Times are A-Changin': self-poisoning and ICU admissions in the northern part of the Netherlands.

INTRODUCTION: We noticed that fewer patients with self-poisoning were transferred from the ED to the Intensive Care Unit (ICU) than previously. To objectify this, we evaluated ED and ICU admissions in two time periods. METHODS: The number of admissions was collected during 1994-1998 and 2010-2014. As a sample survey, full records of patients with an intoxication from January 2010 till December 2010 were studied. RESULTS: From 2010-2014 26 patients/year were admitted from the ED to the ICU; from 1994-1998 51 patients/year (p=0.0001). In 2010, 270 patients presented to our ED; 31 were admitted to the ICU; 1 patient died. Time spent in the ED was 236 min for patients who went home, 290 min for patients who went to a nursing ward and 185 minutes for patients transferred to the ICU. CONCLUSION: We found indeed fewer ICU admissions in recent years. Changing work routines - a longer observation period in the ED, causing a workload shift from the ICU to the ED, more than changing patient or drug characteristics, may be the cause for this development.

Noninvasive beat-to-beat finger arterial pressure monitoring during orthostasis: a comprehensive review of normal and abnormal responses at different ages.

Over the past 30 years, noninvasive beat-to-beat blood pressure (BP) monitoring has provided great insight into cardiovascular autonomic regulation during standing. Although traditional sphygmomanometric measurement of BP may be sufficient for detection of sustained orthostatic hypotension, it fails to capture the complexity of the underlying dynamic BP and heart rate responses. With the emerging use of noninvasive beat-to-beat BP monitoring for the assessment of orthostatic BP control in clinical and population studies, various definitions for abnormal orthostatic BP patterns have been used. Here, age-related changes in cardiovascular control in healthy subjects will be reviewed to define the spectrum of the most important abnormal orthostatic BP patterns within the first 180 s of standing. Abnormal orthostatic BP responses can be defined as initial orthostatic hypotension (a transient systolic BP fall of >40 mmHg within 15 s of standing), delayed BP recovery (an inability of systolic BP to recover to a value of >20 mmHg below baseline at 30 s after standing) and sustained orthostatic hypotension (a sustained decline in systolic BP of ≥20 mmHg occurring 60-180 s after standing). In the evaluation of patients with light-headedness, pre(syncope), (unexplained) falls or suspected autonomic dysfunction, it is essential to distinguish between normal cardiovascular autonomic regulation and these abnormal orthostatic BP responses. The prevalence, clinical relevance and underlying pathophysiological mechanisms of these patterns differ significantly across the lifespan. Initial orthostatic hypotension is important for identifying causes of syncope in younger adults, whereas delayed BP recovery and sustained orthostatic hypotension are essential for evaluating the risk of falls in older adults.

Routine tests and automated urinalysis in patients with suspected urinary tract infection at the ED.

BACKGROUND: Urinary tract infections (UTIs) are frequently encountered. Diagnostics of UTI (urine dipstick, Gram stain, urine culture) lack proven accuracy and precision in the emergency department. Utility of automated urinalysis shows promise for UTI diagnosis but has not been validated. METHODS: A total of 381 cases presenting with fever and/or clinically suspected UTI were analyzed. Diagnosis was based on clinical presentation, urine culture and/ or blood culture, and successful treatment. Performance of standard diagnostics and automated urinalysis (Sysmex UF-1000i) was analyzed at various cutoff values, and diagnostic algorithms were tested. RESULTS: One hundred forty-three (37.5%) cases were diagnosed with UTI. Sensitivity of urine dipstick nitrite was 32.9% and specificity was 93.7%. Sensitivity of urine dipstick leukocyte esterase (3+) was 80.4% and specificity was 82.8%. Receiver operating characteristic curves of automated bacterial and leukocyte count showed area under the curve of 0.851 and 0.872, respectively. Cutoff values of 133 bacteria/µL and 48 leukocytes/µL resulted in >90% sensitivity. Diagnostic values for complicated cases (antibiotics, catheters) were inferior to uncomplicated cases. Algorithms combining dipstick and automated counts did not improve accuracy with the exception of a 5.2% increase in uncomplicated cases (n=247). CONCLUSIONS: Automated leukocyte and bacterial count can be used in the emergency department setting with comparable accuracy compared with standard dipstick analysis with minor improvement when combined.

Pre-hospital care after return of spontaneous circulation: Are we achieving our targets?

Background: Early restoration of normal physiology when return of spontaneous circulation (ROSC) is obtained after an out-of-hospital cardiac arrest (OHCA) reduces the risk of developing post-cardiac arrest syndrome (PCAS). This study aims to investigate if (and to which extent) this can be achieved within the scope of practice of standard emergency medical services (EMS) crews. Methods: A prospective mixed-methods quantitative and qualitative cohort study was performed including adult patients with a non-traumatic OHCA presented to a university hospital emergency department (ED) in the Netherlands after pre-hospital ROSC was obtained. Primary endpoint was the percentage of patients with deranged physiology post-ROSC in whom EMS crews were able to reach recommended treatment targets. Results: During a 32-month period, 160 patients presenting with ROSC after OHCA were included. Median (IQR) pre-hospital treatment duration was 40 (34-51) minutes. When deranged physiology was present (n = 133), it could be restored by EMS crews in 29% of the patients. Although average etCO2 and SpO2 improved gradually over time during pre-hospital treatment, recommended treatment targets could not be achieved in respectively 55% (30/55) and 43% (20/46) of the patients. Similarly, airway problems (24/46, 52%), hypotension (20/23, 87%) and post-anoxic agitation (16/43, 37%) could often not be resolved by EMS crews. The ability to restore normal physiology by EMS could not be predicted based on patient characteristics or in-arrest variables. Conclusion: Deranged physiology after an OHCA is commonly encountered, and often difficult to treat within the scope of practice of regular EMS crews. Involvement of advanced critical care teams with a wider scope of practice at an early stage may contribute to a better outcome for these patients.

What is the potential benefit of pre-hospital extracorporeal cardiopulmonary resuscitation for patients with an out-of-hospital cardiac arrest? A predictive modelling study.

AIM: In this predictive modelling study we aimed to investigate how many patients with an out-of-hospital cardiac arrest (OHCA) would benefit from pre-hospital as opposed to in-hospital initiation of extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: A temporal spatial analysis of Utstein data was performed for all adult patients with a non-traumatic OHCA attended by three emergency medical services (EMS) covering the north of the Netherlands during a one-year period. Patients were considered potentially eligible for ECPR if they had a witnessed arrest with immediate bystander CPR, an initial shockable rhythm (or signs of life during resuscitation) and could be presented in an ECPR-centre within 45 minutes of the arrest. Endpoint of interest was defined as the hypothetical number of ECPR eligible patients after 10, 15 and 20 minutes of conventional CPR and upon (hypothetical) arrival in an ECPR-centre as a fraction of the total number of OHCA patients attended by EMS. RESULTS: During the study period 622 OHCA patients were attended, of which 200 (32%) met ECPR eligibility criteria upon EMS arrival. The optimal transition point between conventional CPR and ECPR was found to be after 15 minutes. Hypothetical intra-arrest transport of all patients in whom no return of spontaneous circulation (ROSC) was obtained after that point (n = 84) would have yielded 16/622 (2.5%) patients being potentially ECPR eligible upon hospital arrival (average low-flow time 52 minutes), whereas on-scene initiation of ECPR would have resulted in 84/622 (13.5%) potential candidates (average estimated low-flow time 24 minutes before cannulation). CONCLUSION: Even in healthcare systems with relatively short transport distances to hospital, consideration should be given to pre-hospital initiation of ECPR for OHCA as it shortens low-flow time and increases the number of potentially eligible patients.

The validation of a serious game for teaching ultrasound skills.

BACKGROUND: Point-of-care ultrasound (POCUS) is an important bedside diagnostic tool and is being taught in several specialties. However, mastering the required psychomotor skills takes time and learning curves are different between students. Especially learning to make the right probe movements with the corresponding changes of the ultrasound image on screen, and integrating it into a 3D mental model takes time. This precious bedside-time of trainers and physicians may be reduced using other learning methods for mastering the psychomotor skills, for example the use of serious games. Such a game is under development but it needs to be validated before widespread use can be advised. In this article we describe the development and the first three steps in the validation of a serious game for ultrasound skills. RESULTS: We have included 18 ultrasound experts and 24 ultrasound novices who played the serious game 'Underwater" and provided feedback. They concluded that "underwater" is fun to play and that movement of the 3D-printed probe resembled real ultrasound probe movements. Participants highly valued the potential of the game for training eye-hand coordination and stability of probe handling, two very important skills in performing ultrasound in real practice. Although we compared several in-game parameters such as distance and speed, no difference was observed between novices and experts. This means that content- and face validity of the serious game is demonstrated but optimal parameters to measure differences between novices and experts still have to be determined. CONCLUSIONS: Our study shows solid content- and face validity of the serious game "UnderWater" for training ultrasound skills, although construct validity could not be demonstrated yet. The game is appreciated as a promising serious game for training eye-hand coordination and learning ultrasound, which may reduce expensive bed-side teaching.

Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis.

AIM: The aim of this study was to examine the quality of manuscripts reporting sepsis health care costs and to provide an overview of hospital-related expenditures for sepsis in adult patients around the world. METHODS: We systematically searched the PubMed, EMBASE, Cochrane and Google Scholar to identify relevant studies between January 2010 and January 2022. We selected articles that provided costs and cost-effectiveness analyses, defined sepsis and described their cost calculation method. All costs were adjusted to 2020 US dollars. Medians and interquartile ranges (IQRs) for various costs of sepsis were calculated. The quality of economic studies was assessed using the Drummond 10-item checklist. RESULTS: Overall, 26 studies met our eligibility criteria. The mean total hospital costs per patient varied largely, between €1101 and €91,951. The median (IQR) of the total sepsis costs per country were €36,191 (€17,158 - €53,349), which equals €50 (€34 - €84) per capita annually. The relative amount of healthcare budget spent on sepsis was 2.65%, which equals 0.33% of the gross national product (GNP). CONCLUSION: While general sepsis costs are high, there is considerable variability between countries regarding the costs of sepsis. Further studies examining the impact on sepsis costs, especially on the general ward, can help justify, design and monitor initiatives on prevention, diagnosis, and treatment of this time-critical and potentially preventable disease.

Plasma proteomic characterization of the development of acute kidney injury in early sepsis patients.

Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design (n = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis.

Elevated lactate during psychogenic hyperventilation.

STUDY OBJECTIVE: Elevated arterial lactate levels are closely related to morbidity and mortality in various patient categories. In the present retrospective study, the relation between arterial lactate, partial pressure of carbon dioxide (Pco(2)) and pH was systematically investigated in patients who visited the emergency department (ED) with psychogenic hyperventilation. METHODS: Over a 5-month period, all the patients who visited the ED of a university hospital with presumed psychogenic hyperventilation were evaluated. Psychogenic hyperventilation was presumed to be present when an increased respiratory rate (>20 min) was documented at or before the ED visit and when somatic causes explaining the hyperventilation were absent. Arterial blood gas and lactate levels (reference values 0.5-1.5 mmol/l) were immediately measured by a point-of-care analyser that was managed and calibrated by the central laboratory. RESULTS: During the study period, 46 patients were diagnosed as having psychogenic hyperventilation. The median (range) Pco(2) for this group was 4.3 (2.0-5.5) kPa, the pH was 7.47 (7.40-7.68) and the lactate level was 1.2 (0.5-4.4) mmol/l. 14 participants (30%) had a lactate level above the reference value of 1.5 mmol/l. Pco(2) was the most important predictor of lactate in multivariate analysis. None of the participants underwent any medical treatment other than observation at the ED or had been hospitalised after their ED visit. CONCLUSIONS: In patients with psychogenic hyperventilation, lactate levels are frequently elevated. Whereas high lactates are usually associated with acidosis and an increased risk of poor outcome, in patients with psychogenic hyperventilation, high lactates are associated with hypocapnia and alkalosis. In this context, elevated arterial lactate levels should not be regarded as an adverse sign.

Influence of gender on the performance of urine dipstick and automated urinalysis in the diagnosis of urinary tract infections at the emergency department.

BACKGROUND: Urinary tract infections (UTIs) are frequently encountered at the Emergency Department (ED). Given the anatomical differences between men and women, we aimed to clarify differences in the diagnostic performance of urinary parameters at the ED. METHODS: A cohort study of adults presenting at the ED with fever and/or clinical suspected UTI. Performance of urine dipstick (UD) and automated urinalysis (UF-1000i) were analysed for the total study population and men and women separately. We focused on 1) UTI diagnosis and 2) positive urine culture (UC, ≥105 CFU/ml) as outcome. RESULTS: In 360 of 917 cases (39.3%) UTI was established (men/women 35.1%/43.6%). Diagnostic accuracy of UD was around 10% lower in women compared to men. Median automated leucocyte and bacterial count were higher in women compared to men. Diagnostic performance by receiver operating analysis was 0.851 for leucocytes (men/women 0.879/0.817) and 0.850 for bacteria (men/women 0.898/0.791). At 90% sensitivity, cut-off values of leucocyte count (men 60/µL, women 43/µL), and bacterial count (men 75/µL, women 139/µL) showed performance differences in favour of men. In both men and women, diagnostic performance using specified cut-off values was not different between normal and non-normal bladder evacuation. UC was positive in 327 cases (men/women 149/178), as with UTI diagnosis, diagnostic values in men outperformed women. CONCLUSIONS: Overall diagnostic accuracy of urinary parameters for diagnosing UTI is higher in men. The described differences in cut-off values for leukocyte and bacterial counts for diagnosing UTI necessitates gender-specific cut-off values, probably reflecting the influence of anatomical and urogenital differences.

Life after a point-of-care ultrasound course: setting up the right conditions!

BACKGROUND: Point-of-care Ultrasound (POCUS) is becoming an important diagnostic tool for internal medicine and ultrasound educational programs are being developed. An ultrasound course is often included in such a curriculum. We have performed a prospective observational questionnaire-based cohort study consisting of participants of a POCUS course for internal medicine in the Netherlands in a 2-year period. We investigated the usefulness of an ultrasound course and barriers participants encountered after the course. RESULTS: 55 participants (49%) completed the pre-course questionnaire, 29 (26%) completed the post-course questionnaire, 11 participants (10%) finalized the third questionnaire. The number of participants who performs POCUS was almost doubled after the course (from 34.5 to 65.5%). Almost all participants felt insufficiently skilled before the course which declined to 34.4% after the course. The majority (N = 26 [89.7%]) stated that this 2-day ultrasound course was sufficient enough to perform POCUS in daily practice but also changed daily practice. The most important barriers withholding them from performing ultrasound are lack of experts for supervision, insufficient practice time and absence of an ultrasound machine. CONCLUSIONS: This study shows that a 2-day hands-on ultrasound course seems a sufficient first step in an ultrasound curriculum for internal medicine physicians to obtain enough knowledge and skills to perform POCUS in clinical practice but it also changes clinical practice. However, there are barriers in the transfer to clinical practice that should be addressed which may improve curriculum designing.

Optimal anatomical location for needle chest decompression for tension pneumothorax: A multicenter prospective cohort study.

OBJECTIVE: Tension Pneumothorax (TP) can occur as a potentially life threatening complication of chest trauma. Both the 2nd intercostal space in the midclavicular line (ICS2-MCL) and the 4th/5th intercostal space in the anterior axillary line (ICS 4/5-AAL) have been proposed as preferred locations for needle decompression (ND) of a TP. In the present study we aim to determine chest wall thickness (CWT) at ICS2-MCL and ICS4/5-AAL in normal weight-, overweight- and obese patients, and to calculate theoretical success rates of ND for these locations based on standard catheter length. METHODS: We performed a prospective multicenter study of a convenience sample of adult patients presenting in Emergency Departments (ED) of 2 university hospitals and 6 teaching hospitals participating in the XXX consortium. CWT was measured bilaterally in ISC2-MCL and ISC4/5-AAL with point of care ultrasound (POCUS) and hypothetical success rates of ND were calculated for both locations based on standard equipment used for ND. RESULTS: A total of 392 patients was included during a 2 week period. Mean age was 51 years (range 18-89), 52% was male and mean BMI was 25.5 (range 16.3-45.0). Median CWT was 26 [IQR 21-32] (range 9-52) mm in ISC2-MCL, and 26 [21-33] (range 10-78) mm in ICS4/5-AAL (p<0.001). CWT in ISC2-MCL was significantly thinner than ICS4/5-AAL in overweight- (BMI 25-30, p<0.001), and obese (BMI>30, p=0.016 subjects, but not in subjects with a normal BMI. Hypothetical failure rates for 45mm Venflon and 50mm Angiocatheter were 2.5% and 0.8% for ICS2-MCL and 6.2% and 2.5% for ISC4/5-AAL (p=0.016 and p=0.052 respectively). CONCLUSION: In overweight- and obese subjects, the chest wall is thicker in ICS 4/5-AAL than in ICS2-MCL and theoretical chances of successful needle decompression of a tension pneumothorax are significantly higher in ICS2-MCL compared to ICS 4/5-AAL.

Point-of-care Ultrasound (PoCUS) for the internist in Acute Medicine: a uniform curriculum.

The use of Point-of-care Ultrasound (PoCUS) is rapidly increasing in internal medicine as it is useful in the primary assessment of acutely ill internal medicine patients for enhanced diagnostics and resuscitation. PoCUS can be taught in a modular fashion including basic core applications and advanced applications which can be combined for a symptom-based approach. Several PoCUS curriculum guidelines, especially for emergency medicine, exist throughout the world but a clear Dutch guideline for internists has not been developed. In this review we propose 'core' ultrasound competencies for internists that may also be incorporated into the European Training Requirements Internal Medicine. We suggest the use of an Entrustable Professional Activities (EPA) competencybased training system with EPAs specifically designed for ultrasound.

A Systematic Review of the Effects of Hyperoxia in Acutely Ill Patients: Should We Aim for Less?

INTRODUCTION: Despite widespread and liberal use of oxygen supplementation, guidelines about rational use of oxygen are scarce. Recent data demonstrates that current protocols lead to hyperoxemia in the majority of the patients and most health care professionals are not aware of the negative effects of hyperoxemia. METHOD: To investigate the effects of hyperoxemia in acutely ill patients on clinically relevant outcomes, such as neurological and functional status as well as mortality, we performed a literature review using Medline (PubMed) and Embase. We used the following terms: hyperoxemia OR hyperoxemia OR ["oxygen inhalation therapy" AND (mortality OR death OR outcome OR survival)] OR [oxygen AND (mortality OR death OR outcome OR survival)]. Original studies about the clinical effects of hyperoxemia in adult patients suffering from acute or emergency illnesses were included. RESULTS: 37 articles were included, of which 31 could be divided into four large groups: cardiac arrest, traumatic brain injury (TBI), stroke, and sepsis. Although a single study demonstrated a transient protective effect of hyperoxemia after TBI, other studies revealed higher mortality rates after cardiac arrest, stroke, and TBI treated with oxygen supplementation leading to hyperoxemia. Approximately half of the studies showed no association between hyperoxemia and clinically relevant outcomes. CONCLUSION: Liberal oxygen therapy leads to hyperoxemia in a majority of patients and hyperoxemia may negatively affect survival after acute illness. As a clinical consequence, aiming for normoxemia may limit negative effects of hyperoxemia in patients with acute illness.

The ABCDE primary assessment in the emergency department in medically ill patients: an observational pilot study.

BACKGROUND: Competency in the Airway Breathing Circulation Disability Exposure (ABCDE) approach is required for working in the emergency department. There is limited knowledge on how often and how completely the ABCDE approach is applied to medical patients. The objectives of this study were to assess the frequency with which the ABCDE approach was used in potentially unstable patients and to determine factors influencing the choice of whether or not to use the ABCDE approach. METHODS: This observational pilot study included 270 medical patients admitted to the emergency department and it was observed if and how completely the ABCDE approach was performed. We registered several factors possibly determining its use. RESULTS: Of the 270 patients included, 206 were identified as possibly unstable patients based on their triage code. The ABCDE approach was used in a minority of these patients (33%). When the ABCDE approach was used, it was done rapidly (generally within 10 minutes) and highly completely (> 80% of needed items). The choice not to use the ABCDE approach was frequently based on a first clinical impression and/or vital signs obtained during triage. The ABCDE approach was used more often with a higher triage code. CONCLUSIONS: We show that the emergency department staff are capable of performing the ABCDE approach rather completely (83%), but it was only used in the minority of potentially unstable patients. Important factors determining this choice were the vital signs on triage and a quick first impression. Whether this adequately selects patients in need for an ABCDE approach is not clear yet.

[Diagnostic image (283). A man with a swollen tongue]. / Diagnose in beeld (283). Een man met een dikke tong.

A 70-year-old man presented with a swollen tongue caused by an angiotensin-converting enzyme inhibitor.

Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions.

OBJECTIVE: In patients with essential hypertension, defects in both the metabolic and vascular actions of insulin have been described. Impaired microvascular function, a well-established abnormality in essential hypertension, may explain part of these defects. In the present study we investigated whether microvascular function is impaired in essential hypertension and relates to insulin's metabolic and vasodilatatory actions. METHODS: We measured 24-h ambulatory blood pressure, capillary recruitment after arterial occlusion, and skin blood flow responses to iontophoresis of acetylcholine and sodium nitroprusside in 18 subjects with untreated essential hypertension and in 18 control subjects. Whole body insulin sensitivity and leg insulin-mediated vasodilatation were assessed with the hyperinsulinaemic clamp technique and plethysmography. RESULTS: Hypertensive, as compared to normotensive, subjects had a decreased insulin sensitivity (0.8+/-0.3 vs. 1.7+/-0. 6 mgkg(-1)min(-1) per pmoll(-1); P<0.001), capillary recruitment after arterial occlusion (21.5+/-5.8 vs. 45.9+/-10.4%; P<0.001), acetylcholine-mediated vasodilatation (331+/-84 vs. 688+/-192%; P<0. 001), and insulin-mediated vasodilatation (median 29.3 vs. 47.2%; P<0.05). Correlation analyses with adjustment for sex, age, body mass index and waist-to-hip ratio showed significant relationships of capillary recruitment after arterial occlusion with blood pressure (r=-0.68; P<0.01), insulin sensitivity (r=+0.55; P<0.01) and insulin-mediated vasodilatation (r=+0.51; P<0.05), which extended from the normotensive to the hypertensive range. CONCLUSION: Skin microvascular function is associated with blood pressure and insulin's metabolic and vasodilatatory actions, both in normotensive and hypertensive subjects. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.

Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency.

Short term GH replacement therapy has been shown to improve body composition and exercise capacity. It is not yet known whether GH replacement remains beneficial over the long term. We assessed the effects of long term GH replacement on body composition, bone mineral density, and cardiac function. Thirty-eight men with childhood-onset GH deficiency were studied for a period of 3-5 yr. Measurements included anthropometry, computed tomographic scanning of abdomen and upper leg, bone densitometry, echo cardiography, and bicycle ergometry. The initial GH dose of 1-3 IU/m2 x day (9-27 microg/kg) was gradually tapered to 1.30+/-0.38 IU/m2 x day (11 g/kg), aiming at physiological insulin-like growth factor I levels. During the study, leg muscle mass progressively increased by 28.7% (P<0.001). Subcutaneous and intraabdominal fat decreased by 30.9% and 46.0%, respectively, after 1 yr (both P<0.001), but demonstrated a partial regain thereafter. Bone mineral density at the lumbar spine, femoral neck, and trochanter gradually increased by 9.6%, 11.1%, and 16.2%, respectively (all P<0.001). Left ventricular mass exceeded baseline values by 14.1% after 1 yr (P<0.001), but returned to pretreatment values thereafter. Stroke volume and cardiac output increased by 16.3% (P = 0.002) and 33.4% (P<0.001), respectively. Maximal work load increased from 189+/-30 to 232+/-41 watts (P<0.001). Thus, long term GH replacement is safe and beneficial. It improves cardiac performance without inducing left ventricular hypertrophy and progressively increases bone mineral density.

The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects.

High levels of TSH are associated with an increased cardiovascular risk. Many cardiovascular risk factors cluster within the insulin resistance syndrome. It is not known whether levels of TSH cluster as well. We conducted this research to test the hypothesis that TSH, insulin sensitivity, and levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) are interdependent in euthyroid subjects. Levels of TSH, free thyroid hormone, and serum lipids were measured in fasting serum samples taken before performance of a hyperinsulinemic euglycemic clamp to assess insulin sensitivity in 46 healthy euthyroid subjects with a mean TSH of 1.8 +/- 0.7 mU/L. Significant age- and sex-adjusted partial correlations of TSH with LDL-C (r = 0.48; P < 0.01) and HDL-C (r = -0.36; P < 0.05) were observed. TSH was not significantly correlated with insulin sensitivity or fasting triglyceride concentrations. In line with these results, we found the associations of TSH with LDL-C and HDL-C to be independent of insulin sensitivity. However, we observed significant effect-modification of the association of TSH with LDL-C by insulin sensitivity (P = 0.02). This effect-modification implies a range of associations of TSH with LDL-C that varies from absent in insulin-sensitive subjects to strongly positive in insulin-resistant subjects. We conclude that the increased cardiovascular risk associated with subclinical hypothyroidism seems to extend itself into the normal range of thyroid function. Importantly, the effect-modification of the association of TSH with LDL-C by insulin sensitivity suggests that insulin-resistant subjects are most susceptible to this increased risk.

The potential role of adenosine in the pathophysiology of the insulin resistance syndrome.

An increased intracellular availability of the co-enzyme A esters of long-chain fatty acids is thought to underlie many aspects of the insulin resistance syndrome. However, the cause of clustering of a hyperdynamic circulation, sympathetic activation, hypertension, hyperuricaemia, and a raised haematocrit in the insulin resistance syndrome remains to be elucidated. We propose a mechanism that expands the etiological role of long-chain fatty acids. By inhibiting adenine nucleotide translocators, elevated intracellular concentrations of the co-enzyme A esters of long-chain fatty acids impair mitochondrial oxidative phosphorylation. This is expected to result in a chronic systemic increase in extracellular adenosine concentrations. As adenosine stimulates the sympathetic nervous system, induces systemic vasodilatation, stimulates erythropoiesis, and induces renal vasoconstriction with renal sodium retention, increased extracellular ADO concentrations may be the common denominator explaining the above-mentioned and still unexplained phenomena associated with the insulin resistance syndrome. Along the same lines, hyperuricaemia can be explained by the fact that adenosine is broken down to urate and because of increased renal urate retention.