Maarten Nijsten

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial

BACKGROUND In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. METHODS We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 μg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. FINDINGS Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5·4%, 95% CI 1·2-9·5, p=0·0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6·6%, 1·3-11·9, p=0·0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7·4, 1·3-13·8, p=0·0188). INTERPRETATION Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship. FUNDING Thermo Fisher Scientific.

Hyperglycaemic index as a tool to assess glucose control : a retrospective study

IntroductionCritically ill patients may benefit from strict glucose control. An objective measure of hyperglycaemia for assessing glucose control in acutely ill patients should reflect the magnitude and duration of hyperglycaemia, should be independent of the number of measurements, and should not be falsely lowered by hypoglycaemic values. The time average of glucose values above the normal range meets these requirements.MethodsA retrospective, single-centre study was performed at a 12-bed surgical intensive care unit. From 1990 through 2001 all patients over 15 years, staying at least 4 days, were included. Admission type, sex, age, Acute Physiology and Chronic Health Evaluation II score and outcome were recorded. The hyperglycaemic index (HGI) was defined as the area under the curve above the upper limit of normal (glucose level 6.0 mmol/l) divided by the total length of stay. HGI, admission glucose, mean morning glucose, mean glucose and maximal glucose were calculated for each patient. The relations between these measures and 30-day mortality were determined.ResultsIn 1779 patients with a median stay in the intensive care unit of 10 days, the 30-day mortality was 17%. A total of 65,528 glucose values were analyzed. Median HGI was 0.9 mmol/l (interquartile range 0.3–2.1 mmol/l) in survivors versus 1.8 mmol/l (interquartile range 0.7–3.4 mmol/l) in nonsurvivors (P < 0.001). The area under the receiver operator characteristic curve was 0.64 for HGI, as compared with 0.61 and 0.62 for mean morning glucose and mean glucose. HGI was the only significant glucose measure in binary logistic regression.ConclusionHGI exhibited a better relation with outcome than other glucose indices. HGI is a useful measure of glucose control in critically ill patients.

Ex vivo Normothermic Machine Perfusion and Viability Testing of Discarded Human Donor Livers

In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion may reduce preservation injury, improve graft viability and potentially allows ex vivo assessment of graft viability before transplantation. We have studied the feasibility of normothermic machine perfusion in four discarded human donor livers. Normothermic machine perfusion consisted of pressure and temperature controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion for 6 h. Two hollow fiber membrane oxygenators provided oxygenation of the perfusion fluid. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal values, reflecting active metabolism by the liver (mean lactate 10.0 ± 2.3 mmol/L at 30 min to 2.3 ± 1.2 mmol/L at 6 h). Bile production was observed throughout the 6 h perfusion period (mean rate 8.16 ± 0.65 g/h after the first hour). Histological examination before and after 6 h of perfusion showed well‐preserved liver morphology without signs of additional hepatocellular ischemia, biliary injury or sinusoidal damage. In conclusion, this study shows that normothermic machine perfusion of human donor livers is technically feasible. It allows assessment of graft viability before transplantation, which opens new avenues for organ selection, therapeutic interventions and preconditioning.

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.

Design and implementation of GRIP: a computerized glucose control system at a surgical intensive care unit

BackgroundTight glucose control by intensive insulin therapy has become a key part of critical care and is an important field of study in acute coronary care. A balance has to be found between frequency of measurements and the risk of hypoglycemia. Current nurse-driven protocols are paper-based and, therefore, rely on simple rules. For safety and efficiency a computer decision support system that employs complex logic may be superior to paper protocols.MethodsWe designed and implemented GRIP, a stand-alone Java computer program. Our implementation of GRIP will be released as free software. Blood glucose values measured by a point-of-care analyzer were automatically retrieved from the central laboratory database. Additional clinical information was asked from the nurse and the program subsequently advised a new insulin pump rate and glucose sampling interval.ResultsImplementation of the computer program was uneventful and successful. GRIP treated 179 patients for a total of 957 patient-days. Severe hypoglycemia (< 2.2 mmol/L) only occurred once due to human error. With a median (IQR) of 4.9 (4.2 – 6.2) glucose measurements per day the median percentage of time in which glucose fell in the target range was 78%. Nurses rated the program as easy to work with and as an improvement over the preceding paper protocol. They reported no increase in time spent on glucose control.ConclusionA computer driven protocol is a safe and effective means of glucose control at a surgical ICU. Future improvements in the recommendation algorithm may further improve safety and efficiency.

Prognostic Value of Admission Glycosylated Hemoglobin and Glucose in Nondiabetic Patients With ST-Segment–Elevation Myocardial Infarction Treated With Percutaneous Coronary Intervention

Background— In nondiabetic patients with ST-segment–elevation myocardial infarction, acute hyperglycemia is associated with adverse outcome. Whether this association is due merely to hyperglycemia as an acute stress response or whether longer-term glycometabolic derangements are also involved is uncertain. It was our aim to determine the association between both acute and chronic hyperglycemia (hemoglobin A1c [HbA1c]) and outcome in nondiabetic patients with ST-segment–elevation myocardial infarction. Methods and Results— This observational study included consecutive patients (n=4176) without known diabetes mellitus admitted with ST-segment–elevation myocardial infarction. All patients were treated with primary percutaneous intervention. Both glucose and HbA1c were measured on admission. Main outcome measure was total long-term mortality; secondary outcome measures were 1-year mortality and enzymatic infarct size. One-year mortality was 4.7%, and mortality after total follow-up (3.3±1.5 years) was 10%. Both elevated HbA1c levels (P<0.001) and elevated admission glucose (P<0.001) were associated with 1-year and long-term mortality. After exclusion of early mortality (within 30 days), HbA1c remained associated with long-term mortality (P<0.001), whereas glucose lost significance (P=0.09). Elevated glucose, but not elevated HbA1c, was associated with larger infarct size. After multivariate analysis, HbA1c (hazard ratio, 1.2 per interquartile range; P<0.01), but not glucose, was independently associated with long-term mortality. Conclusions— In nondiabetic patients with ST-segment–elevation myocardial infarction, both elevated admission glucose and HbA1c levels were associated with adverse outcome. Both of these parameters reflect different patient populations, and their association with outcome is probably due to different mechanisms. Measurement of both parameters enables identification of these high-risk groups for aggressive secondary risk prevention.

Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration: The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial

Background— Administration of the glycoprotein IIb/IIIa inhibitor abciximab is an effective adjunctive treatment strategy during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Although small-scale studies have suggested beneficial effects of intracoronary over intravenous administration of abciximab, this has not been investigated in a medium-scale randomized clinical trial. Methods and Results— A total of 534 ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration within 12 hours of symptom onset were randomized to either an intracoronary or an intravenous bolus of abciximab (0.25 mg/kg). Patients were pretreated with aspirin, heparin, and clopidogrel. The primary end point was the incidence of restored myocardial reperfusion, defined as complete ST-segment resolution. Secondary end points included myocardial reperfusion as assessed by myocardial blush grade, enzymatic infarct size, and major adverse cardiac events at 30 days. The incidence of complete ST-segment resolution was similar in the intracoronary and intravenous groups (64% versus 62%; P=0.562). However, the incidence of myocardial blush grade 2/3 was higher in the intracoronary group than in the intravenous group (76% versus 67%; P=0.022). Furthermore, enzymatic infarct size was smaller in the intracoronary than in the intravenous group (P=0.008). The incidence of major adverse cardiac events was similar in both groups (5.5% versus 6.1%; P=0.786). Conclusions— In ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration, intracoronary administration of abciximab compared with intravenous administration does not improve myocardial reperfusion as assessed by ST-segment resolution. However, intracoronary administration is associated with improved myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927615.

Blunted rise in platelet count in critically ill patients is associated with worse outcome

ObjectiveTo test the hypothesis that a low rate of change of platelet counts (PCs) after admission to the intensive care unit (ICU) is associated with mortality. Low PCs are known to be associated with disease severity in critically ill patients, but the relevance of time-dependent changes of PCs has not been investigated. DesignRetrospective study. SettingA 12-bed surgical ICU of a university hospital. PatientsAll adult patients admitted to the ICU for at least 4 days during a 7-yr period. InterventionsAt admission, Acute Physiology and Chronic Health Evaluation scores were calculated. PCs and leukocyte counts were analyzed from admission to day 10. The daily rise of the PCs (&Dgr;PC/&Dgr;t) from day 2 to day 10 was calculated. Rates for 30-day mortality as well as hospital mortality were determined. Measurements and Main ResultsA total of 1415 admissions were studied. Median PCs (interquartile range) initially decreased and subsequently increased, with a higher PC in 1203 survivors than in 212 nonsurvivors from day 2 onward (302 [range,181–438]·103/mm3/day vs. 129 [range, 62–228]·103/mm3 at day 10;p < 0.001). After stratification of patients per type of surgery, within each group PC was also higher in survivors. Mean &Dgr;PC/&Dgr;t was more than five times higher in survivors compared with nonsurvivors: 30 ± 46·103/mm3/day vs. 6 ± 28·103/mm3/day (p < 0.001). The area under the receiving operating characteristic curve of &Dgr;PC/&Dgr;t for 30-day survival was 0.743 compared with 0.728 for the Acute Physiology and Chronic Health Evaluation. Leukocyte counts showed marginal differences between nonsurvivors and survivors. ConclusionA blunted or absent rise in PCs in critically ill patients is associated with increased mortality. &Dgr;PC/&Dgr;t is a readily available and simple parameter to improve assessment of critically ill patients.

Immediate Postoperative Low Platelet Count is Associated With Delayed Liver Function Recovery After Partial Liver Resection

Objective:To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection. Background:Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans. Methods:In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases, we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin >50 &mgr;mol/L or prothrombin time >20 seconds at any time point between postoperative day 1 and 5. Results:Patients with a low (<100 ×109/L) immediate postoperative platelet count had worse postoperative liver function, higher serum markers of liver injury, and increased mortality compared with patients with normal platelet counts (>1009/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CI, 1.1–122.4; P = 0.04 in multivariate analysis). Conclusion:After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration.

Emergency trauma score: an instrument for early estimation of trauma severity.

Objectives:Early estimation of the mortality risk of severely injured patients is mandatory. To estimate the seriousness of the condition of patients with trauma, we developed the emergency trauma score (EMTRAS) for ease of use, with simple parameters that are available within 30 minutes. Design:Prospective analysis of the German Trauma Registry of multitrauma patients. Setting:EMTRAS was derived from data from 1993 through 2003. Potential parameters that were prognostic for mortality in univariate analysis were evaluated by multivariate binary logistic regression. Selected parameters were then assigned a subscore that varied from 0 to 3. The EMTRAS score was a simple addition of these subscores. EMTRAS was compared with other scores’ receiver operating characteristic curves. After completion, EMTRAS was validated in patients from 2004 and 2005. Patients:A total of 11,533 patients were to be used for developing the score and 3314 patients for validating it. Main Results:The strongest predictors of mortality were age, prehospital Glasgow Coma Scale, base excess (mmol/L), and prothrombin time (% of reference). These parameters were categorized in subscores of 0 through 3. Age: <40, 40 through 60, 61 through 75, and >75 scored 0, 1, 2, and 3, respectively. Glasgow Coma Scale: 13 through 15, 10 through 12, 6 through 9, and 3 through 5 scored 0, 1, 2, and 3, respectively. Base excess: >−1, −5 through −1, −10 through −5.1, and <−10 scored 0, 1, 2, and 3, respectively. Prothrombin time: <80%, 80% through 50%, 49% through 20%, and >20% received a score of 0, 1, 2, and 3, respectively. In the validation dataset, the area under the receiver operating characteristic curve for EMTRAS was 0.828. Conclusions:EMTRAS combines four early parameters from the emergency room and accurately predicts mortality. Knowledge of the anatomical injuries is not necessary. The determination of the EMTRAS will inform caregivers of the seriousness of patients with trauma at an early stage.