Use of Tris-hydroxymethyl aminomethane in severe lactic acidosis due to highly active antiretroviral therapy: a case report.

BACKGROUND: Lactic acidosis is a rare, yet life-threatening adverse drug effect of highly active antiretroviral therapy (HAART), specifically stavudine and lamivudine. These nucleoside analogue reverse transcriptase inhibitors (NRTIs) are commonly used to treat patients infected with the human immunodeficiency virus (HIV). CASE: We report the use of Tris-hydroxymethyl aminomethane (THAM) to treat severe lactic acidosis due to HAART in a 50-year-old African-American woman. NRTIs can cause hyperlactinaemia by interfering with mitochondrial oxidative phosphorylation function, which normally removes H(+) generated by the hydrolysis of adenosine triphosphate. This side-effect is associated with a high mortality in patients infected with HIV. One explanation for this high mortality is that lactic acidosis is typically refractory to treatment with commonly used buffering agents. CONCLUSION: THAM generates serum bicarbonate, and reduces the level of carbon dioxide in arterial blood. Both of these qualities appear to make THAM an ideal agent for treating lactic acidosis caused by HAART.

The use of inferior vena cava filter as a treatment modality for massive pulmonary embolism. A case series and review of pathophysiology.

The use of inferior vena cava (IVC) filter for massive pulmonary emboli (PE) with cardiopulmonary instability has not been clinically studied. We present a case series of six such patients who received an IVC filter with anticoagulation rather than thrombolysis because of high risk of bleeding. Acute pulmonary embolectomy was considered, but was not possible for a variety of individual clinical situations. These six hospitalized patients prospectively followed during their admission. They were triaged to three medical intensive care units (ICUs) and one surgical ICU in three university teaching hospitals. One patient was transferred from another institution. All six patients had severe hypoxia and tenuous cardiopulmonary status. All required high inspiratory oxygen and hemodynamic support; two required mechanical ventilation and vasopressors. An IVC filter was placed emergently and anticoagulation was started immediately All six patients had resolution of pulmonary thromboemboli (PTE) on anticoagulation while the IVC filter prevented further PE. All six patients were discharged home in their pre-critical illness state. None ofthe patients suffered complications from this therapy and had excellent resolution ofcardiopulmonary collapse. The IVC filter placement prevented further major embolic events while the PTE resolved with anticoagulation. An IVC filter should be considered as an adjunct to anticoagulation therapy for those patients with massive PE and cardiopulmonary instability who are not candidates for thrombolysis, and acute pulmonary embolectomy is not readily available or is of very high risk.

The World Trade Center attack. Is critical care prepared for terrorism?

This commentary on the World Trade Center attack is written from the perspective of a New York City critical care service, with a long history of activity in disaster management, which is located at the Montefiore Medical Center/Albert Einstein College of Medicine. The paper describes some of the local concerns of the service in the first hours, the reality of dispersal of victims throughout the New York City hospital system, and some of the resources made available and their utilization. In general, the US Critical Care Medicine System receives massive resources in terms of gross national product expenditure when compared with other developed countries. A large capacity is subsequently in place to provide care to critically ill patients resulting from manmade as well as natural disasters. It was the nature of the World Trade Center attack in terms of the ratio of injured survivors to dead victims that did not allow the full capacity and capability of the system to engage.

Oxygen transport and utilization.

The evaluation and management of oxygen delivery (Do2) and consumption (Vo2) of patients with acute medical and surgical illnesses have been subject to controversy and reevaluation. It has been established that a relationship between oxygen delivery and oxygen consumption exists, and is very complex, particularly in diseases in which various factors individually or collectively affect it. The care of critically ill patients routinely involves the manipulation of the Vo2-Do2 relationship, and extensive research, both experimental and clinical, has been done to improve our understanding of this relationship in health and disease with the hope for improved outcomes. Regional measures of oxygenation are a relatively new area of interest with a limited amount known about the regional relationship between Do2 and Vo2. The adequacy of regional oxygenation appears to play an important role in organ dysfunction in critical illness. Standard measures of assessing systemic oxygenation are often insensitive in detecting tissue hypoxia, which can often vary among and within various organs. New noninvasive technologies to measure the adequacy of regional measures of oxygenation are being developed, with gastrointestinal tonometry getting much clinical attention. The exact role of these technologies in the management of critically ill patients, and whether they will improve survival, has not yet been determined. It is likely that the ability to care successfully for critically ill patients will come from a better understanding of not only global, but also regional, cellular, and subcellular metabolism.

Management training in critical care medicine.

Critical care medicine is the only specialty fellowship which requires formal training in administrative and management skills by its certifying organisation. The rationale for this is the fact that critical care is responsible for some 1% of gross national product, 10% of hospital beds and 30% of acute hospital costs in the USA. The curriculum required during the fellowship training has been defined. In order for critical care medicine to continue to grow as an academic as well as a successful institutional clinical service, it is important that quality training be provided in this non-clinical part of the fellowship curriculum as well as the clinical aspects.

Consensus conferences in critical care medicine. Methodologies and impact.

Consensus conferences for the purposes of producing practice guidelines are occurring with increasing frequency both nationally and internationally. The international collaboration of national sciences in these efforts could have a dramatic impact on international standards of care. Too little emphasis is given to conference evaluations in terms of validity of methods, quality of recommendations, and influence on clinical practice and patient outcome. This article provides an overview of consensus methods used to produce guidelines in critical care. It also discusses the strengths and weaknesses of these methods, and how these may influence consensus guidelines. Finally, a brief overview of theoretically sound methods that can serve as benchmarks to evaluate current methods, and the bases for the development of improved methods is provided.

Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia.

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and free radicals, such as nitric oxide (NO), are mediators of endotoxaemia. Catecholamines are in clinical use to treat the haemodynamic consequences of severe septic shock. Beta-adrenergic agonists exert many of their effects by elevation of intracellular cyclic AMP (cAMP) concentration. Cyclic AMP can modulate endotoxin-induced cytokine and NO production. Here we investigate the effect of isoproterenol pretreatment on the cytokine and NO production induced by bacterial lipopolysaccharide (LPS, 4-10 mg/kg). Pretreatment with isoproterenol (10 mg/kg) blunted the LPS-induced TNF response, increased the LPS-induced formation of interleukin-10 and interleukin-6 and reduced the LPS-induced production of NO in conscious mice. In anaesthetized rats, pretreatment with isoproterenol prevented the LPS-induced suppression of vascular contractility to norepinephrine in the thoracic aorta ex vivo. The hyporeactivity is due to expression of the inducible isoform of NO synthase (iNOS) and was restored by in vitro administration of NG-methyl-L-arginine (L-NMA), an inhibitor of NO synthase. However, L-NMA did not alter vascular contractility in control vessels or in rings taken from the LPS-treated rats pretreated with isoproterenol. Our findings suggest that, in addition to its haemodynamic actions, isoproterenol may also exert beneficial effects by modulating the endotoxin-induced inflammatory response.

Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice.

Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-alpha. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- D-ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-alpha production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-kappaB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-alpha and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.

Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome.

The incidence of multiple organ failure syndrome (MOFS) has increased dramatically in most intensive care units (ICU) in the United States and is now the leading cause of death after sepsis, trauma, and burns (1). Despite advances in resuscitation, availability of potent antibiotics, and modern techniques of organ support (2), the survival of critically ill patients with MOFS has not significantly improved since the syndrome was first described over 2 decades ago (3). In the ICU, the monitoring and management of critically ill patients with MOFS has relied, in large part, on readily available measurements of global hemodynamics and oxygen transport. Given the increased understanding of the special role of splanchnic hypoperfusion in the pathophysiology of sepsis and MOFS (4-5), investigators have focused more recently on regional blood flow and oxygen metabolism in these patients (6). In this article, we first present a clinical overview of sepsis and MOFS. Current concepts of the pathogenesis and pathophysiology of MOFS are discussed, with particular emphasis on the roles of splanchnic ischemia and gut barrier failure in the development of both sepsis and the maintenance of the systemic inflammatory response that leads to MOFS. Alterations in both global and regional oxygen transport in septic shock are described to emphasize the limitations of global monitoring in the assessment of splanchnic tissue oxygenation. The role of gastric tonometry in the monitoring of splanchnic oxygenation and its utility in critically ill patients is then analyzed. In addition, the effects and clinical implications of commonly used vasoactive agents on intestinal oxygenation are discussed. Finally, novel therapeutic strategies based on the "gut-origin hypothesis" of MOFS are reviewed.

Cytokine production and its manipulation by vasoactive drugs.

The management of severe sepsis includes the use of agonists of alpha- and beta-adrenergic, as well as of dopaminergic, receptors. Data suggest that the severe inflammatory immune response seen in sepsis can be modulated by stimulation and inhibition of these receptors both in vitro and in vivo. Specifically, release of tumor necrosis factor and interleukins can clearly be modified. Thus, pharmacologic agents directed at circulatory support may have significant potential for immunomodulation. Since the vasopressor and inotrope support of sepsis is not well standardized, variability in the resulting inflammatory mediator response may have consequences to the efficacy of new immunotherapies. This article provides an overview of the effect of the sympathetic nervous system activity and of receptor manipulation on cytokine response to endotoxin, and adds to the perspective on inhibition of phosphodiesterase in the therapy of septic shock.

Parenteral use of medium-chain triglycerides: a reappraisal.

Over the last two decades, the clinical use of intravenous fat emulsions for the nutritional support of hospitalized patients has become routine. During this time long-chain triglycerides (LCT) derived from soybean and/or safflower oils were the exclusive lipid source for these emulsions, providing both a safe calorically dense alternative to dextrose and essential fatty acids needed for biologic membranes and the maintenance of immune function. During the past decade, the availability of novel experimental triglycerides for parenteral use has generated interest in the use of these substrates for nutritional and metabolic support. Medium-chain triglycerides (MCT), long advocated as a superior substrate for parenteral use, possess many unique physiochemical and metabolic properties that make them theoretically advantageous over their LCT counterparts. Although not yet approved in the United States, preparations containing MCT have been widely available in Europe. Intravenous MCT preparations, either as physical mixtures or structured lipids, have been used clinically in patients with immunosuppresion, critical illness, liver and pulmonary disease and in premature infants. Despite great promise, the clinical data comparing the efficacy of MCT-based lipid emulsions to their LCT counterparts has been equivocal. This may be due in part to the limited nature of the published clinical trials. Measures of efficacy for parenteral or enteral nutritional products has taken on new meaning, in light of the reported experience using immunomodulatory nutrients. Current concerns about cost of medical care and resource use warrant careful deliberation about the utility of any new and expensive therapy. Until clinical data can fulfill expectations derived from animal studies, it is difficult to advocate the general use of MCT-based lipid emulsions. Future clinical studies with MCT-based emulsions should have clear outcome objectives sufficient to prove their theorized metabolic superiority.

Modulation of lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production by dopamine receptor agonists and antagonists in mice.

The effects of various agonist and antagonists of dopamine D1 and D2 receptors on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production was investigated in mice. Pretreatment of animals with bromocryptine or quinpirole, agonists of dopamine D2 receptors caused a blunting of both the TNF-alpha and NO responses to LPS injected intraperitoneally. Sulpiride, an antagonist of dopamine D2 receptors, decreased the LPS-induced TNF-alpha plasma levels in a dose-dependent manner and inhibited the LPS-induced NO production by peritoneal macrophages. Bromocryptine or quinpirole blunted both the TNF-alpha and NO response to LPS. SCH-23390, an antagonist of dopamine D1 receptors did not alter LPS-induced TNF-alpha production, but inhibited LPS-induced NO production. These results indicate that while the D2 subtype of dopamine receptors is involve in the modulation of both LPS-induced TNF-alpha and NO production, dopamine D1 receptors only regulate the production of NO. Since several drugs possess effect on dopamine D2 receptors, the present observations may be of clinical relevance.

Endovascular stented graft repair of a pseudoaneurysm of the subclavian artery caused by percutaneous internal jugular vein cannulation: case report.

In high-risk patients endovascular repair of a pseudoaneurysm with a stented graft is a safe and reasonable treatment option that can preclude significant morbidity and shorten hospital stay. We report a case of pseudoaneurysm of the subclavian artery after internal jugular vein cannulation that was treated successfully with an endovascularly inserted, stented graft. The case report highlights the importance of recognizing this unusual but serious complication of percutaneous internal jugular vein catheterization through careful clinical examination, prompt duplex scanning, and arteriography.

Differential effect of selective block of alpha 2-adrenoreceptors on plasma levels of tumour necrosis factor-alpha, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice.

The effect of selective block of alpha 2-adrenoreceptors on plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and corticosterone induced by bacterial lipopolysaccharide (LPS) was investigated in mice using ELISA and RIA. It was found that the LPS-induced TNF-alpha response was significantly blunted in mice pretreated with CH-38083, a novel and highly selective alpha 2-adrenoreceptor antagonist (the alpha 2/alpha 1 ratio is > 2000). In contrast, LPS-induced increases in both corticosterone and IL-6 plasma levels were further increased by CH-38083. Since it has recently been shown that the selective block of alpha 2-adrenoreceptors located on noradrenergic axon terminals resulted in an increase in the release of noradrenaline (NA), both in the central and peripheral nervous systems, and, in our experiments, that propranolol prevented the effect of alpha 2-adrenoreceptor blockade on TNF-alpha plasma levels induced by LPS, it seems likely that the excessive stimulation by NA of beta-adrenoreceptors located on cytokine-secreting immune cells is responsible for this action. Since it is generally accepted that increased production of TNF-alpha is involved in the pathogenesis of inflammation and endotoxin shock on the one hand, and corticosterone and even IL-6 are known to possess anti-inflammatory properties on the other hand, it is suggested that the selective block of alpha 2-adrenoreceptors might be beneficial in the treatment of inflammation and/or endotoxin shock.

Organization and management of critical care systems in unconventional situations.

Critical care medicine is a field of medicine using the highest concentration of expensive diagnostic and life-support technology for the benefit of a single individual. Conventional use of this resource and specialty is clearly understood, despite the fact that it is not necessarily comparable among different institutions. Some of the major issues in using critical care as a medical tool during extraordinary stress on the hospital, and the potential for using it in unconventional environments outside an established institution, have been reviewed. It is clear that the expertise and multidisciplinary approach can be of great use in disaster response, and a national effort toward integrating critical care into overall medical response is in progress.

Parenteral nutrition and oral intake: effect of glucose and fat infusions.

The effect of intravenous nutrition on voluntary oral intake was studied in healthy male volunteers. Subjects were confined to the Surgical Metabolic Unit for the 17 to 19 day study and were restricted to commercial liquid diet. Each study consisted of three consecutive phases: (1) Ringer's lactate (RL), (2) peripheral parenteral nutrition (PPN) administered for 5 or 6 days as a combination of glucose (caloric load equal to 34% resting energy expenditure, REE), fat (34% REE), and amino acids (17% REE) or a single nutrient infusion of glucose (68% REE), fat (68% REE), glucose (34% REE), or fat (34% REE), and (3) RL for the third period. When all three nutrients or glucose alone (68% REE) were given, subjects decreased daily voluntary food intake within 24 to 48 hr by an amount that closely compensated for the infused calories. Intake was reduced by only 20% to 40% of the infused calories when fat alone (68% REE) was given. There were no significant effects when the lower levels of glucose and fat were given. These data suggest the presence of a postabsorptive control of food intake in humans that is sensitive to the circulating supply of fuels.