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Side Effects of Doxapram Infusion

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Side Effects of Doxapram Infusion European Journal of Europ. J. Intens. Care Med. 2, 87-88 (1976) Intensive Care Medicine © by Springer-Verlag 1976 Side Effects of Doxapram Infusion A. D. Baxter The Middlesex Hospital, London, England Summary. Four cases are reported where patients reacted with severe restlessness, ¢iolence or hallucinations at low doses of doxapram infusion. A possible association with hepatic dysfunction is discussed. These reactions persisted long after the cessation of doxapram infusion and the various treatments used are described. Key words: Doxapram, Infusion, Restlessness, Liver. Introduction at 2.5 mg/min, she became severely agitated, disorientated and unco-operative, without any concurrent change in blood Doxapram hydrochioride is an analeptic agent which, while gases (PaO 2 8.5 kPa, PaCO~ 8.0 kPa) or cardiovascular status. being a powerful stimulator of respiration, has a wide safety Diazepam and then paraldehyde were required to control this margin between the therapeutic and convulsant doses (1). situation but, as a result of this, she later required reintuba- It has been used for stimulating respiration and producing tion and further ventilation. Electrolytes and haemoglobin arousal in the immediate post-operative period, to hasten were normal but liver function tests showed that serum recovery, and to prevent pulmonary complications by si- albumen was 24 g/1, AST 105 iu/1 and bilirubin 20 umol/1. mulating a sigh (2, 3), to permit adequate oxygenation in This was thought to reflect either her mild congestive cardi- acute respiratory failure in chronic bronchitis (4-7) and ac failure or her excessive alcohol intake (one or two bottles in the treatment of barbiturate overdosage (8). of sherry daily). She was later weaned off the ventilator Previous reports have stressed the safety and absence of without doxapram and required no further sedation. serious side effects of the drug; perineal warmth (5, 6, 9), tremor (3, 9), nausea, light headedness (9), sweating, head- ache, twitching, restlessness (6) and confusion (4) have been Case 2 described. These side effects have been said to be short lived because of the short half-life of doxapram in the Mrs M. S., a 72 year old chronic bronchitic, had an ileal plasma. However, more serious and troublesome side effects resection for intestinal obstruction. Post-operatively she may occasionally occur and one patient has been reported was ventilated for twelve hours and then weaned off and as having a frank psychosis with hallucinations during doxa- extubated. After being given 30 mg pentazocine she became pram infusion (6). Of twenty patients treated here with confused and required small doses of diazepam to control doxapram infusion the following four developed severe and this over the next few hours. Seven hours later doxapram violent restlessness, confusion or hallucinations at low was commenced to counteract CO2 retention (PaO2 6.0 doses. kPa, PaCO2 8.0 kPa). After three hours at 2.5 mg/min, she developed agitation, confusion and visual hallucina. tions. Her blood gases had improved to PaO2 11.5 kPa, Case i PaCO2 6.9 kPa. She required diazepam to control the hallucinations etc. and doxapram was continued at a lower Mrs E. P., a 68 year old acute on chronic bronchitic, was dosage for a further seven days with occasional confusion admitted in respiratory failure with PaO2 5.5 kPa, PaCO2 but no further hallucinations. Her cardiovascular status 12.2 kPa breathing air. After 48 hours intermittent positive was stable apart from a tachycardia of 120/rain; haemo- pressure ventilation, she was weaned off the ventilator and globin, electrolytes and liver function tests were normal. extubated. A doxapram infusion was commenced to coun- According to her notes she drank only a little alcohol, but teract carbon dioxide retention on controlled oxygen ther- it has not been possible to question her in detail about apy (PaO2 5.0 kPa, PaCO2 8.5 kPa). After 24 hours infusion this. 88 European Journal of Intensive Care Medicine, Vol. 2, No. 2 (1976) Case 3 and persisted for a relatively short time after the infusion Mr J. T., a 68 year old chronic bronchitic, was admitted was stopped. Although it is well known as a cause of hal- in respiratory failure as a result of a Streptococcus pneu- lucinations, pentazocine was unlikely to be responsible in moniae infection, with blood gases PaO2 4.0 kPa, PaCO2 Case 2 as these occurred 10 hours after a single small dose. 7.1 kPa breathing air. After 24 hours on controlled oxygen All four patients were around the age of seventy years and therapy, physiotherapy and antibiotics, he had developed it may be that the elderly brain is more susceptible to the CO 2 retention (PaO2 5.8 kPa, PaCO2 11.5 kPa on 28% side effects of doxapram. However, other patients in the oxygen), with a reduced level of consciousness. Doxapram same age group have failed to react in this way. was infused at up to 3 mg/min, on which his conscious The restless, confused and violent patient may impose level and blood gases improved (PaO 2 9.0 kPa, PaCO 2 7.2 a considerable burden on the nursing staff. If there is ade- kPa after eight hours). At this stage he became progressively quate nursing staff they may cope simply by restraining more agitated and confused with a marked tremor and need- the patient until the drug is metabolised, which may take ed considerable restraint. This state persisted despite reduc- several hours as in Case 3. Otherwise, sedation may be re- ing the doxapram to 1 mg/min. Agitation ceased when the quired. In Case 2, conventional sedatives were successful doxapram was stopped but he remained confused and dis- but these run the risk of producing further respiratory orientated for a further 24 hours. Cardiovascular status, depression as in Case 1. The transient action of Althesin haemoglobin and electrolytes were normal but liver func- and its lack of "hangover" seemed most attractive for such tion tests revealed bilirubin 22 umol/1 and albumen 24 g/1. a situation despite its own metabolism by the liver. In Case These abnormalities persisted after his recovery and may 4, a very small dose (i ml for a 95 kg patient) proved to reflect his alcohol intake of up to 30 pints of beer daily. be remarkably effective without producing long lasting respiratory depression. This would seem to be worth using Case 4 in further such cases provided that doctors familiar with Mr E. B., a 70 year old mild chronic bronchitic, had a pan- the possible effects of Althesin are available. creatico-duodenectomy for duodenal carcinoma. His pre- operative blood gases were PaO2 10.0 kPa, PaCO2 6.0 kPa Acknowledgements. Thanks are due to Dr. J. Tinker, Director of the Intensive Therapy Unit at the Middlesex Hospital, for permis- breathing air. Post-operatively he developed carbon dioxide sion to report these cases under his care and to Miss C. Hooton for retention after being given opiate analgesia and uncon- her secretarial assistance. trolled oxygen therapy (PaO2 13.0 kPa, PaCO2 11.0 kPa). This responded only partially to naloxone (PaO2 8.1 kPa, PaCO2 8.5 kPa) and a doxapram infusion was started. After References twelve hours at 2 mg/min, his blood gases had improved 1. Luscombe, D.,K., Nicholls, P. J.: Relationships between res- (PaO 2 7.1 kPa, PaCO2 5.9 kPa) but he became very restless, piratory stimulant and convulsive activity of doxapram hydro- agitated and quite violent. This had not improved 30 min- chloride in conscious animals. Pharmacol. Re. Com. 3, 369 utes after stopping doxapram and he was given 1 ml Althe- (1971) sin intravenously. This produced sedation lasting about 2. Gupta, P. K., Dundee, J. W.: Morphine combined with doxa- pram or naloxone. A study of post-operative pain relief. Anaes- 15 minutes after which he had regained his normal com- thesia 29, 33 (1974) posure without any deterioration in his blood gas status. 3. Martin, J. L.: Clinical evaluation of doxapram hydrochloride; His cardiovascular status, haemoglobin and electrolytes a respiratory stimulant. J. Okla. Med. Ass. 66,481 (1973) were normal. Liver function tests were normal despite an 4. Riordan, J. F., Sillett, R, W., McNicol, M. W.: Response to a respiratory stimulant (doxapram) in severe respiratory failure. alcohol intake of up to 30-40 pints of beer per day. Doxa- Brit. J. Di~ Chest 68, 39 (1974) pram was restarted at a lower dose but again caused restless- 5. Riordan, J. F., Sillett, R. W., McNicol, M. W.: A controlled ness after about twelve hours. trial of doxapram in acute respiratory failure. Brit. J. Dis. Chest 68, 57 (1975) Discussion 6. Moser, K. M. et al.: Respiratory stimulation with intravenous doxapram in respiratory failure. New Engl. J. Med. 288, 427 After intravenous administration of doxapram the blood (1973) levels fall rapidly in the first few minutes. It is rapidly me- 7. Edwards, G., Leszczynskz, S. O.: A double blind triai of five tabolised followed by redistribution of the metabolites, respiratory stimulants in acute ventilatory failure. Lancet 2, 226 (1967) high concentrations being found in fat, liver and bile in 8. Dundee, J. IV., Gray, R. C., Gupta, P. W.: Doxapram in the dogs. Only small amounts of metabolites appear in the treatment of acute drug poisoning. Anaesthesia 29, 710 (1974) urine in man (10). 9. Steele, A. D., Rudman, T.: The effect of a new analeptic agent It is likely that the liver is the site of metabolism of on arterial blood gases and minute ventilation in adult males. doxapram and that its action could be enhanced if hepatic Amer. Rev. Resp. Dis. 94, 600 (1966) 10.
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