Evaluating the early impact of Medicaid expansion on trends in diagnosis and treatment of benign gallbladder disease in Kentucky.

BACKGROUND: In January 2014, Kentucky expanded Medicaid coverage in an effort to improve access to healthcare. This study evaluated the early impact of Medicaid expansion on diagnosis and treatment of benign gallbladder disease in Kentucky. METHODS: Administrative claims data were queried for patients undergoing cholecystectomy for benign gallbladder disease between 2011 and 2015. Demographic, procedure, and outcome variables from 2011 to 2013 (PRE) and 2014-2015 (POST) were compared. RESULTS: After Medicaid expansion, patients were more likely to have their operation performed as an outpatient (80.0% vs. 78.2%, p < 0.001). A significant trend was noted toward a shorter hospital stay (p < 0.001) among inpatients. For both inpatients and outpatients, a significant shift was noted toward increased hospital charges (p < 0.001). CONCLUSIONS: The expansion of Kentucky Medicaid in 2014 has been associated with an increase in outpatient cholecystectomy, shorter hospital stays for inpatients, and increased hospital charges for both inpatients and outpatients. Increased charges for all procedures may represent a mechanism for hospitals to offset the cost of providing global care for more patients.

Blunt splenic trauma.

The treatment of blunt splenic injury has evolved over time from splenectomy in all patients to nonoperative management in stable patients with operation reserved for failures of NOM. While rates of OPSI remain low in trauma patients, splenic salvage in stable patients should be attempted. However, clinical evidence of ongoing blood loss or instability should be addressed with prompt splenectomy. Careful patient selection is of paramount importance in nonoperative management of blunt splenic injury.

Timing of prostaglandin exposure is critical for the inhibition of LPS- or IFN-gamma-induced macrophage NO synthesis by PGE2.

Macrophage nitric oxide (NO) synthesis is an integral component of the host defense system. We have previously found that NO and prostaglandins interact in a variety of ways. NO modulates Kupffer cell prostaglandin E2 (PGE2) production and we have recently described the inhibitory effects of PGE2 on NO synthesis in both Kupffer cells and hepatocytes. Activated macrophages produce a number of prostaglandins but studies regarding the capacity of prostaglandins to regulate macrophage NO synthesis have yielded conflicting results. We found that exogenous PGE2 decreased lipopolysaccharide (LPS)-induced NO synthesis in murine resident peritoneal macrophages and in the RAW 264.7 murine macrophage cell line. PGE2 also suppressed NO synthesis in response to interferon-gamma (IFN-gamma) alone and a combination of LPS + IFN-gamma. Inhibition of endogenous PGE2 synthesis with indomethacin or ibuprofen had no effect on NO synthesis. PGE2 added with the activating stimulus was most effective. PGE2 lost the capacity to block NO synthesis if added more than 180 min after LPS. PGE2 decreased inducible NO synthesis (iNOS) mRNA and immunoreactive iNOS protein, consistent with the hypothesis that exogenous PGE2 inhibits macrophage iNOS expression but that the inhibition depends on the time and concentration of prostaglandin exposure.

Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis.

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF-alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS-induced KC TNF-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli.

Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage.

Attempts were made to promote or inhibit nitric oxide (. N = O) synthesis in a murine model of hepatic damage (Corynebacterium parvum followed by lipopolysaccharide; LPS) to determine the role of . N = O in the liver injury. Moderate hepatic damage and increases in circulating NO2-/NO3- levels were detectable after C. parvum alone. Administration of LPS to these mice resulted in severe hepatic damage and acute elevations in circulating nitrogen oxide levels. L-arg had no influence on the C. parvum or LPS-induced changes. NG-monomethyl-L-arginine (NMA) had no effect in the absence of LPS, but when given with LPS, a dose-dependent suppression in plasma NO2-/NO3- levels and an increase in liver injury were seen. The NMA-induced changes were partially reversed by the simultaneous administration of L-arg. These findings suggest a protective role for . N = O in this model.

Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells.

Macrophage production of nitric oxide (.N = O) leads to considerable alterations of vital metabolic pathways in various target cells. The present study tested whether .N = O synthesis by Kupffer cells (KCs), the resident macrophages of the liver, interferes with the secretory function of these cells. As in other macrophage-type cells, the combination of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was a potent stimulus of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by the L-arginine analogue of NG-monomethyl-L-arginine (NMA) resulted in a further increase of PGE2, TXB2, and IL-6 but not IL-1 and TNF-alpha production, indicating specific inhibitory effects of endogenous .N = O synthesis on the secretory activity of KCs. PGE2 production was most sensitive to the suppressive effect of .N = O and increased 24 h after stimulation with LPS and IFN-gamma from 16.3 +/- 4.9 ng/10(6) KCs without NMA to 94.3 +/- 17.9 ng/10(6) KCs with NMA. This effect of NMA was reversed by a 10-fold increase of the L-arginine concentration. No recovery of PGE2 production was seen when .N = O synthesis was blocked after 24 h. NMA treatment increased cyclooxygenase activity more than threefold, suggesting that .N = O inhibits PGE2 and TXB2 production through diminished PGH2 availability. .N = O synthesis did not significantly affect total protein synthesis or viability of the KCs. These results show that .N = O influences the production of specific inflammatory mediators by KCs.

Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury.

Corynebacterium parvum-treated mice produce large amounts of circulating nitrogen oxides and develop a severe liver injury in response to lipopolysaccharide (LPS). Concurrent administration of NG-monomethyl-L-arginine not only suppresses nitric oxide synthesis in these animals but also profoundly increases the hepatic damage following LPS. In this report, we present evidence that the increased hepatic damage from inhibition of nitric oxide synthesis is mediated in part by superoxide and hydroxyl radicals. The hepatic damage induced by suppressing nitric oxide production during endotoxemia could be reduced by treating mice with superoxide dismutase and deferoxamine, scavengers of superoxide and hydroxyl radicals, respectively. This damage could also be prevented by treating mice with the anticoagulant heparin sodium. The results suggest that nitric oxide synthesis during endotoxemia is important in preventing hepatic damage by reducing oxygen radical-mediated hepatic injury and preventing intravascular thrombosis.

The role of nitric oxide in Kupffer cell-hepatocyte interactions.

A certain level of normal or near-normal hepatic function is essential for survival. Over the last few years, the importance of the regulation of hepatic function by the interaction of specific cell populations in the liver has become increasingly evident. Kupffer cells, the fixed hepatic macrophages, have the ability to profoundly affect hepatocyte function, while hepatocytes, in turn, possess the capacity to modify Kupffer cell function. Nitric oxide, produced from the amino acid L-arginine, is a short-lived radical that is a potent mediator of cellular function and cell-cell interaction, and is synthesized by both Kupffer cells and hepatocytes. The purpose of this review is to examine the numerous areas in which nitric oxide may mediate the interactions between Kupffer cells and hepatocytes, and therefore regulate both normal and abnormal hepatic physiology and function.

Inhibition of nitric oxide synthesis during severe shock but not after resuscitation increases hepatic injury and neutrophil accumulation in hemorrhaged rats.

Hemorrhagic shock results in hepatocellular dysfunction and hepatic injury that may contribute to the development of liver failure and multiple organ dysfunction in trauma patients. The specific mediators involved in this process remain incompletely defined. We have previously demonstrated that inhibition of nitric oxide (NO) synthesis in a rat model of moderately severe hemorrhagic shock increases hepatic injury, suggesting that NO synthesis is beneficial after hemorrhage. To further define the role of NO in hepatic function during hemorrhagic shock, rats were subjected to a severe hemorrhagic shock insult in which they were bled to a mean arterial pressure of 40 mmHg until 40% of their shed blood had been returned and then were resuscitated. Rats were treated with the NO synthase inhibitor L-nitroarginine methyl ester (L-NAME) or the NO donor S-nitroso-N-acetylpenicillamine beginning either during the hypotensive period or after resuscitation. When instituted during the hypotensive period, low dose L-NAME infusion significantly increased hepatic injury. When L-NAME was infused after resuscitation, no increase in hepatic injury was detected even when the L-NAME dose was increased by a factor of four. The increased hepatic injury produced by L-NAME was associated with increased myeloperoxidase content in the lung, suggesting that L-NAME led to a greater accumulation of neutrophils during shock. Administration of the NO donor S-nitroso-N-acetylpenicillamine reduced hepatocellular enzyme release. Our results suggest that ongoing NO synthesis during the hypotensive phase of hemorrhagic shock is essential in preventing shock-induced hepatic injury and this may be due, in part, to the interaction between NO and circulating neutrophils.

Utility of clinical parameters of tissue oxygenation in a quantitative model of irreversible hemorrhagic shock.

The aim of this study was to assess the value of parameters of tissue oxygenation in monitoring the progression to irreversibility in a quantitative model of hemorrhagic shock. Rats were bled to a mean arterial pressure of 40 mmHg and were maintained at this level by further blood withdrawal until the compensation endpoint; this point was defined as the time at which the rat was no longer able to maintain its blood pressure at this level and shed blood was required for transfusion. The shock period was maintained until 0%, 20%, 40%, or 50% of the maximum shed blood volume (MBV) had been returned (n = 10 in each group, total n = 40). The animals were then resuscitated with remaining shed blood plus twice MBV as lactated Ringer's solution to MAP > 80 mmHg. Blood gas and serum lactate samples were measured at baseline, compensation endpoint, and at the time of resuscitation, and 24 h survival was recorded. Increasing the severity of shock progressively worsened the acidosis, with increased base deficit and lacticacidemia, and deterioration in central venous oxygen saturation (CvO2). Tissue oxygenation parameters, particularly CvO2, predicted subsequent mortality. Lactate levels only predicted irreversibility in late, severe shock. This quantitative model of hemorrhagic shock showed that tissue oxygenation parameters can be used to monitor the progression from the decompensated phase of hemorrhagic shock to irreversibility. Furthermore, this experimental study suggests that venous indices may be a valuable tool in reflecting the severity of hemorrhagic insult in a setting when arterial blood samples may not be easily available.

Neutrophil accumulation and damage to the gastric mucosa in resuscitated hemorrhagic shock is independent of inducible nitric oxide synthase.

Polymorphonuclear leukocytes (PMN) and inducible nitric oxide synthase (iNOS) appear to play important roles in the liver and in lung injury induced by hemorrhagic shock. Their precise roles in hemorrhagic shock-induced acute gastric mucosal lesions (AGML), however, are still poorly understood. In this study, we investigated the effect of neutropenia on hemorrhagic shock-induced AGML. We also examined the roles of iNOS in PMN infiltration into the mucosa and AGML during hemorrhagic shock by using L-N6-(1-iminoethyl)-lysine, a potent inhibitor of iNOS, and by reverse transcriptase polymerase chain reaction. Remarkable gastric mucosal damage occurs after hemorrhagic shock. PMN depletion caused by Vinblastine pretreatment significantly attenuates this AGML. Although low-dose L-N6-(1-iminoethyl)-lysine (50 microg/kg, iNOS inhibition) has no effect on AGML, high-dose L-N6-(1-iminoethyl)-lysine (250 microg/kg, iNOS + endothelial NOS inhibition) significantly exacerbates AGML without increasing PMN infiltration into the mucosa. The mRNA expression of iNOS in the stomach during hemorrhagic shock cannot be detected by reverse transcriptase polymerase chain reaction. We conclude that PMN play a pivotal role in hemorrhagic shock-induced AGML, iNOS does not regulate PMN infiltration into the mucosa, and endothelial NOS provides important protection against AGML during hemorrhagic shock.

Inhibition of nitric oxide synthase during hemorrhagic shock increases hepatic injury.

The function of nitric oxide (NO) in hemorrhagic shock is controversial. Increased NO synthesis has been temporally correlated with severe shock and has been associated with vascular hyporeactivity to vasoconstrictor agents in isolated vascular rings. Its role in local tissue perfusion, however, is unknown. We studied the role of NO in shock-induced hepatic injury in a rodent model of decompensated hemorrhagic shock by inhibiting its synthesis with Nw-nitro-L-arginine methyl ester (L-NAME). L-NAME infusion (5 micrograms/kg/min) increased the shock-induced hepatic injury and this effect was reversible with L-arginine. L-NAME had only transient effects on systemic mean arterial blood pressure, which quickly returned to pre-L-NAME levels. We conclude that NO synthesis serves a protective function in preventing shock-induced hepatic injury and we postulate that this effect may be due to modulation of the local hepatic circulation.

Metallothionein and HSP-72 are induced in the liver by hemorrhagic shock and resuscitation but not by shock alone.

BACKGROUND: Previous reports have indicated that HSP-72 and metallothionein mRNA undergo induction in the liver after resuscitated hemorrhagic shock. In this study we investigated whether unresuscitated shock triggers induction and whether protein induction also occurs. METHODS: Rats were subjected to resuscitated and unresuscitated shock protocols of varying severity; livers were isolated and processed for Northern, Western, and immunohistochemical analysis. Cadmium binding assay was used to measure metallothionein protein. RESULTS: Unresuscitated shock led to no induction of HSP-72 or metallothionein. Severe resuscitated shock led to prompt induction of HSP-72 mRNA and protein in hepatocytes, up to 20-fold over sham group; metallothionein mRNA induction appeared later than HSP-72 and did not lead to elevated protein levels. Mild resuscitated shock had little effect. CONCLUSIONS: These findings indicate resuscitated severe shock, not shock alone, leads to induction of HSP-72 and metallothionein in the liver. Metallothionein expression lags behind HSP-72 expression.

Management of blunt splenic trauma: significant differences between adults and children.

BACKGROUND: Although highly successful in children, nonoperative management of blunt splenic injury in adults is less defined. The purpose of this study was to determine whether mechanism of injury, grade of splenic injury, associated injuries, and pattern of injury differ between adults and children (younger than 15 years of age). METHODS: Four hundred eleven patients (293 adults and 118 pediatric patients) with blunt splenic injury were admitted to an affiliated adult/pediatric trauma program from 1989 to 1994. Computed tomography (CT) scans were interpreted in a blinded fashion. Mechanism of injury was significantly different for adults versus children (p < 0.05): motor vehicle crash (66.9% versus 23.7%), motorcycle (8.8% versus 0.8%), sports (2.4% versus 16.9%), falls (8.8% versus 25.4%), pedestrian/automobile (4.4% versus 11.0%), bicycle (1.4% versus 9.3%), and other (7.3% versus 12.7%). RESULTS: Higher injury severity scores, lower Glasgow Coma Scales, and higher mortality indicated that the adults were more severely injured than the children. Fifty-nine percent of the adults and 7% of the children required immediate laparotomy for splenic injury. Both CT grade and quantity of blood on CT predicted the need for exploration in adults but not in children. An injury severity score above 15 and high-energy mechanisms correlated with the need for operative intervention. CONCLUSIONS: Rather than children simply being physically different, they are injured differently than adults, hence the high rate of nonoperative management.

Glucagon inhibits hepatocyte nitric oxide synthesis.

OBJECTIVE: To investigate the effects of glucagon on nitric oxide (NO) synthesis in cultured rat hepatocytes. SETTING: Laboratory. MATERIALS: Male Sprague-Dawley rats (weight, 200-250 g). INTERVENTIONS: Isolated rat hepatocytes were cultured with interleukin-1 to stimulate NO synthesis. Glucagon was added at increasing concentrations (from 10(-9) to 2 x 10(-5) mol/L) at the time of interleukin-1 stimulation. Selected cultures were treated with the adenylate cyclase inhibitor, SQ 22536 (from 10(-5) to 10(-3) mol/L). MAIN OUTCOME MEASURES: Nitric oxide synthesis was assessed by measuring the concentrations of culture supernatant nitrite and nitrite plus nitrate, hepatocyte nitric oxide synthase-2 (NOS-2) messenger RNA (mRNA), and NOS-2 protein. RESULTS: Interleukin-1 stimulated hepatocyte NO synthesis, and this synthesis was inhibited by glucagon in a dose-dependent manner. Glucagon inhibited the accumulation of supernatant nitrite and the expression of NOS-2 mRNA and NOS-2 protein. SQ 22536 restored glucagon-induced decreases in NO synthesis. CONCLUSIONS: Glucagon inhibits NO synthesis in interleukin-1-stimulated hepatocytes in vitro. This inhibition seems to be mediated by glucagon-induced changes in cyclic adenosine monophosphate.

Effect of endogenous nitric oxide on mitochondrial respiration of rat hepatocytes in vitro and in vivo.

Nitric oxide, a highly reactive radical, was recently identified as an intermediate of L-arginine metabolism in mammalian cells. We have shown that nitric oxide synthesis is induced in vitro in cultured hepatocytes by supernatants from activated Kupffer cells or in vivo by injecting rats with nonviable Corynebacterium parvum. In both cases, nitric oxide biosynthesis in hepatocytes was associated with suppression of total protein synthesis. This study attempts to determine the effect of nitric oxide biosynthesis on the activity of specific hepatocytic mitochondrial enzymes and to determine whether inhibition of protein synthesis is caused by suppression of energy metabolism. Exposure of hepatocytes to supernatants from activated Kupffer cells led to a 30% decrease of aconitase (Krebs cycle) and complex I (mitochondrial electron transport chain) activity. Using NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, we demonstrated that the inhibition of mitochondrial aconitase activity was due, in part, to the action of nitric oxide. In contrast, in vivo nitric oxide synthesis of hepatocytes from Corynebacterium parvum-treated animals had no effect on mitochondrial respiration. This suggests that inhibition of protein synthesis by nitric oxide is not likely to be mediated by inhibition of energy metabolism.

Percutaneous endoscopic gastrostomy reduces total hospital costs in head-injured patients.

BACKGROUND: Gastrostomies provide reliable long-term enteral access in patients with traumatic brain injuries. The impact of technique of gastrostomy on total hospital cost is not known. METHODS: A retrospective analysis of patients who sustained head trauma and required gastrostomies for long-term enteral access between 1 July 1990 and 1 July 1996 was performed. RESULTS: The patients who received percutaneous endoscopic gastrostomies (PEG) were similar to patients who received Stamm gastrostomies (OPEN) with respect to age, injury severity score, mechanism of injury, associated injuries, complication rates, and deaths. Total hospital costs ($ x 10(3)) were lower for patients who had PEGs placed in the intensive care unit (78.2 +/- 37.4) or endoscopy suite (71.9 +/- 37.7) compared with PEGs placed in the operating room (122.4 +/- 75.7) or OPEN gastrostomies (119.8 +/- 65.1). CONCLUSIONS: In head-injured patients, PEGs are a reliable method of obtaining long-term enteral access with a complication rate equivalent to Stamm gastrostomies. If performed in either the intensive care unit or the endoscopy suite, PEGs are associated with significantly reduced total hospital costs.

The impact of liver dysfunction on outcome in patients with multiple injuries.

Multiple organ dysfunction syndrome (MODS) is the leading cause of late deaths after traumatic injury. The relative importance of dysfunction of individual organ systems in determining outcome from MODS has not been clearly defined. Some studies have suggested that hepatic dysfunction associated with MODS increases mortality, whereas others have suggested that it contributes little to outcome in trauma patients. To clarify the role of the hepatic dysfunction after traumatic injury we retrospectively reviewed all trauma patients with an Injury Severity Score > or = 14 admitted from January 1, 1994 through June 30, 1997 for the presence of hepatic dysfunction defined as a serum bilirubin > or = 2.0 mg/dL. Of the 1962 patients who met the entry criteria 154 developed hepatic dysfunction during their hospital stay. Patients with hepatic dysfunction were older (46 +/- 2 versus 41 +/- 1 years), were more severely injured (Injury Severity Score 31.5 +/- 0.9 versus 23.3 + 0.2), and had a lower prehospital blood pressure (102 +/- 3 versus 117 +/- 1 mm Hg) compared with patients who did not develop hepatic dysfunction. Patients with hepatic dysfunction were more likely to present with shock as reflected in a lower initial emergency room blood pressure (109 +/- 3 versus 128 +/- 1 mm Hg) and base deficit (-6.9 +/- 0.6 versus -3.5 +/- 0.1 mEq/L). Patients who developed hyperbilirubinemia had longer lengths of stay in the intensive care unit (15.8 +/- 1.2 versus 3.4 +/- 0.2 days) and the hospital (27.4 +/- 1.7 versus 11.1 +/- 0.2 days) and a higher in-hospital mortality (16.2% versus 2.5%). These data demonstrate that the development of hepatic dysfunction reflects the severity of injury and is associated with a significantly worse outcome after traumatic injury.

Hemorrhagic shock.

A great deal has been learned about the pathophysiologic condition of hemorrhagic shock. The response of the hormonal and inflammatory mediator systems in patients in hemorrhagic shock appears to represent a distinct set of responses different from those of other forms of shock. The classic neuroendocrine response to hemorrhage attempts to maintain perfusion to the heart and brain, often at the expense of other organ systems. This intense vasoconstriction occurs via central mechanisms. The response of the peripheral microcirculation is driven by local tissue hypoperfusion that results in vasodilation in the ischemic tissue bed. Activation of the systemic inflammatory response by hemorrhage and tissue injury is an important component of the pathophysiologic condition of hemorrhagic shock. Activators of this systemic inflammatory response include ischemia/reperfusion injury and neutrophil activation. Capillary "no-flow" with prolonged ischemia and "no-reflow" with reperfusion may initiate neutrophil activation in patients in hemorrhagic shock. The mechanisms that lead to decompensated and irreversible hemorrhagic shock include (1) "arteriolar hyposensitivity" as manifested by progressive arteriolar vasodilation and decreased responsiveness of the microcirculation to alpha-agonists, and (2) cellular injury and activation of both proinflammatory and counterinflammatory mechanisms. These changes represent a failure of the microcirculation. Redistribution of cardiac output and persistent gut ischemia after adequate resuscitation may also contribute to the development of irreversible hemorrhagic shock. Treatment of hemorrhagic shock includes rapid operative resuscitation to limit activation of the mediator systems and abort the microcirculatory changes that result from hemorrhagic shock. Volume resuscitation and control of hemorrhage, should occur simultaneously. The end point in volume resuscitation of hemorrhagic shock must be maintenance of organ system and cellular function. Whether we use adequate urine output, correction of lactic acidemia, optimization of oxygen delivery, or oxygen consumption as our specific goal, the general objective is to provide adequate crystalloid solution and packed red blood cells to achieve and maintain normal organ and cellular perfusion and function.