Johannes G. van der Hoeven

Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study

BackgroundTemperature management is used with increased frequency as a tool to mitigate neurological injury. Although frequently used, little is known about the optimal cooling methods for inducing and maintaining controlled normo- and hypothermia in the intensive care unit (ICU). In this study we compared the efficacy of several commercially available cooling devices for temperature management in ICU patients with various types of neurological injury.MethodsFifty adult ICU patients with an indication for controlled mild hypothermia or strict normothermia were prospectively enrolled. Ten patients in each group were assigned in consecutive order to conventional cooling (that is, rapid infusion of 30 ml/kg cold fluids, ice and/or coldpacks), cooling with water circulating blankets, air circulating blankets, water circulating gel-coated pads and an intravascular heat exchange system. In all patients the speed of cooling (expressed as°C/h) was measured. After the target temperature was reached, we measured the percentage of time the patients temperature was 0.2°C below or above the target range. Rates of temperature decline over time were analyzed with one-way analysis of variance. Differences between groups were analyzed with one-way analysis of variance, with Bonferroni correction for multiple comparisons. A p < 0.05 was considered statistically significant.ResultsTemperature decline was significantly higher with the water-circulating blankets (1.33 ± 0.63°C/h), gel-pads (1.04 ± 0.14°C/h) and intravascular cooling (1.46 ± 0.42°C/h) compared to conventional cooling (0.31 ± 0.23°C/h) and the air-circulating blankets (0.18 ± 0.2°C/h) (p < 0.01). After the target temperature was reached, the intravascular cooling device was 11.2 ± 18.7% of the time out of range, which was significantly less compared to all other methods.ConclusionCooling with water-circulating blankets, gel-pads and intravascular cooling is more efficient compared to conventional cooling and air-circulating blankets. The intravascular cooling system is most reliable to maintain a stable temperature.

Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients

IntroductionDelirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in intensive care unit (ICU) patients is not well studied. We examined plasma biomarkers in delirious and nondelirious patients and the role of these biomarkers on long-term cognitive function.MethodsIn an exploratory observational study, we included 100 ICU patients with or without delirium and with (inflamed) and without (noninflamed) infection/systemic inflammatory response syndrome (SIRS). Delirium was diagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium, blood was obtained for biomarker analysis. No differences in patient characteristics were found between delirious and nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariate logistic regression analyses were performed. Eighteen months after ICU discharge, a cognitive-failure questionnaire was distributed to the ICU survivors.ResultsIn total, 50 delirious and 50 nondelirious patients were included. We found that IL-8, MCP-1, procalcitonin (PCT), cortisol, and S100-β were significantly associated with delirium in inflamed patients (n = 46). In the noninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Aβ1-42/40, and ratio AβN-42/40 were significantly associated with delirium. In multivariate regression analysis, IL-8 was independently associated (odds ratio, 9.0; 95% confidence interval (CI), 1.8 to 44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95% CI 1.1 to 5.9), and Aβ1-42/40 (OR, 0.03; 95% CI, 0.002 to 0.50) with delirium in noninflamed patients. Furthermore, levels of several amyloid-β forms, but not human Tau or S100-β, were significantly correlated with self-reported cognitive impairment 18 months after ICU discharge, whereas inflammatory markers were not correlated to impaired long-term cognitive function.ConclusionsIn inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium, whereas in noninflamed patients, antiinflammatory cytokine IL-10 and Aβ1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in noninflamed patients. Finally, elevated levels of amyloid-β correlated with long-term subjective cognitive-impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies must confirm these results.The study was registered in the Clinical Trial Register (NCT00604773).

Incidence and short-term consequences of delirium in critically ill patients: A prospective observational cohort study §

BACKGROUNDnDelirium is a serious and frequent psycho-organic disorder in critically ill patients. Reported incidence rates vary to a large extent and there is a paucity of data concerning delirium incidence rates for the different subgroups of intensive care unit (ICU) patients and their short-term health consequences.nnnOBJECTIVESnTo determine the overall incidence and duration of delirium, per delirium subtype and per ICU admission diagnosis. Furthermore, we determined the short-term consequences of delirium.nnnDESIGNnProspective observational study.nnnPARTICIPANTS AND SETTINGnAll adult consecutive patients admitted in one year to the ICU of a university medical centre.nnnMETHODSnDelirium was assessed using the Confusion Assessment Method-ICU three times a day. Delirium was divided in three subtypes: hyperactive, hypoactive and mixed subtype. As measures for short-term consequences we registered duration of mechanical ventilation, re-intubations, incidence of unplanned removal of tubes, length of (ICU) stay and in-hospital mortality.nnnRESULTSn1613 patients were included of which 411 (26%) developed delirium. The incidence rate in the neurosurgical (10%) and cardiac surgery group (12%) was the lowest, incidence was intermediate in medical patients (40%), while patients with a neurological diagnosis had the highest incidence (64%). The mixed subtype occurred the most (53%), while the hyperactive subtype the least (10%). The median delirium duration was two days [IQR 1-7], but significantly longer (P<0.0001) for the mixed subtype. More delirious patients were mechanically ventilated and for a longer period of time, were more likely to remove their tube and catheters, stayed in the ICU and hospital for a longer time, and had a six times higher chance of dying compared to non-delirium ICU patients, even after adjusting for their severity of illness score. Delirium was associated with an extended duration of mechanical ventilation, length of stay in the ICU and in-hospital, as well as with in-hospital mortality.nnnCONCLUSIONSnThe delirium incidence in a mixed ICU population is high and differs importantly between ICU admission diagnoses and the subtypes of delirium. Patients with delirium had a significantly higher incidence of short-term health problems, independent from their severity of illness and this was most pronounced in the mixed subtype of delirium. Delirium is significantly associated with worse short-term outcome.

In Vivo Evidence for Nitric Oxide–Mediated Calcium-Activated Potassium-Channel Activation During Human Endotoxemia

Background— During septic shock, the vasoconstrictor response to norepinephrine is seriously blunted. Animal experiments suggest that hyperpolarization of smooth muscle cells by opening of potassium (K) channels underlies this phenomenon. In the present study, we examined whether K-channel blockers and/or nitric oxide (NO) synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia. Methods and Results— Volunteers received 2 ng/kg Escherichia coli endotoxin intravenously. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Infusion of 4 dose steps of norepinephrine into the brachial artery decreased the FBF ratio (ratio of FBF in the experimental arm to FBF in the control arm) to 84±4%, 70±4%, 55±4%, and 38±4% (mean±SEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101±4%, 92±4%, 83±6%, and 56±7%; n=30; P=0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to norepinephrine from 104±5%, 93±7%, 93±12%, and 69±12% to 89±9%, 73±4%, 59±5%, and 46±8% (n=6; P=0.045). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor NG-monomethyl-l-arginine (L-NMMA; 0.2 mg · min−1 · dL−1 intra-arterially) also restored the norepinephrine sensitivity. In the presence of L-NMMA, TEA did not have an additional effect on the norepinephrine-induced vasoconstriction (n=6; P=0.9). Conclusions— The K-channel blocker TEA restores the attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia. Coadministration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on vascular K channels. In the absence of an effect of the selective adenosine triphosphate–dependent K-channel blocker tolbutamide, we conclude that the blunting effect of endotoxin on norepinephrine-induced vasoconstriction is caused by NO-mediated activation of calcium-activated K channels in the vascular wall.

Predictors of poor neurologic outcome in patients after cardiac arrest treated with hypothermia: a retrospective study

INTRODUCTIONnOutcome studies in patients with anoxic-ischemic encephalopathy focus on the early and reliable prediction of an outcome no better than a vegetative state or severe disability. We determined the effect of mild therapeutic hypothermia on the validity of the currently used clinical practice parameters.nnnMETHODSnWe conducted a retrospective cohort study of adult comatose patients after cardiac arrest treated with hypothermia. All data were collected from medical charts and laboratory files and analyzed from the day of admission to the intensive care unit until day 7, discharge from the intensive care unit or death using the Utstein definitions for the registration of the data.nnnRESULTSnWe analyzed the data of 103 patients. The combination of an M1 or M2 on the Glasgow Coma Scale or absent pupillary reactions or absent corneal reflexes on day 3 was present in 80.6% of patients with an unfavourable and 11.1% of patients with a favourable outcome. The combination of M1 or M2 and absent pupillary reactions to light and absent corneal reflexes on day 3 was present in 14.9% of patients with an unfavourable and none of the patients with a favourable outcome. None of the patients with a favourable outcome had a bilaterally absent somatosensory evoked potential of the median nerve. The value of electroencephalogram patterns in predicting outcome was low, except for reactivity to noxious stimuli.nnnCONCLUSIONSnNo single clinical or electrophysiological parameter has sufficient accuracy to determine prognosis and decision making in patients after cardiac arrest, treated with hypothermia.

Clinical review: The ABC of weaning failure - a structured approach

About 20% to 30% of patients are difficult to wean from invasive mechanical ventilation. The pathophysiology of difficult weaning is complex. Accordingly, determining the reason for difficult weaning and subsequently developing a treatment strategy require a dedicated clinician with in-depth knowledge of the pathophysiology of weaning failure. This review presents a structural framework (ABCDE) for the assessment and treatment of difficult-to-wean patients. Earlier recognition of the underlying causes may expedite weaning from mechanical ventilation.

Bench-to-bedside review: Hypercapnic acidosis in lung injury - from 'permissive' to 'therapeutic'

Modern ventilation strategies for patients with acute lung injury and acute respiratory distress syndrome frequently result in hypercapnic acidosis (HCA), which is regarded as an acceptable side effect (permissive hypercapnia). Multiple experimental studies have demonstrated advantageous effects of HCA in several lung injury models. To date, however, human trials studying the effect of carbon dioxide per se on outcome in patients with lung injury have not been performed. While significant concerns regarding HCA remain, in particular the possible unfavorable effects on bacterial killing and the inhibition of pulmonary epithelial wound repair, the potential for HCA in attenuating lung injury is promising. The underlying mechanisms by which HCA exerts its protective effects are complex, but dampening of the inflammatory response seems to play a pivotal role. After briefly summarizing the physiological effects of HCA, a critical analysis of the available evidence on the potential beneficial effects of therapeutic HCA from in vitro, ex vivo and in vivo lung injury models and from human studies will be reviewed. In addition, the potential concerns in the clinical setting will be outlined.

GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation

The vagus nerve can limit inflammation via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Selective pharmacological stimulation of the alpha7nAChR may have therapeutic potential for the treatment of inflammatory conditions. We determined the anti-inflammatory potential of GTS-21, an alpha7nAChR-selective partial agonist, on primary human leukocytes and compared it with nicotine, the nAChR agonist widely used for research into the anti-inflammatory effects of alpha7nAChR stimulation. Furthermore, we investigated whether the effects of both nicotinic agonists were restricted to specific Toll-like receptors (TLRs) stimulated and explored the mechanism behind the anti-inflammatory effect of GTS-21. GTS-21 and nicotine inhibited the release of pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), monocytes and whole blood independent of the TLR stimulated, with higher potency/efficacy for GTS-21 compared to nicotine. The anti-inflammatory cytokine IL-10 was relatively unaffected by both nicotinic agonists. The effects of GTS-21 and nicotine could not be reversed by nAChR antagonists, while the JAK2 inhibitor AG490 abolished the anti-inflammatory effects. GTS-21 downregulated monocyte cell-surface expression of TLR2, TLR4 and CD14. qPCR analysis demonstrated that the anti-inflammatory effect of GTS-21 is mediated at the transcriptional level and involves JAK2-STAT3 activation. In conclusion, GTS-21 has a profound anti-inflammatory effect in human leukocytes and that GTS-21 is more potent/efficacious than nicotine. The absence of a blocking effect of nAChR antagonists in human leukocytes might indicate different pharmacological properties of the alpha7nAChR in human leukocytes compared to other cell types. GTS-21 may be promising from a therapeutic perspective because of its suitability for human use.

Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients.

IntroductionMetabolic alkalosis is a commonly encountered acid–base derangement in the intensive care unit. Treatment with the carbonic anhydrase inhibitor acetazolamide is indicated in selected cases. According to the quantitative approach described by Stewart, correction of serum pH due to carbonic anhydrase inhibition in the proximal tubule cannot be explained by excretion of bicarbonate. Using the Stewart approach, we studied the mechanism of action of acetazolamide in critically ill patients with a metabolic alkalosis.MethodsFifteen consecutive intensive care unit patients with metabolic alkalosis (pH ≥ 7.48 and HCO3- ≥ 28 mmol/l) were treated with a single administration of 500 mg acetazolamide intravenously. Serum levels of strong ions, creatinine, lactate, weak acids, pH and partial carbon dioxide tension were measured at 0, 12, 24, 48 and 72 hours. The main strong ions in urine and pH were measured at 0, 3, 6, 12, 24, 48 and 72 hours. Strong ion difference (SID), strong ion gap, sodium–chloride effect, and the urinary SID were calculated. Data (mean ± standard error were analyzed by comparing baseline variables and time dependent changes by one way analysis of variance for repeated measures.ResultsAfter a single administration of acetazolamide, correction of serum pH (from 7.49 ± 0.01 to 7.46 ± 0.01; P = 0.001) was maximal at 24 hours and sustained during the period of observation. The parallel decrease in partial carbon dioxide tension was not significant (from 5.7 ± 0.2 to 5.3 ± 0.2 kPa; P = 0.08) and there was no significant change in total concentration of weak acids. Serum SID decreased significantly (from 41.5 ± 1.3 to 38.0 ± 1.0 mEq/l; P = 0.03) due to an increase in serum chloride (from 105 ± 1.2 to 110 ± 1.2 mmol/l; P < 0.0001). The decrease in serum SID was explained by a significant increase in the urinary excretion of sodium without chloride during the first 24 hours (increase in urinary SID: from 48.4 ± 15.1 to 85.3 ± 7.7; P = 0.02).ConclusionA single dose of acetazolamide effectively corrects metabolic alkalosis in critically ill patients by decreasing the serum SID. This effect is completely explained by the increased renal excretion ratio of sodium to chloride, resulting in an increase in serum chloride.

Comparison and clinical suitability of eight prediction models for cardiac surgery-related acute kidney injury

BACKGROUNDnCardiac surgery-related acute kidney injury (CS-AKI) results in increased morbidity and mortality. Different models have been developed to identify patients at risk of CS-AKI. While models that predict dialysis and CS-AKI defined by the RIFLE criteria are available, their predictive power and clinical applicability have not been compared head to head.nnnMETHODSnOf 1388 consecutive adult cardiac surgery patients operated with cardiopulmonary bypass, risk scores of eight prediction models were calculated. Four models were only applicable to a subgroup of patients. The area under the receiver operating curve (AUROC) was calculated for all levels of CS-AKI and for need for dialysis (AKI-D) for each risk model and compared for the models applicable to the largest subgroup (n = 1243).nnnRESULTSnThe incidence of AKI-D was 1.9% and for CS-AKI 9.3%. The models of Rahmanian, Palomba and Aronson could not be used for preoperative risk assessment as postoperative data are necessary. The three best AUROCs for AKI-D were of the model of Thakar: 0.93 [95% confidence interval (CI) 0.91-0.94], Fortescue: 0.88 (95% CI 0.87-0.90) and Wijeysundera: 0.87 (95% CI 0.85-0.89). The three best AUROCs for CS-AKI-risk were 0.75 (95% CI 0.73-0.78), 0.74 (95% CI 0.71-0.76) and 0.70 (95% CI 0.73-0.78), for Thakar, Mehta and both Fortescue and Wijeysundera, respectively. The model of Thakar performed significantly better compared with the models of Mehta, Rahmanian, Fortescue and Wijeysundera (all P-values <0.01) at different levels of severity of CS-AKI.nnnCONCLUSIONSnThe Thakar model offers the best discriminative value to predict CS-AKI and is applicable in a preoperative setting and for all patients undergoing cardiac surgery.