An Empirically Derived Pediatric Cardiac Inotrope Score Associated With Pediatric Heart Surgery.

We aimed to empirically derive an inotrope score to predict real-time outcomes using the doses of inotropes after pediatric cardiac surgery. The outcomes evaluated included in-hospital mortality, prolonged hospital length of stay, and composite poor outcome (mortality or prolonged hospital length of stay). The study population included patients <18 years of age undergoing heart operations (with or without cardiopulmonary bypass) of varying complexity. To create this novel pediatric cardiac inotrope score (PCIS), we collected the data on the highest doses of 4 commonly used inotropes (epinephrine, norepinephrine, dopamine, and milrinone) in the first 24 hours after heart operation. We employed a hierarchical framework by representing discrete probability models with continuous latent variables that depended on the dosage of drugs for a particular patient. We used Bayesian conditional probit regression to model the effects of the inotropes on the mean of the latent variables. We then used Markov chain Monte Carlo simulations for simulating posterior samples to create a score function for each of the study outcomes. The training dataset utilized 1030 patients to make the scientific model. An online calculator for the tool can be accessed at https://soipredictiontool.shinyapps.io/InotropeScoreApp. The newly proposed empiric PCIS demonstrated a high degree of discrimination for predicting study outcomes in children undergoing heart operations. The newly proposed empiric PCIS provides a novel measure to predict real-time outcomes using the doses of inotropes among children undergoing heart operations of varying complexity.

Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent.

The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) - a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules. Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool. DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter. Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies.

Stress-only Tc-99m myocardial perfusion imaging in an emergency department chest pain unit.

BACKGROUND: Stress-only myocardial perfusion imaging (MPI) saves time by eliminating rest imaging, which is important for emergency department (ED) throughput but has not been studied in an ED population. STUDY OBJECTIVE: To determine the prognosis of a normal stress-only MPI study compared to a normal rest-stress MPI and establish its effectiveness in an ED setting. METHODS: All patients evaluated in the ED over 6.5 years who underwent a stress-only technetium-99m gated MPI were compared to those who had a rest-stress study. All-cause mortality was determined using the Social Security Death Index. Survival was analyzed in patients with normal and abnormal MPI results. RESULTS: A total of 4145 studies (2340 stress-only, 1805 rest-stress) were performed. Patients' average age was 57.9 years, 38.5% were male, and most had an intermediate or low pretest risk of coronary artery disease (87.7%). Average follow-up was 35.9 ± 20.9 months. In patients with normal perfusion, at 1 year of follow-up there were 11 deaths in the stress-only group (0.5% 1-year mortality), and 13 deaths in the rest-stress cohort (1.1% 1-year mortality). At the end of follow-up, the stress-only group had a lower all-cause mortality (p < 0.0001) and similar risk adjusted all-cause mortality (p = 0.10) than the rest-stress cohort. Patients with abnormal perfusion demonstrated the expected differential prognosis based on total perfusion deficits in both groups. CONCLUSIONS: A normal stress-only MPI study has a benign 1-year prognosis similar to a rest-stress study when performed in the ED. The ability to triage patients more rapidly and reduce radiation exposure represents an attractive alternative for low-risk patients.

Detección y manejo de síntomas no motores en la enfermedad de Parkinson: impacto en su prevalencia / Detection and management of non-motor symptoms in Parkinson's disease: impact on their prevalence

Background: Non-motor symptoms are common among patients with Parkinson disease and include cognitive, psychiatric, sleep and autonomic dysfunctions. Aim: To determine if the detection of non-motor symptoms along with the appropriate referral to an specialist has an impact on their prevalence after one year follow-up. Material and Methods: We included 60 patients diagnosed with Parkinson´ s disease attending to the Movement Disorder Clinic. The presence of non-motor symptoms was determined by the non-motor symptom questionnaire (NMSQuest). Results: The mean NMSQuest scores at baseline and at one year follow up were 12.6 ± 6.2 and 9.9 ± 5.6, respectively (p < 0.01). The non-motor symptoms that showed a statistically significant differences in frequency between baseline and the final assessment, were constipation (p = 0.04), urinary urgency (p = 0.02), hallucinations (p = 0.04), dizziness (p = 0.02) and vivid dreams (p = 0.04). Conclusions: Intentional search for non-motor symptoms in patients with Parkinson´ s disease along with a multidisciplinary approach has an impact on their prevalence. The change in specific symptoms is probably related to adjustments in dopaminergic management.

[Detection and management of non-motor symptoms in Parkinson's disease: impact on their prevalence]. / Detección y manejo de síntomas no motores en la enfermedad de Parkinson: impacto en su prevalencia.

BACKGROUND: Non-motor symptoms are common among patients with Parkinson disease and include cognitive, psychiatric, sleep and autonomic dysfunctions. AIM: To determine if the detection of non-motor symptoms along with the appropriate referral to an specialist has an impact on their prevalence after one year follow-up. MATERIAL AND METHODS: We included 60 patients diagnosed with Parkinson's disease attending to the Movement Disorder Clinic. The presence of non-motor symptoms was determined by the non-motor symptom questionnaire (NMSQuest). RESULTS: The mean NMSQuest scores at baseline and at one year follow up were 12.6 ± 6.2 and 9.9 ± 5.6, respectively (p < 0.01). The non-motor symptoms that showed a statistically significant differences in frequency between baseline and the final assessment, were constipation (p = 0.04), urinary urgency (p = 0.02), hallucinations (p = 0.04), dizziness (p = 0.02) and vivid dreams (p = 0.04). CONCLUSIONS: Intentional search for non-motor symptoms in patients with Parkinson's disease along with a multidisciplinary approach has an impact on their prevalence. The change in specific symptoms is probably related to adjustments in dopaminergic management.

Home continuous positive inotropic infusion as a bridge to cardiac transplantation in patients with end-stage heart failure.

BACKGROUND: The clinical use of positive inotropic therapy at home in patients awaiting cardiac transplantation has not been reported since United Network for Organ Sharing (UNOS) regulations were changed to allow home infusions in Status 1B patients. METHODS: We observed 21 consecutive patients with UNOS 1B status during positive inotropic therapy at home. We used hemodynamic monitoring at the initiation of therapy to optimize dosing. We selected for home therapy patients with stable clinical status and improved functional capacity during inotropic treatment. Implantable cardioverter defibrillators were placed in all but 1 patient before discharge. RESULTS: Initial positive inotropic therapy included dobutamine in 12 patients (mean dose, 4.5 mcg/kg/min; range, 2.5-7.5 mcg/kg/min), milrinone in 8 patients (mean dose, 0.44 mcg/kg/min; range, 0.375-0.55 mcg/kg/min), and dopamine at a dose of 3 mcg/kg/min in 1 patient. Patients had improved functional capacity (New York Heart Association Class 3.7 +/- 0.1 to 2.4 +/- 0.2, p < 0.01), improved renal function (serum creatinine, 1.5 +/- 0.1 to 1.3 +/- 0.1, p < 0.01), improved resting hemodynamics, and decreased number of hospitalizations during positive inotropic infusion therapy when compared with pre-treatment baseline. Implantable cardioverter defibrillator discharges were infrequent (0.19 per 100 patient days of follow-up). Actuarial survival to transplantation at 6 and 12 months was 84%. CONCLUSIONS: Continuous positive inotropic therapy at home was safe and was associated with decreased health care costs in selected patients awaiting cardiac transplantation.

Positive inotropic drug infusions for patients with heart failure: current controversies and best practice.

Patients who experience severe symptoms of heart failure and repeated hospitalizations for exacerbations may benefit from positive inotropic drug infusion therapy such as dobutamine or milrinone. This article provides an overview of inotropic drug delivery in the home including current controversies and best practices to ensure safe home care policies and practice.

Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact.

BACKGROUND: The use of parenteral positive inotropic agents still remains a major component of therapy for patients with advanced decompensated congestive heart failure (CHF). However, no consensus guidelines have been developed for the appropriate selection of a first-line inotropic therapy. We sought to compare the clinical outcome and economic cost of dobutamine-based and milrinone-based therapy in patients with acute exacerbation of CHF. METHODS AND RESULTS: We retrospectively analyzed the outcome of 329 patients admitted to the heart failure unit with acute exacerbation of CHF. More patients were treated with dobutamine-based therapy (269/329, 81.7%) than with milrinone-based therapy (60/329, 18.3%). Both groups had similar baseline characteristics and similar hemodynamic profiles at baseline, with the exception of higher mean pulmonary arterial pressure in the milrinone group (47 mm Hg vs 42 mm Hg, P <.001). One hundred nine patients (40%) of the dobutamine group required parenteral nitroprusside for hemodynamic optimization compared with 11 patients (18%) in the milrinone group (P <.001). The use of parenteral nitroglycerin and dopamine was similar in both groups. There was no significant difference in the in-hospital mortality rate (dobutamine 7.8% vs milrinone 10%) or clinical outcome between the 2 groups. However, the average direct drug cost per patient was significantly reduced in the dobutamine group compared with the milrinone group ($45 +/- $10 vs $1855 +/- $350, P <.0001). CONCLUSION: Dobutamine-based therapy is an attractive approach for the treatment of decompensated advanced heart failure, achieving comparable clinical efficacy to milrinone with a significantly reduced economic cost.

Low-dose dopamine after kidney transplantation: assessment by Doppler ultrasound.

Low-dose dopamine (LDD) is commonly used after kidney transplantation as a renoprotective agent, although the benefits of dopamine (DA) in this setting are controversial. LDD increases renal blood flow, decreases resistive index (RI) and causes diuresis in normal kidneys. We hypothesised that the vasculature of a denervated renal transplant may not respond to DA in the same way as healthy native kidneys. In a prospective, controlled study, renal blood flow velocity and vascular resistance were measured by Doppler ultrasound in recent kidney transplants (n = 20) over a range of DA doses (0-5 microg/kg/min). Main renal artery velocity was lower in kidneys with acute renal dysfunction than in those with normal function (0.60 +/- 0.31 vs. 0.81 +/- 0.24, respectively, p < 0.05). There was no demonstrable haemodynamic effect of LDD on either RI or main renal artery velocity as measured by Doppler ultrasound. Interestingly, the only significant correlation with mean RI was trough cyclosporin A level (r = 0.57, p < 0.001). Technical or timing factors cannot be used to explain the absence of DA effect, with equivalent doses capable of producing vasodilatation and reduced RI in studies of normal kidneys. In summary, these findings contrast the DA response of healthy native kidneys and may explain studies showing no clinical benefit of LDD in the early post-transplant period. These data suggest an insensitivity of recently implanted kidneys to the vasodilatory effects of LDD, that other factors such as cyclosporin A vasoconstriction may also be important, and question the rationale for routine LDD after kidney transplantation.

HEMA/MMMA microcapsule implants in hemiparkinsonian rat brain: biocompatibility assessment using [3H]PK11195 as a marker for gliosis.

Microencapsulation of dopamine-secreting cells in biocompatible, semi-permeable polymer membranes has been proposed as an alternative strategy for dopamine replacement for Parkinson's disease. In order to assess the viability of this proposal, dopamine-secreting PC12 cells were immunoisolated via microencapsulation in a 75:25 2-hydroxyethyl methacrylate/methyl methacrylate (HEMA/MMA) copolymer. A submerged nozzle-liquid jet method was used to produce small diameter (400 microm) microcapsules, which were stereotaxically implanted in the denervated striatum of hemi-Parkinsonian rats. A 96% survival rate was associated with the implantation surgery and no deleterious side effects were apparent. Light microscopy revealed good biocompatibility between the HEMA/MMA copolymer and the host brain, as evidenced by the absence of gross tissue damage at the neuronal tissue/capsule interface. Autoradiographic analyses using [3H]PK11195 as marker for reactive astrocytes revealed a moderate inflammatory response, confined to the immediate vicinity of the injection tract. Quantitative analyses indicated that the local tissue response did not differ significantly between brains implanted with PC12-containing capsules and those implanted with vehicle-containing capsules. Taken together, these results support the biocompatibility of HEMA/MMA copolymer as well as the feasibility and safety of stereotaxic implantation of microcapsules.

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.

Correlation between measured energy expenditure and clinically obtained variables in trauma and sepsis patients.

BACKGROUND: Indirect calorimetry is the preferred method for determining caloric requirements of patients, but availability of the device is limited by high cost. A study was therefore conducted to determine whether clinically obtainable variables could be used to predict metabolic rate. METHODS: Patients with severe trauma or sepsis who required mechanical ventilation were measured by an open-circuit indirect calorimeter. Several clinical variables were obtained simultaneously. Measurements were repeated every 12 hours for up to 10 days. RESULTS: Twenty-six trauma and 30 sepsis patients were measured 423 times. Mean resting energy expenditure was 36 +/- 7 kcal/kg (trauma) vs 45 +/- 8 kcal/kg (sepsis) (p < .0001). The single strongest correlate with resting energy expenditure was minute ventilation (R2 = 0.61, p < .0001). Doses of dopamine, dobutamine, morphine, fentanyl, and neuromuscular blocking agents each correlated positively with resting energy expenditure. In the case of the inotropics and neuromuscular blockers, there was a probable covariance with severity of illness. A multiple regression equation was developed using minute ventilation, predicted basal energy expenditure, and the presence or absence of sepsis: resting energy expenditure = -11000 + minute ventilation (100) + basal energy expenditure (1.5) + dobutamine dose (40) + body temperature (250) + diagnosis of sepsis (300) (R2 = 0.77, p < .0001). CONCLUSION: Severe trauma and sepsis patients are hypermetabolic, but energy expenditure is predictable from clinical data. The regression equations probably apply only to severe trauma and sepsis. Other studies should be conducted to predict energy expenditure in other patient types.

The effects of dopamine infusion on the postoperative energy expenditure, metabolism, and catecholamine levels of patients after esophagectomy.

Although dopamine is one of the most widely used vasoactive agents, its postoperative thermogenic and metabolic effects have not been studied. In this study, the effects of low-dose dopamine, given at 5 microgram/kg/min, on resting energy expenditure (REE), metabolism, and plasma catecholamine levels were examined in eight postsurgical patients. Dopamine infusion increased REE from 1,839 +/- 171 kcal/day to 2,071 +/- 170 kcal/day, and it decreased to 1,867 +/- 141 kcal/day after cessation of the infusion. Dopamine also increased the plasma levels of glucagon from 109.4 +/- 8.7 pg/ml to 132.5 +/- 8.0 pg/ml, and it decreased to 102.9 +/- 11.1 pg/ml after cessation of the infusion. The plasma levels of dopamine before, during, and after the infusion were 116.1 +/- 18.3, 161.1 +/- 25.6 and 121.4 +/- 17.2 ng/ml, respectively. Insulin and glucose were affected by dopamine, but changes in their plasma levels did not parallel the dopamine levels. Epinephrine and norepinephrine were increased by the infusion of dopamine and continued to increase even after its cessation. The results of this study revealed that low-dose dopamine increased REE in postsurgical patients and that this might be associated with the concomitant increase in plasma glucagon.

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.

A novel, orally active dopamine prodrug TA-870. V. Natriuretic and positive inotropic effects in rats: an assessment after chronic administration.

We investigated the acute natriuretic and positive inotropic effects of the dopamine prodrug TA-870 in rats before and after repeated administration for 2 weeks. Single intraduodenal (i.d.) administration of TA-870 (10-250 mg/kg) to saline-loaded anesthetized rats produced a dose-dependent increase in urinary flow and sodium excretion. It also produced a decrease in renal vascular resistance and an increase in renal blood flow. In another series of normal anesthetized rats, TA-870 caused dose-dependent increases in cardiac contractility [left ventricular dP/dtmax (LV dP/dtmax)] at i.d. doses of 10-250 mg/kg. Although the heart rate was also increased, this effect was much smaller than the effect on LV dP/dtmax. SCH-23390 (0.3 mg/kg i.v.), a selective DA1 dopamine receptor antagonist, strongly inhibited the above diuretic, natriuretic, and renal vasodilatory effects of TA-870. The positive inotropic effect of TA-870 was not inhibited by SCH-23390, but the latter effect was inhibited by pretreatment with propranolol (0.5 mg/kg i.v.). After repeated oral administration of TA-870 to rats (250 mg/kg twice a day for greater than 2 weeks), there was no significant differences in the natriuretic and positive inotropic responses to TA-870 between the TA-870-pretreated and control groups indicating a lack of pharmacological tolerance. In conclusion, TA-870, when administered enterally to rats, produced the natriuretic effect via the DA1 dopamine receptor and positive inotropic effects via the beta 1 adrenergic receptor stimulation, and these effects were not attenuated by chronic treatment with TA-870.

Extension of donor criteria in cardiac transplantation: surgical risk versus supply-side economics.

To combat the continuing shortage of ideal donor hearts, we have used cardiac allografts from high-risk donors for critically ill recipients. We defined high-risk donor variables as age greater than 40 years, systemic (noncardiac) infection, cardiopulmonary resuscitation greater than 3 minutes, ischemic time longer than 5 hours, weight more than 20% less than that of the recipient, and requirements for high doses of inotropes. Of the 305 donors we have used, 73 (23.9%) have been high-risk, with 59/73 (80.8%) exhibiting one variable, 12/73 (16.4%) exhibiting two variables, and 2/73 (2.7%) exhibiting three variables. No correlation was found between the number of donor variables and a poor postoperative result. No infectious complications occurred in 17 patients receiving hearts from potentially infected donors. Hospital mortality rates (30 day) for recipients of high-risk donor versus non-high-risk donor hearts were 8.2% and 6.9%, respectively (not significant). The 1-, 6-, and 12-month actuarial survival rates were 91.7%, 81.2%, and 75.9% for the high-risk donor group and 93.5%, 80.3%, and 77.8% for the non-high-risk donor group (not significant). Among survivors with high-risk donor hearts, mean left ventricular ejection fractions were 0.54 +/- 0.08 at 3 months, 0.55 +/- 0.08 at 1 year, and 0.54 +/- 0.09 at 2 years after transplantation. These results suggest that accepting less than ideal donor hearts can be safe and might be considered when better options are not available.

[Assessment of the cardiac output by impedance cardiography (differential rheography) to give optimum continuous positive pressure ventilation (author's transl)]. / Beurteilung des Herzzeitvolumens durch Impedanzmessung (Differentialrheographie) zur Optimierung der kontinuierlichen Uberdruckbeatmung (CPPV).

It is very important to know the cardiac output in artificial positive pressure ventilation for the determination of the exact dosage of dopamine and the endexpiratory pressure. Invasive monitoring of the cardiac output is not suitable for routine bedside use. In our study we looked into the question of whether the dosage of dopamine in continuous positive pressure ventilation could be controlled by impedance determination. Differential rheography, as described by Kaindl, Polzer, and Schuhfried, was used in the study. Relative changes in cardiac output after dopamine administration are shown with sufficient accuracy using the above-mentioned method.