Bench-to-bedside review: Vasopressin in the management of septic shock

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care--or septic shock--and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 μg/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study.     

Bench-to-bedside review: Inhaled nitric oxide therapy in adults

Nitric oxide (NO) is an endogenous mediator of vascular tone and host defence. Inhaled nitric oxide (iNO) results in preferential pulmonary vasodilatation and lowers pulmonary vascular resistance. The route of administration delivers NO selectively to ventilated lung units so that its effect augments that of hypoxic pulmonary vasoconstriction and improves oxygenation. This 'Bench-to-bedside' review focuses on the mechanisms of action of iNO and its clinical applications, with emphasis on acute lung injury and the acute respiratory distress syndrome. Developments in our understanding of the cellular and molecular actions of NO may help to explain the hitherto disappointing results of randomised controlled trials of iNO.     

Bench-to-bedside review: Leadership and conflict management in the intensive care unit

In the management of critical care units, leadership and conflict management are vital areas for the successful performance of the unit. In this article a practical approach to define competencies for leadership and principles and practices of conflict management are offered. This article is, by lack of relevant intensive care unit (ICU) literature, not evidence based, but it is the result of personal experience and a study of literature on leadership as well on conflicts and negotiations in non-medical areas. From this, information was selected that was recognisable to the authors and, thus, also seems to be useful knowledge for medical doctors in the ICU environment.     

Bench-to-bedside review: Therapeutic management of invasive candidiasis in the intensive care unit

Candida is one of the most frequent pathogens in bloodstream infections, and is associated with significant morbidity and mortality. The epidemiology of species responsible for invasive candidiasis, both at local and worldwide levels, has been changing - shifting from Candida albicans to non-albicans species, which can be resistant to fluconazole (Candida krusei and Candida glabrata) or difficult to eradicate because of biofilm production (Candida parapsilosis). Numerous intensive care unit patients have multiple risk factors for developing this infection, which include prolonged hospitalisation, use of broad-spectrum antibiotics, presence of intravascular catheters, parenteral nutrition, high Acute Physiology and Chronic Health Evaluation score, and so forth. Moreover, delaying the specific therapy was shown to further increase morbidity and mortality. To minimise the impact of this infection, several management strategies have been developed - prophylaxis, empirical therapy, pre-emptive therapy and culture-based treatment. Compared with prophylaxis, empirical and pre-emptive approaches allow one to reduce the exposure to antifungals by targeting only the patients at high risk of candidemia, without delaying therapy until the moment blood Candida is identified in blood cultures. The agents recommended for initial treatment of candidemia in critically ill patients include echinocandins and lipid formulation of amphotericin B.     

Bench-to-bedside review: Mechanisms and management of hyperthermia due to toxicity

Body temperature can be severely disturbed by drugs capable of altering the balance between heat production and dissipation. If not treated aggressively, these events may become rapidly fatal. Several toxins can induce such non-infection-based temperature disturbances through different underlying mechanisms. The drugs involved in the eruption of these syndromes include sympathomimetics and monoamine oxidase inhibitors, antidopaminergic agents, anticholinergic compounds, serotonergic agents, medicaments with the capability of uncoupling oxidative phosphorylation, inhalation anesthetics, and unspecific agents causing drug fever. Besides centrally disturbed regulation disorders, hyperthermia often results as a consequence of intense skeletal muscle hypermetabolic reaction. This leads mostly to rapidly evolving muscle rigidity, extensive rhabdomyolysis, electrolyte disorders, and renal failure and may be fatal. The goal of treatment is to reduce body core temperature with both symptomatic supportive care, including active cooling, and specific treatment options.     

Bench-to-bedside review: Therapeutic options and issues in the management of ventilator-associated bacterial pneumonia

Despite progress in the diagnosis, prevention and therapy for hospital-acquired infections, ventilator-associated pneumonia (VAP) continues to complicate the course of a significant proportion of patients receiving mechanical ventilation. Mortality rates among patients with VAP have been reported to be as high as 72%, and the morbidity associated with VAP is also considerable, adding days to the hospital stay and increasing health care costs. Appropriate initial antimicrobial therapy for patients with VAP has been shown to reduce mortality rates and improve outcomes; therefore, rapid identification of infected patients and timely, accurate selection of effective antimicrobial agents are important clinical goals. The primary organisms responsible for VAP include Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. However, aetiologies differ considerably between intensive care units, and the increase in antibiotic resistance and nosocomial outbreaks worldwide have presented clinicians with a serious dilemma with respect to selecting appropriate empirical therapy. To date, no optimal antimicrobial regimen for the treatment of VAP has been identified, largely because none of the currently marketed antibiotics has a sufficiently extended spectrum of activity to cover all of the potential key pathogens. More active, less toxic antibacterial agents are still needed, in particular to combat problematic pathogens such as multiresistant Gram-negative bacilli and resistant Gram-positive organisms (e.g. methicillin-resistant S aureus).     

Bench-to-bedside review: Resuscitation in the emergency department

Over the past decade the practice of acute resuscitation and its monitoring have undergone significant changes. Utilization of noninvasive mechanical ventilation, goal-directed therapy, restricted fluid volume, blood transfusion and minimally invasive technology for monitoring tissue oxygenation have changed the practice of acute resuscitation. Early diagnosis and definitive treatment of the underlying cause of shock remains the mainstay for survival after successful resuscitation. Patient-centered outcome end-points, in addition to survival, are being utilized to appraise the effectiveness of treatment. Application of medical ethics to the ever changing practice of acute resuscitation has also become a societal expectation.     

Bench-to-bedside review: lactate and the lung

The ability of the isolated lung tissue to take up glucose and to release lactate is potentially similar to that of other body tissues. Nonetheless, when lung lactate exchange was assess in vivo in normal humans, no measurable lactate production could be detected. Lung lactate production may become clinically evident in disease states especially in the patients with acute lung injury or with acute respiratory distress syndrome. Potential mechanisms of lactate production by the injured lung may include not only the onset of anaerobic metabolism in hypoxic zones, but also direct cytokine effects on pulmonary cells and an accelerated glucose metabolism in both the parenchymal and the inflammatory cells infiltrating lung tissue. In addition, as skeletal muscle, lung tissue may show metabolic adaptations in response to systemic mediators and may contribute to the systemic metabolic response to severe illness even in the absence of direct tissue abnormalities.     

Bench-to-bedside review: lactate and the kidney

The native kidney has a major role in lactate metabolism. The renal cortex appears to be the major lactate-consuming organ in the body after the liver. Under conditions of exogenous hyperlactatemia, the kidney is responsible for the removal of 25–30% of all infused lactate. Most of such removal is through lactate metabolism rather than excretion, although under conditions of marked hyperlactatemia such excretion can account for approximately 10–12% of renal lactate disposal. Indeed, nephrectomy results in an approximately 30% decrease in exogenous lactate removal. Importantly and differently from the liver, however, the kidney's ability to remove lactate is increased by acidosis. While acidosis inhibits hepatic lactate metabolism, it increases lactate uptake and utilization via gluconeogenesis by stimulating the activity of phospho-enolpyruvate carboxykinase. The kidney remains an effective lactate-removing organ even during endotoxemic shock. The artificial kidney also has a profound effect on lactate balance. If lactate-buffered fluids are used in patients who require continuous hemofiltration and who have pretreatment hyperlactatemia, the serum lactate levels can significantly increase. In some cases, this increase can result in an exacerbation of metabolic acidosis. If bicarbonate-buffered replacement fluids are used, a significant correction of the acidosis or acidemia can also be achieved. The clinician needs to be aware of these renal effects on lactate levels to understand the pathogenesis of hyperlactatemia in critically ill patients, and to avoid misinterpretations and unnecessary or inappropriate diagnostic or therapeutic activities.     

Bench-to-bedside review: Resuscitation in the emergency department

Over the past decade the practice of acute resuscitation and its monitoring have undergone significant changes. Utilization of noninvasive mechanical ventilation, goal-directed therapy, restricted fluid volume, blood transfusion and minimally invasive technology for monitoring tissue oxygenation have changed the practice of acute resuscitation. Early diagnosis and definitive treatment of the underlying cause of shock remains the mainstay for survival after successful resuscitation. Patient-centered outcome end-points, in addition to survival, are being utilized to appraise the effectiveness of treatment. Application of medical ethics to the ever changing practice of acute resuscitation has also become a societal expectation.     

Bench-to-bedside review: Chloride in critical illness

Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.     

Bench-to-bedside review: Ventilatory abnormalities in sepsis

In septic patients increased central drive and increased metabolic demands combine to increase energy demands on the ventilatory muscles. This occurs at a time when energy supplies are limited and energy production hindered, and it leads to an energy supply-demand imbalance and often ventilatory failure. Problems related to contractile function of the ventilatory muscles also contribute, especially when the clinical course is prolonged. The increased ventilatory activity increases interactions between the ventilatory and cardiovascular systems, and when ventilatory muscles fail and mechanical ventilatory support is required a new set of problems emerges. In this review I discuss factors related to ventilatory muscle failure, giving emphasis to mechanical and supply demand aspects. I also review the implications of changes in ventilatory patterns for heart-lung interactions.     

Bench-to-bedside review: β-Adrenergic modulation in sepsis

Sepsis, despite recent therapeutic progress, still carries unacceptably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an interesting new therapeutic target for septic shock. β-Adrenergic regulation of the immune function in sepsis is complex and is time dependent. However, β₂ activation as well as β₁ blockade seems to downregulate proinflammatory response by modulating the cytokine production profile. β₁ blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. β-Blockers could also be of interest in the systemic catabolic response to sepsis, as they oppose epinephrine which is known to promote hyperglycemia, lipid and protein catabolism. The role of β-blockers in coagulation is less clear cut. They could have a favorable role in the septic pro-coagulant state, as β₁ blockade may reduce platelet aggregation and normalize the depressed fibrinolytic status induced by adre-nergic stimulation. Therefore, β₁ blockade as well as β₂ activation improves sepsis-induced immune, cardiovascular and coagulation dysfunctions. β₂ blocking, however, seems beneficial in the metabolic field. Enough evidence has been accumulated in the literature to propose β- adrenergic modulation, β₁ blockade and β₂ activation in particular, as new promising therapeutic targets for septic dyshomeostasis, modulating favorably immune, cardiovascular, metabolic and coagulation systems.     

Bench-to-bedside review: glucose production from the kidney

Data obtained from net organ balance studies of glucose production lead to the classic view according to which glucose homeostasis is mainly ensured by the liver, and renal glucose production only plays a significant role during acidosis and prolonged starvation. Renal glucose release and uptake, as well as the participation of gluconeogenic substrates in renal gluconeogenesis, were recently re-evaluated using systemic and renal arteriovenous balance of substrates in combination with deuterated glucose dilution. Data obtained using these methods lead one to reconsider the magnitude of renal glucose production as well as its role in various physiological and pathological circumstances. These findings now conduce one to consider that renal gluconeogenesis substantially participates in postabsorptive glucose production, and that its role in glucose homeostasis is of first importance.     

Bench-to-bedside review: Latest results in hemorrhagic shock

Hemorrhagic shock is a leading cause of death in trauma patients worldwide. Bleeding control, maintenance of tissue oxygenation with fluid resuscitation, coagulation support, and maintenance of normothermia remain mainstays of therapy for patients with hemorrhagic shock. Although now widely practised as standard in the USA and Europe, shock resuscitation strategies involving blood replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centers; the primary cause of this is the scarcity of published evidence and lack of randomized controlled clinical trials. Despite enormous efforts to improve outcomes after severe hemorrhage, novel strategies based on experimental data have not resulted in profound changes in treatment philosophy. Recent clinical and experimental studies indicated the important influences of sex and genetics on pathophysiological mechanisms after hemorrhage. Those findings might provide one explanation why several promising experimental approaches have failed in the clinical arena. In this respect, more clinically relevant animal models should be used to investigate pathophysiology and novel treatment approaches. This review points out new therapeutic strategies, namely immunomodulation, cardiovascular maintenance, small volume resuscitation, and so on, that have been introduced in clinics or are in the process of being transferred from bench to bedside. Control of hemorrhage in the earliest phases of care, recognition and monitoring of individual risk factors, and therapeutic modulation of the inflammatory immune response will probably constitute the next generation of therapy in hemorrhagic shock. Further randomized controlled multicenter clinical trials are needed that utilize standardized criteria for enrolling patients, but existing ethical requirements must be maintained.     

Bench-to-bedside review: treating acid-base abnormalities in the intensive care unit--the role of renal replacement therapy

Acid–base disorders are common in critically ill patients. Metabolic acid–base disorders are particularly common in patients who require acute renal replacement therapy. In these patients, metabolic acidosis is common and multifactorial in origin. Analysis of acid–base status using the Stewart–Figge methodology shows that these patients have greater acidemia despite the presence of hypoalbuminemic alkalosis. This acidemia is mostly secondary to hyperphosphatemia, hyperlactatemia, and the accumulation of unmeasured anions. Once continuous hemofiltration is started, profound changes in acid–base status are rapidly achieved. They result in the progressive resolution of acidemia and acidosis, with a lowering of concentrations of phosphate and unmeasured anions. However, if lactate-based dialysate or replacement fluid are used, then in some patients hyperlactatemia results, which decreases the strong ion difference and induces an iatrogenic metabolic acidosis. Such hyperlactatemic acidosis is particularly marked in lactate-intolerant patients (shock with lactic acidosis and/or liver disease) and is particularly strong if high-volume hemofiltration is performed with the associated high lactate load, which overcomes the patient's metabolic capacity for lactate. In such patients, bicarbonate dialysis seems desirable. In all patients, once hemofiltration is established, it becomes the dominant force in controlling metabolic acid–base status and, in stable patients, it typically results in a degree of metabolic alkalosis. The nature and extent of these acid–base changes is governed by the intensity of plasma water exchange/dialysis and by the 'buffer' content of the replacement fluid/dialysate, with different effects depending on whether lactate, acetate, citrate, or bicarbonate is used. These effects can be achieved in any patient irrespective of whether they have acute renal failure, because of the overwhelming effect of plasma water exchange on nonvolatile acid balance. Critical care physicians must understand the nature, origin, and magnitude of alterations in acid–base status seen with acute renal failure and during continuous hemofiltration if they wish to provide their patients with safe and effective care.     

Cyclic antidepressant overdose: A review of current management strategies

Cyclic antidepressant (CA) overdose can produce life-threatening seizures, hypotension, and dysrhythmias. It accounts for up to half of all overdose-related adult intensive care unit admissions and is the leading cause of death from drug overdose in patients arriving at the emergency department alive. Several factors contribute to the significant morbidity and mortality associated with CA overdose. First, CAs are widely prescribed and are dispensed to patients at increased risk for attempting suicide. Second, drugs of this class generally have a low therapeutic toxic ratio. Third, in the majority of fatal cases, the patient dies before reaching a hospital. Finally, and of greatest significance for the clinician, the presenting signs and symptoms of CA overdose may be missed by the physician, even in cases of severe toxicity. Therefore, CAs must be considered early in any case of suspected overdose, and all such cases should be managed as potentially fatal ones. The following case demonstrates the current approach to the patient with significant CA toxicity.     

Bench-to-bedside review: Microdialysis in intensive care medicine

Microdialysis is a technique used to measure the concentrations of various compounds in the extracellular fluid of an organ or in a body fluid. It is a form of metabolic monitoring that provides real-time, continuous information on pathophysiological processes in target organs. It was introduced in the early 1970s, mainly to measure concentrations of neurotransmitters in animal experiments and clinical settings. Using commercial equipment it is now possible to conduct analyses at the bedside by collecting interstitial fluid for measurement of carbohydrate and lipid metabolites. Important research has been reported in the field of neurosurgery in recent decades, but use of metabolic monitoring in critical care medicine is not yet routine. The present review provides an overview of findings from clinical studies using microdialysis in critical care medicine, focusing on possible indications for clinical biochemical monitoring. An important message from the review is that sequential and tissue-specific metabolic monitoring, in vivo, is now available.