Treatment of impaired perfusion in septic shock

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.     

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.     

Clinical review: Vasopressin and terlipressin in septic shock patients

Vasopressin (antidiuretic hormone) is emerging as a potentially major advance in the treatment of septic shock. Terlipressin (tricyl-lysine-vasopressin) is the synthetic, long-acting analogue of vasopressin, and has comparable pharmacodynamic but different pharmacokinetic properties. Vasopressin mediates vasoconstriction via V₁ receptor activation on vascular smooth muscle. Septic shock first causes a transient early increase in blood vasopressin concentrations; these concentrations subsequently decrease to very low levels as compared with those observed with other causes of hypotension. Infusions of 0.01–0.04 U/min vasopressin in septic shock patients increase plasma vasopressin concentrations. This increase is associated with reduced need for other vasopressors. Vasopressin has been shown to result in greater blood flow diversion from nonvital to vital organ beds compared with adrenaline (epinephrine). Of concern is a constant decrease in cardiac output and oxygen delivery, the consequences of which in terms of development of multiple organ failure are not yet known. Terlipressin (one or two boluses of 1 mg) has similar effects, but this drug has been used in far fewer patients. Large randomized clinical trials should be conducted to establish the utility of these drugs as therapeutic agents in patients with septic shock.     

Septic shock and multiple organ failure

OBJECTIVE: To assess the frequency and mortality rates of septic shock in ICU patients and the clinical course of multiple organ failure associated with septic shock. DESIGN: Retrospective case survey. SETTING: Tertiary care center. PATIENTS: During a 2-yr period, 2,469 consecutive intensive care patients were studied regarding the frequency and hospital mortality rates of septic shock. A subset of 1,311 patients was further analyzed for the occurrence of organ system failures within 48 hrs of the onset of septic shock and again 4 to 7 days later. MEASUREMENTS AND MAIN RESULTS: The frequency rate of septic shock was 1.9% (n = 48), with a mortality rate of 72.9% (n = 35) in patients with septic shock. Deaths due to septic shock represented 14.6% of all deaths in the ICU during the study period. Eighteen patients died within 72 hrs of the onset of septic shock. Refractory hypotension was the cause of death in 15 of these 18 patients. Beyond 72 hrs, multiple organ failure accounted for eight of 17 deaths. The mean +/- SD number of organ systems failing at 48 hrs was 3.3 +/- 1.3 in survivors and 4.0 +/- 1.1 in nonsurvivors, and at 4 to 7 days was 2.1 +/- 1.5 in survivors and 4.0 +/- 1.5 in nonsurvivors (p less than .05). None of the specific organ system failures had prognostic value. The number of organ system failures was not related to the duration of hypotension, but had a weak correlation (r2 = .26, p less than .05) with the duration of vasoactive treatment at 4 to 7 days. The prolonged need for norepinephrine therapy was associated with an increased occurrence of renal failure. Thirty (62.5%) patients had positive blood cultures and a mortality rate similar to the mortality rate of patients with negative blood cultures. Patients with negative blood cultures died more often with hypotension (p less than .02). CONCLUSIONS: Septic shock is a major cause of death in intensive care patients. Refractory hypotension is a main cause of early deaths. Later on, multiple organ failure becomes the primary clinical problem and cause of mortality.     

Clinical review: Vasopressin and terlipressin in septic shock patients

Vasopressin (antidiuretic hormone) is emerging as a potentially major advance in the treatment of septic shock. Terlipressin (tricyl-lysine-vasopressin) is the synthetic, long-acting analogue of vasopressin, and has comparable pharmacodynamic but different pharmacokinetic properties. Vasopressin mediates vasoconstriction via V1 receptor activation on vascular smooth muscle. Septic shock first causes a transient early increase in blood vasopressin concentrations; these concentrations subsequently decrease to very low levels as compared with those observed with other causes of hypotension. Infusions of 0.01-0.04 U/min vasopressin in septic shock patients increase plasma vasopressin concentrations. This increase is associated with reduced need for other vasopressors. Vasopressin has been shown to result in greater blood flow diversion from nonvital to vital organ beds compared with adrenaline (epinephrine). Of concern is a constant decrease in cardiac output and oxygen delivery, the consequences of which in terms of development of multiple organ failure are not yet known. Terlipressin (one or two boluses of 1 mg) has similar effects, but this drug has been used in far fewer patients. Large randomized clinical trials should be conducted to establish the utility of these drugs as therapeutic agents in patients with septic shock.     

Vasopressin in vasodilatory and septic shock

PURPOSE OF REVIEW: The aim of this article is to review mechanisms of action of vasopressin and clinical studies of vasopressin in septic shock. RECENT FINDINGS: Arginine vasopressin is an important stress hormone that has both vasoactive and antidiuretic properties. The vasoactive properties of vasopressin have been more applicable clinically because of the discovery by Landry and colleagues that there is a deficiency of vasopressin in septic shock and that infusion of relatively low doses of vasopressin improves responsiveness to infused catecholamines (such as norepinephrine). There are at least 16 clinical studies of infusion of vasopressin in patients who have septic shock. The majority of studies found that vasopressin infusion increased blood pressure and urine output, and decreased the dose requirement of norepinephrine. Several studies showed that vasopressin infusion increased urine output. Both vasopressin and norepinephrine have important adverse effects including decreased cardiac output, decreased heart rate, arrhythmias, myocardial ischemia, mesenteric ischemia, and digital ischemia. SUMMARY: It is still unclear whether there is net benefit from low dose vasopressin infusion in patients who have septic shock. There may be certain patients who benefit but there are few studies of a prolonged vasopressin infusion to determine which patients benefit.     

Vasopresseurs et choc septique

Endothelial dysfunction causes vasodilation and hypotension that characterize septic shock. Many complex molecular pathways lead to major alterations and heterogeneity of the microcirculation. Molecules capable of targeting the mechanisms of the septic vasoplegia are currently in development or under animal experimentation and are still far from a possible clinical use. The vasopressors currently used in clinical practice, vasopressin and its analogue terlipressin and α-adrenergic agonists (norepinephrine, epinephrine) are “blind” vasoconstrictors that do not target vasoplegia where it is dominant. Their effects on blood pressure and organ perfusion pressure are very similar. Their impact on the regional and microcirculation depends on the ratio between the obtained easily measurable macro-hemodynamic effects (cardiac output, blood pressure) and the effect of vasoconstriction on the microcirculation, more difficult to monitor clinically. In this mini-review we discuss the macro- and microcirculatory effects of the different vasopressors in septic shock and examine the published comparative clinical trials to address the following practical questions: what vasopressor should we use, which blood pressure level should we target, and how to monitor its effects?     

Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials

ABSTRACT: INTRODUCTION: Catecholamines are the most used vasopressors in vasodilatory shock. However, the development of adrenergic hyposensitivity and the subsequent loss of catecholamine pressor activity necessitate the search for other options. Our aim was to evaluate the effects of vasopressin and its analogue terlipressin compared with cathecolamine infusion alone in vasodilatory shock. METHODS: Systematic review and meta-analysis of publications between 1966 and 2011. The Medline and CENTRAL databases were searched for studies on vasopressin and terlipressin in critically ill patients. The meta-analysis was limited randomized controlled trials evaluating the use of vasopressin and/or terlipressin compared to cathecolamine in adult patients with vasodilatory shock. The assessed outcomes were: overall survival, changes in the hemodynamic and biochemical variables, a decrease of catecholamine requirements, and adverse events. RESULTS: Nine trials covering 998 participants were included. A meta-analysis using a fixed-effect model showed a reduction in norepinephrine requirement among patients receiving terlipressin or vasopressin infusion compared with control (standardized mean difference, -1.58 [95% CI, -1.73 - -1.44]; p < 0.0001). Overall, vasopressin and terlipressin, as compared with norepinephrine, reduced mortality (relative risk, RR: 0.87 [0.77 - 0.99]; p = 0.04). Vasopressin compared with norepinephrine decreased mortality in adult patients (RR: 0.87 [0.76 - 1.00]; p = 0.05) and in patients with septic shock (42.5 vs. 49.2%, respectively; RR, 0.87 [95% CI, 0.75 - 1.00]; p = 0.05; number needed to treat, 1 to 15). There was no difference between in adverse events between the vasopressin and control groups (RR: 0.98 [0.65 - 1.47]; p = 0.92). CONCLUSIONS: Vasopressin use in vasodilatory shock is safe, associated with reduced mortality, and facilitates weaning of catecholamines. In patients with septic shock vasopressin compared to norepinephrine may decrease mortality also.     

Persistent sepsis-induced hypotension without hyperlactatemia: is it really septic shock?

Purpose

The prognostic value of hyperlactatemia in septic shock is unquestionable. However, as current definitions do not include hyperlactatemia as a mandatory criterion, some hypotensive patients may be diagnosed as having septic shock despite exhibiting normolactatemia. The significance of persistent sepsis-induced hypotension without hyperlactatemia is unclear. Is it really septic shock? Our aim was to determine differences in outcome between patients diagnosed as having septic shock but exhibiting normal vs elevated lactate levels during evolution. We also explored the potential implications of including hyperlactatemia as an obligatory diagnostic criterion.

Methods

We performed retrospective analyses on a cohort of 302 septic shock patients.

Results

When we divided patients according to the presence of hyperlactatemia, 34% evolved without hyperlactatemia and exhibited a very low mortality risk (7.7% compared with 42.9% of those with hyperlactatemia). These patients also presented less severe organ dysfunctions and higher central venous O₂ saturation values, and required lower norepinephrine doses. The potential inclusion of hyperlactatemia in septic shock definition would reduce incidence in 34% but increase absolute mortality risk in 11%.

Conclusions

Persistent sepsis-induced hypotension without hyperlactatemia may not constitute a real septic shock. Our results support the need to review the current definition of septic shock. Hyperlactatemia could represent an objective parameter worth to be explored as a potential diagnostic criterion for septic shock.     

Vasopressin in the ICU

PURPOSE OF THE REVIEW: Vasopressin is one of the most important endogenously released stress hormones during shock. In this review, studies published in the past year that add to our understanding of the use of vasopressin in the ICU are discussed. RECENT FINDINGS: Endogenous vasopressin levels are inappropriately low in adults with severe sepsis but not in children with meningococcal septic shock. Vasopressin but not norepinephrine improved renal blood flow and oxygen delivery and prolonged survival in animal models of septic shock. In human vasodilatory shock, the combination of low-dose vasopressin and norepinephrine was found to be safe and effective. In humans, vasopressin can cause gastrointestinal hypoperfusion and ischemic skin lesions. In hypodynamic animal models of sepsis vasopressin compromised oxygen delivery and decreased systemic and gut blood flow.High-dose bolus vasopressin appeared promising in animal studies of hemorrhagic shock and cardiopulmonary arrest and in a large, randomized clinical trial of vasopressin versus epinephrine in human cardiopulmonary arrest with asystole. However, poor neurologic outcomes raised controversy in introducing vasopressin into CPR guidelines. SUMMARY: There is growing evidence that vasopressin infusion in septic shock is safe and effective. Several studies published this year support the hypothesis that vasopressin should be used as a continuous low-dose infusion (between 0.01 and 0.04 U/min in adults) and not titrated as a single vasopressor agent. However, multiple studies highlight the clinical equipoise that exists regarding the use of vasopressin in vasodilatory shock. Guidelines on management of septic shock recommend "cautious use of vasopressin pending further studies."     

Choice of vasopressor in septic shock: does it matter?

Septic shock is a medical emergency that is associated with mortality rates of 40–70%. Prompt recognition and institution of effective therapy is required for optimal outcome. When the shock state persists after adequate fluid resuscitation, vasopressor therapy is required to improve and maintain adequate tissue/organ perfusion in an attempt to improve survival and prevent the development of multiple organ dysfunction and failure. Controversy surrounding the optimum choice of vasopressor strategy to utilize in the management of patients with septic shock continues. A recent randomized study of epinephrine compared to norepinephrine (plus dobutamine when indicated) leads to more questions than answers.     

Effects of vasopressin in septic shock

Septic shock continues to be one of the leading causes of death in the intensive care unit today. The confluence of many factors contributes to the deterioration of patients' condition in septic shock. Increased levels of nitric oxide, in part, mediate the cardiovascular effects of septic shock. Nitric oxide is major mediator of vasodilation and hypotension as well as myocardial depression. It also contributes to decreased production and release of endogenous vasopressin. Vasopressin effects are actualized by stimulation of V1, V2, and V3 receptors located in various parts of the body. The response is dose dependent. Endogenous vasopressin and angiotensin II act synergistically to preserve and restore blood pressure levels. Decreased circulating vasopressin contributes to adrenal insufficiency via hypothalamic-pituitary-adrenal axis suppression and increased catecholamine resistance to vasopressors. Exogenous vasopressin supplementation in physiologic doses has been shown to improve blood pressure levels and decrease vasopressor needs in patients with septic shock.     

Effect of norepinephrine on the outcome of septic shock

OBJECTIVE: Despite increasingly sophisticated critical care, the mortality of septic shock remains elevated. Accordingly, care remains supportive. Volume resuscitation combined with vasopressor support remains the standard of care as adjuvant therapy, and many consider dopamine to be the pressor of choice. Because of fear of excessive vasoconstriction, norepinephrine is considered to be deleterious. The present study was designed to identify factors associated with outcome in a cohort of septic shock patients. Special attention was paid to hemodynamic management and to the choice of vasopressor used, to determine whether the use of norepinephrine was associated with increased mortality. DESIGN: Prospective, observational, cohort study. SETTING: Intensive care unit of a university hospital. PATIENTS: Ninety-seven adult patients with septic shock. MEASUREMENTS AND MAIN RESULTS: Data from these patients were examined to select variables independently and significantly associated with outcome during the hospital stay. Nineteen clinical, biological, and hemodynamic variables were collected at study entry or during the first 48-72 hrs and analyzed for each patient. A stepwise logistic regression analysis and a model building strategy were used to identify variables independently and significantly associated with outcome. The overall hospital mortality was 73% (71 patients). Five variables were significantly associated with outcome. One factor was strongly associated with a favorable outcome: the use of norepinephrine as part of the hemodynamic support of the patients. The 57 patients who were treated with norepinephrine had significantly lower hospital mortality (62% vs. 82%, p < .001; relative risk = 0.68; 95% confidence interval = 0.54-0.87) than the 40 patients treated with vasopressors other than norepinephrine (high-dose dopamine and/or epinephrine). Four variables were associated with a poor outcome and significantly higher hospital mortality: pneumonia as a cause of septic shock (82% vs. 61%, p < .03; relative risk = 1.47; 95% confidence interval = 1.07-1.77), organ system failure index < or = 3 (92% vs. 60%, p < .001; relative risk = 1.47; 95% confidence interval = 1.17-1.82), low urine output at entry to the study (88% vs. 60%, p < .01; relative risk = 1.44; 95% confidence interval = 1.06-1.87), and admission blood lactate concentration > 4 mmol/L (91% vs. 63%, p < .01; relative risk = 1.60; 95% confidence interval = 1.27-1.84). CONCLUSIONS: Our results indicate that the use of norepinephrine as part of hemodynamic management may influence outcome favorably in septic shock patients. The data contradict the notion that norepinephrine potentiates end-organ hypoperfusion, thereby contributing to increased mortality. However, the present study suffers from some limitation because of its nonrandomized, open-label, observational design. Hence, a randomized clinical trial is needed to clearly establish that norepinephrine improves mortality of patients with septic shock, as compared with high-dose dopamine or epinephrine. Pneumonia as the cause of septic shock, high blood lactate concentration, and low urine output on admission are strong indicators of a poor prognosis. Multiple organ failure is confirmed as a reliable predictor of mortality in septic patients.     

Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality

OBJECTIVE: To define the circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during critical illness and to determine their relationship to the severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the development of multiple organ dysfunction, or mortality. DESIGN: Prospective cohort study. SETTING: University hospital intensive care unit. PATIENTS: A total of 82 critically ill adult patients in four clinically defined groups, namely septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock controls (n = 14). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: During day 1 of septic shock, peak plasma levels of G-CSF, interleukin (IL)-6, and leukemia inhibitory factor (LIF), but not GM-CSF, were greater than in sepsis or shock alone (p < .001), and were correlated among themselves (rs = 0.44-0.77; p < .02) and with the APACHE II score (rs = 0.25-0.40; p = .03 to .18). G-CSF, IL-6, and UF, and sepsis, shock, septic shock, and APACHE II scores were strongly associated with organ dysfunction or 5-day mortality by univariate analysis. However, multiple logistic regression analysis showed that only septic shock remained significantly associated with organ dysfunction and only APACHE II scores and shock with 5-day mortality. Similarly, peak G-CSF, IL-6, and LIF were poorly predictive of 30-day mortality. CONCLUSIONS: Plasma levels of G-CSF, IL-6, and LIF are greatly elevated in critical illness, including septic shock, and are correlated with one another and with the severity of illness. However, they are not independently predictive of mortality, or the development of multiple organ dysfunction. GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock.     

Elevated nucleosome levels in systemic inflammation and sepsis

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.     

Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock

ObjectiveTo determine the frequency and spectrum of myocardial dysfunction in patients with severe sepsis and septic shock using transthoracic echocardiography and to evaluate the impact of the myocardial dysfunction types on mortality.Patients and MethodsA prospective study of 106 patients with severe sepsis or septic shock was conducted from August 1, 2007, to January 31, 2009. All patients underwent transthoracic echocardiography within 24 hours of admission to the intensive care unit. Myocardial dysfunction was classified as left ventricular (LV) diastolic, LV systolic, and right ventricular (RV) dysfunction. Frequency of myocardial dysfunction was calculated, and demographic, hemodynamic, and physiologic variables and mortality were compared between the myocardial dysfunction types and patients without cardiac dysfunction.ResultsThe frequency of myocardial dysfunction in patients with severe sepsis or septic shock was 64% (n=68). Left ventricular diastolic dysfunction was present in 39 patients (37%), LV systolic dysfunction in 29 (27%), and RV dysfunction in 33 (31%). There was significant overlap. The 30-day and 1-year mortality rates were 36% and 57%, respectively. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction.ConclusionMyocardial dysfunction is frequent in patients with severe sepsis or septic shock and has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types. Although evaluation for the presence and type of myocardial dysfunction is important for tailoring specific therapy, its presence in patients with severe sepsis and septic shock was not associated with increased 30-day or 1-year mortality.     

脓毒性休克的临床流行病学调查——1087例全国多中心临床研究

目的：调查国内多器官功能障碍综合征（multiple organ dysfunction syndrome,MODS）患者脓毒性休克的发生、病死情况。方法：采用多中心、现况调查方法,分析2002年3月—2005年1月全国11省市、37家三级医院1 087例MODS患者的病例情况。结果：1087例患者中,发生脓毒性休克的患者占39.7%,28d住院病死率为60.4%,随着年龄的增长,病死率逐渐上升。结论：脓毒性休克具有较高的病死率。年龄≥55岁、黑便、粪便潜血阳性是MODS患者发生脓毒性休克的主要高危因素,而年龄≥50岁、血pH值〈7.35为MODS合并脓毒性休克的患者死亡的高危因素。     

Normal-range blood lactate concentration in septic shock is prognostic and predictive

We hypothesized that lactate levels even within the normal range are prognostic and that low lactate levels predict a beneficial response to vasopressin infusion in septic shock. We conducted a retrospective analysis using the Vasopressin in Septic Shock Trial (VASST) as a derivation cohort (n = 665), then validated using another single-center septic shock cohort, St Paul's Hospital (SPH) cohort (n = 469). Lactate levels were divided into quartiles. The primary outcome variable was 28-day mortality in both cohorts. We used receiver operating characteristic (ROC) curve analysis to compare the prognostic value of lactate concentrations versus Acute Physiology and Chronic Health Evaluation II scores. We then explored whether lactate concentrations might predict beneficial response to vasopressin compared with noradrenaline in VASST. Normal lactate range is less than 2.3 mmol/L. At enrollment, patients in the second quartile (1.4 < lactate < 2.3 mmol/L) had significantly increased mortality and organ dysfunction compared with patients who had lactate ≤ 1.4 mmol/L (quartile 1) (P < 0.0001). Quartile 2 outcomes were as severe as quartile 3 (2.3 ≤ lactate < 4.4 mmol/L) outcomes. Baseline lactate values (ar ea under the ROC curve = 0.63, 0.66; VASST, SPH) were as good as Acute Physiology and Chronic Health Evaluation II scores (area under the ROC curve = 0.66, 0.73; VASST, SPH) as prognostic indicators of 28-day mortality. Lactate concentrations of 1.4 mmol/L or less predicted a beneficial response in those randomized to vasopressin compared with noradrenaline in VASST (P < 0.05). Lactate concentrations within the "normal" range can be a useful prognostic indicator in septic shock. Furthermore, patients whose lactate level is less than or equal to 1.4 mmol/L may benefit from vasopressin infusion.     

On sepsis,troponin and vasopressin: the bitter truth

One of the rationales for the use of vasopressin in septic shock has been its potential cardioprotective mechanisms. Lower heart rates, higher arterial pressures, and fewer norepinephrine doses during vasopressin therapy were hypothesized to protect the heart from myocardial ischemia. In a prospective sub-study of the VASST (Vasopressin in Septic Shock Trial) project, Mehta and colleagues specifically evaluated this hypothesis but failed to find lower cardiac biomarkers or fewer ischemic electrocardiogram changes in patients receiving vasopressin compared with subjects receiving norepinephrine alone. After recent evidence of a lacking survival benefit, the present study results further challenge the future role of vasopressin as a vasopressor in septic shock.In a previous issue of Critical Care, novel insights into the effects of vasopressin in septic shock are presented [1]. Throughout the last 15 years, vasopressin has experienced a lively history as a vasopressor in critical care (Figure ​(Figure1).1). During a time when the intensivists'' belief in the beneficial effects of vasopressors and (sub)normal arterial pressures on tissue perfusion remained unchal-lenged, vasopressin was propagated as a non-adrenergic vasopressor in various shock states. This evolution was fostered by an unrestricted sedation regime accepting over-sedation and, in turn, additional vasodilation. Today, the approach to vasopressors and tissue perfusion has dramatically changed given our evolving understanding that macrocirculation and microcirculation correlate only poorly in sepsis. This may explain why a multi-centered randomized controlled trial [2] and meta-analysis [3] failed to detect a mortality benefit of vasopressin in septic shock despite increasing arterial pressure and reducing norepinephrine doses. One of the principal rationales for vasopressin use has been its non-adrenergic mechanism of action [4]. A substantial decrease in heart rate in response to vasopressin promoted the hypothesis that vasopressin protects from myocardial ischemia.Open in a separate windowFigure 1Timeline of the history of vasopressin, its evolution as a vasopressor agent, and important changes in critical care practice in the last 15 years which have influenced the role of vasopressin. AJRCCM, American Journal of Respiratory and Critical Care Medicine; AKI, acute kidney injury; CCM, Critical Care Medicine; ICM, Intensive Care Medicine; ICU, intensive care unit; RCT, randomized controlled trial; VASST, Vasopressin in Septic Shock Trial.This hypothesis was specifically tested by Mehta and colleagues in a prospective sub-study of the randomized controlled Vasopressin in Septic Shock Trial (VASST) [1]. In 121 patients, heart enzymes and 12-lead electrocardiograms (ECGs) were measured during early septic shock to compare vasopressin and norepinephrine; 21% to 36% of patients showed elevated troponin levels, and there were no inter-group differences. ECG changes suggestive of myocardial ischemia were recorded in 48% of patients, and there were no differences between groups [1].In line with the study''s inclusion and exclusion criteria, the results are restricted to myocardial ischemia in septic shock patients with a low to moderate coronary risk profile. Patients with acute coronary syndromes or de-compensated heart failure were excluded but made up only a minority of the total septic shock population (15%) screened for eligibility in the VASST project. Given that patients with elevated troponin levels in the present study had a higher rate of underlying ischemic heart disease than patients with normal cardiac biomarkers, it cannot be excluded that a combined vasopressin/nor-epinephrine infusion reduces the rate/severity of myocardial ischemia in patients with a high coronary risk profile [5].The authors are to be congratulated on a well-conceived and thoughtfully analyzed study. Hemodynamic data shown in the supplementary material reveal that patients given vasopressin exhibited lower heart rates and norepinephrine doses and higher arterial pressures, confirming that the study population met all criteria to adequately test the postulated hypothesis. Aside from certain limitations (for example, non-standardized measurements of troponin), a potentially relevant shortcoming is the comparatively small population of patients. Although theoretically the study may be underpowered to detect a significant inter-group difference in troponin levels of 0 to 0.2 μg/L, it is questionable whether such a difference is clinically relevant and whether inclusion of more patients would have increased the practical relevance of the results.Another noteworthy finding of this study is the observation that an elevation of cardiac biomarkers or ischemic ECG changes was not independently associated with septic shock mortality but that disease severity assessed by the APACHE II (Acute Physiology and Chronic Health Evaluation II) score was. This is in contrast to earlier studies. As suggested by the authors, the key difference between their study and most previous studies is the adjustment of the statistical analysis for disease severity. Thus, the prognostic value of troponins in septic shock may still be preserved, but the contributory role of myocardial ischemia to septic shock outcome has become seriously questioned by the present results.The 2012 Surviving Sepsis Campaign guidelines include an ungraded statement that vasopressin can be added to norepinephrine with the intent of raising mean arterial pressure or decreasing norepinephrine [6]. Given that vasopressin-mediated increases in arterial pressure to (sub)normal values are unlikely to improve tissue perfusion [7] and may even result in end-organ hypoperfusion in case of microcirculatory failure [8], the role of vasopressin to increase arterial pressure in sepsis can be challenged. Although a vasopressin-mediated reduction of high norepinephrine doses may have more effects than simply decreasing heart rate [9], the present study results also question this rationale.Has vasopressin finally lost its justification as a vasopressor in septic shock? It is defi nitely premature to announce vasopressin''s funeral in sepsis management. However, it is time to realize that there might be shock states other than sepsis in which vasopressin is more likely to exert beneficial effects. Scientific data [9-11] and clinical experience indicate that postcardiotomy vasodilatory shock could be such a state. Although the macrocirculatory responses to vasopressin in septic and postcardiotomy vasodilatory shock are comparable [12], the underlying microcirculatory pathologies are likely to differ dramatically. Severe microcirculatory dysfunction in sepsis may predispose patients to vasoconstrictor-induced aggravation of tissue hypoperfusion, whereas better preserved microcirculatory integrity in postcardiotomy vasodilatory shock [13] may allow improved tissue perfusion in response to a vasopressor-induced increase in arterial pressure.So, let us not despair of the waning star of vasopressin in sepsis, but let us focus on what really matters in shock: reversal of tissue hypoperfusion instead of correction of macrocirculatory deviations [14]. Vasopressin is not lost, but it seems we have to use it where it is likely to affect tissue perfusion more favorably than in septic shock! This could be the case in pathologies with homogeneous vasodilation and a low grade of microcirculatory dysfunction, such as postcardiotomy vasodilatory or anaphylactic shock.     

小剂量氢化可的松对顽固性感染性休克患者去甲肾上腺素使用率及乳酸清除率的影响

目的 观察小剂量氢化可的松对顽固性感染性休克患者去甲肾上腺素使用率和乳酸清除率的影响,探讨补充应激剂量皮质醇激素逆转感染性休克和改善组织氧供的作用.方法 选择经充分液体复苏后仍需去甲肾上腺素维持血压的顽固性感染性休克患者77例,随机双盲分为两组,治疗组在对照组治疗基础上静脉注射小剂量氢化可的松,疗程14 d.比较两组治疗过程中去甲肾上腺紊使用情况及平均动脉压(MAP)和乳酸清除率的变化.结果 两组患者在治疗24 h、7 d、14 d去甲肾上腺素使用率均较治疗即刻明显降低,MAP明显升高(P均<0.01).治疗组治疗7 d时去甲肾上腺素使用率明显低于对照组,且去甲肾上腺素使用时间较对照组缩短(P均<0.05);在治疗24 h、7 d时MAP、乳酸清除率较对照组明显升高(P<0.05或P<0.01).两组患者病死率和重症监护病房(ICU)住院天数比较无显著差异.结论 针对伴有顽固性低血压的感染性休克患者,小剂量应用氢化可的松可缩短缩血管药物的应用时间,减少缩血管药物的用量,改善组织氧供,从而更快地逆转休克状态.