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1.  Noninvasive ventilation and the upper airway: should we pay more attention? 
Critical Care  2013;17(6):245.
In an effort to reduce the complications related to invasive ventilation, the use of noninvasive ventilation (NIV) has increased over the last years in patients with acute respiratory failure. However, failure rates for NIV remain high in specific patient categories. Several studies have identified factors that contribute to NIV failure, including low experience of the medical team and patient–ventilator asynchrony. An important difference between invasive ventilation and NIV is the role of the upper airway. During invasive ventilation the endotracheal tube bypasses the upper airway, but during NIV upper airway patency may play a role in the successful application of NIV. In response to positive pressure, upper airway patency may decrease and therefore impair minute ventilation. This paper aims to discuss the effect of positive pressure ventilation on upper airway patency and its possible clinical implications, and to stimulate research in this field.
PMCID: PMC4059377  PMID: 24314000
2.  Automated patient-ventilator interaction analysis during neurally adjusted non-invasive ventilation and pressure support ventilation in chronic obstructive pulmonary disease 
Critical Care  2014;18(5):550.
Delivering synchronous assist during non-invasive ventilation (NIV) is challenging with flow- or pressure-controlled ventilators, especially in patients with chronic obstructive pulmonary disease (COPD). Neurally adjusted ventilatory assist (NAVA) uses diaphragm electrical activity (EAdi) to control the ventilator. We evaluated patient-ventilator interaction in patients with COPD during NIV with pressure support ventilation (PSV) and NAVA using a recently introduced automated analysis.
Twelve COPD patients underwent three 30-minute trials: 1) PSV with dedicated NIV ventilator (NIV-PSVVision), 2) PSV with intensive care unit (ICU) ventilator (NIV-PSVServo-I), and 3) with NIV-NAVA. EAdi, flow, and airway pressure were recorded. Patient-ventilator interaction was evaluated by comparing airway pressure and EAdi waveforms with automated computer algorithms. The NeuroSync index was calculated as the percentage of timing errors between airway pressure and EAdi.
The NeuroSync index was higher (larger error) for NIV-PSVVision (24 (IQR 15 to 30) %) and NIV-PSVServo-I (21 (IQR 15 to 26) %) compared to NIV-NAVA (5 (IQR 4 to 7) %; P <0.001). Wasted efforts, trigger delays and cycling-off errors were less with NAVA (P <0.05 for all). The NeuroSync index and the number of wasted efforts were strongly correlated (r2 = 0.84), with a drastic increase in wasted efforts after timing errors reach 20%.
In COPD patients, non-invasive NAVA improves patient-ventilator interaction compared to PSV, delivered either by a dedicated or ICU ventilator. The automated analysis of patient-ventilator interaction allowed for an objective detection of patient-ventilator interaction during NIV. In addition, we found that progressive mismatch between neural effort and pneumatic timing is associated with wasted efforts.
PMCID: PMC4207887  PMID: 25307894
3.  Seventy-two hours of mild hypothermia after cardiac arrest is associated with a lowered inflammatory response during rewarming in a prospective observational study 
Critical Care  2014;18(5):546.
Whole-body ischemia and reperfusion trigger a systemic inflammatory response. In this study, we analyzed the effect of temperature on the inflammatory response in patients treated with prolonged mild hypothermia after cardiac arrest.
Ten comatose patients with return of spontaneous circulation after pulseless electrical activity/asystole or prolonged ventricular fibrillation were treated with mild therapeutic hypothermia for 72 hours after admission to a tertiary care university hospital. At admission and at 12, 24, 36, 48, 72, 96 and 114 hours, the patients’ temperature was measured and blood samples were taken from the arterial catheter. Proinflammatory interleukin 6 (IL-6) and anti-inflammatory (IL-10) cytokines and chemokines (IL-8 and monocyte chemotactic protein 1), intercellular adhesion molecule 1 and complement activation products (C1r-C1s-C1inhibitor, C4bc, C3bPBb, C3bc and terminal complement complex) were measured. Changes over time were analyzed with the repeated measures test for nonparametric data. Dunn’s multiple comparisons test was used for comparison of individual time points.
The median temperature at the start of the study was 34.3°C (33.4°C to 35.2°C) and was maintained between 32°C and 34°C for 72 hours. All patients were passively rewarmed after 72 hours, from (median (IQR)) 33.7°C (33.1°C to 33.9°C) at 72 hours to 38.0°C (37.5°C to 38.1°C) at 114 hours (P <0.001). In general, the cytokines and chemokines remained stable during hypothermia and decreased during rewarming, whereas complement activation was suppressed during the whole hypothermia period and increased modestly during rewarming.
Prolonged hypothermia may blunt the inflammatory response after rewarming in patients after cardiac arrest. Complement activation was low during the whole hypothermia period, indicating that complement activation is also highly temperature-sensitive in vivo. Because inflammation is a strong mediator of secondary brain injury, a blunted proinflammatory response after rewarming may be beneficial.
PMCID: PMC4209077  PMID: 25304549
4.  Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction 
Critical Care  2014;18(1):R28.
Diaphragm weakness induced by prolonged mechanical ventilation may contribute to difficult weaning from the ventilator. Hypercapnia is an accepted side effect of low tidal volume mechanical ventilation, but the effects of hypercapnia on respiratory muscle function are largely unknown. The present study investigated the effect of hypercapnia on ventilator-induced diaphragm inflammation, atrophy and function.
Male Wistar rats (n = 10 per group) were unventilated (CON), mechanically ventilated for 18 hours without (MV) or with hypercapnia (MV + H, Fico2 = 0.05). Diaphragm muscle was excised for structural, biochemical and functional analyses.
Myosin concentration in the diaphragm was decreased in MV versus CON, but not in MV + H versus CON. MV reduced diaphragm force by approximately 22% compared with CON. The force-generating capacity of diaphragm fibers from MV + H rats was approximately 14% lower compared with CON. Inflammatory cytokines were elevated in the diaphragm of MV rats, but not in the MV + H group. Diaphragm proteasome activity did not significantly differ between MV and CON. However, proteasome activity in the diaphragm of MV + H was significantly lower compared with CON. LC3B-II a marker of lysosomal autophagy was increased in both MV and MV + H. Incubation of MV + H diaphragm muscle fibers with the antioxidant dithiothreitol restored force generation of diaphragm fibers.
Hypercapnia partly protects the diaphragm against adverse effects of mechanical ventilation.
PMCID: PMC4056638  PMID: 24506836
5.  Systemic Inflammation Decreases Pain Threshold in Humans In Vivo 
PLoS ONE  2013;8(12):e84159.
Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.
Methods and Results
Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20±4 % and 13±3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7±3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.
Conclusions and Significance
In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.
PMCID: PMC3866228  PMID: 24358337
6.  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
7.  Brain Resuscitation in the Drowning Victim 
Neurocritical care  2012;17(3):441-467.
Drowning is a leading cause of accidental death. Survivors may sustain severe neurologic morbidity. There is negligible research specific to brain injury in drowning making current clinical management non-specific to this disorder. This review represents an evidence-based consensus effort to provide recommendations for management and investigation of the drowning victim. Epidemiology, brain-oriented prehospital and intensive care, therapeutic hypothermia, neuroimaging/monitoring, biomarkers, and neuroresuscitative pharmacology are addressed. When cardiac arrest is present, chest compressions with rescue breathing are recommended due to the asphyxial insult. In the comatose patient with restoration of spontaneous circulation, hypoxemia and hyperoxemia should be avoided, hyperthermia treated, and induced hypothermia (32–34 °C) considered. Arterial hypotension/hypertension should be recognized and treated. Prevent hypoglycemia and treat hyperglycemia. Treat clinical seizures and consider treating non-convulsive status epilepticus. Serial neurologic examinations should be provided. Brain imaging and serial biomarker measurement may aid prognostication. Continuous electroencephalography and N20 somatosensory evoked potential monitoring may be considered. Serial biomarker measurement (e.g., neuron specific enolase) may aid prognostication. There is insufficient evidence to recommend use of any specific brain-oriented neuroresuscitative pharmacologic therapy other than that required to restore and maintain normal physiology. Following initial stabilization, victims should be transferred to centers with expertise in age-specific post-resuscitation neurocritical care. Care should be documented, reviewed, and quality improvement assessment performed. Preclinical research should focus on models of asphyxial cardiac arrest. Clinical research should focus on improved cardiopulmonary resuscitation, re-oxygenation/reperfusion strategies, therapeutic hypothermia, neuroprotection, neurorehabilitation, and consideration of drowning in advances made in treatment of other central nervous system disorders.
PMCID: PMC3677166  PMID: 22956050
Drowning; Brain; Asphyxia; Cardiac arrest
8.  Effects of a rapid response system on quality of life: a prospective cohort study in surgical patients before and after implementing a rapid response system 
The aim of a rapid response system (RRS) is to improve the timely recognition and treatment of ward patients with deteriorating vital signs The system is based on a set of clinical criteria that are used to assess patient’s vital signs on a general ward. Once a patient is evaluated as critical, a medical emergency team is activated to more thoroughly assess the patient’s physical condition and to initiate treatment. The medical emergency team included a critical care physician and a critical care nurse.
To assess the effect of an RRS on health-related quality of life (HRQOL).
Prospective cohort study in surgical patients before and after implementing an RRS. HRQOL was measured using the EuroQol-5 dimensions (EQ-5D) and the EQ visual analogue scale (VAS) at pre surgery and at 3 and 6 months following surgery.
No statistical significant effects of RRS implementation on the EQ-5D index and EQ-VAS were found. This was also true for the subpopulation of patients with an unplanned intensive care unit admission. Regarding the EQ-5D dimensions, deterioration in the ‘mobility’ and ‘usual activities’ dimensions in the post-implementation group was significantly less compared to the pre-implementation group with a respective mean difference of 0.08 (p = 0.03) and 0.09 (p = 0.04) on a three-point scale at 6 months. Lower pre-surgery EQ-5D index and higher American Society of Anesthesiologists physical status (ASA-PS) scores were significantly associated with lower EQ-5D index scores at 3 and 6 months following surgery.
Implementation of an RRS did not convincingly affect HRQOL following major surgery. We question if HRQOL is an adequate measure to assess the influence of an RRS. Pre-surgery HRQOL- and ASA-PS scores were strongly associated with HRQOL outcomes and may have abated the influence of the RRS implementation.
PMCID: PMC3655046  PMID: 23635080
Hospital rapid response team; Medical emergency team; Quality of life; EuroQol; General surgery
9.  Haloperidol prophylaxis in critically ill patients with a high risk for delirium 
Critical Care  2013;17(1):R9.
Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.
This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ≥ 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.
In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.
Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.
Trial registration Identifier: NCT01187667.
PMCID: PMC4056261  PMID: 23327295
10.  Crew resource management in the ICU: the need for culture change 
Intensive care frequently results in unintentional harm to patients and statistics don’t seem to improve. The ICU environment is especially unforgiving for mistakes due to the multidisciplinary, time-critical nature of care and vulnerability of the patients. Human factors account for the majority of adverse events and a sound safety climate is therefore essential. This article reviews the existing literature on aviation-derived training called Crew Resource Management (CRM) and discusses its application in critical care medicine. CRM focuses on teamwork, threat and error management and blame free discussion of human mistakes. Though evidence is still scarce, the authors consider CRM to be a promising tool for culture change in the ICU setting, if supported by leadership and well-designed follow-up.
PMCID: PMC3488012  PMID: 22913855
Intensive care; Human factors; Safety climate; Crew resource management
11.  Hyperoxia after cardiac arrest may not increase ischemia-reperfusion injury 
Critical Care  2011;15(3):166.
In the last decade, moderate hypothermia has become the mainstay of treatment in the post-resuscitation period. However, for the damaged brain, optimizing oxygen transport, including arterial oxygenation, may also be important. The current view states that hyperoxia in the immediate post-resuscitation period may worsen cerebral outcome, and international guidelines recommend a target arterial oxygen saturation of 94% to 98%. An article in the previous issue of Critical Care challenges this viewpoint. In an elegant study using a Cox proportional hazards model combined with sensitivity analyses and time period matching, the authors show no independent association between hyperoxia and in-hospital mortality. The present commentary discusses these contradictory findings and suggests a practical solution to solve these differences.
PMCID: PMC3219002  PMID: 21722351
12.  Incidence of cardiac arrests and unexpected deaths in surgical patients before and after implementation of a rapid response system 
Rapid response systems (RRSs) are considered an important tool for improving patient safety. We studied the effect of an RRS on the incidence of cardiac arrests and unexpected deaths.
Retrospective before- after study in a university medical centre. We included 1376 surgical patients before (period 1) and 2410 patients after introduction of the RRS (period 2). Outcome measures were corrected for the baseline covariates age, gender and ASA.
The number of patients who experienced a cardiac arrest and/or who died unexpectedly decreased non significantly from 0.50% (7/1376) in period 1 to 0.25% (6/2410) in period 2 (odds ratio (OR) 0.43, CI 0.14-1.30). The individual number of cardiac arrests decreased non-significantly from 0.29% (4/1367) to 0.12% (3/2410) (OR 0.38, CI 0.09-1.73) and the number of unexpected deaths decreased non-significantly from 0.36% (5/1376) to 0.17% (4/2410) (OR 0.42, CI 0.11-1.59). In contrast, the number of unplanned ICU admissions increased from 2.47% (34/1376) in period 1 to 4.15% (100/2400) in period 2 (OR 1.66, CI 1.07-2.55). Median APACHE ll score at unplanned ICU admissions was 16 in period 1 versus 16 in period 2 (NS). Adherence to RRS procedures. Observed abnormal early warning scores ≤72 h preceding a cardiac arrest, unexpected death or an unplanned ICU admission increased from 65% (24/37 events) in period 1 to 91% (91/101 events) in period 2 (p < 0.001). Related ward physician interventions increased from 38% (9/24 events) to 89% (81/91 events) (p < 0.001). In period 2, ward physicians activated the medical emergency team in 65% of the events (59/91), although in 16% (15/91 events) activation was delayed for one or two days. The overall medical emergency team dose was 56/1000 admissions.
Introduction of an RRS resulted in a 50% reduction in cardiac arrest rates and/or unexpected death. However, this decrease was not statistically significant partly due to the low base-line incidence. Moreover, delayed activation due to the two-tiered medical emergency team activation procedure and suboptimal adherence of the ward staff to the RRS procedures may have further abated the positive results.
PMCID: PMC3425134  PMID: 22716308
Rapid response teams; Outcome and process assessment (health care); General surgery; Hospital mortality; Cardiac arrest
13.  Transcriptome Kinetics of Circulating Neutrophils during Human Experimental Endotoxemia 
PLoS ONE  2012;7(6):e38255.
Polymorphonuclear cells (neutrophils) play an important role in the systemic inflammatory response syndrome and the development of sepsis. These cells are essential for the defense against microorganisms, but may also cause tissue damage. Therefore, neutrophil numbers and activity are considered to be tightly regulated. Previous studies have investigated gene transcription during experimental endotoxemia in whole blood and peripheral blood mononuclear cells. However, the gene transcription response of the circulating pool of neutrophils to systemic inflammatory stimulation in vivo is currently unclear. We examined neutrophil gene transcription kinetics in healthy human subjects (n = 4) administered a single dose of endotoxin (LPS, 2 ng/kg iv). In addition, freshly isolated neutrophils were stimulated ex vivo with LPS, TNFα, G-CSF and GM-CSF to identify stimulus-specific gene transcription responses. Whole transcriptome microarray analysis of circulating neutrophils at 2, 4 and 6 hours after LPS infusion revealed activation of inflammatory networks which are involved in signaling of TNFα and IL-1α and IL-1β. The transcriptome profile of inflammatory activated neutrophils in vivo reflects extended survival and regulation of inflammatory responses. These changes in neutrophil transcriptome suggest a combination of early activation of circulating neutrophils by TNFα and G-CSF and a mobilization of young neutrophils from the bone marrow.
PMCID: PMC3367952  PMID: 22679495
14.  Intravenous magnesium in subarachnoid hemorrhage 
Critical Care  2011;15(3):427.
PMCID: PMC3218975  PMID: 21631908
15.  Effects of Vagus Nerve Stimulation and Vagotomy on Systemic and Pulmonary Inflammation in a Two-Hit Model in Rats 
PLoS ONE  2012;7(4):e34431.
Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO2 (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated.
PMCID: PMC3321011  PMID: 22493690
16.  Titin and diaphragm dysfunction in mechanically ventilated rats 
Intensive Care Medicine  2012;38(4):702-709.
Diaphragm weakness induced by mechanical ventilation may contribute to difficult weaning from the ventilator. For optimal force generation the muscle proteins myosin and titin are indispensable. The present study investigated if myosin and titin loss or dysfunction are involved in mechanical ventilation-induced diaphragm weakness.
Male Wistar rats were either assigned to a control group (n = 10) or submitted to 18 h of mechanical ventilation (MV, n = 10). At the end of the experiment, diaphragm and soleus muscle were excised for functional and biochemical analysis.
Maximal specific active force generation of muscle fibers isolated from the diaphragm of MV rats was lower than controls (128 ± 9 vs. 165 ± 13 mN/mm2, p = 0.02) and was accompanied by a proportional reduction of myosin heavy chain concentration in these fibers. Passive force generation upon stretch was significantly reduced in diaphragm fibers from MV rats by ca. 35%. Yet, titin content was not significantly different between control and MV diaphragm. In vitro pre-incubation with phosphatase-1 decreased passive force generation upon stretch in diaphragm fibers from control, but not from MV rats. Mechanical ventilation did not affect active or passive force generation in the soleus muscle.
Mechanical ventilation leads to impaired diaphragm fiber active force-generating capacity and passive force generation upon stretch. Loss of myosin contributes to reduced active force generation, whereas reduced passive force generation is likely to result from a decreased phosphorylation status of titin. These impairments were not discernable in the soleus muscle of 18 h mechanically ventilated rats.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2504-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3308006  PMID: 22327561
Mechanical ventilation; Diaphragm; Force; Single fiber; Myosin; Titin
17.  Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial 
Critical Care  2012;16(1):R14.
To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed.
Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety.
There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial.
The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI.
Trial Registration NCTNCT00511186
PMCID: PMC3396250  PMID: 22269279
sepsis; systemic inflammatory response syndrome; septic shock; acute renal failure; therapy
18.  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 
Critical Care  2011;15(6):R297.
Delirium 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.
In 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.
In 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.
In 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).
PMCID: PMC3388649  PMID: 22206727
19.  Clinical review: The ABC of weaning failure - a structured approach 
Critical Care  2010;14(6):245.
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.
PMCID: PMC3220047  PMID: 21143773
20.  Dipyridamole augments the antiinflammatory response during human endotoxemia 
Critical Care  2011;15(6):R289.
In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia.
In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo.
Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia.
Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines.
Trial registration
ClinicalTrials (NCT): NCT01091571.
PMCID: PMC3388652  PMID: 22129171
21.  Bench-to-bedside review: Hypercapnic acidosis in lung injury - from 'permissive' to 'therapeutic' 
Critical Care  2010;14(6):137.
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.
PMCID: PMC3220022  PMID: 21067531
22.  The effects of hypertonic fluid administration on the gene expression of inflammatory mediators in circulating leucocytes in patients with septic shock: a preliminary study 
This study was designed to investigate the effect of hypertonic fluid administration on inflammatory mediator gene expression in patients with septic shock.
Design and setting
Prospective, randomized, controlled, double-blind clinical study in a 15-bed mixed intensive care unit in a tertiary referral teaching hospital.
Twenty-four patients, who met standard criteria for septic shock, were randomized to receive a bolus of hypertonic fluid (HT, 250 ml 6% HES/7.2% NaCl) or isotonic fluid (IT, 500 ml 6% HES/0.9% NaCl) administered over 15 minutes. Randomization and study fluid administration was within 24 hours of ICU admission for all patients. This trial is registered with as ACTRN12607000259448.
Blood samples were taken immediately before and 4, 8, 12, and 24 hours after fluid administration. Real-time reverse transcriptase polymerase chain reaction (RT rtPCR) was used to quantify mRNA expression of different inflammatory mediators in peripheral leukocytes. In the HT group, compared with the IT group, levels of gene expression of MMP9 and L-selectin were significantly suppressed (p = 0.0002 and p = 0.007, respectively), and CD11b gene expression tended to be elevated (p = NS). No differences were found in the other mediators examined.
In septic shock patients, hypertonic fluid administration compared with isotonic fluid may modulate expression of genes that are implicated in leukocyte-endothelial interaction and capillary leakage.
The study was performed at the Intensive Care Department, Waikato Hospital, and at the Molecular Genetics Laboratory, University of Waikato, Hamilton, New Zealand.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000259448
PMCID: PMC3217886  PMID: 22044529
23.  Plasma from septic shock patients induces loss of muscle protein 
Critical Care  2011;15(5):R233.
ICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.
Plasma was derived from septic shock patients within 24 hours after hospital admission (n = 21) and healthy controls (n = 12). From nine patients with septic shock plasma was additionally derived at two, five and seven days after ICU admission. These plasma samples were added to skeletal myotubes, cultured from murine myoblasts. After incubation for 24 hours, myotubes were harvested and analyzed on myosin content, mRNA expression of E3-ligase and Nuclear Factor Kappa B (NFκB) activity. Plasma samples were analyzed on cytokine concentrations.
Myosin content was approximately 25% lower in myotubes exposed to plasma from septic shock patients than in myotubes exposed to plasma from controls (P < 0.01). Furthermore, patient plasma increased expression of E3-ligases Muscle RING Finger protein-1 (MuRF-1) and Muscle Atrophy F-box protein (MAFbx) (P < 0.01), enhanced NFκB activity (P < 0.05) and elevated levels of ubiquitinated myosin in myotubes. Myosin loss was significantly associated with elevated plasma levels of interleukin (IL)-6 in septic shock patients (P < 0.001). Addition of antiIL-6 to septic shock plasma diminished the loss of myosin in exposed myotubes by approximately 25% (P < 0.05). Patient plasma obtained later during ICU stay did not significantly reduce myosin content compared to controls.
Plasma from patients with septic shock induces loss of myosin and activates key regulators of proteolysis in skeletal myotubes. IL-6 is an important player in sepsis-induced muscle atrophy in this model. The potential to induce atrophy is strongest in plasma obtained during the early phase of human sepsis.
PMCID: PMC3334781  PMID: 21958504
25.  Early and late outcome after single step dilatational tracheostomy versus the guide wire dilating forceps technique: a prospective randomized clinical trial 
Intensive Care Medicine  2011;37(7):1103-1109.
Percutaneous tracheostomy is frequently performed in long-term ventilated patients in the intensive care unit (ICU). Unfortunately, despite many years of experience, the optimal technique is still unknown, especially considering the occurrence of late complications. The purpose of this study was to determine which of the two most frequently used percutaneous tracheostomy techniques performs best with the emphasis on late complications.
This prospective randomized trial involved 120 patients, comparing two techniques of percutaneous tracheostomy, the guide wire dilating forceps (GWDF) and the single step dilatational tracheostomy (SSDT) technique.
Sixty patients in each group underwent a percutaneous tracheostomy and were followed for up to 3 months after decannulation. The majority of complications in both groups were minor (58.3% in the GWDF group and 61.7% in the SSDT group). We found a trend towards more major perioperative complications in the GWDF group versus the SSDT group, 10.0 versus 1.7% (p = 0.06). One patient in the SSDT group developed a significant tracheal stenosis. However, this may also have been related to prolonged translaryngeal intubation. Results of magnetic resonance imaging (MRI) investigations showed only minor tracheal changes. Only 37.5% of patients in the GWDF group and 31.8% in the SSDT group had no complaints after their percutaneous tracheostomy.
Compared with the GWDF, the SSDT shows a trend toward less major perioperative complications with a comparable long-term outcome.
PMCID: PMC3127000  PMID: 21484081
Percutaneous; Tracheostomy; Guide wire dilating forceps; Single step tracheostomy; Complications

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