Name: observational study protocol for repeated clinical examination and critical care ultrasonography within the simple intensive care studies
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Description: Watch this Scientific Journal Video about Observational Study Protocol for Repeated Clinical Examination and Critical Care Ultrasonography Within the Simple Intensive Care Studies at JoVE.com

We would like to thank all members of the SICS-Study group that have been involved within the SICS-I and have participated in brainstorm sessions about the current protocol. We would also like to thank the research bureau of our Critical Care department and its coordinators for their support; dr. W. Dieperink and M. Onrust. Furthermore, we would like to thank the ICU Studentsteam and the student-researchers who have structurally included patients into SICS-II so far; J. A. de Bruin, B. E. Keuning, drs. K. Selles.

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B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Restricting+volumes+of+resuscitation+fluid+in+adults+with+septic+shock+after+initial+management:+the+CLASSIC+randomised,+parallel-group,+multicentre+feasibility+trial.">Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial.</a> Intensive Care Medicine. 42 (11), 1695-1705 (2016).</li><li>Prowle, J. R., Kirwan, C. J., Bellomo, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluid+management+for+the+prevention+and+attenuation+of+acute+kidney+injury.">Fluid management for the prevention and attenuation of acute kidney injury.</a> Nature reviews. Nephrology. 10 (1), 37-47 (2014).</li><li>Gambardella, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Congestive+kidney+failure+in+cardiac+surgery:+the+relationship+between+central+venous+pressure+and+acute+kidney+injury.">Congestive kidney failure in cardiac surgery: the relationship between central venous pressure and acute kidney injury.</a> Interactive CardioVascular and Thoracic Surgery. 23 (5), 800-805 (2016).</li><li>Chen, K. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peripheral+Edema,+Central+Venous+Pressure,+and+Risk+of+AKI+in+Critical+Illness.">Peripheral Edema, Central Venous Pressure, and Risk of AKI in Critical Illness.</a> Clinical journal of the American Society of Nephrology : CJASN. 11 (4), 602-608 (2016).</li><li>Song, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Value+of+the+combination+of+renal+resistance+index+and+central+venous+pressure+in+the+early+prediction+of+sepsis-induced+acute+kidney+injury.">Value of the combination of renal resistance index and central venous pressure in the early prediction of sepsis-induced acute kidney injury.</a> Journal of critical care. 45, 204-208 (2018).</li><li>Zhang, L., Chen, Z., Diao, Y., Yang, Y., Fu, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Associations+of+fluid+overload+with+mortality+and+kidney+recovery+in+patients+with+acute+kidney+injury:+A+systematic+review+and+meta-analysis.">Associations of fluid overload with mortality and kidney recovery in patients with acute kidney injury: A systematic review and meta-analysis.</a> Journal of Critical Care. 30 (4), (2015).</li><li>Simple Intensive Care Studies II - Full Text View. ClinicalTrials.gov Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT03577405">https://clinicaltrials.gov/ct2/show/NCT03577405</a> (2018)</li><li>Statistical analysis plan Simple Intensive Care Studies-I DETAILED STATISTICAL ANALYSIS PLAN (SAP) 1. Administrative information 1.1. Title, registration, versions and revisions. ClinicalTrials.gov Available from: <a target="_blank" href="https://clinicaltrials.gov/ProvidedDocs/24/NCT02912624/SAP_000.pdf">https://clinicaltrials.gov/ProvidedDocs/24/NCT02912624/SAP_000.pdf</a> (2018)</li><li>Simple Observational Critical Care Studies - Full Text View - ClinicalTrials.gov. ClinicalTrials.gov Available from: <a target="_blank" href="https://clinicaltrials.gov/ct2/show/NCT03553069">https://clinicaltrials.gov/ct2/show/NCT03553069</a> (2018)</li><li>Ait-Oufella, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alteration+of+skin+perfusion+in+mottling+area+during+septic+shock.">Alteration of skin perfusion in mottling area during septic shock.</a> Annals of Intensive Care. 3 (1), 31 (2013).</li><li>Teasdale, G., Jennett, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+Coma+and+Impaired+Consciousness:+A+Practical+Scale.">Assessment of Coma and Impaired Consciousness: A Practical Scale.</a> The Lancet. 304 (7872), 81-84 (1974).</li><li>Detsky, M. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Discriminative+Accuracy+of+Physician+and+Nurse+Predictions+for+Survival+and+Functional+Outcomes+6+Months+After+an+ICU+Admission.">Discriminative Accuracy of Physician and Nurse Predictions for Survival and Functional Outcomes 6 Months After an ICU Admission.</a> JAMA. 317 (21), 2187 (2017).</li><li>Lipson, A. R., Miano, S. J., Daly, B. J., Douglas, S. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Accuracy+of+Nurses'+Predictions+for+Clinical+Outcomes+in+the+Chronically+Critically+Ill.">The Accuracy of Nurses' Predictions for Clinical Outcomes in the Chronically Critically Ill.</a> Research &amp; reviews. Journal of nursing and health sciences. 3 (2), 35-38 (2017).</li><li>Lichtenstein, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=BLUE-protocol+and+FALLS-protocol:+two+applications+of+lung+ultrasound+in+the+critically+ill.">BLUE-protocol and FALLS-protocol: two applications of lung ultrasound in the critically ill.</a> Chest. 147 (6), 1659-1670 (2015).</li><li>Tang, W. H. W., Kitai, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intrarenal+Venous+Flow:+A+Window+Into+the+Congestive+Kidney+Failure+Phenotype+of+Heart+Failure.">Intrarenal Venous Flow: A Window Into the Congestive Kidney Failure Phenotype of Heart Failure.</a> JACC: Heart Failure. 4 (8), 683-686 (2016).</li><li>Jeong, S. H., Jung, D. C., Kim, S. H., Kim, S. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+venous+doppler+ultrasonography+in+normal+subjects+and+patients+with+diabetic+nephropathy:+Value+of+venous+impedance+index+measurements.">Renal venous doppler ultrasonography in normal subjects and patients with diabetic nephropathy: Value of venous impedance index measurements.</a> Journal of Clinical Ultrasound. 39 (9), 512-518 (2011).</li><li>Iida, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+Implications+of+Intrarenal+Hemodynamic+Evaluation+by+Doppler+Ultrasonography+in+Heart+Failure.">Clinical Implications of Intrarenal Hemodynamic Evaluation by Doppler Ultrasonography in Heart Failure.</a> JACC: Heart Failure. 4 (8), 674-682 (2016).</li><li>Lang, R. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recommendations+for+Cardiac+Chamber+Quantification+by+Echocardiography+in+Adults:+An+Update+from+the+American+Society+of+Echocardiography+and+the+European+Association+of+Cardiovascular+Imaging.">Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.</a> European Heart Journal - Cardiovascular Imaging. 16 (3), 233-271 (2015).</li><li>Hiemstra, B., Eck, R. J., Keus, F., van der Horst, I. C. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+examination+for+diagnosing+circulatory+shock.">Clinical examination for diagnosing circulatory shock.</a> Current opinion in critical care. 23 (4), 293-301 (2017).</li><li>Vignon, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Basic+critical+care+echocardiography:+validation+of+a+curriculum+dedicated+to+noncardiologist+residents.">Basic critical care echocardiography: validation of a curriculum dedicated to noncardiologist residents.</a> Critical care medicine. 39 (4), 636-642 (2011).</li><li>Jensen, M. B., Sloth, E., Larsen, K. M., Schmidt, M. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transthoracic+echocardiography+for+cardiopulmonary+monitoring+in+intensive+care.">Transthoracic echocardiography for cardiopulmonary monitoring in intensive care.</a> European journal of anaesthesiology. 21 (9), 700-707 (2004).</li><li>Koster, G., van der Horst, I. C. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Critical+care+ultrasonography+in+circulatory+shock.">Critical care ultrasonography in circulatory shock.</a> Current opinion in critical care. 23 (4), 326-333 (2017).</li><li>Haitsma Mulier, J. L. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+resistive+index+as+an+early+predictor+and+discriminator+of+acute+kidney+injury+in+critically+ill+patients;+A+prospective+observational+cohort+study.">Renal resistive index as an early predictor and discriminator of acute kidney injury in critically ill patients; A prospective observational cohort study.</a> PloS one. 13 (6), 0197967 (2018).</li><li>Micek, S. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluid+balance+and+cardiac+function+in+septic+shock+as+predictors+of+hospital+mortality.">Fluid balance and cardiac function in septic shock as predictors of hospital mortality.</a> Critical care. 17 (5), 246 (2013).</li></ol>

Authors have nothing to disclose.

All examinations need to be performed according to the protocol. Physical examination only has value if performed according to pre-specified definitions23. Laboratory values should be collected according protocol to obtain all values. Clear, interpretable CCUS images are key to answer the research question of this study, as described in Step 3.3. If poor quality images are obtained, the measurements and analyses described in Step 5 cannot be performed, and the purpose of repeated measurements expires. Three important measures are taken to minimize the risk of obtaining low quality images. First, student-researchers who perform CCUS in our study are trained by an experienced cardiologist-intensivist. Literature shows that a short training program is well suited to obtain basic competence in CCUS24. Second, the student researchers are supervised by a senior student-researcher during their first 20 exams so they may receive hands on feedback. Last, all acquired cardiac and kidney images will be reassessed and validated by an independent expert of a Cardiac Imaging Core Laboratory and an experienced abdominal radiologist, respectively to ensure that data is reliable.
To ensure image quality, researchers also need to pay attention to other aspects. Re-applying ultrasound gel or repositioning the probe so that it makes better contact with the skin of the patient is sometimes required to ensure optimal image quality. It is also important to take enough time to acquire the most optimal image and if there are doubts a senior researcher, i.e., a supervising cardiologist-intensivist or core laboratory technician, should be consulted before the clinical examination is completed. Continuous evaluation and validation of all ultrasonographic images is ensured by enforcing the protocolized steps displayed in Figure 1. In addition, student-researchers and experts frequently exchange feedback, making it easy to quickly implement protocol changes to further increase the quality of images and measurements. This frequent verification makes systematic errors easy to detect so that the CCUS training for future student-researchers can be adapted accordingly. Furthermore, monthly meetings open to all team members allows thorough evaluation and (if necessary) modifications of the protocol.
Round the clock availability for patient screening and inclusion is another key element for the successful implementation of this study. This can only be achieved by having a dedicated team of student-researchers, a large team of students to provide support, and good coordination with the ICU caregivers. This coordination takes place by regular low stake contact between caregivers and researchers about possible improvements to optimize collaboration with standard care.
A limitation of this protocol is that successfully conducting CCUS is dependent on the accessibility of the pre-specified positions where the probe is placed. During the SICS-I, it was already shown that cardiac CCUS cannot be performed when patients require drains, gauzes or wound dressings which obstruct the theoretically optimal echocardiographic window1. Additionally, the possibility to obtain a proper subcostal window via transthoracic echocardiography, which is required for the IVC measurements, has previously been shown to be potentially limited in a general ICU population25. The 24/7 availability required by this protocol to carry out the different examinations at different time points is also a potential limitation, as some centers may lack the capacity to do so. Even in a large academic hospital such as the UMCG, ensuring this has led to delays in the start of the study. Another limitation intrinsic to ultrasonographic measurements is the inter-observer variability of the measurements. For patient inclusion to be guaranteed 24/7, it is impossible for one researcher to conduct all clinical examinations in all included patients. This study aims to have the same researcher carry out all ultrasound measurement in one same patient to minimize variability at the individual level, but for the entire cohort, inter-observer variability remains an issue.
Ultrasonographic imaging of multiple organs can be a fast, safe, and effective structure for visualizing organ perfusion and function. It is a convenient tool that all medical professionals should be able to use, and for which few measurements based on a simple, standardized protocol should generally provide reliable measurements.
Furthermore, most observational studies evaluating the use of ultrasonography, and particularly of echocardiography, are retrospective in nature or include only a small number of patients.26 This protocol allows a structural 24/7 screening of an unselected cohort of critically ill patients, of which subpopulations of interest can be defined, thus allowing for the simultaneous investigation of multiple research questions.
Moreover, despite it being known that clinical variables in critical care are highly dynamic and reciprocally influence each other, most studies have only investigated the additive value of singular ultrasound measurements of specific organs27,28. This is the first protocol to focus on repeated measures, whole body ultrasound and venous congestion. We expect that the SICS-II will provide a more accurate reflection of patients&#39; hemodynamic status during ICU admission.
The current structure used in SICS can be applied to a large number of settings, and the addition of other elements is currently being studied. Its strength lies in the combination of a basic research line and an adaptive line in which new variables can easily be added to the CRFs so that new research questions can be investigated. An example of this adaptability is the addition of extensive ventricular wall assessment by deformation imaging, i.e., strain on short term, to the regular protocol in a specific subset of patients.
Moreover, patient inclusion is currently exclusively taking place in the ICU and part of the patients&#39; care trajectory is now missed. ICU patients are often first admitted to the emergency department (ED), and stay in the regular hospital ward after ICU discharge. Therefore, the SICS aims to include patients at an earlier stage by including patients upon ED arrival and register interventions and hemodynamic function from initial hospital admission onwards. Furthermore, plans to conduct CCUS after ICU-discharge to regular wards are also ongoing so that all patients can be measured at each predefined study time. Another important aspect is the expandability of the protocol to other centers: its simplicity allows easy adaptation by centers which can start inclusion themselves.
Lastly, the development and successful implementation of a structured CCUS protocol may also have clinical ramifications. Despite being used for research purposes only, it could be implemented for clinical CCUS by medical doctors after the proposed short training period. It would then be interesting to assess if facilitating CCUS training to (inexperienced) physicians would decrease additional diagnostic testing.

Patients admitted to the Intensive Care Unit (ICU) are the most critically ill with high rates of co- and multi-morbidities, independent of their admission diagnosis. Therefore, the ICU is the setting to investigate co- and multi-morbidity, their negative impact on patient outcomes, and how critical illness may lead to complications that contribute to additional multi-morbidities. To gain insight in this heterogeneous patient group detailed examination of each individual patient is of utmost interest.
The Simple Intensive Care Studies (SICS) research line is designed with the goal of evaluating the prognostic and diagnostic value of a comprehensive selection of clinical, hemodynamic and biochemical variables in ICU patients collected by a dedicated team of student-researchers coordinated by medical experts. One of the primary objectives of the SICS-I is to investigate the combination of clinical examination findings best associated with shock defined by cardiac output (CO) measured by critical care ultrasonography (CCUS)1. The SICS-II uses the structure of the SICS-I but adds repeated clinical examination, biochemical analysis and CCUS. The primary focus of SICS-II is to quantify venous congestion and identify variables that may contribute to its development. Repeated measurements provide dynamic information on the course of a patient&#39;s illness. Studies show that fluid overload is present in critically ill patients and fluid overload is associated with new morbidities. We thus focus on venous congestion in these patients. Moreover, several studies have suggested the possible negative effects of excessive fluid administration2,3,4,5,6. Fluid overload can be perceived as venous congestion or venous fluid overload, which may be observed by an increased central venous pressure (CVP) or peripheral edema. Elevated pressure in the central venous system may contribute to reduced organ perfusion followed by organ failure, but no exact definition of venous congestion exists.
Previous studies that suggested negative effects associated with excessive fluid administration used single surrogate measurements of venous congestion such as CVP, IVC collapsibility, fluid balance and/or peripheral edema7,8,9,10. To the best of our knowledge, the SICS-II is the first study to perform repeated CCUS of multiple organs combined with findings from clinical examination to assess the hemodynamic status of ICU patients. The focus on this multi-organ ultrasonography technique is important as organ failure or diminished organ function always influences the entire hemodynamic system. We expect that data from repeated examinations in SICS-II will help to unravel the pathophysiology and consequences of venous congestion. Consequently, this may help to improve earlier identification of critically ill patients at risk of venous congestion and guide the optimization of fluid administration. Additionally, the association between venous congestion and short- and long-term organ failure can be explored. Finally, the successful implementation of the SICS-II protocol would make evident that carrying out a large prospective study with a dedicated team of student-researchers is feasible and can yield quality data to investigate clinical problems.
Here, the procedure to perform comprehensive clinical examination of ICU patients with the goal of measuring venous congestion is demonstrated. A concise protocol of SICS-II was published on clinicaltrials.gov11. After the first initial clinical examination, a maximum of three additional clinical examinations, biochemical analyses and CCUS are conducted. Physical examination comprises of variables which reflect peripheral perfusion/microcirculation such as capillary refill time (CRT) or mottling as well as variables of the macrocirculation such as blood pressure, heart rate and urine output. Also, standard care laboratory values are registered (e.g., lactate, pH). Subsequently, CCUS of the heart, lungs, IVC and kidney is performed to obtain information on perfusion. Further methods will be elaborated within our statistical analysis plan, as was done in the SICS-I12.
Based on 138 patients included between 14-05-2018 and 15-08-2018, repeated measurements of a broad array of clinical variables within this structure seem feasible. We also show that independent validation is feasible. The SICS-II exemplifies a valuable methodology for enabling researchers to accurately register changes in variables of interest and can thus act as a guide to conducting research that reflects the progression in patients&#39; condition as seen in daily practice. The SICS-II study is carried out daily by a team of 2-3 student-researchers at all times, with a senior supervisor available on call. These student-researchers are trained in performing the physical examination and CCUS. They execute all the steps of the following protocol and are responsible for patient inclusion both during working hours and in the weekends. In addition, a larger ICU student team of around 30 students participate in evening and night shifts, to conduct the initial clinical examination (within 3 h of admittance) of new patients. Figure 1 presents a schematic summary of the study protocol, and Figure 2 and 3 display the Case Report Forms (CRF) used to register data upon collection.

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	<tbody>
		<tr height="40">
			<td height="40" style="height:40px;width:216px;">Ultrasound machine</td>
			<td style="width:123px;">GE Healthcare</td>
			<td style="width:217px;">0144VS6</td>
			<td style="width:167px;">Ultrasound machine, GE Vivid S6</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Ultrasound machine</td>
			<td>GE Healthcare</td>
			<td>3507VS6</td>
			<td>Ultrasound machine, GE Vivid S6</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Ultrasound machine</td>
			<td>GE Healthcare</td>
			<td>0630VS6</td>
			<td>Ultrasound machine, GE Vivid S6</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:216px;">Ultrasound gel</td>
			<td>Parker</td>
			<td>01-08</td>
			<td>Aquasonic 100 ultrasound transmission gel</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Temperature probe</td>
			<td>DeRoyal</td>
			<td>81-010400EU</td>
			<td>Skin Temperature Sensor&#160;</td>
		</tr>
	</tbody>
</table>

observational study protocol for repeated clinical examination and critical care ultrasonography within the simple intensive care studies

Longitudinal evaluations of critically ill patients by combinations of clinical examination, biochemical analysis and critical care ultrasonography (CCUS) may detect adverse events of interventions such as fluid overload at an early stage. The Simple Intensive Care Studies (SICS) is a research line that focuses on the prognostic and diagnostic value of combinations of clinical variables.
The SICS-I specifically focused on the use of clinical variables obtained within 24 h of acute admission for prediction of cardiac output (CO) and mortality. Its sequel, SICS-II, focuses on repeated evaluations during ICU admission. The first clinical examination by trained researchers is performed within 3 h after admission consisting of physical examination and educated guessing. The second clinical examination is performed within 24 h after admission and includes physical examination and educated guessing, biochemical analysis and CCUS assessments of heart, lungs, inferior vena cava (IVC) and kidney. This evaluation is repeated at days 3 and 5 after admission. CCUS images are validated by an independent expert, and all data is registered in an online secured database. Follow-up at 90 days includes registration of complications and survival status according to patient&#39;s medical charts and the municipal person registry. The primary focus of SICS-II is the association between venous congestion and organ dysfunction.
The purpose of publishing this protocol is to provide details on the structure and methods of this on-going prospective observational cohort study allowing answering multiple research questions. The design of the data collection of combined clinical examination and CCUS assessments in critically ill patients are explicated. The SICS-II is open for other centers to participate and is open for other research questions that can be answered with our data.

The purpose of these representative results is to illustrate the feasibility of the protocol.
Patients 
In total, 663 patients were admitted to the ICU between 14-05-2018 and 15-08-2018. Of these, 208 patients were eligible for inclusion (reasons for exclusion are displayed in Figure 4). A number of 49 patients were excluded as there was no possibility to perform the CCUS due to ongoing resuscitation efforts. Seven patients refused to participate (no informed consent) and in four patients CCUS was impossible, e.g., due to prone positioning for mechanical ventilation or vacuum assisted closure of large wounds, resulting in 138 included patients with data for analysis.
CCUS validation and image quality 
Extensive validation of cardiac imaging is planned. Renal ultrasonography validation has been initiated. So far, images of 21 patients (15%) were validated. In 18 patients (86%) images appeared of sufficient quality. All reasons for disapproval of images were listed and returned for feedback to the researcher who performed the ultrasonography. The name of the researcher who performed the ultrasonography is recorded to be able to asses inter- and intra-observer variability using the Intraclass Correlation Coefficient (ICC). Exact statistical methods will be described in our statistical analysis plan, as was done in the SICS-I12.
Example case: Patient X, middle aged female 
Patient X was admitted after she was found with impaired consciousness and low blood pressure. All obtained measurements are shown in Table 1. All variables were obtained within the required time set without missing data, illustrating the possible feasibility of this protocol. Within 3 hours after admission the first clinical examination was performed. During this examination the patient was sedated, intubated and needed vasopressor treatment. The second clinical examination was performed ten hours later and showed stable vitals after 700 mL of fluid infusion. Vasopressors were reduced. CCUS and biochemical analysis showed normal cardiac, IVC and renal function (Figure 5, Figure 6 and Figure 7). At T3, two days later, the vasopressors were stopped but cumulative positive fluid balance had risen to 6 liters, accompanied by an increased CO, wider IVC and diminished renal perfusion and function reflected by increased serum creatinine. At T4, 5 days after admission, fluid balance and serum creatinine had risen even further, where the patient developed stage 3 AKI. The patient died 2 days later due to multi organ failure with unclear origin, at 7 days after admission.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58802/58802fig1.jpg" /> 
Figure 1: SICS-II study overview.&#160;Timeline of the SICS-II study from patient admission to Intensive Care to the final step of data registration. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/58802/58802fig2.jpg" /> 
Figure 2: Case Report Form (CRF) for clinical examination 1.&#160;CRF to be filled by the ICU team students or student-researchers when conducting the first clinical examination. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/58802/58802fig3.jpg" /> 
Figure 3:&#160;Case Report Form (CRF) for clinical examinations 2, 3 and 4.&#160;CRF to be filled by the ICU team students or student-researchers when conducting the second, third and fourth clinical examinations. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/58802/58802fig4.jpg" /> 
Figure 4:&#160;SICS-II patient inclusion and exclusion chart.&#160;Flowchart describing the criteria for patient inclusion and exclusion in the SICS-II study until 15-08-2018. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/58802/58802fig5.jpg" /> 
Figure 5: Apical views showing change in cardiac function.&#160;(A) Image of the heart on an AP4CH view during CCUS conducted during clinical examination 2 (T=2); (B) Image of the heart VTI pulse wave signal on T=2, showing a CO of 5.6 L/min; (C) Image of the heart on an AP5CH view during CCUS conducted during clinical examination 3 (T=3); (D) Image of the heart VTI pulse wave signal on T=3, showing a CO of 8.3 L/min. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/58802/58802fig6.jpg" /> 
Figure 6: M-mode image of the inferior vena cava (IVC) for diameter measurements.&#160;Image showing, on top, the IVC in real-time, and, below, the M-mode image representing the IVC diameter changes, from which the collapsibility can be calculated. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/58802/58802fig7.jpg" /> 
Figure 7: The various elements of renal ultrasonography.&#160;(A) Image of the right kidney during CCUS; (B) Image showing, on top, the Doppler flow in the renal arteries, and, below, the flow wave from which the renal resistive index is calculated; (C) Image showing, on top, the Doppler flow in the renal veins, and, below, the flow wave from which the venous impedance index is calculated; (D) Image illustrating the measurement of renal length. <a href="https://www.jove.com/files/ftp_upload/58802/58802fig7large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table fo:keep-together.within-page="1">
	<tbody>
		<tr>
			<td>Variable</td>
			<td>T1 
			Day 1, at 00:38</td>
			<td>T2 
			Day 1, at 10:53</td>
			<td>T3 
			Day 3, at 10:14</td>
			<td>T4 
			Day 5, at 10:20</td>
		</tr>
		<tr>
			<td>Heart rate (bpm)</td>
			<td>110</td>
			<td>124</td>
			<td>122</td>
			<td>98</td>
		</tr>
		<tr>
			<td>Respiratory rate (breaths per min)</td>
			<td>24</td>
			<td>15</td>
			<td>26</td>
			<td>12</td>
		</tr>
		<tr>
			<td>Systolic blood pressure (mmhg)</td>
			<td>100</td>
			<td>115</td>
			<td>130</td>
			<td>118</td>
		</tr>
		<tr>
			<td>Diastolic blood pressure (mmhg)</td>
			<td>61</td>
			<td>69</td>
			<td>66</td>
			<td>65</td>
		</tr>
		<tr>
			<td>Mean arterial pressure (mmhg)</td>
			<td>73</td>
			<td>80</td>
			<td>84</td>
			<td>81</td>
		</tr>
		<tr>
			<td>Cumulative fluid balance (mL)</td>
			<td>0</td>
			<td>704</td>
			<td>7272</td>
			<td>12338</td>
		</tr>
		<tr>
			<td>Mechanical ventilation</td>
			<td>PEEP 5, FiO2 40%</td>
			<td>PEEP 5, FiO2 40%</td>
			<td>PEEP 5, FiO2 30%</td>
			<td>PEEP 5, FiO2 30%</td>
		</tr>
		<tr>
			<td>CRT sternum (seconds)</td>
			<td>1.5</td>
			<td>2</td>
			<td>4</td>
			<td>3</td>
		</tr>
		<tr>
			<td>Central temperature (&#9702; C)</td>
			<td>37.6</td>
			<td>37.5</td>
			<td>38.0</td>
			<td>37.4</td>
		</tr>
		<tr>
			<td>Urinary output previous hour (mL)</td>
			<td>117</td>
			<td>60</td>
			<td>0</td>
			<td>10</td>
		</tr>
		<tr>
			<td>Administered inotropic agents</td>
			<td>Noradrenaline 
			0.1 mg/ml 
			3.0 ml/h</td>
			<td>Noradrenaline 
			0.1 mg/ml 
			1.0 ml/h</td>
			<td>none</td>
			<td>none</td>
		</tr>
		<tr>
			<td>Administered sedative agents</td>
			<td>Propofol 
			20 mg/ml 
			5.0 ml/h</td>
			<td>none</td>
			<td>none</td>
			<td>none</td>
		</tr>
		<tr>
			<td>APACHE IV score</td>
			<td>92</td>
			<td>88</td>
			<td>87</td>
			<td>90</td>
		</tr>
		<tr>
			<td>SOFA score</td>
			<td>8</td>
			<td>8</td>
			<td>5</td>
			<td>8</td>
		</tr>
		<tr>
			<td>LVOT (cm)</td>
			<td>N.A.</td>
			<td>2.4</td>
			<td>2.4</td>
			<td>2.4</td>
		</tr>
		<tr>
			<td>Cardiac output (L/min)</td>
			<td>N.A.</td>
			<td>5.6</td>
			<td>8.34</td>
			<td>9.89</td>
		</tr>
		<tr>
			<td>TAPSE (mm)</td>
			<td>N.A.</td>
			<td>25</td>
			<td>26</td>
			<td>21</td>
		</tr>
		<tr>
			<td>RV S&#8217; (cm/s)</td>
			<td>N.A.</td>
			<td>14</td>
			<td>15</td>
			<td>12</td>
		</tr>
		<tr>
			<td>IVC inspiratory diameter (cm)</td>
			<td>N.A.</td>
			<td>1.14</td>
			<td>1.24</td>
			<td>1.10</td>
		</tr>
		<tr>
			<td>IVC expiratory diameter (cm)</td>
			<td>N.A.</td>
			<td>1.27</td>
			<td>1.38</td>
			<td>1.50</td>
		</tr>
		<tr>
			<td>Kerley B lines (total)</td>
			<td>N.A.</td>
			<td>6</td>
			<td>2</td>
			<td>4</td>
		</tr>
		<tr>
			<td>Renal length (cm)</td>
			<td>N.A.</td>
			<td>10.59</td>
			<td>N.A.</td>
			<td>N.A.</td>
		</tr>
		<tr>
			<td>Intrarenal venous flow pattern</td>
			<td>N.A.</td>
			<td>Continuous</td>
			<td>Continuous</td>
			<td>Continuous</td>
		</tr>
		<tr>
			<td>Doppler Renal RI</td>
			<td>N.A.</td>
			<td>0.61</td>
			<td>0.75</td>
			<td>0.70</td>
		</tr>
		<tr>
			<td>VII</td>
			<td>N.A.</td>
			<td>0.33</td>
			<td>0.56</td>
			<td>0.68</td>
		</tr>
	</tbody>
</table>
Table 1: A random SICS-II patient.&#160;Patient X, middle aged female admitted to the ICU after being found with impaired consciousness. Abbreviations: bpm = beats per minute, CRT = capillary refill time, LVOT = left ventricular outflow tract, TAPSE = tricuspid annular plane systolic excursion, RV S&#39; = right ventricular systolic excursion, IVC = inferior vena cava, RRI = Renal resistive index, VII = venous impedance index, N.A. = not applicable.
<table fo:keep-together.within-page="1">
	<tbody>
		<tr>
			<td>Variable</td>
			<td>Unit</td>
			<td>Source</td>
			<td>Obtained at</td>
		</tr>
		<tr>
			<td>Lactate</td>
			<td>mmol/L</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Chloride</td>
			<td>mmol/L</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>pH</td>
			<td></td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 ho difference</td>
		</tr>
		<tr>
			<td>PCO2</td>
			<td>kPa</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>PaO2</td>
			<td>kPa</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>HCO3-</td>
			<td>mmol/L</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Hemoglobin</td>
			<td>mmol/L</td>
			<td>Arterial blood gas analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Leukocytes</td>
			<td>10 x 10-9/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Trombocytes</td>
			<td>10 x 10-9/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>HS Troponine</td>
			<td>ng/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>ASAT</td>
			<td>U/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>ALAT</td>
			<td>U/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Total bilirubin</td>
			<td>uoml/L</td>
			<td>Serum analysis</td>
			<td>From standard care, as close as possible too each clinical examination, max 12 h difference</td>
		</tr>
		<tr>
			<td>Creatinine</td>
			<td>umol/L</td>
			<td>Serum analysis</td>
			<td>All measurements from start of ICU admission</td>
		</tr>
		<tr>
			<td>Urine volume</td>
			<td>ml</td>
			<td>Urine collection of 24 h</td>
			<td>All measurements from start of ICU admission</td>
		</tr>
		<tr>
			<td>Creatinine</td>
			<td>mmol/24 h</td>
			<td>Urine analysis</td>
			<td>All measurements from start of ICU admission</td>
		</tr>
	</tbody>
</table>
Table 2: List of biochemical variables obtained.&#160;All patient biochemical variables collected during the study are listed here.

Watch this Scientific Journal Video about Observational Study Protocol for Repeated Clinical Examination and Critical Care Ultrasonography Within the Simple Intensive Care Studies at JoVE.com

Observational Study Protocol for Repeated Clinical Examination and Critical Care Ultrasonography Within the Simple Intensive Care Studies

Structured protocols are necessary to provide answers on research questions in critically ill patients. The Simple Intensive Care Studies (SICS) provides an infrastructure for repeated measurements in critically ill patients including clinical examination, biochemical analysis and ultrasonography. SICS projects have specific focus but the structure is flexible to other investigations.

Longitudinal evaluations of critically ill patients by combinations of clinical examination, biochemical analysis and critical care ultrasonography (CCUS) ...

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SCIENTISTS IN ACTION

Use of a Central Venous Line for Fluids, Drugs and Nutrient Administration in a Mouse Model of Critical Illness

This protocol describes a centrally catheterized mouse model of prolonged critical illness. We combine the cecal ligation and puncture method to induce sepsis with the use of a central venous line for fluids, drugs and nutrient administration to mimic the human clinical setting. Critically ill patients require intensive medical support in order to survive. While the majority of patients will recover within a few days, about a quarter of the patients need prolonged intensive care and are at high risk of dying from non-resolving multiple organ failure. Furthermore, the prolonged phase of critical illness is hallmarked by profound muscle weakness, and endocrine and metabolic changes, of which the pathogenesis is currently incompletely understood. The most widely used animal model in critical care research is the cecal ligation and puncture model to induce sepsis. This is a very reproducible model, with acute inflammatory and hemodynamic changes similar to human sepsis, which is designed to study the acute phase of critical illness. However, this model is hallmarked by a high lethality, which is different from the clinical human situation, and is not developed to study the prolonged phase of critical illness. Therefore, we adapted the technique by placing a central venous catheter in the jugular vein allowing us to administer clinically relevant supportive care, to better mimic the human clinical situation of critical illness. This mouse model requires an extensive surgical procedure and daily intensive care of the animals, but it results in a relevant model of the acute and prolonged phase of critical illness.

This protocol describes a centrally catheterized mouse model of prolonged critical illness. We combine the cecal ligation and puncture method to induce sepsis with the use of a central venous line for fluids, drugs and nutrient administration to mimic the human clinical setting.

This protocol describes a centrally catheterized mouse model of prolonged critical illness. We combine the cecal ligation and puncture method to induce ...

Objective Nociceptive Assessment in Ventilated ICU Patients: A Feasibility Study Using Pupillometry and the Nociceptive Flexion Reflex

The concept of objective nociceptive assessment and optimal pain management have gained increasing attention. Despite the known negative short- and long-term consequences of unresolved pain or excessive analgosedation, adequate nociceptive monitoring remains challenging in non-communicative, critically ill adults. In the intensive care unit (ICU), routine nociceptive evaluation is carried out by the attending nurse using the Behavior Pain Scale (BPS) in mechanically ventilated patients. This assessment is limited by medication use (e.g., neuromuscular blocking agents) and the inherent subjective character of nociceptive evaluation by third parties.
Here, we describe the use of two nociceptive reflex testing devices as tools for objective pain evaluation: the pupillary dilation reflex (PDR) and nociception flexion reflex (NFR). These measurement tools are non-invasive and well tolerated, providing clinicians and researchers with objective information regarding two different nociceptive processing pathways: (1)&#160;the pain-related autonomic reactivity&#160;and (2) the ascending component of the somatosensory system. The use of PDR and NFR measurements are currently limited to specialized pain clinics and research institutions because of impressions that these are technically demanding or time-consuming procedures, or even because of a lack of knowledge regarding their existence.
By focusing on the two abovementioned nociceptive reflex assessments, this study evaluated their feasibility as a physiological pain measurement method in daily practice. Pursuing novel technologies for evaluating the analgesia level in unconscious patients may further improve individual pharmacological treatment and patient related outcome measures. Therefore, future research must include large well-designed clinical trials in a real-life environment.

Pain assessment in anesthetized patients who cannot communicate with the outside world in any way remains challenging despite the development of innovative objective pain evaluation tools. In this project, the pupillary dilation reflex and the nociception flexion reflex are assessed in critically ill, mechanically ventilated adult patients.

The concept of objective nociceptive assessment and optimal pain management have gained increasing attention. Despite the known negative short- and ...

Protocol and Guidelines for Point-of-Care Lung Ultrasound in Diagnosing Neonatal Pulmonary Diseases Based on International Expert Consensus

Ultrasound is a safe bedside imaging tool that obviates the use of ionizing radiation diagnostic procedures. Due to its convenience, the lung ultrasound has received increasing attention from neonatal physicians. Nevertheless, clear reference standards and guideline limits are needed for accurate application of this diagnostic modality. This document aims to summarize expert opinions and to provide precise guidance to help facilitate the use of the lung ultrasound in the diagnosis of neonatal lung diseases.

Lung ultrasound is a noninvasive and valuable tool for bedside evaluation of neonatal lung diseases. However, a relative lack of reference standards, protocols and guidelines may limit its application. Here, we aim to develop a standardized neonatal lung ultrasound diagnostic protocol to be used in clinical decision-making.

Ultrasound is a safe bedside imaging tool that obviates the use of ionizing radiation diagnostic procedures. Due to its convenience, the lung ultrasound ...

A Protocol to Set Up Needle-Free Connector with Positive Displacement on Central Venous Catheter in Intensive Care Unit

Needle-free connectors were initially designed and promoted to avoid blood exposure for healthcare workers. Some recent data suggest that the latest generation of connectors (with positive displacement) may be of interest for reducing central venous line infections. We have been using needle-free connectors for several years in our intensive care unit and here we present a protocol for installing these connectors on central venous catheters. After insertion of the catheter and control of the permeability of the lines, the connectors must be purged with 0.9% NaCl before being connected. The connectors replace all disposable caps used on infusion stopcocks and manifolds. All the connectors are changed every 7 days as recommended by the manufacturer (except when there is macroscopic contamination, which requires an immediate change of the connector). Before each injection, the connector must be disinfected for at least 3 seconds with 70% isopropyl alcohol. The connectors must not be disconnected (unless changed), as the injection is done through the device. Setting up the connectors slightly increases the total time required to place the catheter and there is no formal evidence that these connectors reduce the incidence of infectious or thrombotic complications. However, these devices simplify the management of central venous lines and prevent the catheter circuit from &#34;opening&#34; once it has been sterilely installed.

We present a protocol to show the installation of a needle-free connector with positive displacement on a central venous catheter.

Needle-free connectors were initially designed and promoted to avoid blood exposure for healthcare workers. Some recent data suggest that the latest ...

Clinical Practice Protocol of Creative Music Therapy for Preterm Infants and Their Parents in the Neonatal Intensive Care Unit

Creative music therapy for preterm infants and their parents (CMT) has emerged as a promising family-integrated early intervention involving communicative musicality to improve infant development, parental well-being, and bonding. It aims at relaxing and nurturing the infant as well as promoting safety and social interaction for the parent-infant dyad. A music therapist specially trained in CMT hums or sings in an infant-directed, improvised, lullaby style continually adjusting to the individual needs, expressions, and breathing pattern of the preterm infant. Based on the principles of family-integrated care, the family is incorporated individually in the therapeutic process, namely by delivering CMT during kangaroo care (KC) and by motivating and facilitating parental vocal interaction with their infant to strengthen the parent-infant bonding. CMT aims at relaxing, stimulating, and coregulating premature infants at a time when many other interventions are still risky and can overwhelm the vulnerable patient group. CMT may be advantageous not by educating and teaching parents, but rather by uncovering the intuitive capacities of parenting that are often overshadowed by the traumatic experience of preterm birth. However, CMT can only be provided when the infants are clinically stable. CMT with parental integration is feasible when parents are available and receptive to participate. This paper presents a detailed protocol on how to use CMT to empower preterm infants and their families.

Creative music therapy for preterm infants and their parents has emerged as a promising family-integrated early intervention. We present a detailed protocol on how to use vocal interaction, humming, or singing to empower preterm infants and their families.

Creative music therapy for preterm infants and their parents (CMT) has emerged as a promising family-integrated early intervention involving communicative ...

Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent need to find effective therapies. Preclinical studies have shown that inhaled halogenated agents may have beneficial effects in animal models of ARDS. The development of new devices to administer halogenated agents using modern intensive care unit (ICU) ventilators has significantly simplified the dispensing of halogenated agents to ICU patients. Because previous experimental and clinical research suggested potential benefits of halogenated volatiles, such as sevoflurane or isoflurane, for lung alveolar epithelial injury and inflammation, two pathophysiologic landmarks of diffuse alveolar damage during ARDS, we designed an animal model to understand the mechanisms of the effects of halogenated agents on lung injury and repair. After general anesthesia, tracheal intubation, and the initiation of mechanical ventilation, ARDS was induced in piglets via the intratracheal instillation of hydrochloric acid. Then, the piglets were sedated with inhaled sevoflurane or isoflurane using an ICU-type device, and the animals were ventilated with lung-protective mechanical ventilation during a 4 h period. During the study period, blood and alveolar samples were collected to evaluate arterial oxygenation, the permeability of the alveolar-capillary membrane, alveolar fluid clearance, and lung inflammation. Mechanical ventilation parameters were also collected throughout the experiment. Although this model induced a marked decrease in arterial oxygenation with altered alveolar-capillary permeability, it is reproducible and is characterized by a rapid onset, good stability over time, and no fatal complications.
We have developed a piglet model of acid aspiration that reproduces most of the physiological, biological, and pathological features of clinical ARDS, and it will be helpful to further our understanding of the potential lung-protective effects of halogenated agents delivered through devices used for inhaled ICU sedation.

We describe a model of hydrochloric acid-induced acute respiratory distress syndrome (ARDS) in piglets receiving sedation with halogenated agents, isoflurane and sevoflurane, through a device used for inhaled intensive care sedation. This model can be used to investigate the biological mechanisms of halogenated agents on lung injury and repair.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent ...

A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats

Sepsis and septic shock remain the leading cause of death in intensive care units. Despite significant improvements in sepsis management, mortality still ranges between 20 and 30%. Novel treatment approaches in order to reduce sepsis-related multiorgan failure and death are urgently needed. Robust animal models allow for one or multiple treatment approaches as well as for testing their effect on physiological and molecular parameters. In this article, a simple animal model is presented.
First, general anesthesia is induced in animals either with the use of volatile or by intraperitoneal anesthesia. After placement of an intravenous catheter (tail vein), tracheostomy, and insertion of an intraarterial catheter (tail artery), mechanical ventilation is started. Baseline values of mean arterial blood pressure, arterial blood oxygen saturation, and heart rate are recorded.
The injection of lipopolysaccharides (1 milligram/kilogram body weight) dissolved in phosphate-buffered saline induces a strong and reproducible inflammatory response via the toll-like receptor 4. Fluid corrections as well as the application of norepinephrine are performed based on well-established protocols.
The animal model presented in this article is easy to learn and strongly oriented towards clinical sepsis treatment in an intensive care unit with sedation, mechanical ventilation, continuous blood pressure monitoring, and repetitive blood sampling. Also, the model is reliable, allowing for reproducible data with a limited number of animals in accordance with the 3R (reduce, replace, refine) principles of animal research. While animal experiments in sepsis research cannot easily replaced, repetitive measurements allow for a reduction of animals and keeping septic animals anesthetized diminishes suffering.

Here, we present a reproducible intensive care unit-oriented endotoxin model in rats.

Sepsis and septic shock remain the leading cause of death in intensive care units. Despite significant improvements in sepsis management, mortality still ...

Hemodynamic Precision in the Neonatal Intensive Care Unit using Targeted Neonatal Echocardiography

Targeted neonatal echocardiography (TnECHO) refers to the use of comprehensive echocardiographic evaluation and physiologic data to obtain accurate, reliable, and real-time information on developmental hemodynamics in sick newborns. The comprehensive assessment is based on a multiparametric approach that overcomes the reliability issues of individual measurements, allows for earlier recognition of cardiovascular compromise and promotes enhanced diagnostic precision and timely management. TnECHO-driven research has led to an enhanced understanding of the mechanisms of illness and the development of predictive models to identify at-risk populations. This information may then be used to formulate a diagnostic impression and provide individualized guidance for the selection of cardiovascular therapies. TnECHO is based on the expert consultative model in which a neonatologist, with advanced training in neonatal hemodynamics, performs comprehensive and standardized TnECHO assessments. The distinction from point of care ultrasonography (POCUS), which provides limited and brief one-time assessments, is important. Neonatal hemodynamics training is a 1-year structured program designed to optimize image acquisition, measurement analysis, and hemodynamic knowledge (physiology, pharmacotherapy) to support cardiovascular decision-making. Neonatologists with hemodynamic expertise are trained to recognize deviations from normal anatomy and appropriately refer cases of possible structural abnormalities. We provide an outline of neonatal hemodynamics training, the standardized TnECHO imaging protocol, and an example of representative echo findings in a hemodynamically significant patent ductus arteriosus.

Presented here is a protocol to perform comprehensive neonatal echocardiography by trained neonatologists in the neonatal intensive care unit. The trained individuals provide longitudinal assessments of heart function, systemic and pulmonary hemodynamics in a consultative role. The manuscript also describes the requirements to become a fully trained neonatal hemodynamics specialist.

Targeted neonatal echocardiography (TnECHO) refers to the use of comprehensive echocardiographic evaluation and physiologic data to obtain accurate, ...

Ultrasound in Evaluating Diaphragm Dysfunction and Monitoring Treatment

Measuring Diaphragm Thickness and Function Using Point-of-Care Ultrasound

The diaphragm is the main component of the respiratory muscle pump. Diaphragm dysfunction can cause dyspnea and exercise intolerance, and predisposes affected individuals to respiratory failure. In mechanically ventilated patients, the diaphragm is susceptible to atrophy and dysfunction through disuse and other mechanisms. This contributes to failure to wean and poor long-term clinical outcomes. Point-of-care ultrasound provides a valid and reproducible method for evaluating diaphragm thickness and contractile activity (thickening fraction during inspiration) that can be readily employed by clinicians and researchers alike. This article presents best practices for measuring diaphragm thickness and quantifying diaphragm thickening during tidal breathing or maximal inspiration. Once mastered, this technique can be used to diagnose and prognosticate diaphragm dysfunction, and guide and monitor response to treatment over time in both healthy individuals and acute or chronically ill patients.

Author Spotlight: Unraveling the Impact of Mechanical Ventilation on Diaphragm Function and Patient Outcomes 

Diaphragm thickness and function can be assessed in healthy individuals and critically ill patients using point-of-care ultrasound. This technique offers an accurate, reproducible, feasible, and well-tolerated method for evaluating diaphragm structure and function.

The diaphragm is the main component of the respiratory muscle pump. Diaphragm dysfunction can cause dyspnea and exercise intolerance, and predisposes ...

Enhancing Pulmonary Infection Treatment Using M-ROSE

Microbiological Rapid On-Site Evaluation for Pulmonary Infectious Diseases

The prompt initiation of empirical anti-infective therapy is crucial in patients presenting with unexplained pulmonary infection. Although imaging acquisition is relatively straightforward in clinical practice, its lack of specificity often necessitates additional time-consuming tests such as sputum culture, bronchoalveolar-lavage fluid culture, or genetic sequencing to identify the underlying etiology of the disease accurately. Moreover, the limited efficacy of empirical anti-infective treatment may contribute to antibiotic misuse. Recent advancements in interpreting microbial background on rapid on-site evaluation (ROSE) slides have enabled clinicians to promptly obtain samples through bronchoscopy (e.g., alveolar lavage, mucosal brushing, tissue clamp), facilitating bedside staining and interpretation that provides essential microbial background information. Consequently, this establishes a foundation for developing targeted anti-infection treatment and individualized drug therapy plans. With a better understanding of which pathogens are causing infections in real-time, physicians can avoid unnecessary broad-spectrum antibiotics contributing to antibiotic resistance. Establishing a rapid and standardized M-ROSE workflow within respiratory medicine departments or intensive care units will greatly assist physicians in formulating accurate treatment strategies for patients, which holds significant clinical implications.

Author Spotlight: Advancing Pathogen Detection and Disease Assessment in Real-Time Using M-ROSE

The protocol here demonstrates a fast and standardized microbiological rapid on-site evaluation (M-ROSE) workflow, including three steps: slide making, staining, and interpretation. This protocol will help physicians make rapid clinical decisions.