Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse.

OBJECTIVE: To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses with an average age of 7.6 ± 6.5 years. METHODS: Four treatment groups were studied: 1) 0.04 mg kg(-1) detomidine SL; 2) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.075 mg kg(-1) yohimbine intravenously (IV); 3) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 4 mg kg(-1) tolazoline IV; and 4) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.12 mg kg(-1) atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored. RESULTS: Chin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume. CONCLUSIONS AND CLINICAL RELEVANCE: At the doses administered in this study, the alpha2 -adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete.

Tolazoline-induced apnea in mule deer (Odocoileus hemionus).

Eighteen mule deer (Odocoileus hemionus) and six Columbia black-tailed deer (Odocoileus hemionus columbianus) were held in pens and repeatedly anesthetized from April 2004 through June 2005 as part of an external parasite study. Deer were anesthetized using a combination of Telazol and xylazine hydrochloride (HCL) administered intramuscularly. Tolazoline HCL was slowly administered at 4 mg/kg intravenously to reverse the effects of xylazine with good results. For 17 of the 19 mule deer anesthesias in the fall of 2004, a mean dose of 7.3 mg/kg of intravenous tolazoline (range 6.1-8.4 mg/kg) was given by mistake. This paper describes clinical signs of apnea, muscle tensing, and fasciculations immediately following intravenous administration of tolazoline HCL in mule deer (O. hemionus) at 1.5-3 times the recommended dose. Mean dose for black-tailed deer during this time was 8.1 mg/kg (range 5.5-12.4 mg/kg) with no clinical signs as seen in the mule deer. Based on these findings, intravenous tolazoline use in mule deer is recommended at < or = 4 mg/kg.

A novel approach for percutaneous treatment of massive nonocclusive mesenteric ischemia: tolazoline and glycerol trinitrate as effective local vasodilators.

Nonocclusive mesenteric ischemia (NOMI) generally affects patients with low cardiac output, resulting in splanchnic hypoperfusion. It includes all forms of mesenteric ischemia without vessel occlusion and makes up between 20 and 30% of all cases of acute mesenteric ischemia. We present the case of a 84-year-old man with a history of total atrioventricular block developing NOMI. This was diagnosed by percutaneous selective catheter arteriography (PSCA), which demonstrated remarkable abrupt termination of the jejunal vasculature and multiple severe spasms of the colonic arteries. Control PSCA after local intraarterial vasodilator therapy (LIVT) with tolazoline and glycerol trinitrate documented an excellent therapeutic result with a completely unremarkable vasculature. Although LIVT was complicated by severe cardiovascular complications inclusive of cardiac arrest with the need of cardiopulmonary resuscitation, the patient fully recovered and was discharged after implantation of a cardiac pacemaker in good clinical condition 7 days later.

Tissue Residue Levels after Immobilization of Rocky Mountain Elk ( Cervus elaphus nelsoni) using a Combination of Nalbuphine, Medetomidine, and Azaperone Antagonized with Naltrexone, Atipamezole, and Tolazoline.

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

Oliguria and tolazoline pharmacokinetics in the newborn.

Tolazoline treatment of neonates has been reported since 1965. Dosages increased from pulse doses of 1 to 2 mg/kg to continuous infusions of 10 mg/kg X h before neonatal plasma tolazoline concentrations were measured. We developed a microassay for tolazoline and determined neonatal distribution volume, 1.61 +/- 0.21 L/kg, and disposition rate constant (beta), 0.0027 +/- 0.005 min-1 (mean +/- SEM). Half-life (gamma) ranged from 1.47 to 41.25 (median = 4.43) hours and correlated inversely with urine output (x); y (h) = -0.46 + 7.63/x (mL/kg X h), r = .61, P less than .05. The highest plasma tolazoline concentration in a neonate was 20.3 mg/L. Lethal tolazoline concentrations in lambs ranged from 21.8 to 56.8 mg/L. Initial tolazoline concentrations during infusions and after 1- to 2-mg/kg pulse doses ranged from 0.35 to 2.3 mg/L and PaO2 increased greater than or equal to 15 mm Hg in 64% of 14 treatments. The average neonatal pharmacokinetics predict that each 1 mg of tolazoline HCl per kilogram pulse dose will increase the plasma concentration of tolazoline base by 0.5 mg/L. The plasma concentration should remain constant with infusion dose increments of 0.16 mg of tolazoline HCl per kilogram per hour for every 1.0-mg/kg loading dose. Tolazoline dose requirements for specific patients will vary, especially with renal dysfunction. Reduced tolazoline doses were used to treat two patients, concentrations remained constant, and PaO2 was maintained. Tolazoline doses derived from neonatal kinetics are less than current infusion doses and may avoid high concentrations.

Endotracheal administration of tolazoline in hypoxia-induced pulmonary hypertension.

STUDY OBJECTIVE: To compare the pulmonary and systemic vascular responses to intravenously (IV) and endotracheally (ET) administered tolazoline (Tz) in newborn lambs with hypoxia-induced pulmonary hypertension. DESIGN: Randomized, controlled study design. METHODS: Twenty lambs, 2 to 7 days of age, were anesthetized, intubated, and surgically catheterized for continuous physiologic monitoring and cardiac output measurements using radiolabeled microspheres. After a postoperative stabilization period, the lambs were ventilated with a hypoxic gas mixture which was titrated to increase mean pulmonary artery pressure (MPAP) 30% to 50% above baseline. Each animal was randomly assigned to receive either IV-Tz (2 mg/kg), ET-Tz (4 mg/kg), or ET-saline (Sal, control group). RESULTS: ET-Tz significantly (P < .05) reduced MPAP, PVRI (pulmonary vascular resistance index), MPAP/mean artery pressure (MAP) and PVRI/systemic vascular resistance index (SVRI), but not SVRI. IV-Tz lowered (P < .05) MPAP, PVRI, and PVRI/SVRI but also produced significant reductions in MAP and SVRI while only transiently decreasing MPAP/MAP: MPAP/MAP and PVRI/SVRI ratios were consistently lower in the ET-Tz animals than either the IV-Tz or ET-Sal animals. CONCLUSIONS: Our results suggest that ET-Tz produced a more selective pulmonary vascular response than IV-Tz and may warrant further investigation for potential clinical applications.

Pulmonary administration of vasoactive substances by perfluorochemical ventilation.

OBJECTIVES: Therapeutic management of respiratory distress syndrome, pneumonia, and pulmonary hypertension includes delivery of biologically active agents to the neonatal lung. However, mechanical abnormalities of the lung, intrapulmonary shunting, ventilation-perfusion mismatching, and elevated surface tension impede effective systemic or intratracheal delivery of agents to the lung during conventional gas ventilation. The objective of this study was to test the hypothesis that perfluorochemical (PFC) liquid ventilation can be used for pulmonary administration of vasoactive drugs (PAD) and to compare these responses to those elicited with intravascular (IV) administration during tidal liquid ventilation. METHODS: Cardiovascular responses of 16 preterm and neonatal lambs to randomized doses of acetylcholine, epinephrine, and priscoline were studied. Physiologic gas exchanged and acid-base balance were maintained using previously described tidal liquid ventilation techniques. In subgroups of animals, the distribution pattern of carbon 1- and choline 14-labeled dipalmitoylphosphatidylcholine (14C-DPPC) in saline and the responses to priscoline after hypoxia-induced pulmonary hypertension and hypoxemia administered during liquid ventilation were studied. RESULTS: Dose-response curves for PAD and IV administration demonstrated progressive, dose-dependent, cholinergic responses to acetylcholine (decreased mean systemic arterial pressure [MAP] and heart rate), sympathomimetic responses to epinephrine (increased MAP and heart rate), and alpha-adrenergic blockade responses to priscoline (decreased MAP and mean pulmonary arterial pressure). Compared with IV administration, PAD of priscoline resulted in a significantly greater decrease in pulmonary relative to systemic arterial pressure; this response was potentiated by hypoxia, reduced pulmonary pressures to near normal values, and improved oxygenation. The 14C-DPPC in saline was distributed relatively homogeneously throughout the lung by PAD, with 80% of the lung pieces receiving amounts of 14C-DPPC with +/-20% of the mean value. CONCLUSIONS: This study demonstrates that vasoactive agents can be delivered to the lung directly by PAD during PFC liquid ventilation. The inherent advantages of this method relate to the physical properties of PFC liquid ventilation as a vehicle (respiratory gas solubility, low surface tension-enhancing distribution, and inertness precluding interaction) and physiological properties of the lung as an exchanger.

Pulmonary artery catheter placement with two-dimensional echocardiographic guidance: a technique applicable in critically ill neonates.

In nine critically ill neonates with persistent fetal circulation, femoral venous catheters were inserted at the bedside to initiate treatment and provide venous access. After femoral vein puncture or cutdown, a 5-F sheath was placed in the inferior vena cava through the femoral vein. With use of two-dimensional echocardiographic guidance, a 5-F balloon angiographic catheter was advanced through the inferior vena cava into the right atrium and subsequently manipulated through the tricuspid valve and into the main pulmonary artery. No major complications were attributable to the procedure. When performed by a pediatric cardiologist, this technique is as safe as umbilical catheter placement.

Use of tolazoline in newborn infants with diaphragmatic hernia and severe cardiopulmonary disease. A preliminary report.

Two newborn infants with congenital diaphragmatic hernia, one of whom died, had significant improvement in arterial oxygen tension (Pao2) after intravenous administration of tolazoline (Priscoline) (1 to 2 mg. per kilogram). In both infants, systemic hypotension developed within minutes of administration of the drug and required pharmacologic and hemodynamic intervention. The response to tolazoline was more dramatic in the infant who survived, and his oxygen requirements were significantly reduced after the use of this drug. The infant who died also had a significant response to tolazoline. Tolazoline appears to be an important pharmacologic agent for use in the postoperative care of infants with diaphragmatic hernia and associated hypoxemia and acidosis.

Treatment of experimental frostbite with intra-arterial sympathetic blocking drugs.

A number of experimental and clinical studies have shown that early regional surgical sympathectomy decreases tissue loss following frostbite, presumably by relieving vasospasm and increasing blood flow. This study was performed to determine if a decrease in tissue loss following a standard cold injury could be obtained following a regional "medical sympathectomy" achieved by the intra-arterial administration of sympathetic blocking drugs. A standard cold injury was produced in rabbits and the animals were divided into nine treatment groups. Various treatment modalities were evaluated, including rapid rewarming, intra-arterial reserpine and tolazoline, and intravenous low molecular weight dextran. In the slowly rewarmed animals, the usual clinic situation, the regional intra-arterial administration of reserpine and tolazoline significantly reduced tissue loss, equalling the results obtained in the rapidly rewarmed group. These results indicate that the early achievement of a regional "medical sympathectomy" may be of benefit in reducing tissue loss following frostbite in patients, especially in those in whom rapid rewarming cannot be performed.

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats.

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 mug), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 mug), but induced marked behavioural changes. Central pretreatment with mepyramine (200 mug, i.c.v.) or procaine (600 mug i.c.v.), reduced the hypotension evoked by clonidine (25 mug), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 mug, i.c.v.) or tolazoline (200 mug, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.

The role of alpha-adrenergic mechanisms within the area postrema in dopamine-induced emesis.

Intracerebroventricular injection of dopamine (0.5-4.0 mg) produced dose-dependent and short-lasting emesis (1-8 min) in cats, which was abolished after ablation of the area postrema. Relatively selective alpha 2-adrenoceptor antagonists (yohimbine and idazoxan) and a mixed alpha 1- and alpha 2-adrenoceptor antagonist (tolazoline), but not a non-selective alpha 1-adrenoceptor antagonist (prazosin), injected intracerebroventricularly inhibited the emesis induced by intracerebroventricular dopamine. However, dopamine receptor antagonists (chlorpromazine, droperidol, spiperone, domperidone, triflupromazine, sulpiride and metoclopramide), an antimuscarinic drug (atropine), a ganglionic blocking agent (mecamylamine), an opioid receptor antagonist (naloxone) and a 5-HT receptor antagonist (methysergide), all injected intracerebroventricularly, had no significant effect on emesis evoked by intracerebroventricular dopamine. The emetic response to intracerebroventricular dopamine was attenuated in cats pretreated with intracerebroventricular reserpine, 6-hydroxydopamine, alpha-methyl-p-tyrosine and hemicholinium-3. It is postulated that dopamine-induced emesis is mediated through the release of noradrenaline acting at alpha 2-adrenoceptors and that it depends on the integrity of monoaminergic and possibly cholinergic structures within the area postrema. It appears, therefore, that the emetic effect of intracerebroventricular dopamine is mediated by adrenergic rather than dopaminergic mechanisms in the area postrema, at least in the cat.

Effects of yohimbine and tolazoline on isoproterenol and angiotensin II-induced water intake in rats.

Subcutaneous administration of the alpha 2-adrenoreceptor antagonists, yohimbine and tolazoline, at doses up to 1000 micrograms/kg, had no effect on water intake of female rats. However, when these compounds were administered SC in combination with either the beta-adrenoreceptor agonist, isoproterenol (10 to 25 micrograms/kg, SC), or with angiotensin II (200 micrograms/kg, SC), water intake was enhanced. In contrast, intraventricular administration of either tolazoline (10 and 20 micrograms/kg) or yohimbine (300 micrograms/kg) failed to augment the dipsogenic response to angiotensin II (150 micrograms/kg, SC). Thus, the enhancing effect of these alpha 2-adrenoreceptor antagonists on isoproterenol- and angiotensin II-induced water intakes appears to be manifested peripherally, rather than centrally. In view of the fact that clonidine, an alpha 2-adrenoreceptor agonist, has been shown to inhibit water intake induced by both isoproterenol and angiotensin II, the results suggest that the alpha 2-adrenoreceptor may play a role in modulating water intake induced by these two dipsogenic agents.

Devastating distal arterial trauma and continuous intraarterial infusion of tolazoline.

Trauma due to motor vehicles accident and urban violence have made distal arterial reconstruction an increasingly important part of the surgeon's work. During the 20 month period from October 1980 to May 1982, 13 patients with below the knee and 2 patients with forearm trauma had nonviable extremities despite fastidious vascular and orthopedic reconstruction. A continuous intraarterial infusion of tolazoline into the femoral or brachial arteries restored vascular perfusion and viability in 13 of 15 patients (87 percent), with eventual limb salvage in 67 percent. Seven of 15 patients (47 percent) had transient systemic hypertension. There was no mortality. There exists in patients with these catastrophic injuries a local low-flow state due to a combination of distal arterial spasm and venous outflow obstruction. Tolazoline, a peripheral alpha-adrenergic blocking agent, increases blood flow, albeit nonnutritionally, and thus theoretically prevents thrombosis due to stasis in the repaired distal vessel. When limb loss seems inevitable, a trial of intraarterial tolazoline is justified.

Stability of dopamine hydrochloride injection in the presence of dobutamine hydrochloride, tolazoline hydrochloride, and theophylline injections.

Dopamine hydrochloride is widely used to increase blood pressure, cardiac output, and peripheral perfusion in critically ill newborn infants and children with shock and congestive heart failure. These patients often require numerous other intravenous drugs such as dobutamine, tolazoline, and theophylline concurrently, but have limited venous access. As a result, two or more of these drugs may be administered through the same intravenous site. The objective of our study was to determine the physical compatibility and chemical stability of dopamine with dobutamine, tolazoline, and theophylline using simulated conditions encountered in the neonatal intensive care unit. Dopamine, dobutamine, tolazoline, and theophylline were studied at concentrations of 120 mg/100 mL, 120 mg/100 mL, 400 mg/100 mL, and 400 mg/500 mL, respectively, in 5% dextrose injection. The flow rate of dopamine was 0.3 mL/h while all combination drugs were run at 1 mL/h. Aliquots were collected at hourly intervals for 5 hours. A simultaneous static experiment was also performed by mixing dopamine with each combination drug in a ratio of 1:3 and allowing these to stand at room temperature. Samples were obtained at 0.5-hour intervals for 3 hours. Each aliquot was inspected visually for any change in color and clarity and analyzed in triplicate for dopamine content using high performance liquid chromatographic technique with electrochemical detection. Linear regression analysis was performed on the mean values of dopamine concentrations to assess its degradation. Dopamine was found to be physically and chemically stable with dobutamine, tolazoline, and theophylline. Thus, dopamine can be infused concurrently with any of these drugs in 5% dextrose injected at frequently used concentrations in newborn infants.

Endotracheal tolazoline administration in neonates with persistent pulmonary hypertension.

OBJECTIVES: Our purpose was to study the effectiveness of endotracheal tolazoline (ET-Tz) in the treatment of neonatal persistent pulmonary hypertension (PPHN). STUDY DESIGN: ET-Tz was administered to 12 neonates with a clinical diagnosis of PPHN. The gestational age ranged from 25 to 42 weeks, and the birth weights from 850 to 3612 gm. The dose of tolazoline ranged from 1 to 2.5 mg/kg. RESULTS: There was a significant increase (p < 0.005) in the mean levels of oxygen saturation and the arterial oxygen tension, and a significant decrease (p < 0.005) in the oxygenation index, between the pretolazoline and the posttolazoline groups, but arterial carbon dioxide tension did not change. After the initial analysis, the groups were subdivided into preterm and term subgroups, because we secondarily observed that the average changes from predose to postdose levels in the above parameters were significantly different (p < 0.001) in the two subgroups by Student's paired t test. CONCLUSIONS: The data indicate that ET-Tz is effective in improving oxygenation in neonates with PPHN, particularly sick preterm infants. The endotracheal route is preferred because it is devoid of significant side effects (e.g., hypotension and flushing). A randomized, controlled, double-blinded, multicenter trial for the use of ET-Tz in PPHN is warranted.

A new approach to congenital posterolateral diaphragmatic hernia.

The theory is advanced that increased pulmonary vascular resistance, resulting in a state of fetal circulation, with right-to-left shunting through the ductus arteriosus, is the main reason that many patients do not survive after repair of a diaphragmatic hernia. Three patients are presented (who, by Raphaely's criteria, were destined for a fatal outcome) in whom the ductus was ligated, and vasodilator drugs were infused into the pulmonary artery. All three demonstrated definite improvement in oxygenation. Two expired after 6 days, one of whom was found at autopsy to have intestinal volvulus and gangrene, and the other multiple plumonary emboli. One case, so managed, survived. The suggestion is made that pulmonary hypoplasia is not the main reason for the high mortality rate after diaphragmatic hernia repair, and that additional laboratory and clinical investigation of the pulmonary circulation may lead to significant improvement in results.

Effect of tolazoline on persistent hypoxemia in severe hyaline membrane disease.

Ten critically-ill preterm infants with severe hyaline membrane disease received tolazoline because of persistent hypoxemia refractory to the administration of 100% oxygen and mechanical ventilation. Seven infants (70%) responded immediately with an increase in PaO2 greater than or equal to 20 mmHg in the umbilical arterial gas within 60 minutes after bolus infusion (1 to 2 mg/kg) of tolazoline. Twenty-four hours later after the tolazoline infusion, the FiO2 had been decreased from 1.0 to a mean of 0.82 +/- 0.16, and the MAP from 16.5 +/- 1.8 to 15.6 +/- 4.5 cm H2O. Four of 7 infants (57%) who had an immediate response survived, whereas none survived out of 3 infants who failed to respond initially. Three infants experienced relatively severe complications possibly related to tolazoline. There appears to be a place for the use of tolazoline in a severely hypoxemic infant with hyaline membrane disease who is being ventilated, and in whom arterial oxygenation cannot be improved by a further increase in the inspired oxygen concentration or by an alteration of ventilator settings.

Limb-threatening lower extremity ischemia successfully treated with intra-arterial infusion--case reports.

The authors present two patients with acute arterial vasospasm of the lower extremities causing marked ischemia. One patient had a history of Raynaud's disease, the second had been taking Cafergot for migraine headaches. Both patients's were given a test dose of intra-arterial tolazoline (50 mg). The patient with Raynaud's disease demonstrated marked improvement diffusely and was successfully treated with overnight infusion of papaverine. The second patient, taking Cafergot, demonstrated no angiographic response to tolazoline. It was speculated that the arteries of this patient were thrombosed. The patient was successfully treated with urokinase and remained free of pain at the 15-month follow-up.

Extracorporeal membrane oxygenation with veno-venous bypass and apneic oxygenation for treatment of severe neonatal respiratory failure.

Seven newborn infants with life-threatening respiratory failure were treated with veno-venous (V-V) extracorporeal lung support and apneic oxygenation after maximal ventilatory and pharmacological treatment failed. Diagnosis were meconium aspiration syndrome in 3 cases, respiratory distress syndrome in 2, sepsis in 1, congenital diaphragmatic hernia in 1. Before ECMO 6 infants received tolazoline, 4 surfactant, 3 high frequency ventilation, 1 prostaglandin E, 1 epoprostenol, 2 nitric oxide. Newborns were highly hypoxemic at admission and all but one underwent rescue cannulation. V-V bypass was performed with a single lumen single cannula and tidal flow was generated by an alternating clamp using a non-occlusive roller pump. The mean duration of bypass was 162.4 +/- 162.3 hours and infants were extubated 94.5 +/- 74.8 hours after decannulation. Five newborns survived and two died. Growth and neurologic development of the older children is normal. The extracorporeal lung support with V-V bypass associated with apneic oxygenation was effective in reversing severe neonatal respiratory failure unresponsive to maximal ventilatory and pharmacological support. An early referral, prior to meeting ECMO criteria, is important in order to avoid hypoxic complications preceding ECMO.