Int J Clin Pract  2009;63:1494-1508

Hyponatraemia is a commonly encountered electrolyte abnormality in hospitalised patients and is associated with significant morbidity and mortality. The fact that most cases of hyponatraemia are the result of water imbalance rather than sodium imbalance underscores the role of antidiuretic hormone (ADH) in the pathophysiology. Hyponatraemia can be classified according to the measured plasma osmolality as isotonic, hypertonic or hypotonic. Hyponatraemia with a normal plasma osmolality usually indicates pseudohyponatraemia, while hyponatraemia because of a high plasma osmolality is typically caused by hyperglycaemia. After excluding isotonic and hypertonic causes, hypotonic hyponatraemia is further classified according to the volume status of the patient as hypovolaemic, hypervolaemic or euvolaemic. Hypovolaemic hyponatraemia is accompanied by extracellular fluid (ECF) volume deficit, while hypervolaemic hyponatraemia manifests with ECF volume expansion. The syndrome of inappropriate ADH (SIADH) should be suspected in any patient with euvolaemic hyponatraemia with a urine osmolality above 100 mOsm/kg and urine sodium concentration above 40 mEq/l. In the management of any hyponatraemia regardless of the patient’s volume status, it is advised to restrict free water and hypotonic fluid intake. Hypertonic saline and vasopressin antagonists can be used to correct symptomatic hyponatraemia. The rate of correction is dependent upon the duration, degree of hyponatraemia and the presence or absence of symptoms. Symptomatic acute hyponatraemia (< 48 h) is a medical emergency requiring rapid correction to prevent the worsening of brain oedema. In asymptomatic patients with chronic hyponatraemia (> 48 h or unknown duration), fluid restriction and close monitoring alone are sufficient, while a slow correction by 0.5 mEq/l/h may be attempted in symptomatic patients. Excessive rapid correction should be avoided in both acute and chronic hyponatraemia, because it can lead to irreversible neurological complications including central osmotic demyelination.

Clinical Infectious Diseases 2007;44:159–177

This document presents guidelines for developing institutional programs to enhance antimicrobial stewardship, an activity that includes appropriate selection, dosing, route, and duration of antimicrobial therapy. The multifaceted nature of antimicrobial stewardship has led to collaborative review and support of these recommendations by the following organizations: American Academy of Pediatrics, American Society of Health‐System Pharmacists, Infectious Diseases Society for Obstetrics and Gynecology, Pediatric Infectious Diseases Society, Society for Hospital Medicine, and Society of Infectious Diseases Pharmacists. The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms (such as Clostridium difficile), and the emergence of resistance. Thus, the appropriate use of antimicrobials is an essential part of patient safety and deserves careful oversight and guidance. Given the association between antimicrobial use and the selection of resistant pathogens, the frequency of inappropriate antimicrobial use is often used as a surrogate marker for the avoidable impact on antimicrobial resistance. The combination of effective antimicrobial stewardship with a comprehensive infection control program has been shown to limit the emergence and transmission of antimicrobial‐resistant bacteria. A secondary goal of antimicrobial stewardship is to reduce health care costs without adversely impacting quality of care.

Critical Care 2010;14:205

You are director of a large multi-disciplinary ICU. You have recently read that hospital-wide antibiotic stewardship programs have the potential to improve the quality and safety of care, and to reduce the emergence of multi-drug resistant organisms and overall costs. You are considering starting one of these programs in your ICU, but are concerned about the associated infrastructure costs. You are debating whether it is worth bringing the concept forward to your hospital’s administration to consider investing in.

Statement for debate
Antibiotic stewardship programs improve patient outcomes and cost-effectiveness in critically ill patients in the ICU.

Critical Care 2010, 14:R25

Higher lactate concentrations within the normal reference range (“relative hyperlactatemia”) are not considered clinically significant. We tested the hypothesis that relative hyperlactatemia is independently associated with an increased risk of hospital death.

Methods
Retrospective observational study of prospectively obtained intensive care database of 7155 consecutive critically ill patients admitted to the Intensive Care Units (ICUs) of four Australian university hospitals. We assessed the relationship between ICU admission (LacADM), maximal (LacMAX) and time-weighted (LacTW) lactate levels and hospital outcome in all patients and in those patients whose LacADM (n=3964), LacMAX (n=2511) and LacTW (n=4584) lactate was under 2 mmol^.L^-1 (relative hyperlactatemia).

Results
We obtained 172,723 lactate measurements. Higher LacADM and LacTW concentration within the reference range was independently associated with increased hospital mortality (LacADM: odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3-3.5, P=0.01; LacTW OR 3.7, 95% CI 1.9-7.00, P<0.0001). This significant association was first detectable at lactate concentrations > 0.75 mmol^.L^-1. Furthermore, in patients whose lactate never exceeded 2 mmol^.L^-1, higher LacTW remained strongly associated with higher hospital mortality (LacTW OR 4.8, 95% CI 1.8-12.4, P<0.001).

Conclusions
In critically ill patients, relative hyperlactataemia is independently associated with increased hospital mortality. Blood lactate concentrations >0.75 mmol^.L^-1 can be used by clinicians to identify patients at higher risk of death. The current reference range for lactate in the critically ill may need to be re-assessed.

Crit Care Med 2010;38:283-287

Severity scores such as Acute Physiology and Chronic Health Evaluation II have been advocated as entry criteria for clinical trials and in clinical decision-making. We present ten reasons why we believe this approach is not appropriate and may even be detrimental.

Data sources
Available relevant literature from authors’ personal databases and personal knowledge of past and future clinical trial development.

Data synthesis
Severity scores were not designed for use in individual patients or for therapeutic decision-making for specific interventions. Difficulties with the time window needed to calculate these scores and the need to administer therapies early further limit their use in this context. The complex nature of the scores makes it difficult to use them at the bedside and there is considerable interobserver variability in score calculation. Inclusion of chronic health and age points in severity scores may prevent younger, previously healthy patients, with similar acute physiological dysfunction and therefore total lower severity scores, from trial inclusion or from receiving therapies that may be beneficial.

Conclusions
We believe severity of illness scores are poor surrogates for risk stratification and should not be used as a criterion for patient enrollment into clinical trials or as the basis for individual treatment decisions.

Critical Care 2009, 13:228

In 2008, the interest in metabolic and endocrine issues and their consequences in critically ill patients was high. A large proportion of the research papers related to these issues was related to the metabolism of glucose and its control and to the changes in body composition, including muscular weakness. In Critical Care, original reports from investigations of glucose physiology and clinical data from observational and interventional studies were published. Important reports of the effects of hormone analogues, such as vasopressin and hydrocortisone, and early antioxidants in selected subpopulations were also available in 2008.

Critical Care 2009, 13:225

Original research contributions published in Critical Care in 2008 in the fields of respirology and critical care medicine are summarized. Eighteen articles were grouped into the following categories: acute lung injury and acute respiratory distress syndrome, mechanical ventilation, mechanisms of ventilator-induced lung injury, and tracheotomy decannulation and non-invasive ventilation.

Critical Care 2009, 13:227

We summarize original research in the field of critical care nephrology accepted or published during 2008 in Critical Care and, when considered relevant or directly linked to this research, in other journals. Three main topics have been identified for a rapid overview. (1) The classification of acute kidney injury, with particular attention to differences and similarities between the RIFLE and AKIN classifications. (2) Fluid balance in patients requiring renal replacement therapy (RRT) has been shown as an independent risk factor for mortality in critically ill patients: current evidence and uncertainties are described. (3) Management of anticoagulation during RRT has been explored by several researchers in 2008: diagnosis of heparin-induced thrombocytopenia, the use of tirofiban and optimal anticoagulation during drotrecogin A activated treatment have been evaluated.

Critical Care 2009, 13:226

Eleven papers on trauma published in Critical Care during 2008 addressed traumatic brain injury (TBI), burns, diagnostic concerns and immunosuppression. In regard to TBI, preliminary results indicate the utility of either magnetic resonance imaging (MRI) or ultrasound in measuring optic nerve sheath diameter to identify elevated intracranial pressure (ICP) as well as the potential benefit of thiopental for refractory ICP. Another investigaticc7960on demonstrated that early extubation of TBI patients whose Glasgow Coma Scale score was 8 or less did not result in additional incidence of nosocomial pneumonia. Another study indicated that strict glucose control resulted in worse outcomes during the first week after TBI, but improved outcomes after the second week. Another paper showed the prolonged neuroprotective advantages of proges-terone administration in TBI patients. There was also guidance on improved classifications of renal complications in burn patients. Another study found that patients with inhalation injuries and increased interleukin-6 (IL-6) and IL-10 and decreased IL-7 had increased mortality rates. One literature review described the disadvantages of prolonged immobilization or additional use of MRI for ruling out cervical spine injuries in obtunded TBI patients already cleared by computerized tomography scans. Other investigators found that higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels may be useful markers for post-traumatic cardiac impairment. Finally, an experimental model showed that both splenic apoptosis and lymphocytopenia may occur shortly after severe hemorrhage, thus increasing the threat of immunosuppression in those with severe blood loss.

Critical Care 2009, 13:224

The present report highlights the most important papers appearing in Critical Care and other major journals about severe sepsis, the systemic inflammatory response and multiorgan dysfunction over the past year. A number of these clinical and laboratory studies will have a considerable impact on the sepsis research agenda for years to come. The steroid controversy, the debate over tight glycemic control, the colloid versus crystalloid issue, the value of selective decontamination of the digestive tract, the enlarging role of biomarkers, the value of genomics and rapid diagnostic techniques have all been prominently featured in recent publications. Basic research into novel predictive assays, genetic polymorphisms, and new molecular methods to risk-stratify and to determine treatment options for sepsis have occupied much of the Critical Care publications relating to sepsis pathophysiology in 2008. We will attempt to briefly summarize what we consider to be the most significant contributions to the sepsis literature over the last year, and their likely ramifications in the future, for critical care clinicians, clinical investigators and basic researchers alike.

Critical Care 2009, 13:229

We review key research papers in cardiology and intensive care published during 2008 in Critical Care. We quote studies on the same subject published in other journals if appropriate. Papers have been grouped into three categories: (a) cardiovascular biomarkers in critical illness, (b) haemodynamic management of septic shock, and (c) haemodynamic monitoring.

Critical Care Medicine 2009;37:2536-2544

To examine the predisposing factors for hypoglycemia in medical-surgical intensive care unit patients treated with intensive insulin therapy and to assess its association with mortality.

Design
Nested-cohort study within a randomized controlled trial.

Setting
Tertiary care intensive care unit.

Participants
Medical-surgical intensive care unit patients with admission blood glucose of >6.1 mmol/L or 110 mg/dL who were enrolled in a randomized controlled trial comparing intensive insulin therapy with conventional insulin therapy.

Interventions
None.

Exposure
Hypoglycemia was defined as blood glucose <=2.2 mmol/L or 40 mg/dL and intensive care unit mortality was the primary outcome.

Measurements and main results
Among the 523 patients included in the study, hypoglycemia occurred in 84 (16%). Intensive insulin therapy was independently associated with increased risk of hypoglycemia (adjusted odds ratio, 50.65; 95% confidence interval, 17.36-147.78; p < .0001). Other variables associated with an increased risk of hypoglycemia included female gender, diabetes, Acute Physiology and Chronic Health Evaluation II, mechanical ventilation, continuous veno-venous hemodialysis, and intensive care unit length of stay. When adjusted to potential confounders, hypoglycemia was not significantly associated with increased mortality (adjusted hazard ratio, 1.31; 95% confidence interval, .70-2.46; p = .40). Patients with admission blood glucose of <=10 mmol/L had an increased mortality with hypoglycemia (adjusted hazard ratio, 4.43; 95% confidence interval, 1.36-14.44; p = .01). Crude analysis showed significant association of mortality with blood glucose levels of <=1.2 mmol/L (adjusted hazard ratio, 2.92; 95% confidence interval, 1.05-8.11; p = .04). When adjusted analysis was performed, similar trend was seen but was not statistically significant (adjusted hazard ratio, 2.56; 95% confidence interval, .85-7.70; p = .10).

Conclusions
Our study showed significant increase of hypoglycemia with intensive insulin therapy. Although hypoglycemia was not independently associated with increased risk of death, increased mortality could not be excluded with severe hypoglycemia and in patients admitted with blood glucose of <=10 mmol/L.

Crit Care Med 2008; 36:1330-1349

To update the practice parameters for the evaluation of adult patients who develop a new fever in the intensive care unit, for the purpose of guiding clinical practice.

Participants
A task force of 11 experts in the disciplines related to critical care medicine and infectious diseases was convened from the membership of the Society of Critical Care Medicine and the Infectious Diseases Society of America. Specialties represented included critical care medicine, surgery, internal medicine, infectious diseases, neurology, and laboratory medicine/microbiology.

Evidence
The task force members provided personal experience and determined the published literature (MEDLINE articles, textbooks, etc.) from which consensus was obtained. Published literature was reviewed and classified into one of four categories, according to study design and scientific value.

Consensus process
The task force met twice in person, several times by teleconference, and held multiple e-mail discussions during a 2-yr period to identify the pertinent literature and arrive at consensus recommendations. Consideration was given to the relationship between the weight of scientific evidence and the strength of the recommendation. Draft documents were composed and debated by the task force until consensus was reached by nominal group process.

Conclusions
The panel concluded that, because fever can have many infectious and noninfectious etiologies, a new fever in a patient in the intensive care unit should trigger a careful clinical assessment rather than automatic orders for laboratory and radiologic tests. A cost-conscious approach to obtaining cultures and imaging studies should be undertaken if indicated after a clinical evaluation. The goal of such an approach is to determine, in a directed manner, whether infection is present so that additional testing can be avoided and therapeutic decisions can be made.

NEJM 2009;360:20-31

Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting.

Methods
We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in the Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance.

Results
A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively.

Conclusions
In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD

JAMA 2008;300:933-944.

The American Diabetes Association and Surviving Sepsis Campaign recommend tight glucose control in critically ill patients based largely on 1 trial that shows decreased mortality in a surgical intensive care unit. Because similar studies report conflicting results and tight glucose control can cause dangerous hypoglycemia, the data underlying this recommendation should be critically evaluated.

Objective
To evaluate benefits and risks of tight glucose control vs usual care in critically ill adult patients.

Data Sources
MEDLINE (1950-2008), the Cochrane Library, clinical trial registries, reference lists, and abstracts from conferences from both the American Thoracic Society (2001-2008) and the Society of Critical Care Medicine (2004-2008).

Study Selection
We searched for studies in any language in which adult intensive care patients were randomly assigned to tight vs usual glucose control. Of 1358 identified studies, 34 randomized trials (23 full publications, 9 abstracts, 2 unpublished studies) met inclusion criteria.

Data Extraction and Analysis
Two reviewers independently extracted information using a prespecified protocol and evaluated methodological quality with a standardized scale. Study investigators were contacted for missing details. We used both random- and fixed-effects models to estimate relative risks (RRs).

Results
Twenty-nine randomized controlled trials totaling 8432 patients contributed data for this meta-analysis. Hospital mortality did not differ between tight glucose control and usual care overall (21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85-1.03). There was also no significant difference in mortality when stratified by glucose goal ([1] very tight: ≤110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77-1.04; or [2] moderately tight: <150 mg/dL; 17.3% vs 18.0%; RR, 0.99; 95% CI, 0.83-1.18) or intensive care unit setting ([1] surgical: 8.8% vs 10.8%; RR, 0.88; 95% CI, 0.63-1.22; [2] medical: 26.9% vs 29.7%; RR, 0.92; 95% CI, 0.82-1.04; or [3] medical-surgical: 26.1% vs 27.0%; RR, 0.95; 95% CI, 0.80-1.13). Tight glucose control was not associated with significantly decreased risk for new need for dialysis (11.2% vs 12.1%; RR, 0.96; 95% CI, 0.76-1.20), but was associated with significantly decreased risk of septicemia (10.9% vs 13.4%; RR, 0.76; 95% CI, 0.59-0.97), and significantly increased risk of hypoglycemia (glucose ≤40 mg/dL; 13.7% vs 2.5%; RR, 5.13; 95% CI, 4.09-6.43).

Conclusion
In critically ill adult patients, tight glucose control is not associated with significantly reduced hospital mortality but is associated with an increased risk of hypoglycemia.

BMJ 2007;335:xxx-xxx

To determine whether clinicians’ prognoses in patients with severe acute exacerbations of obstructive lung disease admitted to intensive care match observed outcomes in terms of survival.

Design
Prospective cohort study.

Setting
92 intensive care units and three respiratory high dependency units in the United Kingdom.

Participants
832 patients aged 45 years and older with breathlessness, respiratory failure, or change in mental status because of an exacerbation of COPD, asthma, or a combination of the two.

Main outcome measures
Outcome predicted by clinicians. Observed survival at 180 days.

Results
517 patients (62%) survived to 180 days. Clinicians’ prognoses were pessimistic, with a mean predicted survival of 49% at 180 days. For the fifth of patients with the poorest prognosis according to the clinician, the predicted survival rate was 10% and the actual rate was 40%. Information from a database covering 74% of intensive care units in the UK suggested no material difference between units that participated and those that did not. Patients recruited were similar to those not recruited in the same units.

Conclusions
Because decisions on whether to admit patients with COPD or asthma to intensive care for intubation depend on clinicians’ prognoses, some patients who might otherwise survive are probably being denied admission because of unwarranted prognostic pessimism.

Cardiovascular morbidity and mortality resulting from congestive heart failure are major concerns for the critical care physician. Although heart failure is commonly associated with impaired systolic function, in up to one half of cases, heart failure occurs exclusively on the basis of an impairment of diastolic function. Diastole is the summation of processes by which the heart loses its ability to generate force and shorten and returns to its precontractile state. The two principal processes responsible for diastole are relaxation and passive pressure-volume properties of the ventricle. Echocardiography provides a comprehensive, noninvasive evaluation of diastolic filling of the ventricle, myocardial relaxation, and ventricular stiffness; the information obtained by echocardiography has prognostic value and is a guide to proper therapy. This article reviews the physiology of diastole, the pathogenesis of diastolic heart failure, and the diagnosis of diastolic dysfunction, with a focus on the diagnostic utility of echocardiography and an emphasis on those areas of greatest interest to the critical care physician.

Critical Care 2007, 11:R43

Conventional pulsed wave Doppler parameters are known to be preload dependent, whereas newly proposed Doppler indices may be less influenced by variations in loading conditions. The aim of the present study was to evaluate the effects of haemodialysis-induced preload reduction on both conventional and new Doppler parameters for the assessment of left ventricular (LV) diastolic function.

Methods
This prospective observational study was conducted in a medical-surgical intensive care unit (ICU) and nephrology department of a teaching hospital. In total, 37 haemodialysis patients with end-stage renal disease (age [mean ± standard deviation]: 52 ± 13 years) and eight ventilated ICU patients with acute renal failure receiving vasopressor therapy (age 57 ± 16 years; Simplified Acute Physiology Score II 51 ± 17) were studied. Echocardiography was performed before and after haemodialysis. Conventional pulsed wave Doppler indices of LV diastolic function as well as new Doppler indices, including Doppler tissue imaging early diastolic velocities (E’ wave) of the septal and lateral portions of the mitral annulus, and propagation velocity of LV inflow at early diastole (Vp) were measured and compared before and after ultrafiltration.

Results
The volume of ultrafiltration was greater in haemodialysis patients than in ICU patients (3.0 ± 1.1 l versus 1.9 ± 0.9 l; P = 0.005). All conventional pulsed wave Doppler parameters were altered by haemodialysis. In haemodialysis patients, E’ velocity decreased after ultrafiltration when measured at the septal mitral annulus (7.1 ± 2.5 cm/s versus 5.9 ± 1.7 cm/s; P = 0.0003), but not at its lateral portion (8.9 ± 3.1 cm/s versus 8.3 ± 2.6 cm/s; P = 0.37), whereas no significant variation was observed in ICU patients. Vp decreased uniformly after ultrafiltration, the difference being significant only in haemodialysis patients (45 ± 11 cm/s versus 41 ± 13 cm/s; P = 0.04). Although of less magnitude, ultrafiltration-induced variations in Doppler parameters were also observed in haemodialysis patients with altered LV systolic function.

Conclusion
In contrast to other Doppler parameters, Doppler tissue imaging E’ maximal velocity measured at the lateral mitral annulus represents an index of LV diastolic function that is relatively insensitive to abrupt and marked preload reduction.

Anaesthesia 2007;62:796-801

We assessed the minimal remifentanil dosage required for tracheal tube tolerance in awake and spontaneously breathing patients after major abdominal surgery. Forty postoperative patients received remifentanil 0.1 μg^.kg^-1.min, which was reduced in steps of 0.025 μg^.kg^-1.min every 30 min. Respiratory response subscore of comfort scale (CSRR), Ramsay sedation scale (RSS), visual analogue scale (VAS), respiratory rate, and minute ventilation were recorded. Spontaneous respiration with no or little response to ventilation (CSRR 2) in co-operative, oriented and tranquil patients (RSS 2) was defined as the main outcome and study endpoint. Thirty-one patients (77.5%) reached a CSRR 2 and RSS 2 with remifentanil 0.025 μg^.kg^-1.min and nine patients (22.5%) required remifentanil 0.05 μg^.kg^-1.min. Analgesia was sufficient in all patients (VAS = 30). Remifentanil 0.025−0.05 μg^.kg^-1.min achieves satisfactory tracheal tube tolerance in awake and spontaneously breathing patients.

Anaesthesia 2007;62:760–768

The bias, precision and tracking ability of five different pulse contour methods were evaluated by simultaneous comparison of cardiac output values from the conventional thermodilution technique (COtd). The five different pulse contour methods included in this study were: Wesseling’s method (cZ); the Modelflow method; the LiDCO system; the PiCCO system and a recently developed Hemac method. We studied 24 cardiac surgery patients undergoing uncomplicated coronary artery bypass grafting. In each patient, the first series of COtd was used to calibrate the five pulse contour methods. In all, 199 series of measurements were accepted by all methods and included in the study. COtd ranged from 2.14 to 7.55 l^.min^-1, with a mean of 4.81 l^.min^-1. Bland-Altman analysis showed the following bias and limits of agreement: cZ, 0.23 and − 0.80 to 1.26 l^.min^-1; Modelflow, 0.00 and − 0.74 to 0.74 l^.min^-1; LiDCO, – 0.17 and − 1.55 to 1.20 l^.min^-1; PiCCO, 0.14 and − 1.60 to 1.89 l^.min^-1; and Hemac, 0.06 and − 0.81 to 0.93 l^.min^-1. Changes in cardiac output larger than 0.5 l^.min^-1 (10%) were correctly followed by the Modelflow and the Hemac method in 96% of cases. In this group of subjects, without congestive heart failure, with normal heart rhythm and reasonable peripheral circulation, the best results in absolute values as well as in tracking changes in cardiac output were measured using the Modelflow and Hemac pulse contour methods, based on non-linear three-element Windkessel models.