Summary. Tuberculosis is re-emerging as a leading public health problem worldwide, largely due to the lack of a fully protective vaccine, the acquired immunodeficiency associated with HIV-co-infection and the increasing number of drug-resistant mycobacteria. There is substantial epidemiological evidence that the host genetic make-up affects the development of clinical tuberculosis in humans. Here we review population-based and patient-based molecular studies that have implicated various genes in polygenic and monogenic susceptibility to mycobacterial disease. We further discuss the possibility of a continuous spectrum between these two poles of tuberculosis genetics.

Patients with severe sepsis are often treated with vasoactive agents in an attempt to restore cardiovascular function. Catecholamines, either administered as part of sepsis therapy or endogenously released as part of the early host response to injury, can influence the activation of inflammatory pathways during severe infection. This brief review discusses current knowledge of the interactions between exogenous and endogenous catecholamines on the one hand, and inflammatory responses activated during sepsis on the other hand.

When fluid therapy fails to restore adequate arterial pressure, therapy with vasopressors should be started. Dopamine and norepinephrine are both effective to increase blood pressure. In some patients norepinephrine may be a more effective agent. In case of inadequate organ perfusion dobutamine can be associated to the vasopressor agent used. Both drugs can be titrated separately to maintain arterial pressure and cardiac output. Epinephrine can be considered for refractory hypotension or to increase cardiac output, although adverse effects are common. Clinical experience with phenylephrine is limited.

Vasoactive agents are commonly used to correct hypotension or to increase cardiac output in septic patients. However, these agents may influence blood flow distribution and cellular metabolic needs, so that the balance between oxygen supply and demand can be threatened. In this article, we will review the regional effects of vasoactive agents with particular reference to the splanchnic circulation. Among vasopressor agents, dopamine and norepinephrine usually increase splanchnic blood flow. The effects of epinephine have been studied less. The effects of dopamine and norepinephrine on the gut mucosa are inconsistent, while epinephrine worsens mucosal acidosis and endotoxin-induced histologic lesions. The use of low doses of dopamine (“dopaminegic doses”) has not been shown to provide any substantial benefit on splanchnic circulation. Among inotropic agents, dobutamine and dopexamine similarly increase splanchnic blood flow, but dobutamine improve gut mucosal acidosis in most patients, while dopexamine has more variable effects on this parameter. The effects of non-adrenergic vasoactive agents are also discussed briefly.

Objectives: to review the rational for taking cardiac output as a goal for the therapeutic strategy to resuscitate septic shock or severe sepsis. This review concerns the main physiological items implicating cardiac output in sepsis. The goals of hemodynamic resuscitation are detailed, with proposed therapies. After volume loading, the use of vasopressors is frequently needed, especially catecholamines. New vasopressors are under investigation, especially vasopressin, with promising preliminary results.

The cytochrome P450 (P450 or CYP) monooxygenases, CYP2D6, CYP2C19 and CYP2C9, display polymorphism. CYP2D6 and CYP2C19 have been studied extensively and, despite their low abundance in the liver, they have been found to catalyze the metabolism of many drugs. CYP2D6 has many allelic variants, whereas CYP2C19 has only seven. Most variants are translated into inactive, truncated proteins or fail to express any protein. There is, as yet, no clear information about the other CYPs (CYP1A1, CYP2A6, CYP2B6, CYP2E1 and CYP3A4/5) polymorphism.

Abstract. A large proportion of the population is exposed to infectious agents and yet few succumb to disease for, as yet, undetermined reasons. Mannose binding lectin (MBL) plays a key role in the host response to infection through the activation of the lectin complement pathway and probably through acting as an opsin. Variations in the level of circulating MBL are observed, are genetically determined and may explain some of the host variation in susceptibility to disease. In particular, individuals with genetic variants that reduce levels are susceptible to a range of infections including meningococcal disease. However, the variants are common in the general population (around 30%) and a beneficial role may explain their prevalence as they may represent “balanced” polymorphisms. Further work is required to understand the specific mode of action of MBL in each disease and establish effective treatment regimes.

Cardiovascular dysfunction contributes importantly to the high mortality of septic shock, which remains in excess of 50%. Non-survivors are characterized by an inadequate response to fluid resuscitation and catecholamine infusions. A number of recent reports suggest that vasopressin, a non-catecholamine vasopressor, may contribute usefully to the cardiovascular management of septic shock and other forms of vasodilatory shock. Here we review the clinical studies to date of vasopressin use in septic shock and other vasodilatory shock. We then review the known physiology of vasopressin to help understand why vasopressin may be beneficial in this setting. In general, humans having severe vasodilatory shock demonstrate low endogenous vasopressin blood concentration. Low-dose vasopressin infusion in this setting increases blood vasopressin concentration to that observed in hypotension of other causes, results in an increase in mean arterial pressure, and reduces the need for additional α-adrenergic vasopressor infusions. Current studies in low numbers of patients suggest that low-dose vasopressin may increase urine output in this setting. Vasopressin infusion increases blood pressure by V1 receptor stimulation on vascular smooth muscle. This vasoconstrictor effect is less pronounced in the cerebral, coronary, and renal circulations. Diminished vasoconstriction in some regional circulations may be contributed to by nitric oxide-mediated vasodilation resulting from oxytocin receptor stimulation by low-dose vasopressin. Thus, low-dose vasopressin infusion may be a useful adjunct to fluid resuscitation and catecholamine infusion in severe septic shock and other forms of vasodilatory shock.

The management of septic shock in the critically ill patient is based on appropriate treatment of the infective source, by removal or drainage of septic foci and adequate antibiotic therapy, and on supportive intensive care. The main stay of cardiovascular support is the correct administration of resuscitative fluid therapy in order to permit adequate tissue perfusion. Only when this has failed should additional support such as vasopressors and inotropes be contemplated. Fluid therapy in sepsis should have the same guiding principles as fluid therapy in other contexts: rational choice of fluid type, based on knowledge of individual fluid properties, and a logical approach to titration of fluid volume. However septic shock presents some additional unique challenges that may both influence the choice of fluid type and necessitate use of more advanced techniques to titrate fluid volume. In particular the problems of vascular leak and widespread inflammatory activation need to be addressed. There is evidence that choice of fluid may modulate inflammatory mechanisms. Appropriate choice of fluid can probably also minimise loss of volume from the intra-vascular space and subsequent development of tissue oedema. Loss of circulating volume due to increased vascular permeability is one of the reasons why high volumes of fluid are commonly required during resuscitation of the septic patient. High volume resuscitation brings with it the necessity of careful titration of fluid therapy with appropriate monitoring and an increased risk of fluid associated adverse effects becoming clinically relevant.