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PubMed1991

Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity.

We hypothesized that enteral doxapram would effectively treat apnea of prematurity without the appearance of major side effects. Of 16 infants, 10 (BW 1,520 +/- 102 g) received doxapram alone and 6 (BW 1,020 +/- 35 g) received doxapram plus theophylline. Apneas decreased from 16.7 +/- 1.9 to 2.1 +/- 0.6 in infants receiving doxapram alone, and from 38.2 +/- 4.4 to 7.9 +/- 2.2 apneas/24 h in those receiving doxapram plus theophylline. This was associated with an increase in alveolar ventilation, a shift of the ventilatory response to CO2 to the left, and no change in the immediate ventilatory response to 100% oxygen. Side effects included premature teeth buds corresponding to the lower central incisors, prevalence of occult blood in stool and necrotizing enterocolitis. The findings suggest that doxapram effectively controls apnea when given enterally, but should be used cautiously because of potentially harmful side effects.

Apnea↗
PubMed2006

The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration.

TWIK-related acid-sensitive K(+)-1 (TASK-1 [KCNK3]) and TASK-3 (KCNK9) are tandem pore (K(2P)) potassium (K) channel subunits expressed in carotid bodies and the brainstem. Acidic pH values and hypoxia inhibit TASK-1 and TASK-3 channel function, and halothane enhances this function. These channels have putative roles in ventilatory regulation and volatile anesthetic mechanisms. Doxapram stimulates ventilation through an effect on carotid bodies, and we hypothesized that stimulation might result from inhibition of TASK-1 or TASK-3 K channel function. To address this, we expressed TASK-1, TASK-3, TASK-1/TASK-3 heterodimeric, and TASK-1/TASK-3 chimeric K channels in Xenopus oocytes and studied the effects of doxapram on their function. Doxapram inhibited TASK-1 (half-maximal effective concentration [EC50], 410 nM), TASK-3 (EC50, 37 microM), and TASK-1/TASK-3 heterodimeric channel function (EC50, 9 microM). Chimera studies suggested that the carboxy terminus of TASK-1 is important for doxapram inhibition. Other K2P channels required significantly larger concentrations for inhibition. To test the role of TASK-1 and TASK-3 in halothane-induced immobility, the minimum alveolar anesthetic concentration for halothane was determined and found unchanged in rats receiving doxapram by IV infusion. Our data indicate that TASK-1 and TASK-3 do not play a role in mediating the immobility produced by halothane, although they are plausible molecular targets for the ventilatory effects of doxapram.

Anesthetics, Inhalation↗
PubMed1987

Doxapram on blunted respiratory chemosensitivity to hypoxia in hypoxemic, chronic obstructive pulmonary disease.

We investigated a possible effect of doxapram (a respiratory stimulant) on the peripheral chemoreceptors in man (8 control subjects, 11 bronchitics, and 4 emphysematous). In addition, we determined whether infusion of doxapram could augment blunted chemosensitivity to hypoxia or hypercapnia seen in both chronic obstructive pulmonary disease (COPD) patients and normal subjects. Doxapram infusion caused a significant increase in delta VE/delta SaO2 (p less than 0.05), as well as delta Po.1/delta SaO2 (p less than 0.05) in control subjects, although the changes in both delta VE/delta PeAco2 (where, PeAco2 = end-tidal Pco2) and delta Po.1/delta PeAco2 did not attain significant level. Control subjects with low baseline delta Po.1/delta SaO2 showed significantly larger changes in both delta Po.1/delta SaO2 and delta VE/SaO2 during doxapram infusion than the patients with chronic bronchitis (0.02 less than p less than 0.05). We conclude that doxapram increases chemosensitivity to hypoxia and slightly increase chemosensitivity to hypercapnia, indicating its primary action being stimulation of peripheral chemoreceptors, and doxapram stimulates chemoreceptors little in patients with chronic bronchitis, whereas blunted hypoxic response in normal subjects could be increased markedly.

Adolescent↗
PubMed1986

Haemodynamic and respiratory effects of post-operative doxapram and almitrine in patients following pneumonectomy.

Respiratory analeptics have been shown to give important increases in pulmonary vascular resistance and pulmonary arterial pressure in hypoxaemic respiratory failure patients, but no studies have been carried out in the post-operative recovery period. The aim of this study was to compare the haemodynamic and respiratory effects of doxapram and almitrine infusion given over 1 h in patients who had just undergone pneumonectomy. Two hours after the end of anaesthesia, three groups of randomly selected patients were therefore given 3 mg kg-1 doxapram (n = 10), 1 mg kg-1 almitrine (n = 10) or placebo (n = 10). Measurements were made before and 15, 30, 60, 90, 120 and 180 min after the beginning of the infusion. There was an immediate 15-20% fall (P less than 0.01) in PaCO2 and a 20% rise in PaO2 (P less than 0.005), identical for both drugs; the variations in the placebo group became significant only after 60 min. Heart rate and cardiac index did not change. Mean arterial pressure did not change with doxapram, but decreased by 20% during the infusion of almitrine (P less than 0.01), remaining low until the 90th min (P less than 0.05). This hypotension was due to a decrease in peripheral arterial resistance (P less than 0.05) and a small decrease in right atrial pressure (P less than 0.05). The mean pulmonary arterial and wedge pressures were increased before starting the infusion, and did not vary significantly. Pulmonary arterial resistance increased with both analeptics but only significantly with the doxapram (P less than 0.05) at 5, 60 and 90 min; however, there was no significant difference between doxapram and almitrine. The post-operative respiratory efficiency of these drugs has been confirmed, there being no difference between almitrine and doxapram. The haemodynamic effects were moderate, especially with almitrine. Both of these drugs, therefore, may be recommended for use after lung surgery.

Almitrine↗
PubMed1979

[Effect of almitrine on arterial gases in patients with chronic respiratory insufficiency. Comparison with doxapram. Preliminary results].

We compared the effects of almitrine and doxapram on the arterial blood gases and ventilation of patients with chronic respiratory insufficiency and chronic hypercapnia and hypoxemia. Sixteen long-term in-patients were randomly allocated to one of the following treatment groups: the first group (8 patients) received IV almitrine 0.5 mg/kg and the second group (8 patients) IV doxapram 1 mg/kg by IV perfusion during 30 min. All gave their informed consent. Arterial blood gases and ventilation were measured 10 min and 5 min before treatment, at the 5th, 15th and 25th min of perfusion time, and 5, 10 and 15 min after infusion. There was a marked increase in paO2 in almitrine-treated patients, which was maximum at the 25th min of infusion (+ 14.6 mm Hg, p < 0.001), but only a slight improvement was observed in the doxapram group (+ 3.3 mm Hg, p < 0.05). After almitrine the maximum mean paCO2 decrease was at the 10th min after perfusion (-6.9 mm Hg, p < 0.001); after doxapram the maximum decrease, although highly significant, was much less (-2.8 mm Hg, p < 0.01). Thus, at the presently used and well-tolerated doses, almitrine is much more efficient than doxapram in improving gas exchange in patients with chronic hypoxemia and hypercapnia. However, complementary studies using higher dosage of doxapram are warranted.

Aged↗
PubMed1979

Effect of doxapram on control of breathing in cats.

The effects of doxapram infusion (0.25 mg.kg-1. min-1) were studied in cats anaesthetized with pentobarbitone (35 mg . kg-1 intraperitoneally). Cats were studied breathing 50 per cent oxygen and the responses to two concentrations of inspired carbon dioxide were measured. Doxapram infusion increased pulmonary ventilation by increasing both tidal volume and respiratory frequency, and also caused increases in the volume inspired in the first 0.5 second after the onset of an inspiration (V0.5) and the pressure generated in the airway 0.5 second after the onset of an inspiration when the airway had been occluded (P degrees 0.5). V 0.5, P degrees 0.5 and the mean inspiratory flow rate (VT/VI) were essentially equivalent indices of inspiratory drive. Doxapram infusion did not alter the effective impedance of the respiratory system (P degrees 0.5/V 0.5). Doxapram infusion increased the ventilatory response to carbon dioxide. The slope of the ventilatory response to carbon dioxide was increased and the response line was shifted to the left. We conclude that the increase in pulmonary ventilation caused by doxapram infusion is due almost entirely to increased inspiratory neuromuscular drive (P degrees 0.5).

Animals↗
PubMed1975

A controlled trail of doxapram in acute respiratory failure.

The efficacy of a respiratory stimulant (doxapram) in antagonizing carbon dioxide retention associated with controlled oxygen therapy (28 per cent) in acute-on-chronic respiratory failure was assessed by a double-blind crossover trial in eight patients. PaCO2 rose in egery case during the placebo in the initial treatment period (mean increase 10 mm Hg). In those patients receiving doxapram initially PaCO2 fell in three and rose in one (mean decrease 4 mm Hg). All who has shown a rise in PaCO2 during the initial period on placebo showed a fall in the subsequent period on doxapram. In the six patients who completed the study, mean PaCO2 at the end of the doxapram period was significantly lower than the end of the placebo period (60 mm Hg against 67 mm M Hg). In three patients the rise in PaCO2 was accompanied by significant impairment in the level of consciousness which was reversed during the doxapram period. PaCO2 was not significantly different during either treatment period. No serious unwanted effects were encountered.

Acute Disease↗
PubMed1989

Effects of caffeine and doxapram perfusion on local cerebral glucose utilization in conscious rats.

The quantitative autoradiographic 2-[14C]deoxyglucose method was used to measure the effects of a continuous infusion of the respiratory stimulants, caffeine or doxapram, 18 mg/kg per h, on local cerebral glucose utilization in the adult male rat. Local cerebral glucose utilization was measured in 54 cerebral structures from different systems. Caffeine induced widespread increases in energy metabolism, resulting in a significant increase in glucose utilization in 25 structures out of the 54 studied. These increases were distributed within all systems studied, sensory, extrapyramidal motor, limbic and hypothalamic systems. In addition, caffeine induced a non-significant, 10-15%, increase in local cerebral glucose utilization in central respiratory areas. Doxapram infusion did not change the rates of glucose utilization in any of the structures. The rates of local cerebral glucose utilization were significantly lower after doxapram than after caffeine exposure in five cerebral areas, among which were three central respiratory areas. The results confirm the absence of side-effects of doxapram as compared to caffeine when used as respiratory stimulant, especially in neonates. These results also favor a preferentially central action of caffeine on respiratory areas and a more peripheral action of doxapram on chemoreceptors, at least at therapeutic levels.

Animals↗
PubMed1991

Ventilatory response to keto-doxapram in intact and carotid body denervated lambs.

We aimed to investigate the role of the carotid bodies in the ventilatory response to keto-doxapram, and whether this response was dose-dependent; we studied two group (n = 5 per group) of awake, intact and carotid-body denervated (CBD) lambs, aged 10-15 days. At 20 min intervals, they received 0.5, 1.0, 2.5 and 5.0 m g/kg mg/kg of keto-doxapram as an intravenous bolus infusion. Plasma keto-doxapram was measured (HPLC). Ventilation was recorded via a face mask and a pneumotachograph. In intact lambs, an immediate dose-dependent increase in minute ventilation (V1) was observed. At 2 min, VI increased from baseline by 125 +/- 28, 212 +/- 49, 378 +/- 41 and 637 +/- 92 mol.kg 1.min 1 (mean +/- SE, P less than 0.01) corresponding to the foregoing incremental doses. A significant correlation was observed between the peak VI and the corresponding plasma keto-doxapram concentrations (r = 0.73, P less than 0.0003). In CBD lambs, VI increased significantly less than in intact animals. In conclusion, early ventilatory response to keto-doxapram depends mainly on intact carotid bodies, and the effect is dose-dependent.

Animals↗
PubMed1995

Doxapram stimulates dopamine release from the intact rat carotid body in vitro.

Hypoxic chemotransduction by the carotid body is believed to involve inhibition of K+ channels in type I cells, leading to depolarization and the opening of Ca2+ channels which triggers catecholamine release. We have investigated whether the clinically used ventilatory stimulant doxapram (which, like hypoxia, blocks K+ channels in isolated type I cells) also stimulates catecholamine release from the intact carotid body in vitro, by pre-incubating tissues with [3H]tyrosine. 3H overflow was evoked by raised extracellular [K+] (60 mM) and by cyanide (2 mM). Doxapram (15-150 microM) also evoked 3H overflow in a concentration dependent manner, and doxapram-evoked release was inhibited by the Ca2+ channel blocker nifedipine (5 microM). Analysis of released tritiated compounds suggested that doxapram preferentially stimulated the release of dopamine. Our results indicate that the mechanism of action of doxapram shares similarities with that of hypoxia in the carotid body.

Animals↗
PubMed2000

Doxapram accentuates white matter injury in neonatal rats following bilateral carotid artery occlusion.

The effect of the respiratory stimulant, doxapram, on white matter damage was investigated in neonatal rats under cerebral ischemia. Five-day-old rats underwent bilateral carotid artery occlusion with or without 50 mg/kg i.p. of doxapram. Their brains were neuropathologically examined 48 h later. Doxapram induced about a 20% decrease of PCO(2) for 90 min, but did not cause any neuropathological abnormalities. Bilateral carotid artery occlusion resulted in mild cerebrocortical lesions in 67% of pups, and white matter lesions in the internal capsule in 44%. Doxapram, in addition to bilateral carotid artery occlusion, produced more severe white matter injury in the internal capsule (injury score; 0.67+/-0.87 vs. 1.70+/-0.48, P<0.05) and in the subcortical white matter (0.33+/-0. 67 vs. 1.10+/-0.54, P<0.05). These results demonstrated that the use of doxapram under an ischemic condition accentuates white matter damage in neonatal rats.

Animals↗
PubMed2006

Doxapram and aminophylline on bispectral index under sevoflurane anaesthesia: a comparative study.

BACKGROUND AND OBJECTIVE: To evaluate and compare the effect of two clinically available central nervous system stimulants, namely doxapram and aminophylline on arousal from sevoflurane anaesthesia and bispectral index. METHODS: This randomized, double-blind, placebo-controlled, prospective study was conducted in 90 adult females, ASA I-II, scheduled for elective lower abdominal surgeries at Taipei Medical University Hospital. At 5 min before the completion of surgery, under sevoflurane anaesthesia, patients were divided into three groups to receive doxapram 1 mg kg(-1), aminophylline 2 mg kg(-1) or saline placebo intravenous. Standard vital signs, end-tidal CO(2), end-expiratory sevoflurane concentration, bispectral index and neuromuscular blockade were measured plus clinical parameters of recovery from general anaesthesia. RESULTS: Compared with the control group, patients receiving doxapram or aminophylline showed a similarly faster recovery from sevoflurane anaesthesia correlated with increase in bispectral index. CONCLUSION: Intravenous administration of doxapram 1 mg kg(-1) or aminophylline 2 mg kg(-1) hastened the early recovery from sevoflurane anaesthesia. The arousal effect of aminophylline and doxapram appears to be similar.

Adult↗
PubMed1991

Gastrointestinal absorption of doxapram in neonates.

Doxapram was administered orally to six premature babies (3 males, 3 females) with refractory apnea at a mean gestational age of 29 +/- 2.3 weeks, mean birthweight of 1142 +/- 359 gm and a mean postnatal age of 24 days. They received 12, 24, and 36 mg/kg/6 hr on day 1, 2, and 3, respectively, assuming a bioavailability of 50%. Serial plasma doxapram concentrations, determined by high-performance liquid chromatography, increased with incremental doses. The drug underwent oxidative metabolism, producing ketodoxapram, the plasma concentration of which remained stable during treatment. The ratio of plasma concentrations to oral doses ranged from 0.10 to 0.12, suggesting that doxapram is poorly absorbed in the newborn. Oral doxapram may replace the intravenous infusion but doses may have to be increased to, but not exceeding, 24 mg/kg/6 hr to achieve therapeutic plasma concentrations. Interpatient variability, poor absorption and gastrointestinal adverse effects caution against the routine use of oral doxapram.

Administration, Oral↗
PubMed1978

A study of naloxone and doxapram as agents for the reversal of neuroleptanalgesic respiratory depression in the conscious rabbit.

The effectiveness of naloxone and doxapram in reversing the respiratory depressant actions of fentanyl and droperidol in the rabbit has been examined. Both drugs did not reverse fully the depression of respiratory frequency produced by the neuroleptanalgesic agents. Doxapram also failed to reverse fully the depression of minute volume produced by fentanyl and droperidol, although naloxone was adequate in this respect. However, analysis of arterialized venous blood showed that both naloxone and doxapram not only prevented the increase in PCO2 caused by fentanyl and droperidol, but caused also a significant decrease. A reduction in PCO2 was seen also when either naloxone or doxapram was given to untreated rabbits. With doxapram this appeared to be a result of pure respiratory stimulation. Naloxone also produced a reduction in standard bicarbonate.

Animals↗
PubMed1979

A pharmacokinetic study of doxapram in patients and volunteers.

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi-exponential fashion. The mean half-life from 4-12 h was 3.4 h (range 2.4-4.1h), the mean apparent volume of distribution was 1.5 1 kg-1 and the whole body clearance was 370 ml min-1. 2. Enteric-coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half-life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady-state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion régime.

Administration, Oral↗
PubMed2004

Effects of doxapram HCl on laryngeal function of normal dogs and dogs with naturally occurring laryngeal paralysis.

OBJECTIVES: To compare the effects of IV doxapram on glottic size and arytenoid motion in normal dogs and in dogs with laryngeal paralysis. STUDY DESIGN: Prospective experimental and clinical trials. ANIMALS: Six healthy dogs weighing 24.5 +/- 3.9 kg and six dogs weighing 27.4 +/- 11.5 kg suspected of having laryngeal paralysis. METHODS: Dogs were pre-medicated with acepromazine and butorphanol, and a light plane of anesthesia was induced with isoflurane by mask. Videoendoscopic examination of laryngeal function was recorded before (baseline) and after IV doxapram administration. Normalized glottal gap area (NGGA) at maximal inspiration and expiration, and percentage change in height, width, area, and NGGA were calculated with measurements from digitized images of the glottal gap. RESULTS: Active arytenoid motion was present in all normal dogs at baseline. After doxapram administration, depth of respiration appeared greater, but arytenoid motion, as measured by percentage change in NGGA, and in area and width, did not significantly increase in normal dogs. No arytenoid motion was detected in dogs with laryngeal paralysis at baseline; however, rima glottidis NGGA of dogs with laryngeal paralysis was greater at inspiration and expiration than normal dogs. After doxapram administration, dogs with laryngeal paralysis developed paradoxical arytenoid motion and significant, negative percentage change in area (-61%) and NGGA (-145%) because of inward collapse of the arytenoids during inspiration. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of doxapram during laryngeal examination is useful for differentiating normal dogs from dogs with laryngeal paralysis. Dogs with laryngeal paralysis may suffer extreme glottic constriction with vigorous respirations, and may require intubation during examination.

Animals↗
PubMed2005

Doxapram inhibits carotid sinus baroreceptors in rabbits.

1 To clarify the effects of doxapram on the baroreflex, we recorded carotid sinus nerve (CSN) activity in isolated and perfused carotid artery bifurcations of rabbits. 2 The CSN activity due to chemoreceptor stimulation was blocked by resection of the nerve branches from the carotid body. After the resection, the CSN activity was correlated to increase of carotid sinus (CS) pressure. 3 Administration of doxapram reduced the CSN activity originating from baroreceptors. The effect of doxapram on baroreceptors was dose dependent and reversible. 4 It is unlikely that doxapram altered CS wall mechanics because CS pressure did not change in the presence of the drug. 5 We conclude that doxapram acts on the cardiovascular system in part by inhibiting the negative feedback loop that originates in CS baroreceptors.

Animals↗
PubMed1990

Doxapram infusion during halothane anaesthesia in ponies.

Doxapram, 0.05 mg/kg bodyweight/min, was infused during the second hour of 2 h halothane anaesthesia in six ponies. Two of the ponies were anaesthetised on a second occasion as controls and given 5 per cent dextrose in place of the doxapram. Respiratory depression typical of halothane anaesthesia in ponies developed in the first hour of anaesthesia and continued during the second hour in the control animals. During doxapram infusion arterial carbon dioxide tension decreased and pH increased. Arterial blood pressure increased but there was no change in pulse rate, the electrocardiogram or arterial oxygen tension. Anaesthesia lightened during doxapram infusion necessitating an increase in the vapouriser setting in order to prevent arousal. Recovery from anaesthesia appeared unaffected by the doxapram infusion.

Anesthesia↗