Simple Intensive Care Studies I (SICS-I)
Simple Intensive Care Studies I (SICS-I)
Circulatory shock is a condition of generalized inadequate blood flow through the body,
 leading to insufficient tissue perfusion and inadequate delivery of oxygen and other
 nutrients, to the extent that tissues are damaged. Four basic mechanisms of circulatory
 failure are distinguished, caused by a scale of underlying illnesses: distributive,
 hypovolemic, obstructive and cardiogenic shock. The last three types are characterized by a
 low cardiac output and hypovolemia. Distributive shock is characterized by peripheral
 circulation failure, with a low systemic vascular resistance, a disturbed microcirculation
 and a high cardiac output. Frequently, these forms overlap.

 Shock is a common problem in the intensive care unit (ICU) as it affects about one third of
 the patients. Septic shock appears to be the most common type, followed by cardiogenic and
 hypovolemic shock. The diagnosis of shock is based on clinical examination with use of
 well-known circulatory parameters such as blood pressure and heart rate; biochemical
 parameters such as lactate and direct (semi-)invasive measurement of cardiac output and other
 variables.

 Since cardiac output is an important determinant of oxygen delivery, many different methods
 of measuring cardiac output have been suggested. These methods range from non-invasive to
 invasive measurements with central lining. The most invasive method, the pulmonary artery
 catheter (PAC) has long been considered the optimal form of monitoring cardiac output by
 using thermodilution. However, this technique is associated with adverse events, such as
 bleeding, and there is no clear evidence of improved outcome. Therefore, numerous other
 techniques have been proposed, ranging from systems that use the dilution technique but only
 require central venous and peripheral artery lines; to less invasive tools that estimate
 cardiac output based on the arterial pressure waveform; and to non-invasive echocardiography.

 Despite technical advances, much remains unknown about the value of conventionally used
 hemodynamic parameters for estimating cardiac output. A distinction between macro- and
 microcirculatory parameters can be made. Commonly used macro-circulatory parameters are heart
 rate, systolic and diastolic blood pressure, mean arterial pressure and central venous
 pressure. Lactate is used as a proxy for microcirculatory status. Over the years several
 other measurements have been suggested to improve insight in the hemodynamics of a certain
 patient or a group of patients. Skin temperature, capillary refill, mottling score and
 urinary output are used for hemodynamic assessment of the peripheral circulation and tissue
 perfusion. Most of these parameters have not been evaluated in a large prospective study and
 especially a combination of all these parameters has not directly been correlated to cardiac
 output.

 More knowledge on the predictive value of all hemodynamic parameters in estimating cardiac
 output could assist physicians in earlier detection of impaired hemodynamics without the need
 for invasive or advanced methods. In this study the investigators aim to evaluate all
 hemodynamic parameters in a large unselected population of critically ill patients and to
 correlate them to cardiac output.

 Purpose:

 The purpose of this study is to create an infrastructure for a registry flexible to
 incorporate temporarily added specific research questions on the outcome of critically ill
 patients.
Registry procedures:

 Eligible patients will be included within 24 hours after their arrival on the Intensive Care
 Unit. After inclusion all study parameters will be obtained once through physical examination
 combined with transthoracic echocardiography. Mortality will be assessed at 90 days after
 admission. In addition, mortality follow-up will be cut-off at 7 and 30 days after admission.

 Monitoring:

 Monitoring will be performed by independent researchers of the department of anaesthesiology
 of the UMCG. Audits are planned to take place once a year.

 Quality assurance plan:

 Recruitment:

 Inclusion of patients and measurements of variables (both conventional hemodynamic variables
 and cardiac output) will be performed by the study coordinator or a co-researcher under
 supervision and responsibility of the principle investigator. Informed consent will be
 obtained.

 Source data verification:

 At inclusion all conventional hemodynamic variables are derived by physical examination and
 recording data from the basic hemodynamic monitoring (Philips ImageVue monitor with tracing
 of heart rate, electrocardiogram (ECG), SpO2, arterial pressure from arterial line pressure
 measurement and/or from non-invasively blood pressure monitoring). In addition, a
 transthoracic echocardiography (TTE) will be performed to non-invasively determine the
 cardiac output by using the diameter of the aortic annulus, the velocity time integral (VTI)
 of the Doppler flow and the heart rate. All variables are predefined (see data dictionary) to
 standardize all measurements by student researchers.

 For the performance of the TTE the student researchers will be trained to visualize the
 parasternal 2 chamber view, apical 4 and 5 chamber view according to the international
 standards (ACC/ESC) and to measure the left ventricular outflow tract VTI and the diameter of
 the aortic annulus. The training was given by an experienced cardiologist-intensivist. All
 measurements were validated by an echocardiography technician (core laboratory) who was
 blinded for all other measurement outcomes. General patient characteristics and laboratory
 measurements were recorded from electronic patient charts and the APACHE II and IV,
 Simplified Acute Physiology Score II (SAPS) scores are extracted from our local National
 Intensive Care Evaluation database. Follow-up of all-cause mortality is acquired using the
 municipal personal records database.

 Standard Operation Procedures

 Data collection:

 Within 24 hours of ICU admission, all hemodynamic variables will be obtained through a
 onetime physical examination combined with transthoracic echocardiography. Other variables
 (i.e. lab values) will be obtained from the electronic patient charts at a later moment. The
 rationale and specific details of measuring each variable are described extensively below.

 Systemic circulatory variables:

 -  Cardiac output (CO): it will be measured by transthoracic echocardiography, performed by
 different trained researchers. Both cardiac output and cardiac index (i.e. cardiac
 output corrected for body surface area) will be calculated.

 -  Stroke volume (SV): this will be automatically calculated by dividing cardiac output by
 heart rate, both measured by transthoracic echocardiography.

 -  Heart rate (HR): it will be recorded from the bedside electrocardiographic monitor. In
 case of an irregular rhythm (i.e. atrial fibrillation) the investigators will use the
 mean heart rate over a minute. Apart from heart rate the presence of atrial fibrillation
 will be recorded.

 -  Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure
 (MAP): these will be obtained by intravascular measurement using an arterial line, which
 is part of usual care. To allow for comparison, these variables will also be measured
 using a sphygmomanometer. In the latter case, mean arterial pressure will be calculated
 using the following formula: MAP = (SBP + 2*DBP)/3

 -  Central venous pressure (CVP): this will be recorded in case a central venous line is
 present in the internal jugular or subclavian vene.

 Micro- and peripheral circulatory variables:

 -  Capillary refill time (CRT): this will be measured after 15 seconds of exerting firm
 pressure preferably on the distal phalanx of the index finger and on the central part of
 the knee. The original upper limit of a normal CRT was considered to be 2 seconds by
 Champions' Trauma score. However Schriger and Baraff examined CRT in a healthy
 population and discovered it to be age and temperature dependent, with an upper limit
 for healthy older adults of 4.5 seconds. In a recent study Ait-Oufella et al found that
 an index CRT upper limit of 2.4 seconds is predictive of 14 day mortality in septic
 shock patients. The investigators will therefore both use a cut-off value of 4,5 seconds
 and a continuous measure of CRT.

 -  Skin temperature (Tskin): this will be measured subjectively and objectively. The
 subjective measure will be conducted by palpating the patient's extremities. A
 distinction between either 'warm' or 'cold' will be made using the dorsal surface of the
 hands of the examiner. Patients will be considered to have 'cold' skin extremities if
 all examined extremities are considered cool, or if only the lower extremities are cool
 despite warm upper extremities.

 To objectify the skin temperature, the use of a central-to-peripheral and
 peripheral-to-ambient temperature difference (respectively dTc-p and dTp-a) or the
 forearm-to-finger skin-temperature gradient (Tskin-diff) have been proposed in literature.
 The investigators will make use of the central-to-peripheral measurements:

 -  Central-to-peripheral temperature difference (dTc-p): to measure this difference the
 investigators will compare bladder temperature, as measured by a bladder thermistor
 catheter, with foot temperature, measured by a skin probe (DeRoyal Skin Temperature
 Sensor product nr 81-010400EU) on either the left or the right big toe. The
 investigators will use bladder temperature as a surrogate for central temperature, and
 toe temperature as a peripheral measure. In literature a temperature difference of
 either 5°C or 7 °C is generally used as an upper limit. The investigators will therefore
 regard values higher than 7°C as abnormal.

 -  The mottling score: this score was described by Ait-Oufella et al in 2011. Mottling is
 the patchy discoloration of the skin caused by microcirculatory dysfunction. It usually
 involves the area around the knee. The Mottling score ranges from 0 -5, depending on the
 extensiveness of the mottled area. A score of 0-1 is regarded mild, 2-3 moderate and 4-5
 severe.

 -  Urine output (ml/kg/h): this is also measured as part of regular care. The investigators
 will use both the urine output over the hour before examination and the mean urine
 output per hour, calculated using the six hours prior to the physical examination. If
 these data are unavailable, the mean urine output of the previous hour(s) will be
 calculated depending on the available data. In patients with pre-existing renal failure
 the urinary output will not be used.

 Other variables:

 -  Respiratory rate: this will be recorded of the bedside electrocardiographic monitor. If
 a patient is on mechanical ventilation, see below.

 -  AVPU scale: this can be used to obtain a quick impression of a patients state of
 consciousness and consists of the options: 'Alert', 'responsive to Voice', 'responsive
 to Pain' and 'Unresponsive.' It is often applied in the emergency room and the general
 wards as part of the 'MEWS' (Modified Early Warning Score). The investigators will score
 the AVPU scale as a separate item.

 -  Cardiac murmurs: the investigators will auscultate the heart for the presence of a
 murmur. The potential cause of a cardiac murmur ranges from completely innocent to
 advanced valvular disease, each with its own distinctive characteristics. For study
 purposes, the investigators will score this item as: present or absent.

 -  Crepitations: the investigators will auscultate the lungs for crepitations, or crackles.
 In general a distinction between in- or expiratory and fine or coarse crepitations is
 made. Crepitations can be a symptom of several diseases, ranging from pneumonia and
 pulmonary edema to interstitial lung fibrosis. For study purposes, the investigators
 will only make a distinction in: present or absent.

 -  Serum lactate, creatinine and hemoglobin: these are determined as part of regular care.
 For study purposes the investigators will use the value closest to our examination.
 Other biochemical values will also be recorded.

 -  Mechanical ventilation: data on the presence and type of mechanical ventilation will be
 gathered, as well as basic information on respiratory conditions (i.e. PEEP and
 respiratory rate). Note: in case of mechanical ventilation the value 'respiratory rate'
 will be filled in twice in the CRF. If both values are the same, it will be assumed that
 the patient breathes at a machine-set respiratory rate. If they differ, spontaneous
 breathing will be assumed.

 -  Inotrope-, vasopressor and sedative use: any inotrope or vasopressin requirement, type,
 dose and speed will be recorded.

 -  Estimations of pump function and peripheral circulation: an estimation will be made,
 either by a member of the treating team, or by the researcher.

 After the physical examination has been performed, information on the following general
 characteristics will be extracted from patient files: demographic data, diagnoses and
 severity of illness as evaluated by the APACHE II and IV scores, Simplified Acute Physiology
 Score II (SAPS) and the Sequential Organ Failure Assessment (SOFA). Furthermore the
 investigators will collect EMV scores, lab values (details are described above), urine output
 (details are described above), routine admission ECG's and routine admission thorax photo's.
 After 90 days the investigators will assess the patient files again to gather information on
 total ICU stay in days and 7-, 28- and 90-day mortality.

 Data management:

 Data will be recorded using OpenClinica and transferred for analysis. After transfer from
 OpenClinica, all data will be managed in a database created using Stata version 14.1
 (StataCorp, College Station, TX) All study subjects will receive a study subject ID, compiled
 of the study name and their inclusion number. This study subject ID will be used in both
 OpenClinica and Stata. Only a researcher with 'study director' account properties in
 OpenClinica will be able to link study subject ID to patient number. Images will be saved
 anonymously and will be coded in a systematic fashion, using the study subject ID, session
 number, and image contents.

 Sample size assessment:

 There are no previous studies with data on including a combination of all available
 hemodynamic variables into one model estimating cardiac output and mortality. This makes it
 difficult to calculate sample size. The investigators will therefore make an estimation based
 on the number of ICU admissions per year. Each year 3000 patients are admitted to one of four
 ICU units. Approximately 1500 of these admissions are unplanned emergency admissions. The
 investigators estimate that half of these unplanned admissions fulfill the inclusion
 criteria. This leaves 750 patients eligible for inclusion. However, the investigators assume
 that they will not be able to include all eligible patients for logistic and practical
 reasons. Therefore the investigators aim to include 400 patients per year. With emergency
 admission critical care mortality approaching 25% this will enable us to include at least ten
 variables in the final model for predicting mortality (acknowledging that at least 10 events
 are necessary for each variable included in the final model). We will describe the power and
 detectable difference in a detailed statistical analysis plan (SAP).

 Plan for missing data:

 Primary analyses will be performed with imputation for missing data using multiple
 imputations. Robustness of conclusions will be checked by secondary sensitivity analyses only
 including available data. We will describe additional information in a detailed statistical
 analysis plan.

 Statistical analysis plan:

 The investigators will use the general characteristics to create a baseline table.
 Statistical analyses will be performed using the Stata (StataCorp, College Station, TX). Data
 will be presented as means with standard deviation if normally distributed or as medians with
 ranges in case of skewed data.

 Univariate analyses will be conducted and all variables with p<0.1 will be included in the
 multivariate models. Multivariate analyses will be conducted using a stepwise model. Cardiac
 output will be modeled using linear regression and mortality will be modeled using logistic
 regression. All analyses will be adjusted for age and gender; other general characteristics
 will not be added to the model standardly. All analyses will be tested two-sided and p-values
 of less than 0.015 will be considered statistical significant. Multiplicity issues are
 described in our detailed SAP.

 If sample size permits, the investigators will conduct an analysis in different
 subpopulations. Examples of subpopulations that may be eligible for further analysis are
 those with different types of shock (distributive, obstructive, hypovolemic, cardiogenic),
 CVVH, heart failure by any cause, myocardial infarction, atrial fibrillation or surgery
 versus no-surgery patient groups.
Inclusion Criteria:

 -  Emergency admission

 -  Expected stay > 24 hours

 Exclusion Criteria:

 -  Age < 18 years

 -  Planned admission (either after surgery or for other reasons)

 -  Withdrawn or unable to obtain informed consent

 -  Continuous resuscitation efforts or mechanical circulatory support