Zidovudine (ZDV) treatment during pregnancy, delivery and the postnatal period is effective in reducing the maternal-infant transmission of the human immunodeficiency virus. Reported adverse effects in the neonate during this long-term treatment are bone marrow suppression and elevation in aspartate aminotransferase activity. We report a case of severe ZDV-associated lactic acidosis in a neonate, which resolved rapidly following discontinuation of ZDV. The mechanisms leading to this side effect are poorly understoo

Biollaz, J.

Buchwalder, P.

Chesaux, J.

Micheli, J.

Scalfaro, P.

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Intensive Care Med (1998) 24:247-250 © Springer-Verlag 1998 P. Scalfaro J. J. Chesaux P. A. Buchwalder J. Biollaz J. L. Micheli Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment Received: 26 June 1997 Accepted: 1December 1997 R Scalfaro - J. L. Micheli Division of Neonatology, University Hospital, CH-1011 Lausanne, Switzerland J. J. Chesaux Department ofPaediatrics, University Hospital, CH-10I i Lausanne, Switzerland E A. Buchwalder. J. Biollaz Division of Clinical Pharmacology, University Hospital, CH-1011 Lausanne, Switzerland E Scalfaro ({~) Telethon Institute for Child Health Research, Princess Margaret Hospital forChildren, RO.Box 855, West Perth WA 6872, Australia Fax: +61 (8) 93883414 email: pietros @ ichr.uwa.edu.au Abstract Zidovudine (ZDV) treat- ment during pregnancy, delivery and the postnatal period is effective in reducing the maternal- infant trans- mission of the human immunodefi- ciency virus. Reported adverse f- fects in the neonate during this long- term treatment are bone marrow suppression and elevation in aspar- tate aminotransferase activity. We report a case of severe ZDV-associ- ated lactic acidosis in a neonate, which resolved rapidly following discontinuation of ZDV. The mech- anisms leading to this side effect are poorly understood. Key words H IV  infection • Zidovudine. Neonate.  Prophylaxis. Lactic acidosis Introduction The prophylactic zidovudine (ZDV)  treatment of HIV- positive mothers during pregnancy and delivery and of her neonate during the first 6 weeks of life has been shown to decrease the transmission rate of H IV  from 26 to 8 % in a recent randomised, double-blind, place- bo-controlled trial [1]. The risk-benefit ratio of the re- commended regimen clearly favours prophylaxis. There are theoretical and rare but severe risks, which, how- ever, have to be known when starting prophylactic ZDV treatment for a mother and her neonate. Case report A 16-year-old African primigravida, was diagnosed HIV-positive at 24 weeks of gestation (CDC AIDS classification: A2) and re- ceived prophylactic ZDV treatment according to Swiss national guidelines [2]. Following an uneventful pregnancy, a 2.5-kg girl was delivered electively at 35 weeks of gestation by caesarean sec- tion under intravenous (i.v.) ZDV administration. Umbilical pH was 7.27. Apgar score was 6/5/8. There was progressive onset of se- vere respiratory distress due to persistent fetal circulation (PFC) diagnosed on the basis of refractory hypoxemia (fractional inspired oxygen 1.0, arterial oxygen tension 39 mm Hg, arterial-alveolar 02 tension ratio 0.06) with normal chest X-ray, absence of congenital heart disease and s suprasystemic pulmonary pressure on echo Doppler. Treatment included intubation and mechanical ventila- tion with morphine sedation, correction of anaemia (haemoglobin 248 Table 1 Clinical and laboratory values before, during and after the occurrence of severe lactic acidosis in a zidovudine-treated neo- nate (FIO 2 fractional inspired oxygen, PaC02, PaO 2 arterial car- bon dioxide and oxygen tensions, BE base excess, ASAT aspartate aminotransferase, ALAT alanine aminotransferase, V ventilated, N normal, NA not available) Age in days 6 7 8 9 10 11 12 16 FIO2 (%) 0.30 0.25 Respiratory rate (min <) V 65 Heart rate (min -1) 136 140 Mean arterial pressure (mm Hg) 44 42 Urine output (ml/kg per h) 5.0 3.2 Body weight (g) NA 2860 Enteral formula (ml/24 h) 40 70 i.v. dextrose-amino acid solution (ml/24 h) 220 210 Total fluids (ml/kg per 24 h) 104 110 pH 7.42 7.36 paco2 (mmHg) 38.6 43.3 PaO 2 (mmHg) 95.4 109.5 BE (mmol/1) 0.7 -1.0 lactic acid (mmol/1) 1.9 NA Na (mmol/1) 137 137 K (mmol/1) 5.6 5.6 Urea (mmol/1) 3.4 2.9 Creatinine (mmol/1) 65 69 ASAT (IU/1) 31 NA ALAT (IU/1) 5 NA 0.29 0.21 0.30 0.28 0.21 0.21 60 90 V 70 60 50 152 160 140 158 146 140 58 68 64 64 60 50 4.7 3.4 2.6 5.3 2.8 N 2880 2740 NA 2610 2580 2540 120 160 0 0 160 420 190 90 240 300 150 0 124 100 100 120 124 168 7.35 7.14 7.36 7.38 7.38 7.36 47.4 25.3 34.0 42.0 NA NA 85.2 79.5 91 90 NA NA 0.9 -18.9 -8.5 -0.1 -1.9 -2.4 NA 14.0 2.6 2.0 NA NA 144 142 143 144 141 143 5.1 5.7 4.0 2.9 6.2 5.9 NA 7.2 7.2 2.8 NA NA NA 64 NA 50 NA NA NA 40 96 40 NA NA NA 9 13 22 NA NA a All day 9 values were collected 2 h prior to reintubation 103 g/l, mean corpuscular volume 117 fl), inotropic support, alkali- nization by hyperventilation a d bicarbonate administration, and continuous intravenous magnesium therapy [3]. Ampicillin was given from days 1 to 10. Continued ZDV prophylaxis against HIV transmission was administered orally at a dose of 2 mg/kg every 6 h the first day, then with the same dosage i.v. from days 2 to 7 and orally from days 8to 9. PFC resolved over 48 h and the patient was successfully extu- bated on day 7 after moderate fluid restriction and three doses of frusemide (0.8 mg/kg) on days 5 and 6. Fluids were given according to our unit's policy with a dextrose-amino acid solution during the first 13 days. The total amount of i.v. amino acids was always less than 3.0 g/kg per day. Enteral feeds with formula were started on day 2 (i.v. to enteral fluid ratio given in Table 1). The patient was doing well, breathing spontaneously in air, par- tially enterally fed on day 9, when she developed a sudden onset of respiratory distress without haemodynamic instability (Table 1). On physical examination, a mild hepatomegaly and five petechial lesions on the abdomen were noted. There was no abdominal dis- tension or tenderness. Laboratory analysis howed an unexpected increase in serum lactate at 14 retool/1 with severe metabolic acido- sis partially compensated for by hyperventilation (Table 1) con- firmed on repeat analysis. The patient was reintubated due to clin- ical worsening of the respiratory distress. Acute management in- cluded the administration of 2 mEq/kg of bicarbonate and 10 ml/ kg of albumin and discontinuation f both the enteral feeds and ZDV treatment. After 18 h the infant was successfully extubated. Investigations showed a twofold increase in aspartate amino- transferase (ASAT) and a slight increase in urea. Blood glucose, blood cell count, coagulation, renal function, serum creatinine ki- nase, bilirubin, chest and abdominal X-ray and blood, urine and stool cultures were all normal. Lactate and ASAT values returned to normal within 6 and 14 h, respectively. The metabolic acidosis disappeared over 24 h without repeated bicarbonate administra- tion. More common causes for lactic acidosis uch as hypoxia, shock or hypotension were excluded on a clinical basis (cf. also Table 1). The patient was discharged on day 28. ZDV treatment has not been reinstated and no alternative antiviral prophylactic treatment introduced. At 11-month follow-up, the patient showed no clinical or serological signs of HIV infection, no metabolic acidosis and normal growth and development. Discussion Zidovudine ,  a nucleos ide ana logue phosphory la ted  by thymid ine k inase in heal thy and H IV - in fec ted  cells, is a potent  inhib i tor  of H IV  reverse t ranscr iptase and has also a weak aff inity for the mammal  DNA po lymerase-  Y. Usual  adverse effects in the neonate  are a mi ld mac- rocytic anaemia  and a sl ight increase in ASAT [4]. Anaemia  is cons idered to be due to the sensit ivity of er- ythrocyte precursor  cells to ZDV. The increase in ASAT may be of hepat ic  or muscular  origin and usual ly has a benign course. Both  side effects were observed in this pat ient  with no major  consequences.  Severe lactic acidosis in ZDV- t reated  adults was re- cently descr ibed.  Chat tha  et al. [5] repor ted  seven A IDS pat ients (aged 43 + 8 years)  with card iovascular  col lapse and severe lactic acidosis (14.3 + 2.6 mmol/1), despite having normal  cardiac funct ion and oxygen de- livery. Four  of these pat ients  were receiv ing long-term ZDV therapy. It was conc luded that ZDV-assoc ia ted  lactic acidosis was a major  comorb id  event  leading to 249 death. Since then, other similar adult cases have been reported [6]. In this patient, the development of lactic acidosis on day 9 resolved rapidly following discontinuation of ZDV. This suggests that ZDV therapy alone or in con- junction with other factors may be responsible for this side effect. There was no clear evidence implicating amore common cause for lactic acidosis, like circulatory insufficiency, infection or metabolic imbalance. The pa- tient was in good clinical condition when the acidosis suddenly developed over a few hours. Although mild hy- povolaemia may have contributed, it is unlikely to be a major causative factor underlying the severe acidotic episode. The only clinical signs (mild liver enlargement and a few petechiae) were not consistent with any par- ticular aetiology. In the absence of a more likely cause a pharmacological explanation has to be considered. Plasma levels of ZDV were not determined in this case, therefore a pharmacokinetic explanation for the observed toxic event can be hypothesised but not proved. The dose of ZDV given to this 35-week-old in- fant was that recommended forneonates [2]. One could argue that administering the same dose i.v. as the orally recommended one may have played a role. However, since a decreased first-pass metabolism and a greater bioavailability of ZDV (89 vs 60-70%) have been shown in neonates after oral administration compared to infants [7], the increase in the drug exposure follow- ing i.v. administration is minimal and unlikely to play a crucial role in the adverse vent. Total body clearance of ZDV is influenced by gesta- tional age and liver metabolic maturity because ZDV is mainly eliminated by hepatic metabolism to a glucuro- nide compound. The rest undergoes tubular enal excre- tion. The serum half-life is 3 h in neonates compared to nearly 2 h in older infants [7]. Competition for ZDV glucuronidation with endogenous substrates (bilirubin) or durgs (morphine) is a possible interaction leading to increased plasma levels. Furthermore, it has been shown that renal ZDV excretion can be inhibited by drugs transported by either the tubular organic anion or ca- tion transport system [8]. Drug interaction at this level (with morphine and frusemide in this case), in addition to immature renal function, is therefore a possibility. This patient did receive these drugs, but only during the first 6 days and at minimal dosage, which makes their potential interaction negligible. The adult cases usually show a latency of several months between the initiation of ZDV treatment and the occurrence of lactic acidosis. This patient was ex- posed to ZDV during nearly 3 months, as this drug easi- ly crosses the placenta. To our knowledge, there is no ex- planation why there is such a long delay between the start of ZDV treatment and the development of lactic acidosis. A subclinical direct cytotoxic effect may be hy- pothesised: the affinity of ZDV for mitochondrial DNA polymerase-7 reduces mitochondrial DNA synthesis, which may contribute to a delayed cytotoxicity as shown in vitro [9]. This may lead to increased lactate produc- tion by reducing the oxidation of the reduced form of ni- cotinamide-adenine dinucleotide (NAD) to NAD+ [10]. It is questionable whether the initial persistent fetal circulation or another unrecognised condition may have played a role in the pathogenesis of the lactic acidosis in this patient, possibly by unmasking a sub- clinical biological toxicity. The occurrence several days after the recovery of the circulatory problems, the fact that lactate values were normal before the collapse, and the good clinical condition of the patient when the lactate increased to not support his hypothesis. The recommended length of neonatal prophylactic ZDV therapy is 6 weeks, a decision based on the risk of finding maternal infected cells in the neonate's circula- tion during the first few weeks of life. This case could contribute in the decision making concerning the opti- mal length of neonatal ZDV therapy when considering the risk-benefit ratio. In conclusion, severe lactic acidosis is a life-threaten- ing, though rare, side effect of neonatal ZDV therapy of which the paediatric and neonatal intensivist must be aware. The optimal ength of postnatal therapy has still to be established and should consider this possible com- plication. We cannot conclude whether the severe lactic acidosis een in this patient was dose-dependent. References 1. Connor EM, Sperling RS, Gelber R, Ki- selev R Scott G, O'Sullivan MJ, Van- Dyke R, Bey M, Shearer W, Jacobson RL et al (1994) Reduction of maternal- infant transmission of human immuno- deficiency virus type i with zidovudine treatment. N Engl J Med 331: 1173-1180 2. P~idiatrische AIDS-Gruppe Schweiz (PAGS), Kommission der Schweizeri- schen Gesellschaft fir P~idiatrie, Sub- kommission Klinik (SKK) der Eidge- n6ssischen Kommission ftir AIDS-Fra- gen (EKAF), Arbeitsgruppe HIV der Schweizerischen Gesellschaft far Gyn/~- kologie und Geburtshilfe (1994) Zido- vudine zur Prophylaxe der HIV Ober- tragung von der infizierten Mutter auf ihr Kind. Schweiz ,~rztezeitung 75: 1508-1509 3. Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A (1995) Mag- nesium sulphate as an alternative and safe treatment for severe persistent pul- monary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed 72: F184-187 250 4. Monpoux F, Dageville C, Bongain A, Sirvent N, Maillotte AM, Mariani R, Gillet JY (1997) Tol6rance biologique de l'azidothymidine administr6e en p6r- iode p6rinatale chez le nouveau-n~ de m6re VIH-1 s6ropositive. Ann Pediatr 44:87-93 5. Chattha G, Arieff AI, Cummings C, Tierney LM Jr (1993) Lactic acidosis complicating the acquired immunodefi- ciency syndrome. Ann Intern Med 118: 37-39 6. Masio C, Jacomet C, Jupas JJ, Lebrette MG, Rozenbaum W (1994) Acidose lactique chez des patients infectds par le VIH. La Presse M6dicale 23:717 7. Boucher FD, Modlin JF, Weller S, Ruff A, Mirochnick M, Pelton S, Wilfert C, McKinney R Jr, Crain MJ, Elkins MM et al (1993) Phase I evaluation of zido- vudine administered toinfants exposed at birth to the human immunodeficien- cy virus. J Pediatr 122:137-144 8. Chatton JY, Munafo A, Chave JR Stein- hauslin F, Roch-Ramel F, Glauser MR Biollaz J (1992) Trimethoprim, alone or in combination with sulphamethoxa- zole, decreases the renal excretion of zi- dovudine and its glucuronide. Br J Clin Pharmaco134:551-554 9. Chen CH, Vazquez-Padua M, Cheng YC (1991) Effect of anti-human immu- nodeficiency virus nucleoside analogs on mitochondrial DNA and its implica- tion for delayed toxicity. Mol Pharma- col 39:625-628 10. Gopinath R, Hutcheon M, Cheema- Dhadli S, Halperin M (1992) Chronic lactic acidosis in a patient with acquired immunodeficiency syndrome and mito- chondrial myopathy: biochemical stu- dies. J Am Soc Nephrol 3:1212-1219 

Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment

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Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment

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