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1.  Heliox Improves Carbon Dioxide Removal during Lung Protective Mechanical Ventilation  
Introduction. Helium is a noble gas with low density and increased carbon dioxide (CO2) diffusion capacity. This allows lower driving pressures in mechanical ventilation and increased CO2 diffusion. We hypothesized that heliox facilitates ventilation in patients during lung-protective mechanical ventilation using low tidal volumes. Methods. This is an observational cohort substudy of a single arm intervention study. Twenty-four ICU patients were included, who were admitted after a cardiac arrest and mechanically ventilated for 3 hours with heliox (50% helium; 50% oxygen). A fixed protective ventilation protocol (6 mL/kg) was used, with prospective observation for changes in lung mechanics and gas exchange. Statistics was by Bonferroni post-hoc correction with statistical significance set at P < 0.017. Results. During heliox ventilation, respiratory rate decreased (25 ± 4 versus 23 ± 5 breaths min−1, P = 0.010). Minute volume ventilation showed a trend to decrease compared to baseline (11.1 ± 1.9 versus 9.9 ± 2.1 L min−1, P = 0.026), while reducing PaCO2 levels (5.0 ± 0.6 versus 4.5 ± 0.6 kPa, P = 0.011) and peak pressures (21.1 ± 3.3 versus 19.8 ± 3.2 cm H2O, P = 0.024). Conclusions. Heliox improved CO2 elimination while allowing reduced minute volume ventilation in adult patients during protective mechanical ventilation.
PMCID: PMC4274833  PMID: 25548660
2.  Study protocol of a randomised controlled trial comparing perioperative intravenous insulin, GIK or GLP-1 treatment in diabetes–PILGRIM trial 
BMC Anesthesiology  2014;14(1):91.
Diabetes mellitus (DM) is associated with poor outcome after surgery. The prevalence of DM in hospitalised patients is up to 40%, meaning that the anaesthesiologist will encounter a patient with DM in the operating room on a daily basis. Despite an abundance of published glucose lowering protocols and the known negative outcomes associated with perioperative hyperglycaemia in DM, there is no evidence regarding the optimal intraoperative glucose lowering treatment. In addition, protocol adherence is usually low and protocol targets are not simply met.
Recently, incretins have been introduced to lower blood glucose. The main hormone of the incretin system is glucagon-like peptide–1 (GLP-1). GLP-1 increases insulin and decreases glucagon secretion in a glucose-dependent manner, resulting in glucose lowering action with a low incidence of hypoglycaemia.
We set out to determine the optimal intraoperative treatment algorithm to lower glucose in patients with DM type 2 undergoing non-cardiac surgery, comparing intraoperative glucose-insulin-potassium infusion (GIK), insulin bolus regimen (BR) and GPL-1 (liragludite, LG) treatment.
This is a multicentre randomised open label trial in patients with DM type 2 undergoing non-cardiac surgery. Patients are randomly assigned to one of three study arms; intraoperative glucose-insulin-potassium infusion (GIK), intraoperative sliding-scale insulin boluses (BR) or GPL-1 pre-treatment with liraglutide (LG). Capillary glucose will be measured every hour. If necessary, in all study arms glucose will be adjusted with an intravenous bolus of insulin. Researchers, care givers and patients will not be blinded for the assigned treatment. The main outcome measure is the difference in median glucose between the three study arms at 1 hour postoperatively. We will include 315 patients, which gives us a 90% power to detect a 1 mmol l−1 difference in glucose between the study arms.
The PILGRIM trial started in January 2014 and will provide relevant information on the perioperative use of GLP-1 agonists and the optimal intraoperative treatment algorithm in patients with diabetes mellitus type 2.
Trial registration, NCT02036372
PMCID: PMC4240889  PMID: 25419179
Diabetes mellitus type 2; Perioperative management; GLP-1 agonist
3.  Safety and effectiveness using dexmedetomidine versus propofol TCI sedation during oesophagus interventions: a randomized trial 
BMC Gastroenterology  2013;13:176.
Endoscopic treatment of early neoplastic lesions in oesophagus has evolved as a valid and less invasive alternative to surgical resection. These endoscopic interventions are minimal invasive treatment options usually done with sedation on an outpatient basis. The aim of this trial is to determine the safety and effectiveness of dexmedetomidine sedation compared to the standard used propofol TCI sedation during endoscopic oesophageal interventions.
The study will be performed as a randomized controlled trial. The first 64 consenting patients will be randomized to either the propofol or the dexmedetomidine group. Following endoscopy patients and gastroenterologists have to fill in questionnaires (PSSI, CSSI) (see abbreviations) about their sedation experiences. Additionally, patients have to accomplish the Trieger test before and after the procedure. Patient monitoring includes time adapted HR, SO2, ECG, NIBP, exCO2, NICO, sweat conductance measurement, OAA/S, and the Aldrete score. Effectiveness of sedation, classified by satisfaction levels and pain and sedation score measured by questionnaires is the primary outcome parameter. Respiratory and hemodynamic complications are surrogate parameters for the secondary outcome parameter “safety”.
The acceptance level among patients after propofol sedation is high. Dexmedetomidine is a relatively new representative for procedural sedation. Has this new form of conscious sedation the potential to be safer and more effective for patients and endoscopists than propofol during endoscopic oesophageal interventions?
Trial registration
This trial is registered in the ISRCTN Register (ISRCTN 68599804). It will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Departments of Anesthesiology and Gastroenterology & Hepatology of the Academic Medical Center of Amsterdam are responsible for the design and conduct of the trial.
PMCID: PMC3922843  PMID: 24377675
Procedural sedation; Dexmedetomidine; Endoscopic oesophageal intervention
4.  Heliox Allows for Lower Minute Volume Ventilation in an Animal Model of Ventilator-Induced Lung Injury 
PLoS ONE  2013;8(10):e78159.
Helium is a noble gas with a low density, allowing for lower driving pressures and increased carbon dioxide (CO2) diffusion. Since application of protective ventilation can be limited by the development of hypoxemia or acidosis, we hypothesized that therefore heliox facilitates ventilation in an animal model of ventilator–induced lung injury.
Sprague-Dawley rats (N=8 per group) were mechanically ventilated with heliox (50% oxygen; 50% helium). Controls received a standard gas mixture (50% oxygen; 50% air). VILI was induced by application of tidal volumes of 15 mL kg-1; lung protective ventilated animals were ventilated with 6 mL kg-1. Respiratory parameters were monitored with a pneumotach system. Respiratory rate was adjusted to maintain arterial pCO2 within 4.5-5.5 kPa, according to hourly drawn arterial blood gases. After 4 hours, bronchoalveolar lavage fluid (BALF) was obtained. Data are mean (SD).
VILI resulted in an increase in BALF protein compared to low tidal ventilation (629 (324) vs. 290 (181) μg mL-1; p<0.05) and IL-6 levels (640 (8.7) vs. 206 (8.7) pg mL-1; p<0.05), whereas cell counts did not differ between groups after this short course of mechanical ventilation. Ventilation with heliox resulted in a decrease in mean respiratory minute volume ventilation compared to control (123±0.6 vs. 146±8.9 mL min-1, P<0.001), due to a decrease in respiratory rate (22 (0.4) vs. 25 (2.1) breaths per minute; p<0.05), while pCO2 levels and tidal volumes remained unchanged, according to protocol. There was no effect of heliox on inspiratory pressure, while compliance was reduced. In this mild lung injury model, heliox did not exert anti-inflammatory effects.
Heliox allowed for a reduction in respiratory rate and respiratory minute volume during VILI, while maintaining normal acid-base balance. Use of heliox may be a useful approach when protective tidal volume ventilation is limited by the development of severe acidosis.
PMCID: PMC3799754  PMID: 24205139
5.  Effects of helium and air inhalation on the innate and early adaptive immune system in healthy volunteers ex vivo 
Helium inhalation protects myocardium, brain and endothelium against ischemia/reperfusion injury in animals and humans, when applied according to specific “conditioning” protocols. Before widespread use of this “conditioning” agent in clinical practice, negative side effects have to be ruled out. We investigated the effect of prolonged helium inhalation on the responsiveness of the human immune response in whole blood ex vivo.
Male healthy volunteers inhaled 30 minutes heliox (79%He/21%O2) or air in a cross over design, with two weeks between measurements. Blood was withdrawn at T0 (baseline), T1 (25 min inhalation) and T2-T5 (1, 2, 6, 24 h after inhalation) and incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), T-cell stimuli anti-CD3/ anti-CD28 (TCS) or RPMI (as control) for 2, 4 and 24 hours or not incubated (0 h). An additional group of six volunteers inhaled 60 minutes of heliox or air, followed by blood incubation with LPS and RPMI. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-γ (IFN-γ) and interleukin-2 (IL-2) was analyzed by cytometric bead array. Statistical analysis was performed by the Wilcoxon test for matched samples.
Incubation with LPS, LTA or TCS significantly increased TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to incubation with RPMI alone. Thirty min of helium inhalation did not influence the amounts of TNF-α, IL-1β, IL-6, IL-8, IFN-γ and IL-2 in comparison to air. Sixty min of helium inhalation did not affect cytokine production after LPS stimulation.
We conclude that 79% helium inhalation does not affect the responsiveness of the human immune system in healthy volunteers.
Trial registration
Dutch Trial Register: NTR2152
PMCID: PMC3495766  PMID: 23006534
Noble gas; Side effects; Cell-mediated immunity; Ischemia-reperfusion injury; Whole blood stimulation
6.  Remote Ischemic Conditioning to Protect against Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(7):e42179.
Remote ischemic conditioning is gaining interest as potential method to induce resistance against ischemia reperfusion injury in a variety of clinical settings. We performed a systematic review and meta-analysis to investigate whether remote ischemic conditioning reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia reperfusion injury.
Methods and Results
Medline, EMBASE and Cochrane databases were searched for randomized clinical trials comparing remote ischemic conditioning, regardless of timing, with no conditioning. Two investigators independently selected suitable trials, assessed trial quality and extracted data. 23 studies in patients undergoing cardiac surgery (15 studies), percutaneous coronary intervention (four studies) and vascular surgery (four studies), comprising in total 1878 patients, were included in this review. Compared to no conditioning, remote ischemic conditioning did not reduce mortality (odds ratio 1.22 [95% confidence interval 0.48, 3.07]) or major adverse cardiovascular events (0.65 [0.38, 1.14]). However, the incidence of myocardial infarction was reduced with remote ischemic conditioning (0.50 [0.31, 0.82]), as was peak troponin release (standardized mean difference −0.28 [−0.47, −0.09]).
There is no evidence that remote ischemic conditioning reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events. However, remote ischemic conditioning did reduce the incidence of peri-procedural myocardial infarctions, as well as the release of troponin.
PMCID: PMC3409156  PMID: 22860077
7.  Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial) 
BMC Anesthesiology  2011;11:11.
Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome.
This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.
Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre- or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%.
The RICO-trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery.
Trial registration under NCT01107184.
PMCID: PMC3119027  PMID: 21605453
8.  Morphine induces preconditioning via activation of mitochondrial KCa channels 
Canadian Journal of Anaesthesia  2010;57(8):767-773.
Mitochondrial calcium sensitive potassium (mKCa) channels are involved in cardioprotection induced by ischemic preconditioning. In the present study we investigated whether morphine-induced preconditioning also involves activation of mKCa channels.
Isolated rat hearts (six groups; each n = 8) underwent global ischemia for 30 min followed by a 60-min reperfusion. Control animals were not further treated. Morphine preconditioning (MPC) was initiated by two five-minute cycles of morphine 1 μM infusion with one five-minute washout and one final ten-minute washout period before ischemia. The mKCa blocker, paxilline 1 μM, was administered, with and without morphine administration (MPC + Pax and Pax). As a positive control, we added an ischemic preconditioning group (IPC) alone and combined with paxilline (IPC + Pax). At the end of reperfusion, infarct sizes were determined by triphenyltetrazoliumchloride staining.
Infarct size was (mean ± SD) 45 ± 9% of the area at risk in the Control group. The infarct size was less in the morphine or ischemic preconditioning groups (MPC: 23 ± 8%, IPC: 20 ± 5%; each P < 0.05 vs Control). Infarct size reduction was abolished by paxilline (MPC + Pax: 37 ± 7%, P < 0.05 vs MPC and IPC + Pax: 36 ± 6%, P < 0.05 vs IPC), whereas paxilline alone had no effect (Pax: 46 ± 7%, not significantly different from Control).
Cardioprotection by morphine-induced preconditioning is mediated by activation of mKCa channels.
PMCID: PMC2899019  PMID: 20461490
Morphine; Preconditioning; mKCa; Infarct size
9.  Influence of the interleukin-converting enzyme inhibitor HMR-3480 on myocardial stunning in pigs in vivo 
The proinflammatory cytokine interleukin-1 beta is converted into its active form by interleukin-1 beta-converting enzyme (ICE). Circulating cytokines may promote myocardial dysfunction (stunning) after ischemia.
To investigate whether ICE inhibition by HMR-3840 improves myocardial stunning in vivo.
Anesthetized (isoflurane and fentanyl) pigs were used for measurement of left ventricular (LV) pressure, cardiac output and blood flow in the left anterior descending coronary artery (LAD) and left circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening and mean systolic thickening velocity in the anteroapical and posterobasal walls. The animals were subjected to 10 min of LAD occlusion followed by 4 h of reperfusion. The ICE inhibitor (flow-adjusted to achieve coronary plasma concentrations of 10 μg/mL) (ISCH, n=7) or the vehicle (CON, n=7) was infused via a side branch into the LAD during ischemia, or during ischemia and the first 60 min of reperfusion (REP, n=6).
Occlusion of the LAD resulted in systolic outward movement (bulging) of the anteroapical wall during ischemia in all groups. Infusion of the ICE inhibitor had no effect on functional recovery when given during ischemia or when given during reperfusion (at the end of reperfusion in the anteroapical wall, values for systolic wall thickening were: CON 17.3±7.3%, ISCH 23.2±9.8% and REP 19.3±6.1%; and values for mean systolic thickening velocity were: CON 4.3±1.1 mm/s, ISCH 6.1±3.9 mm/s and REP 5.2±1.7 mm/s; all P values not significant for CON versus ISCH or REP). LAD blood flow was not affected by HMR-3840 (23.4±5.2 mL/min versus 24.3±8.1 mL/min; P not significant). Global myocardial function (LV pressure, maximum rate of LV pressure increase and cardiac output) was not different between controls and treatment groups during reperfusion.
ICE inhibition by HMR-3480 had no effect on myocardial stunning in pigs in vivo.
PMCID: PMC2323758  PMID: 18650993
Caspase inhibitor; HMR-3480; Pig; Regional myocardial function; Sonomicrometry; Stunning
10.  Perioperative strategy in colonic surgery; LAparoscopy and/or FAst track multimodal management versus standard care (LAFA trial) 
BMC Surgery  2006;6:16.
Recent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track recovery programs. Both focus on a faster recovery and shorter hospital stay.
The randomized controlled multicenter LAFA-trial (LAparoscopy and/or FAst track multimodal management versus standard care) was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients having segmental colectomy for malignant disease.
The LAFA-trial is a double blinded, multicenter trial with a 2 × 2 balanced factorial design. Patients eligible for segmental colectomy for malignant colorectal disease i.e. right and left colectomy and anterior resection will be randomized to either open or laparoscopic colectomy, and to either standard care or the fast track program. This factorial design produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track program (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track program (d). Primary outcome parameter is postoperative hospital length of stay including readmission within 30 days. Secondary outcome parameters are quality of life two and four weeks after surgery, overall hospital costs, morbidity, patient satisfaction and readmission rate.
Based on a mean postoperative hospital stay of 9 +/- 2.5 days a group size of 400 patients (100 each arm) can reliably detect a minimum difference of 1 day between the four arms (alfa = 0.95, beta = 0.8). With 100 patients in each arm a difference of 10% in subscales of the Short Form 36 (SF-36) questionnaire and social functioning can be detected.
The LAFA-trial is a randomized controlled multicenter trial that will provide evidence on the merits of fast track perioperative care and laparoscopic colorectal surgery in patients having segmental colectomy for malignant disease.
PMCID: PMC1693570  PMID: 17134506

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