Structure and mode of action

Doxapram is a monohydrated pyrolidinone derivative that acts through both stimulation of peripheral chemoreceptors and direct action on the respiratory center. Its pharmacological effects are summarized in TableJ.

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Table 2 Pharmacological effects of doxapram

Clinical use

Although doxapram was originally introduced in the mid-1960s, its therapeutic role is still a matter of debate. Its earliest application was in the reversal of drug-induced respiratory depression, and subsequently in reducing the pulmonary complications following anesthesia. Doxapram has been shown to reduce the effects of opiates on respiratory drive without altering their analgesic effect. Early studies showed that, when doxapram is administered postoperatively as a single dose combined with morphine, the incidence of postoperative cough and sputum expectoration is reduced compared with administration of morphine alone. These findings have not been repeated in more recent studies and doxapram is now used infrequently for this purpose.

Doxapram is now used more commonly to support patients with acute on chronic hypercapnic respiratory failure. Doxapram increases minute volume, at low doses through increased tidal volume and in higher doses by increased respiratory rate, and may support such patients by reducing the need for mechanical support of ventilation while the underlying cause of the exacerbation is treated. Theoretical objections have been raised to the use of doxapram in this circumstance. Experimental work has shown that, in normal subjects, doxapram increases oxygen consumption concomitant with the increase in minute volume. In ventilated patients in whom doxapram has been used during weaning, diaphragmatic dysfunction has been shown to increase as a result of an increase in end-expiratory volume. Some authors cite this as evidence contraindicating the use of doxapram in patients with chronic lung disease. The recent evidence of the role of respiratory muscle fatigue in the context of acute on chronic respiratory failure again argues against the use of a drug that may further increase muscle dysfunction. However, at lower blood levels (1.6-3.0 pg/ml) than those used in these studies, ventilation has been found to increase without changes in O 2 consumption or CO2 production.

In clinical studies of patients in acute respiratory failure who have not received mechanical ventilation ( MoseL.et...a/; 1973; .Rio..r.d.an e.t,,al, 1975; Jeffrey et,a/: 1993), doxapram has been shown to be of benefit in improving arterial pH and reducing PaCO2. Little or no effect on PaO2 has been found. Although not a controlled trial of doxapram therapy, in the study by Jefffreyetai (1993) doxapram was used as a continuous infusion when the pH could not be kept above 7.25 while on controlled oxygen therapy in 37 of 139 patients all presenting with PaO2 £ 6.5 kPa and PaCO2 3 6.5 kPa. Doxapram was introduced into the regimen at a time determined by a protocol based on these blood gas measurements. Seventy per cent (26/37) survived, with only three receiving mechanical ventilation. It is of note that those patients in whom pH continued to fall while on doxapram had a poor prognosis. This was most apparent 12 to 18 h after starting treatment and may be an indication to consider mechanical support. The overall episode survival of patients in this study was good at 88 per cent. In the last few years, a similar effect has been shown with non-invasive intermitent positive-pressure ventilation, but this facility is not available in many centers and may not be tolerated by patients in severe respiratory distress. Therefore doxapram retains a useful role in the support of such patients.

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