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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.

Purpose: To compare the vasodilating effect and safety of intraarterial verapamil with the long-accepted standard vasodilators nitroglycerin and tolazoline in hand angiography., Materials and Methods: The authors studied 25 patients who underwent brachial artery angiography. In 22 cases, there was poor or moderate visualization of the forearm and hand vasculature. To improve blood flow to the periphery, subsequent angiograms with intraarterial vasodilating agents were obtained. First, nitroglycerin was administered (n = 22). In cases of continuous poor or moderate visualization of the forearm and hand vasculature, another angiogram was obtained with verapamil (n = 21). If opacification remained poor or moderate, eventually tolazoline was injected (n = 20). To avoid pharmacologic interactions of the different vasodilating drugs, a minimum 15-minute interval between series was observed. The degree of opacification of the forearm and hand arteries was graded on a scale from 1 to 5: visualization of the forearm arteries only was defined as 1, of the forearm arteries and superficial/deep palmar arch as 2, of the forearm arteries, superficial/deep palmar arch, and digital arteries to the level of the metacarpophalangeal joints as 3, to the level of the proximal interphalangeal joints as 4, and to the distal interphalangeal joints as 5., Results: All three vasodilating agents demonstrated highly significant improvement in blood flow; verapamil and tolazoline showed statistically greater effects than nitroglycerin. Verapamil caused the fewest and least severe adverse effects., Conclusion: Intraarterial verapamil and tolazoline are comparable in terms of vasodilatory efficacy in hand arteries. However, because of its favorable adverse effect profile, verapamil is recommended for optimizing visualization of the peripheral arterial vascular system.

Persistent pulmonary hypertension of the newborn (PPHN) remains one of the most challenging situations in the neonatal intensive care unit, and it is associated with high mortality and morbidity. The optimal treatment for PPHN is controversial. We report our 9-year experience in the management of PPHN through a retrospective review of 29 neonates with persistent pulmonary hypertension. The diagnosis of PPHN is made by echocardiography and/or preductal and postductal oxygen tension difference. The treatment modalities include supportive medical care, vasodilator therapy, mechanical ventilation and correction of underlying conditions. The wide diversity of etiologies of PPHN, the complications of vasodilator therapy, the management of assisted ventilation, the mortality and the morbidity are evaluated. There are 29 patients enrolled in this study, including 18 male and 11 female babies. Twenty-two patients (72%) are referred from other hospitals. The mean birth body weight is 2707 +/- 693 grams (range: 1450-4100 grams) and the mean gestational age is 37.1 +/- 3.1 weeks (range: 31-41 weeks). The underlying clinical conditions include meconium aspiration syndrome (n = 8), perinatal asphyxia (n = 7), respiratory distress syndrome (n = 5), sepsis and/or pneumonia (n = 4), congenital diaphragmatic hernia (n = 3) and idiopathic persistent fetal circulation (n = 2). In addition to supportive medical care and correction of underlying clinical conditions, most of the patients receive vasodilator therapy (Tolazoline) and nonhyperventilation respirator management. The overall mortality rate is 27.6% (8/29). The duration on ventilator therapy in the survival group (9.3 +/- 8.6 days) is not significantly different from in the mortality group (6.0 +/- 7.1 days) (p = 0.13). There is also no statistically significant difference between these two groups both in the maximal alveolar-arterial oxygen tension difference (594 +/- 53 mmHg and 613 +/- 37 mmHg, p = 0.145) and in the maximal oxygenation index (49.7 +/- 29.6 and 61.1 +/- 36.9, p = 0.172) before vasodilator therapy. However, twenty-four hours after treatment, these two parameters change significantly with the former changes to 426 +/- 198 mmHg and 643 +/- 7 mmHg, respectively (p < 0.001), and the latter changes to 21.6 +/- 15.8 and 82.3 +/- 54.8, respectively (p < 0.001). Skin rash, gastrointestinal hemorrhage, hypotension and hyponatremia are the most common complications of Tolazoline therapy. Eight patients have pulmonary complications including pneumothorax (n = 5) and pulmonary interstitial emphysema (n = 3). Two patients develop chronic lung disease. Three patients have neurodevelopmental handicap. In conclusion, we achieve a survival rate of nearly 75% in PPHN mainly with the administration of Tolazoline therapy and the nonhyperventilation respirator approach. Further well-controlled and multicenter studies with newer treatment modalities are crucial for the improvement of survival of PPHN in Taiwan.

Clinical signs of tolazoline toxicosis developed in a 4-year-old llama that received 2 doses of tolazoline hydrochloride to reverse xylazine-induced sedation. The full first dose (4.3 mg/kg [2.0 mg/lb] of body weight) was erroneously injected i.v., and the second dose was administered half i.v., half i.m. 45 minutes later, because the llama became weak and recumbent. Signs of anxiety, hyperesthesia, profuse salivation, and tachypnea were the first detectable clinical signs of tolazoline toxicosis. Convulsions, hypotension, gastrointestinal tract hypermotility, and diarrhea also developed. The llama was treated successfully with i.v. administration of diazepam, phenylephrine, and lactated Ringer's solution supplemented with potassium chloride and oxygen administered via nasal insufflation. We suggest that the maximum dose of tolazoline administered at any one time to llamas not exceed 2 mg/kg (0.91 mg/lb). Furthermore, tolazoline should be administered slowly i.v. or i.m. to reduce the risk of adverse reactions.

Tolazoline is a potent vasodilator of arteries and veins and has a powerful effect on the pulmonary vasculature, reducing hypoxic pulmonary vasoconstriction and lowering pulmonary artery pressure. Intravenous tolazoline lowers the mean pulmonary arterial pressure and resistance and increases the cardiac index when given to infants with persistent pulmonary hypertension (PPHN). Endotracheally administered tolazoline decreases mean pulmonary arterial pressure and pulmonary vascular resistance, and improves oxygenation without the harmful decline in the systemic arterial pressure. The purpose of our study was to examine the pharmacokinetic and pharmacodynamic characteristics of endobronchial tolazoline to determine the relationship between endobronchial tolazoline administration, plasma concentration, and its effects on the cardiovascular and respiratory systems. Tolazoline was administered endobronchially to seven dogs, and its serum concentration and the hemodynamic parameters were monitored for 270 min postdelivery. It was found that 15 sec after dosing, tolazoline plasma concentrations started to increase significantly above baseline levels, reaching a maximum of 9.3+/-8.0 microg x mL(-1) The volume of distribution was 1657+/-321 mL x kg(-1) after 1 2.4+/-1 6.6 min. The extent of tolazoline absorption was 319+/-38 microg x min(-1) mL(-1). The total body clearance was 10.9 +/-4.8 mL x min(-1) x Kg(-1) and the elimination half-life was 156+/-81 min. Endobronchial tolazoline produced an initial short-lived decrease in the mean blood pressure in all the dogs, but thereafter the blood pressure increased gradually above baseline levels. Immediately following endobronchial tolazoline a significant tachycardia developed, peaking at 90 min. Subsequently, the heart rate gradually decreased and stabilized at values above baseline for 200 min. We conclude that an endobronchial bolus dose of tolazoline is effectively absorbed, produces measurable pharmacological effects, and may be beneficial in the therapy of persistent pulmonary hypertension of the newborn.

A 2-day-old newborn was treated with tolazoline for persistent pulmonary hypertension due to meconium aspiration syndrome. Hypoxemia improved during continuous tolazoline infusion, but gastrointestinal bleeding occurred. After treatment with cimetidine, there was a rapid deterioration with decreased oxygen saturation and arterial PO2 values. Tolazoline induces a dilatation of the pulmonary vascular system by stimulating H2 receptors. Cimetidine, an H2 blocker, may partially abolish the effect of tolazoline. However, given the clinically significant result to the interaction between tolazoline and cimetidine we report, the use of cimetidine in tolazoline induced upper gastrointestinal hemorrhage should deserve more attention.

Cimetidine therapy used for the treatment of gastric bleeding due to tolazoline therapy in a newborn infant was temporally associated with episodes of severe hypoxemia. It appears likely that the histamine H2 receptor blocked by cimetidine obviated the pulmonary vasodilator effect of tolazoline therapy.

Vascular complications after liver transplantation include occlusion or stenosis near the sites of anastomosis in the hepatic artery, portal vein, and vena cava. Balloon angioplasty of these stenoses carries little risk and is a useful procedure for the treatment of these problems. Here we describe the case of a liver transplant patient who underwent balloon angioplasty for stenosis of the hepatic artery and who developed spasms of the hepatic artery which were aggravated following intraarterial administration of Tolazoline.

A newborn was treated with tolazoline for persistent pulmonary hypertension. Oxygenation improved during continuous infusion of the drug, but gastrointestinal bleeding occurred. Therefore, cimetidine was given. After this there was a rapid deterioration with decrease of oxygen saturation and arterial pO2 values. Tolazoline induces a dilatation of the pulmonary vascular system by stimulating H1 and H2 receptors. Blocking of H2 receptors by cimetidine abolishes the effect of tolazoline at least partially. Our case shows that the interaction between tolazoline and cimetidine is of clinical significance. The recommendation to use cimetidine as prophylaxis against gastrointestinal side-effects induced by tolazoline can no longer be maintained.

Tolazoline's complex pharmacologic effects likely represent the algebraic sum of primary, secondary, and possibly tertiary interactions with histamine and adrenergic receptors. Oxygenation improves initially in the majority of neonates with PPHN treated with tolazoline. Preliminary studies of tolazoline pharmacokinetics in the newborn indicate current doses are excessive and lead to accumulation, which may contribute to adverse effects, including cardiotoxicity.

The combined application of Tolazoline and Dopamine for the treatment of the persistent fetal circulation syndrome showed that Dopamine prevented the most common side effects of Tolazoline i.e. systemic hypotension and oliguria. The authors emphasize the importance of continuous monitoring of the systemic blood pressure in infants during this treatment.

A neonate, managed with tolazoline for pulmonary hypertension after repair of a congenital diaphragmatic hernia, developed a duodenal perforation. The role of tolazoline in this condition is discussed, and possible measures to reduce its gastrointestinal side effects are proposed.

Forty-six neonates with hypoxemia were treated with tolazoline, a pulmonary vasodilator, within the first two days of life. Eight of ten (80%) infants without apparent lung disease responded with a mean increase in PaO2 of 116 torr within one hour of beginning tolazoline infusions. One of the responding infants and two nonresponders died. Thirty-six additional infants with a variety of pulmonary disorders had severe hypoxemia which was refractory to mechanical ventilation. Twenty-one (58%) responded with a mean increase in PaO2 of 130 torr within one hour after beginning tolazoline and 13 (62%) of these survived. Fifteen patients had little or no improvement in PaO2 following tolazoline and only three (20%) of these infants survived. Responders could not be distinguished from nonresponders by clinical or laboratory features prior to therapy with tolazoline. Fourteen infants experienced complications possibly related to tolazoline.

Oliguria in the neonate usually reflects a fall in glomerular filtration rate (GFR) secondary to prerenal disturbances such as hypovolemia, hypotension, hypoxemia and cardiac failure, or to vasoactive drugs such as indomethacin and tolazoline. The action of such drugs on renal function is reviewed, as well as the pharmacological measures that can be tried to prevent or blunt their renal side effects. The efficacy and side effects of dopamine, furosemide and mannitol, frequently used in oliguric states due to either prerenal disturbances or to vasoactive drugs, are discussed. It is concluded that available data in newborn infants do not definitely prove the efficacy of dopamine and furosemide in preventing acute renal insufficiency and that, in neonates with established oliguria, administration of mannitol, dopamine and/or furosemide can be tried, with little hope, however, of markedly improving GFR.

The pharmacological effects of Tolazoline were studied in newborns with different types of pulmonary diseases. The drug was given when the arterial pO2 remained below 6,65 kP in spite of PEEP, and when the right-to-left shunt was greater than 60%. Continuous monitoring of arterial blood pressure and pO2 were of particular importance. Permanent improvement was found in 50%. Transitional improvement in 30% of the cases and in the remaining 20% the drug had no observable effect.

Perinatal anoxia, or postnatal hypoxemia, as seen during respiratory distress syndrome, profoundly affects renal function. Hypoxemic neonates present with decreased water excretion, impaired diluting ability, urine acidification, glomerular filtration rate and renal perfusion. Stimulation of the renin-angiotensin system may explain, at least in part, the pathogenesis of the hypoxemia-induced renal changes. The renal defects are reversible upon restoring normoxemia, extracellular fluid volume and cardiac output. The neonatal kidney can also be affected by iatrogenic manipulations. Drugs acting efficiently on several target-organs can profoundly impair renal function. Tolazoline, sometimes used as a pulmonary vasodilator in persistent pulmonary hypertension of the premature infant, can increase renal vascular resistance with consequent renal failure. Indomethacin, a prostaglandin-synthetase inhibitor used to medically close a patent ductus arteriosus, can depress glomerular filtration and water excretion in the newborn infant. Aminoglycosides are widely used in neonatology. They can easily accumulate in neonates whose GFR is low. Their nephrotoxicity may be lower in neonates than in adults, but is certainly not negligible. Experimental studies and a clinical observation have shown that captopril, a competitive inhibitor of the angiotensin-converting enzyme can produce renal damage in the fetus. Recent progress in pharmacology has provided the neonatologist with effective drugs which are of great value in the neonatal ward. They should however always be used with caution if detrimental side-effects are to be avoided.

There were 47 seriously-ill neonates with medical causes of respiratory distress and 10 infants with severe respiratory distress secondary to a congenital diaphragmatic hernia treated with tolazoline according to a strict protocol designed to manage persistent fetal circulation (PFC). Of the 47 infants, 28 (60%) had a positive response defined as an increase in the pO2 greater than or equal to 24 mm Hg within 4 hr of beginning the drug. Of 7 infants, 4 with congenital diaphragmatic hernia had a positive response. The mean increase in the pO2 for the 47 infants was statistically significant (p less than .05). Of the 47 infants with medical disorders, 27 survived (survival 57%), whereas only 2 of the 10 infants with congenital diaphragmatic hernia and severe persistent fetal circulation survived (survival 28%). Erythema (60%), hematest positive gastric aspirates (55%), thrombocytopenia (45%), hyponatremia (40%) and increased gastric aspirates (36%) were the most common adverse effects occurring during tolazoline infusion. Hypotension occurred in nine cases, but was transient. Of the 27 survivors, 20 with medical causes of persistent fetal circulation were evaluated at age 1 yr. Eighty percent of these infants studied were considered normal as defined by an MDI and PI of the Bayley Scales of greater than or equal to 70. These data suggest that tolazoline is a useful adjunct in the management of neonates with PFC. In addition, tolazoline was more effective in mechanically ventilated neonates treated with respiratory paralytic agents. Although tolazoline resulted in a significant improvement in the paO2 in 4 infants with congenital diaphragmatic hernia, it did not appear to improve mortality in these infants.

Tolazoline Hydrochloride is a pulmonary vasodilator that is used for the treatment of pulmonary hypertension of the newborn. Two patients who were receiving Tolazoline by infusion developed duodenal ulceration and subsequent intestinal perforation. This undesirable side effect of Tolazoline may be prevented by the concomitant use of antacids to maintain gastric pH greater than 5.

Persiting pulmonary arterial hypertension, whether secondary to known lung disease or apparently idiopathic, may induce refractory hypoxaemia in the newborn. Tolazoline, pulmonary vasodilator of choice here, was used to treat this syndrome in 13 newborns. Therapeutic indications, precautions and possible side-effects are discussed.

Prerenal failure (i.e: functional renal insufficiency or vasomotor nephropathy) is the main cause of acute renal failure in the neonate. The renin-angiotensin system and endogenous renal adenosine intervene in the pathophysiological mechanisms of functional renal insufficiency. Mechanical ventilation, indomethacin and tolazoline may favor or worsen vasomotor nephropathies. Prerenal failure is treated by 1) correction of hypovolemia, systemic hypotension, hypoxemia and acidosis; 2) administration of furosemide and of low doses of dopamine.

Gastric hypersecretion following administration of tolazoline resulted in severe hypochloremic alkalosis in an infant with persistent fetal circulation. An initial bolus injection of 2 mg/kg was followed by an infusion of 5 mg/kg/hr for 24 hours. The infusion was then maintained at 2 mg/kg/hr for the next four days. Volume of gastric secretions exceeded 25 ml/kg/24 hr. Weaning from tolazoline and replacement of chloride and potassium corrected the metabolic alkalosis.

The immature kidney may be adversely affected by a variety of vasoactive or diuretic drugs, either administered to the mother during pregnancy, or to the neonate. Inhibitors of the angiotensin-converting enzyme administered to the hypertensive pregnant woman can severely and sometimes definitely impair renal function in the fetus, leading to postnatal anuria. Pathogenesis involves interference with the renin-angiotensin system and the prostaglandins. Beta-adrenergic agents administered during labor depress glomerular filtration rate transiently. Tolazoline, an alpha-adrenergic blocking agent useful in the treatment of persistent pulmonary hypertension of the neonate induces intense renal vasoconstriction with consequent hypoperfusion. Indomethacin, a prostaglandin synthetase inhibitor used for the pharmacological closure of a patent ductus arteriosus, also increases renal vascular resistance, and decreases urine output. Furosemide, the drug most often used in oliguric neonates, may also adversely affect the newborn infant. Its use has been associated with an increase in the incidence of patent ductus arteriosus, hypercalciuria, nephrocalcinosis and secondary hyperparathyroidism. These observations demonstrate that the proper use of drugs requires that the therapeutic endpoint be clearly defined and the predictable side effects be anticipated.

Thirty-nine critically ill infants with pulmonary disease received tolazoline because of severe hypoxemia refractory to administration of 100% O2 and mechanical ventilation. Twenty-seven (69%) of the infants responded with an increase in PaO2 greater than or equal to 20 torr in the first umbilical arterial gas after completion of the initial ten-minute infusion (1 to 2 mg/kg) of the drug. A response was not correlated with survival. The overall survival was 46%, essentially unchanged from our previous report (44%). Infants with hyaline membrane disease had the poorest survival rate (33%). Complications associated with the use of tolazoline occurred in 82% of the infants. A hypotensive reaction, defined as a 25% decrease in mean arterial pressure from the pre-tolazoline level, occurred in 67% of the infants, and more commonly in the infants with RDS (87%). In 11 infants who did not respond to the initial dose of tolazoline, the dose was increased up to 10 mg/kg/hour; only one infant responded, and eight (73%) had a hypotensive reaction.

Gastric ulcerations were observed in an infant with persistent foetal circulation treated with tolazoline. The first symptoms were noted 14 hours after institution of therapy, and free air in the abdomen was visualised 34 hours later. It is suggested that the ulcerations may have been a side effect of tolazoline. The concomitant use of cimetidine may prevent this complication.

Adverse drug reactions have been noted to occur in one of three newborns admitted to intensive care units. The factors associated with adverse drug reactions and the adverse reactions to commonly used medications in neonatal intensive care units are discussed. Methods of preventing or reducing these undesired effects are suggested.

We randomly assigned 24 neonates with hypoxemia to receive tolazoline hydrochloride. Thirteen received a single dose (SD) of 2 mg/kg intravenously, and 11 received a SD of 2 mg/kg plus a 2 mg/kg/h intravenous infusion (SDI). Increase in PaO2 greater than or equal to 15 mm Hg within 20 min of administration was more common in SDI patients. Hypotension and gastrointestinal bleeding occurred more often in SDI patients. Survival could not be related to the method of administration or initial relief of hypoxemia with tolazoline.