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PubMed1996

Comparison of the acute effects on gas exchange of nasal ventilation and doxapram in exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Nasal intermittent positive pressure ventilation (NIPPV) is useful in exacerbations of chronic obstructive pulmonary disease (COPD) complicated by ventilatory failure. The effects of NIPPV were compared with those of the respiratory stimulant doxapram on gas exchange in patients with COPD and acute ventilatory failure. METHODS: Patients admitted with acute exacerbations of COPD and type 2 respiratory failure (Pao2 < 8 kPa and PaCO2 > 6.7 kPa) who did not improve with conventional treatment were randomised to receive either NIPPV or intravenous doxapram. Blood gas tensions were monitored for four hours. RESULTS: In nine patients who received NIPPV the arterial PaO2 improved from a mean (SE) of 5.9 (0.4) kPa to a maximum of 8.1 (0.6) kPa which was maintained at four hours. Eight patients who received doxapram had a similar baseline Pao2 of 5.6 (0.4) kPa which rose to a maximum of 7.3 (0.5) kPa but this was not maintained at four hours. The improvement in Pao2 in patients on NIPPV was accompanied by a fall in Paco2 but, in contrast, in those who received doxapram there was no improvement in Paco2. CONCLUSIONS: NIPPV may be more effective than doxapram in the management of acute ventilatory failure complicating COPD.

Doxapram↗
PubMed1999

Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants.

AIM: To study the effect of doxapram on the frequency of apnoea, bradycardia and hypoxaemia. METHODS: Fifteen infants, median gestational age at birth 27 weeks (range 24-30), age at study 27 days (12-60), with >/=6 episodes of bradycardia or hypoxaemia/6 h despite serum caffeine levels in the therapeutic range, received doxapram either intravenously (0.5-2 mg/kg/h) or orally (2-8 mg/kg every 2 h). Six-hour recordings of pulse oximeter saturation (S(P)O(2)), pulse waveforms, ECG, breathing movements and nasal airflow were performed immediately before as well as 1, 3 and 6 days after onset of treatment. Recordings were analysed for apnoea (>/=4 s), bradycardia (heart rate < 2/3 of baseline) and hypoxaemia (S(P)O(2) </=80%). RESULTS: There was no difference between enteral and intravenous administration; results are therefore presented for the total group. Doxapram resulted in a significant decrease in the frequency of apnoea [22 (11-27) vs. 14 (7-23)/h, p < 0.01], bradycardia [3 (0-7) vs. 1 (0-3)/h, p < 0.01] and hypoxaemia [8 (0-18) vs. 2 (0- 17)/h, p < 0.01] already after 1 day of treatment, which was sustained throughout the 6-day study period. Side effects included an increase in the proportion of time spent awake [5 (0-24) vs. 12% (3-28), p < 0.01] and in gastric residuals [0% of feeding volume (0-5) vs. 4% (0-19), p < 0.05]. Enteral was switched to intravenous doxapram in 3 of 9 infants because of gastrointestinal side effects. CONCLUSION: Doxapram substantially reduced the frequency of apnoea, bradycardia and hypoxaemia in these patients with caffeine-resistant apnoea of prematurity. Enteral administration, however, was not tolerated in a significant proportion (33%) of infants.

Apnea↗
PubMed2003

Doxapram produces a dose-dependent reduction in the shivering threshold in rabbits.

Dopamine is a thermoregulatory neurotransmitter that provokes hypothermia when injected in or near the hypothalamus. Doxapram stimulates release of dopamine from carotid bodies, but is known to have central effects that are probably, at least in part, similarly mediated. We thus tested the hypothesis that doxapram produces a substantial, dose-dependent reduction in the shivering threshold in rabbits. Twenty-four rabbits, anesthetized with isoflurane, were randomly assigned to 1) saline (control), 2) 0.25 mg x kg(-1) x h(-1) doxapram, or 3) 0.50 mg x kg(-1) x h(-1) doxapram. These doses are within the recommended range for humans. Body temperature was reduced at a rate of 2 degrees to 3 degrees C/h by perfusing water at 10 degrees C through a U-shaped thermode positioned in the colon. Core temperatures were recorded from the distal esophagus. A blinded observer evaluated shivering. Core temperature at the onset of shivering defined the threshold. Data were analyzed with a one-way analysis of variance; P < 0.05 was considered statistically significant. Hemodynamic and respiratory responses were comparable in the groups. The control rabbits shivered at 36.3 degrees +/- 0.3 degrees C, those given 0.25 mg x kg(-1) x h(-1) doxapram shivered at 34.8 degrees +/- 0.5 degrees C, and those given 0.50 mg x kg(-1) x h(-1) shivered at 33.7 degrees +/- 0.6 degrees C. All the shivering thresholds significantly (P < 0.001) differed from one another. The magnitude of this inhibition, if similar in humans, would be clinically important.

Anesthesia, Inhalation↗
PubMed1991

Lack of a pharmacokinetic interaction between doxapram and theophylline in apnea of prematurity.

To examine the possibility of a pharmacokinetic interaction between doxapram and theophylline, both drugs (1.5 mg/kg/h doxapram, and 0.5 mg/kg/h theophylline) were administered in that order and in reverse order to patients with apnea of prematurity. During the therapeutic steady state phase of doxapram considerable serum theophylline concentrations were found despite discontinuation of the latter drug for at least 48 h. Serum doxapram concentrations during theophylline steady state were negligible. Pretreatments of theophylline failed to alter the pharmacokinetic indices of doxapram. Thus, a lack of pharmacokinetic interaction between the two drugs was demonstrated.

Apnea↗
PubMed1989

[A pharmacologic respiratory stimulant, doxapram, used in acute deterioration in patients with chronic respiratory failure].

In a controlled study with random allocation, the effect of doxapram (Dopram), a respiratory stimulant, was evaluated in 25 patients with acute on chronic respiratory failure requiring ventilator support. Eleven patients were allocated to mechanical ventilation and 14 to treatment with doxapram given as a variable rate infusion. In the doxapram group only four were transferred to mechanical ventilation after 1 1/2 to three days of treatment. In these patients, the problem giving rise to the acute exacerbation, was not under control at the time of ventilator intervention. In the remainder of the group, antibiotics, diuretics and bronchodilators had successfully treated the exacerbation. All patients were discharged alive. In the doxapram-treated group duration of hospitalization was nine days compared to 14 days (median values) in the ventilator-treated group. Only minor side-effects from doxapram were observed, and it is concluded that this respiratory stimulant can be used as a primary drug in patients with acute respiratory failure and chronic airflow limitation.

Aged↗
PubMedDate not supplied

[Oral administration of doxapram in preterm neonates with aminophylline-resistant idiopathic apnea crisis].

Doxapram is an analeptic capable of stimulating both central and periferal areas of the respiratory system. During the last few years, intravenous infusion of doxapram has been carried out, with success, for the treatment of idiopathic apnea in preterm infants otherwise unresponsive to methylxantine. Since doxapram has a tendency to precipitate into various solution containing amino acids and calcium gluconate, oral administration has been suggested. The Authors in this study have seen that in 18 preterm infants suffering from idiopathic apnea unresponsive to amynofillina, an oral administration of doxapram at 12 mg/kg/6h resulted in a complete recovery from apnea spells in 66.7% of cases, while 22.2% gave a partial positive response and only 11.1% a negative result. Furthermore the Authors would like to stress that doxapram showed a good tolerance level when administered orally. In fact, no side effects which were previously reported in other publications were presented in the infants studied.

Administration, Oral↗
PubMed1979

The disposition of intravenous doxapram in man.

The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg . kg-1) and by intravenous infusion (6.5 mg . kg-1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances 5.9 and 5.6 ml . min-1 . kg-1) following i.v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 microgram . ml-1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 microgram . ml-1 from 15--25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.

Adult↗
PubMed1983

The effects of doxapram, diazepam, phenobarbital and pentylenetetrazol on suprathreshold and threshold stimulations in amygdaloid kindled rats.

Amygdaloid kindled rats were utilized to determine the effects of the respiratory stimulant, doxapram (7.5-60 mg/kg) on seizures elicited by suprathreshold or threshold electrical stimulation. For comparison, a single dose of pentylenetetrazol (30 mg/kg), phenobarbital (40 mg/kg) and diazepam (2 mg/kg) were also tested in the same paradigm. With suprathreshold stimulation, doxapram did not increase the intensity of seizures. Neither the afterdischarge duration (AD) nor the behavioral rank (BR) were increased with doses high enough to cause systemic signs of toxicity. Similarly, the convulsant pentylenetetrazol did not increase AD or BR after suprathreshold stimulation. The anticonvulsants phenobarbital and diazepam significantly reduced both AD and BR after suprathreshold stimulation. Seizure thresholds tended to be higher after the various doses of doxapram with no consistent effect on elicited AD or BR. Pentylenetetrazol did not change threshold values, but was found to increase AD and BR at threshold. Both phenobarbital and diazepam raised thresholds with a significant decrease in elicited AD and BR. It would appear that the respiratory stimulant doxapram has little proconvulsant activity in this model of epilepsy.

Amygdala↗
PubMed1986

The effects of doxapram on breathing, heart rate and blood pressure in fetal lambs.

In experiments to assess its value in the study of fetal arterial chemoreceptor reflexes, doxapram (0.5 - 2 mg i.a.) given to unanaesthetized fetal lambs in utero in low voltage electrocortical activity stimulated fetal breathing in 73% of trials. The response began within a few seconds and lasted up to 5 min. This response to doxapram was present in intact or mid-collicular brainstem transected fetuses and after bilateral section of the carotid sinus nerves and cervical vagosympathetic trunks (denervation). In intact and brainstem transected fetuses, doxapram injections were followed by a modest rise in arterial pressure and a small fall in heart rate. After denervation the rise in arterial pressure was fourfold and the heart rate increased. Electrocortical activity and limb movements were not affected in any group of lambs, and fetal breathing was not induced during isocapnic hypoxia. It is concluded that doxapram stimulates fetal breathing by a central action below the pons, and that it can therefore not be used to study peripheral arterial chemoreceptor function in utero.

Animals↗
PubMed1986

Physiologic effects of doxapram in idiopathic apnea of prematurity.

Twelve premature infants with significant apnea of prematurity while receiving therapeutic doses of aminophylline were given an intravenous infusion of doxapram, 2 or 2.5 mg/kg/hr. The ventilatory effects of the medication were monitored by means of face mask spirometry and airway occlusion studies. Doxapram therapy was associated with significant increases in minute ventilation, tidal volume, mean inspiratory flow, and airway pressure 100 msec after occlusion. Respiratory frequency and the relative duration of inspiration and expiration were unchanged. Paco2 decreased significantly during the infusion. The apnea attack rate, monitored by continuous recording, was significantly reduced after the first 6 hours of therapy. Six hours after starting doxapram, mean arterial blood pressure was significantly elevated, and continued to increase during the 24 hours of therapy. Doxapram is effective in treatment of apnea of prematurity refractory to aminophylline, and appears to act by increasing respiratory center output.

Aminophylline↗
PubMed1980

Quantitation of doxapram in blood, plasma and urine.

Methods for the quantitation of doxapram in blood, plasma and urine have been developed. Following extraction, gas-liquid chromatography was used to separate doxapram from basic metabolites. Doxapram was detected by mass spectrometry for blood and plasma assays, and by flame ionisation for urine assays. The limit of reliable quantitation in blood and plasma was 10 ng and in urine 500 ng, the coefficients of variation being 6.37%, 1.72% and 2.31% respectively. To illustrate the clinical applicability of the assay methods, plasma, blood and urine levels were monitored in a premature newborn following an intravenous infusion of doxapram.

Apnea↗
PubMed1978

A study of the enhanced toxicity of doxapram in rodents treated with narcotic analgesics.

It has been shown in both mice and rats that the LD50 value for doxapram is reduced in rodents treated with narcotic analgesics. In both species the site of the toxic interaction appears to be the cardiovascular system. Doxapram alone, in sub-lethal doses, appears to cause conduction defects in the heart and this action of doxapram is increased in rodents treated with morphine. The enhancement of the toxicity of doxapram by morphine appears to involve an action in the central nervous system probably not related to respiratory depression.

Analgesics, Opioid↗
PubMed1989

Effect of oral doxapram on morphine-induced changes in the ventilatory response to carbon dioxide.

A double-blind crossover volunteer trial has been carried out to determine if oral doxapram reduces the respiratory depression caused by morphine 0.12 mg kg-1 i.m. Doxapram was given to the subjects 90 min before the morphine and significantly reduced the displacement of the ventilatory response to carbon dioxide caused by the morphine. This occurred despite the fact that the plasma concentrations of doxapram were significantly lower when the subject had been given morphine than when a placebo injection had been administered. Doxapram alone in doses of 300 mg and 600 mg did not alter significantly the respiratory variables measured in this study.

Administration, Oral↗
PubMed1993

Double-blind comparison between doxapram and pethidine in the treatment of postanaesthetic shivering.

Sixty patients who shivered after routine surgery under general anaesthesia were allocated randomly to receive normal saline (n = 20), doxapram 1.5 mg kg-1 (n = 20) or pethidine 0.33 mg kg-1 (n = 20). Both doxapram and pethidine were effective in treating postoperative shivering 2-3 min after i.v. administration. In the group who received normal saline, 15 patients were still shivering 10 min after treatment, whilst in the doxapram group only three patients were shivering at that time. In the pethidine group, all patients had stopped shivering by 7 min after treatment. We conclude that both doxapram and pethidine were effective in the treatment of postoperative shivering.

Adolescent↗
PubMed1981

Electroencephalographic evidence of arousal in dogs from halothane after doxapram, physostigmine, or naloxone.

The clinical impressions of enhanced arousal from halothane anesthesia and improvement of postanesthesia recovery scores after doxapram, physostigmine, or naloxone have not been verified in laboratory studies based on the effect of these drugs on MAC. With induction of anesthesia, a shift in the amplitude of the EEG from low to high occurs at anesthetic concentrations well below MAC and appears to coincide with the loss of consciousness. The authors examined the effect of arousal agents on the end-tidal halothane concentration required to produce this shifting EEG. In 24 unmedicated dogs, the end-tidal halothane concentration was elevated to 20 per cent above the shift point concentration (from 0.61 +/- 0.03 to 0.73 +/- 0.03 per cent) and maintained at this level for 30 min. Doxapram, 1 mg/kg, iv, and physostigmine, 0.03 mg/kg, iv, converted the EEG from a high amplitude to a low amplitude tracing in 22 +/- 3 s in eight of eight, and 225 +/- 37 s in seven of eight dogs, respectively. The end-tidal halothane concentration required to restore the shifting EEG was elevated above control for 50 +/- 7 min and 109 +/- 7 min, respectively. Naloxone, 0.06 mg/kg, iv, produced an awake EEG in two of eight dogs in 233 +/- 18 s which persisted for 22 +/- 4 min, and a transiently shifting EEG in three of eight dogs between 200 and 240 s. Naloxone 0.006, mg/kv, iv, produced an awake EEG in 80 +/- 8 s in four of four dogs who had previously received doxapram 3 h earlier. In this model doxapram and physostigmine paralleled the clinically observed onset and duration of arousal. The inconstant arousal from halothane anesthesia induced by naloxone was interpreted in terms of an opiate receptor independent action.

Anesthesia, Inhalation↗
PubMedDate not supplied

Respiratory psychophysiology and anxiety: cognitive intervention in the doxapram model of panic.

UNLABELLED: The goals of this study were to: a) confirm prior evidence that the respiratory stimulant doxapram induces panic attacks and produces excessive hyperventilation in patients with panic disorder and b) explore the impact of cognitive mediators on symptom and respiratory responses. METHOD: Thirty-two subjects (16 patients and 16 controls) received doxapram (0.5 mg/kg) and placebo infusions while symptom, respiratory, and heart rate responses were monitored. Subjects were randomly assigned to receive either a standard introduction or a cognitive intervention designed to reduce the panic responses of panic patients to laboratory challenges. RESULTS: Doxapram was a potent and specific panicogenic agent, inducing panic in 75% of patients and 12.5% of controls. Compared with controls, patients also showed a greater decrease in end tidal carbon dioxide (CO2) and greater increases in minute ventilation, respiratory frequency, and heart rate. The cognitive intervention substantially attenuated the excessive hyperventilatory response of patients but did not fully normalize their breathing patterns. Tidal volume was the only respiratory measure not significantly altered by the cognitive intervention. CONCLUSIONS: In patients with panic disorder, doxapram (0.5 mg/kg) triggers panic attacks about as potently as 7% CO2 and more potently than 5% CO2 or lactate. Psychological factors can modulate the appearance of ventilatory abnormalities in panic patients, but persistent respiratory disturbances were still seen. Psychological factors and respiratory physiology both appear to be important phenomena in laboratory panic.

Adult↗
PubMed1982

Doxapram and the fractured femur.

In a double-blind trial the effects of a single dose of doxapram (1--1.5 mg/kg) on the postoperative arterial oxygen tension of patients who had undergone surgical fixation of a fractured neck of femur was measured. In contrast to other reports of the effect of a single dose of doxapram, there was no improvement in arterial oxygen tension with respect to the control group. It is reasoned that doxapram may exert its effect by increasing the functional residual capacity in the immediate postoperative period. The central analeptic properties of doxapram may be grossly underestimated. The widely held assumption that patients with a fractured neck of femur are significantly hypoxic pre-operatively is questioned.

Aged↗
PubMed1988

Patient-controlled analgesia with a mixture of pethidine and doxapram hydrochloride. A comparison of the incidence of respiratory dysrhythmias with pethidine alone.

Twenty-four patients who underwent elective cholecystectomy received double-blind increments of either pethidine 30 mg or a mixture of pethidine 30 mg and doxapram 45 mg delivered on a patient-controlled basis. A loading dose of doxapram 100 mg or saline was administered. There was no difference in respiratory depression as indicated by respiratory frequency and end tidal carbon dioxide concentration. The incidence of respiratory apnoea was similar in the two groups but apnoea was of shorter duration in patients who received doxapram, although the difference was not significant. Patients who received doxapram assessed overall pain as worse on a linear analogue scale (p less than 0.05) but demanded similar amounts of pethidine. There was no difference in pain on movement.

Adult↗