Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

The effects of doxapram on haematology, serum biochemical parameters and erythrocyte oxidant/ antioxidant status in dogs anaesthetized with propofol.

The present prospective randomized experimental study was designed to determine the effects of doxapram on haematological, serum biochemical and antioxidant status in dogs after propofol anaesthesia. Twenty-four healthy male mixed breed dogs, aged 1-2 years, weighing 20.4 ± 2.6 kg was studied. Each dog was anaesthetized twice, with at least one week for washout. Animals were sedated with acepromazine (0.1 mg/kg) intramuscularly. Forty minutes later, anaesthesia was induced using intravenous (IV) propofol (4 mg/kg) titration and maintained for 30 min by propofol (0.2 mg kg-1  min-1 ). After propofol was discontinued, doxapram (2 mg/kg) hydrochloride was administrated IV in PD treatment while an equal volume of saline was administrated in PS treatment. Blood parameters were analysed in four times: immediately before sedation (T1), after treatment (T2), after complete recovery (T3) and 24 hr later (T4). Haematological assessments revealed no significant difference between treatments except in haematocrit which was significantly reduced at T4 (24 hr later) in PD. A decreasing trend of all haematological variables was observed after doxapram administration until recovery, except monocyte, mean corpuscular haemoglobin, red blood cell distribution width and platelet count. Serum urea, creatinine, glucose, cholesterol, direct bilirubin concentration and alanine aminotransferase activity were not changed following doxapram administration compared to the PS treatment. After doxapram administration, Creatinine (T3), Albumin (T2) and Protein (T2 & T3) decreased while Glucose (T2 & T3) and BT (T3) increased. Antioxidant parameters measured showed no difference between treatments or time. Doxapram (2 mg/kg) IV did not induce any major negative effects on haematological, serum biochemical variables and oxidant/antioxidant status in dogs after propofol anaesthesia.

Emergence agitation in adults: risk factors in 2,000 patients.

PURPOSE: The study was designed to determine the incidence of postoperative agitation following general anesthesia in 2,000 adult patients and to examine the associated risk factors. METHODS: The study enrolled 2,000 adults who were scheduled for surgery under general anesthesia in a single institution during December 2007 to December 2008. The following risk factors were examined: age, gender, ASA physical status, type of surgery, anesthesia technique (inhalational or intravenous), administration of neostigmine or doxapram, adequate postoperative analgesia, pain, presence of a tracheal tube, and presence of a urinary catheter. RESULTS: Agitation occurred in 426 patients (21.3%). It was more common in males (28.1%) than in females (16.1%) (P = 0.017) and more prevalent after inhalational (27.8%) than total intravenous (7.5%) anesthesia (P = 0.001). Agitation was more common after oral cavity and otolaryngological surgery than after other types of surgery. Multivariate analysis showed that use of doxapram (odds ratio [OR] = 9.2; 95% confidence interval [CI] = 6.2 - 15.4; P = 0.002) and pain (OR = 8.2; 95% CI = 4.5 - 16.9; P < 0.001) were the most important risk factors associated with emergence agitation. Other causes were the presence of a tracheal tube and/or a urinary catheter. Adequate postoperative analgesia was associated with less agitation (OR = 0.4; 95% CI = 0.1 - 0.4; P = 0.006). CONCLUSION: Doxapram administration, pain, and presence of a tracheal tube and/or a urinary catheter appear to be the most important causes of postoperative agitation. To avoid this complication, it is suggested, whenever possible, to use intravenous anesthesia, to remove endotracheal tubes and urinary catheters as early as possible, and to provide adequate postoperative analgesia.

Blood potassium and urine aldosterone after doxapram therapy for preterm infants.

OBJECTIVE: We often encounter infants who developed hypokalaemia following low-dose doxapram for apnea of prematurity (AOP). AIMS: To determine changes in blood potassium (K+) levels after doxapram administration. STUDY DESIGN: We studied infants born before 30 weeks gestation. Doxapram (0.1-0.3 mg/kg/h) in addition to methylxanthines was used to treat AOP refractory to methylxanthines. RESULTS: Twenty-five infants received doxapram were studied. Fifty-two percent developed hypokalemia (<3.0 mEq/L) during doxapram administration. Time after starting doxapram to nadir blood K+ (<3.0 mEq/L) level was 11 days. Blood K+ levels normalized after 5 days of stopping doxapram administration. Data at 10 days before and after and at the time of doxapram administration were, respectively: lowest blood K+ level: 3.9, 3.0, and 3.6 mEq/L; urine aldosterone: 90, 206, and 146 pg/µg creatinine. Blood pH, blood pressure and urine volume were similar. CONCLUSIONS: Doxapram-induced hypokalemia may be due to an inappropriate increase in aldosterone levels.

Long-Term Neurodevelopmental Outcome after Doxapram for Apnea of Prematurity.

BACKGROUND: Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP). OBJECTIVE: To evaluate the effect of doxapram on long-term neurodevelopmental outcome in preterm infants as its safety still needs to be established. METHODS: From a retrospective cohort of preterm infants with a gestational age (GA) <30 weeks and/or a birth weight <1,250 g, born between 2000 and 2010, infants treated with doxapram (n = 142) and a nontreated control group were selected (n = 284). Patient characteristics and clinical and neurodevelopmental outcome data at 24 months' corrected age were collected. Neurodevelopmental delay (ND) was defined as having a Mental or Psychomotor Developmental Index (MDI/PDI) <-1 standard deviation (SD), cerebral palsy, or a hearing or visual impairment. Odds ratios (OR) were calculated using multiple logistic regression analyses adjusting for potential confounders. RESULTS: Infants treated with doxapram had a lower GA compared to controls. The number of infants with a MDI or PDI <-1 SD was not different between the groups. The risk of the combined outcome death or ND was significantly lower in the doxapram group after adjusting for confounding factors (OR = 0.54, 95% CI: 0.37, 0.78). Doxapram-treated infants had a higher risk of bronchopulmonary dysplasia and patent ductus arteriosus, but a lower risk of spontaneous intestinal perforation. All other morbidities were not different between the groups. CONCLUSIONS: This study suggests that doxapram is not associated with an increased risk of ND. These findings need to be confirmed or refuted by a large, well-designed, placebo-controlled randomized trial.

Doxapram increases corticotropin-releasing factor immunoreactivity and mRNA expression in the rat central nucleus of the amygdala.

Doxapram causes panic anxiety in humans. To determine whether doxapram alters corticotropin-releasing factor (CRF) expression in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), or bed nucleus of the stria terminalis (BNST), we used immunohistochemistry to measure CRF peptide in these brain areas after doxapram injection. Doxapram injection significantly increased CRF-like immunoreactivity (CRF-IR) within the CeA, but not in the BNST or PVN, and this increase was significant 2h after injection. In addition, doxapram significantly increased CRF mRNA expression within the CeA, and this was most prominent 30min after injection. These results suggest that doxapram selectively increases CRF expression within the CeA, and that this is mediated by increased CRF gene transcription. This increase in CRF-IR within the CeA might explain the doxapram-induced anxiety reaction.

Doxapram-induced panic attacks and cortisol elevation.

Numerous agents with differing biological properties and central nervous system (CNS) effects can induce panic attacks in predisposed individuals. A potential explanation of this finding is that panic disorder patients are more likely to panic than normal control subjects when given a panicogen due to an excessive fear response to somatic arousal. We test this hypothesis by using doxapram, a panicogen with minimal CNS effects, to induce panic in patients and control subjects. Doxapram was given to six subjects with panic disorder with or without agoraphobia and four healthy volunteers. Measures comprised the Acute Panic Inventory, the Borg Exertion scale, the 10-point Anxiety Scale, the 10-point Apprehension Scale, cortisol, prolactin, and MHPG, all obtained at baseline and multiple time points after the doxapram infusion. All panic disorder patients panicked with doxapram, whereas no control subjects had a panic attack. Panic patients had similar levels of breathlessness with doxapram compared with control subjects. Although panic patients had higher levels of anxiety and apprehension, these did not change significantly with doxapram compared with control levels. Doxapram led to similar increases in cortisol and prolactin in both groups, and MHPG was consistently elevated in panic patients, but unaffected by doxapram. These results show that doxapram is a useful panicogen in the study of panic disorder. Since the panic patients and control subjects had similar levels of physiological and psychological arousal, but the panic patients were more likely to have a panic attack, this lends support to the concept of a sensitized fear network in panic disorder patients.

QT interval lengthening in premature infants treated with doxapram.

OBJECTIVE: Doxapram, routinely used in premature infants treated for apnea of prematurity unresponsive to methylxanthines, has been related to cardiac conduction disorders. This study was designed to evaluate doxapram cardiac and general tolerance and its relationship to drug plasma concentrations in very premature infants. METHODS: Forty infants (mean +/- SEM, 28.9 +/- 0.3 weeks of gestation) who were given intravenous doxapram, 0.5 to 1 mg/kg per hour, at 15.9 +/- 2.4 days of life were evaluated prospectively. Electrocardiograms were monitored before and during the first 3 days of treatment. QT interval corrected for heart rate (QTc) longer than 440 ms was regarded as clinically pertinent, given that it is considered a significant risk of conduction disorder leading to torsades de pointes and sudden death. Other side effects were recorded. Toxic plasma concentration of doxapram and ketodoxapram was set at >4 mg/L. RESULTS: A statistically significant but moderate lengthening of QTc interval has been observed from 394 +/- 4 ms before doxapram to 409 +/- 4 ms at 48 and 72 hours of treatment (P =.0065). For 6 patients, QTc interval became longer than 440 ms without any other rhythm or conduction disorder. Digestive disorders were observed in 20 infants but 9 presented with concomitant septicemia. No relationship was found between presence or absence of adverse effects and drug plasma concentrations. CONCLUSION: Our study enlightened the lengthening effect of doxapram on QTc interval in premature infants with a risk of exceeding the 440 ms threshold that is considered life-threatening. This finding emphasizes the need for electrocardiogram follow-up when using doxapram in neonates.

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.

Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation.

BACKGROUND: When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory effort and tendency to develop hypoventilation and apnea, particularly in very preterm infants. Doxapram stimulates breathing and appears to act via stimulation of both the peripheral chemoreceptors and the central nervous system. This effect might increase the chance of successful tracheal extubation. OBJECTIVES: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with doxapram reduce the use of intubation and IPPV, or reduce other morbidity, without clinically important side effects? In this regard, how does doxapram compare with standard treatment or with an alternative treatment such as methylxanthine or CPAP? Subgroup analyses were prespecified according to birth weight and/or gestational age, use of co-interventions (methylxanthines or nasal CPAP), and route of administration (intravenous or oral). SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE and EMBASE. SELECTION CRITERIA: Eligible studies included published trials utilising random or quasi-random patient allocation in which preterm or low birth weight infants being weaned from IPPV were given doxapram compared with standard care or other treatments, to facilitate weaning from IPPV and endotracheal extubation. Trials were independently assessed by the authors before inclusion. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each author extracted data separately; the results were compared and any differences resolved. The data were synthesized using the standard method of Neonatal Review Group with use of relative risk and risk difference. MAIN RESULTS: Two trials involving a total of 85 infants compared doxapram and placebo. In both the individual trials and the meta-analyses there were no significant differences between the doxapram and placebo groups in any of the outcomes (failed extubation, death before discharge, respiratory failure, duration of IPPV, side effects, oxygen at 28 days or oxygen at discharge). There was a trend towards an increase in side effects (hypertension or irritability leading to cessation of treatment) in the doxapram group [summary RR 3.21 (0.53, 19.43). In one of these two trials (Huon 1998) an 'alarming rise in blood pressure' occurred in five infants in the doxapram group and none of the controls, although in only one was treatment withdrawn. One additional trial involving only eight infants compared doxapram with aminophylline, but there were insufficient data for meaningful analysis. REVIEWER'S CONCLUSIONS: The evidence does not support the routine use of doxapram to assist endotracheal extubation in preterm infants who are eligible for methylxanthine and/or CPAP. The results should be interpreted with caution because the small number of infants studied does not allow reliable assessment of the benefits and harms of doxapram. Further trials are required to evaluate the benefits and harms of doxapram compared with no treatment or with other treatments, such as methylxanthines or CPAP, to evaluate whether it is more effective in infants not responding to these other treatments, and to assess whether the drug is effective when given orally.

The effect of doxapram-induced hyperventilation on respiratory mechanics in horses.

To investigate the influence of increased respiratory frequency on respiratory mechanics in the horse, measurements were made in two groups of seven tracheostomized horses before and after the administration of doxapram. The horses in group I had normal base line values for respiratory mechanics, whereas the horses in group II had significantly lower values of dynamic compliance (Cdyn), higher respiratory resistance (R), and a higher total change in pleural pressure (delta P). The administration of 0.3 mg kg-1 doxapram intravenously resulted in a significant increase in respiratory frequency (fR), R, delta P, tidal volume (VT), and peak to peak respiratory flow (V), and a decrease in Cdyn in both groups of horses. The group II horses had significantly greater increases in R and delta P than the horses in group I.

Doxapram and hypokalaemia in very preterm infants.

BACKGROUND: We observed two preterm infants who developed severe hypokalaemia following doxapram. We therefore wished to review the possible association between doxapram and severe hypokalaemia. STUDY DESIGN: A retrospective study of preterm infants born before 32 weeks of gestation and hospitalised in our intensive care unit in 2004. For each infant, treatment with doxapram or with any drug known to interfere with potassium metabolism, potassium intakes and episodes of hypokalaemia have been recorded. RESULTS: Out of 105 infants, 54 received doxapram. Doxapram-treated infants were significantly younger and had a lower birth weight. Doxapram treated infants were more likely to receive caffeine, furosemide, insulin and mechanical ventilation. There was no difference between the two groups for the other parameters. Hypokalaemia was frequently encountered in our population since it occurred in 76% of enrolled patients and severe hypokalaemia (potassium plasma level below 3 mmol/l) was found in 41%. Bivariate analysis underlined several risk factors for severe hypokalaemia: use of doxapram, gestational age below 28 weeks, use of mechanical ventilation, furosemide, ibuprofen, insulin and postnatal corticosteroids. Cox model's multivariate analysis showed that administration of furosemide and doxapram significantly increased the occurrence of severe hypokalaemia with relative risks of 4.9 (95% CI 1.9 to 12.5) and 8.2 (95% CI 3.1 to 21.7), respectively. CONCLUSIONS: This retrospective study underlines the high incidence of severe hypokalaemia in very preterm infants and an increased risk of severe hypokalaemia during doxapram treatment. We recommend potassium monitoring during any use of doxapram.