animals exposed to 35% HS. Sprague-Dawley male rats (n = 24, 300-350 g) were divided into four groups: HS 15 (produced over 15 min), HS 30 (produced over 30 min), and HS with MMPI (2.5 mg/kg British Biotech 1101: HS15 + MMPI, HS30 + MMPI). Mean arterial blood pressure (MAP), serum TNF-alpha,levels, and hepatic resting membrane potentials (E(m)) were obtained. A Student t test was performed. TNF-alpha levels for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were 474, 40, 32, and 50 pg/ml, respectively. The hepatic resting membrane potentials for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were -26, -30, -23, and -31 mV, respectively. In conclusion, circulating TNF-alpha levels are affected by the rate of bleeding in hemorrhagic shock. However, despite the differences in the magnitude of TNF-alpha in untreated animals, hepatic integrity was compromised. Interestingly, MMPI, an inhibitor of TNF-alpha convertase, stabilizes the membrane potential in both types of hemorrhagic shock.

Effect of cigarette smoke on endothelial regeneration in vivo and nitric oxide levels.

BACKGROUND: Cigarette smoking accelerates atherosclerosis and restenosis after vascular reconstruction. The mechanisms by which smoking alters vessel structure after injury are unclear. This study examined the effects of cigarette smoking on endothelial regeneration, an important component of arterial remodeling. MATERIALS AND METHODS: Adult male rats were subjected to balloon injury of the thoracic aorta and exposed to mainstream cigarette smoke via a Griffith-type smoking machine for 2 weeks. Control groups included rats which were restrained in the machine but not smoked and a group not utilizing the machine. Aortic reendothelialization was determined using Evan's blue staining of the arterial surface. Serum levels of nitric oxide were measured to determine if smoke exposure altered this potential endothelial cell mitogen. RESULTS: Cigarette smoking increased aortic endothelial regeneration (78.4 +/- 4.6% vs 59.2 +/- 2.1%, P < 0.05) and was associated with an increase in serum nitric oxide level (59.9 +/- 7. 1 microM vs 28.5 +/- 1.8 microM, P < 0.05). Daily restraint alone in the smoking machine had no effect on endothelial regeneration. CONCLUSIONS: This is the first report on the effects of smoking on endothelial regeneration and demonstrates that smoking increases reendothelialization after large vessel injury and serum levels of nitric oxide, an EC mitogen.