Secondary prevention after acute coronary syndrome (ACS) is essential to reduce morbidity and mortality, but related studies have been fairly small or performed as clinical trials with non-representative patient selection. Long-term follow-up data are also minimal. A nurse-led follow-up for risk factor improvement may be effective, but the evidence is limited.The aims of this study are to perform an adequately sized, nurse-led, long-term secondary preventive follow-up with inclusion of an unselected population of ACS patients. The focus will be on lipid and blood pressure control as well as tobacco use and physical activity.The study will consist of a randomized, controlled, long-term, population-based trial with two parallel groups. Patients will be included during the initial hospital stay. Important outcome variables are total cholesterol, low-density lipoprotein (LDL) cholesterol, and sitting systolic and diastolic blood pressure. Outcomes will be measured after 12, 24, and 36 months of follow-up. Trained nurses will manage the intervention group with the aim of achieving set treatment goals as soon as possible. The control group will receive usual care. At least 250 patients will be included in each group to reliably detect a difference in mean LDL of 0.5 mmol/L and in mean systolic blood pressure of 5 mmHg.The study is ongoing and recruitment of participants will continue until December 31, 2014.This study will test the hypothesis that a nurse-led, long-term follow-up after an ACS with a focus on achieving treatment goals as soon as possible is an effective secondary preventive method. If proven effective, this method could be implemented in general practice at a low cost.International Standard Randomized Controlled Trial Number (ISRCTN): 96595458; http://www.controlled-trials.com/ISRCTN96595458 (Archived by WebCite at http://www.webcitation.org/6RlyhYTYK). Clinical trials have identified several treatments with proven secondary preventive efficacy after an acute coronary syndrome (ACS) . ImplemeTo simplify secondary preventive follow-up procedures while also retaining a high level of treatment adherence, different strategies of telephone support have been evaluated -6. DespiTo improve secondary prevention, we have designed a trial with several important components. First, all patients after an ACS will be considered for inclusion regardless of age, and this population-based design will include all residents in the county of Jämtland, Sweden. Second, a maximally simplified, nurse-based, telephone follow-up protocol will be used, which will minimize resources needed as well as patient exclusions and make the methodology easy to implement. Third, a routine for prompt medication adjustment will be used to reach set treatment goals as quickly as possible. Finally, a long-term follow-up is planned with risk factor evaluation after 12, 24, and 36 months.We hypothesize that in ACS patients, this nurse-based, telephone follow-up will reduce risk factor levels more effectively than usual care.This study is planned as a randomized, controlled trial with two parallel groups and an allocation ratio of 1:1.Ethics approval has been received from the Ethics Committee, Umea University 09-142M). This paper presents the design of the study according to CONSORT requirements [-142M. ThAll patients living in the county of Jämtland, Sweden, who were hospitalized with a diagnosis of myocardial infarction or unstable angina will be assessed for inclusion. Östersund Hospital is the only hospital in the county, and all patients, those in terminal care excluded, with symptoms of a suspected ACS are referred for diagnostic evaluation. It is a rural catchment area with a population of approximately 125,000 inhabitants. A routine for identification of all patients in the hospital with a possible ACS has been established in previous studies, and during a 3-month test period, the study nurses identified all patients with a final ACS diagnosis. In the present study, an ACS was defined as myocardial infarction type 1 or unstable angina with electrocardiogram changes (ST depression or T wave changes) suggesting myocardial ischemia. All patients with the physical and mental capacity to communicate by telephone will be eligible, which means that those with deafness or dementia will be excluded. The other exclusion criteria are severe, often terminal, disease and participation in another ongoing trial.All eligible patients will be informed about the study and asked to give written informed consent. They will receive standard information about ACS concerning pathophysiology and risk factors according to established clinical practice during their hospitalization. They will also be offered a follow-up visit to a cardiology nurse and an outpatient follow-up according to usual care.A study nurse will contact patients randomized to the intervention group by phone 1 month after discharge. Before the call, a blood sample for lipids will be taken and a standardized blood pressure control performed. Blood pressure will be measured after 5 minutes in the sitting position and after 1 minute standing. A district nurse will perform the tests; for patients in the intervention group living close to the hospital, a study nurse will do the testing. Cardiac symptoms and self-reported adherence with medication will be recorded. During the call, the patient will be informed about the test results and whether a change in medication is necessary. Tobacco use, physical activity, and dietary habits will be discussed. Smoking cessation will be encouraged and supported. Physical activity of moderate intensity 30 minutes or more on most days of the week will be encouraged but also adjusted to the individual patient’s capacity. Dietary advice to reduce saturated fat and increase fruit and vegetable intake will be given. If the patient’s cholesterol or blood pressure values are above target, medication will be adjusted after contact from a study physician. Tests will be repeated within approximately 4 weeks, and further adjustments made if necessary until target values are reached or no further changes can be considered realistic. The same routine, with an Hb1C test added, will be applied after 12, 24, and 36 months. The patient’s motivation to follow instructions will be assessed.The target values are systolic blood pressure <140/<90 mmHg, total cholesterol <4.5 mmol/L, and low-density lipoprotein (LDL) cholesterol <2.5 mmol/L  ,11.Patients randomized to the usual care group will also be contacted by phone 1 month following discharge after blood pressure and lipid profile measurements. Cardiac symptoms, self-reported compliance, tobacco use, and physical activity will be recorded. The treating physician, usually a general practitioner, will provide all medical care and receive the test results (lipid profile and blood pressure), and no additional intervention will be given as a result of participation in the study. The scheduled controls of blood pressure and lipids in the study will be additive to the usual follow-up performed by the general practitioner. The same routine, with an Hb1C test added, will be applied after 12, 24, and 36 months . ParticiThe number of visits to the patient’s treating physician as well as visits to a nurse will be recorded to develop a picture of the number of medical assessments in the control and intervention groups.Outcomes will be measured after 12, 24, and 36 months of follow-up. Outcome variables are total cholesterol, LDL cholesterol, and sitting systolic and diastolic blood pressure as well as the proportion of patients achieving the set target for these variables. Standing systolic and diastolic blood pressure, smoking rates, the proportion of patients treated with different secondary preventive drugs, diabetes control by Hb1C, and change in body mass index (BMI) and physical activity will also be measured. The LDL value at 36 months will be analyzed as the primary outcome. Analyses of the secondary outcomes will be exploratory. Blood pressure measurements are standardized as described above, and LDL values are calculated from the serum concentrations of cholesterol and fasting triglycerides using the Friedewald formula. Smoking (yes/no) and physical activity (duration/week) are self reported. Deaths are available in the hospital records and will be recorded to detect any survival difference between groups.A difference between groups in mean LDL of 0.5 mmol/L and in mean systolic blood pressure of 5 mmHg is considered clinically relevant and requires study groups of approximately 200 participants to be reliably detected . Study groups of at least 250 participants are planned to allow for drop-outs. This sample size is also adequate for detection of clinically meaningful group differences in smoking rates (10%), proportion reaching treatment goals (10%), change in BMI (1.0), and change in physical activity , calculated with two-tailed alpha .05, power 80%.The random allocation sequence will be computer generated in blocks of four and stratified for sex and type of ACS . A sealed, colored envelope will have a serial number on the outside and a folded sheet of paper inside with the group allocation written on it, which will be impossible to read from the outside. The study coordinators will enroll participants and assign them to interventions in order according to the serial number. The random allocation sequence will be computer generated by the study manager, who is not involved in the randomization process.t test for independent groups. Proportions will be compared using the chi-square test. The primary analysis will be performed according to the intention-to-treat principle using a linear regression model adjusting for sex and type of ACS. The adjustment is made to reflect the stratified randomization process. Per protocol analyses will also be performed. Secondary outcomes will be analyzed using the primary analysis model when continuous, and a logistic regression model, adjusting for the same covariates, when outcomes are binary. To assess indications of differential treatment effects across subgroups , tests for interaction will be performed, although this aim is secondary because the study is not powered for this particular purpose. Adjustment for relevant baseline covariates will be performed in additional exploratory analyses of primary and secondary outcomes to evaluate the effect of possible baseline imbalance. All tests will be two-sided, and a P value of <.05 will be considered significant.Mean values of blood pressure and lipid variables in the intervention and control groups will be compared using the The study is ongoing and recruitment of participants will continue until December 31, 2014.Different approaches have been used to recruit patients for secondary prevention studies after an ACS. Some have involved contacting patients participating in rehabilitation programs , and othA randomized design is necessary to reliably evaluate the effect of the intervention. Some investigators use a prospective cohort design, which makes it difficult to draw conclusions in terms of efficacy, particularly if the drop-out rate is high . The desWe use an associated study physician for the intervention group to obtain immediate decisions about more qualified treatment changes. Based on the results of previous studies, rapid treatment decisions by someone directly involved in the study are related to more effective risk factor control .The duration of follow-up has varied substantially among studies ,14. A foDifferent treatment goals for lipids and blood pressure have been used in different trials, but an LDL goal of <2.5 mmol/L and a blood pressure goal of <140/<90 are common . These gSecondary prevention after an ACS needs to be improved and to include a larger proportion of the patients. Importantly, the treatment goals need to be maintained over the long term. Even in trials that largely rely on telephone follow-up, the proportion of the target population eventually included has so far been small ,6,17.The present trial is designed to be simple and to require a minimum of health care resources while simultaneously giving patients an effective secondary prevention. The methodology can be widely generalized and makes the inclusion of a majority of the ACS population possible, regardless of the health care system.


Intracerebral hemorrhage is associated with poor clinical outcome and high mortality. Research and treatment modalities have focused on the expansion of the primary hematoma through blood pressure control and activation of coagulation factors. However, clinical trials have failed to show decreased rates of death or disability in intracerebral hemorrhage following hospital initiation of blood pressure control. However, as clinical deterioration often occurs immediately after onset, pre-hospital initiation of blood pressure control may be more ideal.Relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies were searched.Trends indicating improved clinical outcome in intracerebral hemorrhage after hospital-initiated intensive systolic blood pressure control  have been demonstrated. Statistical significance may not have been obtained because of late treatment times of blood pressure control that approached median 4–6 hours after clinical onset. One trial utilizing glyceryl trinitrate in the pre-hospital setting has been shown to significantly decrease blood pressure within fifteen minutes and improve 90-day clinical outcome.Glyceryl trinitrate represents an ideal pre-hospital blood pressure medication because it can be delivered via sublingual or transdermal routes, has a quick and graded onset of action, has neuroprotective effects, maintains cerebral perfusion, and has an established record of safety. As intracerebral hemorrhage requires prompt action to prevent clinical deterioration, more emphasis on pre-hospital therapies for blood pressure reduction will become essential in future therapies. Of an estimated 795,000 new strokes per year, intracerebral hemorrhage (ICH) accounts for 10% of all strokes , one-yeaThe primary phase of ICH–hematoma expansion–remains the target of research and treatment as rapid expansion has been associated with neurological deterioration and worse outcome ,6. AlthoWhile promoting coagulation has the potential for reducing expansion, it has not been shown to improve outcome or reduce disability . HoweverMany patients presenting to the emergency department with ICH will have already deteriorated due to hemorrhage expansion. Studies using CT imaging report hematoma growth in greater than 70% of patients within the first three hours of symptom onset  with onlThese studies show that the vast majority of hematoma expansion occurs during the initial phase. This is the period of time when initial symptoms are recognized and where hematoma expansion is most volatile as evidenced by the CTA spot sign. Treatment outside of this phase is unlikely to yield significant effect on outcome, and the earliest time windows for treatment, including pre-hospital treatment of blood pressure may be needed to prevent clinical deterioration and obtain optimum clinical results.CT-perfusion studies have shown that intensive blood pressure control does not precipitate perihematomal ischemia in ICH patients . As inteIn the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) pilot, intensive systolic blood pressure (SBP) control  resulted in significantly less mean proportional hematoma growth (P=0.04) and relative risk of hematoma growth (P=0.05) . These pIn the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) pilot trial, 60 patients were enrolled in three tiers of increasingly intensive blood pressure goals. Primary clinical outcomes (death and severe disability defined by Rankin scores of 4 to 6) were measured at 90 days. Although primary outcome did not meet statistical significance, measured variables such as hematoma expansion, perihematomal edema, and 90-day Rankin score all showed trends favoring the intensive blood pressure control group . As the Several reasons may explain the lack of statistical significance for primary outcome found in INTERACT2 and the ATACH pilot. First may be a greater relevance of secondary mechanisms of injury in ICH–perihematomal edema, blood-brain-barrier destruction, and upregulation of inflammatory mediators–towards overall clinical outcome . Second Glyceryl trinitrate (GTN) as a pre-hospital therapy in ICH is promising because of four properties: (1) alternative entry routes besides oral or intravenous , (2) quick and graded onset of action, (3) neuroprotective effects, and (4) established record of safety.Transdermal and sublingual GTN have been studied for many years in myocardial ischemia, congestive heart failure, and ischemic stroke. GTN acts primarily via vascular smooth muscle relaxation, which leads to arterial and venous vasodilation. This has the effect of decreasing cardiac output and improving myocardial oxygen supply-to-demand ratio. The rapid metabolism of oral GTN is circumvented through transdermal and sublingual routes. With a more rapid onset time (3 minutes) and shorter duration (10–30 minutes), sublingual GTN can be used in combination with slower onset (30–60 minutes) and longer duration transdermal GTN . TransdeGTN has also demonstrated neuroprotective properties in preclinical stroke models. GTN acts as an inhibitor of apoptosis  through Extensive safety experience with transdermal GTN in both ischemic stroke and ICH is currently being evaluated in the Efficacy of Nitric Oxide in Acute Stroke (ENOS) trial. ENOS is enrolling 3500 acute ischemic stroke and ICH patients randomizing to GTN patch (5 mg over 24 hours) or placebo. Trial enrollment is anticipated to complete in October 2013 and is nearing completion with final results anticipated within the year. Initial results from ENOS have already provided strong reassurance regarding the safety of GTN with the evaluation committee recommending completion of the trial. Included in GTN’s excellent safety profile is its ability to lower blood pressure without decreasing cerebral perfusion as evidenced by preliminary data publications from the ENOS group that did not show worse 90-day clinical outcome in patients with significant (>50%) carotid stenosis ,36,37.In ICH, theoretical concerns regarding venodilatory effects on intracranial pressure (ICP) are nullified by actual physiologic studies in humans. In individuals with normal starting ICPs, GTN produces only minimal and transient increases in ICP . In indiRecently, a single-center, single-blinded randomized controlled study, the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT) evaluated the use of pre-hospital transdermal GTN in patients with ischemic stroke and ICH. Paramedics randomized 41 patients (25 in the GTN group and 16 placebo). The GTN group had SBPs significantly reduced by 21 mmHg at 15 minutes (P=0.049) and 18 mmHg at 2 hours (P=0.030). Blood pressure reduction was associated with improved functional outcome and significantly better 90-day Rankin score in the GTN group (P=0.017). Post-hoc analysis also showed a promising relationship with a correlation coefficient of −0.296 (P=0.06) [Currently only two blood pressure medications have been studied for pre-hospital blood pressure control: GTN studied in RIGHT and lisinopril studied in PIL-FAST. In PIL-FAST, paramedics administered a crushed 5 mg tablet of lisinopril sublingually. This medication was continued over 7 days. As a small pilot trial, 6 patients received lisinopril compared to 8 patients in the placebo arm. Comparison of pre-hospital lisinopril and GTN administration on systolic blood pressures is shown in Ideally, patients with diagnosed ICH would be recruited into prehospital clinical trials of therapy. Realistically however, stroke subtype cannot be diagnosed without imaging as clinical deficits in ICH and ischemic stroke are based on lesion sites that can occur in either disease. Preliminary data on 538 patients consecutively enrolled in FAST-MAG (with 134 patients having ICH) did show ICH associated with higher SBP and DBP, younger age, less frequent atrial fibrillation, higher median Los Angeles Motor Scores (LAMS), male gender, Hispanic ethnicity, and earlier evaluation times in relation to ischemic stroke .A more recent multivariable analysis of a larger dataset of 731 cases (164 with ICH) was performed by randomly assigning to derivation and validation datasets, using all variables available at time of paramedic encounter in a backward stepdown linear, additive logistic regression and classification tree analysis. The performance of a simple logistic model using seven binary predictors  showed a sensitivity of 87.2% and specificity of 67.3% with overall accuracy of 77.2%. The validation dataset showed 75.4% specificity and 72.4% sensitivity . These bPre-hospital use of anti-hypertensive treatment for ICH patients not verified by imaging will inevitably treat ischemic stroke patients. The International Stroke Trial (IST) found a U-shaped distribution of blood pressure outcomes, with both higher and lower pressures associated with poor outcomes . HoweverMoreover, for patients eligible for thrombolysis who are also severely hypertensive with SBP>185 mmHg, early initiation of antihypertensive therapy to reach this goal SBP is supported by positive results in multiple clinical trials . In factIntracerebral hemorrhage is associated with poor clinical outcome and high mortality. Efforts to improve mortality have largely focused on hematoma expansion through intensive blood pressure control. Hospital-based blood pressure control may often be too late as clinical deterioration can occur immediately after ICH onset. To date, only lisinopril and GTN have been evaluated as pre-hospital medication for blood pressure control. GTN represents an ideal pre-hospital blood pressure control medication because it can be delivered via alternative transdermal or sublingual routes, has a quick and graded onset of action, has neuroprotective effects, and has an established record of safety. Its feasibility and effectiveness as a pre-hospital blood pressure medication has been evaluated through RIGHT, which showed a significant early reduction of blood pressure. As acute neurological injury requires prompt action, more emphasis on pre-hospital therapies such as GTN will become essential in future therapies .


These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca The long-term regulation of systemic arterial blood pressure is a topic beset with a remarkable degree of controversy. Many textbooks teach that systemic vascular resistance (SVR) is the primary factor in this long-term regulation  via what we can regard as Ohm's Law for the systemic circulation:where CVP is central venous pressure and An alternative view is that it is more helpful to think of Equation 1 in a rearranged form:where MAP is determined slowly over time by the need for the circulation to be in “mass balance” (a view expanded on below), and SVR is set by many known (and as yet unknown) structural, neural, humoral, and pharmacological factors. In this approach ts Hall, . It is ats Hall, .short-term changes in arterial blood pressure are very commonly brought about by changes in SVR, either spontaneously or therapeutically. A truly integrative approach is needed to separate causation from association, and thus the topic provides an outstanding educational challenge as well as a scientific battlefield.Several associations between SVR and MAP make it difficult for researchers and healthcare workers to form a clear view about cause and effect. First, SVR is indeed typically raised in hypertension—an association that does not necessarily imply direct causation. Secondly, it seems likely that the physiological processes that commonly lead to changes in the kidney and its vasculature, which may be the direct cause of hypertension, concurrently elevate SVR by affecting blood vessels throughout the body. Thirdly, many drugs that act on the kidney to ameliorate hypertension also act on the wider circulation to lower SVR. Fourthly, The aim of this paper is both educational and scientific. We give the basis for the view that renal mechanisms regulate arterial blood pressure on a time scale of days to years. We then review what is known about how antihypertensive drugs act upon the kidney to achieve a sustained reduction in arterial pressure. This enables a clear distinction to be drawn between the incidental effects these drugs have elsewhere on the body, which may be harmful or beneficial, and their primary therapeutic renal actions in hypertension.closed circulation  and an unchanged renal blood flow (RBF), whilst a measurement of renal vascular resistance (if defined as MAP/RBF) would show it to have decreased. Such an intervention would be analogous to the surgical removal of a renal artery stenosis, a classic example of “secondary hypertension,” eliminating an excessive pressure drop across the vessels entering the kidney, so that from the glomerular capillaries onwards nothing is different after the intervention when compared with before the intervention. It will become clear that the actions of several families of drugs converge on this common pathway.+ and other ionic reabsorption from the renal tubule into the peritubular capillaries: a tubular, epithelial, mode of action. Inhibition of the active component of reabsorption has to translate into a readjustment of Starling forces to maintain reabsorption and keep the body in sodium and water balance. This in turn requires a lower hydrostatic pressure in the peritubular capillaries and throughout the renal vascular bed, including the glomerular capillaries. Some antihypertensive drugs are associated with a reduction in GFR and appear to have their main renal action on inhibition of active Na+ and water reabsorption, and the consequent resetting of the Starling forces across the tubular epithelium. A review of the literature leads to surprises in this area.The “non-vascular” route to modifying the pressure at which the kidney operates involves the inhibition of active NaIf an antihypertensive can be associated with a fall in GFR, under what circumstances may one be associated with a rise in GFR? In fact, a large family of drugs is capable of bringing about an increase in hydrostatic pressure gradient along the efferent arteriole of the kidney, generated either by an increased resistance in, or a higher blood flow through, these vessels. These drugs achieve marked afferent arteriolar dilatation with a degree of inhibition of active tubular reabsorption, combining a vascular action with a tubular action.We are fortunate in having two sound, long-standing methods for measuring RBF and GFR in humans. Both rely on measuring “renal clearance.” The clearance of a substance in the blood is the volume of blood from which the substance can be regarded as having been completely eliminated in unit time, and is therefore measured in units such as ml/min. A small derivative of glycine, para-aminohippurate (PAH), is both filtered at the renal glomerulus and secreted in the renal tubule. This almost complete removal of PAH from blood passing through the kidney leads to its renal clearance being a measure of RBF  there has been much interest in attempting to measure Pglom and observe changes in these variables associated with essential hypertension and with antihypertensive medication. Unfortunately, direct measurement of Pglom has not proved possible in humans, and researchers remain dependent upon the approach of Gómez published over half a century ago , which we here write as K, and writing the Starling relationship for glomerular filtration as follows:Domingo Gómez derived Ptub is the hydrostatic pressure in Bowman's space  and Π is the oncotic pressure of plasma. Ptub is commonly assumed in humans to be similar to that measured directly in other mammals , defined as the resistance of blood vessels between the large arteries and the glomerular capillaries:Of special interest in relation to hypertension is the question of whether a major contributor to the condition is an abnormally elevated afferent arteriolar resistance  than that of the glomerular capillaries that the net filtration pressure across the tubule-capillary barrier would be approximately zero. This can be expressed as:yielding pressures in the peritubular capillaries of around 35 mmHg. If Equation (6) is taken as precise, a combination of Equations  then gives:Some authors prefer to complete the picture of renal vascular behavior by including the venular resistance, defined as:v is the pressure in the renal veins, commonly assumed to be around 10 mmHg. Clearly, there is an assumption here that the urine flow is so small in comparison with RBF that it can be ignored from the calculation of the resistance of the venules. The small fraction of the filtrate is labeled “Urine” in Figure where Pv was ~6 mmHg) until it wedged in a smaller vein and recorded a pressure taken to be that of the peritubular capillaries, Ppc  by a substantial number of mmHg. Direct puncture measurements in small mammals have tended to suggest this too. Ichikawa and Brenner, using direct puncture measurements in rats, found that both Ppc and Ptub were close to 15 mmHg whilst Π was ~25 mmHg, suggesting a net reabsorption Starling pressure between the tubule and peritubular capillary of about 25 mmHg  then becomes an underestimate of the true value by of the order of 50%.Venular pressure can be measured in humans directly by passing a catheter into the renal veins. In 1970, Lowenstein et al. developed the technique of advancing a 0.9 mm diameter polyethylene catheter from the renal vein . Interestingly this is somewhat lower than the value he found for normotensives (63 mmHg).Gómez proceeded to examine the magnitudes of Rn Gomez, . A strikA. He noted that RA tended to correlate with SVR in a pattern in which a doubling in SVR was associated with an approximate 5-fold increase in RA. This early analysis pointed strongly toward an abnormally intense increase in RA as the defining feature of essential hypertension. It appeared that some mechanism was capable of increasing arteriolar resistance throughout the body, but was unusually potent in its effects on the renal afferent arterioles  to MAPo would result in cessation of renal sodium clearance, MAP − MAPo must equal the net filtration pressure across the glomerular capillaries (Pglom − Ptub − Π) whilst on the normal diet. For the group of patients as a whole, application of this approach predicted mean values of Pglom and RA that were respectively 7% lower and 6% higher than those obtain using Gómez's formulae. An important advantage of the approach of Kimura et al. is that no assumption needs to be made about the value of the glomerular permeability coefficient, K. A significant drawback, however, is the complexity and duration of the experiments required, including the compliance of patients with a low sodium diet for at least 1 week. Comparison of the results from the two approaches suggests that they both provide satisfactory means for estimating Pglom and RA, but the estimation of RE and RV remains problematic, for reasons discussed above. Rat experiments have shown a fair agreement between values of Pglom obtained using the pressure-natriuresis extrapolation and direct puncture of glomerular capillaries  remains well established, and allows some confidence in concluding that human studies demonstrating a rise or fall in GFR in individuals to whom antihypertensive drugs are administered are experiencing a corresponding rise or fall, respectively, in Pglom. We make use of this assumption in deducing changes in the hydrostatic pressure profile along the renal vasculature.Despite difficulties estimating PKimura and colleagues examined the pressure-natriuresis relationship for eight hypertensive patients using exposure to three different values of sodium excretion to assess to what extent they could regard the relationship as linear . Mefruside moved the line toward the horizontal and lowered MAP over the range of sodium intakes.We have already noted the concept that this intercept gives information about the net filtration pressure at the glomerulus, implying that, if the intercept were to remain unchanged during administration of a drug, then for any given value of MAP the value of Pglom − Ptub − Π) was approximately zero and that Pglom was close to (Ptub+ Π), which is commonly taken to equal 35 mmHg. If the imaginary drug were capable of inhibiting all active reabsorption of solutes from the renal tubule, we would then have a situation where the filtered sodium load entering the renal tubule from the glomerulus in a very low GFR  was all lost in the urine!It is interesting to consider what the significance would have been were a drug like mefruside able to render the line completely horizontal so that MAP became independent of sodium intake. Following the approach of Gómez given earlier, this would imply that the net filtration pressure across the glomerular capillaries (Pwithout there being a large change in MAP. Bie has noted that modest acute body loading with sodium (over 2–3 h) can lead to a rapid substantial change in renal sodium excretion rate without a change in MAP, and that this phenomenon is strong evidence either for a vigorous macular densa tubulo-glomerular feedback mechanism, or for a further, as yet unidentified, regulator of renal function  had been found on drug therapy. In the tables below we present statistically significant changes in renal hemodynamic variables or indicate no change. A point of note arises in relation to the overall RVR defined and calculated by most authors as follows:We surveyed the literature for studies in healthy humans and patients with hypertension in which measurements of arterial blood pressure and renal hemodynamics had been made in the control condition of no drug therapy and following a minimum of 1 week of sustained drug therapy. We included only those in which a statistically significant fall in MAP , “glomerular filtration rate,” “renal blood flow,” and “renal plasma flow.” We surveyed titles and abstracts to select human studies on both healthy volunteers and patients with hypertension that was found not to be attributable to secondary (known) causes. Reference lists from publications identified in this way were surveyed for further relevant publications.1-blockers , an α2-agonist (clonidine), an imidazoline I1 receptor agonist (moxonidine), α-methyldopa, and Ca++-channel blockers (CCBs) . Where measured, these studies invariably show a fall in RVR or RA, usually in the presence of an unchanged RBF; the exceptions to the latter were diltiazem, nifedipine, nitredipine, and isradipine, which showed an increase in RBF. With regard to GFR, most studies found no change, but a rise was noted in three studies involving nifedipine and amlodipine. The families of agents represented in Table glom for the reasons discussed above. The associated profile of the renal vascular hydrostatic pressure resulting from this mechanism of drug action is depicted in Figure Table glom and the individual changes in RA and RE following chronic administration of these agents. The several findings with amlodipine, and single studies with two other drugs of this class, suggested that an unchanged or elevated RE may be associated with a rise in Pglom and a rise in GFR. A single study (of diltiazem) found a marked reduction in both RA and RE, accompanied by a rather distinctive fall in Pglom in the presence of unchanged GFR and a large rise in RBF  blockers suggests a slightly different pattern similar to most of the drugs in the vasodilator group of Table For the increased GFR associated with the ACE-inhibitors to exist in the presence of a presumed unchanged sodium and water balance for the body as a whole, tubular reabsorption of sodium and water must be enhanced to counter the excess flux of filtrate. Given that these drugs are associated with an inhibition of the action of angiotensin II and aldosterone on sodium uptake by the proximal and distal tubules respectively, this finding suggests that the enhanced reabsorption is driven by a dominant increase in the passive Starling forces moving filtrate across into the peritubular capillaries. This would require a lower hydrostatic pressure in the peritubular capillaries during drug therapy, which would in turn require a greater pressure drop across the efferent arterioles, as blood passed from the glomerular into the peritubular capillaries. The different roles of the afferent and efferent arterioles in the action of this family of drugs are particularly striking. Figure Table glom and Ppc unchanged. If a lowering of Ppc is required to overcome a degree of inhibition of active sodium reabsorption by these drugs, interestingly this seems not to translate back upstream into a lowering of Pglom, given that GFR remains unaltered by these drugs. The exception to this pattern is indapamide. Its profile appears to be best described by Figure The pattern of diuretic behavior seen in Table We have observed remarkable similarities of action of several families of antihypertensive agents that fairly selectively dilate the afferent arteriole, thereby permitting the kidney to operate at a new, lower MAP, with indices of renal function downstream of the afferent arteriole left unchanged Figure . The simA pure directly-acting dilator of the afferent arteriole might be expected to mimic the consequence of a surgical removal of a renal artery stenosis and thereby lead to a fall in MAP that does not depend upon the urinary sodium secretion, as demonstrated in patients with renovascular hypertension  feedback mechanism by furosemide  and enhances active sodium re-absorption  appear unique in achieving their hypotensive action in association with a fall in GFR. They are also distinctive in reducing RBF and, in some studies, elevating RVR. We argue above, in relation to Figure 2 stimulation with apoptotic reduction in cell numbers  involves a permeability coefficient that is itself under physiological and possibly pharmacological control.We noted above that the effect of non-selective β-blocking drugs is somewhat analogous to a reduction in renal tissue, despite preservation of normal daily elimination of sodium and water. One possibility that we have not entertained so far is an influence of drugs on glomerular mesangial cells. These smooth-muscle-like cells in the glomerulus have the potential to reduce the filtration coefficient K and modify blood flow to the glomerulus  an increase in RE has been measured in the presence of an unchanged RBF , renin antagonists , and surgical renal denervation. So far, these studies have not made the long-term assessment of human renal hemodynamics a priority, so it is currently not possible to assess the renal changes brought about with any precision. Interestingly, a similar paucity of data is evident for the mode of action of agents that chronically elevate MAP such as non-steroidal anti-inflammatory drugs, corticosteroids and alcohol. Furthermore, older antihypertensive agents that had to some extent fallen out of fashion—such as indapamide . Dr. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Purpose. To investigate blood pressure and heart rate variability in patients with primary open-angle glaucoma (POAG) to detect disturbed blood pressure regulation. Methods. Thirty-one patients with POAG (mean age 68 ± 10 years) and 48 control subjects (mean age 66 ± 10 years) were included in a prospective study. Continuous blood pressure and heart rate were simultaneously and noninvasively recorded over 30 min . Data were analyzed calculating univariate linear (time domain and frequency domain), nonlinear  and bivariate  indices. Results. Using nonlinear methods, glaucoma patients were separated with more parameters compared to linear methods. In POAG, nonlinear univariate indices (pW113 and pW120_Sys) were increased while the indices pTH10_Sys and pTH11_Sys reflect a reduction of dominant patterns. Bivariate indices  were increased in POAG. The optimum set consisting of six parameters  revealed a sensitivity of 83.3% and specificity of 80.6%. Conclusions. Nonlinear uni- and bivariate indices of continuous recordings of blood pressure and heart rate are altered in glaucoma. Abnormal blood pressure variability suggests disturbed autonomic regulation in patients with glaucoma. Glaucoma is a multifactorial chronic progressive disease, characterized by the loss of ganglion cells which leads to typical damage of the optic nerve and to visual field loss. The pathogenic concepts of glaucoma may be divided into a mechanical, pressure-related, and a vascular approach. It is well established that the main risk factor for glaucoma is individually elevated intraocular pressure. In addition, systemic vascular factors like arterial hypertension and hypotension, cardiovascular diseases, vasospasms, and others have been identified to play a significant role in the disease as well as impaired ocular blood flow –3.In this context, disturbed vascular regulation may increase the susceptibility of the optic nerve and the ganglion cells to fluctuations in ocular perfusion pressure. Systemic blood pressure regulation and local mechanisms (autoregulation) need to maintain ocular blood flow at a constant level despite changes in perfusion pressure , 5. It hThe present prospective pilot study investigates the autonomic blood pressure regulation in patients with primary open-angle glaucoma (POAG) and controls. Systolic and diastolic blood pressure and heart rate variability was noninvasively and continuously assessed to characterize systemic vascular dysregulations using linear and nonlinear methods. The hypothesis is that POAG patients exhibit a different pattern of blood pressure and heart rate variability compared to controls as defined by using nonlinear analyzing methods.Thirty-one patients with POAG and 48 age-matched controls were included in a prospective pilot study. All patients with POAG had a detailed ophthalmological examination; intraocular pressure was measured using Goldmann applanation tonometry. Patient's history was explored with special interest on cardiovascular risk factors . The systemic medications were recorded, but only the status of treated arterial hypertension was included in the analysis. Participants were recruited from the Department of Ophthalmology at the University of Aachen. Informed consent was obtained from all subjects. Adherence to the Declaration of Helsinki for research involving human subjects is confirmed. Ethics approval was granted by the committee of ethics at the University of Aachen.To measure cardiovascular biosignals, blood pressure, and electrocardiogram, the diagnostic system “Glaucoscreen”  was used.Synchronous ECG and blood pressure time series were continuously recorded over a period of 30 minutes in a lying position at rest using Glaucoscreen ; see Figures Systemic blood pressure variability (BPV) and heart rate variability (HRV) were analyzed offline . For data preprocessing, the time series of successive beat-to-beat intervals (BBIs) and of systolic as well as diastolic pressure values were extracted. HRV is the BBI length variability also called RR variability  whereas BPV represents the variability of successive systolic or diastolic blood pressure values corresponding to the related heart beats. In a further step, artefacts and/or ectopic beats and other disturbances (either R peaks recognized incorrectly or R peaks generated not in sinus rhythm) were detected within the RR time series and replaced (applying an adaptive filter) by interpolated “normal” beats to generate normal-to-normal (NN) beat time series representing normal sinus rhythm of the heart.HRV and systolic and diastolic BPV standard parameters were calculated from time  and freqIn addition to these linear analysis methods, Symbolic Dynamics (SyD) and Joint Symbolic Dynamics (JSD), two nonlinear methods were applied in this study. Results of SyD analysis have been shown to be sufficient for the investigation of complex systems and describe dynamic aspects within time series. SyD is a nonlinear method which describes the global short- and long-term dynamics of beat-to-beat variability on the basis of symbolization and was introduced by Kurths and Voss et al. , 15. TheThe symbols “0” and “2” reflect slight deviations  from the mean NN interval, and the symbols “1” and “3” reflect stronger deviations  from the mean NN interval.Then, the symbol strings are transformed into word series where each word consists of three successive symbols. This leads to a range of 64 different word types . Then, estimates from the word distribution using the probability of occurrence (pWxxx) of each word type within NN interval time series are calculated .On the basis of these word types, the number of all word types with a probability of occurrence of more than yyy percent (pTHyyy for HRV and _ pTHyyy _Sys/Dia for BPV) was separately counted .The SyD indices were all calculated for the heart rate and systolic and diastolic blood pressure time series.W according to the transformation rules using an alphabet A = {0,1}. Thereby, symbol “1” represents increasing values  and symbol “0” decreasing and unchanged values  applying a threshold level equal to zero.The JSD  16] is  is 16] ik = 64) in detail; see Afterwards, short patterns (words of length consisting of 3 symbols) were formed  was applied for statistical analysis to figure out significant (p < 0.05) and highly significant (p < 0.001) parameters differentiating between patients with glaucoma and controls. For highly significant parameters, the multivariate stepwise discriminant function analysis was performed to calculate the specific sensitivity and specificity and the area under the receiver operating characteristics (ROC) curve (AUC) applying the best set of six parameters.The analysis was performed on the basis of the HRV/BPV indices . The nonparametric Mann-Whitneyp < 0.05 probability of being normal (one of which should have p < 0.01), not contiguous with the blind spot, or (c) corrected pattern standard deviation (CPSD) was abnormal with p < 0.05. All parameters were confirmed on two consecutive visual fields performed with Humphrey Field Analyzer. All patients with POAG had IOP values above 21 mmHg without treatment in their medical history. Visual field examinations were performed with the Humphrey Field Analyzer .Thirty-one patients with POAG and 48 age-matched volunteers were included in this prospective pilot study. Patients with POAG had a glaucomatous excavation of the optic disc and glaucomatous visual field defects as defined by the European Glaucoma Society . The diaThe control subjects did not have any ophthalmologic disease, showed IOP values below 22 mmHg, and did not receive any topical treatment. Visual field examinations did not reveal any significant visual field loss. Visual field parameters (mean deviation (MD) and pattern SD (PSD), Humphrey Visual Field Analyzer) were within normal range and the glaucoma hemifield test was within normal limits. Healthy controls presented in funduscopy a normal optic nerve head appearance .Volunteers and patients with POAG with an acute cardiovascular or cerebrovascular event within the last 6 months or with known heart rhythm disorders were excluded from this study.Patients with glaucoma and controls were matched for age, sex, and treated arterial hypertension. All patients with glaucoma were on topical IOP lowering therapy that might influence the results.Thirty-one patients with POAG  and 48 control subjects  were included in this study.Patients with POAG had on the right eye a mean IOD of 15 ± 3 mmHg  and on the left eye a mean IOD of 17 ± 5 mmHg . IOD of the healthy controls was never above 21 mmHg; mean IOD for the right eye was 15 ± 3 mmHg and for the left eye 14 ± 3 mmHg. All patients suffering from POAG were on topical IOP lowering medications. Seventeen patients used carbonic anhydrase inhibitors, 24 patients ß-blockers, 6 patients brimonidine, and 19 patients prostaglandins. Twenty-nine patients with POAG and 23 controls confirmed in their medical history treated arterial hypertension. The clinical data  of both groups are shown in In the group of POAG, patients had a mean diastolic blood pressure of 89 ± 9 mmHg and a mean systolic blood pressure of 145 ± 17 mmHg. The controls showed a mean diastolic blood pressure of 86 ± 12 mmHg and a mean systolic blood pressure of 147 ± 17 mmHg. Mean heart rate in the group of POAG was 68 ± 10/min; healthy controls showed a mean heart rate of 67 ± 10/min. The mean as well as standard deviation of the heart rate and diastolic and systolic blood pressure did not significantly differ between the two investigated groups.Looking at the time series of heart rate and systolic blood pressure, more parameters belonging to the nonlinear analysis methods (SyD) were able to significantly separate control subjects and patients with POAG compared to the time series of diastolic blood pressure, where only one SyD parameter could separate the two groups significantly .Applying the method of JSD, more significant parameters were detected when analyzing the interaction of the time series diastolic blood pressure and heart rate compared to the interaction of time series systolic blood pressure and heart rate. The univariate indices pW113 and pW120_Sys  were increased in POAG. That means an increase of patterns with a valley-like behavior of heart rate patterns and an increase of systolic BPV patterns with a start of a plateau phase.The univariate indices pTH10_Sys and pTH11_Sys  reflect a reduction of dominant patterns at the expense of an increased probability of occurrence of other word types (an increase of pTH3). That means that POAG exhibit a higher systolic BPV than controls.Finally, the indices JSDdia29, JSDdia50, and JSDdia52 were increased in POAG. These indices characterize the coupling between heart rate and diastolic blood pressure. Interestingly all these indices may be found directly or in neighborhood to the word types representing diametric behavior . These word types demonstrate a behavior oppositional to the typical baroreflex response .Overall, only single linear indices from time and frequency domain analysis showed significant differences between groups. All significant parameters are shown in Tables The optimum set consisting of six parameters  revealed a sensitivity of 83.3%, a specificity of 80.6%, and an AUC of 82.3%.Ocular blood flow is an important factor in glaucomatous optic neuropathy and, together with ocular perfusion pressure, is directly affected by systemic blood pressure , 18. TheLocal blood flow of the optic nerve head is organized by autoregulation . AutoregIn addition to the concept of autoregulation, systemic blood pressure and heart rate are influenced by systemic mechanisms of regulation. The concept of systemic vascular dysregulation in glaucoma affecting recurrent ischemic episodes of the optic nerve caused by an impaired capacity to compensate low perfusion pressures has been described before , 21. TheIn our study, blood pressure and heart rate variability was noninvasively assessed to characterize systemic vascular dysregulation in glaucoma patients and controls. Nonlinear analyzing parameters of blood pressure and heart rate data were significantly different. The nonlinear model was designed to account for complex interactions of the continuously gained values characterizing systemic blood pressure and heart rate variability and dysregulation. In contrast, only singular linear indices from time and frequency domain showed significances. However, these indices could not contribute to the discrimination between glaucoma and controls in the same level as the nonlinear methods SyD and JSD. The optimum set consisting of 6 indices revealed a sensitivity of 83.3% and a specificity of 80.6%. Interestingly, in this set only, indices from nonlinear dynamics (Symbolic Dynamics) were included. In this context, we should emphasize that we do not believe that the identification of abnormal blood pressure or heart rate patterns would probably be a tool to identify glaucoma patients. But the measurement of systemic autonomic dysregulation might be an important method to identify patients with an increased risk for progression due to an impaired capacity of optic nerve head perfusion.Methods of heart rate variability (HRV) and BPV based on nonlinear system theory and beat-to-beat dynamics have gained recent interest as they may reveal dedicated changes of autonomic regulations. These methods have been already used in other studies, investigating risk estimation for sudden cardiac death in patients with cardiomyopathy  or examiThere are various types of different fractal scaling measures, complexity measures, power law analysis, measures of Symbolic Dynamics, turbulence, and acceleration/deceleration of heart rate and blood pressure and they have been studied in various patient populations , 30.In this study, especially indices from SyD (univariate) and JSD  exhibit significant impairments in the cardiovascular regulation in glaucoma patients. These results support the idea that glaucoma is not just a process involving the eye but may be a manifestation of a more generalized autonomic dysfunction that is in agreement with the findings of Brown et al. and others , 32. AndEven the sensitivity of baroreflex control of heart rate is depressed in glaucoma patients ; the numHowever, it might be too early for this method for a more specific interpretation of the data. Further studies have to show if our pilot results can be reproduced in a larger scaled investigation. A major limiting factor of this prospective study is the possible influence of other systemic vascular diseases and topical and systemic medications possibly affecting ocular blood flow. A large controlled prospective study would be appropriate to investigate such confounding factors and to validate the results of this study. Secondly, this approach has to be investigated in patients with normal tension glaucoma as well, to learn if the same or other parameters will be found to be altered in these patients.In conclusion, these alterations in blood pressure variability and coupling with heart rate suggest modified autonomic regulation due to a vascular dysfunction in patients suffering from glaucoma. The importance of the vascular influence for the pathogenesis of glaucoma is again emphasized by this study. Further studies need to show if the method is valuable to identify systemic autonomic dysfunction in glaucoma. Patients with systemic autonomic dysfunction might be at higher risk for progression of the disease due to a higher susceptibility of the optic nerve to fluctuations in intraocular pressure or ocular perfusion pressure.


The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of “rare” disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed. The world population is ageing, and life expectancy  is steadily increasing. Because of increased longevity, the proportion of individuals aged 65 years and older (referred to as the elderly) is growing worldwide. Given these demographic changes, the impact of asthma is expected to rise in the next years. The management of asthma in the elderly follows international guidelines that apply to all ages, although most recommendations are an arbitrary extrapolation of what has been tested in younger subjects. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Many specific factors affect treatment of the elderly. They often undertake a number of medications as they frequently suffer from different diseases and comorbidities. Polypharmacy increases the risk of low adherence and of interactions between different drugs. Furthermore elderly patients may present cognitive dysfunction that results in a decreased memory, which in turn affects the compliance to the treatments. The changes in body composition and metabolism that characterize aging process should also be carefully taken into account. The pharmacological effect of systemic drugs may be affected by the reduced activity of kidney and liver and by the decrease in muscle mass, fat and body water. In elderly individuals with respiratory allergies, the ‘course’ of the disease is considered too advanced, and therefore the therapeutic value of specific immunotherapy is considered very limited. Physicians often face the requests of patients who ask for complementary/alternative medicines (CAMs). Thus, it is urgent to become aware of the efficacy and contraindication of CAMs in order to provide patients with scientifically-supported information, especially in older populations. Strategies to increase physical and sports activity participation among older people should include the awareness of the benefits and minimize the perceived risks of physical activity. Despite advances in the management of asthma independently of age, there is an urgent need for targeted, disease-modifying asthma treatments. It is necessary to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with asthma. It is clear that the delivery of biologics or advanced immunotherapy requires a special attention in the elderly, where comorbidities are often present.The current article undergoes the main aspects of pharmacological and non pharmacological approaches to asthmatic subjects of advanced ages, with special focus on safety issues, and highlights the practical considerations to be taken into account when managing elderly asthmatics in clinical settings.Inhaled corticosteroids (ICS) are widely used in the treatment of patients with asthma, in that, they represent the cornerstone of the pharmacological management of the disease. However, high-dose regimens and long-term use of ICS may be associated with increased risk of side-effects, which are mostly important in the elderly populations. The GINA guidelines  clearly The pharmacokinetic and pharmacodynamics features of the ICSs are influenced by several factors, such as the particle size and the formulation of the aerosol. These factors can affect the systemic bioavalaibility, which is responsible for the potential suppression of the hypothalamic-pituitary-adrenal axis. The bioavailability is also influenced by the protein binding and the process of bioactivation by first pass metabolism of the liver. All these passages can be altered in the most advanced ages, and should be taken into account, by using the minimum efficacy dose of ICS.With no doubt, the most serious potential side effect is the increased incidence of pneumonia, which has been observed in patients with COPD both in controlled clinical trials and case–control analyses . There iPatients and physicians are often concerned about the use of ICSs and the occurrence, or worsening, of diabetes. Suissa and collaborators  found thBeta-2 agonists, both short- and long-acting (SABA and LABA), are widely used in elderly asthmatic patients and their efficacy is well established ,10. AsidBesides these general indications, there are certain therapeutic concerns related to the beta-2 adrenergic administration, unique to older patients, which deserve to be addressed. Among these, the most important seems to be the greater probability of adverse effects, in the setting of multiple comorbidities . HypokalThe use of anticholinergic drugs in elderly should take into consideration the detrimental effect of aging on the parasympathetic activity and the possible occurrence of adverse events. Ipratropium bromide is a short-acting anticholinergic bronchodilator that is routinely used for COPD, and is less commonly used as first-line therapy to treat asthma. However, ipratropium is often prescribed in combination with albuterol for the treatment of acute exacerbations of asthma in emergency rooms. Results of previous research studies showed the benefit of using the combination therapy in adults with acute asthma (mean age 34.3 ± 10.5 years), leading to a decreased rate of hospital admission compared with albuterol alone . TiotropLong acting anticholinergic are well tolerated in the elderly. Dry mouth, and unpleasant taste can occur and these adverse events can contribute, in older people, to reduced ability to speak, mucosal damage, denture misfit, poor appetite, malnutrition risk and respiratory infection due to the reduction of antimicrobial activity of saliva. In males, urinary outflow can be observed and a reduction of gastrointestinal motility has been documented in adults. Moreover, anticholinergics increase intraocular pressure and can cause dilatation of pupil and blurred vision. Cardiovascular effects have been deeply explored in COPD patients, and the available results regarding their safety may be considered encouraging. Due to the reduced metabolism and drug elimination in older patients, anticholinergic drugs may induce, in continuous users, mild cognitive impairment. Finally, in 3 patients out 1000 a paradoxical bronchocostriction may occur . On the Systemic glycocorticoids  are listed as second line option in GINA guidelines step 5 and at low dose . Their use is limited to adults with poor control and reserved to elderly patients who may have more benefit than side effects, which increase with the dose administered. They are to be administered when flares-up of symptoms develop in the course of well-controlled treatment and when acute emergency occurs, including hospital care. Use of oral steroids in asthma was more liberally prescribed in the past, when the concepts of steroid-resistance and dependence were developed. Nowadays, systemic steroids are the final approch when all other strategies have failed or are not applicable. About 40% of asthmatic patients above 75 yrs of age do not control their asthma, and this is only partly related to cortisonophobia of both patients and doctors. Obesity is another factor predisposing to diminished steroid response, even after adjusting for body weight. When serious life threatening acute episodes occur, or on emergency hospital admission, prednisolone at 1/mg/kg (with maximum of 50 mg) is recommended . From a Side effects due to systemic glycocorticoid treatment include glucose intolerance , gastrointestinal bleeding (in patients with known disease or gastrectomized for previous ulcers) and blood pressure control (not a main problem since step-up antihypertensive therapy controls the increase). Depression and changes of mood are frequent, especially in the elderly populations, and other side effects such as catharact, glaucoma, osteoporosis and adrenal insufficiency may occur in the long-term treatment. The danger of immunosuppression is not common and it is even less frequent than with inhaled corticosteroids . When elderly patients are discharged from hospital, adherence to treatment abruptly ceases and a flare-up of symptoms after discontinuation of systemic steroids is considered a bad prognostic sign and indication of greater severity of asthma .There are two different licensed leukotriene (LT) Antagonists (LTRA) for asthma treatment: a) a 5- lipoxygenase enzyme inhibitor named zileuton, and three LT-1 antagonists named montelukast, pranlukast, zafirlukast. In the COMPACT  study moTheophylline, a methylxanthine, has been used as a bronchodilator in the treatment of asthma for more than 80 years, and remains a widely prescribed drug, because it is cheap and readily available . UnfortuIn general, the use of theophylline is limited by its adverse effects, which range from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias, rarely myocardial infarction and seizures. Theophylline is metabolized primarily by the liver, and commonly interacts with other medications. The available data indicate that the clearance of theophylline is reduced by 22-35% in elderly people, and that it is furtherly decreased by concomitant diseases, particularly liver (50% decrease) and heart (50% decrease) disease. Theophylline clearance is also influenced by diet: low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef increase the clearance and decrease half-life. Curiously, theophylline clearance is increased by 80% in elderly tobacco smokers. However, appropriate studies have not demonstrated geriatric-specific problems that would limit the usefulness of theophylline in the elderly. In conclusion, the main roles of theophylline in asthma of the elderly are in severe disease as an adjunct to ICS and LABA, particularly in conditions of corticosteroids resistance and in smokers . CautionThe phosphodiesterase (PDE) 4 inhibitor roflumilast is available for COPD treatment, and its use in asthma can be an interesting add-on therapeutic option in severe asthma with frequent exacerbation and neutrophilic inflammation. Its therapeutic use of is limited by side-effects, which are dose-dependent and the range of efficacy/tolerability is narrow. No difference in safety or efficacy was found between older and young patients and no cardiovascular risks emerged in studies . The maiTo date, omalizumab, a monoclonal anti-IgE humanized antibody, is the only specific target therapy available, and recognised as an add-on therapy in severe persistent asthmatics with inadequately controlled symptoms, regardless of age. Despite the high safety profile of omalizumab, an association between the use of omalizumab and the occurrence of hyperglycemia has been recently documented, and related to the sucrose contained in the vials . Taking Infliximab, a chimeric anti-TNF-α monoclonal antibody (mAb) and etanercept, a soluble TNF-α receptor linked to human Fc of IgG1, showed significant improvements in lung function and in the exacerbation rate, particularly in patients with severe steroid-resistant asthma. However, conflicting efficacy results obtained with other TNF-α blockers have cooled the use of these biologicals in asthmatic patients . The cruSubcutaneous immunotherapy (SCIT) is the historical route of administration and consists of allergen extract injections which can only be performed with a medical observation. The guidelines on the treatment of allergic diseases rarely focus on the elderly population and often ignore this population completely. Several placebo-controlled studies that demonstrated efficacy have included subjects up to 60 years of age. Unfortunately, studies that support the safety and effectiveness of SCIT in the elderly are not blinded. The European Academy of Allergy and Clinical Immunology advises specific immunotherapy as a relative contraindication for elderly patients . The CanIn conclusion, we are in agreement with the statements reported in the “Third Update Practice Parameter on Allergen Immunotherapy” which recommend that the risk/benefit assessment for SCIT should be carefully evaluated in the elderly population because they might have co-morbid medical conditions that could increase the risks . HoweverThe awareness of the efficacy and safety of allergic specific sublingual immunotherapy (SLIT) in geriatric patients is sometimes controversial. In part it is also due to the disbelief of the clinical benefits, and of the positive impact on health care costs in this age of life. In addition, it is generally known that the immune system in the elderly is down-regulated in comparison with young people and that allergies do not occur, so as not to require any more therapy. However, the reports of increased levels of total and specific IgE and consequent increase in immunological disorders are raising in literature in the last few years . From thRecently, it has been proved that the dendritic cells (DCs) in the elderly have an activated phenotype and an increased secretion of pro-inflammatory cytokines, which are responsible for the infiltration of eosinophils, the airway remodeling and the increase of asthma and chronic respiratory diseases . In the The safety of SLIT is confirmed by the fact that after more than 500 million doses administered to humans and 20 years of use there are no reports of fatalities; only few cases of anaphylaxis have been reported , only thSLIT has been demonstrated to reduce significantly both symptoms and medications, thus improving quality of life (QoL) ; this coIn conclusions, SLIT is an effective and safe therapeutic option, and the only approach that can change the course of allergic respiratorydiseases; however, its use in the elderly is still not widespread. A prerequisite before starting on a SLIT, especially in the geriatric patient, is to involve the allergic patient through correct information about the various aspects of his disease: from diagnosis, pharmacological treatment options, costs, side effects, management methods, thus to verify if the patient is able to deal with the SLIT.The United Nations Food and Agricultural Organization and the World Health Organization define probiotics as “live microorganisms, which, when administered in adequate amounts, confer a health benefit to the host” . PrebiotIn older people, alterations of both innate and acquired immunity have been shown Table , resultiRespiratory bacterial infections are among the most important causes of morbidity and mortality from communicable diseases worldwide. Streptococcus pneumoniae frequently colonizes the upper respiratory tract. Local host immunity is essential to control colonizing pathogens by preventing overgrowth, spread, and invasion. Asthma is commonly considered an independent risk factor for invasive pneumococcal disease. The pneumococcal conjugate vaccine, PCV13, is currently recommended for all adults 65 years or older, in particular in older asthmatics. The 23-valent pneumococcal polysaccharide vaccine PPSV23 is also recommended for use in adults of 65 years of age who smoke cigarettes or who have asthma. Physicians and other health care professionals should therefore encourage vaccinations in elderly asthmatic patients.The use of Complementary/Alternative Medicines (CAMs) is an impressive emergent phenomenon in Western Countries. This widespread use is common at any age, including older people . BronchiAcupuncture is a cornerstone of the Traditional Chinese Medicine, and is widely used for chronic illness, including asthma. The most recent reviews  includedHomeopathy is based on the belief that symptoms of a disease can be cured by the same substance that provokes them, if given at ultra-dilution. Homeopathic remedies are therefore chosen according to symptoms, not to disease, and prepared with a special manual technique called “potentiation”. Homeopathy has been extensively studied in allergic diseases, and there are well-conducted and rigorous trials in both asthma and rhinitis, -68, but tylophora indica, boswellia serrata, pychrorryza kurroa, koleus forskholii, gynko biloba, urtica and others. All these studies are in general of low quality, but in many cases, a clinical effect can be measured in several diseases, including bronchial asthma. This is not surprising, because most of the herbs utilized contain pharmacologically active ingredients. Positive results were obtained in rhinitis and asthma with the mixtures of herbs used in the traditional Chinese medicine, which contain ephedrine and atropine. No study has specifically addressed its use in older populations. The active ingredients may also induce undesirable side effects [The traditional allopathic medicine is largely based on subtances derived from plants and herbs . The literature on herbal remedies is impressive, due to the large variety of herbs and their combinations used:  effects . Moreove effects . Product effects , which m effects .Physical techniques  have been proposed in patients with chronic respiratory illness with the aim of improving the respiratory pattern. The majority of clinical trials of chiropractic/spinal manipulation in asthma ,74 faileIn conclusions, available scientific evidence does not support a role for CAM in the treatment of asthma in the elderly. The studies in the literature often have significant design flaws that weaken the conclusions such as insufficient number of patients, lack of proper controls and indadequate blinding.For the elderly asthmatic, exercise represents at the same time both a goal and a precious tool for treatment. On the one side, in fact, regular participation in sports and physical activity is one of the best ways for older adults, including those with chronic diseases, to promote independence, increase quality of life and improve aerobic capacity, breathing pattern, muscle strength . On the Exercise-induced bronchoconstriction (EIB) with- and without underlying asthma may occur also in the elderly asthmatic practicing sports, even with a higher frequency than in the general adult population taking into consideration all the comorbidities and physiological changes associated with aging previously cited. Sports with prolonged effort of more than 5–8 minutes or in cold and dry environments represent major risk factors . Swimming is still a controversial issue, and therefore it should be avoided for the potential risk related to chlorine byproducts inhalation. Treatment should follow the general guidelines and recommendations that apply to adults, with the limit of an arbitrary extrapolation due to the paucity of specific clinical trials in patients over 65 years. Finally, elderly athletes involved in International Association of Athletics Federations (IAAF) or in official masters’ competitions, must be aware about anti-doping regulations that apply not only to some anti-asthmatic drugs  but also to several drugs widely used to treat older adults’ comorbidities .The contribution of patient adherence to clinical success cannot be overestimated , and cliAging is associated with the development of numerous chronic diseases. Thus, it is quite common that elderly asthmatic subjects have additional chronic diseases, which may interfere with adherence to asthma treatment and control. Many epidemiological studies ,86 reporThe impact of comorbidities on asthma control of elderly asthmatics has been explored by few studies with conflicting results. According to a Canadian study , althougAsthma is frequently associated with nasal/sinonasal comorbidities such as rhinitis  or chronic rhinosinusitis , and these conditions may act as aggravating factors for asthma itself. Rhinitis in the elderly seems to have peculiar clinical and cytologic characteristics , and thetorsades de pointes. These effects have been observed in case of large doses of overdoses, however the potential cardiac comorbidities should be carefully assessed when prescribing an antihistamine drug [Antihistamines are a mainstay in the treatment of allergic respiratory diseases due to their H1 receptors antagonism. The first-generation anti H-1  are effective on allergic inflammation but they have well-known side effects, due to the lack of specificity for the H1 receptor . Sedatioine drug . The chaine drug ,95.The second-generation of H-1 receptor antagonists  provide a better safety and tolerability profile due to their low cross blood brain barrier and greater specificity for their receptor . The proFor many other classes of drugs, clinical trials with intranasal steroids were generally conducted in adults, typically included those 65 years and older, but without reporting data specific to this population. However, there is a consensus in considering intranasal steroids as the first-line treatment for moderate to severe allergic rhinitis in the elderly, effectively treating all symptoms of rhinitis . A randoAnother concern in using intranasal corticosteroids in older patients is the possible effect of these agents in fostering glaucoma. A case–control study of 9793 patients, age 66 or older, with a new diagnosis of borderline glaucoma, open angle glaucoma, or ocular hypertension, and 38325 controls randomly selected showed that there was no increased risk for these diseases with intranasal steroid use. The risk of ocular side effects appears to be negligible due to the low systemic bioavailability of most available intranasal steroid preparations . In concc intervals were reported in literature [Topically administered antihistamines are clinically effective, with the advantage of delivering the medication directly to the target area. Common adverse events of inhaled antihistamines are usually mild and include bitter taste, headache, dry mouth, sedation and application site irritation. More relevant side effects, mainly related to the first generation molecules, including urinary retention, prolonged QT interval, arrhythmias and constipation are however more prevalent in elderly patients due to the commonly observed comorbidities, such as heart diseases, prostatic hypertrophy and narrow angle glaucoma. Moreover, elderly patients usually take many drugs, thus increasing the risk of interaction between medications. Therefore, the antihistamine selection for the treatment of concomitant allergic rhinitis in elderly asthmatic patients should be made carefully and topical II generation molecules should be preferred . In subjterature .At last, a novel intranasal formulation, combining the second generation antihistamine azelastine hydrochloride and fluticasone propionate in a single device, has been recently developed, showing superiority over its single components . AlthougThe most recent research identified some promising “biological” approaches that could be successfully applied also in the elderly, and new treatment modalities have been introduced, mainly concerning biological agents or immunotherapy developments  Table 22. Of notFor about one century, specific immunotherapy has been administered only subcutaneously, but in the last 20 years, the sublingual route has been accepted as a viable alternative, and its use is nowadays largely diffused . This moFor long time, it was assumed that allergic respiratory disorders are typical of children, adolescents and young adults. In fact, most clinical trials were designed to include patients below 65 years of age. The time has come to face with allergic diseases in older ages, and this carries safety concerns and implications for efficacy. The management of allergic asthma in the elderly will only be successful when clinical randomized trials and observational real-life studies will be specifically conceived for older individuals.


Venlafaxine is the first antidepressant that acts via inhibiting serotonin and noradrenaline reuptake. Hypertension is observed in doses exceeding 300 mg/day and is the most feared complication. We report a patient with accelerated hypertension after venlafaxine use observed at a dose of 150 mg/day. A 23-year-old patient with symptoms of insomnia, depression, anhedonia, fatigue admitted our clinic. Venlafaxine at a dose of 75 mg/day was initiated after he was diagnosed with major depressive disorder. After 5 months, venlafaxine dose was uptitrated to 150 mg/day due to inadequate response to drug. After using venlafaxine for ten months at the dose of 150 mg/day, he admitted our clinic with headache and epistaxis. He was hospitalized after his blood pressure was measured as 210/170 mmHg. No secondary causes for hypertension were found, and venlafaxine treatment was considered possible etiologic factor. After stopping venlafaxine treatment, his blood pressure was reverted back to normal limits. While mild elevation of blood pressure could be observed after venlafaxine treatment, this case shows that accelerated hypertension with a diastolic blood pressure rise above 120 mmHg could be observed at relatively low doses of venlafaxine. Close monitoring of blood pressure is necessary after initiation of treatment, as accelerated hypertension could cause endorgan damage with potentially catastrophic results. Major depressive disorder (MDD) is the fourth most common disease diagnosed worldwide, with an annual prevalence of 6.6% and a lifelong prevalence of 16.2% [Venlafaxine is the first product that was commercially available for the treatment of major depression among all the serotonin-norepinephrine reuptake inhibitors . At highIn this paper, we report a patient with MDD who experienced accelerated hypertension with blood pressure measurements as high as 210/170 during venlafaxine use. No other secondary causes for hypertension were found, and blood pressure decreased to normal levels right after the drug was stopped.A 23-year-old male patient diagnosed with major depressive disorder, visited our institution, and was complaining from persistent symptoms despite the antidepressant therapy. At his initial visit, the patient had been suffering from insomnia, depression, anhedonia, irritability, inability to concentrate, and fatigue for about a year.Psychological examination revealed slowing of movements, reduced facial expressions, and decrease in his self-care. He had normal orientation of time, space, and person.Cardiovascular examination was normal at the initial visit, with a blood pressure of 120/70 mmHg and a heart rate of 76 beats/per minute. He had no family history for essential hypertension, chronic renal disorders, or similar chronic diseases.He was diagnosed with major depressive disorder according to the Structured Clinical Interview for DSM-IV (SCID-1)  and 75 mDespite missing his visits, the patient said that he was strictly obeying the medication schedule. However, his symptoms had not regressed and the dose of venlafaxine was increased to 150 mg/day.At the 10th month of the therapy, he readmitted our institution with a complaint of headache and epistaxis. On physical examination, his blood pressure was measured as 210/170 mmHg, and he was subsequently hospitalized with a diagnosis of accelerated hypertension.After hospitalization, his blood pressure was normalised with the administration of a short acting oral ACE inhibitor. Biochemical analyses including urinalysis and renal function tests, echocardiographic examination, and fundoscopic examination were performed to rule out end organ damage and malignant hypertension. Left ventricular dimensions, wall thickness, and ejection fraction were found to be normal on the echocardiography. Both fundoscopy and renal function tests revealed normal results.Venlafaxine treatment was stopped as it was thought to be the main predisposal factor for the patient's high blood pressure levels, while a secondary cause was continued to be searched. Renal Doppler ultrasound examination revealed normal renal dimensions and parenchyma without any stenosis.The protein and vinyl mandelic acid levels were measured within normal limits in the 24-hour urine test. Other biochemical analyses, including blood sodium and potassium levels, were all normal. After stopping venlafaxine treatment, a decrease below 140/90 mmHg in the blood pressure was observed; no additional drug use was needed for lowering the blood pressure.The patient was discharged from hospital one week after the initial admission. A 24-hour ambulatory blood pressure monitoring was performed one month after the index event and average blood pressure values which were measured 2 times a day (in the morning and at night) were below 130/80 mmHg.Venlafaxine is used in the treatment of major depressive disorder, generalized anxiety disorder, treatment-resistant depression, and chronic pain syndrome . The druAt higher doses, the drug also inhibits the dopamine reuptake . At doseAt lower doses, the adverse effects of venlafaxine, including nausea, vomiting, gastrointestinal adverse effects, and sexual dysfunction, are similar to that of other SSRIs, while at higher doses it becomes similar to that of norepinephrine reuptake inhibitors . While aIn our case, the blood pressure increased after increasing daily venlafaxine dose to 150 mgs. However, the diastolic blood pressure over 120 mmHg was much more than the expected level. Although we did not observe any complications—such as acute encephalopathy, heart failure, or papilledema—in our patient, such an acute and dramatic increase of blood pressure could be life-threatening.Depressive mood correlates with blood pressure , 18 and To our knowledge, only one case of accelerated hypertension (where diastolic blood pressure raised above 120 mmHg) after venlafaxine use has been reported previously. It was a female patient treated for anxiety, depression, and alcohol abuse, and her blood pressure was measured as 220/140 mmHg nine days after the initiation of risperidone and 75 mg/day venlafaxine . In contTwo other cases were reported to have developed hypertension after venlafaxine use; however, in both cases, the diastolic pressure was below 120 mmHg. In the first case, a female patient with high-normal blood pressure became hypertensive one week after the initiation of 150 mg/day venlafaxine treatment. Repeated measurement was planned one week after the first measurement which revealed a blood pressure of 162/110 mmHg . In the Our patient was younger than these patients reported previously, thus we looked for a secondary cause for hypertension. Particularly, pheochromocytoma was searched, as we hypothesised that venlafaxine could enhance hypertensive crises observed in this condition. However, the urine analysis for vanillylmandelic acid, a metabolite for catecholamines, revealed normal results. Urinalysis, renal ultrasound, and renal artery Doppler examinations were all normal, which ruled out the possibility for any renal diseases. Similarly, congenital vascular lesions that may cause hypertension, such as aortic coarctation, were not observed. The dramatic decrease soon after the venlafaxine treatment stopped also pointed out to drug-induced hypertension.In conclusion, venlafaxine use was identified as the predisposal factor for the accelerated hypertension in our patient. So far, reports and studies showed venlafaxine may cause mild elevation in blood pressure, which are more important in the long term. However, our study suggests that accelerated hypertension with a diastolic blood pressure rise above 120 mmHg could be observed soon after the venlafaxine administration. While hypertensive complications did not develop in our patient, such a sudden increase in blood pressure could cause stroke or similar disabling conditions. Therefore, patients on venlafaxine should be warned for a potential rise in blood pressure, and a regular followup should be planned for hypertension.


Adverse effects, treatment resistance and high costs associated with pharmacological treatment of hypertension have led to growing interest in non-pharmacological complementary therapies such as music interventions. This meta-analysis aims to provide an overview of reported evidence on the efficacy of music interventions in the treatment of hypertension.A systematic literature search was conducted for publications on the effect of music interventions on blood pressure in adult hypertensive subjects published between January 1990-June 2014. Randomized controlled trials with a follow-up duration ≥28 days were included. Blood pressure measures were pooled using inverse variance weighting.Of the 1689 abstracts reviewed, 10 randomized controlled trials were included. Random-effects pooling of the music intervention groups showed a trend toward a decrease in mean systolic blood pressure (SBP) from 144 mmHg(95 % CI:137–152) to 134 mmHg(95 % CI:124–144), and in mean diastolic blood pressure (DBP) from 84 mmHg(95 % CI:78–89) to 78 mmHg(95 % CI:73–84). Fixed-effect analysis of a subgroup of 3 trials with valid control groups showed a significant decrease in pooled mean SBP and DBP in both intervention and control groups. A comparison between music intervention groups and control groups was not possible due to unavailable measures of dispersion.This systematic review and meta-analysis revealed a trend towards a decrease in blood pressure in hypertensive patients who received music interventions, but failed to establish a cause-effect relationship between music interventions and blood pressure reduction. Considering the potential value of this safe, low-cost intervention, well-designed, high quality and sufficiently powered randomized studies assessing the efficacy of music interventions in the treatment of hypertension are warranted.The online version of this article (doi:10.1186/s12872-016-0244-0) contains supplementary material, which is available to authorized users. Hypertension has been documented as a major risk factor for cardiovascular morbidity and mortality , 2. PrevMusic interventions have been found to affect clinical outcomes in various situations, including short-term effects on blood pressure during medical procedures such as surgery to long-term effects in the treatment of sleep disorders or depression –8. A recMusic interventions can be administered in different ways. They can be either live or recorded and administered either with or without the involvement of a music therapist. Moreover, the music intervention can be chosen by the patient, by a music therapist or by a healthcare practitioner – the latter especially in the case of research. There are various definitions of music-based interventions, such as ‘music therapy’, ‘receptive music’ and ‘music medicine’. According to the definition of the American Music Therapy Association, music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program . The theSeveral studies have been performed to examine the possible effects of music on hypertension. These studies are usually small in sample-size and an overview of reported outcomes is lacking. To investigate the potential anti-hypertensive effect of music interventions, we conducted a systematic review and meta-analysis of prospective randomized controlled trials that assessed the effect of music interventions on blood pressure in hypertensive patients.In this article, we describe the effects of several types of music interventions in patients with hypertension. Overall, we will use the broader term music interventions. However when we specifically differentiate the interventions, we will refer to music therapy when a specific intervention includes the involvement of a music therapist in a therapeutic relationship. Music interventions without this therapeutic relationship will be referred to as recorded music interventions.This systematic review was conducted according to the PRISMA guidelines . The stuMethods of analysis and inclusion criteria were specified and documented in advance. Only the most recent or most complete study was included if there was an overlap in study populations. In case of disagreement on the inclusion of a paper, an agreement was negotiated.Microsoft Office Excel 2011  was used for data extraction and statistical analyses. The following patient and study characteristics were recorded: age, sex, systolic and diastolic blood pressure at baseline, history of hypertension, use of antihypertensive medication, comorbidities, details of music intervention and length of follow-up. Primary outcome measures were reduction in SBP and DBP and mean SBP and DBP at last follow-up. Secondary outcome measures were effects of music on anxiety and quality of life.p-value <0.05.Weighted pooling was conducted on the patient characteristics. Mean SBP and DBP at baseline and at final follow up and mean reduction in SBP and DBP were pooled using inverse variance weighting in a random-effects model. When the number of studies was not sufficiently large to reliably estimate the tau-squared statistic (<4 studies), a fixed-effect model was used as well . StudiesThe literature search resulted in 1689 publications. Ten of these studies, encompassing a total of 296 patients, met all of the described criteria and were included in the systematic review . This, as well as incomplete outcome data, gave rise to a moderate to high risk of bias in the included studies. Publication bias may have affected the outcomes, as some abstracts were unavailable as full-text articles Fig. .Our results show that current studies on the effect of music interventions on lowering blood pressure in hypertensive patients do not provide evidence on a possible cause-effect relationship. Since music interventions may be of beneficial value in hypertensive patients, presenting a potential adjuvant to standard pharmacological treatment, there is a need for further high quality research on the subject. Music interventions could not only be of value in case of multidrug therapy or treatment resistant hypertension, but might also be offered as a durable treatment modality in developing countries. However, well-designed high-quality, sufficiently powered randomized controlled trials are first required to establish a cause-effect relationship between music interventions and blood pressure reduction in hypertensive patients.This research, ideally in the form of large, well-reported randomized controlled trials following the CONSORT statement for nonpharmacological trials with clearly-defined interventions and controls and adequate statistical analyses, could explore the ability of music interventions in lowering blood pressure in a large population, examine the permanence of the reduction in blood pressure and elucidate which patients could benefit most . The infThis systematic review and meta-analysis found a trend towards a decrease in blood pressure in hypertensive patients who received music interventions. Unfortunately, this decrease does not provide proof for a cause-effect relationship, as a formal comparison with the control group is lacking. Therefore the most important conclusion of this study is that the quest for answers is still ongoing. Considering the potential value of this safe, low-cost intervention, there is an urgent need for well-designed, high quality, sufficiently powered randomized studies that assess the efficacy of music interventions in lowering blood pressure.The datasets supporting the conclusions of this article are included within the article .