Joep Lagro

Recurrence of Hyperprolactinemia after Withdrawal of Dopamine Agonists: Systematic Review and Meta-Analysis

CONTEXT Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas. DATA SOURCES PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made with respect to language. STUDY SELECTION Studies reporting the proportion of normoprolactinemic patients after withdrawal of dopamine agonist or studies in which this proportion could be calculated were eligible. Both observational studies and clinical trials were eligible. Nineteen studies were included in the meta-analysis, with a total of 743 patients. DATA EXTRACTION Data extraction was performed by two reviewers independently. DATA SYNTHESIS The pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was 21% in a random effects model [95% confidence interval (CI), 14-30%; I(2) 81%). Stratified analysis showed higher proportions of treatment success in idiopathic hyperprolactinemia (32%; 95% CI, 5-80%), compared with both microprolactinomas (21%; 95% CI, 10-37%), and macroprolactinomas (16%; 95% CI, 6-36%). In a random effects meta-regression adjusting for cause of hyperprolactinemia, a longer treatment duration was associated with treatment success (P = 0.015), whereas the use of cabergoline showed a trend of effect (P = 0.07). CONCLUSIONS This meta-analysis showed that hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of treatment success was highest when cabergoline was used for at least 2 yr.

Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer's disease.

BACKGROUND Understanding the relationship between vascular disease and Alzheimers disease (AD) will enhance our insight into this disease and pave the way for novel therapeutic research. Cerebrovascular dysfunction, expressed as impaired cerebral autoregulation and cerebral vasomotor reactivity, has been observed in transgenic mouse models for AD. Translation to human AD is limited and conflicting however. OBJECTIVE To investigate if impaired cerebral autoregulation and cerebral vasomotor reactivity, found in animal models for AD, are present in human sporadic AD. METHODS In 12 patients with mild to moderate AD (75 SD 4 yr) and 24 controls matched for age and history of hypertension, all without diabetes, we measured blood pressure (Finapres) and cerebral blood flow-velocity (transcranial Doppler). Cerebral autoregulation was assessed during changes in blood pressure induced by single and repeated sit-stand maneuvers. Cerebral vasomotor reactivity was assessed during hyperventilation and inhalation of 5 % carbon dioxide. RESULTS During single sit-stands, controls had a 4% (SD 8) decrease in cerebrovascular resistance during a reduction in blood pressure, and an 8 % (SD 11) increase during a rise in blood pressure, indicating normal cerebral autoregulation. These changes were not seen in AD (p=0.04). During repeated sit-stands, blood pressure fluctuated by 20 % of baseline. This led to larger fluctuations in cerebral blood flow in AD (27 (6) %) than in controls (22 (6) %, p < 0.05). Cerebral vasomotor reactivity to hypercapnia was reduced in AD (42.7 % increase in CBFV, versus 79.5 % in controls, p = 0.03). CONCLUSION Observations of impaired cerebrovascular function (impaired autoregulation and vasoreactivity) in transgenic mouse models for AD were confirmed in patients with sporadic AD.

Oscillations in cerebral blood flow and cortical oxygenation in Alzheimer's disease

In Alzheimers disease (AD) cerebrovascular function is at risk. Transcranial Doppler, near-infrared spectroscopy, and photoplethysmography are noninvasive methods to continuously measure changes in cerebral blood flow velocity (CBFV), cerebral cortical oxygenated hemoglobin (O(2)Hb), and blood pressure (BP). In 21 patients with mild to moderate AD and 20 age-matched controls, we investigated how oscillations in cerebral blood flow velocity (CBFV) and O(2)Hb are associated with spontaneous and induced oscillations in blood pressure (BP) at the very low (VLF = 0.05 Hz) and low frequencies (LF = 0.1 Hz). We applied spectral and transfer function analysis to quantify dynamic cerebral autoregulation and brain tissue oxygenation. In AD, cerebrovascular resistance was substantially higher (34%, AD vs. control: Δ = 0.69 (0.25) mm Hg/cm/second, p = 0.012) and the transmission of very low frequency (VLF) cerebral blood flow (CBF) oscillations into O(2)Hb differed, with increased phase lag and gain (Δ phase 0.32 [0.15] rad; Δ gain 0.049 [0.014] μmol/cm/second, p both < 0.05). The altered transfer of CBF to cortical oxygenation in AD indicates that properties of the cerebral microvasculature are changed in this disease.

Diastolic blood pressure drop after standing as a clinical sign for increased mortality in older falls clinic patients.

Background: Orthostatic hypotension, postprandial hypotension, and carotid sinus hypersensitivity are hypotensive syndromes with high prevalence in older people. However, their pathophysiology and prognostic significance remain largely unknown. Methods: In a retrospective cohort study of 313 consecutive patients visiting our falls outpatient clinic, we examined the clustering of orthostatic hypotension, postprandial hypotension, and carotid sinus hypersensitivity in the same patients, which might reflect a shared similar pathophysiology. The value of hypotensive syndrome presence and the degree of blood pressure decline as prognostic indicators for mortality were assessed using Cox proportional hazards analyses. Results: In 313 patients (mean age 78.7 ± 8.0 years), 168 of 309 (54%), 175 of 302 (58%), and 143 of 272 (53%) were diagnosed with orthostatic hypotension, postprandial hypotension, and sinus carotid hypersensitivity, respectively. There was no clustering of the hypotensive syndromes. During a median follow-up of 23.0 months, 58 (19%) patients died. Orthostatic hypotension, but not postprandial hypotension or carotid sinus hypersensitivity, predicted mortality [hazard ratio 1.97; 95% confidence interval (CI) 1.11–3.47]. After adjusting for age, comorbidity and other baseline characteristics, this relationship was no longer significant. However, orthostatic hypotension with severe diastolic blood pressure decline of at least 20 mmHg remained a powerful independent predictor of mortality (hazard ratio 2.50; 95% CI 1.20–5.22). Conclusions: In falls clinic patients, hypotensive syndromes did not cluster and did not independently predict mortality. However, orthostatic hypotension with severe diastolic blood pressure decline was a powerful independent predictor of mortality and might be used prognostically as an easily available cardiovascular sign of increased mortality risk.

Impaired Systolic Blood Pressure Recovery Directly After Standing Predicts Mortality in Older Falls Clinic Patients

BACKGROUND Normally, standing up causes a blood pressure (BP) drop within 15 seconds, followed by recovery to baseline driven by BP control mechanisms. The prognostic value of this initial BP drop, but also of the recovery hereafter, is unknown. The aim of this study was to examine the prognostic value of these BP characteristics in response to standing. METHODS In a retrospective cohort study of 238 consecutive patients visiting our falls outpatient clinic, we examined the relation between all-cause mortality and BP decline and recovery directly after active standing up with Cox proportional hazards analyses. RESULTS Of 238 patients (mean age 78.4 ± 7.8 years), during a median follow-up of 21.0 months, 36 (15%) patients died. Neither absolute nor relative (%) initial BP drop after standing predicted mortality. In contrast, the magnitude of BP recovery 40-60 seconds after standing was associated with mortality, even after adjustment for age, comorbidity, and other baseline characteristics. When systolic BP had recovered to less than 80% of prestanding baseline after 60 seconds of standing, this was a powerful independent predictor of mortality (hazard ratio: 3.00; 95% confidence interval 1.17-7.68). CONCLUSIONS Failure to recover from BP decline in the first minute after active standing up is associated with excess mortality in falls clinic patients. A recovery of systolic BP to less than 80% of baseline after 60 seconds may be used as an easily available cardiovascular marker for increased mortality risk in older falls clinic patients.

Hypotensive Syndromes Are Not Associated With Cognitive Impairment in Geriatric Patients

To investigate the association of the hypotensive syndromes orthostatic hypotension (OH), postprandial hypotension (PPH), and carotid sinus hypersensitivity (CSH) with cognitive impairment (mild cognitive impairment/dementia). Continuous measurements of blood pressure (Finapres) were performed during active standing, meal test, and carotid sinus massage, among 184 elderly patients presenting with falls. Mild cognitive impairment (MCI) and dementia were diagnosed following a multidisciplinary assessment. The study design was a retrospective cohort study. The OH, PPH, and CSH were observed in 104 (58%), 108 (64%), and 78 (51%) patients, respectively. A total of 79 (43%) patients were cognitively impaired (MCI impairment n = 44; dementia n = 35). The prevalence of cognitive impairment varied little across the hypotensive syndromes (32%-43%) and was similar in patients with and without hypotensive syndromes (P = .59). In this geriatric population with a high prevalence of both hypotensive syndromes and cognitive impairment, patients with one or more hypotensive syndromes were not likely to have cognitive impairment.

Baroreflex function is reduced in Alzheimer's disease: a candidate biomarker?

The baroreflex (BR) reflects autonomic blood pressure control. Alzheimers disease (AD) affects the autonomic system. Detailed properties of BR in AD are unknown. We hypothesized that BR is reduced in AD, and is influenced by autonomic effects of cholinesterase inhibitors (ChEI). BR was determined in 18 AD patients, 11 patients with mild cognitive impairment (MCI) and 19 healthy control subjects. In AD, BR was measured again after ChEI treatment. Receiver operating characteristic analysis was used to define a BR cutoff value, which was then tested in an independent validation sample of 16 AD, 18 MCI, and 18 control subjects. BR was lower in AD compared with MCI (p < 0.05) and in MCI compared with healthy control subjects (p < 0.01). Receiver operating characteristic analysis between AD and healthy control subjects yielded a sensitivity of 89% and a specificity of 94%. ChEI treatment increased BR with 66% (p < 0.01). BR was reduced in AD and increased after treatment with ChEI. BR might be a good biomarker to further explore the link between cardiovascular disease and AD.

Expert and patient consensus on a dynamic model for shared decision-making in frail older patients

OBJECTIVE Shared decision-making (SDM) is widely recommended as a way to support patients in making healthcare choices. Due to an ageing population, the number of older patients will increase. Existing models for SDM are not sufficient for this patient group, due to their multi-morbidity, the lack of guidelines and evidence applicable to the numerous combinations of diseases. The aim of this study was to gain consensus on a model for SDM in frail older patients with multiple morbidities. METHODS We used a three-round Delphi study to reach consensus on a model for SDM in older patients with multiple morbidities. The expert panel consisted of 16 patients (round 1), and 59 professionals (rounds 1-3). In round 1, the SDM model was introduced, rounds 2 and 3 were used to validate the importance and feasibility of the SDM model. RESULTS Consensus for the proposed SDM model as a whole was achieved for both importance (91% panel agreement) and feasibility (76% panel agreement). CONCLUSIONS SDM in older patients with multiple morbidities is a dynamic process. It requires a continuous counselling dialogue between professional and patient or proxy decision maker. PRACTICE IMPLICATIONS The developed model for SDM in clinical practice may help professionals to apply SDM in the complex situation of the care for older patients.

Slowing Down of Recovery as Generic Risk Marker for Acute Severity Transitions in Chronic Diseases.

Objective:We propose a novel paradigm to predict acute attacks and exacerbations in chronic episodic disorders such as asthma, cardiac arrhythmias, migraine, epilepsy, and depression. A better generic understanding of acute transitions in chronic dynamic diseases is increasingly important in critical care medicine because of the higher prevalence and incidence of these chronic diseases in our aging societies. Data Sources:PubMed, Medline, and Web of Science. Study Selection:We selected studies from biology and medicine providing evidence of slowing down after a perturbation as a warning signal for critical transitions. Data Extraction:Recent work in ecology, climate, and systems biology has shown that slowing down of recovery upon perturbations can indicate loss of resilience across complex, nonlinear biologic systems that are approaching a tipping point. This observation is supported by the empiric studies in pathophysiology and controlled laboratory experiments with other living systems, which can flip from one state of clinical balance to a contrasting one. We discuss examples of such evidence in bodily functions such as blood pressure, heart rate, mood, and respiratory regulation when a tipping point for a transition is near. Conclusions:We hypothesize that in a range of chronic episodic diseases, indicators of critical slowing down, such as rising variance and temporal correlation, may be used to assess the risk of attacks, exacerbations, and even mortality. Identification of such early warning signals over a range of diseases will enhance the understanding of why, how, and when attacks and exacerbations will strike and may thus improve disease management in critical care medicine.

Multilevel Bayesian networks for the analysis of hierarchical health care data

OBJECTIVE Large health care datasets normally have a hierarchical structure, in terms of levels, as the data have been obtained from different practices, hospitals, or regions. Multilevel regression is the technique commonly used to deal with such multilevel data. However, for the statistical analysis of interactions between entities from a domain, multilevel regression yields little to no insight. While Bayesian networks have proved to be useful for analysis of interactions, they do not have the capability to deal with hierarchical data. In this paper, we describe a new formalism, which we call multilevel Bayesian networks; its effectiveness for the analysis of hierarchically structured health care data is studied from the perspective of multimorbidity. METHODS Multilevel Bayesian networks are formally defined and applied to analyze clinical data from family practices in The Netherlands with the aim to predict interactions between heart failure and diabetes mellitus. We compare the results obtained with multilevel regression. RESULTS The results obtained by multilevel Bayesian networks closely resembled those obtained by multilevel regression. For both diseases, the area under the curve of the prediction model improved, and the net reclassification improvements were significantly positive. In addition, the models offered considerable more insight, through its internal structure, into the interactions between the diseases. CONCLUSIONS Multilevel Bayesian networks offer a suitable alternative to multilevel regression when analyzing hierarchical health care data. They provide more insight into the interactions between multiple diseases. Moreover, a multilevel Bayesian network model can be used for the prediction of the occurrence of multiple diseases, even when some of the predictors are unknown, which is typically the case in medicine.