Update on Cilostazol: A Critical Review of Its Antithrombotic and Cardiovascular Actions and Its Clinical Applications.

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated.

Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder.

AIMS: Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study. METHODS: 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment. RESULTS: Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers. CONCLUSION: CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819.

Evidence and Current Use of Levosimendan in the Treatment of Heart Failure: Filling the Gap.

Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review.

Current pharmacological treatments for chronic obstructive pulmonary disease (COPD) are mostly limited to inhaled bronchodilators and corticosteroids. Azithromycin can contribute to exacerbation prevention. Roflumilast, a phosphodiesterase (PDE) 4 inhibitor administered orally, also prevents exacerbations in selected patients with chronic bronchitis, recurrent exacerbations, severe airflow limitation and concomitant therapy with long-acting inhaled bronchodilators. This outcome likely results from anti-inflammatory effects since PDE4 is expressed by all inflammatory cell types involved in COPD. The use of this agent is, however, limited by side-effects, particularly nausea and diarrhea. To address remaining unmet needs and enrich therapeutic options for patients with COPD, inhaled dual PDE3/4 inhibitors have been developed, with the aim of enhancing bronchodilation through PDE3 inhibition and modulating inflammation and mucus production though PDE4 inhibition, thus producing a potentially synergistic effect on airway calibre. Experimental preclinical data confirmed these effects in vitro and in animal models. At present, RPL554/ensifentrine is the only agent of this family in clinical development. It decreases sputum markers of both neutrophilic and eosinophilic inflammation in patients with COPD. Clinical Phase II trials confirmed its bronchodilator effect and demonstrated clinically meaningful symptom relief and quality of life improvements in these patients. The safety profile appears satisfactory, with less effects on heart rate and blood pressure than salbutamol and no other side effect. Altogether, these data suggest that ensifentrine could have a role in COPD management, especially in addition to inhaled long-acting bronchodilators with or without corticosteroids since experimental studies suggest potentiation of ensifentrine effects by these agents. However, results from ongoing and future Phase III studies are needed to confirm both beneficial effects and favourable safety profile on a larger scale and assess other outcomes including exacerbations, lung function decline, comorbidities and mortality.

Literature review and meta-analysis of the efficacy of cilostazol on limb salvage rates after infrainguinal endovascular and open revascularization.

BACKGROUND: Current clinical guidelines recommend the use of cilostazol in the treatment of patients with infrainguinal peripheral artery disease (PAD) who experience intermittent claudication. However, the role of cilostazol therapy in patients with advanced PAD and critical limb ischemia (CLI) remains unclear. To conduct a meta-analysis of randomized controlled trials and cohort studies that evaluated the effect of cilostazol vs standard antiplatelet therapy on limb-related and arterial patency-related outcomes. We also reviewed literature pertinent to the effect of cilostazol on wound healing in patients with advanced PAD. METHODS: We performed a MEDLINE, EMBASE, COCHRANE (CENTRAL), SCOPUS, and US Clinical Trials database search for all trials and studies since 1999 that compared cilostazol with standard antiplatelet therapy in the setting of infrainguinal PAD revascularization procedures (endovascular or open). Aggregate data was collected from four randomized control trials and six retrospective cohort studies. The end point incidence ratios and treatment effects were generated from each study and reported as hazard ratios (HR) using a random-effect model. We also reviewed 10 studies that evaluated the effect of cilostazol on wound healing in patients with advanced PAD. RESULTS: From more than 25,000 total patients, 3136 patients met our inclusion criteria. All patients had at least lifestyle-impacting intermittent claudication, and more than 50% met the definition of CLI (Rutherford class ≥4). Patient age range was 53 to 83 years, and the majority were male (66%). The mean follow-up time averaged 2 years across all studies. Meta-analysis revealed that cilostazol treatment favored amputation-free survival (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69-0.91), limb salvage rate (HR, 0.42; 95% CI, 0.27-0.66), decreased repeat revascularization (risk ratio [RR], 0.44; 95% CI, 0.37-0.52), and decreased restenosis (RR, 0.68; 95% CI, 0.61-0.76). Cilostazol treatment also increased freedom from target lesion revascularization (RR, 1.35; 95% CI, 1.21-1.53) with no difference in all-cause mortality. Effective wound healing was found to be an inconsistent outcome measure in patients receiving cilostazol therapy. CONCLUSIONS: We observed that cilostazol therapy has a beneficial impact on all limb-related and arterial patency-related outcomes, but no effect on all-cause mortality in patients with advanced PAD and CLI undergoing revascularization procedures. Additional studies are needed to evaluate the effect of cilostazol therapy on wound healing in patients with advanced PAD.

Extended-Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HFpEF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HFpEF. Methods and Results The MilHFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double-blind, placebo-controlled pilot study in 23 patients with symptomatic HFpEF. Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6-minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone-treated patients compared with placebo (+10±13 versus -3±15; P=0.046). Six-minute walk distance also tended to improve in the treatment group compared with placebo (+22 [-8 to 49] versus -47 [-97 to 12]; P=0.092). Heart rate (-1±5 versus -2±9 bpm; P=0.9) and systolic blood pressure (-3±18 versus +1±12 mm Hg; P=0.57) were unchanged. Early filling velocity/early mitral annular velocity (-0.3±3.0 versus -1.9±4.8; P=0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HFpEF. Further longer-term studies are warranted to establish the role of this therapeutic approach in HFpEF. Registration URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616000619448.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.

Efficacy of Cilostazol in Prevention of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis.

OBJECTIVES: Cilostazol, a selective inhibitor of phosphodiesterase 3, may reduce symptomatic vasospasm and improve outcome in patients with aneurysmal subarachnoid hemorrhage considering its anti-platelet and vasodilatory effects. We aimed to analyze the effects of cilostazol on symptomatic vasospasm and clinical outcome among patients with aneurysmal subarachnoid hemorrhage (aSAH). PATIENTS AND METHODS: We searched PubMed and Embase databases to identify 1) prospective randomized trials, and 2) retrospective trials, between May 2009 and May 2017, that investigated the effect of cilostazol in patients with aneurysmal aSAH. All patients were enrolled after repair of a ruptured aneurysm by clipping or endovascular coiling within 72hours of aSAH. fixed-effect models were used to pool data. We used the I2 statistic to measure heterogeneity between trials. RESULTS: Five studies were included in our meta-analysis, comprised of 543 patients with aSAH (cilostazol [n=271]; placebo [n=272], mean age, 61.5years [SD, 13.1]; women, 64.0%). Overall, cilostazol was associated with a decreased risk of symptomatic vasospasm (0.31, 95% CI 0.20 to 0.48; P<0.001), cerebral infarction (0.32, 95% CI 0.20 to 0.52; P <0.001) and poor outcome (0.40, 95% CI 0.25 to 0.62; P<0.001). We observed no evidence for publication bias. Statistical heterogeneity was not present in any analysis. CONCLUSION: Cilostazol is associated with a decreased risk of symptomatic vasospasm and may be clinically useful in the treatment of delayed cerebral vasospasm in patients with aSAH. Our results highlight the need for a large multi-center trial to confirm the observed association.

Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia.

OBJECTIVE: A multidisciplinary approach is required to treat critical limb ischemia. We determined the poor prognostic factors of ischemic ulcer healing after optimal arterial revascularization, and assessed the efficacy of the medication therapy using cilostazol, which is a selective inhibitor of phosphodiesterase 3. METHODS: In this retrospective, single-center, cohort study, 129 limbs that underwent infrainguinal arterial revascularization for Rutherford class 5 critical limb ischemia were reviewed. The primary end point was the ulcer healing time after arterial revascularization. The secondary end point was the amputation-free survival rate. RESULTS: Of the 129 limbs, endovascular therapy was performed in 69 limbs, and surgical reconstructive procedures were performed in 60 limbs for initial therapy. Complete ulcer healing was achieved in 95 limbs (74%). The median ulcer healing time was 90 days. In multivariate analysis, no cilostazol use significantly inhibited ulcer healing ( p = 0.0114). A white blood cell count >10,000 ( p = 0.0185), a major defect after debridement ( p = 0.0215), and endovascular therapy ( p = 0.0308) were significant poor prognostic factors for ulcer healing. Additionally, ischemic heart disease ( p < 0.0001), albumin levels <3 g/dl ( p = 0.0016), no cilostazol use ( p = 0.0078), and a major defect after debridement ( p = 0.0208) were significant poor prognostic factors for amputation-free survival rate. CONCLUSIONS: Ulcer healing within 90 days after arterial revascularization is impaired by no cilostazol use, a white blood cell count >10,000, a major defect after debridement, and endovascular therapy. Furthermore, cilostazol improves amputation-free survival rate in patients with critical limb ischemia.

Safety of cilostazol in peripheral artery disease: a cohort from a primary healthcare electronic database.

BACKGROUND: Cilostazol has been associated with spontaneous reports of cardiovascular adverse events and serious bleeding. The objective of this study is to determine the relative risk of cardiovascular adverse events or haemorrhages in patients with peripheral artery disease treated with cilostazol in comparison to pentoxifylline users. METHODS: Population-based cohort study including all individuals older than 40 who initiated cilostazol or pentoxifylline during 2009-2011 in SIDIAP database. The two treatment groups were matched through propensity score (PS). RESULTS: Nine thousand one hundred twenty-nine patients met inclusion criteria and after PS matching, there were 2905 patients in each group. 76% of patients were men, with similar mean ages in both groups (68.8 for cilostazol and 69.4 for pentoxifylline). There were no differences in bleeding, cerebrovascular and cardiovascular events between both groups. CONCLUSIONS: Patients treated with cilostazol were different from those treated with pentoxifylline at baseline, so they were matched through PS. We did not find differences between treatment groups in the incidence of bleeding or cardiovascular and cerebrovascular events. Cilostazol should be used with precaution in elderly polymedicated patients.

Cilostazol induced migraine does not respond to sumatriptan in a double blind trial.

BACKGROUND: Cilostazol is an inhibitor of phosphodiesterase 3 and thus causes accumulation of cAMP. It induces migraine-like attacks in migraine patients. Whether the cilostazol model responds to sumatriptan in migraine patients and therefore is valid for testing of future anti-migraine medications has never been investigated. METHODS: In a cross-over study, 30 patients received cilostazol (200 mg p.o.) on two separate days each day followed by oral self-administered placebo or sumatriptan 50 mg. We recorded headache characteristics and associated symptoms using a questionnaire. The 30 participants were asked to subsequently treat their spontaneous attacks with sumatriptan (50 mg) or placebo in a double-blind cross-over design and 15 participants did so. RESULTS: Cilostazol induced headache with some migraine characteristics in all participants; 18 patients on the sumatriptan day and 19 patients on the placebo day fulfilled criteria for a migraine-like attack. The difference in median headache intensity between sumatriptan and placebo at 2 h was not significant (p = 0.09), but it was at 4 h (p = 0.017). During spontaneous attacks, the difference between placebo and sumatriptan was not significant at 2 h (p = 0.26), but it was highly significant at 4 h (p = 0.006). CONCLUSION: The cilostazol model in migraine patients could not be validated by a sufficient sumatriptan response. The model may perhaps respond to new drugs that act intracellularly or directly on ion channels. TRIAL REGISTRATION: The study is registered on clinicaltrials.gov ( NCT02486276 ).

Cilostazol Improves Wound Healing in Patients Undergoing Open Bypass for Ischemic Tissue Loss: A Propensity Score Matching Analysis.

BACKGROUND: Few reports have described the effects of medication on the wound healing of ischemic ulcers after revascularization. This study was conducted to investigate the effects of cilostazol on wound healing in patients who underwent infrainguinal bypass for ischemic tissue loss. METHODS: Two hundred sixty-three limbs undergoing de novo infrainguinal bypass for tissue loss from January 2004 to December 2015 were divided into 2 groups based on whether or not cilostazol was administered after surgery. The end point was wound healing. The 1-year outcomes of the groups were analyzed using the Kaplan-Meier method, and a propensity score matching analysis was performed to examine the effects of cilostazol on wound healing. In addition, the significant predictors were determined using a Cox proportional hazards regression analysis. RESULTS: Sixty-one and 202 limbs were included in the cilostazol and non-cilostazol group, respectively. The cilostazol group showed superior wound healing to the non-cilostazol group (cilostazol versus non-cilostazol, 1-year wound healing rate: 92% vs. 81%; median wound healing time: 45 vs. 78 days, P = 0.002). The results of the cilostazol group remained superior after a propensity score matching (cilostazol versus non-cilostazol, 1-year wound healing rate: 95% vs. 83%; median wound healing time: 45.5 vs. 57 days, P = 0.048). A Cox proportional hazards regression analysis indicated that foot infection, Rutherford classification, diabetes mellitus, coronary artery disease, angiosome, the administration of cilostazol, and graft patency were significant factors that influenced wound healing. CONCLUSIONS: The postoperative use of cilostazol help to promote wound healing after open surgery.

Effect of phosphodiesterase inhibitors on renal functions and oxidant/antioxidant parameters in streptozocin-induced diabetic rats.

The goal of this study was to investigate the effect of different phosphodiesterase inhibitors (PDEIs), on renal oxidant/antioxidant balance in diabetic rats. Our study was conducted on 125 rats, diabetes was induced in 100 rats by a single administration of streptozocin (STZ). Diabetic rats were divided into four equal groups. The first group was assigned as diabetic control, the remaining three groups were treated with pentoxifylline, sildenafil and milrinone via drinking water for 15 successive days, another group of 25 normal rats was assigned as non-diabetic control. Significant increase in plasma levels of glucose, urea, creatinine, malondialdehyde (MDA), and nitric oxide (NO) with a concomitant decrease in the levels of insulin, reduced glutathione (GSH), glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were observed in diabetic rats. These alterations were reverted back to near normal level after treatment with PDEIs. Our data seem to suggest a potential role of PDEIs in maintaining health in diabetes by reducing the progression of diabetic nephropathy.

Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol.

Introduction The phosphodiesterase-3-inhibitor cilostazol induces migraine-like attacks in patients with migraine without aura, and may be used as a pharmacological trigger in human experimental models of migraine. However, the reproducibility of cilostazol-induced migraine-like attacks has never been investigated. Methods We performed a post-hoc analysis of clinical data from two brain-imaging studies including subjects who had received cilostazol 200 mg orally. Only subjects who developed migraine-like attacks on study day 1 were included on study day 2. After cilostazol ingestion, subjects and the investigator recorded headache intensity and characteristics once every hour on a purpose-developed questionnaire. Primary end-points included incidence and time to onset of migraine-like attacks between two separate study days. Results Thirty-four subjects completed both experimental days and were included in this study. Thirty-four out of 34 subjects (100%) developed migraine-like attacks after cilostazol ingestion on both study days 1 and 2. Time to onset of migraine was five hours (range 1-8 hours) on study day 1 and four hours (range 1-8 hours) on study day 2, p = 0.16. We found no difference in median peak headache score, median time to peak headache score, or median time to intake of rescue medication between study days 1 and 2. Conclusion A second-time administration of cilostazol reproduces migraine-like attacks in all subjects who report an attack after their first cilostazol induction. There was no difference in time to migraine onset between separate inductions. Experimental migraine provocation using cilostazol is a highly efficient and useful approach for studying the ictal phase of migraine without aura.

Cilostazol adjunctive therapy in treatment of negative symptoms in chronic schizophrenia: Randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of cilostazol, a selective inhibitor of phosphodiesterase III, as an adjunctive to risperidone in alleviating the negative symptoms of schizophrenia. METHODS: Eighty-four in-patients with diagnosis of chronic schizophrenia participated in a randomized, placebo-controlled trial and underwent 8 weeks of treatment with either cilostazol (50 mg twice a day) or placebo as an adjuvant to risperidone. Participants were assessed using the positive and negative syndrome scale (PANSS) at baseline and at weeks 2, 4, 6, and 8. The primary outcome measure of the trial was to evaluate the efficacy of cilostazol compared to placebo in improving the PANSS negative subscale score. RESULT: General linear model repeated measures demonstrated significant effect for time × treatment interaction on negative subscale scores (p < .001) and PANSS total (p = .006) but did not demonstrate significant effect on the PANSS positive (p = .37) and general (p = .06) subscales. Frequency of adverse events was not significantly different between the 2 treatment groups. No serious adverse event was observed. CONCLUSION: An 8-week course of treatment with cilostazol as an adjunct to risperidone showed a favorable safety and efficacy profile in patients with schizophrenia.

Cilostazol May Improve Maturation Rates and Durability of Vascular Access for Hemodialysis.

Cilostazol is effective in controlling pathophysiological pathways similar or identical to those involved in nonmaturation and failure of the arteriovenous access. This case-control study examined whether cilostazol would improve maturation rates and durability of vascular access for hemodialysis. The treatment group included 33 patients who received cilostazol for ≥30 days prior to creation of a dialysis access and continued with cilostazol therapy for ≥60 days after surgery. The matched (gender, age, race, diabetes, and the year of surgery) control group included 116 patients who underwent the same procedure but did not receive cilostazol prior to and at least 3 months after surgery. Primary outcomes were maturation and, for those that matured, time of functioning access, defined as the time from the first use to irreparable failure of the access. Secondary outcomes were time to maturation, complications, and time to first complication. Study group patients were 3.8 times more likely to experience fistula maturation compared to the controls (88% vs 66%, RR = 3.8, 95% confidence interval: 1.3-11.6, P = .016). Fewer patients in the study group had complications (76% vs 92%, P = .025), and the time from construction of the fistula to the first complication was longer (345.6 ± 441 days vs 198.3 ± 185.0 days, P = .025). Time to maturation was similar in both groups (119.3 ± 62.9 days vs 100.2 ± 61.7 days, P = .2). However, once matured, time to failure was significantly longer in the treatment group (903.7 ± 543.6 vs 381.6 ± 317.2 days, P = .001). Multivariate analysis confirmed that the likelihood of maturation was significantly higher in the treatment group patients. These results suggest that dialysis access patients may benefit from preoperative and postoperative cilostazol therapy. If confirmed by a randomized trial, this treatment will have a major beneficial impact on patients dependent on a well-functioning access for their hemodialysis.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

INTRODUCTION: Milrinone is an inotrope widely used for treatment of cardiac failure. Because previous meta-analyses had methodological flaws, we decided to conduct a systematic review of the effect of milrinone in critically ill adult patients with cardiac dysfunction. METHODS: This systematic review was performed according to The Cochrane Handbook for Systematic Reviews of Interventions. Searches were conducted until November 2015. Patients with cardiac dysfunction were included. The primary outcome was serious adverse events (SAE) including mortality at maximum follow-up. The risk of bias was evaluated and trial sequential analyses were conducted. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: A total of 31 randomised clinical trials fulfilled the inclusion criteria, of which 16 provided data for our analyses. All trials were at high risk of bias, and none reported the primary composite outcome SAE. Fourteen trials with 1611 randomised patients reported mortality data at maximum follow-up (RR 0.96; 95% confidence interval 0.76-1.21). Milrinone did not significantly affect other patient-centred outcomes. All analyses displayed statistical and/or clinical heterogeneity of patients, interventions, comparators, outcomes, and/or settings and all featured missing data. DISCUSSION: The current evidence on the use of milrinone in critically ill adult patients with cardiac dysfunction suffers from considerable risks of both bias and random error and demonstrates no benefits. The use of milrinone for the treatment of critically ill patients with cardiac dysfunction can be neither recommended nor refuted. Future randomised clinical trials need to be sufficiently large and designed to have low risk of bias.

Predictors of respiratory instability in neonates undergoing patient ductus arteriosus ligation after the introduction of targeted milrinone treatment.

INTRODUCTION: The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. METHODS: A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. RESULTS: Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. CONCLUSIONS: Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course.