[Benefits of time-limited trials in intensive-care medicine]. / De waarde van een in tijd gelimiteerde behandeling op de IC.

A time-limited trial (TLT) is an option to deal with scarce ICU-beds. A TLT is an agreement made at an early stage of ICU-admission to initiate treatment for a certain period of time to gain a realistic understanding of the patient's chances of a meaningful recovery. If the patient improves, treatment will be continued. However, if treatment goals are not achieved, palliative care is initiated. Chang et. al. investigated the efficacy of introduction of this method. The study was conducted in 2017-2019 and consisted of the structural introduction of TLTs for ICU-patients at risk for non-beneficial ICU-treatments. The main outcome of the study is that after introduction of TLTs, the median stay at the ICU or in the hospital significantly decreased without an increase in mortality. A TLT can be of added value in Dutch ICUs, provided that the staff fully supports the method and is properly trained before implementation.

Time-limited trial of intensive care treatment: an overview of current literature.

In critically ill patients, it is frequently challenging to identify who will benefit from admission to the intensive care unit and life-sustaining interventions when the chances of a meaningful outcome are unclear. In addition, the acute illness not only affects the patients but also family members or surrogates who often are overwhelmed and unable to make thoughtful decisions. In these circumstances, a time-limited trial (TLT) of intensive care treatment can be helpful. A TLT is an agreement to initiate all necessary treatments or treatments with clearly delineated limitations for a certain period of time to gain a more realistic understanding of the patient's chances of a meaningful recovery or to ascertain the patient's wishes and values. In this article, we discuss current research on different aspects of TLTs in the intensive care unit. We propose how and when to use TLTs, discuss how much time should be taken for a TLT, give an overview of the potential impact of TLTs on healthcare resources, describe ethical challenges concerning TLTs, and discuss how to evaluate a TLT.

Practical Use of Lactate Levels in the Intensive Care.

Hyperlactatemia is a strong predictor of mortality in diverse populations of critically ill patients. In this article, we will give an overview of how lactate is used in the intensive care unit. We describe the use of lactate as a predictor of outcome, as a marker to initiate therapy and to monitor adequacy of initiated treatments.

Modified dixon-based renal dynamic contrast-enhanced MRI facilitates automated registration and perfusion analysis.

PURPOSE: Renal dynamic contrast-enhanced (DCE) MRI provides information on renal perfusion and filtration. However, clinical implementation is hampered by challenges in postprocessing as a result of misalignment of the kidneys due to respiration. We propose to perform automated image registration using the fat-only images derived from a modified Dixon reconstruction of a dual-echo acquisition because these provide consistent contrast over the dynamic series. METHODS: DCE data of 10 hypertensive patients was used. Dual-echo images were acquired at 1.5 T with temporal resolution of 3.9 s during contrast agent injection. Dixon fat, water, and in-phase and opposed-phase (OP) images were reconstructed. Postprocessing was automated. Registration was performed both to fat images and OP images for comparison. Perfusion and filtration values were extracted from a two-compartment model fit. RESULTS: Automatic registration to fat images performed better than automatic registration to OP images with visible contrast enhancement. Median vertical misalignment of the kidneys was 14 mm prior to registration, compared to 3 mm and 5 mm with registration to fat images and OP images, respectively (P = 0.03). Mean perfusion values and MR-based glomerular filtration rates (GFR) were 233 ± 64 mL/100 mL/min and 60 ± 36 mL/minute, respectively, based on fat-registered images. MR-based GFR correlated with creatinine-based GFR (P = 0.04) for fat-registered images. For unregistered and OP-registered images, this correlation was not significant. CONCLUSION: Absence of contrast changes on Dixon fat images improves registration in renal DCE MRI and enables automated postprocessing, resulting in a more accurate estimation of GFR. Magn Reson Med 80:66-76, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography.

OBJECTIVES: Relatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated. METHODS: This study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma. RESULTS: MRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366 days post RDN, MRA showed a new stenosis (25-49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable. CONCLUSIONS: We observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12 months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients. KEY POINTS: • The incidence of vascular changes 12 months post RDN was 3.1%. • No renal vascular or parenchymal changes other than stenoses were observed. • Ablations were applied near the stenosis in only one of three patients.

Renal denervation in hypertensive patients not on blood pressure lowering drugs.

INTRODUCTION: Studies on the blood pressure lowering effect of renal denervation (RDN) in resistant hypertensive patients have produced conflicting results. Change in medication usage during the studies may be responsible for this inconsistency. To eliminate the effect of medication usage on blood pressure we focused on unmedicated hypertensive patients who underwent RDN. METHODS AND RESULTS: Our study reports on a cohort of patients, who were not on blood pressure lowering drugs at baseline and during follow-up, from eight tertiary centers. Data of patients were used when they were treated with RDN and had a baseline office systolic blood pressure (SBP) ≥140 mmHg and/or 24-h ambulatory SBP ≥130 mmHg. Our primary outcome was defined as change in office and 24-h SBP at 12 months after RDN, compared to baseline. Fifty-three patients were included. There were three different reasons for not using blood pressure lowering drugs: (1) documented intolerance or allergic reaction (57 %); (2) temporary cessation of medication for study purposes (28 %); and (3) reluctance to take antihypertensive drugs (15 %). Mean change in 24-h SBP was -5.7 mmHg [95 % confidence interval (CI) -11.0 to -0.4; p = 0.04]. Mean change in office SBP was -13.1 mmHg (95 % CI -20.4 to -5.7; p = 0.001). No changes were observed in other variables, such as eGFR, body-mass-index and urinary sodium excretion. CONCLUSION: This explorative study in hypertensive patients, who are not on blood pressure lowering drugs, suggests that at least in some patients RDN lowers blood pressure.

Denervation of the renal arteries in metabolic syndrome: the DREAMS-study.

Chronic elevation of sympathetic nervous system is a key factor in metabolic syndrome. Because renal denervation (RDN) is thought to modulate sympathetic activity, we performed the Denervation of the Renal Arteries in Metabolic Syndrome (DREAMS)-study to investigate the effects of RDN on insulin sensitivity and blood pressure (BP) in patients with metabolic syndrome. Twenty-nine patients fulfilling the criteria for metabolic syndrome and who used a maximum of 1 antihypertensive or 1 antidiabetic drug or 1 of both gave informed consent and were treated by RDN. Glucose tolerance tests and 24-hour ambulatory BP measurements were performed at baseline, at 6 and 12 months of follow-up. Moreover, we performed self-monitored BP measurements at home every month. To assess sympathetic activity, we performed muscle sympathetic nerve activity and heart rate variability measurements at baseline and follow-up. The majority of the included patients was men (57%), mean body mass index was 31±5 kg/m(2). Median insulin sensitivity as assessed by the Simple Index assessing Insulin Sensitivity oral glucose tolerance test did not change at 6- and 12-month follow-up (P=0.60 and P=0.77, respectively). Mean 24-hour BP decreased by 6±12/5±7 mm Hg 12 months after RDN (P=0.04/0.01). However, self-monitored BP measurements data showed no reduction over time. Measurements of sympathetic activity showed no reduction in systemic sympathetic activity. In conclusion, RDN did not lead to a significant improvement of insulin sensitivity ≤12 months after treatment. Although a significant reduction in ambulatory BP was observed in this nearly drug-naïve population, the self-monitored BP measurements data suggest that this may be explained by regression to the mean. Moreover, no effect in systemic sympathetic activity was observed.

Effects of renal denervation on end organ damage in hypertensive patients.

BACKGROUND: Renal denervation (RDN) is believed to reduce sympathetic nerve activity and is a potential treatment for resistant hypertension. The present study investigated the effects of RDN on end organ damage (EOD). DESIGN: The present study was a prospective cohort study (registered as NCT01427049). METHODS: Uncontrolled hypertensive patients underwent a work-up prior to and one year after RDN. Cardiac magnetic resonance (CMR) imaging was used to determine left ventricular (LV)-mass; pulse wave analysis and pulse wave velocity (PWV) were used for evaluation of central blood pressure (BP) and arterial stiffness and 24-hour urine was collected for assessment of urinary albumin excretion. The 24-hour ambulatory BP measurement (ABPM) was used to evaluate the effect of RDN on BP. RESULTS: Fifty-four patients gave informed consent for study participation. Mean age was 58 ± 10 years, 50% were male. One year after RDN, mean ABPM decreased by 7 ± 18/5 ± 11 mm Hg (p = 0.01/p < 0.01). In the patients followed-up in a standardised fashion ABPM decreased by 5 ± 18/4 ± 12 mm Hg (n = 34; p = 0.11/p = 0.09). Mean body surface area indexed LV-mass decreased by 3.3 ± 11.5 g/m(2) (corresponding to a 3 ± 11% reduction; p = 0.09). PWV increased by 2.9 (-2.2 to +6.1) m/s (p = 0.04). Augmentation index corrected for 75 beats per min did not change (median increase 3.0 (-7 to +17) mm Hg; p = 0.89). Urinary albumin excretion did not change during follow-up (mean decrease 10 ± 117 mg/24 hour; p = 0.61). CONCLUSION: In the current study, we observed a modest effect from renal denervation. Moreover, RDN did not result in a statistical significant effect on end organ damage 12 months after treatment.

Renal BOLD-MRI relates to kidney function and activity of the renin-angiotensin-aldosterone system in hypertensive patients.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are key factors in the pathophysiology of hypertension. Renal hypoxia is the putative mechanism stimulating both systems. Blood oxygen level-dependent MRI (BOLD-MRI) provides a noninvasive tool to determine renal oxygenation in humans. The aim of the current study was to investigate the relation between blood pressure (BP) and kidney function with renal BOLD-MRI. Moreover, the relation between direct and indirect variables of the RAAS and sympathetic nervous system and renal BOLD-MRI was studied. METHOD: Seventy-five hypertensive patients (38 men) were included. Antihypertensive medication was temporarily stopped. Patients collected urine during 24 h (sodium, catecholamines), blood samples were taken (creatinine, renin, aldosterone), a captopril challenge test was performed, and ambulatory BP was measured. RESULTS: Mean age was 58 (±11) years, day-time BP was 167 (±19)/102 (±16) mmHg, and estimated glomerular filtration rate was 75 (±18) ml/min per 1.73 m). In multivariable regression analysis, renal medullary R2*-values inversely related to estimated glomerular filtration rate (P = 0.02). Moreover, the BP-lowering effect of captopril positively related to cortical (P = 0.02) and medullary (P = 0.008) R2*-values, as well as to P90 (P = 0.02). CONCLUSION: In patients with hypertension, kidney function relates to medullary R2*-values. Activation of the RAAS is also positively related to the renal R2*-values.

The blood pressure-lowering effect of renal denervation is inversely related to kidney function.

OBJECTIVES: In renal denervation (RDN), a wide range in the blood pressure (BP)-lowering effect has been reported. On the basis of the current knowledge of pathophysiology, we hypothesized that the BP-lowering effect of RDN would be inversely related to kidney function. Second, we investigated whether direct and indirect variables of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) would be related as well. METHODS: Sixty-seven patients from a prospective cohort of patients treated with RDN with completed 6 months follow-up were included. Data collected during routine standardized work-up before RDN were used: 24-h urine excretion of creatinine, albumin, sodium and catecholamines, plasma creatinine, renin activity and aldosterone, ambulatory BP-monitoring and a captopril challenge test. When considered well tolerated, antihypertensive drugs were stopped before these investigations. RESULTS: The BP-lowering was inversely related to estimated glomerular filtration rate (eGFR) in patients who stopped antihypertensive drugs prior to testing (ß: 0.46, P = 0.013). There was a positive relation between SBP at baseline and the BP-lowering effect of RDN (ß:-0.55 mmHg per mmHg, P < 0.001). Parameters related to the rennin-angiotensin system (aldosterone, captopril test) and the sympathetic nervous system (dipping pattern and catecholamines in urine) positively related to the BP-lowering effect of RDN. CONCLUSION: The present explorative study shows an inverse relation between the BP-lowering effect of RDN and eGFR. Second, we found relations between variables of the RAAS and SNS with the BP-lowering effect of RDN. The data complement current concepts on pathophysiology of sympathetic hyperactivity and hypertension and may give some insight in the wide range of the effect of RDN.

Renal denervation in multiple renal arteries.

BACKGROUND: In most previous studies investigating efficacy of renal denervation (RDN), patients with multiple renal arteries are generally excluded from treatment. This study was designed to determine the prevalence of multiple renal arteries in patients referred for RDN, to propose a classification for anatomical eligibility and to investigate the relation between the presence of multiple arteries and blood pressure (BP)-lowering effect. MATERIALS AND METHODS: Patients referred for RDN who underwent noninvasive imaging of the renal arteries before treatment were included in present analysis. Eligible patients were treated. Renal function and BP were evaluated 6 months after treatment. RESULTS: Hundred and twenty-six patients referred for RDN were included in present analysis. Thirty-four per cent had multiple arteries. Sixty-nine patients underwent RDN. Office BP significantly reduced from 195 (± 26)/106 (± 14) mmHg to 165 (± 24)/95 (± 14) mmHg (P < 0·001). BP reduction in patients with multiple arteries which were all treated was comparable to patients with solitary arteries. However, patients with multiple which were not all treated showed a trend towards a less pronounced effect of RDN (ß: 11·6, P = 0·11). The proposed classification appeared useful by identifying eligible anatomy. Renal function at 6 months did not differ from baseline in all subgroups. CONCLUSIONS: Based on our results and the high prevalence of multiple arteries, it seems reasonable not to exclude patients with multiple renal arteries from RDN. Current analysis suggests that BP reduction may be less pronounced in patients with multiple renal arteries of whom not all arteries were treated.

Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study.

Renal denervation (RDN) is a promising novel treatment for resistant hypertension. Effectiveness of treatment is, however, highly variable and unpredictable. Incomplete denervation of the renal nerves is a plausible explanation for the variable blood pressure lowering effect of RDN. Here, we present for the first time a histopathological evaluation of the effects of RDN on perivascular nerves of the renal arteries in a human patient. Our findings potentially have important implications for future directions with RDN.

The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial.

The first studies on renal denervation (RDN) suggest that this treatment is feasible, effective, and safe in the short term. Presently available data are promising, but important uncertainties exist; therefore, SYMPATHY has been initiated. SYMPATHY is a multicenter, randomized, controlled trial in patients randomized to RDN in addition to usual care (intervention group) or to continued usual care (control group). Randomization will take place in a ratio of 2 to 1. At least 300 participants will be included to answer the primary objective. Sample size may be extended to a maximum of 570 to address key secondary objectives. The primary objective is to assess whether RDN added to usual care compared with usual care alone reduces blood pressure (BP) (ambulatory daytime systolic BP) in subjects with an average daytime systolic BP ≥135, despite use of ≥3 BP-lowering agents, 6 months after RDN. Key secondary objectives are evaluated at 6 months and at regular intervals during continued follow-up and include the effect of RDN on the use of BP-lowering agents, in different subgroups (across strata of estimated glomerular filtration rate and of baseline BP), on office BP, quality of life, and cost-effectiveness.

Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.

OBJECTIVES: Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1α by cobalt chloride (CoCl2) preconditioning. METHODS: First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIFα was induced by CoCl2 in drinking water (2 mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1α was determined by immunohistochemistry. RESULTS: Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1α upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1α confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFα. CoCl2 preconditioning prior to phenol reduced both ΔMAP (+10 ± 2 vs. +20 ± 3%, P=0.015) and ΔRVR (+21 ± 11 vs. +90 ± 26%, P=0.003). CONCLUSION: Acute RNH leads to renal vasoconstriction and increased renal HIF-1α. Increasing HIF-1α by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.

Eligibility for percutaneous renal denervation: the importance of a systematic screening.

OBJECTIVE: Percutaneous renal denervation (pRDN) is a new and promising therapy for resistant hypertension. Among patients suspected of having resistant hypertension, the actual presence of this condition needs to be well established; pseudoresistant hypertension and significant white-coat effect (WCE) should be excluded. This analysis presents the results of a standardized screening programme for patients referred for pRDN. METHODS: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were subsequently discussed in a multidisciplinary team. The screening included a 24-h ambulatory blood pressure measurement (ABPM), collection of plasma, urine and saliva, and finally imaging of the renal arteries. RESULTS: From August 2010 till October 2012, 181 patients were referred for pRDN. Mean blood pressure (BP) was 182/100 mmHg, and median use was three antihypertensives. Ultimately, 121 patients (67%) were excluded from pRDN. Main reasons for exclusion were BP-related. Twenty-three patients (19%) had an office SBP less than 160 mmHg and 26 patients (22%) showed a WCE. Fourteen patients (12%) had a so far undetected underlying cause of hypertension, the majority being primary aldosteronism (n = 11). Nine patients had an ineligible renal anatomy. CONCLUSION: A high percentage of patients were excluded from treatment with pRDN due to secondary causes of hypertension, WCE or a BP below the currently advised thresholds. Treatment of these excluded patients would lead to inappropriate use of pRDN, leading most likely to little benefit for the patients and a burden to healthcare. Therefore, it is recommended to use a standardized screening before treatment with pRDN.

Renal denervation as therapy for hypertension: potentials and unanswered questions.

In 2005, cardiovascular diseases globally accounted for 30% of an estimated total of 58 million deaths. Hypertension is one of the major contributors to these events. Unfortunately, about two-thirds of all hypertensive patients do not reach treatment goals despite maximal drug treatment. Percutaneous catheter-based renal denervation as a therapy for uncontrolled hypertension is an intriguing idea, especially for patients with resistant hypertension. The first short-term results from a randomized trial are promising: 84% of the patients had a blood pressure (BP) reduction of ≥10 mmHg and 39% had a systolic BP of ≤140 mmHg 6 months after treatment. However, several questions remain unanswered. To gain more insight, initiatives should be started aiming at assessing safety of the treatment, sustainability of the BP-lowering effect, cost-effectiveness, and the effect on cardiovascular event rate. Many European centres have now started to perform renal denervation or are in the process of starting it up. Therefore, we call for an international collaboration effort to compose cohorts and conduct randomized trials to address the remaining issues at this point in time.

Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options.

Abundant evidence shows that chronic kidney disease (CKD) is a disease state characterized by increased sympathetic activation. Kidney injury (ischemia) plays a central role in this pathogenesis. Sympathetic excitation is associated with an increased risk of cardiovascular morbidity and mortality. Several pharmacologic strategies are developed to decrease sympathetic activity. However, these medications have limitations. Percutaneous catheter-based renal denervation has the potential to become a new treatment option for CKD. This current report focuses on the effects of sympathetic hyperactivity in CKD, and gives an overview in experimental as well as clinical evidence for a central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Moreover, the effect of pharmacologic treatment and the potential beneficial effect of renal denervation will be discussed.

Evidence and consequences of the central role of the kidneys in the pathophysiology of sympathetic hyperactivity.

Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload - such as heart failure - and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.

Changes and tracking of fat mass in pubertal girls.

Puberty is a critical period in body composition development. The influence of puberty on the development of fat mass asks for further investigation. We investigated the development of fat mass during puberty in a longitudinal prospective study in 152 healthy nonobese white girls, initial ages between 9 to 12 years. The influence of menarcheal age and the existing of tracking of fat mass have been analyzed. In 10 years time, participants were measured on eight time points. Various anthropometric data were collected, breast development was staged according to Tanner and body composition was determined with the dual-energy X-ray absorptiometry (DXA) scan. Calculations were made with the use of a linear mixed model. Fat mass increases from 7.9 kg (23.6%) at B1 to 18.5 kg (29.3%) at B5. Fat mass is higher in girls with an early menarche than in girls with a late menarche from B2. Girls in the quartile with initially the lowest fat mass have a chance of being in the same quartile after 10 years of 77% (P < 0.001). Girls in the quartile with initially the highest fat mass, have a risk of staying in the highest quartile of 55% (P < 0.001). Menarcheal age is of great influence on the development of fat mass. Girls with an early menarche, will have a bigger fat mass, especially at the end of puberty. Tracking of fat mass exists: a high amount of fat mass in early puberty will continue to exist at young adulthood.