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.

Interest of low-dose hydrocortisone therapy during brain-dead organ donor resuscitation: the CORTICOME study.

INTRODUCTION: Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial. METHODS: In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102). RESULTS: Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 - 9.49). CONCLUSIONS: Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.

Advancing the science of organ donor management.

There is an increasing burden of responsibility for intensivists to optimize donation potential after the declaration of brain death in patients with catastrophic brain injury. Best practice for donor management, if present, has been formed on low quality and mainly observational studies or consensus. In particular, research into the use of corticosteroids has shown varied benefit. The specific and limited results of the CORTICOME study are less important than the systematic methodology and the development of rigour in the study of deceased organ donation. Donor management would benefit from continued systematic analysis of current literature, understanding of the physiologic basis for therapy, and further prospective controlled trials. Worldwide collaboration partnerships and funding are needed to optimize the management of deceased organ donation.

A prospective, randomized, double-blind comparison of 2% mepivacaine with 1 : 20,000 levonordefrin versus 2% lidocaine with 1 : 100,000 epinephrine for maxillary infiltrations.

The purpose of this prospective, randomized, double-blind crossover study was to compare the anesthetic efficacy of 2% mepivacaine with 1 : 20,000 levonordefrin versus 2% lidocaine with 1 : 100,000 epinephrine in maxillary central incisors and first molars. Sixty subjects randomly received, in a double-blind manner, maxillary central incisor and first molar infiltrations of 1.8 mL of 2% mepivacaine with 1 : 20,000 levonordefrin and 1.8 mL of 2% lidocaine with 1 : 100,000 epinephrine at 2 separate appointments spaced at least 1 week apart. The teeth were electric pulp tested in 2-minute cycles for a total of 60 minutes. Anesthetic success (obtaining 2 consecutive 80 readings with the electric pulp tester within 10 minutes) was not significantly different between 2% mepivacaine with 1 : 20,000 levonordefrin and 2% lidocaine with 1 : 100,000 epinephrine for the central incisor and first molar. However, neither anesthetic agent provided an hour of pulpal anesthesia.

Involvement of central alpha1-adrenoceptors on renal responses to central moxonidine and alpha-methylnoradrenaline.

Moxonidine (alpha2-adrenoceptor/imidazoline receptor agonist) injected into the lateral ventricle induces diuresis, natriuresis and renal vasodilation. Moxonidine-induced diuresis and natriuresis depend on central imidazoline receptors, while central alpha1-adrenoceptors are involved in renal vasodilation. However, the involvement of central alpha1-adrenoceptors on diuresis and natriuresis to central moxonidine was not investigated yet. In the present study, the effects of moxonidine, alpha-methylnoradrenaline (alpha2-adrenoceptor agonist) or phenylephrine (alpha1-adrenoceptor agonist) alone or combined with previous injections of prazosin (alpha1-adrenoceptor antagonist), yohimbine or RX 821002 (alpha2-adrenoceptor antagonists) intracerebroventricularly (i.c.v.) on urinary sodium, potassium and volume were investigated. Male Holtzman rats (n = 5-18/group) with stainless steel cannula implanted into the lateral ventricle and submitted to gastric water load (10% of body weight) were used. Injections of moxonidine (20 nmol) or alpha-methylnoradrenaline (80 nmol) i.c.v. induced natriuresis (196 +/- 25 and 171 +/- 30, respectively, vs. vehicle: 101 +/- 9 microEq/2 h) and diuresis (9.0 +/- 0.4 and 12.3 +/- 1.6, respectively, vs. vehicle: 5.2 +/- 0.5 ml/2 h). Pre-treatment with prazosin (320 nmol) i.c.v. abolished the natriuresis (23 +/- 4 and 76 +/- 11 microEq/2 h, respectively) and diuresis (5 +/- 1 and 7.6 +/- 0.8 ml/2 h, respectively) produced by i.c.v. moxonidine or alpha-methylnoradrenaline. RX 821002 (320 nmol) i.c.v. abolished the natriuretic effect of alpha-methylnoradrenaline, however, yohimbine (320 nmol) did not change renal responses to moxonidine. Phenylephrine (80 nmol) i.c.v. induced natriuresis and kaliuresis that were blocked by prazosin. Therefore, the present data suggest that moxonidine and alpha-methylnoradrenaline acting on central imidazoline receptors and alpha2-adrenoceptors, respectively, activate central alpha1-adrenergic mechanisms to increase renal excretion.

Serum mepivacaine concentrations after intraoral injection in young children.

The authors measured plasma concentrations of mepivacaine in 36 children from the ages of 2 to 5 years who received dental care under light general anesthesia. The subjects were randomly assigned to receive either 2 percent mepivacaine hydrochloride with 1:20,000 levonordefrin or 3 percent mepivacaine hydrochloride without vasoconstrictor. The volume of anesthetic injected depended on the planned procedures for each patient. Blood samples (3 mL) were drawn from an intravenous line before and 5, 10, 20, 30, 45, and 60 minutes after mepivacaine injection. The serum was collected and analyzed by gas-liquid chromatography. Mean serum concentrations, normalized to a dose of 1 mg/kg body weight, reached a peak of 0.67 +/- 0.42 microgram/mL (mean +/- SD) after 3 percent mepivacaine and 0.63 +/- 0.21 microgram/mL after 2 percent mepivacaine with levonordefrin. Levonordefrin had no significant effect on the plasma concentrations. However, because of the higher concentration of mepivacaine in the 3 percent formulation, it was potentially 1.5 times as toxic (P < 0.002) on a volume basis. Statistical analysis also suggested that the maximum recommended dose of 3 mg/lb could result in potentially toxic blood concentrations in a small percentage of pediatric patients. The authors conclude that 3 percent mepivacaine should not be used when relatively large volumes of local anesthetic must be administered to small children and recommend that the maximum dose of mepivacaine not exceed 5 mg/kg.

Anesthetic efficacy and heart rate effects of the supplemental intraosseous injection of 2% mepivacaine with 1:20,000 levonordefrin.

OBJECTIVE: The purpose of this study was to determine the anesthetic efficacy and heart rate effects of a supplemental intraosseous injection of 2% mepivacaine with 1:20,000 levonordefrin. STUDY DESIGN: Through use of a repeated-measures design, 40 subjects randomly received 3 combinations of injections at 3 separate appointments. The combinations were as follows: inferior alveolar nerve (IAN) block (with 3% mepivacaine) + intraosseous injection of 1.8 mL of 2% mepivacaine with 1:20,000 levonordefrin; IAN block + intraosseous injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine (positive control); IAN block + mock intraosseous injection (negative control). Each first molar, second molar, and second premolar was blindly tested with a pulp tester at 2-minute cycles for 60 minutes after injection. Anesthesia was considered successful when 2 consecutive readings of 80 were obtained. Heart rate (pulse rate) was measured with a pulse oximeter. RESULTS: One hundred percent of the subjects had lip numbness with the IAN block + intraosseous mock technique and IAN block + intraosseous techniques. The anesthetic success rates for IAN block + mock intraosseous injection, IAN block + intraosseous lidocaine, and IAN block + intraosseous mepivacaine, respectively, were as follows: 80%, 100%, and 100% for the first molar; 90%, 100%, and 100% for the second molar; 77%, 97%, and 97% for the second premolar. For the first molar and second premolar, the differences were significant (P< .05) when the intraosseous mepivacaine and lidocaine techniques were compared with the IAN block + mock intraosseous injection. There were no significant differences between the intraosseous mepivacaine and lidocaine techniques. Eighty percent of the subjects had a mean increase in heart rate of 23-24 beats per minute with the intraosseous injection of the mepivacaine and lidocaine solutions; there were no significant differences between results with the 2 solutions. CONCLUSIONS: We concluded that intraosseous injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 2% mepivacaine with 1:20,000 levonordefrin, used to supplement an IAN block, significantly increased anesthetic success in first molars and second premolars. The 2 solutions were equivalent with regard to intraosseous anesthetic success rate, failure rate, and heart rate increase after IAN block.

alpha-2-Adrenergic activation of proopiomelanocortin-containing neurons in the arcuate nucleus causes opioid-mediated hypotension and bradycardia.

Treatment of rats for 4 days with alpha-methyldopa, 200 mg/kg/day i.p., increases steady state levels of proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus, as measured by DNA excess solution hybridization. The increase is prevented by parallel treatment with yohimbine, 2 mg/kg/day i.p., but not by naltrexone, 2 mg/kg/day i.p. Treatment with the peripheral vasodilator hydralazine, 2 mg/kg/day, does not affect POMC mRNA levels. In situ hybridization histochemistry with a cRNA probe for POMC indicates that POMC-containing cells are located within the confines of the arcuate nucleus both in control and in alpha-methyldopa-treated rats, and confirms the increase in POMC mRNA in the latter. Microinjection of 2 micrograms of alpha-methylnorepinephrine unilaterally into the arcuate nucleus of urethane-anesthetized rats causes hypotension and bradycardia, which can be inhibited by 200 ng of yohimbine microinjected into the same site, or by 100 ng l-naloxone microinjected into the ipsilateral nucleus tractus solitarii, but not into the arcuate nucleus. These findings are interpreted to indicate that activation of alpha 2-adrenergic receptors located on POMC-containing neurons in the arcuate nucleus causes beta-endorphin release and stimulation of opiate receptors in the NTS, which results in hypotension and bradycardia, and that this mechanism contributes to the hypotensive action of alpha-methyldopa.

Crucial role of the accumbens nucleus in the neurotransmitter interactions regulating motor control in mice.

Previous work, based on systemic drug administration, has shown that neurotransmitter interactions between dopaminergic, adrenergic, glutamatergic and cholinergic systems are involved in locomotor control in mice. In an attempt to identify the target sites in the brain of these interactions, we have started a series of experiments, where the drugs are administered intracerebrally in mice. The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA antagonist MK-801 were investigated by means of local application in the accumbens nucleus of monoamine-depleted and monoaminergically intact mice, respectively. The threshold dose of AP-5 was lower in depleted than in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomotor effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were registered in monamine-depleted mice after local application in the accumbens or entopeduncular nucleus (= medial pallidum). Both AP-5 and CNQX stimulated locomotor activity in the accumbens, but had no effects in the entopeduncular nucleus. We have previously shown synergistic interactions with regard to locomotor stimulation in monoamine-depleted mice, between an NMDA antagonist and an alpha 2-adrenoceptor agonist or a dopamine D1 agonist (all drugs given systemically). In the present study the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline was applied intracerebrally in combination with a subthreshold dose of MK-801 given intraperitoneally: Locomotor stimulation was produced after alpha-methyl-noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or thalamus. Likewise, local application of the D1 agonist SKF 38393, in combination with a subthreshold dose of MK-801 given intraperitoneally, point to an important role of the accumbens nucleus in motor control. Previous experiments based on systemic drug administration have also shown a synergistic interaction between a muscarine antagonist and an alpha 2-adrenoceptor agonist in monoamine-depleted mice. Local application of the muscarine antagonist methscopolamine, in combination with the alpha 2-adrenoceptor agonist clonidine given intraperitoneally, showed that the striatum, in this case both the ventral and dorsal parts of the striatum, is an important target for the muscarine antagonist. Unilateral injection of AP-5 into the accumbens nucleus of mice induces rotational behaviour: Previous findings have shown that the rotation is ipsilateral in monoaminergically intact animals, whereas monoamine-depleted animals rotate contralaterally. In addition, these findings have shown that dopamine D2 receptor stimulation seems to determine whether AP-5 will induce ipsilateral or contralateral rotation. In the present study we report further evidence for a crucial role of the D2 receptor in this respect. Finally, the rotational effects of AP-5 injected into the dorsal striatum or hippocampus were investigated: As after AP-5 application into the accumbens nucleus, monoaminergically intact mice rotated ipsilaterally, whereas monoamine-depleted animals rotated contralaterally, following AP-5 application in the dorsal striatum or the hippocampus. The present data show that the accumbens nucleus has an important role in motor control. Both glutamatergic, muscarine cholinergic, dopaminergic and alpha-adrenergic systems are involved in the control of motor functions in the accumbens nucleus.

Pulpal anesthesia efficacy of four lidocaine solutions injected with an intraligamentary syringe.

Four lidocaine solutions that differed in concentration or vasoconstrictor composition were compared for efficacy of pulpal anesthesia. These drugs were injected in a double-blind manner with the use of an intraligamentary syringe to the periodontal ligament of maxillary lateral incisors. These teeth were subjected to electric pulp test stimulation that yielded absolute sensation threshold values. It was found that there was no dose response relationship between the local anesthetic concentration and the efficacy of pulpal anesthesia. Lidocaine 2% with vasopressin 25 IU% and noradrenaline bitartrate produced a noticeably shorter duration of pulpal anesthesia in comparison with the other three drugs. The results indicated that the nature of vasoconstrictors when added to the local anesthetic can affect the efficacy of pulpal anesthesia using the intraligamentary model.

Alpha 2-adrenoceptor-mediated inhibition of bulbospinal barosensitive cells of rat rostral medulla.

Bulbospinal barosensitive neurons of the rostral ventrolateral medulla (RVLM cells; presumed sympathetic vasomotor premotor neurons) were recorded with iontophoretic electrodes in urethan-anesthetized rats. The majority of these cells were insensitive to intravenous clonidine (Clo; up to 20 micrograms/kg) and insensitive to iontophoretically applied Clo or alpha-methylnorepinephrine (alpha-MNE). These cells (n = 47 of 76) had a spinal conduction velocity of 4.1 +/- 0.2 m/s and a mean firing rate of 20 +/- 1 spikes/s. A second population (n = 29) was powerfully inhibited by intravenous Clo (5-10 micrograms/kg, activity decreased by 83 +/- 11%), iontophoretically applied Clo (decreased by 51 +/- 7%), and iontophoresis of alpha-MNE (decreased by 69 +/- 3%). These cells had a slower conduction velocity (2.0 +/- 0.3 m/s) and a much slower discharge rate (6 +/- 1 spikes/s). Both populations were pulse synchronous at resting arterial pressure. The inhibitory effects produced by iontophoresis of alpha-MNE or Clo were reduced to the same degree (86-98%) by iontophoresis of idazoxan (an alpha 2-adrenergic antagonist with imidazoline structure) and by iontophoresis of piperoxan (65-77%, a nonimidazoline alpha 2-antagonist). The inhibition of RVLM cells by intravenous Clo was reversed by iontophoresis of idazoxan and by intravenous injection of yohimbine (nonimidazoline alpha 2-antagonists). These data suggest that 1) intravenous Clo only inhibits a subpopulation of RVLM sympathetic premotoneurons, possibly the C1 adrenergic cells, 2) this effect of Clo is due to activation of alpha 2-adrenergic receptors rather than nonadrenergic imidazoline binding sites, and 3) these alpha 2-receptors are located on or close to the Clo-sensitive cells and may be continuously activated by endogenously released catecholamines.

Vasoconstrictive agents commonly used in combination with local anesthetics: a literature review.

A review of the current medical literature concerning the use of various vasoconstrictive agents with local anesthetics is presented. These agents are employed in podiatry primarily for the purpose of prolonging the duration of anesthesia and surgical hemostasis. Epinephrine, phenylephrine, levonordefrin, felypressin, and norepinephrine have all been utilized in conjunction with the local anesthetics by the various medical professions. Although controversy surrounds the use of these agents, this article should assist the podiatric physician in making an informed decision.

Hypotensive response in spontaneously hypertensive rats following microinjection of alpha-methylnoradrenaline in the caudal brain-stem.

Local microinjection of 1.25 nmol (-)-alpha-methylnoradrenaline in the A2-region of the nucleus tractus solitarii (NTS) caused a decrease of blood pressure and heart rate in both spontaneous hypertensive rats (SHR) and Wistar-Kyoto (W/K) rats. Although the maximal responses in both strains did not differ, the decrease in blood pressure lasted longer in the SHR. These results do not support the concept of a diminished sensitivity of catecholaminergic receptors in the NTS of SHR to alpha-methylnoradrenaline.

Indoleamine accumulating neurons in the retina of chicken and pigeon. A comparison with the dopaminergic neurons.

Recently a special group of indoleamine accumulating neurons has been described in the retina of some mammals and goldfish. These neurons are characterized by their ability to accumulate indoleamines, whereby they become visible in the fluorescence microscope. They do not show any spontaneuos fluorescence. The indoleamine accumulating neurons are in this study shown to be present in the retina of chicken and pigeon. Their cell bodies differ from the earlier described cell bodies of the same type in other species in being larger and bottle shaped instead of round or oval, and in being situated further cutwards in the inner nuclear layer. Their terminals ramify in three sublayers in the inner plexiform layer. No indoleamine containing neurons could, however, be seen to fluoresce in normal retina of chick embryos, newborn chicken, older chicken or pigeons.

Hemodynamic effects of systemic and central administration of alpha-methyldopa.

Systemic and regional hemodynamic changes were measured in five restained conscious rhesus monkeys before and after a 2-hour intravenous infusion of 50 mg/kg of alpha-methyldopa and, in another group of five monkeys, 5 to 10 mg injected into a lateral cerebral ventricle. Both routes of administration evoked similar degrees of hypotension, bradycardia and decreased cardiac output, although the cerebral intraventricular (i.c.v.) injections had more immediate and long-lasting effects. Both groups had a similar pattern of changes in the redistribution of cardiac output and blood flow that lasted at least 4 hours. Blood flow was maintained in the hepatic and renal arteries and decreased in skeletal muscle, heart, brain and skin. In contrast, i.c.v. injections of alpha-methyldopamine and alpha-methylnorepinephrine given at the same site evoked dose-related pressor responses that lasted up to 4 hours. The data suggest that alpha-methyldopa has important central action that inhibits sympathetic outflow, but that its hypotensive effect is either mediated only by endogenously formed metabolites or that its mechanism of action is not directly related to these metabolites at sites around the lateral and third cerebral ventricles in the monkey.

Role of central and peripheral mechanisms in the action of alpha-methyldopa on blood pressure and renin secretion.

The mechanism by which alpha-methyldopa lowers arterial pressure and suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were prevented by adjusting a suprarenal aortic clamp. After intravenous alpha-methyldopa (100 mg/kg) mean arterial pressure (MAP) decreased form 127+/-3 to a mean minimum of 107+/-4 mm Hg (P less than .01) and plasma renin activity (PRA) decreased from 20.6+/-4.8 to 10.9+/-1.7 ng/ml/3 hr (P less than .05). Blockade of peripheral dopa decarboxylase with intravenous carbidopa (20 mg/kg) significantly attenuated the hypotensive action of intravenous alpha-methyldopa but MAP still decreased from 145+/-6 to 130+/-5 mm Hg(P less than .001). Intravenous carbidopa completely abolished the fall in PRA produced by intravenous alpha-methyldopa (16.8+/-2.8 to 16.9+/-2.1 ng/ml/3 hr.) Intraventricular carbidopa (3 microng/kg/min) did not block the hypotensive (135+/-8 to 113+/-7 mm Hg, P less than .01) or renin-lowering effect (24.3+/-5 to 13.4+/-3.2 ng/ml/3 hr, P less than .01) of intravenous alpha-methyldopa (0.5 mg/kg decreased MAP from 118 +/- 5 to 104 +/- 5 mm Hg (P less than 0.001) but had no effect on PRA (23.4+/-6 TO 19.4+/-7 NG/ML/3 hr.) Intraventricular alpha-methylnorepinephrine (2 microng/kg) also decreased MAP from 127+/-5 to 112+/-3mm Hg (P less than .006) but again failed to significantly alter PRA (36.1+/-11.8 to 37.2+/-15 ng/ml/3 hr). These results indicate that there is both a central and peripheral component to the antihypertensive effect of alpha-methyldopa in the dog and that the suppression of renin secretion results from a peripheral action of the drug.

Centrally induced hypotension and bradycardia after administration of alpha-methylnoradrenaline into the area of the nucleus tractus solitarii of the rat.

1 In anaesthetized rats, bilateral injections of alpha-methylnoradrenaline, noradrenaline or adrenaline into the area of the nucleus tractus solitarii (NTS) of the brain stem caused dose-dependent decreases of systemic arterial blood pressure and heart rate. The effects of alpha-methylnoradrenaline were most pronounced and lasted longest. 2 The cardiovascular effects of alpha-methylnoradrenaline appeared to be restricted to the medio-caudal part of the NTS. 3 Prior administration of the alpha-adrenoceptor blocking agent, phentolamine, reversed the fall in blood pressure and heart rate induced by alpha-methylnoradrenaline into an increase. 4 Systemic administration of atropine combined with vagotomy potentiated the inhibitory effects of alpha-methylnoradrenaline on the cardiovascular system.