Double dissociation of dopamine and subthalamic nucleus stimulation on effortful cost/benefit decision making.

Deep brain stimulation (DBS) and dopaminergic therapy (DA) are common interventions for Parkinson's disease (PD). Both treatments typically improve patient outcomes, and both can have adverse side effects on decision making (e.g., impulsivity).1,2 Nevertheless, they are thought to act via different mechanisms within basal ganglia circuits.3 Here, we developed and formally evaluated their dissociable predictions within a single cost/benefit effort-based decision-making task. In the same patients, we manipulated DA medication status and subthalamic nucleus (STN) DBS status within and across sessions. Using a series of descriptive and computational modeling analyses of participant choices and their dynamics, we confirm a double dissociation: DA medication asymmetrically altered participants' sensitivities to benefits vs. effort costs of alternative choices (boosting the sensitivity to benefits while simultaneously lowering sensitivity to costs); whereas STN DBS lowered the decision threshold of such choices. To our knowledge, this is the first study to show, using a common modeling framework, a dissociation of DA and DBS within the same participants. As such, this work offers a comprehensive account for how different mechanisms impact decision making, and how impulsive behavior (present in DA-treated patients with PD and DBS patients) may emerge from separate physiological mechanisms.

Novel lower-extremity dexterity assessment for Parkinson's disease: validation against measures of arm dexterity and general mobility.

PURPOSE: To establish criterion and construct validity of a novel, clinically feasible assessment of lower-extremity dexterity for PD patients. METHODS: Thirty-three PD patients performed a unilateral lower-extremity dexterity task "off" and "on" dopaminergic medications with each leg. The task involves iteratively tapping targets with the foot in a specified pattern, and the measured outcome is the time to complete the movement sequence, with longer times indicating worse performance. We correlated leg movement time with standard, validated measures of gait (comfortable and maximal walk speeds), general mobility (timed up and go), upper-extremity dexterity (9-Hole Pegboard), and elements of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). RESULTS: We found significant relationships between lower extremity dexterity and each of these tasks "off" and "on" medications. Task performance also captures known features of PD, including dopamine-mediated improvement in performance and asymmetrical symptom presentation. CONCLUSIONS: This task provides a simple assessment of lower extremity function that correlates with validated measures of dexterity, gait, and mobility. It provides objective, continuous data, is inexpensive, requires little technical expertise/equipment, has a small physical footprint, and can be administered quickly. These features increase the feasibility of implementing this assessment tool in clinical settings.Implications for rehabilitationWe introduce a novel task that captures lower extremity dexterity in individuals with Parkinson's disease (PD).The task is validated against gold standard measures of upper extremity dexterity, gait, and general mobility.Performance on the task is sensitive to known features of PD, including dopamine-mediated improvements and asymmetrical symptom presentation.The task is easy to implement and provides higher quality data compared to other common clinical assessments (e.g., MDS-UPDRS).

Epidemiology, monitoring, and treatment strategy in cardiogenic shock. A multinational cross-sectional survey of ESC-acute cardiovascular care association research section.

AIMS: Cardiogenic shock (CS) is a life-threatening condition burdened by mortality in up to 50% of cases. Few recommendations exist with intermediate-low level of evidence on CS management and no data on adherence across centres exist. We performed a survey to frame CS management at multinational level. METHODS AND RESULTS: An international cross-sectional survey was created and approved by European Society of Cardiology-Acute Cardiovascular Care Association board. A total of 337 responses from 60 countries were obtained. Data were assessed by the hospital level of care of the participants. The most common cause of CS was AMI (AMI-CS-79.9%) with significant difference according to hospital levels (P = 0.001), followed by acutely decompensated heart failure (HF) (13.4%), myocarditis (3.5%), and de novo HF (1.75%). In 37.8%, percutaneous coronary intervention (PCI) is performed to all CS-patients as a standard approach, whereas 42.1% used PCI if electrocardiogram suggestive of ischaemia and 20.1% only if Universal definition of myocardial infarction criteria are fulfilled. Management (catecholamine titration and mechanical circulatory support escalation) is driven by mean arterial pressure (87.1%), echocardiography (84.4%), and lactate levels (83.4%). Combination of vasopressor and inotrope is chosen with the same frequency (37.7%) than inotrope alone as first-line pharmacological therapy (differences amongst hospital levels; P > 0.5). Noradrenaline is first-line vasopressor (89.9%) followed by dopamine (8.5%), whereas dobutamine is confirmed as the first-line inotrope (65.9%). CONCLUSION: Cardiogenic shock management is heterogenous and often not adherent to current recommendations. Quality improvement on an international level with evidence-based quality indicators should be developed to standardize diagnostic and therapeutic pathways.

A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene.

PURPOSE: To report the identification of a novel mutation in the CACNA1S gene that encodes the alpha-1-subunit (Cav1.1) of the voltage-gated skeletal muscle L-type calcium channel in a patient with malignant hyperthermia. CLINICAL FINDINGS: An otherwise healthy 34-yr-old female developed fulminant malignant hyperthermia (MH) under sevoflurane anesthesia during laparoscopic donor nephrectomy. The first sign was an increase in end-tidal CO(2). Malignant hyperthermia was suspected early, and resuscitative measures, including supportive and specific treatment, were successfully implemented. The patient rejected the open muscle biopsy for the Caffeine-Halothane Contracture Test (CHCT); therefore, only molecular genetic testing was performed. Sequencing of the entire ryanodine receptor type 1 transcript did not reveal any MH causative mutations. However, a novel homozygous mutation, p.Arg1086Ser, was identified in the CACNA1S gene that encoded for the alpha-1-subunit of the skeletal muscle L-type calcium channel (Cav1.1). A CACNA1S mutation, p.Arg1086His, involving the same Arg1086 residue that is mutated in our patient has previously been reported in association with MH in three independent families. CONCLUSION: The homozygous p.Arg1086Ser mutation of CACNA1S, the gene that encodes the alpha-1-subunit of the voltage-gated skeletal muscle L-type calcium channel, is a novel mutation associated with malignant hyperthermia.

Oral midodrine is effective for the treatment of hypotension associated with carotid artery stenting.

Hypotension is commonly encountered during carotid artery stenting (CAS), mediated by vagal stimulation and suppression of sympathetic outflow. Some patients require treatment with intravenous vasopressors (dopamine, nor-epinephrine, or phenylephrine). The authors describe the successful use of the oral agent midodrine as an alternative to intravenous vasopressors in the treatment of hypotension related to CAS. Of 55 patients who underwent elective CAS, 19 (35%) experienced significant hypotension, and 15 (27%) required vasopressor therapy. Eleven patients received intravenous dopamine infusion in an intensive care setting, whereas 4 received oral midodrine in a regular telemetry unit. All patients eventually recovered and were discharged without any residual cardiovascular or neurological complications. No major side effects were noted with the use of both dopamine and midodrine. Cost of hospitalization was significantly higher in the dopamine group because of the need for ICU admission.

Treatment of the acute decompensation of heart failure: efficacy and pharmacoeconomics of early initiation of therapy in the emergency department.

Most patients admitted with acute decompensated heart failure (ADHF) go through the emergency department as their initial point of care. New diagnostic tests hold the promise to improve the clinical accuracy of the emergency physicians' diagnosis. Beyond that there is growing recognition that the treatment provided initially has an important impact on the subsequent inpatient course. Basic care for ADHF has involved oxygen as needed, diuretics, and, occasionally, topical or sublingual nitroglycerin. A substantial proportion of patients are treated with vasoactive agents including inotropes and vasodilators such as nitroglycerin and nesiritide. Unfortunately, inotropes have not been demonstrated to improve the outcome of heart failure and, in fact, may be deleterious. The newer agent, nesiritide, has the advantage of being a balanced vasodilator with favorable effects on diuresis, symptom relief, and neurohormones. Evidence from registries indicates that early initiation of nesiritide compared to delayed initiation leads to improved outcomes with shorter lengths of stay, shorter stays in the intensive care unit, and a lower mortality rate. This article reviews the initial management of ADHF, the role of early initiation of vasodilator therapy, and the pharmacoeconomics of nesiritide treatment.

New approaches to the treatment of sepsis.

The clinical spectrum of sepsis, severe sepsis, and septic shock is responsible for a growing number of deaths and excessive health care expenditures. Until recently, despite multiple clinical trials, no intervention provided a beneficial outcome in septic patients. Within the last 2 years, studies that involved drotrecogin alfa (activated), corticosteroid therapy, and early goal-directed therapy showed efficacy in those with severe sepsis and septic shock. These results have provided optimism for reducing sepsis-related mortality.

Pre-operative optimisation employing dopexamine or adrenaline for patients undergoing major elective surgery: a cost-effectiveness analysis.

OBJECTIVE: To compare the cost and cost-effectiveness of a policy of pre-operative optimisation of oxygen delivery (using either adrenaline or dopexamine) to reduce the risk associated with major elective surgery, in high-risk patients. METHODS: A cost-effectiveness analysis using data from a randomised controlled trial (RCT). In the RCT 138 patients undergoing major elective surgery were allocated to receive pre-operative optimisation employing either adrenaline or dopexamine (assigned randomly), or to receive routine peri-operative care. Differential health service costs were based on trial data on the number and cause of hospital in-patient days and the utilisation of health care resources. These were costed using unit costs from a UK hospital. The cost-effectiveness analysis related differential costs to differential life-years during a 2 year trial follow-up. RESULTS: The mean number of in-patient days was 16 in the pre-optimised groups (19 adrenaline; 13 dopexamine) and 22 in the standard care group. The number (%) of deaths, over a 2 year follow-up, was 24 (26%) in the pre-optimised groups and 15 (33%) in the standard care group. The mean total costs were EUR 11,310 in the pre-optimised groups and EUR 16,965 in the standard care group. Life-years were 1.68 in the pre-optimised groups and 1.46 in the standard care group. The probability that pre-operative optimisation is less costly than standard care is 98%. The probability that it dominates standard care is 93%. CONCLUSIONS: Based on resource use and effectiveness data collected in the trial, pre-operative optimisation of high-risk surgical patients undergoing major elective surgery is cost-effective compared with standard treatment.

Assessment of therapy for arterial hypotension in critically ill preterm infants.

The aim of this paper is to assess the efficacy of albumin and dopamine compared with albumin and dobutamine in treating hypotension in preterm newborn infants (PNI). A randomized, open-label, prospective, cross-over study, was designed on 66 PNI whose weights were between 1,000 to 1,500 g, and persistent hypotension, defined as a mean arterial pressure (MAP) of < 30 mmHg. Infants were randomly allocated to two groups and received a 5% albumin infusion at a dosage of 20 mL/kg, in 30 min. Thereafter, one group received dopamine and the other dobutamine at doses of 5 microg/kg/min. If there was not an increase in MAP values > 30 mmHg, the infusions were increased every 20 min by 2.5 microg/kg/min, up to a maximum of 10 microg/kg/min. Treatment failure was considered when there was no pressure response within 2 hr after the infusion started; then patients were changed to the other catecholamine. Statistical analysis was done with student's t-test, x2, and Fisher's exact probability test. There were no differences between groups in initial features. Overall, MAP was normalized with dopamine in 29 of 33 infants and with dobutamine in 25 of 33 infants (p > 0.05). The initial dosage of 5 microg/kg/min, was adequate in 22 infants treated with dopamine and in 13 treated with dobutamine (p < 0.05). The change from dopamine to dobutamine was successful in three out of four patients, while changing from dobutamine to dopamine was adequate in seven out of eight patients. Dopamine is recognized as the drug of choice to treat hypotension in PNI. Since our results showed only small differences in responses, it is proposed that dobutamine is also as efficacious and useful as dopamine.

Continuous home ambulatory intravenous inotropic drug therapy in severe heart failure: safety and cost efficacy.

Some patients with dilated cardiomyopathy who are inotrope dependent but remain well by undergoing infusions can be managed by ambulatory infusions at home. We report our results in 20 patients awaiting heart transplantation, unable to be weaned from intravenous inotropic therapy on 2 or more occasions, but who were well while receiving inotropes and received home ambulatory infusions. The patients were treated with ACE inhibitors, digoxin, diuretics, vasodilators, close electrolyte management, and low-dose amiodarone for those with more than four-beat ventricular tachycardia. Infusions were delivered by a tunneled subclavian catheter and syringe driver. Thirteen patients received dopamine, four received dobutamine, and three received both. Mean duration of inotropic therapy was 5 months with 70% of the time spent as an outpatient. Eleven patients received transplants, two remain on the waiting list, and seven died after being removed from the list because of general deterioration or renal dysfunction. There were no sudden deaths. Actuarial survival was 71% at 3 months, which is not less than that expected for an inotrope-dependent population. All patients with idiopathic dilated cardiomyopathy survived to transplantation. In contrast, all three with right heart failure caused by pulmonary vascular disease and four of seven with ischemic cardiomyopathy died. Inpatient days were reduced by 70%, leading to considerable cost savings. Home ambulatory inotropic therapy is safe, cost-effective, best suited to those with idiopathic dilated cardiomyopathy, and dramatically reduces inpatient hospital duration.

Treatment of parkinsonian syndromes in developing countries.

Parkinsonism is the commonest extrapyramidal disorder. The condition arises when the striatonigral dopamine content falls below a critical value. The principle of treatment is dopamine replacement or counteracting the effects of acetycholine, the neurotransmitter which is in abundance. The choice of drug is determined by availability, cost, and side effects. The most commonly prescribed drugs in developing countries are the anticholinergics, which are the least expensive. The dopamine-replacement agents are second-line drugs and it appears as if low doses are effective in improving rigidity, gait abnormality, and postural instability. The use of dopa-agonist drugs is more limited, because of cost and side effects. Surgical management of cases is still in its infancy in developing countries. This review also highlights the more recent modes of management practised mainly in developed countries.

Dopexamine (dopacard, Speywood).

Catecholamine inotropes, chemically based on dopamine and active in the sympathetic nervous system, are used to provide haemodynamic support to critically ill patients. The latest of these, dopexamine, is a promising addition to this important class of drugs with wide application in intensive care.

Estados depresivos resistentes

La depresión resistente (refractaria) es una causa considerable de mortalidad e intentos de suicidio consumados, aunque en los últimos tiempos hemos sido testigos de un gran avance en la terapúutica antidepresiva farmacológica, existe un grupo de pacientes que se mantiene "resistente" a la medicación. Obviamente habrá que estudiar más detenidamente y objetivamente el porqué de las limitaciones terapéuticas. Se menciona que aproximadamente un 30 por ciento de pacientes no presentan una respuesta significativa a los productos farmacológicos convencionales o el TEC. Lamentablemente los investigadores clínicos y la industria farmaceutica poco se han dedicado a investigar en este tema. Nuevamente tendremos que preguntarnos si existe la verdadera depresión refractaria o si ésta es consecuncia de nuestas limitaciones terapéuticas y diagnósticas.

Assessment of myocardial damage by circulating cardiac myosin light chain I after heart transplantation.

The purpose of this study was to evaluate the cardiac damage by cardiac myosin light chain I after transplantation. This study included 30 patients who underwent cardiac operations and who were divided into three groups. These groups consisted of (1) control group, 15 valvular patients without coronary disease (no electrocardiography changes and creatine kinase MB isoenzyme of 100 micrograms/L or less); (2) infarction group, eight patients (six coronary bypass and two valvular patients with perioperative infarction pattern in the electrocardiography and creatine kinase MB isoenzyme of 100 micrograms/L or more; and (3) transplantation group, seven transplant patients (six heart and one heart-lung). The peak cardiac myosin light chain I value in the transplantation group (32.9 +/- 3.4 micrograms/L) was comparable to the infarction group (27.6 +/- 2.6 micrograms/L), and both of them were significantly higher than the control group (9.2 +/- 0.9 micrograms/L) (p < 0.01). Peak cardiac myosin light chain I levels in the control and transplantation groups correlated with the ischemic time (r = 0.48, p < 0.05 and r = 0.67, p < 0.05, respectively). The total dose of dopamine in the transplantation group correlated with the peak cardiac myosin light chain I (r = 0.67, p < 0.05), and with the cardiac myosin light chain I value on day 7 (r = 0.88, p < 0.01). This study suggests that circulating cardiac myosin light chain I estimations are useful to evaluate myocardial damage after transplantation during postoperative week 1.

Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study.

OBJECTIVE: To determine the effects of optimizing oxygen delivery (DO2) to "supranormal" levels on morbidity and mortality in patients with sepsis, septic shock, and adult respiratory distress syndrome. DESIGN: A prospective, randomized, controlled trial. SETTING: A 16-bed surgical intensive care unit (ICU) and 14-bed mixed medical/surgical ICU in two separate hospitals in the University of Hawaii Surgical and Internal Medicine Residency programs. PATIENTS: During a 1-yr period, 67 patients who had pulmonary artery catheters and who met the criteria for sepsis or septic shock, adult respiratory distress syndrome, or hypovolemic shock were enrolled in the study. Patients admitted to the ICU who were < 18 yrs old, or with a do-not-resuscitate order, or those patients who faced imminent death (< 24 hrs), such as those patients with uncontrollable hemorrhage or brain death, were excluded from the study. INTERVENTIONS: Patients were randomized into treatment and control groups. The treatment group was assigned a therapeutic DO2 indexed (DO2I) goal of > 600 mL/min/m2. Interventions to attain this goal included fluid boluses, administration of blood products, and the use of inotropes. The control group was not assigned to a specific therapeutic goal other than "normal" values of DO2I of 450 to 550 mL/min/m2. Every attempt was made to reach the therapeutic goals within the first 24 hrs after entry into the study. Hemodynamic measurements were obtained on study patients every 4 hrs until the end of the study. The severity of illness was evaluated using the Therapeutic Intervention Scoring System, and the Acute Physiology and Chronic Health Evaluation II scoring system. MEASUREMENTS AND MAIN RESULTS: There were 32 patients in the control group and 35 patients in the treatment group. The groups were similar in age, sex, number of organ dysfunctions, Acute Physiology and Chronic Health Evaluation II and Therapeutic Intervention scores. There were no statistical differences between the two groups in mortality, development of organ failure, ICU days, and hospital days. Upon analysis, it became apparent that the patients comprised clinically distinct subgroups, including: a) a treatment group who achieved supranormal DO2I; b) a control group with normal DO2I; c) a treatment group who failed to reach target DO2I; d) a control group who self-generated to high DO2I values; and e) a small number of patients who could not even reach a normal DO2I of 450 mL/min/m2. These subgroups were found to be similar and matched. The mortality rate was significantly lower for patients in groups who reached supranormal values of DO2I whether treated or self-generated as compared with patients who reached normal DO2I values (14% vs. 56%, p = .01). CONCLUSIONS: Although there was no statistically significant difference in the control vs. treatment groups, subgroup analysis demonstrated a strong, significant difference between patients with supranormal values of oxygen transport vs. patients with normal levels of DO2. Supranormal values of DO2I, whether self-generated or as a result of treatment, resulted in a statistically significant decrease in mortality rate. This study adds to the weight of evidence that current standard of care of treating critically ill patients to normal DO2I should be reconsidered, and that maximizing to high DO2I might be a more appropriate therapeutic end-point.

Dopexamine hydrochloride in chronic congestive heart failure with improved cardiac performance without increased metabolic cost.

Dopexamine hydrochloride is a new intravenous, short-acting agent with agonist activity at beta 2-adrenergic and DA1-dopaminergic receptors. The effects of dopexamine hydrochloride infusion on systemic and coronary hemodynamics, myocardial metabolism and the neuroendocrine system were evaluated in 10 patients with chronic severe congestive heart failure at baseline, at rates of 1, 2, 4 and 6 micrograms/kg/min at 15-minute intervals, and after a 1-hour infusion of the "optimal" dose. Right atrial pressure was reduced by 25% (p less than 0.01), pulmonary capillary wedge pressure by 26% (p less than 0.05), systemic vascular resistance by 44% (p less than 0.001) and pulmonary vascular resistance by 34% (p less than 0.01) after the optimal dose. Heart rate increased by 17% (p less than 0.01), rate-pressure product by 17% (p less than 0.01) and stroke volume index by 31% (p less than 0.001). There was no change in mean arterial pressure, myocardial oxygen consumption, coronary sinus blood flow, myocardial oxygen extraction or norepinephrine balance. None of the patients demonstrated net myocardial lactate production. These findings suggest that dopexamine hydrochloride improves systemic hemodynamics and cardiac performance without adversely affecting myocardial energetics or norepinephrine balance. Thus, dopexamine hydrochloride may be a useful agent for the short-term treatment of congestive heart failure.