Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation... Show moreRationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear.Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy.Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (Pa-O2, 55-80mmHg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (Pa-O2, 110-150mmHg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included.Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved Pa-O2 was 75mmHg (interquartile range, 70-84) and 115mmHg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively.Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Show less
Background: Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is... Show moreBackground: Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is associated with poor patient-centered outcomes. Nevertheless, a fundamental knowledge gap remains regarding optimal oxygenation for critically ill patients. In this randomized clinical trial, we aim to compare ventilation that uses conservative oxygenation targets with ventilation that uses conventional oxygen targets with respect to mortality in ICU patients.Methods: The "ConservatIve versus CONventional oxygenation targets in Intensive Care patients" trial (ICONIC) is an investigator-initiated, international, multicenter, randomized clinical two-arm trial in ventilated adult ICU patients. The ICONIC trial will run in multiple ICUs in The Netherlands and Italy to enroll 1512 ventilated patients. ICU patients with an expected mechanical ventilation time of more than 24 h are randomized to a ventilation strategy that uses conservative (PaO2 55-80 mmHg (7.3-10.7 kPa)) or conventional (PaO2 110-150 mmHg (14.7-20 kPa)) oxygenation targets. The primary endpoint is 28-day mortality. Secondary endpoints are ventilator-free days at day 28, ICU mortality, in-hospital mortality, 90-day mortality, ICU- and hospital length of stay, ischemic events, quality of life, and patient opinion of research and consent in the emergency setting.Discussion: The ICONIC trial is expected to provide evidence on the effects of conservative versus conventional oxygenation targets in the ICU population. This study may guide targeted oxygen therapy in the future. Show less
Moes, D.J.A.R.; Westerloo, D.J. van; Arend, S.M.; Swen, J.J.; Vries, A. de; Guchelaar, H.J.; ... ; Paassen, J. van 2021
Background and Objective In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including... Show moreBackground and Objective In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients. Methods This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed. Results Overall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (V-d) was 4.34 L, maximum elimination rate (V-max) was 4.19 mu g/day, and concentration at which the elimination pathway is half saturated (K-m) was 0.22 mu g/mL. Interindividual variability was identified for CL (18.9%) and V-d (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUC(inf 1st DOSE)) was 938 [+/- 190] mu g/mL*days. All patients had tocilizumab exposure above 1 mu g/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing. Conclusions This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation. Show less
In the last decade, ultrasound has found its place in the intensive care unit (ICU). Initially, ultrasound was used primarily to increase the safety and efficacy of line insertion, but currently... Show moreIn the last decade, ultrasound has found its place in the intensive care unit (ICU). Initially, ultrasound was used primarily to increase the safety and efficacy of line insertion, but currently many intensivists use point-of-care ultrasound (POCUS) to aid in making the diagnosis, monitoring therapy, and supporting therapeutic interventions. In this series, we aim to highlight one specific POCUS technique at a time, which we believe will prove to be useful in your clinical practice. This specific article will focus on assessment of right ventricular (RV) size and function, and the application of tricuspid annular plane systolic excursion (TAPSE). RV assessment during focused cardiac ultrasound (FoCUS) depends, currently, on visual evaluation - 'eyeballing' - of the RV size and function and left and right ventricular interaction. However, 'eyeballing' is subjective, depends on experience and may be misleading if done by unexperienced sonographers. Objective measurements of RV size and function are necessary and provide an additional understanding of RV performance. There are different ways to assess the RV objectively. Many of these measurements, however, require a lot of training and are not yet available in portable devices. Evaluation of TAPSE is a validated and reproducible way of evaluating RV function and only requires the utilisation of M-mode or a 2D measurement. TAPSE, assessed in the apical four-chamber view, is sometimes difficult to measure, especially in mechanically ventilated patients. In recent years subcostal variants have been introduced: the subcostal echocardiographic assessment of tricuspid annular kick (SEATAK) and the subcostal-TAPSE (S-TAPSE). These measurements are alternatives when the 'classical' TAPSE cannot reliably be evaluated. Show less
This article is part of the point-of-care ultrasound (POCUS) series. During cardiopulmonary resuscitation, bedside ultrasound has important clinical value for confirming a diagnosis, establishing a... Show moreThis article is part of the point-of-care ultrasound (POCUS) series. During cardiopulmonary resuscitation, bedside ultrasound has important clinical value for confirming a diagnosis, establishing a prognosis and in therapeutic decision-making. In this article we provide a practical review on how to implement and apply POCUS during cardiopulmonary resuscitation and discuss its merits and pitfalls. Show less
Vos, J.; Westerloo, D.J. van; Kleinsteuber, S.P.C.; Prehn, J. van; Arbous, M.S. 2021
In the last decade, ultrasound has found its place in the intensive care unit (ICU). Initially, ultrasound was used primarily to increase the safety and efficacy of line insertion, but now many... Show moreIn the last decade, ultrasound has found its place in the intensive care unit (ICU). Initially, ultrasound was used primarily to increase the safety and efficacy of line insertion, but now many intensivists use point-of-care ultrasound (POCUS) to aid in diagnosis, assess therapy and support therapeutic interventions. In this series, we aim to highlight one specific POCUS technique at a time, which we believe will prove to be useful in your clinical practice. Focused cardiac ultrasound (FoCUS) is an important tool for the intensivist and can help in, among other things, diagnosing undifferentiated shock, evaluating the response to therapy and guiding procedures. FoCUS has, until recently, been performed with transthoracic echocardiography (TTE). FoCUS-TTE is, however, not always possible and not without problems. In this issue, we aim to describe the merits and pitfalls of focused transoesophageal echocardiography (FoCUS-TEE) in the ICU. Show less
Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria... Show moreSystemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. Young (2 months) and middle-aged mice (13-14 months) were intraperitoneally challenged with live Escherichia coli (E. coli) or saline. The mice were sacrificed at 2, 3 and 7 days after inoculation; for all time points, the mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h after inoculation. Microglial response was monitored by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry, and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. We observed an increased microglial cell number and moderate morphologically activated microglial cells in middle-aged mice, as compared to young mice, after intraperitoneal challenge with live E. coli. Flow cytometry of microglial cells showed higher CD45 and CD11b expressions in middle-aged infected mice compared to young infected mice. The brain expression levels of pro-inflammatory genes were higher in middle-aged than in young infected mice, while middle-aged infected mice had similar expression levels of these genes in the systemic compartment. We conclude that systemic challenge with live bacteria causes an age-dependent neuro-inflammatory and microglial response. Our data show signs of an age-dependent disconnection of the inflammatory transcriptional signature between the brain and the systemic compartment. Show less
Background: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in... Show moreBackground: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients.Methods: Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints.Results: We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging - 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor.Conclusions: Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days. Show less
In the last docade ultrasound has found its place in the intensive care unit. Initially, ultrasound was used primarily to increase safety and efficacy of line insertions but now many intensivists... Show moreIn the last docade ultrasound has found its place in the intensive care unit. Initially, ultrasound was used primarily to increase safety and efficacy of line insertions but now many intensivists use point-of-care ultrasound (POCUS) to aid in diagnosis, assessment of therapy and to guide therapeutic interventions. In this series we aim to highlight one specific POCUS technique at a time, which we believe will prove to be useful in clinical practice. Our aim is to provide the reader with a short and practical description of the technique as well as its merits and pitfalls. In this issue we describe the use of the rapid ultrasound in shock (RUSH) protocol to quickly investigate shock in the ICU. Show less
Background: Using ultrasound as a guidance tool during central venous catheter placement has repeatedly been shown to improve procedural safety. More recent evidence has shown its potential as a... Show moreBackground: Using ultrasound as a guidance tool during central venous catheter placement has repeatedly been shown to improve procedural safety. More recent evidence has shown its potential as a diagnostic modality to detect placement-associated complications. A protocol combining these modalities is lacking. This article uses the Indication, Acquisition, Interpretation and Medical decision-making (I-AIM) model, common to other ultrasound protocols, to provide a systematic ultrasound approach to guide central venous catheter placement and assess potential related complications. It is part of a larger series published in this journal.Methods: Relevant articles were found in a thorough search in PubMed using the MeSH terms: "diagnostic imaging" or "ultrasonography" or "sonography" and "central venous catheter" or "central venous cannulation" and "complications" or "placement procedure". Studies conducted on patients younger than 18 years and studies conducted in animals were excluded. Two independent researchers evaluated the articles for relevance and quality. The results of the various studies were used to create the following structured ultrasound approach.Recommended approach: Following the I-AIM model, acquiring the most valuable images is subdivided into patient, probe, picture and protocol considerations. Ultrasound guidance during central venous catheter placement should be conducted in four steps: pre-cannulation, confirming patency, dynamic guidance during insertion, and confirmation of intravenous central venous catheter position. After these steps, ultrasound should be used in the diagnostic evaluation of malposition and iatrogenic pneumothorax.Conclusions: This model provides a comprehensive and ready to use ultrasound approach to guide central venous catheter placement and assess potential placement associated complications. Show less
Background: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor... Show moreBackground: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor it, despite the fact that little is known about the ultrasound appearance due to the novelty of the illness. The aim of this manuscript is to characterise the lung ultrasonographic appearance of critically ill patients with SARS-CoV-2 pneumonia, with particular emphasis on its relationship with the time course of the illness and clinical parameters.Methods: Adult patients from the intensive care unit of two academic hospitals who tested positive for SARS-CoV-2 were included. Images were analysed using internationally recognised techniques which included assessment of the pleura, number of B-lines, pathology in the PLAPS (posterolateral alveolar and/or pleural syndrome) point, bedside lung ultrasound in emergency profiles, and the lung ultrasound score. The primary outcomes were frequencies, percentages and differences in lung ultrasound findings overall and between short (<= 14 days) and long (>14 days) durations of symptoms and their correlation with clinical parameters.Results: In this pilot observational study, 61 patients were included with 76 examinations available for analysis. 26% of patients had no anterior lung abnormalities, while the most prevalent pathological ultrasound findings were thickening of the pleura (42%), >= 3 B-lines per view (38%) and presence of PLAPS (74%). Patients with "long" duration of symptoms presented more frequently with a thickened and irregular pleura (32 (21%) versus 11 (9%)), C-profile (18 (47%) versus 8 (25%)) and pleural effusion (14 (19%) versus 3 (5%)), compared to patients with short duration of symptoms. Lung ultrasound findings did not correlate with arterial oxygen tension/inspiratory oxygen fraction ratio, fluid balance or dynamic compliance.Conclusion: SARS-CoV-2 results in significant, but not specific, ultrasound changes, with decreased lung sliding, thickening of the pleura and a B-profile being the most commonly observed. With time, a thickened and irregular pleura, C-profile and pleural effusion become more common findings. When screening patients, a comprehensive ultrasound protocol might be necessary. Show less
Grim, C.C.A.; Helmerhorst, H.J.F.; Schultz, M.J.; Winters, T.; Voort, P.H.J. van der; Westerloo, D.J. van; Jonge, E. de 2020
BACKGROUND: Little is known to what extent attitudes of ICU clinicians are influenced by new insights and recommendations to be more conservative with oxygen therapy. Our aim was to investigate... Show moreBACKGROUND: Little is known to what extent attitudes of ICU clinicians are influenced by new insights and recommendations to be more conservative with oxygen therapy. Our aim was to investigate whether implementation of a conservative oxygenation guideline structurally changed self-reported attitudes and actual clinical practice. METHODS: After the implementation of a conservative oxygen therapy guideline in 3 teaching hospitals in the Netherlands, ICU clinicians were surveyed regarding their attitudes toward oxygen therapy. The survey results were compared with survey results taken before the introduction of the new guideline. Arterial blood gas analysis data and ventilator settings were retrieved from all patients admitted to the participating ICUs in the studied period, and changes after implementing the guideline were assessed. RESULTS: In total, 180 ICU clinicians returned the survey. Compared to before implementation of a conservative oxygen guideline, more clinicians chose a preferred P-aO2 and an oxygen saturation measured from an arterial sample (S-aO2) limit after implementation of the guideline. In general, clinicians reported a more conservative approach toward management of F(IO2 )and less frequently increased the F-IO2. In the period after the active implementation of the guideline, 5,840 subjects were admitted to the participating ICUs and 101,869 arterial blood gas analyses were retrieved. Actual practice changed with overall lower oxygenation levels (median P-aO2 77.93 mm Hg, compared to 86.93 mm Hg before implementation) of arterial blood and a decrease of PEEP and F-IO2. CONCLUSIONS: Implementing a conservative oxygenation guideline was an effective method that changed self-reported attitudes and actual clinical practice and improved adherence to conservative oxygenation targets in a short period of time. Show less
Vreeswijk, S.M.E.; Arbous, M.S.; Matta, J.E.L.; Westerloo, D.J. van 2020
We present a case of a 30-year-old man who developed exertional heatstroke which was complicated by liver failure. He was transferred to our centre for a possible liver transplantation but... Show moreWe present a case of a 30-year-old man who developed exertional heatstroke which was complicated by liver failure. He was transferred to our centre for a possible liver transplantation but unfortunately succumbed to multiorgan failure. In a review of literature we discuss the diagnosis and treatment of heatstroke, the possible underlying pathophysiology and overlap with malignant hyperthermia. Show less
This article is part of the point-of-care ultrasound (POCUS) series. During the Coronavirus Disease 2019 (COVID-19) pandemic, we have been managing large numbers of infected patients whilst... Show moreThis article is part of the point-of-care ultrasound (POCUS) series. During the Coronavirus Disease 2019 (COVID-19) pandemic, we have been managing large numbers of infected patients whilst maintaining high-quality healthcare. In this article we aim to provide a short and practical description on how point-of-care lung ultrasound can be of use to facilitate diagnosis and treatment in critically ill patients diagnosed with COVID-19. Show less
We present the case of a 45-year-old patient who was brought to our emergency department with an out-of-hospital cardiac arrest. The patient arrived 45 minutes after collapse due to ventricular... Show moreWe present the case of a 45-year-old patient who was brought to our emergency department with an out-of-hospital cardiac arrest. The patient arrived 45 minutes after collapse due to ventricular fibrillation. The initial rhythm at arrival to the emergency department was asystole. His laboratory results showed profound lactic acidosis (lactate of 21 mmol/l and pH of 6.6). Time to arrival, rhythm at presentation and the observed lactic acidosis were all interpreted as prognostic signs of a poor outcome but, despite that, it was decided to treat the patient with extracorporeal cardiopulmonary resuscitation (ECPR). Subsequently percutaneous coronary intervention was performed. In contrast to the poor prognosis, the patient was discharged on day 6 with no discernible neurological deficit. This case illustrates that despite biochemical data suggesting profound tissue ischaemia/hypoxia, the outcome of ECPR may be excellent. Such data cannot be reliably used as a single indicator to decide whether or not ECPR should be initiated. Show less
Background: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen... Show moreBackground: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen therapy by clinicians from a large representative sample of intensive care units (ICUs) in the Netherlands.Methods: In April 2019, 36 ICUs in the Netherlands were approached and asked to send out a questionnaire (59 questions) to their nursing and medical staff (ICU clinicians) eliciting self-reported behaviour and attitudes towards oxygen therapy in general and in specific ICU case scenarios.Results: In total, 1361 ICU clinicians (71% nurses, 24% physicians) from 28 ICUs returned the questionnaire. Of responding ICU clinicians, 64% considered oxygen-induced lung injury to be a major concern. The majority of respondents considered a partial pressure of oxygen (PaO2) of 6-10 kPa (45-75 mmHg) and an arterial saturation (SaO(2)) of 85-90% as acceptable for 15 minutes, and a PaO2 7-To kPa (53-75 mmHg) and SaO(2) 90-95% as acceptable for 24-48 hours in an acute respiratory distress syndrome (ARDS) patient. In most case scenarios, respondents reported not to change the fraction of inspired oxygen (FiO(2)) if SaO(2) was 90-95% or PaO2 was 12 kPa (90 mmHg).Conclusion: A representative sample of ICU clinicians from the Netherlands were concerned about oxygen-induced lung injury, and reported that they preferred PaO2 and SaO(2) targets in the lower physiological range and would adjust ventilation settings accordingly. Show less
In the last decade ultrasound has found its place in the intensive care unit. Initially ultrasound was used primarily to increase safety and efficacy of line insertion but now many intensivists use... Show moreIn the last decade ultrasound has found its place in the intensive care unit. Initially ultrasound was used primarily to increase safety and efficacy of line insertion but now many intensivists use point-of-care ultrasound (POCUS) to aid in diagnosis, assessment of therapy and therapeutic interventions. In this series we aim to highlight one specific POCUS technique at a time, which we believe will prove to be useful in your clinical practice. In this issue our aim is to provide you with a short and practical description of the measurement of E-point septal separation to identify a severely reduced left ventricular ejection fraction. Show less
