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PubMed2005

Brain hemodynamic effects of doxapram in preterm infants.

BACKGROUND: Doxapram is a respiratory stimulant widely used for the treatment of idiopathic apnea of prematurity, although it has been demonstrated that it can induce a transient decrease of cerebral blood flow and that isolated mental delay in infants weighing <1,250 g is associated with the total dosage and duration of doxapram therapy. OBJECTIVES: To evaluate the effects of doxapram on cerebral hemodynamics in preterm infants using cerebral Doppler ultrasonography and near-infrared spectroscopy. METHODS: Preterm infants who required treatment with doxapram for apnea of prematurity unresponsive to caffeine were treated with doxapram at an hourly dose of 0.5 mg x kg(-1).h(-1), followed by 1.5 and 2.5 mg x kg(-1).h(-1). RESULTS: 20 preterm infants were studied. Doxapram induced a significant decrease of oxygenated hemoglobin (O(2)Hb) and cerebral intravascular oxygenation (HbD = O(2)Hb - HHb) and an increase of HHb and CtOx concentrations, while cerebral blood volume and cerebral blood flow velocity did not change. CONCLUSIONS: Doxapram infusion induces the increase of cerebral oxygen consumption and requirement and the contemporary decrease of oxygen delivery probably mediated by a decrease of cerebral blood flow. Caution must be recommended in prescribing this drug for apnea of prematurity.

Apnea↗
PubMed1988

Pharmacokinetics of doxapram in idiopathic apnea of prematurity.

Pharmacokinetics of doxapram were determined in 13 infants with idiopathic apnea of prematurity uncontrolled by aminophylline and caffeine. Doxapram was maintained for 72-96 h at a constant infusion rate of 2-2.5 mg/kg/h. Plasma doxapram levels were measured by gas liquid chromatography. The infants studied had a birth weight of 1,247 +/- 240 g (mean +/- SD), a gestational age of 29.4 +/- 2 weeks and were 9.9 +/- 6 days old. Steady-state plasma doxapram levels reached by all infants averaged 5.8 +/- 1.8 mg/l. Half-life was 6.6 +/- 5.7 h, plasma clearance 0.44 +/- 0.1 litres/kg/h, and calculated volume of distribution 4 +/- 2.7 litres/kg. Doxapram controlled apnea successfully in 12 of 13 babies. A significant fall in PaCO2 and reduction in the rate of apnea was seen within 6-8 h with corresponding doxapram levels of 3.7 +/- 1.8 mg/l. The factors influencing the pharmacokinetics of doxapram in newborns are presently unknown.

Apnea↗
PubMed1979

Respiratory and nonrespiratory effects of doxapram in congenital central hypoventilation syndrome.

Doxapram is a respiratory stimulating drug that affects both peripheral chemoreceptors and medullary respiratory and nonrespiratory neurons. We administered doxapram 60 2 infants with congenital central hypoventilation syndrome. In 6 separate trials at a dose range of 0.32 to 2.0 mg per kg of body weight per min, quiet-sleep tidal volume increased from 4.9 +/- 1.0 to 8.5 +/- 0.9 ml per kg of body weight, minute ventilation increased from 140 +/- 38 to 286 +/- 31 ml per kg of body weight per min, and alveolar PCO2 decreased from 60 +/- 5 to 32 +/- 2 mm Hg. In all instances, the maximal quiet-sleep ventilatory response was achieved within 10 min. The ventilatory response to steady-state CO2 breathing was not improved with doxapram. A continuous infusion of doxapram for 5.2 days in one infant successfully maintained normal quiet-sleep ventilation. In both infants, multiple nonrespiratory effects of doxapram occurred; enteral administration was associated only with generalized neuromuscular stimulation, but the 5-day intravenous infusion was also associated with acute hepatotoxicity and a perforated duodenal ulcer. The medullary respiratory neurons in central hypoventilation syndrome may be incapable of responding to doxapram, and the ventilatory responses observed may be due entirely to stimulation of peripheral chemoreceptors. Although quiet-sleep ventilation can be successfully maintained with intravenous and enteral administration of doxapram, and tachyphylaxis has not been observed, we have been unable to avoid at least the neuromuscular manifestations of nonrespiratory medullary stimulation.

Chemical and Drug Induced Liver Injury↗
PubMed1981

Biphasic effect of doxapram on hypnotic activity of pentobarbital in mice.

The effect of doxapram, a respiratory stimulant, on the pentobarbital sleeping time was investigated in mice. The sleeping time induced by the intraperitoneal injection of pentobarbital was prolonged 0--120 min after the administration of doxapram (25-100 mg/kg, i.p.). The pretreatment with doxapram 60 min before had no effect on the anesthetic time induced by ether and on the sleeping time induced by the intracerebroventricular injection of pentobarbital, while increased the lethality of pentobarbital only slightly and the levels of pentobarbital in the plasma and brain significantly. The activities of pentobarbital oxidase and aminopyrine N-demethylase in the 9000 X g supernatant fraction of the liver were inhibited by the pretreatment with doxapram 60 min before the test. On the other hand, 12-24 hr after the injection of doxapram the pentobarbital sleeping time was markedly shortened. Thus, the biphasic effect of doxapram, prolongation at first and shortening later, on the pentobarbital sleeping time was observed. It is possible that doxapram inhibits the hepatic microsomal drug-metabolizing enzymes without an increase in the sensitivity of the central nervous system at first and stimulates these enzymes during the second phase.

Animals↗
PubMed1999

Combination acetaminophen and doxapram potentiated hepatotoxicity in mouse primary cultured hepatocytes.

Doxapram-induced potentiation of acetaminophen-induced reductions in cell viability and apoptosis was examined in mouse primary cultured hepatocytes. Loss of viability following exposure of acetaminophen and/or doxapram in cultured hepatocytes was assessed by monitoring [3H]-thymidine incorporation and mitochondrial activity, and apoptosis of hepatocytes was determined by nuclear microscopic observation and from detection of a ladder-like DNA fragmentation pattern in agarose gel electrophoresis. The combination of acetaminophen (5 mM) and doxapram (10, 20, 50 or 100 microM) potentiated the reduction in cell viability and increased lipid peroxide levels of hepatocytes. Hepatocytes exposed for 24 h to acetaminophen (5 mM) plus doxapram (100 microM) showed atrophy of nuclei including chromatin condensation and a ladder-like DNA fragmentation pattern characteristic of apoptosis. Antioxidant (N-acetylcysteine), iron-chelator (deferoxamine), intracellular calcium ion chelator (quin 2-AM), endonuclease inhibitor (aurintricarboxylic acid) and poly (ADP-ribose) polymerase inhibitor (3-aminobenzamide) all improved the viability of cells and eliminated the ladder-like DNA fragmentation in cells exposed to acetaminophen plus doxapram. In conclusion, the combination acetaminophen and doxapram potentiated the reduction in cell viability and apoptosis in mouse primary cultured hepatocytes. We suggest that careful observation for hepatotoxicity is recommended when acetaminophen and doxapram are prescribed simultaneously.

Acetaminophen↗
PubMed1991

Low-dose doxapram for apnea unresponsive to aminophylline in very low birthweight infants.

This study was designed to test whether the addition of low-dose (less than or equal to 1.5 mg/kg/h) doxapram may help wean from positive airway pressure very low birthweight (less than or equal to 1250 g) infants with apnea unresponsive to aminophylline. Doxapram infusion was started at 0.1 to 0.5 mg/kg/h and increased as necessary up to a maximum of 1.5 mg/kg/h. Average birthweight (N = 12) was 1026 +/- 170 g (mean +/- SD, range 740 to 1250), gestational age 27.8 +/- 2.6 weeks (range 24 to 34), postnatal age 24.2 +/- 9.4 days (range 13 to 40), central spun hematocrit 44% +/- 4% (range 38% to 48%), and theophylline level 57.1 +/- 7.7 mumol/L. Doxapram therapy resulted in weaning to a head box in 11 of 12 patients; two required a subsequent course after stopping doxapram. Since the only observed toxicity was mild irritability in one patient, we conclude that very low birthweight infants with apnea unresponsive to aminophylline and older than 1 week of age often respond to the addition of low-dose doxapram with only minimal side effects. Since there was a negative correlation between theophylline level and the effective doxapram dose (r = -.64, N = 13, P less than .05), we recommend that treatment with doxapram be considered in the United States only in those infants with a theophylline level greater than or equal to 88.8 mumol/L, in order to limit the cumulative dose of benzyl alcohol administered.

Aminophylline↗
PubMed1988

Serum doxapram and respiratory neuromuscular drive in normal man.

To investigate the means by which doxapram affects the control of ventilation, ventilatory function and P0.1 have been related to serum doxapram concentration during a 45-min infusion of doxapram hydrochloride in 7 healthy, conscious subjects under normoxic conditions. Serum doxapram concentrations increased during the infusion: 1.88, 2.48, 3.42, and 3.97 micrograms/ml after 5, 10, 30 and 45 min, respectively. The majority of significant changes in the measurements from the baseline were observed at 30 and 45 min: VE, VT, P0.1, P0.1/end-tidal CO2 tension, VT/Ti and blood pressure were increased, and end-tidal CO2 tension was decreased. No significant changes in Pdimax, Ti/Ttot, VE/P0.1, and P0.1/(VT/Ti) were observed. A correlation was observed between the % increases in P0.1 and VE and doxapram concentration, and between VE and P0.1. The doxapram-induced increase in VE appears to be caused by increased neural drive. It is related to the serum drug concentration in the conscious subject.

Adult↗
PubMed2006

Doxapram shortens recovery following sevoflurane anesthesia.

PURPOSE: A randomized, double blind controlled trial was undertaken to investigate the effect of doxapram on recovery times and bispectral index following sevoflurane anesthesia. METHODS: Upon completion of surgery under sevoflurane anesthesia, 60 adult patients were randomly allocated to receive either doxapram hydrochloride 1 mg.kg(-1) iv or saline placebo. Clinical recovery from anesthesia was assessed by time to eye opening on verbal command, hand squeezing on command, time to extubation, and the Aldrete recovery score. Bispectral index values, systolic blood pressure, and heart rate were recorded at baseline (before anesthesia), during surgery, and every minute for 15 min after administration of the study drug. RESULTS: Time to eye opening was shorter in the doxapram group compared with the control group (6.9 +/- 2.2 min vs 9.9 +/- 3.1 min, P < 0.05). Mean bispectral index scores were also higher in the doxapram group compared with the saline placebo seven to eight minutes following administration of the study medication (P < 0.05). More rapid emergence was associated with a greater increase in heart rate with doxapram (P < 0.05 compared with placebo), but no differences in systolic blood pressure responses were observed in comparison with placebo. CONCLUSION: We conclude that doxapram 1 mg.kg(-1) hastens early recovery from sevoflurane anesthesia, and this arousal effect correlates with higher bispectral index values.

Adult↗
PubMed1983

The ventilatory effects of doxapram in normal man.

1. To determine the mode of action of doxapram in man we have measured ventilation, oxygen uptake, CO2 production, hypoxic and hypercapnic ventilatory responses in six healthy men before and during intravenous infusion to maintain a constant plasma level. 2. Doxapram changed neither resting oxygen uptake nor CO2 production but produced a substantial increase in resting ventilation at both levels of end-tidal CO2 studied. 3. Doxapram increased the ventilatory response to isocapnic hypoxia from -0.8 +/- 0.4 litre min-1 (%SaO2)-1 to -1.63 +/- 0.9 litres min-1 (%SaO2)-1. This was similar to the increase in hypoxic sensitivity which resulted from raising the end-tidal CO2 by 0.5 kPa without adding doxapram. 4. The slope of the ventilatory response to rebreathing CO2 rose from 11.6 +/- 5.3 litres min-1 kPa-1 to 20.4 +/- 9.8 litres min-1 kPa-1 during doxapram infusion. 5. The marked increase in the ventilatory response to CO2 implies that doxapram has a central action, but the potentiation of the hypoxic drive also suggests that the drug acts on peripheral chemoreceptors, or upon their central connections, at therapeutic concentrations in normal unanaesthetized subjects.

Adult↗
PubMed2004

Effect of doxapram on cerebral blood flow velocity in preterm infants.

BACKGROUND: Doxapram is used to treat apnea of prematurity when there is an insufficient response to methylxanthine treatment. As an unwanted side effect, reduced cerebral perfusion has been seen in methylxanthine-treated infants while effects of doxapram on the cerebral perfusion have not been studied yet. PATIENTS AND METHODS: Fifteen preterm infants treated with doxapram were included in the study. Birth weight ranged from 380 g to 1150 g (median 740 g), gestational age from 24 to 27 weeks (median 26 weeks). Infants received a doxapram loading dose (2.5 mg/kg) over a 30-minute period, followed by a continuous infusion of 0.5 mg/kg/h. Using Doppler sonography, blood flow velocities and the resistance index were measured in the anterior cerebral artery. Measurements were performed at baseline and 30 and 120 minutes after the start of doxapram. RESULTS: Maximal systolic blood flow velocity (V(max)) decreased significantly after the infants had received the loading dose (V(max) baseline: 40.7 cm/s +/- 6.9 [mean +/- SD]; V(max) 30 min: 35 cm/s +/- 8.9; p = 0.0017) but returned to near baseline values at 120 min (38.5 +/- 9.0, p = 0.22). End-diastolic, time-averaged, and time-averaged maximal velocities did not change significantly at 30 or 120 min. CONCLUSIONS: Doxapram induced a significant decrease in maximal cerebral blood flow velocity. Further studies are needed to assess whether this decrease may be critical to cerebral white matter perfusion in the vulnerable preterm infant.

Anterior Cerebral Artery↗
PubMedDate not supplied

[A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders].

The objective of this study was to prove the superiority of doxapram compared to theophylline therapy in apneas of prematurity in very low birth weight infants. Therefore all VLBW infants (gestational age < 35 weeks) were randomized if they had in a 2 hours-interval more than 2 apneas, 4 bradycardias or 4 oxygen desaturations. They received either theophylline (loading dose 5 mg/kg b. w., 3 mg/kg b. w. bid) or doxapram by continuous infusion of 0.5 mg/kg/h. Apneas, bradycardias and desaturations were recorded from the trend analysis of our monitoring system over the first 3-days and a 7 days period and compared statistically (Mann-Whitney U-test). Plasma levels of both drugs and a polysomnographic recording were obtained during steady state conditions in parallel to a behavioral observation according to Prechtl. The recorded events were again compared using the Mann-Whitney U-test. Twenty patients were treated with theophylline, 14 with doxapram. In 9 patients of each group we could perform a polysomnography and behavioral observation. The incidence of apneas, bradycardias and desaturations in a 7 days-interval was not significantly different between both groups. Analyzing the first 3 days of treatment, however, we could detect a significantly lower rate of apneas in the doxapram group (2.5 apneas compared to 7 in the theophylline group, p < 0.037). In the polysomnographic recording and in our behavioral observations we could not record any significant differences between both groups. Therefore we can conclude that theophylline and doxapram are comparable in the treatment of apneas of prematurity, however, doxapram is superior to theophylline in reducing the rate of apneas in the first 3 days of treatment.

Apgar Score↗
PubMed1977

Interactions between morphine and doxapram in the rabbit and mouse.

Certain actions of doxapram, administered alone and in combination with morphine, have been examined in the rabbit and the mouse. Single doses of doxapram were capable of stimulating respiration in both species. There was an increase in tidal volume in the rabbit and an increase in respiratory rate in the mouse. In both species the duration of action of single doses of doxapram was less than 15 min. In morphine-treated rabbits and mice single doses of doxapram affected neither the time course nor the intensity of the respiratory depression. In the rabbit repeated doses of doxapram did not produce tachyphylaxis with respect to the effect on tidal and minute volumes, and effectively reversed the respiratory depressant actions of morphine. The usefulness of this action must be balanced against the enhanced toxicity of doxapram observed in morphine-treated mice.

Animals↗
PubMed1975

Potencies of doxapram and hypoxia in stimulating carotid-body chemoreceptors and ventilation in anesthetized cats.

The effects of doxapram on carotid chemoreceptor activity and on ventilation (phrenic-nerve activity) were tested before and after denervation of the peripheral chemoreceptors in cats. Doxapram was found to be a potent stimulus to the carotid chemoreceptors; the stimulation produced by 1.0 mg/kg doxapram, iv, equalled that produced by a Pao2 of 38 torr. Doxapram also increased phrenic-nerve activity in doses as low as 0.2 mg/kg, iv. After denervation of the peripheral chemoreceptors, doxapram in doses as large as 6 mg/kg failed to stimulate ventilation. It is concluded that (in anesthetized cats) doxapram in doses of less than 6 mg/kg increases ventilation by direct stimulation of the carotid, and, probably, the aortic, chemoreceptors, not by a direct effect on the medullary respiratory center.

Anesthesia↗
PubMed1997

The minimum effective doses of pethidine and doxapram in the treatment of post-anaesthetic shivering.

This study was designed to find the minimum effective doses of doxapram and pethidine to stop post-anaesthetic shivering. Two hundred and twenty healthy patients who shivered following routine surgery were allocated randomly to receive one of 10 doses of doxapram (0.18, 0.23, 0.29, 0.35, 0.41, 0.47, 0.7, 0.93, 1.17 and 1.4 mg.kg-1), one of five doses of pethidine (0.12, 0.18, 0.23, 0.29 and 0.35 mg.kg-1) or saline. Probit analysis demonstrated that the number of patients who stopped shivering with doxapram was independent of the amount of drug given in this dose range. The lowest dose of doxapram (0.18 mg.kg-1) was significantly more effective than placebo (p < 0.01). For pethidine there was a dose-dependent effect on shivering to a maximum of 95% of patients successfully treated with 0.35 mg.kg-1. We conclude that 0.35 mg.kg-1 of pethidine is the minimum dose required to treat post-anaesthetic shivering effectively. We also conclude that 0.18 mg.kg-1 of doxapram is as effective as 1.4 mg.kg-1 in the treatment of post-anaesthetic shivering. Further study is required to find the minimum effective dose of doxapram.

Adolescent↗
PubMedDate not supplied

Low-dose doxapram therapy in premature infants and its CSF and serum concentrations.

The efficacy of low-dose doxapram therapy (0.2 mg/kg/h) in combination with methylxanthines was evaluated in 20 premature infants with idiopathic apnea unresponsive to methylxanthines alone, and in 13 premature infants with secondary apnea. The serum concentrations of doxapram and, in some infants, the simultaneous cerebrospinal fluid and serum concentrations were measured, and the correlation between cerebrospinal fluid and serum concentrations in the postnatal period was determined. The following results were obtained: 1) In idiopathic apnea of prematurity, low-dose doxapram therapy was as effective as a dose of 1.0-2.5 mg/kg/h and the side effects were few, mild, and reversible. 2) In premature infants over seven days of age, serum concentrations of doxapram were almost stable but were significantly lower than in infants within the first six days of life. 3) The ratio of the cerebrospinal fluid to serum doxapram concentration was 0.48 +/- 0.13 (mean +/- SD). There was a good correlation between cerebrospinal fluid and serum concentrations (r = 0.933, p less than 0.001). The initial doxapram dose can be set as low as 0.2 mg/kg/h in very young premature infants with idiopathic apnea of prematurity unresponsive to methylxanthines.

Aminophylline↗
PubMed1993

Sex-related differences in rat liver microsomal enzymes and their induction by doxapram.

The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10-120 mg kg-1 day-1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg-1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg-1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg-1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b5 content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.

Animals↗
PubMed1992

Metabolic and cardiorespiratory effects of doxapram and theophylline in sleeping newborn piglets.

To evaluate the contribution of a change in metabolic rate to ventilatory changes after the administration of respiratory stimulants, we studied the effect of two respiratory stimulants, doxapram and theophylline, on ventilation and metabolic rate during sleep in piglets. Metabolic rate (O2 consumption and CO2 production) was measured in a metabolic chamber, and alveolar ventilation (VA) was derived from arterial PCO2 and CO2 production. We studied the animals during a baseline period and for 2 h after the administration of theophylline or doxapram. With doxapram, there was no change in VA, metabolic rate, or arterial PCO2. In contrast, with theophylline, VA increased [20 +/- 14% (SD), P less than 0.003] as a result of both an increased metabolic rate and hyperventilation. Doxapram, however, increased mean blood pressure (from 67 +/- 11 to 75 +/- 13 mmHg, P less than 0.005), whereas theophylline did not result in blood pressure changes. In summary, during quiet sleep, doxapram, unlike theophylline, does not stimulate either respiration or metabolic rate. We speculate that the previous reports of increased ventilation after the administration of doxapram are due to the general stimulation of activity in the awake state, an effect not seen during sleep.

Animals↗
PubMed1997

Almitrine and doxapram decrease fatigue and increase subsequent recovery in isolated rat diaphragm.

The effects of almitrine bimesylate and doxapram HCl on isometric force produced by in vitro rat diaphragm were studied during direct muscle activation at 37 degrees C. Doxapram and almitrine ameliorate respiratory failure clinically by indirectly increasing phrenic nerve activity. This study was carried out to investigate possible direct actions of these agents on the diaphragm before and after fatigue of the fibers. Two age groups of animals were chosen [6-14 wk (group 1) and 50-55 wk (group 2)] because it is known that increasing age decreases a muscle fiber's resistance to fatigue. Muscle strips were isolated from both group 1 and group 2 and directly stimulated (2-ms pulse duration, 5-15 V) to produce twitch tensions of 1.3 and 2.1 N/cm2, respectively. At low concentrations, doxapram (</=20 microg/ml) and almitrine (</=12 microg/ml) had no effect on twitch contraction or 100-Hz tetanic tension. However, 40 microg/ml doxapram and 30 microg/ml almitrine increased twitch tension by 9.0 +/- 1.4 and 11.6 +/- 1.9%, respectively, in animals of group 2 (n = 5). A fatigue protocol consisting of low-frequency stimulation (30-Hz trains, 250-ms duration every 2 s for 5 min) caused a reduction of twitch tension in animals of group 1 (48 +/- 4% of control) and group 2 (28 +/- 4% of control). At 90 min postfatigue, the twitch tension recovered to 72 +/- 3 and 42 +/- 2% of control values in group 1 and group 2, respectively. In the presence of doxapram (20 microg/ml), there was a significant increase in the recovery of twitch tension at 90 min in group 1 and group 2 (84.5 +/- 3.2 and 80.1 +/- 2.8%, respectively) compared with controls at 90 min postfatigue. In the presence of almitrine (12 microg/ml), there was a full recovery from fatigue in group 1 animals (100% of control) and a recovery to 95.6 +/- 2.1% of control in group 2 animals at 90 min. These results demonstrate a significant improvement in the rapidity and magnitude of recovery from fatigue in the rat diaphragm muscle in the presence of both doxapram and, especially, almitrine. These effects may be due to changes in intracellular calcium, ADP/ATP ratios, or oxygen free radical scavenging.

Almitrine↗