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1.  Early hemodynamic resuscitation in septic shock: understanding and modifying oxygen delivery 
Critical Care  2014;18(1):111.
In a previous issue of Critical Care, researchers have focused on the venous-to-arterial carbon dioxide difference (Pv-aCO2) as a surrogate marker for systemic perfusion in patients with septic shock. Although the complex mechanisms responsible for an increased Pv-aCO2 in septic shock need to be further unraveled, the potential prognostic value of Pv-aCO2 seems clinically relevant and useful in daily practice in view of its easy availability.
PMCID: PMC4015123  PMID: 24602317
2.  Effect of off-hour staffing in Chinese ICUs 
Critical Care  2013;17(6):1011.
Analysis of Chinese ICU staffing in relation to final outcome yields comparable results as those reported in Western ICUs. This underlines the general principle that we would all like to apply in our hospitals; that is, availability of knowledgeable staff that are adequately trained to recognize and treat an acutely deteriorating critically ill patient as soon as possible.
PMCID: PMC4056116  PMID: 24499737
3.  Conventional Hemodynamic Resuscitation May Fail to Optimize Tissue Perfusion: An Observational Study on the Effects of Dobutamine, Enoximone, and Norepinephrine in Patients with Acute Myocardial Infarction Complicated by Cardiogenic Shock 
PLoS ONE  2014;9(8):e103978.
To investigate the effects of inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock.
Methods and Results
Thirty patients with cardiogenic shock were included. Patients received dobutamine, enoximone, or norepinephrine. We performed hemodynamic measurements at baseline and after titration of the inotropic agent until cardiac index (CI) ≥2.5 L.min−1.m−2 or mixed-venous oxygen saturation (SvO2) ≥70% (dobutamine or enoximone), and mean arterial pressure (MAP) ≥70 mmHg (norepinephrine). As parameters of tissue perfusion, we measured central-peripheral temperature gradient (delta-T) and sublingual perfused capillary density (PCD). All patients reached predefined therapeutic targets. The inotropes did not significantly change delta-T. Dobutamine did not change PCD. Enoximone increased PCD (9.1 [8.9–10.2] vs. 11.4 [8.4–13.9]−2; p<0.05), and norepinephrine tended to decrease PCD (9.8 [8.5–11.9] vs. 8.8 [8.2–9.6]−2, p = 0.08). Fifteen patients (50%) died within 30 days after admission. Patients who had low final PCD (≤10.3−2; 64%) were more likely to die than patients who had preserved PCD (>10.3−2; mortality 72% vs. 17%, p = 0.003).
This study demonstrates the effects of commonly used inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Despite hemodynamic optimization, tissue perfusion was not sufficiently restored in most patients. In these patients, mortality was high. Interventions directed at improving microcirculation may eventually help bridging the gap between improved hemodynamics and dismal patient outcome in cardiogenic shock.
PMCID: PMC4118994  PMID: 25084171
4.  Choosing the correct metrics for glucose control 
Critical Care  2014;18(2):414.
PMCID: PMC4056047  PMID: 25029332
5.  Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial 
Trials  2013;14:400.
Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis.
This will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged ≥18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates.
This will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival.
Trial registration NCT01785290.
EudraCT number: 2012-004012-66.
PMCID: PMC4222562  PMID: 24261644
Critically ill; Delirium; Haloperidol; Intensive care; Mortality; Prevention; Prophylaxis; Randomized trial
6.  Cumulative lactate and hospital mortality in ICU patients 
Both hyperlactatemia and persistence of hyperlactatemia have been associated with bad outcome. We compared lactate and lactate-derived variables in outcome prediction.
Retrospective observational study. Case records from 2,251 consecutive intensive care unit (ICU) patients admitted between 2001 and 2007 were analyzed. Baseline characteristics, all lactate measurements, and in-hospital mortality were recorded. The time integral of arterial blood lactate levels above the upper normal threshold of 2.2 mmol/L (lactate-time-integral), maximum lactate (max-lactate), and time-to-first-normalization were calculated. Survivors and nonsurvivors were compared and receiver operating characteristic (ROC) analysis were applied.
A total of 20,755 lactate measurements were analyzed. Data are srpehown as median [interquartile range]. In nonsurvivors (n = 405) lactate-time-integral (192 [0–1881] min·mmol/L) and time-to-first normalization (44.0 [0–427] min) were higher than in hospital survivors (n = 1846; 0 [0–134] min·mmol/L and 0 [0–75] min, respectively; all p < 0.001). Normalization of lactate <6 hours after ICU admission revealed better survival compared with normalization of lactate >6 hours (mortality 16.6% vs. 24.4%; p < 0.001). AUC of ROC curves to predict in-hospital mortality was the largest for max-lactate, whereas it was not different among all other lactate derived variables (all p > 0.05). The area under the ROC curves for admission lactate and lactate-time-integral was not different (p = 0.36).
Hyperlactatemia is associated with in-hospital mortality in a heterogeneous ICU population. In our patients, lactate peak values predicted in-hospital mortality equally well as lactate-time-integral of arterial blood lactate levels above the upper normal threshold.
PMCID: PMC3599274  PMID: 23446002
Lactate; Critically ill; Intensive care units; In-hospital mortality
7.  The effect of acute kidney injury on long-term health-related quality of life: a prospective follow-up study 
Critical Care  2013;17(1):R17.
Acute kidney injury (AKI) is a serious complication in critically ill patients admitted to the Intensive Care Unit (ICU). We hypothesized that ICU survivors with AKI would have a worse health-related quality of life (HRQOL) outcome than ICU survivors without AKI.
We performed a long-term prospective observational study. Patients admitted for > 48 hours in a medical-surgical ICU were included and divided in two groups: patients who fulfilled RIFLE criteria for AKI and patients without AKI. We used the Short-Form 36 to evaluate HRQOL before admission (by proxy within 48 hours after admission of the patient), at ICU discharge, hospital discharge, 3 and 6 months following ICU discharge (all by patients). Recovery in HRQOL from ICU-admission onwards was assessed using linear mixed modelling.
Between September 2000 and January 2007 all admissions were screened for study participation. We included a total of 749 patients. At six months after ICU discharge 73 patients with AKI and 325 patients without AKI could be evaluated. In survivors with and without AKI, the pre-admission HRQOL (by proxy) and at six months after ICU discharge was significantly lower compared with an age matched general population. Most SF-36 dimensions changed significantly over time from ICU discharge. Change over time of HRQOL between the different AKI Rifle classes (Risk, Injury, Failure) showed no significant differences. At ICU discharge, scores were lowest in the group with AKI compared with the group without AKI for the physical functioning, role-physical and general health dimensions. However, there were almost no differences in HRQOL between both groups at six months.
The pre-admission HRQOL (by proxy) of AKI survivors was significantly lower in two dimensions compared with the age matched general population. Six months after ICU discharge survivors with and without AKI showed an almost similar HRQOL. However, compared with the general population with a similar age, HRQOL was poorer in both groups.
PMCID: PMC4057105  PMID: 23356544
8.  Systemic and Urinary Neutrophil Gelatinase-Associated Lipocalins Are Poor Predictors of Acute Kidney Injury in Unselected Critically Ill Patients 
Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLERISK days, RIFLEINJURY days, and RIFLEFAILURE days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27–0.63) and 0.53 (CI 0.38–0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33–0.62) and 0.48 (CI 0.33–0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37–0.58) and 0.26 (CI 0.03–0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.
PMCID: PMC3483834  PMID: 23119153
9.  Tricuspid Valve Regurgitation as a Presenting Symptom of Metastasized Carcinoid Tumor 
Case Reports in Gastroenterology  2012;6(3):643-649.
A 66-year-old woman was diagnosed with hepatic metastasized carcinoid tumor of the ileocecal junction resulting in elevated plasma chromogranin A levels and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Further examination showed right-sided heart failure with severe tricuspid valve regurgitation. Carcinoid tumors produce serotonin which leads to flushing, secretory diarrhea, bronchospasm and hypotension, known as carcinoid syndrome. Serotonin is metabolized to 5-HIAA, which is inactive, in the liver and the lungs. However, hepatic metastases may result in direct exposure of the heart to serotonin, which induces plaque-like deformities on the tricuspid valve, and in turn induces valve regurgitation. This condition is known as carcinoid heart disease. Tricuspid valve regurgitation may induce risk of massive blood loss in case of liver surgery through high-volume backflow in the hepatic veins. This report shows the clinical relevance of carcinoid heart disease in the perioperative setting.
PMCID: PMC3492999  PMID: 23139656
Carcinoid tumor; Carcinoid heart disease; Serotonin; Tricuspid valve regurgitation
10.  Mild hypoglycemia is strongly associated with increased intensive care unit length of stay 
Hypoglycemia is associated with increased mortality in critically ill patients. The impact of hypoglycemia on resource utilization has not been investigated. The objective of this investigation was to evaluate the association of hypoglycemia, defined as a blood glucose concentration (BG) < 70 mg/dL, and intensive care unit (ICU) length of stay (LOS) in three different cohorts of critically ill patients.
This is a retrospective investigation of prospectively collected data, including patients from two large observational cohorts: 3,263 patients admitted to Stamford Hospital (ST) and 2,063 patients admitted to three institutions in The Netherlands (NL) as well as 914 patients from the GLUCONTROL trial (GL), a multicenter prospective randomized controlled trial of intensive insulin therapy.
Patients with hypoglycemia were more likely to be diabetic, had higher APACHE II scores, and higher mortality than did patients without hypoglycemia. Patients with hypoglycemia had longer ICU LOS (median [interquartile range]) in ST (3.0 [1.4-7.1] vs. 1.2 [0.8-2.3] days, P < 0.0001), NL (5.2 [2.6-10.3] vs. 2.0 [1.3-3.2] days, P < 0.0001), and GL (9 [5-17] vs. 5 [3-9] days, P < 0.0001). For the entire cohort of 6,240 patients ICU LOS was 1.8 (1.0-3.3) days for those without hypoglycemia and 3.0 (1.5-6.7) days for those with a single episode of hypoglycemia (P < 0.0001). This was a consistent finding even when patients were stratified by severity of illness or survivor status. There was a strong positive correlation between the number of episodes of hypoglycemia and ICU LOS among all three cohorts.
This multicenter international investigation demonstrated that hypoglycemia was consistently associated with significantly higher ICU LOS in heterogeneous cohorts of critically ill patients, independently of severity of illness and survivor status. More effective methods to prevent hypoglycemia in these patients may positively impact their cost of care.
PMCID: PMC3273438  PMID: 22115519
hypoglycemia; intensive care unit; length of stay; resource utilization; APACHE II; mortality; intensive insulin therapy
11.  The Academic Medical Center Linear Disability Score for evaluation of physical reserve on admission to the ICU: can we query the relatives? 
Critical Care  2011;15(5):R212.
Evaluating the pre-morbid functional status in critically ill patients is important and frequently done using the physical component score (PCS) of the Short Form 36, although this approach has its limitations. The Academic Medical Center Linear Disability Score (ALDS) is a recently developed generic item bank used to measure the disability status of patients with a broad range of diseases. We aimed to study whether proxy scoring with the ALDS could be used to assess the patients' functional status on admission for cardiac care unit (CCU) or ICU patients and how the ALDS relates to the PCS using the Short Form 12 (SF-12).
Patients and proxies completed the ALDS and SF-12 score in the first 72 hours following ICU scheduled surgery (n = 14), ICU emergency admission (n = 56) and CCU emergency admission (n = 70).
In all patients (n = 140) a significant intra-class correlation was found for the ALDS (0.857), the PCS (0.798) and the mental component score (0.679) between patients and their proxy. In both scheduled and emergency admissions, a significant correlation was found between patients and their proxy for the ALDS, although the lowest correlation was found for the ICU scheduled admissions (0.755) compared with the ICU emergency admissions (0.889). In CCU patients, the highest significant correlation between patients and proxies was found for the ALDS (0.855), for the PCS (0.807) and for the mental component score (0.740).
Relatives in close contact with critically ill patients can adequately reflect the patient's level of disability on ICU and CCU admission when using the ALDS item bank, which performed at least as well as the PCS. The ALDS could therefore be a useful alternative for the PCS of the SF-12.
PMCID: PMC3334756  PMID: 21917138
12.  Mild hypoglycemia is independently associated with increased mortality in the critically ill 
Critical Care  2011;15(4):R173.
Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.
Prospectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.
We analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively.
Mild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality
PMCID: PMC3387616  PMID: 21787410
13.  Clinical review: Strict or loose glycemic control in critically ill patients - implementing best available evidence from randomized controlled trials 
Critical Care  2010;14(3):223.
Glycemic control aiming at normoglycemia, frequently referred to as 'strict glycemic control' (SGC), decreased mortality and morbidity of adult critically ill patients in two randomized controlled trials (RCTs). Five successive RCTs, however, failed to show benefit of SGC with one trial even reporting an unexpected higher mortality. Consequently, enthusiasm for the implementation of SGC has declined, hampering translation of SGC into daily ICU practice. In this manuscript we attempt to explain the variances in outcomes of the RCTs of SGC, and point out other limitations of the current literature on glycemic control in ICU patients. There are several alternative explanations for why the five negative RCTs showed no beneficial effects of SGC, apart from the possibility that SGC may indeed not benefit ICU patients. These include, but are not restricted to, variability in the performance of SGC, differences among trial designs, changes in standard of care, differences in timing (that is, initiation) of SGC, and the convergence between the intervention groups and control groups with respect to achieved blood glucose levels in the successive RCTs. Additional factors that may hamper translation of SGC into daily ICU practice include the feared risk of severe hypoglycemia, additional labor associated with SGC, and uncertainties about who the primarily responsible caregiver should be for the implementation of SGC.
PMCID: PMC2911685  PMID: 20550725
14.  Serum and urine cystatin C are poor biomarkers for acute kidney injury and renal replacement therapy 
Intensive Care Medicine  2010;37(3):493-501.
To evaluate whether cystatin C in serum (sCyC) and urine (uCyC) can predict early acute kidney injury (AKI) in a mixed heterogeneous intensive care unit (ICU), and also whether these biomarkers can predict the need for renal replacement therapy (RRT).
Multicenter prospective observational cohort study in patients ≥18 years old and with expected ICU stay ≥72 h. The RIFLE class for AKI was calculated daily, while sCyC and uCyC were determined on days 0, 1, and alternate days until ICU discharge. Test characteristics were calculated to assess the diagnostic performance of CyC.
One hundred fifty-one patients were studied, and three groups were defined: group 0 (N = 60), non-AKI; group 1 (N = 35), AKI after admission; and group 2 (N = 56), AKI at admission. We compared the two days prior to developing AKI from group 1 with the first two study days from group 0. On Day –2, median sCyC was significantly higher (0.93 versus 0.80 mg/L, P = 0.01), but not on Day –1 (0.98 versus 0.86 mg/L, P = 0.08). The diagnostic performance for sCyC was fair on Day –2 [area under the curve (AUC) 0.72] and poor on Day –1 (AUC 0.62). Urinary CyC had no diagnostic value on either of the two days prior to AKI (AUC <0.50). RRT was started in 14 patients with AKI; sCyC and uCyC determined on Day 0 were poor predictors for the need for RRT (AUC ≤0.66).
In this study, sCyC and uCyC were poor biomarkers for prediction of AKI and the need for RRT.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-2087-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3042095  PMID: 21153403
Urine cystatin C; Serum cystatin C; Acute kidney injury; Renal replacement therapy; Predictive biomarkers; Intensive care unit
15.  No agreement of mixed venous and central venous saturation in sepsis, independent of sepsis origin 
Critical Care  2010;14(6):R219.
Controversy remains regarding the relationship between central venous saturation (ScvO2) and mixed venous saturation (SvO2) and their use and interchangeability in patients with sepsis or septic shock. We tested the hypothesis that ScvO2 does not reliably predict SvO2 in sepsis. Additionally we looked at the influence of the source (splanchnic or non-splanchnic) of sepsis on this relationship.
In this prospective observational two-center study we concurrently determined ScvO2 and SvO2 in a group of 53 patients with severe sepsis during the first 24 hours after admission to the intensive care units in 2 Dutch hospitals. We assessed correlation and agreement of ScvO2 and SvO2, including the difference, i.e. the gradient, between ScvO2 and SvO2 (ScvO2 - SvO2). Additionally, we compared the mean differences between ScvO2 and SvO2 of both splanchnic and non-splanchnic group.
A total of 265 paired blood samples were obtained. ScvO2 overestimated SvO2 by less than 5% with wide limits of agreement. For changes in ScvO2 and SvO2 results were similar. The distribution of the (ScvO2 - SvO2) (< 0 or ≥ 0) was similar in survivors and nonsurvivors. The mean (ScvO2 - SvO2) in the splanchnic group was similar to the mean (ScvO2 - SvO2) in the non-splanchnic group (0.8 ± 3.9% vs. 2.5 ± 6.2%; P = 0.30). O2ER (P = 0.23) and its predictive value for outcome (P = 0.20) were similar in both groups.
ScvO2 does not reliably predict SvO2 in patients with severe sepsis. The trend of ScvO2 is not superior to the absolute value in this context. A positive difference (ScvO2 - SvO2) is not associated with improved outcome.
PMCID: PMC3219992  PMID: 21114844
16.  Treatment of hypophosphatemia in the intensive care unit: a review 
Critical Care  2010;14(4):R147.
Currently no evidence-based guideline exists for the approach to hypophosphatemia in critically ill patients.
We performed a narrative review of the medical literature to identify the incidence, symptoms, and treatment of hypophosphatemia in critically ill patients. Specifically, we searched for answers to the questions whether correction of hypophosphatemia is associated with improved outcome, and whether a certain treatment strategy is superior.
Incidence: hypophosphatemia is frequently encountered in the intensive care unit; and critically ill patients are at increased risk for developing hypophosphatemia due to the presence of multiple causal factors. Symptoms: hypophosphatemia may lead to a multitude of symptoms, including cardiac and respiratory failure. Treatment: hypophosphatemia is generally corrected when it is symptomatic or severe. However, although multiple studies confirm the efficacy and safety of intravenous phosphate administration, it remains uncertain when and how to correct hypophosphatemia. Outcome: in some studies, hypophosphatemia was associated with higher mortality; a paucity of randomized controlled evidence exists for whether correction of hypophosphatemia improves the outcome in critically ill patients.
Additional studies addressing the current approach to hypophosphatemia in critically ill patients are required. Studies should focus on the association between hypophosphatemia and morbidity and/or mortality, as well as the effect of correction of this electrolyte disorder.
PMCID: PMC2945130  PMID: 20682049
17.  Hospital mortality is associated with ICU admission time 
Intensive Care Medicine  2010;36(10):1765-1771.
Previous studies have shown that patients admitted to the intensive care unit (ICU) after “office hours” are more likely to die. However these results have been challenged by numerous other studies. We therefore analysed this possible relationship between ICU admission time and in-hospital mortality in The Netherlands.
This article relates time of ICU admission to hospital mortality for all patients who were included in the Dutch national ICU registry (National Intensive Care Evaluation, NICE) from 2002 to 2008. We defined office hours as 08:00–22:00 hours during weekdays and 09:00–18:00 hours during weekend days. The weekend was defined as from Saturday 00:00 hours until Sunday 24:00 hours. We corrected hospital mortality for illness severity at admission using Acute Physiology and Chronic Health Evaluation II (APACHE II) score, reason for admission, admission type, age and gender.
A total of 149,894 patients were included in this analysis. The relative risk (RR) for mortality outside office hours was 1.059 (1.031–1.088). Mortality varied with time but was consistently higher than expected during “off hours” and lower during office hours. There was no significant difference in mortality between different weekdays of Monday to Thursday, but mortality increased slightly on Friday (RR 1.046; 1.001–1.092). During the weekend the RR was 1.103 (1.071–1.136) in comparison with the rest of the week.
Hospital mortality in The Netherlands appears to be increased outside office hours and during the weekends, even when corrected for illness severity at admission. However, incomplete adjustment for certain confounders might still play an important role. Further research is needed to fully explain this difference.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-1918-1) contains supplementary material, which is available to authorized users.
PMCID: PMC2940016  PMID: 20549184
Hospital mortality; Admission time; ICU; Severity of illness; APACHE II
18.  Implementing glucose control in intensive care: a multicenter trial using statistical process control 
Intensive Care Medicine  2010;36(9):1556-1565.
Glucose control (GC) with insulin decreases morbidity and mortality of critically ill patients. In this study we investigated GC performance over time during implementation of GC strategies within three intensive care units (ICUs) and in routine clinical practice.
All adult critically ill patients who stayed for >24 h between 1999 and 2007 were included. Effects of implementing local GC guidelines and guideline revisions on effectiveness/efficiency-related indicators, safety-related indicators, and protocol-related indicators were measured.
Data of 17,111 patient admissions were evaluated, with 714,141 available blood glucose levels (BGL) measurements. Mean BGL, time to reach target, hyperglycemia index, sampling frequency, percentage of hyperglycemia events, and in-range measurements statistically changed after introducing GC in all ICUs. The introduction of simple rules on GC had the largest effect. Subsequent changes in the protocol had a smaller effect than the introduction of the protocol itself. As soon as the protocol was introduced, in all ICUs the percentage of hypoglycemia events increased. Various revisions were implemented to reduce hypoglycemia events, but levels never returned to those from pre-implementation. More intensive implementation strategies including the use of a decision support system resulted in better control of the process.
There are various strategies to achieve GC in routine clinical practice but with variable success. All of them were associated with an increase in hypoglycemia events, but GC was never stopped. Instead, these events have been accepted and managed. Statistical process control is a useful tool for monitoring phenomena over time and captures within-institution changes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-1924-3) contains supplementary material, which is available to authorized users.
PMCID: PMC2926931  PMID: 20533024
Glucose control; Glucose regulation; Critical care; Clinical guideline; Statistical process control; Decision support system
19.  Accumulation of advanced glycation end (AGEs) products in intensive care patients: an observational, prospective study 
Oxidative stress plays an important role in the course and eventual outcome in a majority of patients admitted to the intensive care unit (ICU). Markers to estimate oxidative stress are not readily available in a clinical setting. AGEs accumulation has been merely described in chronic conditions, but can also occur acutely due to oxidative stress. Since AGEs have emerged to be stable end products, these can be a marker of oxidative stress. Skin autofluorescence (AF) is a validated marker of tissue content of AGEs. We hypothesized that AGEs accumulate acutely in ICU patients.
We performed an observational prospective study in a medical surgical ICU in a university affiliated teaching hospital. All consecutively admitted ICU patients in a 2 month period were included. Skin AF was measured using an AGE reader in 35 consecutive ICU patients > 18 yrs. As a comparison, historical data of a control group (n = 231) were used. These were also used to calculate age-adjusted AF-levels (AFadj). Values are expressed as median and interquartile range [P25-P75]. Differences between groups were tested by non parametric tests. P < 0.05 was considered statistically significant.
AFadj values were higher in ICU patients (0.33 [0.00 - 0.68]) than in controls (-0.07 [-0.29 - 0.24]; P < 0.001). No differences in skin AFadj were observed between acute or planned admissions, or presence of sepsis, nor was skin AFadj related to severity of disease as estimated by APACHE-II score, length of ICU, hospital stay or mortality.
Acute AGE accumulation in ICU patients was shown in this study, although group size was small. This can possibly reflect oxidative stress in ICU patients. Further studies should reveal whether AGE-accumulation will be a useful parameter in ICU patients and whether skin AF has a predictive value for outcome, which was not shown in this small study.
PMCID: PMC2887805  PMID: 20500823
20.  Conceptual issues specifically related to health-related quality of life in critically ill patients 
Critical Care  2009;13(1):118.
During recent years increasing attention has been given to the quality of survival in critical care. Health-related quality of life (HRQOL) is an important issue both for patients and their families. Furthermore, admission to the intensive care unit can have adverse psychological effects in critically ill patients. Recent studies conducted in critically ill patients have measured HRQOL. However, usually absent from such reports are evaluations of conceptual issues, addressing factors such as why HRQOL should be measured in critically ill patients, how to define and standardize domains of HRQOL, whether proxies can provide useful information about HRQOL in critically ill patients, whether response shift occurs in critically ill patients, and whether post-traumatic stress disorder (PTSD) occurs in critically ill patients. Some studies reported moderate agreement between patients and their proxies, although lower levels of agreement may be reported for psychosocial or physical functioning. Response shift (adaptation and change in perception) appears to be an important phenomenon and likely to be present, but it is seldom measured when estimating HRQOL in critically ill patients. Furthermore, vigilance for symptoms of PTSD and early interventions to prevent PTSD are needed.
PMCID: PMC2688122  PMID: 19239721
21.  Glucontrol, no control, or out of control? 
Intensive Care Medicine  2009;36(1):173-174.
PMCID: PMC2807589  PMID: 19777206
22.  Occurrence of delirium is severely underestimated in the ICU during daily care 
Intensive Care Medicine  2009;35(7):1276-1280.
Delirium is associated with prolonged intensive care unit (ICU) stay and higher mortality. Therefore, the recognition of delirium is important. We investigated whether intensivists and ICU nurses could clinically identify the presence of delirium in ICU patients during daily care.
All ICU patients in a 3-month period who stayed for more than 48 h were screened daily for delirium by attending intensivists and ICU nurses. Patients were screened independently for delirium by a trained group of ICU nurses who were not involved in the daily care of the patients under study. The Confusion Assessment Method for the ICU (CAM-ICU) was used as a validated screening instrument for delirium. Values are expressed as median and interquartile range (IQR; P25–P75).
During the study period, 46 patients (30 male, 16 female), median age 73 years (IQR = 64–80), with an ICU stay of 6 days (range 4–11) were evaluated. CAM-ICU scores were obtained during 425 patient days. Considering the CAM-ICU as the reference standard, delirium occurred in 50% of the patients with a duration of 3 days (range 1–9). Days with delirium were poorly recognized by doctors (sensitivity 28.0%; specificity 100%) and ICU nurses (sensitivity 34.8%; specificity 98.3%). Recognition did not differ between hypoactive or active status of the patients involved.
Delirium is severely under recognized in the ICU by intensivists and ICU nurses in daily care. More attention should be paid to the implementation of a validated delirium-screening instrument during daily ICU care.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-009-1466-8) contains supplementary material, which is available to authorized users.
PMCID: PMC2698979  PMID: 19350214
Delirium; Critical care medicine; CAM-ICU; ICU; Recognition
23.  Off hour admission to an intensivist-led ICU is not associated with increased mortality 
Critical Care  2009;13(3):R84.
Caring for the critically ill is a 24-hour-a-day responsibility, but not all resources and staff are available during off hours. We evaluated whether intensive care unit (ICU) admission during off hours affects hospital mortality.
This retrospective multicentre cohort study was carried out in three non-academic teaching hospitals in the Netherlands. All consecutive patients admitted to the three ICUs between 2004 and 2007 were included in the study, except for patients who did not fulfil APACHE II criteria (readmissions, burns, cardiac surgery, younger than 16 years, length of stay less than 8 hours). Data were collected prospectively in the ICU databases. Hospital mortality was the primary endpoint of the study. Off hours was defined as the interval between 10 pm and 8 am during weekdays and between 6 pm and 9 am during weekends. Intensivists, with no responsibilities outside the ICU, were present in the ICU during daytime and available for either consultation or assistance on site during off hours. Residents were available 24 hours a day 7 days a week in two and fellows in one of the ICUs.
A total of 6725 patients were included in the study, 4553 (67.7%) admitted during daytime and 2172 (32.3%) admitted during off hours. Baseline characteristics of patients admitted during daytime were significantly different from those of patients admitted during off hours. Hospital mortality was 767 (16.8%) in patients admitted during daytime and 469 (21.6%) in patients admitted during off hours (P < 0.001, unadjusted odds ratio 1.36, 95%CI 1.20–1.55). Standardized mortality ratios were similar for patients admitted during off hours and patients admitted during daytime. In a logistic regression model APACHE II expected mortality, age and admission type were all significant confounders but off-hours admission was not significantly associated with a higher mortality (P = 0.121, adjusted odds ratio 1.125, 95%CI 0.969–1.306).
The increased mortality after ICU admission during off hours is explained by a higher illness severity in patients admitted during off hours.
PMCID: PMC2717451  PMID: 19500333
24.  Cardiac tamponade, an unusual and fatal complication of esophagus dilatation for benign stenosis: a case report 
Cases Journal  2008;1:419.
We present a patient with a fatal late esophago-pericardial fistula three months after dilatation for benign oesophagus stenosis
Case presentation
A 71-year-old caucasian male with a known benign esophagus stenosis was referred to the ICU. On arrival an asystole developed which proved to be due to a large pericardial effusion. Pericardial fluids were drained, but the patients' condition worsened and he died due to multiple organ failure. Postmortum investigation revealed an esophago-pericardial fistula.
Causes of an acute tamponade should also be sought in semirecent events, such as manipulation to the oesophagus months before the acute critical illness.
PMCID: PMC2628645  PMID: 19108748
25.  Evidence-lost to tight glycemic control? 
Critical Care  2008;12(5):430.
PMCID: PMC2592756  PMID: 18983697

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