Publications by authors named "Petr Waldauf"

56 Publications

Long-term outcome after midline lumbar fusion for the treatment of lumbar spine instability due to degenerative disease.

World Neurosurg 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurosurgery, Tomas Bata Regional Hospital, Zlin, Czech Republic (Havlickovo nabrezi 600, 762 75 Zlin). Electronic address:

Background: New surgical techniques have been developed to minimize perioperative damage to paravertebral stabilizing musculotendinous system. Among them, midline lumbar fusion (MIDLF) shows to be a viable option. With data on MIDLF remaining scarce, we assessed its long-term clinical and radiological effects.

Methods: In our prospective cohort study, patients having undergone MIDLF for degenerative spinal instability were evaluated. Before and after operation, subjects were clinically and radiologically examined. Peri- and postoperative complications were recorded. Follow-up period was two years. Statistical analysis was performed, with p ≤ 0.05 considered significant.

Results: Sixty-four patients (average age 58.9 ± 10.7 years, 41 [64.1%] women) were included. The most frequent indication for MIDLF was degenerative spondylolisthesis grade I (28 cases, 43.8%), the prevalent spinal segment to be fused was L4/5 (35 cases, 54.7%). Mean duration of surgery was 148.2 ± 28.9 minutes. Relief of lower back pain (LBP) and leg pain (LP) was significant and stable in the postoperative period, as assessed by visual analog scale (VAS; p ˂ 0.001). On aggregate, 86.9% subjects reported fair, good, or excellent outcomes in terms of pain relief on MacNab score 2 years after surgery. Patients´ level of function in activities of daily living improved significantly: from Oswestry disability index (ODI) 66.8 ± 9.8 before to 33.9 ± 16.5 two years after surgery (p ˂ 0.001). On X-ray and CT scans at 12 months, interbody fusion occurred in 46 patients (73.4%), 13 cases (20.3%) were inconclusive, and in 4 cases (6.3%) there was no fusion. No damage to the neural or vascular structures and no failure of hardware or screw loosening were recorded.

Conclusions: MIDLF is an efficient and safe method for surgical treatment of lumbar spine instability. Its limited invasiveness contributes to better preservation of paravertebral muscles, and thus to enhanced postoperative spinal stability.
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http://dx.doi.org/10.1016/j.wneu.2021.07.108DOI Listing
July 2021

Can functional electrical stimulation-assisted cycle ergometry replace insulin infusion in patients? A nested substudy in a randomized controlled trial with 6 months' follow-up.

JPEN J Parenter Enteral Nutr 2021 Jun 24. Epub 2021 Jun 24.

Department of Anaesthesia and Intensive Care Medicine, Charles University, The Third Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.

Background: Functional electrical stimulation-assisted cycle ergometry (FESCE) can deliver active exercise to critically ill patients, including those who are sedated. Aerobic exercise is known to stimulate skeletal muscle glucose uptake. We asked whether FESCE can reduce intravenous insulin requirements and improve insulin sensitivity in intensive care unit (ICU) patients.

Method: We performed an a priori-planned secondary analysis of data from an outcome-based randomized controlled trial (NCT02864745) of FESCE-based early-mobility program vs standard of care in mechanically ventilated patients. We analyzed glucose profile, glucose intake, and insulin requirements during ICU stay in all enrolled patients. In a nested subgroup, we performed hyperinsulinemic (120 mIU/min/m ) euglycemic clamps at days 0, 7, and 180 (n = 30, 23, and 11, respectively).

Results: We randomized 150 patients 1:1 to receive intervention or standard of care. Seventeen (23%) patients in each study arm had a history of diabetes. During ICU stay, patients received 137 ± 65 and 137 ± 88 g/day carbohydrate (P = .97), and 31 vs 35 (P = .62) of them required insulin infusion to maintain blood glucose 8.61 ± 2.82 vs 8.73 ± 2.67 mM (P = .75, n = 11,254). In those treated with insulin, median daily dose was 53 IU (interquartile range [IQR], 25-95) vs 62 IU (IQR, 26-96) in the intervention and control arm, respectively (P = .44). In the subgroup of patients undergoing hyperglycemic clamps, insulin sensitivities improved similarly and significantly from acute and protracted critical illness to 6 months after discharge.

Conclusion: The FESCE-based early-mobility program does not significantly reduce insulin requirements in critically ill patients on mechanical ventilation.
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http://dx.doi.org/10.1002/jpen.2213DOI Listing
June 2021

Functional electrical stimulation-assisted cycle ergometry-based progressive mobility programme for mechanically ventilated patients: randomised controlled trial with 6 months follow-up.

Thorax 2021 07 30;76(7):664-671. Epub 2021 Apr 30.

Department of Anaesthesiology and Intensive Care Medicine, 3rd Faculty of Medicine and FNKV University Hospital, Charles University, Prague, Czech Republic

Purpose: Functional electrical stimulation-assisted cycle ergometry (FESCE) enables in-bed leg exercise independently of patients' volition. We hypothesised that early use of FESCE-based progressive mobility programme improves physical function in survivors of critical care after 6 months.

Methods: We enrolled mechanically ventilated adults estimated to need >7 days of intensive care unit (ICU) stay into an assessor-blinded single centre randomised controlled trial to receive either FESCE-based protocolised or standard rehabilitation that continued up to day 28 or ICU discharge.

Results: We randomised in 1:1 ratio 150 patients (age 61±15 years, Acute Physiology and Chronic Health Evaluation II 21±7) at a median of 21 (IQR 19-43) hours after admission to ICU. Mean rehabilitation duration of rehabilitation delivered to intervention versus control group was 82 (IQR 66-97) versus 53 (IQR 50-57) min per treatment day, p<0.001. At 6 months 42 (56%) and 46 (61%) patients in interventional and control groups, respectively, were alive and available to follow-up (81.5% of prespecified sample size). Their Physical Component Summary of SF-36 (primary outcome) was not different at 6 months (50 (IQR 21-69) vs 49 (IQR 26-77); p=0.26). At ICU discharge, there were no differences in the ICU length of stay, functional performance, rectus femoris cross-sectional diameter or muscle power despite the daily nitrogen balance was being 0.6 (95% CI 0.2 to 1.0; p=0.004) gN/m less negative in the intervention group.

Conclusion: Early delivery of FESCE-based protocolised rehabilitation to ICU patients does not improve physical functioning at 6 months in survivors.

Trial Registration Number: NCT02864745.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223653PMC
July 2021

Left bundle branch pacing compared to left ventricular septal myocardial pacing increases interventricular dyssynchrony but accelerates left ventricular lateral wall depolarization.

Heart Rhythm 2021 Apr 28. Epub 2021 Apr 28.

Cardiocenter, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.

Background: Nonselective His-bundle pacing (nsHBp), nonselective left bundle branch pacing (nsLBBp), and left ventricular septal myocardial pacing (LVSP) are recognized as physiological pacing techniques.

Objective: The purpose of this study was to compare differences in ventricular depolarization between these techniques using ultra-high-frequency electrocardiography (UHF-ECG).

Methods: In patients with bradycardia, nsHBp, nsLBBp (confirmed concomitant left bundle branch [LBB] and myocardial capture), and LVSP (pacing in left ventricular [LV] septal position without proven LBB capture) were performed. Timings of ventricular activations in precordial leads were displayed using UHF-ECG, and electrical dyssynchrony (e-DYS) was calculated as the difference between the first and last activation. Duration of local depolarization (Vd) was determined as width of the UHF-QRS complex at 50% of its amplitude.

Results: In 68 patients, data were collected during nsLBBp (35), LVSP (96), and nsHBp (55). nsLBBp resulted in larger e-DYS than did LVSP and nsHBp [- 24 ms (-28;-19) vs -12 ms (-16;-9) vs 10 ms (7;14), respectively; P <.001]. nsLBBp produced similar values of Vd in leads V-V (36-43 ms vs 38-43 ms; P = NS in all leads) but longer Vd in leads V-V (47-59 ms vs 41-44 ms; P <.05) as nsHBp. LVSP caused prolonged Vd in leads V-V compared to nsHBp and longer Vd in leads V-V compared to nsLBBp (44-51 ms vs 36-43 ms; P <.05) regardless of R-wave peak time in lead V or QRS morphology in lead V present during LVSP.

Conclusion: nslbbp preserves physiological LV depolarization but increases interventricular electrical dyssynchrony. LV lateral wall depolarization during LVSP is prolonged, but interventricular synchrony is preserved.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.025DOI Listing
April 2021

Ventricular activation pattern assessment during right ventricular pacing: Ultra-high-frequency ECG study.

J Cardiovasc Electrophysiol 2021 May 11;32(5):1385-1394. Epub 2021 Mar 11.

Cardiocenter, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.

Background: Right ventricular (RV) pacing causes delayed activation of remote ventricular segments. We used the ultra-high-frequency ECG (UHF-ECG) to describe ventricular depolarization when pacing different RV locations.

Methods: In 51 patients, temporary pacing was performed at the RV septum (mSp); further subclassified as right ventricular inflow tract (RVIT) and right ventricular outflow tract (RVOT) for septal inflow and outflow positions (below or above the plane of His bundle in right anterior oblique), apex, anterior lateral wall, and at the basal RV septum with nonselective His bundle or RBB capture (nsHBorRBBp). The timings of UHF-ECG electrical activations were quantified as left ventricular lateral wall delay (LVLWd; V8 activation delay) and RV lateral wall delay (RVLWd; V1 activation delay).

Results: The LVLWd was shortest for nsHBorRBBp (11 ms [95% confidence interval = 5-17]), followed by the RVIT (19 ms [11-26]) and the RVOT (33 ms [27-40]; p < .01 between all of them), although the QRSd for the latter two were the same (153 ms (148-158) vs. 153 ms (148-158); p = .99). RV apical capture not only had a longer LVLWd (34 ms (26-43) compared to mSp (27 ms (20-34), p < .05), but its RVLWd (17 ms (9-25) was also the longest compared to other RV pacing sites (mean values for nsHBorRBBp, mSp, anterior and lateral wall captures being below 6 ms), p < .001 compared to each of them.

Conclusion: RVIT pacing produces better ventricular synchrony compared to other RV pacing locations with myocardial capture. However, UHF-ECG ventricular dysynchrony seen during RVIT pacing is increased compared to concomitant capture of basal septal myocytes and His bundle or proximal right bundle branch.
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http://dx.doi.org/10.1111/jce.14985DOI Listing
May 2021

Resumption of Cardiac Activity after Withdrawal of Life-Sustaining Measures.

N Engl J Med 2021 01;384(4):345-352

From the Children's Hospital of Eastern Ontario (S.D.), Children's Hospital of Eastern Ontario Research Institute (S.D., L.H., A. van Beinum, M.H., H.T.), Faculty of Medicine (S.D.) and Centre for Health Law, Policy, and Ethics (J.A.C.), University of Ottawa, Canadian Blood Services (L.H., S.D.S.), Carleton University (A. van Beinum), the Dynamical Analysis Lab (N.B.S., C.H., A.S.), Clinical Epidemiology Program (N.B.S., C.H., A.S.), and Clinical Epidemiology Program Methods Centre (T.R.), Ottawa Hospital Research Institute, the Departments of Critical Care and General Surgery (G.P.) and Surgery (A.S.) and Division of Thoracic Surgery (A.S.), Ottawa Hospital, and Interventional Cardiology Program, University of Ottawa Heart Institute (D. So), Ottawa, the Department of Critical Care, Trauma and Neurosurgery Program, St. Michael's Hospital (A. Baker), Li Ka Shing Knowledge Institute, Unity Health-St. Michael's Hospital (J.O.F., D. Scales), University of Toronto (J.O.F.), Mount Sinai Hospital (S.M., L.M.) and Interdepartmental Division of Critical Care Medicine (S.M., L.M., D. Scales), University of Toronto, Department of Critical Care Medicine, Sunnybrook Health Sciences Centre (D. Scales), and the Canadian Donation and Transplantation Research Program (H.T.), Toronto, the Departments of Critical Care and Anesthesia, Dalhousie University, Halifax, NS (S.B.), the Departments of Medicine and Critical Care Medicine, Queen's University, Kingston, ON (J.G.B., D.M.M.), the Department of Medicine (Critical Care), Research Centre of the University of Montreal Hospital (M.C.), the Department of Critical Care, Division of Pulmonary Medicine, McGill University (J.S.), McGill University Health Centre and Research Institute (J.S., S.D.S.), Transplant Québec (M.W.), and the Division of Critical Care, Montreal Children's Hospital (S.D.S.), Montreal, the Department of Anesthesiology, Université de Sherbrooke and Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Sherbrooke, Sherbrooke, QC (F. D'Aragon), the Departments of Critical Care Medicine, Community Health Sciences, and Medicine, Cumming School of Medicine (C.J.D.), and the Departments of Critical Care Medicine and Clinical Neurosciences (A.H.K.), University of Calgary, and Calgary Zone, Alberta Health Services (C.J.D.), Calgary, the Department of Clinical Neurological Sciences, London Health Sciences Centre (T.G.), Schulich School of Medicine and Dentistry (T.G.), the Department of Psychology, King's University College (L.N.), and the Department of Medicine and the Brain and Mind Institute (M. Slessarev), Western University, London, ON, the Division of Critical Care, Departments of Medicine and Anesthesia, University of British Columbia, Vancouver (G.I.), the Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton (D.J.K.), the Department of Medicine, McMaster University, and Hamilton Health Sciences Centre, Hamilton, ON (M.M.), and the Division of Pediatric Intensive Care, CHU de Québec, Centre Mère-Enfant Soleil, and the Department of Pediatrics, Faculté de Médecine, Université Laval, Quebec City, QC (M.W.) - all in Canada; Safar Center for Resuscitation Research, Critical Care Medicine Department, University of Pittsburgh School of Medicine, Pittsburgh (C.D.); Charles University, Third Faculty of Medicine and FNKV University Hospital (F. Duska, M. Schmidt, P.W.), and the Department of Palliative Medicine, First Faculty of Medicine, Charles University and General University Hospital (K.R.), Prague, Czech Republic; NHS Blood and Transplant, Bristol (D.G., D.H.), and Adult Critical Care, Nottingham University Hospitals NHS Trust, Nottingham (D.G., D.H.) - both in the United Kingdom; and the Department of Intensive Care Medicine, Maastricht University Medical Center, and the School of Health Professions Education, Maastricht University (W.N.K.A.M.), and the Heart and Vascular Center, Maastricht University Medical Center (J.T.W.), Maastricht, the Netherlands.

Background: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied.

Methods: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity.

Results: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients.

Conclusions: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.).
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http://dx.doi.org/10.1056/NEJMoa2022713DOI Listing
January 2021

The economic and psychological impact of cancellations of elective spinal surgeries in the COVID-19 era.

Br J Neurosurg 2021 Jan 18:1-5. Epub 2021 Jan 18.

Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital Prague, Prague, Czech Republic.

Background: The adoption of health care restrictions due to the COVID-19 pandemic led to the cancellation of elective surgical care. However, the impact on patients is unknown.

Objective: To evaluate the psychological and economic impact of the cancellation of scheduled spinal operations.

Methods: We identified 50 patients with cancelled surgeries between 16 March 2020 and 24 April 2020. Forty-nine (98%) participants were contacted, with whom the modified WES-Pi questionnaire was filled in during a telephone interview.

Results: Of the 49 respondents, 28 (57.2%) were aged <65 years. The most often reported problem (85.7%) was an ongoing limitation in basic daily activities. At least moderate sadness was experienced by 65.3% and disappointment by 73.5% of the patients. More than 80% reported concerns about the continuation and 73.5% about the progression of their symptoms. Out of 27 employees (55.1%), 63% could not work due to severe pain or movement limitation ( < .001). The inability to work was associated with anger ( = .037). The work-related impact of the cancellation was associated with stress ( < .0001) and concerns about continuing the symptoms ( = .004). Two-third of patients would undergo immediate surgery despite the current epidemic situation.

Conclusions: The cancellations of elective spinal surgeries have a serious psychological impact on patients. This together with potential economic consequences is especially evident in employees unable to work due to pain or movement disability. The information is beneficial for health management. Every effort should be made to resume planned surgical treatment if the epidemiological situation allows it.
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http://dx.doi.org/10.1080/02688697.2020.1868404DOI Listing
January 2021

Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU.

Trials 2020 Jul 8;21(1):631. Epub 2020 Jul 8.

Czech Anaesthesia Clinical Trials and Audit Network and Department of Anaesthesia and Intensive Care, Masaryk's Hospital, Ústí nad Labem, Czech Republic.

Background: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.

Methods: Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT).

Participants: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy.

Interventions: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14.

Secondary Outcomes: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90.

Discussion: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival.

Trial Registration: Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).
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http://dx.doi.org/10.1186/s13063-020-04566-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341702PMC
July 2020

Are There Any Risk Factors Associated with the Presence of Cauda Equina Syndrome in Symptomatic Lumbar Disk Herniation?

World Neurosurg 2020 09 6;141:e600-e605. Epub 2020 Jun 6.

Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital Prague, Prague, Czech Republic.

Objective: Risk factors for developing cauda equina syndrome (CES) caused by lumbar disk herniation (LDH) remain controversial and have not been established yet. The aim of the study was to investigate whether there is a relationship among age, sex, body mass index (BMI), or the degree of spinal canal compromise and the presence of CES in patients undergoing lumbar microdiskectomy.

Methods: Between 2015 and 2019, 506 patients who had an operation for LDH compressing the dural sac were prospectively identified. The "prolapse-to-canal ratio" (PCR) was calculated as a proportion of the cross-sectional area of the disk prolapse compared with the total cross-sectional area of the spinal canal.

Results: In total, 35 CES (6.9%) patients were identified. Multivariate logistic regression, adjusted for age, gender, BMI, and PCR, shows that only PCR was associated with the presence of CES (P < 0.001, area under the curve 0.7431). BMI was not associated with an increased risk of CES.

Conclusions: This study demonstrates a significant correlation between the size of LDH relative to size of the spinal canal and the presence of CES. A finding of LDH causing >60% obstruction of the spinal canal should be considered a red flag, and such patients need to be watched more closely.
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http://dx.doi.org/10.1016/j.wneu.2020.05.260DOI Listing
September 2020

Negative prognostic impact of PD-L1 expression in tumor cells of undifferentiated (anaplastic) carcinoma with osteoclast-like giant cells of the pancreas: study of 13 cases comparing ductal pancreatic carcinoma and review of the literature.

Virchows Arch 2020 11 18;477(5):687-696. Epub 2020 May 18.

Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic.

Pancreatic carcinoma remains one of the leading cancer-related causes of death worldwide and is generally characterized by a dismal prognosis and limited potential for oncologic treatment. A rare subvariant of pancreatic cancer, undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), has an unpredictable prognosis according to many previous studies, with unexpectedly long survival in individual cases. In this study, we collected, retrospectively, 13 cases of well-documented UCOGCs and performed immunohistochemistry focused on the expression of the programmed death-ligand 1 (PD-L1) and several other potential therapeutic and predictive markers (PanTRK, p53, MSH2, PMS2, and the number of tumor-infiltrating lymphocytes), to explore their correlation with the follow-up of the patients. As a control group, we examined 24 cases of conventional pancreatic ductal adenocarcinoma (PDAC). In our results, PanTRK was negative in all 24 cases. P53 did not show any significant differences between UCOGCs and PDACs, and the entire cohort was MSH2, MLH1, PMS2, and MSH6 positive. Significant differences were present in the analysis of PD-L1: UCOGCs were found to express PD-L1 significantly more frequently and have a higher number of tumor-infiltrating lymphocytes than PDAC. The expression of PD-L1 was related to significantly shorter survival in patients with UCOGC and in the entire cohort. Patients with PD-L1 negative UCOGCs displayed surprisingly long survival in comparison to PD-L1 positive UCOGCs and PDACs (both PD-L1+ and PD-L1-). We compared our results with previously published data, and, after statistical analysis, we were able to identify PD-L1 as an effective prognostic marker of UCOGC and suggest a strong need for a clinical trial of immune checkpoint immunotherapy in patients with advanced PD-L1 positive UCOGC.
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http://dx.doi.org/10.1007/s00428-020-02830-8DOI Listing
November 2020

Effects of Rehabilitation Interventions on Clinical Outcomes in Critically Ill Patients: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Crit Care Med 2020 07;48(7):1055-1065

Department of Anaesthesia and Intensive Care, Charles University, 3 Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.

Objectives: To assess the impact of rehabilitation in ICU on clinical outcomes.

Data Sources: Secondary data analysis of randomized controlled trials published between 1998 and October 2019 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Study Selection: We have selected trials investigating neuromuscular electrical stimulation or cycling exercises or protocolized physical rehabilitation as compared to standard of care in critically ill adults.

Data Extraction: Mortality, length of stay in ICU and at hospital, days on mechanical ventilator, and adverse events.

Data Synthesis: We found 43 randomized controlled trials (nine on cycling, 14 on neuromuscular electrical stimulation alone and 20 on protocolized physical rehabilitation) into which 3,548 patients were randomized and none of whom experienced an intervention-related serious adverse event. The exercise interventions had no influence on mortality (odds ratio 0.94 [0.79-1.12], n = 38 randomized controlled trials) but reduced duration of mechanical ventilation (mean difference, -1.7 d [-2.5 to -0.8 d], n = 32, length of stay in ICU (-1.2 d [-2.5 to 0.0 d], n = 32) but not at hospital (-1.6 [-4.3 to 1.2 d], n = 23). The effects on the length of mechanical ventilation and ICU stay were only significant for the protocolized physical rehabilitation subgroup and enhanced in patients with longer ICU stay and lower Acute Physiology and Chronic Health Evaluation II scores. There was no benefit of early start of the intervention. It is likely that the dose of rehabilitation delivered was much lower than dictated by the protocol in many randomized controlled trials and negative results may reflect the failure to implement the intervention.

Conclusions: Rehabilitation interventions in critically ill patients do not influence mortality and are safe. Protocolized physical rehabilitation significantly shortens time spent on mechanical ventilation and in ICU, but this does not consistently translate into long-term functional benefit. Stable patients with lower Acute Physiology and Chronic Health Evaluation II at admission (<20) and prone to protracted ICU stay may benefit most from rehabilitation interventions.
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http://dx.doi.org/10.1097/CCM.0000000000004382DOI Listing
July 2020

Minimally invasive surgery and one-day care.

Cas Lek Cesk 2020 ;159(1):22-25

Due to population aging in developed countries, it has become necessary to prepare a functional health care plan for the elderly. One of the possibilities to improve postoperative outcomes and recovery in elderly patients is to perform common surgical procedures in the regime of one-day surgery. We compared elderly patients who underwent surgery in a large university hospital with elderly patients who underwent surgery in a facility dedicated to one-day surgery. The homogeneity and clinical outcomes of the two groups were statistically analyzed. Complications were assessed according to the Clavien-Dindo classification. There were no statistically significant differences in demographic data and pre-operative risk assessment (ASA). The one-day surgery group had fewer complications and a shorter average hospital stay. Advanced age is not the only criterion for assessing the biological state of the patient and therefore does not always necessitate surgical care in a university hospital setting with a high volume of acute and complicated cases. Many elderly patients will benefit from a more individualized approach and healthcare facilities that specialize solely in elective procedures. When indicating elderly patients for one-day surgery, their health status is more important than their calendar age.
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July 2020

Pheochromocytoma With Adrenergic Biochemical Phenotype Shows Decreased GLP-1 Secretion and Impaired Glucose Tolerance.

J Clin Endocrinol Metab 2020 06;105(6)

Center for Experimental Medicine and Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Context: Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied.

Objective: To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy.

Methods: In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins.

Results: During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet β cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01).

Conclusions: Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.
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http://dx.doi.org/10.1210/clinem/dgaa154DOI Listing
June 2020

The role of vascularization on changes in ligamentum flavum mechanical properties and development of hypertrophy in patients with lumbar spinal stenosis.

Spine J 2020 07 13;20(7):1125-1133. Epub 2020 Mar 13.

Centrum Patos, Regional Hospital Liberec, Czech Republic.

Background Context: Ligamentum flavum (LF) induced lumbar spinal stenosis (LSS) is conditioned not only by its "gathering" but especially by hypertrophy. Previous studies have examined the pathophysiology and biochemical changes that cause the hypertrophy. Some studies have described a link between chronic LF inflammation and neovascularization but others have reported highly hypovascular LF tissue in LSS patients. Currently, there is no practical application for our knowledge of the pathophysiology of the LF hypertrophy. Considerations for future treatment include influencing this hypertrophy at the level of tissue mediators, which may slow the development of LSS. To our knowledge, there is no study of micromechanical properties of native LF to date.

Purpose: (1) To clarify the changes in vascularization, chondroid metaplasia, and the presence of inflammatory cell infiltration in LF associated with LSS. (2) To quantify changes in the micromechanical properties associated with LF degenerative processes.

Study Design/setting: Vascular density analysis of degenerated and healthy human LF combined with measurement of micromechanical properties.

Methods: The study involved 35 patients who underwent surgery between November 1, 2015 and October 1, 2016. The LSS group consisted of 20 patients and the control group consisted of 15 patients. LF samples were obtained during the operation and were used for histopathological and nanoindentation examinations. Sample vascularization was examined as microvascular density (L), which was morphometrically evaluated using semiautomatic detection in conjunction with NIS-Elements AR image analysis software. Samples were also histologically examined for the presence of chondroid metaplasia and inflammation. Mechanical properties of native LF samples were analyzed using the Hysitron TI 950 TriboIndenter nanomechanical testing system.

Results: Vascular density was significantly lower in the LSS group. However, after excluding the effect of age, the difference was not significant. There was high association between L and age. With each increasing year of age, L decreased by 11.5 mm. Vascular density decreased up to the age of 50. Over the age of 50, changes were no longer significant and L appeared to stabilize. No correlation was observed between L and the presence of inflammation or metaplasia; however, LSS patients had a significantly increased incidence of chondroid metaplasia and inflammatory signs. The mechanical properties of control group samples showed significantly higher stiffness than those samples obtained from the LSS group.

Conclusion: This study showed that L changes were not dependent on LSS but were age-dependent. Vascular density was found to decrease up to the age of 50. A significantly higher incidence of chondroid metaplasia and inflammation was observed in LSS patients. The mechanical property values measured by nanoindentation showed high microstructural heterogeneity of the tested ligaments. Our results showed that healthy ligaments were significantly stiffer than LSS ligaments.

Clinical Significance: Prevention of the loss of LF vascularization during aging may influence stiffness of LF which in turn may slow down the LF degenerative processes and delay onset of LSS.
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http://dx.doi.org/10.1016/j.spinee.2020.03.002DOI Listing
July 2020

High resolution respirometry to assess function of mitochondria in native homogenates of human heart muscle.

PLoS One 2020 15;15(1):e0226142. Epub 2020 Jan 15.

OXYLAB - Laboratory of Mitochondrial Physiology, Department of Anaesthesia and Intensive Care, Third Faculty of Medicine, Charles University and FNKV University Hospital, Prague, Czech Republic.

Impaired myocardial bioenergetics is a hallmark of many cardiac diseases. There is a need of a simple and reproducible method of assessment of mitochondrial function from small human myocardial tissue samples. In this study we adopted high-resolution respirometry to homogenates of fresh human cardiac muscle and compare it with isolated mitochondria. We used atria resected during cardiac surgery (n = 18) and atria and left ventricles from brain-dead organ donors (n = 12). The protocol we developed consisting of two-step homogenization and exposure of 2.5% homogenate in a respirometer to sequential addition of 2.5 mM malate, 15 mM glutamate, 2.5 mM ADP, 10 μM cytochrome c, 10 mM succinate, 2.5 μM oligomycin, 1.5 μM FCCP, 3.5 μM rotenone, 4 μM antimycin and 1 mM KCN or 100 mM Sodium Azide. We found a linear dependency of oxygen consumption on oxygen concentration. This technique requires < 20 mg of myocardium and the preparation of the sample takes <20 min. Mitochondria in the homogenate, as compared to subsarcolemmal and interfibrillar isolated mitochondria, have comparable or better preserved integrity of outer mitochondrial membrane (increase of respiration after addition of cytochrome c is up to 11.7±1.8% vs. 15.7±3.1%, p˂0.05 and 11.7±3.5%, p = 0.99, resp.) and better efficiency of oxidative phosphorylation (Respiratory Control Ratio = 3.65±0.5 vs. 3.04±0.27, p˂0.01 and 2.65±0.17, p˂0.0001, resp.). Results are reproducible with coefficient of variation between two duplicate measurements ≤8% for all indices. We found that whereas atrial myocardium contains less mitochondria than the ventricle, atrial bioenergetic profiles are comparable to left ventricle. In conclusion, high resolution respirometry has been adapted to homogenates of human cardiac muscle and shown to be reliable and reproducible.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961865PMC
April 2020

Health-related quality of life determinants in survivors of a mass methanol poisoning outbreak: six-year prospective cohort study.

Clin Toxicol (Phila) 2020 09 8;58(9):870-880. Epub 2020 Jan 8.

Department of Occupational Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

The effect of acute methanol poisoning on the follow-up quality of life of survivors in mass poisoning outbreaks is not known. The objective of this is to study the impact of visual and central nervous system (CNS) sequelae of methanol poisoning on long-term health-related quality of life (QoL) of survivors, its clinical determinants, and dynamics. A total of 54 patients with confirmed methanol poisoning (mean age 46.7 ± 13.4 years, 9 females) were examined consequently three times within six-year prospective cohort study and compared to 23 controls with the history of chronic alcohol abuse. The following tests were performed: SF-36 QoL questionnaire, visual evoked potentials (VEP) of optic nerve, ocular examination with retinal nerve fiber layer (RNFL) thickness measurement, brain magnetic resonance imaging (MRI), and biochemical and toxicological tests. Acute methanol poisoning led to significant decrease in physical component summary (PCS) compared to PCS of age-adjusted controls (mean score with SD 46.8 ± 11.0 versus 52.3 ± 9.4 points;  = .003). In 17/40 (42.5%) patients with three rounds of examination, signs of severe disability (≤30 points in at least one score) were present six years after discharge, with negative dynamics of PCS score during the observation period. The patients with abnormal RNFL thickness had lower PCS (mean difference 10.5 points; 95%CI 3.5-17.5,  = .004) and mental component summary score (9.5 points; 95%CI 1.9-17.1,  = .015) compared to the patients with normal RNFL. Signs of physical and mental adaptation to long-term visual sequelae were registered with gradual reduction of difference in most of physical and mental components scores compared to the patients with normal RNFL during six years of observation. Signs of hemorrhagic brain lesions were associated with permanent decrease of PCS score (mean difference 7.4 points; 95%CI 0.6-14.0;  = .033), bodily pain (8.7 points; 95%CI 1.6-17.6;  = .018), and social functioning (8.2 points; 95%CI 3.0-17.4;  = .005) six years after discharge. No effect of type of antidote (fomepizole versus ethanol) and extracorporeal enhanced elimination modality (intermittent hemodialysis versus continuous renal replacement therapy) applied in hospital on long-term QoL was found (all  > .05). Acute methanol poisoning was associated with a significant decrease of health-related quality of life of survivors persisting for at least six years after discharge. The more pronounced decrease in QoL scores was observed in the patients with hemorrhagic brain lesions and visual sequelae of poisoning with abnormal RNFL thickness.
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http://dx.doi.org/10.1080/15563650.2019.1702994DOI Listing
September 2020

Using pCO Gap in the Differential Diagnosis of Hyperlactatemia Outside the Context of Sepsis: A Physiological Review and Case Series.

Crit Care Res Pract 2019 4;2019:5364503. Epub 2019 Dec 4.

Department of Anaesthesia and Intensive Care Medicine, The Third Faculty of Medicine, Charles University and FNKV University Hospital, Prague, Czech Republic.

Introduction: There is an inverse relationship between cardiac output and the central venous-arterial difference of partial pressures of carbon dioxide (pCO gap), and pCO gap has been used to guide early resuscitation of septic shock. It can be hypothesized that pCO gap can be used outside the context of sepsis to distinguish type A and type B lactic acidosis and thereby avoid unnecessary fluid resuscitation in patients with high lactate, but without organ hypoperfusion.

Methods: We performed a structured review of the literature enlightening the physiological background. Next, we retrospectively selected a series of case reports of nonseptic critically ill patients with elevated lactate, in whom both arterial and central venous blood gases were simultaneously measured and the diagnosis of either type A or type B hyperlactataemia was conclusively known. In these cases, we calculated venous-arterial CO and O content differences and pCO gap.

Results: Based on available physiological data, pCO can be considered as an acceptable surrogate of venous-arterial CO content difference, and it should better reflect cardiac output than central venous saturation or indices based on venous-arterial O content difference. In our case report of nonseptic patients, we observed that if global hypoperfusion was present (i.e., in type A lactic acidosis), pCO gap was elevated (>1 kPa), whilst in the absence of it (i.e., in type B lactic acidosis), pCO gap was low (<0.5 kPa).

Conclusion: Physiological rationale and a small case series are consistent with the hypothesis that low pCO gap in nonseptic critically ill is suggestive of the absence of tissue hypoperfusion, mandating the search for the cause of type B lactic acidosis rather than administration of fluids or other drugs aimed at increasing cardiac output.
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http://dx.doi.org/10.1155/2019/5364503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914888PMC
December 2019

Functional electrical stimulation-assisted cycle ergometry in the critically ill: protocol for a randomized controlled trial.

Trials 2019 Dec 16;20(1):724. Epub 2019 Dec 16.

Department of Anaesthesiology and Intensive Care Medicine, Charles University, 3rd Faculty of Medicine and KAR FNKV University Hospital, Fac Med 3, Srobarova 50, 10034, Prague, Czech Republic.

Background: Intensive care unit (ICU)-acquired weakness is the most important cause of failed functional outcome in survivors of critical care. Most damage occurs during the first week when patients are not cooperative enough with conventional rehabilitation. Functional electrical stimulation-assisted cycle ergometry (FES-CE) applied within 48 h of ICU admission may improve muscle function and long-term outcome.

Methods: An assessor-blinded, pragmatic, single-centre randomized controlled trial will be performed. Adults (n = 150) mechanically ventilated for < 48 h from four ICUs who are estimated to need > 7 days of critical care will be randomized (1:1) to receive either standard of care or FES-CE-based intensified rehabilitation, which will continue until ICU discharge.

Primary Outcome: quality of life measured by 36-Item Short Form Health Survey score at 6 months.

Secondary Outcomes: functional performance at ICU discharge, muscle mass (vastus ultrasound, N-balance) and function (Medical Research Council score, insulin sensitivity). In a subgroup (n = 30) we will assess insulin sensitivity and perform skeletal muscle biopsies to look at mitochondrial function, fibre typing and regulatory protein expression.

Trial Registration: ClinicalTrials.gov, NCT02864745. Registered on 12 August 2016.
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http://dx.doi.org/10.1186/s13063-019-3745-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915865PMC
December 2019

Both selective and nonselective His bundle, but not myocardial, pacing preserve ventricular electrical synchrony assessed by ultra-high-frequency ECG.

Heart Rhythm 2020 04 2;17(4):607-614. Epub 2019 Dec 2.

Cardiocenter, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.

Background: Right ventricular myocardial pacing leads to nonphysiological activation of heart ventricles. Contrary to this, His bundle pacing preserves their fast activation. Ultra-high-frequency electrocardiography (UHF-ECG) is a novel tool for ventricular depolarization assessment.

Objective: The purpose of this study was to describe UHF-ECG depolarization patterns during myocardial and His bundle pacing.

Methods: Forty-six patients undergoing His bundle pacing to treat bradycardia and spontaneous QRS complexes without bundle branch block were included. UHF-ECG recordings were performed during spontaneous rhythm, pure myocardial para-Hisian capture, and His bundle capture. QRS duration, QRS area, depolarization time in specific leads, and the UHF-ECG-derived ventricular dyssynchrony index were calculated.

Results: One hundred thirty-three UHF-ECG recordings were performed in 46 patients (44 spontaneous rhythm, 28 selective His bundle, 43 nonselective His bundle, and 18 myocardial capture). The mean QRS duration was 117 ms for spontaneous rhythm, 118 ms for selective, 135 ms for nonselective, and 166 ms for myocardial capture (P < .001 for nonselective and myocardial capture compared to each of the other types of ventricular activation). The calculated dyssynchrony index was shortest during spontaneous rhythm (12 ms; P = .02 compared to selective and P = .09 compared to nonselective), and it did not differ between selective and nonselective His bundle capture (16 vs 15 ms; P > .99) and was longest during myocardial capture of the para-Hisian area (37 ms; P < .001 compared to each of the other types of ventricular activation).

Conclusion: In patients without bundle branch block, both types of His bundle, but not myocardial, capture preserve ventricular electrical synchrony as measured using UHF-ECG.
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http://dx.doi.org/10.1016/j.hrthm.2019.11.016DOI Listing
April 2020

Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles.

PLoS One 2019 4;14(10):e0217254. Epub 2019 Oct 4.

OXYLAB - Mitochondrial Physiology Lab: Charles University, 3rd Faculty of Medicine and FNKV University Hospital, Prague, Czech Republic.

Introduction: Propofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues-a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics.

Methods: We obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5-100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes.

Results: We found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat's tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes.

Conclusion: In human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777831PMC
March 2020

Diagnosing acute acid-base disorders.

Vnitr Lek 2019 ;65(6):400-404

Traditional diagnostic approach to acute acid-base disorders is based on the assessment of bicarbonate buffer system, in which pH is determined by the ratio of [HCO3-] to pCO2. This, in turn, creates basis for distinguishing metabolic and respiratory disorders, and defines the term “compensation”. The use of electroneutrality advantageously complements the bicarbonate-based approach when dealing with complex acid-base disorders. It is possible to simplify this approach so it can be applied only using mental arithmetics. In principle, the space created by strong ion difference (which can be simplified to [Na+]-[Cl-]) is shared by negative charges on albumin and bicarbonate. In turn, a shrinkage of this space ([Na+]-[Cl-]  36 mM causes alka-losis, as well as a decrease in albumin concentration (for every 10 g/L of albumin, 3 mM is freed to be occupied by [HCO3-]). Lastly, if the sum of negative charges on albumin and [HCO3-] is lower than estimated strong ion difference, an unmeasured anion must be present. This concept is explained on commented case reports.
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October 2019

Efficacy and safety of 1C class antiarrhythmic agent (propafenone) for supraventricular arrhythmias in septic shock compared to amiodarone: protocol of a prospective randomised double-blind study.

BMJ Open 2019 09 3;9(9):e031678. Epub 2019 Sep 3.

Anaesthesia and Intensive Care, 1st Medical Faculty, Charles University and General University Hospital in Prague, Prague, Czech Republic, EU.

Introduction: Supraventricular arrhythmias contribute to haemodynamic compromise in septic shock. A retrospective study generated the hypothesis that propafenone could be more effective than amiodarone in achieving and maintaining sinus rhythm (SR). Certain echocardiographic parameters may predict a successful cardioversion and help in the decision on rhythm or rate control strategy.

Methods And Analysis: The trial includes septic shock patients with new-onset arrhythmia, but without severe impairment of the left ventricular ejection fraction. After baseline echocardiography, the patient is randomised to receive a bolus and maintenance dose of either amiodarone or propafenone. The primary outcome is the proportion of patients that have achieved rhythm control at 24 hours after the start of the infusion. The secondary outcomes are the percentages of patients that needed rescue treatments (DC cardioversion or unblinding and crossover of the antiarrhythmics), the recurrence of arrhythmias, intensive care unit mortality, 28-day and 1-year mortality. In the posthoc analysis, we separately assess subgroups of patients with pulmonary hypertension and right ventricular dysfunction. In the exploratory part of the study, we assess whether the presence of a transmitral diastolic A wave and its higher velocity-time integral is predictive for the sustainability of mechanical SR and whether the indexed left atrial endsystolic volume is predictive of recurrent arrhythmia. Considering that the restoration of SR within 24 hours occurred in 74% of the amiodarone-treated patients and in 89% of the patients treated with propafenone, we plan to include 200 patients to have an 80% chance to demonstrate the superiority of propafenone at p=0.05.

Ethics And Dissemination: The trial is recruiting patients according to its second protocol version approved by the University Hospital Ethical Board on the 6 October 2017 (No. 1691/16S-IV). The results will be disseminated through peer reviewed publications and conference presentations.

Trial Registration Number: NCT03029169.
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http://dx.doi.org/10.1136/bmjopen-2019-031678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731952PMC
September 2019

Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient: a cross-sectional study.

Crit Care 2019 05 22;23(1):185. Epub 2019 May 22.

Department of Intensive Care Medicine, Research VUmc Intensive Care (REVIVE), Amsterdam Medical Data Science (AMDS), Amsterdam Cardiovascular Sciences (ACS), Amsterdam Infection and Immunity Institute (AI&II), Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.

Methods: In May 2018, we carried out a cross-sectional study by sending out an online survey on antibiotic dosing to more than 20,000 intensive care professionals. Questions were designed to cover relevant topics in pharmacokinetics related to intensive care antibiotic dosing. The preliminary pass mark was set by members of the examination committee for the European Diploma of Intensive Care using a modified Angoff approach. The final pass mark was corrected for clinical relevance as assessed for each question by international experts on pharmacokinetics.

Results: A total of 1448 respondents completed the survey. Most of the respondents were intensivists (927 respondents, 64%) from 97 countries. Nearly all questions were considered clinically relevant by pharmacokinetic experts. The pass mark corrected for clinical relevance was 52.8 out of 93.7 points. Pass rates were 42.5% for intensivists, 36.1% for fellows, 24.8% for residents, and 5.8% for nurses. Scores without correction for clinical relevance were worse, indicating that respondents perform better on more relevant topics. Correct answers and concise clinical background are provided.

Conclusions: Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient. This should be addressed given the importance of adequate antibiotic exposure in critically ill patients with sepsis. Solutions include improved education, intensified pharmacy support, therapeutic drug monitoring, or the use of real-time bedside dosing software. Questions may provide useful for teaching purposes.
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http://dx.doi.org/10.1186/s13054-019-2438-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532162PMC
May 2019

Blood Pressure Profile, Catecholamine Phenotype, and Target Organ Damage in Pheochromocytoma/Paraganglioma.

J Clin Endocrinol Metab 2019 11;104(11):5170-5180

Center of Hypertension, Third Department of Medicine, First Faculty of Medicine and General Faculty Hospital, Charles University in Prague, Prague 2, Czech Republic.

Context: Impaired diurnal blood pressure (BP) variability is related to higher cardiovascular risk.

Objective: To assess diurnal variability of BP and its relation to target organ damage (TOD) and catecholamine phenotype in a consecutive sample of pheochromocytoma/paraganglioma (PPGL).

Design: We included 179 patients with PPGL All patients underwent 24 hours of ambulatory BP monitoring to determine dipping status. Differences in plasma metanephrine or urine adrenaline were used to distinguish catecholamine biochemical phenotype. To evaluate TOD, renal functions, presence of left ventricle hypertrophy (LVH), and the subgroup (n = 111) carotid-femoral pulse wave velocity (PWV) were assessed. Structural equation modeling was used to find the relationship among nocturnal dipping, catecholamine phenotype, and TOD parameters.

Results: According to the nocturnal dipping, patients were divided into the three groups: dippers (28%), nondippers (40%), and reverse dippers (32%). Reverse dippers were older (P < 0.05), with a higher proportion of noradrenergic (NA) phenotype (P < 0.05), a higher prevalence of diabetes mellitus (P < 0.05), and sustained arterial hypertension (P < 0.01) and its duration (P < 0.05), as opposed to the other groups. All parameters of TOD were more pronounced only in reverse dippers compared with nondippers and dippers. The presence of NA phenotype (=absence of adrenaline production) was associated with reverse dipping and TOD (LVH and PWV).

Conclusions: Patients with reverse dipping had more substantial TOD compared with other groups. The NA phenotype plays an important role, not only in impaired diurnal BP variability but also independently from dipping status in more pronounced TOD of heart and vessels.
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http://dx.doi.org/10.1210/jc.2018-02644DOI Listing
November 2019

Lactate production without hypoxia in skeletal muscle during electrical cycling: Crossover study of femoral venous-arterial differences in healthy volunteers.

PLoS One 2019 1;14(3):e0200228. Epub 2019 Mar 1.

Department of Anaesthesia and Intensive Care Medicine, Kralovske Vinohrady University Hospital and The Third Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: Aim of the study was to compare metabolic response of leg skeletal muscle during functional electrical stimulation-driven unloaded cycling (FES) to that seen during volitional supine cycling.

Methods: Fourteen healthy volunteers were exposed in random order to supine cycling, either volitional (10-25-50 W, 10 min) or FES assisted (unloaded, 10 min) in a crossover design. Whole body and leg muscle metabolism were assessed by indirect calorimetry with concomitant repeated measurements of femoral venous-arterial differences of blood gases, glucose, lactate and amino acids.

Results: Unloaded FES cycling, but not volitional exercise, led to a significant increase in across-leg lactate production (from -1.1±2.1 to 5.5±7.4 mmol/min, p<0.001) and mild elevation of arterial lactate (from 1.8±0.7 to 2.5±0.8 mM). This occurred without widening of across-leg veno-arterial (VA) O2 and CO2 gaps. Femoral SvO2 difference was directly proportional to VA difference of lactate (R2 = 0.60, p = 0.002). Across-leg glucose uptake did not change with either type of exercise. Systemic oxygen consumption increased with FES cycling to similarly to 25W volitional exercise (138±29% resp. 124±23% of baseline). There was a net uptake of branched-chain amino acids and net release of Alanine from skeletal muscle, which were unaltered by either type of exercise.

Conclusions: Unloaded FES cycling, but not volitional exercise causes significant lactate production without hypoxia in skeletal muscle. This phenomenon can be significant in vulnerable patients' groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396965PMC
December 2019

Immature granulocytes as a sepsis predictor in patients undergoing cardiac surgery.

Interact Cardiovasc Thorac Surg 2019 06;28(6):845-851

Department of Anaesthesiology, Resuscitation and Intensive Medicine, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Objectives: Usefulness of immature granulocyte percentage (IG%) to discriminate between postoperative non-infective systemic inflammatory response syndrome (SIRS) and sepsis was tested in cardiac surgical patients.

Methods: A retrospective analysis of 124 patients who developed non-infective SIRS and sepsis after elective cardiac surgery was performed. Predictive ability of IG% to predict sepsis was compared to procalcitonin (PCT), white blood cell count, temperature and different biomarker combinations using receiver operating characteristic and logistic regression analysis. The optimal cut-off points, diagnosis sensitivity and specificity were calculated.

Results: There were 44 patients diagnosed with sepsis and 80 patients with non-infective SIRS. In receiver operating characteristic analysis, area under the curve was higher for IG% (0.71) and PCT (0.72) compared to white blood cell count (0.62) and temperature (0.58). The best cut-off value for IG% was 1.45% (sensitivity 70.5%, specificity 60%) and 1.43 µg/l for PCT (sensitivity 65.9%, specificity 75%). The combination of IG% and PCT provided the best sepsis prediction (area under the curve of 0.8, sensitivity 63.6% and specificity 88.8%).

Conclusions: In cardiac surgical patients, IG% is a helpful marker with the moderate ability to discriminate between sepsis and non-infective SIRS, comparable to serum PCT. A combination of these parameters increased the test's overall predictive ability by improving its specificity.
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http://dx.doi.org/10.1093/icvts/ivy360DOI Listing
June 2019

Epidemiology, etiology, and types of severe adult brachial plexus injuries requiring surgical repair: systematic review and meta-analysis.

Neurosurg Rev 2020 Apr 17;43(2):443-452. Epub 2018 Jul 17.

Department of Plastic Surgery, First Faculty of Medicine, Charles University and Hospital Na Bulovce, Prague, Czech Republic.

The literature describing epidemiology, etiology, and types of serious brachial plexus injuries (BPIs) is sparse. The aim of this review was to investigate the epidemiological and etiopathogenetical data of serious BPIs undergoing surgical reconstruction. A systematic search was conducted from January 1985 to December 2017. All studies that reported data about prevalence of specific types and causes of BPIs in adults treated surgically were included and cumulatively analyzed. Ten studies including 3032 patients were identified. The pooled prevalence of closed BPIs was 93% (95% CI: 87-97%), lacerations accounted for 3% (95% CI: 1-6%), and gunshot wounds (GSWs) for 3% (95% CI: 0-7%). The prevalence of male patients was 93% (95% CI: 90-96%) and female cases 7% (95% CI: 4-10%). The most common cause of closed BPI was motorcycle accidents with 67% (95% CI: 49-82%) prevalence followed by car crashes with 14% (95% CI: 8-20%). Other causes were rare. Ninety percent (95% CI: 78-98%) of patients suffered from a supraclavicular or combined supra-/infraclavicular trauma, while 10% (95% CI: 2-22%) from isolated infraclavicular injury. The prevalence of complete lesions was 53% (95% CI: 47-58%) followed by upper plexus lesion with 39% (95% CI: 31-48%) and lower plexus injury with 6% (95% CI: 1-12%). This meta-analysis demonstrates that the typical patient suffering from severe BPI is a male after motorcycle accident with closed supraclavicular injury causing complete or slightly less commonly upper plexus palsy. Lacerations and GSWs of brachial plexus are rare.
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http://dx.doi.org/10.1007/s10143-018-1009-2DOI Listing
April 2020

Time Factor and Disc Herniation Size: Are They Really Predictive for Outcome of Urinary Dysfunction in Patients With Cauda Equina Syndrome?

Neurosurgery 2018 12;83(6):1193-1200

The Centre for Spinal Studies and Surgery, QMC, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Background: Timing of surgery and the importance of the size of disc prolapse in cauda equina syndrome (CES) remain controversial.

Objective: To investigate whether there is a relationship between postoperative urinary function, preoperative duration of neurogenic lower urinary tract dysfunction (NLUTD), and the level of canal compromise.

Methods: Seventy-one patients operated for CES were prospectively identified between 2010 and 2013. Fifty-two cases with preoperative NLUTD were included. The "Prolapse: Canal ratio" (PCR) was calculated as a proportion of cross-sectional area of disc prolapse on total cross-sectional area of spinal canal.

Results: Median of preoperative duration of NLUTD was 72 h (48; 132) and period from first assessment to surgery 10.5 h (7; 18.5). Urinary incontinence was seen in 46.2% of patients, 38.4% had painless retention and 15.4% had painful retention. In 38.5% of cases, urinary symptoms persisted for more than 20 mo postoperatively. There was no correlation between duration of preoperative NLUTD and urinary dysfunction persistence (P = .921). The outcome was not significantly influenced by having surgery more than the 48 h after presentation (P = .135). Preoperative incontinence persisted in 58% and painless retention in 30% of cases. The mean PCR was 0.6 ± 0.18. There was no correlation between PCR and outcome (P = .537) even after adjusting for duration of preoperative NLUTD (P = .7264).

Conclusion: No significant correlation was demonstrated between the preoperative duration of urinary dysfunction, the size of disc herniation relative to size of spinal canal, and postoperative urinary function in a large consecutive series of patients with CES.
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http://dx.doi.org/10.1093/neuros/nyx607DOI Listing
December 2018

Effects of Propofol on Cellular Bioenergetics in Human Skeletal Muscle Cells.

Crit Care Med 2018 03;46(3):e206-e212

Department of Anaesthesia and Intensive Care of Královské Vinohrady University Hospital and The Third Faculty of Medicine, OXYLAB-Laboratory for Mitochondrial Physiology, Charles University, Prague, Czech Republic.

Objectives: Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells.

Design: In vitro study on human skeletal muscle cells.

Settings: University research laboratories.

Subjects: Patients undergoing hip surgery and healthy volunteers.

Interventions: Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1-10 μg/mL propofol for 96 hours.

Measurements And Main Results: Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II-IV. Although cell survival and basal oxygen consumption rate were only affected by 10 μg/mL of propofol, concentrations as low as 1 μg/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated.

Conclusions: Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria.
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http://dx.doi.org/10.1097/CCM.0000000000002875DOI Listing
March 2018
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