Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.

CONTEXT: Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. OBJECTIVE: To determine whether depletion of haCBG is related to mortality in septic shock. DESIGN: A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72 hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28 days from Intensive Care Unit admission. RESULTS: Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P < 0.009, P = 0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. CONCLUSIONS: Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Clinical use of lactate monitoring in critically ill patients.

Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols.

Inability to obtain deferred consent due to early death in emergency research: effect on validity of clinical trial results.

PURPOSE: To illustrate the impact on the validity of trial results due to excluding patients from a randomized controlled trial for whom no deferred consent could be obtained after randomization because study procedures had already been finished. METHODS: The unadjusted and adjusted primary outcome measures of a recent randomized controlled multicentre study in the field of intensive care medicine were compared, including (n = 348) or excluding (n = 289) patients with missing deferred consent. RESULTS: Thirty-nine patients (11%) died early, before the patient or his/her proxy could be approached and consent be obtained. In another 20 patients (6%), it was not possible to inform proxies and ask consent within the period of study procedures. A significant treatment effect (p = 0.006) in the adjusted analysis became non-significant (p = 0.35) when the patients with missing deferred consent were excluded. CONCLUSIONS: Exclusion of patients without obtained deferred consent can reduce statistical power, introduce selection bias, make randomization asymmetrical, decrease external validity and thereby jeopardize study results. This may have implications for emergency research in various disciplines.

Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.

RATIONALE: It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves outcome. OBJECTIVES: To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU) patients admitted with a lactate level of greater than or equal to 3.0 mEq/L. METHODS: Patients were randomly allocated to two groups. In the lactate group, treatment was guided by lactate levels with the objective to decrease lactate by 20% or more per 2 hours for the initial 8 hours of ICU stay. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value) during this period. The primary outcome measure was hospital mortality. MEASUREMENTS AND MAIN RESULTS: The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat population (348 patients), hospital mortality in the control group was 43.5% (77/177) compared with 33.9% (58/171) in the lactate group (P = 0.067). When adjusted for predefined risk factors, hospital mortality was lower in the lactate group (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87; P = 0.006). In the lactate group, Sequential Organ Failure Assessment scores were lower between 9 and 72 hours, inotropes could be stopped earlier, and patients could be weaned from mechanical ventilation and discharged from the ICU earlier. CONCLUSIONS: In patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. Clinical trial registered with www.clinicaltrials.gov (NCT00270673).

Low tissue oxygen saturation at the end of early goal-directed therapy is associated with worse outcome in critically ill patients.

INTRODUCTION: The prognostic value of continuous monitoring of tissue oxygen saturation (StO2) during early goal-directed therapy of critically ill patients has not been investigated. We conducted this prospective study to test the hypothesis that the persistence of low StO2 levels following intensive care admission is related to adverse outcome. METHODS: We followed 22 critically ill patients admitted with increased lactate levels (>3 mmol/l). Near-infrared spectroscopy (NIRS) was used to measure the thenar eminence StO2 and the rate of StO2 increase (RincStO2) after a vascular occlusion test. NIRS dynamic measurements were recorded at intensive care admission and each 2-hour interval during 8 hours of resuscitation. All repeated StO2 measurements were further compared with Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II and hemodynamic physiological variables: heart rate (HR), mean arterial pressure (MAP), central venous oxygen saturation (ScvO2) and parameters of peripheral circulation (physical examination and peripheral flow index (PFI)). RESULTS: Twelve patients were admitted with low StO2 levels (StO2 <70%). The mean scores for SOFA and APACHE II scores were significantly higher in patients who persisted with low StO2 levels (n = 10) than in those who exhibited normal StO2 levels (n = 12) at 8 hours after the resuscitation period (P < 0.05; median (interquartile range): SOFA, 8 (7 to 11) vs. 5 (3 to 8); APACHE II, 32(24 to 33) vs. 19 (15 to 25)). There was no significant relationship between StO2 and mean global hemodynamic variables (HR, P = 0.26; MAP, P = 0.51; ScvO2, P = 0.11). However, there was a strong association between StO2 with clinical abnormalities of peripheral perfusion (P = 0.004), PFI (P = 0.005) and RincStO2 (P = 0.002). The persistence of low StO2 values was associated with a low percentage of lactate decrease (P < 0.05; median (interquartile range): 33% (12 to 43%) vs. 43% (30 to 54%)). CONCLUSIONS: We found that patients who consistently exhibited low StO2 levels following an initial resuscitation had significantly worse organ failure than did patients with normal StO2 values, and found that StO2 changes had no relationship with global hemodynamic variables.

Blood lactate monitoring in critically ill patients: a systematic health technology assessment.

OBJECTIVE: To decide whether the use of blood lactate monitoring in critical care practice is appropriate. We performed a systematic health technology assessment as blood lactate monitoring has been implemented widely but its clinical value in critically ill patients has never been evaluated properly. DATA SOURCE: PubMed, other databases, and citation review. STUDY SELECTION: We searched for lactate combined with critically ill patients as the target patient population. Two reviewers independently selected studies based on relevance for the following questions: Does lactate measurement: 1) perform well in a laboratory setting? 2) provide information in a number of clinical situations? 3) relate to metabolic acidosis? 4) increase workers' confidence? 5) alter therapeutic decisions? 6) result in benefit to patients? 7) result in similar benefits in your own setting? 8) result in benefits which are worth the extra costs? DATA EXTRACTION AND SYNTHESIS: We concluded that blood lactate measurement in critically ill patients: 1) is accurate in terms of measurement technique but adequate understanding of the (an)aerobic etiology is required for its correct interpretation; 2) provides not only diagnostic but also important prognostic information; 3) should be measured directly instead of estimated from other acid-base variables; 4) has an unknown effect on healthcare workers' confidence; 5) can alter therapeutic decisions; 6) could potentially improve patient outcome when combined with a treatment algorithm to optimize oxygen delivery, but this has only been shown indirectly; 7) is likely to have similar benefits in critical care settings worldwide; and 8) has an unknown cost-effectiveness. CONCLUSIONS: The use of blood lactate monitoring has a place in risk-stratification in critically ill patients, but it is unknown whether the routine use of lactate as a resuscitation end point improves outcome. This warrants randomized controlled studies on the efficacy of lactate-directed therapy.

Association between blood lactate levels, Sequential Organ Failure Assessment subscores, and 28-day mortality during early and late intensive care unit stay: a retrospective observational study.

OBJECTIVES: To evaluate whether the level and duration of increased blood lactate levels are associated with daily Sequential Organ Failure Assessment (SOFA) scores and organ subscores and to evaluate these associations during the early and late phases of the intensive care unit stay. DESIGN: Retrospective observational study. SETTING: Mixed intensive care unit of a university hospital. PATIENTS: 134 heterogeneous intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We calculated the area under the lactate curve above 2.0 mmol/L (lactateAUC>2). Daily SOFA scores were collected during the first 28 days of intensive care unit stay to calculate initial (day 1), maximal, total and mean scores. Daily lactateAUC>2 values were related to both daily SOFA scores and organ subscores using mixed-model analysis of variance. This was also done separately during the early (<2.75 days) and late (>2.75 days) phase of the intensive care unit stay.Compared with normolactatemic patients (n = 78), all median SOFA variables were higher in patients with hyperlactatemia (n = 56) (initial SOFA: 9 [interquartile range 4-12] vs. 4 [2-7]; maximal SOFA: 10 [5-13] vs. 5 [2-9]; total SOFA: 28 [10-70] vs. 9 [3-41]; mean SOFA: 7 [4-10] vs. 4 [2-6], all p < .001). The overall relationship between daily lactateAUC>2 and daily SOFA was an increase of 0.62 SOFA-points per 1 day.mmol/L of lactateAUC>2 (95% confidence interval, 0.41-0.81, p < .00001). During early intensive care unit stay, the relationship between lactateAUC>2 and SOFA was 1.01 (95% confidence interval, 0.53-1.50, p < .0005), and during late intensive care unit stay, this was reduced to 0.50 (95% confidence interval, 0.28-0.72, p < .0005). Respiratory (0.30, 0.22-0.38, p < .001) and coagulation (0.13, 0.09-0.18, p < .001) subscores were most strongly associated with lactateAUC>2. CONCLUSIONS: Blood lactate levels were strongly related to SOFA scores. This relationship was stronger during the early phase of intensive care unit stay, which provides additional indirect support for early resuscitation to prevent organ failure. The results confirm that hyperlactatemia can be considered as a warning signal for organ failure.

Prognostic value of blood lactate levels: does the clinical diagnosis at admission matter?

BACKGROUND: Hyperlactatemia and its reduction after admission in the intensive care unit (ICU) have been related to survival. Because it is unknown whether this equally applies to different groups of critically ill patients, we compared the prognostic value of repeated lactate levels (a) in septic patients versus patients with hemorrhage or other conditions generally associated with low-oxygen transport (LT) (b) in hemodynamically stable versus unstable patients. METHODS: In this prospective observational two-center study (n = 394 patients), blood lactate levels at admission to the ICU (Lac(T0)) and the reduction of lactate levels from T = 0 to T = 12 hours (DeltaLac(T0-12)) and from T = 12 to T = 24 hours (DeltaLac(T12-24)), were related to in-hospital mortality. RESULTS: Reduction of lactate was associated with a lower mortality only in the sepsis group (DeltaLac(T0-12): hazard ratio [HR] 0.34, p = 0.004 and DeltaLac(T12-24): HR 0.24, p = 0.003), but not in the LT group (DeltaLac(T0-12); HR 0.78, p = 0.52 and DeltaLac(T12-24); HR 1.30, p = 0.61). The prognostic values of Lac(T0), DeltaLac(T0-12), and DeltaLac(T12-24) were similar in hemodynamically stable and unstable patients (p = 0.43). CONCLUSIONS: Regardless of the hemodynamic status, lactate reduction during the first 24 hours of ICU stay is associated with improved outcome only in septic patients, but not in patients with hemorrhage or other conditions generally associated with LT. We hypothesize that in this particular group a reduction in lactate is not associated with improved outcome due to irreversible damage at ICU admission.

The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients.

OBJECTIVE: The physical examination of peripheral perfusion based on touching the skin or measuring capillary refill time has been related to the prognosis of patients with circulatory shock. It is unclear, however, whether monitoring peripheral perfusion after initial resuscitation still provides information on morbidity in critically ill patients. Therefore, we investigated whether subjective assessment of peripheral perfusion could help identify critically ill patients with a more severe organ or metabolic dysfunction using the Sequential Organ Failure Assessment (SOFA) score and lactate levels. DESIGN: : Prospective observational study. SETTING: Multidisciplinary intensive care unit in a university hospital. PATIENTS: Fifty consecutive adult patients admitted to the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were considered to have abnormal peripheral perfusion if the examined extremity had an increase in capillary refill time (>4.5 seconds) or it was cool to the examiner hands. To address reliability of subjective inspection and palpation of peripheral perfusion, we also measured forearm-to-fingertip skin-temperature gradient (Tskin-diff), central-to-toe temperature difference (Tc-toe), and peripheral flow index. The measurements were taken within 24 hours of admission to the intensive care after hemodynamic stability was obtained (mean arterial pressure >65 mm Hg). Changes in SOFA score during the first 48 hours were analyzed (delta-SOFA). Individual SOFA score was significantly higher in patients with abnormal peripheral perfusion than in those with normal peripheral perfusion (9 +/- 3 vs. 7 +/- 2, p < 0.05). Tskin-diff, Tc-toe, and peripheral flow index were congruent with the subjective assessment of peripheral perfusion. The proportion of patients with delta-SOFA score >0 was significantly higher in patients with abnormal peripheral perfusion (77% vs. 23%, p < 0.05). The logistic regression analysis showed that the odds of unfavorable evolution are 7.4 (95% confidence interval 2-19; p < 0.05) times higher for a patient with abnormal peripheral perfusion. The proportion of hyperlactatemia was significantly different between patients with abnormal and normal peripheral perfusion (67% vs. 33%, p < 0.05). The odds of hyperlactatemia by logistic regression analysis are 4.6 (95% confidence interval 1.4-15; p < 0.05) times higher for a patient with abnormal peripheral perfusion. CONCLUSIONS: Subjective assessment of peripheral perfusion with physical examination following initial hemodynamic resuscitation in the first 24 hours of admission could identify hemodynamically stable patients with a more severe organ dysfunction and higher lactate levels. Patients with abnormal peripheral perfusion had significantly higher odds of worsening organ failure than did patients with normal peripheral perfusion following initial resuscitation.

Deferred proxy consent in emergency critical care research: ethically valid and practically feasible.

Important ethical aspects apply to the process of obtaining consent in emergency critical care research: the incapacity of almost all patients for giving informed consent and the emergency and life-threatening nature of the conditions involved, resulting in short therapeutic time frames. We argue that deferred proxy consent is the preferable substitute for informed patient consent in emergency critical care research. However, researchers can face two problems when using this consent procedure. First, can proxies give a valid judgment for consent or refusal in the acute phase of the life-threatening illness of their relative, and second, what should researchers do with already obtained data when study procedures are finished (e.g., because the patient has died) before proxies can be informed and consent be sought? We propose approaching the relatives with information about the trial and asking them for consent only if it is ethically valid to do so. The first psychological distress may prohibit a complete understanding of the information, which is necessary for a true and valid informed proxy consent. In addition, we recommend using the study data if study procedures are finished before proxies can be informed and consent be sought, provided sufficient privacy measures have been applied.

The prognostic value of blood lactate levels relative to that of vital signs in the pre-hospital setting: a pilot study.

INTRODUCTION: A limitation of pre-hospital monitoring is that vital signs often do not change until a patient is in a critical stage. Blood lactate levels are suggested as a more sensitive parameter to evaluate a patient's condition. The aim of this pilot study was to find presumptive evidence for a relation between pre-hospital lactate levels and in-hospital mortality, corrected for vital sign abnormalities. METHODS: In this prospective observational study (n = 124), patients who required urgent ambulance dispatching and had a systolic blood pressure below 100 mmHg, a respiratory rate less than 10 or more than 29 breaths/minute, or a Glasgow Coma Scale (GCS) below 14 were enrolled. Nurses from Emergency Medical Services measured capillary or venous lactate levels using a hand-held device on arrival at the scene (T1) and just before or on arrival at the emergency department (T2). The primary outcome measured was in-hospital mortality. RESULTS: The average (standard deviation) time from T1 to T2 was 27 (10) minutes. Non-survivors (n = 32, 26%) had significantly higher lactate levels than survivors at T1 (5.3 vs 3.7 mmol/L) and at T2 (5.4 vs 3.2 mmol/L). Mortality was significantly higher in patients with lactate levels of 3.5 mmol/L or higher compared with those with lactate levels below 3.5 mmol/L (T1: 41 vs 12% and T2: 47 vs 15%). Also in the absence of hypotension, mortality was higher in those with higher lactate levels. In a multivariable Cox proportional hazard analysis including systolic blood pressure, heart rate, GCS (all at T1) and delta lactate level (from T1 to T2), only delta lactate level (hazard ratio (HR) = 0.20, 95% confidence interval (CI) = 0.05 to 0.76, p = 0.018) and GCS (HR = 0.93, 95% CI = 0.88 to 0.99, p = 0.022) were significant independent predictors of in-hospital mortality. CONCLUSIONS: In a cohort of patients that required urgent ambulance dispatching, pre-hospital blood lactate levels were associated with in-hospital mortality and provided prognostic information superior to that provided by the patient's vital signs. There is potential for early detection of occult shock and pre-hospital resuscitation guided by lactate measurement. However, external validation is required before widespread implementation of lactate measurement in the out-of-hospital setting.

Why opioids and sedatives may prolong life rather than hasten death after ventilator withdrawal in critically ill patients.

The process of death in patients in whom cardiorespiratory support is withdrawn is related to the occurrence of tissue hypoxia that results from an imbalance between the demand for oxygen and the delivery of oxygen to the organs. Limiting the demand for oxygen may thus delay the occurrence of tissue hypoxia. Because the demand for oxygen increases significantly after ventilator withdrawal and because sedatives and opioids are known to decrease the demand for oxygen in patients with cardiorespiratory distress, these agents might thus actually prolong life rather than hasten death.

Hyperglycemia in children with meningococcal sepsis and septic shock: the relation between plasma levels of insulin and inflammatory mediators.

CONTEXT: Hyperglycemia and insulin resistance are common findings in critically ill adult patients and are associated with increased morbidity and mortality. OBJECTIVES: The objective of this study was to investigate the hyperglycemic response to critical illness in children. DESIGN: The study was designed as an observational cohort study. SETTING: The study was set in a university-affiliated pediatric intensive care unit. PATIENTS: Six children with meningococcal sepsis (MS) without shock and 10 children with meningococcal septic shock (MSS) were patients. MAIN OUTCOME MEASURES: Differences in blood glucose levels (measured during 72 h after admission) and differences in plasma levels of glucoregulatory hormones (insulin, GH, IGF-I, cortisol, glucagons, leptin), soluble cytokine receptors (sTNF-R55, R75, sIL-1R2), and IL-6 (measured on d 3) between MS and MSS patients were assessed. RESULTS: Blood glucose levels on d 2 and 3 were higher in MSS patients than in MS patients [7.5 (3.9-13.0) vs. 5.1 (4.0-6.0) and 6.5 (4.0-9.9) vs. 5.5 (4.8-6.8) mmol/liter, both P < 0.05]. Maximum blood glucose values recorded in individual patients were higher in MSS patients [9.3 (6.5-13) vs. 7.2 (6.2-9.9), P < 0.05] and correlated with severity of illness (r = 0.833, P < 0.001). Insulin levels in MSS patients were significantly lower (7.2 vs. 19.0 mU/liter, P < 0.001), compatible with insufficient insulin response to hyperglycemia, whereas MS patients showed insulin resistance. Insulin levels correlated inversely with levels of sTNF-R55 and R75 (r = -0.814 and -0.878, both P < 0.001), suggesting suppression of the proinflammatory response on insulin secretion. CONCLUSION: Hyperglycemia associated with hypoinsulinemia rather than insulin resistance may be the normal pathophysiological response in acute MSS in children. Our study emphasizes that application of intensive insulin therapy in critically ill children demands further investigation.