Jan Bakker

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. DesignMultiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. SettingA total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. PatientsA total of 797 patients with septic shock diagnosed for <24 hrs. InterventionsPatients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL·kg−1·hr−1 (2.5 mg·kg−1·hr−1 546C88) and titrated up to a maximum rate of 0.4 mL·kg−1·hr−1 to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. Measurements and Main ResultsHemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p < .001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. ConclusionsIn this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.

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).

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

ObjectiveCirculatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock.MethodsThe European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575–590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit? (2) Should we monitor preload and fluid responsiveness in shock? (3) How and when should we monitor stroke volume or cardiac output in shock? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock? Four types of statements were used: definition, recommendation, best practice and statement of fact.ResultsForty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring.ConclusionsThis consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock.

Noninvasive monitoring of peripheral perfusion

BackgroundEarly hemodynamic assessment of global parameters in critically ill patients fails to provide adequate information on tissue perfusion. It requires invasive monitoring and may represent a late intervention initiated mainly in the intensive care unit. Noninvasive monitoring of peripheral perfusion can be a complementary approach that allows very early application throughout the hospital. In addition, as peripheral tissues are sensitive to alterations in perfusion, monitoring of the periphery could be an early marker of tissue hypoperfusion. This review discusses noninvasive methods for monitoring perfusion in peripheral tissues based on clinical signs, body temperature gradient, optical monitoring, transcutaneous oximetry, and sublingual capnometry.DiscussionClinical signs of poor peripheral perfusion consist of a cold, pale, clammy, and mottled skin, associated with an increase in capillary refill time. The temperature gradients peripheral-to-ambient, central-to-peripheral and forearm-to-fingertip skin are validated methods to estimate dynamic variations in skin blood flow. Commonly used optical methods for peripheral monitoring are perfusion index, near-infrared spectroscopy, laser Doppler flowmetry and orthogonal polarization spectroscopy. Continuous noninvasive transcutaneous measurement of oxygen and carbon dioxide tensions can be used to estimate cutaneous blood flow. Sublingual capnometry is a noninvasive alternative for gastric tonometry.

Use of a peripheral perfusion index derived from the pulse oximetry signal as a noninvasive indicator of perfusion.

ObjectivePeripheral perfusion in critically ill patients frequently is assessed by use of clinical signs. Recently, the pulse oximetry signal has been suggested to reflect changes in peripheral perfusion. A peripheral perfusion index based on analysis of the pulse oximetry signal has been implemented in monitoring systems as an index of peripheral perfusion. No data on the variation of this index in the normal population are available, and clinical application of this variable in critically ill patients has not been reported. We therefore studied the variation of the peripheral perfusion index in healthy adults and related it to the central-to-toe temperature difference and capillary refill time in critically ill patients after changes in clinical signs of peripheral perfusion. DesignProspective study. SettingUniversity-affiliated teaching hospital. PatientsOne hundred eight healthy adult volunteers and 37 adult critically ill patients. InterventionsNone. Measurements and Main ResultsCapillary refill time, peripheral perfusion index, and arterial oxygen saturation were measured in healthy adults (group 1). Capillary refill time, peripheral perfusion index, arterial oxygen saturation, central-to-toe temperature difference, and hemodynamic variables were measured in critically ill patients (group 2) during different peripheral perfusion profiles. Poor peripheral perfusion was defined as a capillary refill time >2 secs and central-to-toe temperature difference ≥7°C. Peripheral perfusion index and arterial oxygen saturation were measured by using the Philips Medical Systems Viridia/56S monitor. In group 1, measurements were made before and after a meal. In group 2, two measurements were made, with the second measurement taken when the peripheral perfusion profile had changed. A total of 216 measurements were carried out in group 1. The distribution of the peripheral perfusion index was skewed and values ranged from 0.3 to 10.0, median 1.4 (inner quartile range, 0.7–3.0). Seventy-four measurements were carried out in group 2. A significant correlation between the peripheral perfusion index and the core-to-toe temperature difference was found (R2= .52;p < .001). A cutoff peripheral perfusion index value of 1.4 (calculated by constructing a receiver operating characteristic curve) best reflected the presence of poor peripheral perfusion in critically ill patients. Changes in peripheral perfusion index and changes in core-to-toe temperature difference correlated significantly (R = .52, p < .001). ConclusionsThe peripheral perfusion index distribution in the normal population is highly skewed. Changes in the peripheral perfusion index reflect changes in the core-to-toe temperature difference. Therefore, peripheral perfusion index measurements can be used to monitor peripheral perfusion in critically ill patients.

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.

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

IntroductionA 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 patients 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.MethodsIn 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.ResultsThe 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.ConclusionsIn 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 patients 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.

Administration of the nitric oxide synthase inhibitor NG-methyl- L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: Results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002)

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure ≥70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DesignMulticentered, randomized, placebo-controlled, safety and efficacy study. SettingForty-eight intensive care units in Europe, North America, and Australia. PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization. InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main ResultsRequirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p = .004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. ConclusionsIn this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

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 (&dgr;-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 &dgr;-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.

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.