Right man, right time, right place? - On the time course of the mediator orchestra in septic shock

Appropriate timing of treatment assumes particular importance in critical care. Lange and colleagues recently reported on the time course of the different nitric oxide synthase (NOS) isoforms, nitrosative stress, and poly(ADP-ribosylation) during Pseudomonas aeruginosa pneumonia-induced ovine septic shock. Initially, endothelial NOS expression was increased together with markers of peroxynitrite formation, DNA damage, and nuclear factor-kappa-B activation. Later on, measurable NOS activity and nitric oxide production resulted mainly from inducible NOS activation. These results emphasize the need for long-term, large-animal studies investigated over days so that future therapeutic interventions can be better tailored and matched to the exact time course of the activation of the mediator orchestra

Vasopressin and ischaemic heart disease: more than coronary vasoconstriction?

During advanced vasodilatory shock, arginine vasopressin (AVP) is increasingly used to restore blood pressure and thus to reduce catecholamine requirements. The AVP-related rise in mean arterial pressure is due to systemic vasoconstriction, which, depending on the infusion rate, may also reduce coronary blood flow despite an increased coronary perfusion pressure. In a murine model of myocardial ischaemia, Indrambarya and colleagues now report that a 3-day infusion of AVP decreased the left ventricular ejection fraction, ultimately resulting in increased mortality, and thus compared unfavourably with a standard treatment using dobutamine. The AVP-related impairment myocardial dysfunction did not result from the increased left ventricular afterload but from a direct effect on cardiac contractility. Consequently, the authors conclude that the use of AVP should be cautioned in patients with underlying cardiac disease

Pulmonary and renal protection: targeting PARP to ventilator-induced lung and kidney injury?

Both acute lung injury and acute kidney injury (AKI) are frequent and serious problems in intensive care medicine. Therefore, the avoiding of any iatrogenic insult to these organs is of great importance. While an increasing body of evidence suggests that mechanical ventilation is capable of inducing lung and distant organ injury, the complex underlying molecular mechanisms remain insufficiently understood. In the previous issue of Critical Care, Vaschetto and colleagues reported the results of an experimental study designed to further explore pathways linking injurious ventilation with AKI. The authors demonstrated that scavenging of peroxynitrite or inhibiting poly(ADP-ribose) polymerase (PARP) afforded protection against AKI induced by double-hit lung injury. Although PARP inhibition or peroxynitrite detoxification or both may become viable candidates for a protective strategy in this setting, the implementation of a lung-protective ventilatory strategy remains the only clinical tool to mitigate the lung biotrauma and its systemic consequences

Metabolic effects of phosphodiesterase III inhibitors: another reason to promote their use?

Phosphodiesterase III inhibitors combine positive inotropic and vasodilator properties. These inhibitors are therefore frequently used to treat low cardiac output and/or severe left heart failure associated with cardiac surgery. Their effects on energy metabolism and visceral organ function are not well studied, however, particularly in comparison with their 'competitors' in daily practice (that is, catecholamines)

Year in review 2009: Critical Care - shock

The research papers on shock that have been published in Critical Care throughout 2009 are related to four major subjects: first, alterations of heart function and, second, the role of the sympathetic central nervous system during sepsis; third, the impact of hemodynamic support using vasopressin or its synthetic analog terlipressin, and different types of fluid resuscitation; as well as, fourth, experimental studies on the treatment of acute respiratory distress syndrome. The present review summarizes the key results of these studies together with a brief discussion in the context of the relevant scientific and clinical background published both in this and other journals

Central venous oxygen saturation and emergency intubation – another piece in the puzzle?

A recent multicentre observational study examined the effect of emergency intubation on central venous oxygen saturation (SCVo2) in critically ill patients. The main finding was that SCVo2 significantly increases 15 minutes after emergency intubation and institution of mechanical ventilation with 100% oxygen, especially in those patients with pre-intubation SCVo2 values <70%, regardless of whether these patients suffered from severe sepsis. However, in only one-quarter of this subgroup was the SCVo2 normalized to ≥70% solely by this intervention. In contrast, in patients with pre-intubation SCVo2 ≥70%, the SCVo2 failed to increase after intubation. A rise in SCVo2 can be expected when whole body oxygen extraction remains unchanged after intubation and ventilation with pure oxygen

Vasopressin in vasodilatory shock: hemodynamic stabilization at the cost of the liver and the kidney?

Infusing arginine vasopressin (AVP) in advanced vasodilatory shock is usually accompanied by a decrease in cardiac index and systemic oxygen transport. Whether or not such a vasoconstriction impedes regional blood flow and thus visceral organ function, even when low AVP is used, is still a matter of debate. Krejci and colleagues now report, in this issue of Critical Care, that infusing 'low-dose' AVP during early, short-term, normotensive and normodynamic fecal peritonitis-induced porcine septicemia markedly reduced both renal and portal blood flow, and consequently total hepatic blood flow, whereas hepatic arterial flow was not affected. This macrocirculatory response was concomitant with reduced kidney microcirculatory perfusion, whereas liver micro-circulation remained unchanged. From these findings the authors conclude that the use of AVP to treat hypotension should be cautioned against in patients with septic shock. Undoubtedly, given its powerful vasoconstrictor properties, which are not accompanied by positive inotropic qualities (in contrast with most of the equally potent standard care 'competitors', namely catecholamines), the safety of AVP is still a matter of concern. Nevertheless, the findings reported by Krejci and colleagues need to be discussed in the context of the model design, the timing and dosing of AVP as well as the complex interaction between visceral organ perfusion and function

Sepsis therapy: what's the best for the mitochondria?

It is suspected that mitochondrial dysfunction is a major cause of organ failure in sepsis and septic shock. A study presented in this issue of Critical Care revealed that liver mitochondria from pigs treated with norepinephrine during endotoxaemia exhibit greater in vitro respiratory activity. The investigators provide an elegant demonstration of how therapeutic interventions in sepsis may profoundly influence mitochondrial respiration, but many aspects of mitochondrial function in sepsis remain to be clarified