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Perinatal adverse effects of nalbuphine given during parturition
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infusion. Results were comparable when the acidosis was induced by HC 1. We have obtained similar results in skeletal muscle in vivo. Rapid internal alkalinisation by bicarbonate is perhaps harder to explain than acidification. However, Gleeson et al’ have presented evidence for a sodium/bicarbonate co-transporter in hepatocytes in addition to sodium/proton exchange, which might provide the explanation. Ritter et al themselves pointed out that sodium/proton and chloride/bicarbonate transport mechanisms may vary between different cell types and we wonder why they have arrived at such a far-reaching conclusion on the basis of results from a single cell type. Controversy over the clinical use of bicarbonate infusions is not resolved by the study of Ritter et al. There is a potential risk of intracellular acidosis from CO2 evolution-but only when CO2 excretion by the lungs is restricted. Medical Unit, Cellular Mechanisms Research Group, London Hospital Medical College, London E1 1BB, UK
R. A. ILES J. S. BEECH
Jacobs MH. The production of intracellular acidity by neutral and alkaline solutions containing carbon dioxide. Am J Physiol 1920; 53: 457-63. 2. Rink TJ, Tsien RY, Pozzan T. Cytoplasmic pH and free Mg+ in lymphocytes. J Cell Biol 1982; 95: 189-96. 3. Bersin RM, Aneff AI. Improved hemodynamic function during hypoxia with carbicarb, a new agent for the management of acidosis. Circulation 1988; 77: 1.
227-33. 4.
Shapiro JI, Whalen M, Kucera R, Kindig N, Filley G, Chan L. Brain pH responses to sodium bicarbonate and carbicarb during systemic acidosis. Am J Physiol 1989;
256: H1316-21. JS, Iles RA. The effect of reversal of metabolic acidosis on liver pH: an assessment of bicarbonate therapy Abstracts. Eighth annual meeting of Society Magnetic Resonance in Medicine, 1989. 555. 6. Beech JS, Cohen RD, lies RA. Hepatic intracellular pH response to sodium bicarbonate in diabetic ketoacidosis. Clin Sci 1990; 23 (suppl): (in press). 7. Gleeson D, Smith ND, Boyer JL. Bicarbonate-dependent and -independent intracellular pH regulatory mechanisms in rat hepatocytes. J Clin Invest 1989; 84: 312-21. 5. Beech
Perinatal adverse effects of
nalbuphine given during parturition
SIR,-Nalbuphine hydrochloride is a narcotic agonist-antagonist, which is as potent as morphine in the control of severe pain.l It has been proposed as an alternative to other analgesics for the control of labour pain2 and reported to be safe for the mother and the child.3 However, we are aware of only one study that has reported side-effects in neonatal babies.’ We report two cases of perinatal adverse effects of nalbuphine given during labour. Patient 1.-A 31 -year-old woman, gravida 3 para 1, was admitted to the labour ward after onset of contractions at 40 weeks’ gestation. Cervical dilatation was 5 cm when she received an intravenous bolus of 10 mg nalbuphine. Fetal monitoring immediately showed bradycardia at 60 beats per min. Fetal heart rate rose to 120 beats per min within 10 min but its variability remained low. Three hours later, another deceleration at 60 beats per min was noted and the baby was delivered vaginally with forceps. The baby weighed 2730 g and had an Apgar score of seven at 1 min. However, at 3 min after birth (3-5 hours after the administration of nalbuphine) apnoea and cyanosis necessitated artificial ventilation, with rapid improvement. On arrival at the ward the baby had hypotonia and mild respiratory depression. Routine laboratory tests were normal. Bacteriological cultures remained negative. On discharge at day 5 neurological examination was normal. Patient 2.-A 24-year-old woman, gravida 1 para 1, was admitted at 35 weeks’ gestation for premature rupture of membranes and onset of contractions. She received initially 10 mg nalbuphine intramuscularly 5-5 hours before delivery, followed by 10 mg intravenously and 10 mg subcutaneously, given simultaneously. She had a normal vaginal delivery 1 hour later. The baby weighed 2680 g. Apgar score was six at 1 min and three at 3 min. He was intubated for aponea and maintained on mechanical ventilation for eighteen hours for respiratory depression. Routine laboratory tests were normal, peripheral blood cultures remained negative. On discharge neurological examination was normal. All narcotic analgesics are known to induce respiratory depression. With nalbuphine this side-effect is lessened because of the drug’s ceiling effect of repeated or large doses.1 Although
nalbuphine is regarded as safe for use during parturition, its placental transfer is high, rapid, and variable, with a fetal to maternal ratio ranging from 0-5 to 6.5 Fetal plasma concentrations are about the same as or higher than maternal concentrations, and could cause respiratory and cardiac depression. In our first case fetal respiratory distress occurred after the administration of an intravenous bolus of 10 mg nalbuphine shortly before delivery. In our second case, immature hepatic and renal function could have contributed to accumulation of the drug in the baby. No concomitant analgesic drug was given during labour. Although nalbuphine concentrations were not measured at birth, we believe this drug was responsible for the fetal distress in view of the sequence of events and the negative clinical and laboratory findings. Nalbuphine should be used with caution during parturition to avoid reversible respiratory depression in the newborn baby. In contrast with a previous report the route of administration and the interval between times of injection and delivery seem to be of importance. We recommend that nalbuphine is given subcutaneously,6 and is not used around the expected time of
delivery. Unit of Clinical Pharmacology, Hôpital Robert Debré, 75019 Paris, France
MARIANNE GUILLONNEAU EVELYNE JACQZ-AIGRAIN
Services of Gynaecology and Obstetrics and Anaesthetics and Recovery, Hôpital Bichat, Paris
ALINE DE CREPY HAMID ZEGGOUT
1. Errick
JK, Heel RC. Nalbuphine. a preliminary review of its pharmacological properties and therapeutic effecacy. Drugs 1983; 26: 191-211. 2. Franck M, McAteer EJ, Cattermole R, Loughnan B, Stafford LB, Hitchcock AM. Nalbuphine for obstetric analgesia: a comparison of nalbuphine with pethidine for pain relief m labour when administered by patient-controlled analgesia (PCA). Anaesthesia 1987; 42: 697-703. 3. Podlas J, Brelant BD. Patient-controlled analgesia with nalbuphine during labour. Obstet Gynecol 1987; 70: 202-04. 4. Wahab SA, Askalani AH, Amar RA, Ramada ME, Neweigy SB, Saleh AA. Effect of some recent analgesics on labour pain and maternal and fetal blood gases and pH. Int J Gynaecol Obstet 1988; 26: 75-80. 5. Wilson SJ, Errick JD, Balkon J. Pharmacokinetics of nalbuphine during parturition. Am J Obstet Gynecol 1986; 155: 340-44. 6. Wilson CM, McClean E, Moore J, Dundee JW. A double-blind comparison of intramuscular pethidine and nalbuphine in labour. Anaesthesia 1986; 41: 1207-13.
Fever associated with chronic retinol
therapy SIR,-The chronic ingestion of high doses of retinol can produce toxic effects on the skin, bones, liver, and the central nervous system. Patients with retinol toxicity usually present with diverse symptoms and the diagnosis may be difficult. We describe a patient on chronic treatment with high doses of retinol who presented with fever of unknown origin. This 17-year-old woman was seen on March 21, 1988, with a 2-month history of fever. She had been receiving retinol (between 50 000 and 200 000 units/day) since October 15, 1989. Her temperature ranged from 37-5° to 39° C, and was continuous, and barely responded to antipyretics (aspirin and paracetamol). The only associated symptoms were a slight headache and asthenia; her general condition was otherwise good. Initially the fever was attributed to rhinorrhea and odynophagia, and later to a urinary infection. One specimen of urine was culture-positive. She was treated with norfloxacin, and although the infection receded, the fever continued. From Feb 8 to 25, her intake of vitamin A was temporarily suspended and her temperature fell; but it rose again when she resumed taking retinol. Urine cultures were negative on Feb 2, 1988, and March 3, 1988. There were no abnormal physical findings on admission. Blood counts, renal function, and thyroid function were normal. She had no antibodies to Salmonella typhi, Brucella, Toxoplasma, hepatitis B virus, and Epstein-Barr virus. A tuberculin test was negative, as well as cultures of blood, urine, faeces, and a pharyngeal swab. She was negative for antinuclear antibodies, rheumatoid factor, and antistreptolysins. Chest and paranasal sinus X-rays were normal. Retinol plasma levels were 885 ug/dl (normal values in our laboratory 30-60 fig/dl). Retinol therapy was withdrawn on March
infusion. Results were comparable when the acidosis was induced by HC 1. We have obtained similar results in skeletal muscle in vivo. Rapid internal alkalinisation by bicarbonate is perhaps harder to explain than acidification. However, Gleeson et al’ have presented evidence for a sodium/bicarbonate co-transporter in hepatocytes in addition to sodium/proton exchange, which might provide the explanation. Ritter et al themselves pointed out that sodium/proton and chloride/bicarbonate transport mechanisms may vary between different cell types and we wonder why they have arrived at such a far-reaching conclusion on the basis of results from a single cell type. Controversy over the clinical use of bicarbonate infusions is not resolved by the study of Ritter et al. There is a potential risk of intracellular acidosis from CO2 evolution-but only when CO2 excretion by the lungs is restricted. Medical Unit, Cellular Mechanisms Research Group, London Hospital Medical College, London E1 1BB, UK
R. A. ILES J. S. BEECH
Jacobs MH. The production of intracellular acidity by neutral and alkaline solutions containing carbon dioxide. Am J Physiol 1920; 53: 457-63. 2. Rink TJ, Tsien RY, Pozzan T. Cytoplasmic pH and free Mg+ in lymphocytes. J Cell Biol 1982; 95: 189-96. 3. Bersin RM, Aneff AI. Improved hemodynamic function during hypoxia with carbicarb, a new agent for the management of acidosis. Circulation 1988; 77: 1.
227-33. 4.
Shapiro JI, Whalen M, Kucera R, Kindig N, Filley G, Chan L. Brain pH responses to sodium bicarbonate and carbicarb during systemic acidosis. Am J Physiol 1989;
256: H1316-21. JS, Iles RA. The effect of reversal of metabolic acidosis on liver pH: an assessment of bicarbonate therapy Abstracts. Eighth annual meeting of Society Magnetic Resonance in Medicine, 1989. 555. 6. Beech JS, Cohen RD, lies RA. Hepatic intracellular pH response to sodium bicarbonate in diabetic ketoacidosis. Clin Sci 1990; 23 (suppl): (in press). 7. Gleeson D, Smith ND, Boyer JL. Bicarbonate-dependent and -independent intracellular pH regulatory mechanisms in rat hepatocytes. J Clin Invest 1989; 84: 312-21. 5. Beech
Perinatal adverse effects of
nalbuphine given during parturition
SIR,-Nalbuphine hydrochloride is a narcotic agonist-antagonist, which is as potent as morphine in the control of severe pain.l It has been proposed as an alternative to other analgesics for the control of labour pain2 and reported to be safe for the mother and the child.3 However, we are aware of only one study that has reported side-effects in neonatal babies.’ We report two cases of perinatal adverse effects of nalbuphine given during labour. Patient 1.-A 31 -year-old woman, gravida 3 para 1, was admitted to the labour ward after onset of contractions at 40 weeks’ gestation. Cervical dilatation was 5 cm when she received an intravenous bolus of 10 mg nalbuphine. Fetal monitoring immediately showed bradycardia at 60 beats per min. Fetal heart rate rose to 120 beats per min within 10 min but its variability remained low. Three hours later, another deceleration at 60 beats per min was noted and the baby was delivered vaginally with forceps. The baby weighed 2730 g and had an Apgar score of seven at 1 min. However, at 3 min after birth (3-5 hours after the administration of nalbuphine) apnoea and cyanosis necessitated artificial ventilation, with rapid improvement. On arrival at the ward the baby had hypotonia and mild respiratory depression. Routine laboratory tests were normal. Bacteriological cultures remained negative. On discharge at day 5 neurological examination was normal. Patient 2.-A 24-year-old woman, gravida 1 para 1, was admitted at 35 weeks’ gestation for premature rupture of membranes and onset of contractions. She received initially 10 mg nalbuphine intramuscularly 5-5 hours before delivery, followed by 10 mg intravenously and 10 mg subcutaneously, given simultaneously. She had a normal vaginal delivery 1 hour later. The baby weighed 2680 g. Apgar score was six at 1 min and three at 3 min. He was intubated for aponea and maintained on mechanical ventilation for eighteen hours for respiratory depression. Routine laboratory tests were normal, peripheral blood cultures remained negative. On discharge neurological examination was normal. All narcotic analgesics are known to induce respiratory depression. With nalbuphine this side-effect is lessened because of the drug’s ceiling effect of repeated or large doses.1 Although
nalbuphine is regarded as safe for use during parturition, its placental transfer is high, rapid, and variable, with a fetal to maternal ratio ranging from 0-5 to 6.5 Fetal plasma concentrations are about the same as or higher than maternal concentrations, and could cause respiratory and cardiac depression. In our first case fetal respiratory distress occurred after the administration of an intravenous bolus of 10 mg nalbuphine shortly before delivery. In our second case, immature hepatic and renal function could have contributed to accumulation of the drug in the baby. No concomitant analgesic drug was given during labour. Although nalbuphine concentrations were not measured at birth, we believe this drug was responsible for the fetal distress in view of the sequence of events and the negative clinical and laboratory findings. Nalbuphine should be used with caution during parturition to avoid reversible respiratory depression in the newborn baby. In contrast with a previous report the route of administration and the interval between times of injection and delivery seem to be of importance. We recommend that nalbuphine is given subcutaneously,6 and is not used around the expected time of
delivery. Unit of Clinical Pharmacology, Hôpital Robert Debré, 75019 Paris, France
MARIANNE GUILLONNEAU EVELYNE JACQZ-AIGRAIN
Services of Gynaecology and Obstetrics and Anaesthetics and Recovery, Hôpital Bichat, Paris
ALINE DE CREPY HAMID ZEGGOUT
1. Errick
JK, Heel RC. Nalbuphine. a preliminary review of its pharmacological properties and therapeutic effecacy. Drugs 1983; 26: 191-211. 2. Franck M, McAteer EJ, Cattermole R, Loughnan B, Stafford LB, Hitchcock AM. Nalbuphine for obstetric analgesia: a comparison of nalbuphine with pethidine for pain relief m labour when administered by patient-controlled analgesia (PCA). Anaesthesia 1987; 42: 697-703. 3. Podlas J, Brelant BD. Patient-controlled analgesia with nalbuphine during labour. Obstet Gynecol 1987; 70: 202-04. 4. Wahab SA, Askalani AH, Amar RA, Ramada ME, Neweigy SB, Saleh AA. Effect of some recent analgesics on labour pain and maternal and fetal blood gases and pH. Int J Gynaecol Obstet 1988; 26: 75-80. 5. Wilson SJ, Errick JD, Balkon J. Pharmacokinetics of nalbuphine during parturition. Am J Obstet Gynecol 1986; 155: 340-44. 6. Wilson CM, McClean E, Moore J, Dundee JW. A double-blind comparison of intramuscular pethidine and nalbuphine in labour. Anaesthesia 1986; 41: 1207-13.
Fever associated with chronic retinol
therapy SIR,-The chronic ingestion of high doses of retinol can produce toxic effects on the skin, bones, liver, and the central nervous system. Patients with retinol toxicity usually present with diverse symptoms and the diagnosis may be difficult. We describe a patient on chronic treatment with high doses of retinol who presented with fever of unknown origin. This 17-year-old woman was seen on March 21, 1988, with a 2-month history of fever. She had been receiving retinol (between 50 000 and 200 000 units/day) since October 15, 1989. Her temperature ranged from 37-5° to 39° C, and was continuous, and barely responded to antipyretics (aspirin and paracetamol). The only associated symptoms were a slight headache and asthenia; her general condition was otherwise good. Initially the fever was attributed to rhinorrhea and odynophagia, and later to a urinary infection. One specimen of urine was culture-positive. She was treated with norfloxacin, and although the infection receded, the fever continued. From Feb 8 to 25, her intake of vitamin A was temporarily suspended and her temperature fell; but it rose again when she resumed taking retinol. Urine cultures were negative on Feb 2, 1988, and March 3, 1988. There were no abnormal physical findings on admission. Blood counts, renal function, and thyroid function were normal. She had no antibodies to Salmonella typhi, Brucella, Toxoplasma, hepatitis B virus, and Epstein-Barr virus. A tuberculin test was negative, as well as cultures of blood, urine, faeces, and a pharyngeal swab. She was negative for antinuclear antibodies, rheumatoid factor, and antistreptolysins. Chest and paranasal sinus X-rays were normal. Retinol plasma levels were 885 ug/dl (normal values in our laboratory 30-60 fig/dl). Retinol therapy was withdrawn on March