J.G. van der Hoeven

Children with unexplained chronic pain: substantial impairment in everyday life

Aims: To describe and quantify impairment in an outpatient population of children with chronic pain of unknown origin (UCP). Methods: A total of 149 children who presented with pain of at least three months’ duration and without a satisfactory explanation at presentation were studied. Number of somatic complaints (Children’s Somatisation Inventory, CSI), pain intensity (VAS, 0–10 cm), functional disability (Child Health Questionnaire (CHQ-CF) and clinical history), and general health perceptions (CHQ) were determined. Results: Mean age of the children was 11.8 years; 73% were girls. Overall, 72% suffered impairment in sports activities, 51% reported absence from school, 40% experienced limitations in social functioning, and 34% had problems with sleeping. Mean number of somatic symptoms differed significantly between boys (8.4) and girls (10.7). The CHQ-CF scores for physical functioning, role/social functioning, and general health perceptions were 76.4, 70.7, and 57.5, respectively, indicating substantial impairment on all domains. The mean pain intensity was 4.7 for current and 7.1 for worst pain. Children solely evaluated by a general practitioner prior to referral reported less, though still substantial, impairment. Low general health perceptions, impaired role/social functioning, high pain intensity, and having headache or musculoskeletal pain were independent predictors of having significant impairment. Conclusions: Referred children with UCP show substantial impairment on multiple domains in daily life.

Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study

Objectives To develop and validate a delirium prediction model for adult intensive care patients and determine its additional value compared with prediction by caregivers. Design Observational multicentre study. Setting Five intensive care units in the Netherlands (two university hospitals and three university affiliated teaching hospitals). Participants 3056 intensive care patients aged 18 years or over. Main outcome measure Development of delirium (defined as at least one positive delirium screening) during patients’ stay in intensive care. Results The model was developed using 1613 consecutive intensive care patients in one hospital and temporally validated using 549 patients from the same hospital. For external validation, data were collected from 894 patients in four other hospitals. The prediction (PRE-DELIRIC) model contains 10 risk factors—age, APACHE-II score, admission group, coma, infection, metabolic acidosis, use of sedatives and morphine, urea concentration, and urgent admission. The model had an area under the receiver operating characteristics curve of 0.87 (95% confidence interval 0.85 to 0.89) and 0.86 after bootstrapping. Temporal validation and external validation resulted in areas under the curve of 0.89 (0.86 to 0.92) and 0.84 (0.82 to 0.87). The pooled area under the receiver operating characteristics curve (n=3056) was 0.85 (0.84 to 0.87). The area under the curve for nurses’ and physicians’ predictions (n=124) was significantly lower at 0.59 (0.49 to 0.70) for both. Conclusion The PRE-DELIRIC model for intensive care patients consists of 10 risk factors that are readily available within 24 hours after intensive care admission and has a high predictive value. Clinical prediction by nurses and physicians performed significantly worse. The model allows for early prediction of delirium and initiation of preventive measures. Trial registration Clinical trials NCT00604773 (development study) and NCT00961389 (validation study).

Delirium in critically ill patients: Impact on long-term health-related quality of life and cognitive functioning.

Objective:To examine the impact of delirium during intensive care unit stay on long-term health-related quality of life and cognitive function in intensive care unit survivors. Design:Prospective 18-month follow-up study. Setting:Four intensive care units of a university hospital. Patients:A median of 18 months after intensive care discharge, questionnaires were sent to 1,292 intensive care survivors with (n = 272) and without (n = 1020) delirium during their intensive care stay. Measurements and Main Results:The Short Form-36v1, checklist individual strength-fatigue, and cognitive failure questionnaire were used. Covariance analysis was performed to adjust for relevant covariates. Of the 915 responders, 171 patients were delirious during their intensive care stay (median age 65 [interquartile range 58–85], Acute Physiology and Chronic Health Evaluation II score 17 [interquartile range 14–20]), and 745 patients were not (median age 65 [interquartile range 57–72], Acute Physiology and Chronic Health Evaluation II score 13 [interquartile range 10–16]). After adjusting for covariates, no differences were found between delirium and nondelirium survivors on the Short Form-36 and checklist individual strength-fatigue. However, survivors who had suffered from delirium reported that they made significantly more social blunders, and their total cognitive failure questionnaire score was significantly higher, compared to survivors who had not been delirious. Survivors of a hypoactive delirium subtype performed significantly better on the domain mental health than mixed and hyperactive delirium patients. Duration of delirium was significantly correlated to problems with memory and names. Conclusions:Intensive care survivors with delirium during their intensive care unit stay had a similar adjusted health-related quality of life evaluation, but significantly more cognitive problems than those who did not suffer from delirium, even after adjusting for relevant covariates. In addition, the duration of delirium was related to long-term cognitive problems.

Accuracy of bedside glucose measurement from three glucometers in critically ill patients

Objective:Implementation of strict glucose control in most intensive care units has resulted in increased use of point-of-care glucose devices in the intensive care unit. The aim of this study was to determine the reliability of point-of-care testing glucose meters among critically ill patients under intensive insulin treatment. Design:Prospective observational study. Patients:Intensive care unit and non-intensive care unit patients in a tertiary care teaching hospital. Measurements:A glucose oxidase method was used to validate the point-of-care testing devices. Three different point-of-care testing devices, Accu-Chek Sensor (Roche Diagnostics), Precision (Abbott Diagnostics), and HemoCue were tested. Glucose measurements were performed in duplicate by an experienced technician under standardized conditions in the hospitals laboratory, using arterial (intensive care unit patients) and arterial or venous (non-intensive care unit patients) heparinized whole blood samples. Main Results:A strong correlation was found between the glucose oxidase method and the Accu-Chek device (r2 = .9596, p < 0.001). Mean absolute difference between the glucose oxidase and Accu-Chek was −0.32 mmol/L (95% confidence interval −0.84 to 1.48 mmol/L). Using the International Organization for Standardization (ISO) criteria, 27 of 197 samples (13.7%) were inaccurate. In all samples that failed to meet the ISO criteria, glucose values measured by the Accu-Chek device were higher compared with the glucose oxidase method. In another set of experiments among intensive care unit patients, strong positive correlations were also found between the other point-of-care testing devices and the glucose oxidase method. However, paired samples from Accu-Chek, HemoCue, and Precision failed the ISO criteria in 9 of 82 (11.0%), 4 of 82 (4.9%), and 11 of 82 (13.4%) of cases, respectively. In non-intensive care unit patients paired samples from Accu-Chek, HemoCue, and Precision failed the ISO criteria in 3 of 120 (2.5%), 11 of 120 (9.2%), and 16 of 120 (13.3%) cases, respectively. Conclusions:Under standardized conditions, glucose results from three point-of-care testing devices were inaccurate in both intensive care unit and non-intensive care unit patients. Among intensive care unit patients, inaccurate glucose readings were most frequently falsely elevated, resulting in misinterpretation of high glucose values with subsequent inappropriate insulin administration or masking of true hypoglycemia.

Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study

RATIONALE Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known. OBJECTIVES To investigate the effects of IFN-γ and GM-CSF on immunoparalysis in vivo in humans. METHODS We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN-γ (100 μg/day; n = 6), GM-CSF (4 μg/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6). MEASUREMENTS AND MAIN RESULTS In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-α plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-γ group, TNF-α concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL-10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-α response during visit 2 was significantly less pronounced in the IFN-γ group (P = 0.01). Moreover, compared with placebo, treatment with IFN-γ increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-γ, but were not statistically significant compared with placebo. CONCLUSIONS IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.

Dynamic indices do not predict volume responsiveness in routine clinical practice

BACKGROUND Dynamic indices, including pulse pressure, systolic pressure, and stroke volume variation (PPV, SPV, and SVV), are accurate predictors of fluid responsiveness under strict conditions, for example, controlled mechanical ventilation using conventional tidal volumes (TVs) in the absence of cardiac arrhythmias. However, in routine clinical practice, these prerequisites are not always met. We evaluated the effect of regularly used ventilator settings, different calculation methods, and the presence of cardiac arrhythmias on the ability of dynamic indices to predict fluid responsiveness in sedated, mechanically ventilated patients. METHODS We prospectively evaluated 47 fluid challenges in 29 consecutive cardiac surgery patients. Patients were divided into different groups based on TV. Dynamic indices were calculated in various ways: calculation over 30 s, breath-by-breath (with and without excluding arrhythmias), and with correction for TV. RESULTS The predictive value was optimal in the group ventilated with TVs >7 ml kg(-1) with correction for TV, calculated breath-by-breath, and with exclusion of arrhythmias [area under the curve (AUC)=0.95, 0.93, and 0.90 for PPV, SPV, and SVV, respectively]. Including patients ventilated with lower TVs decreased the predictive value of all dynamic indices, while calculating dynamic indices over 30 s and not excluding cardiac arrhythmias further reduced the AUC to 0.51, 0.63, and 0.51 for PPV, SPV, and SVV, respectively. CONCLUSIONS PPV, SPV, and SVV are the only reliable predictors of fluid responsiveness under strict conditions. In routine clinical practice, factors including low TV, cardiac arrhythmias, and the calculation method can substantially reduce their predictive value.

Monitoring of the Respiratory Muscles in the Critically Ill

Evidence has accumulated that respiratory muscle dysfunction develops in critically ill patients and contributes to prolonged weaning from mechanical ventilation. Accordingly, it seems highly appropriate to monitor the respiratory muscles in these patients. Today, we are only at the beginning of routinely monitoring respiratory muscle function. Indeed, most clinicians do not evaluate respiratory muscle function in critically ill patients at all. In our opinion, however, practical issues and the absence of sound scientific data for clinical benefit should not discourage clinicians from having a closer look at respiratory muscle function in critically ill patients. This perspective discusses the latest developments in the field of respiratory muscle monitoring and possible implications of monitoring respiratory muscle function in critically ill patients.

Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.

The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function

RATIONALE Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers. OBJECTIVES To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function. METHODS In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 μg/kg bolus followed by 0.1/0.2 μg/kg/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity. MEASUREMENTS AND MAIN RESULTS The placebo group showed a 9% (P=0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuro-mechanical efficiency of the diaphragm during loading improved by 21% (P<0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P<0.05). CONCLUSIONS The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.

Emergency cricothyrotomy: a randomised crossover trial comparing the wire-guided and catheter-over-needle techniques

In a randomised crossover trial, we compared a wire‐guided cricothyrotomy technique (Minitrach) with a catheter‐over‐needle technique (Quicktrach). Performance time, ease of method, accuracy in placement and complication rate were compared. Ten anaesthesiology and 10 ENT residents performed cricothyrotomies with both techniques on prepared pig larynxes. The catheter‐over‐needle technique was faster than the wire‐guided (48 compared to 150 s, p < 0.001) and subjectively easier to perform (VAS‐score 2.1 vs. 5.6, p < 0.001). Correct positioning of the cannula could be achieved in 95% and 85%, respectively (NS). There was one complication in the catheter‐over‐needle group compared to five in the wire‐guided group. We conclude that the wire‐guided minitracheotomy kit is unsuitable for emergency cricothyrotomies performed by inexperienced practitioners. On the other hand, the catheter‐over‐needle technique appears to be quick, safe and reliable.