Journal of Perinatology (2013) 33, 903–904 & 2013 Nature America, Inc. All rights reserved 0743-8346/13 www.nature.com/jp

PERINATAL/NEONATAL CASE PRESENTATION Thinking outside of the blue box: a case presentation of neonatal methemoglobinemia

M van de Vijver1, E Parish1 and N Aladangady1,2,3

We report the case of a full-term neonate who presented with cyanosis from birth secondary to methemoglobinemia precipitated by the obstetric use of bupivacaine in a spinal anaesthetic for caesarean delivery.

Journal of Perinatology (2013) 33, 903–904; doi:10.1038/jp.2013.74 Keywords: methemoglobinemia; bupivacaine; cyanosis; spinal anaesthetic

INTRODUCTION besides persisting clinical cyanosis not responding to supple- Cyanosis in the newborn can be due to methemoglobinemia, an mental oxygen. The umbilical cord gases were acceptable (arterial intra-erythrocytic hemoglobin abnormality. Methemoglobinemia pH 7.27, BE À 3.5 and venous pH 7.31, BE À 2.8) but showed a is the presence of a higher than normal level of methemoglobin raised MetHb (laboratory normal range o2% concentration of (MetHb) ferric (Fe3 þ ) rather than ferrous (Fe2 þ ) hemoglobin in total Hb) of 12.5% on venous and 11.5% on arterial gas. He was the blood. MetHb has a decreased affinity for oxygen causing transferred to the neonatal intensive care unit at 20 min of age. tissue hypoxia. On admission his capillary blood gas showed a raised MetHb of Methemoglobinemia can be inherited or acquired. Acquired 12.4% (pH 7.28, pCO2 6.3, BE À 4.9, lactate 3.2, glucose 4.7). An methemoglobinemia is more common and occurs after exposure arterial blood gas at 1 h of life showed a partial pressure of oxygen to an agent that oxidizes hemoglobin to MetHb. Inherited (pO2) of 11.3 kPa (pH 7.39, pCO2 4.5, pO2 11.3, BE À 4) and a methemoglobinemia occurs when there is an enzyme cytochrome calculated oxygen saturation of 93%. A repeat capillary blood gas b5 reductase defect or with hemoglobin M disease. It also arises at 7.5 h of life showed a mild compensated metabolic acidosis (pH with pyruvate kinase and glucose-6-phosphate dehydrogenase 7.36, pCO2 4.3, BE À 6) and a MetHb of 13.8%, taken 8 h from deficiency. administration of maternal spinal anesthetic. He had a partial septic screen and received IV benzylpenicillin and gentamicin but was never thought be clinically septic. Chest X-ray and initial blood results were normal besides a borderline hemoglobin of À 1 CASE 12.4 g dl . He initially required incubator oxygen (45% FiO2)to A 3.1-kg male neonate was born at 39 þ 3 weeks gestation by maintain saturations measured by pulse oximeter above 95%, emergency cesarean section for breech presentation. The mother which was weaned over 36 h. Cyanosis resolved by 24 h of age was started on Labetalol at 38 weeks gestation for pregnancy- but he continued to have a generalized grayish discoloration. induced hypertension and no intrapartum antibiotics were given. The acidosis normalized by day two (pH 7.40, BE À 1). Maximum À 1 Delivery otherwise followed an uneventful antenatal course with C-reactive protein was o5mgl , blood culture was negative at 5 no significant family history. days incubation and he remained clinically well. Before delivery, a spinal anesthetic for maternal analgesia was The methemoglobinemia persisted although improved and was administered containing 2.5 ml of 0.5% bupivacaine with 0.3 mg monitored requiring no treatment. Maternal MetHb level was diamorphine (total 12.5 mg intrathecal bupivacaine dose). normal. His G6PD level, hemoglobin electrophoresis and blood The mother subsequently developed a high spinal blockade film were normal. He was discharged home on day 4 with a MetHb resulting in a respiratory arrest requiring conversion to general of 11.4%. anesthetic (using 350 mg thiopentone and 100 mg suxame- On follow up, his MetHb was 8.4% on day 26 of life. At 2 months thonium). Hypotension was managed with 400 mg phenylephrine. of life, further clinical assessment was normal, his Hb level was À 1 The mother’s first arterial blood gas once intubated and ventilated 9.5 g dl with a MetHb of 4.9%. Subsequent MetHb on day 301 of was acidotic (pH 7.18, pCO2 6.2, base excess (BE) À 11, MetHb life was 1.3%. Enzymatic estimation of cytochrome b5 reductase 1.2). She was transferred to intensive care unit and subsequently was not performed as the prompt resolution and non-recurrence fully recovered. on follow up excludes enzyme deficiency as a cause. At delivery, the neonate required cardiopulmonary resuscitation with intubation at 3 min of age. He self-extubated by 10 min of age. By 15 min of age, his oxygen saturations were 86% in air and DISCUSSION required 50% fraction of inspired oxygen (FiO2) by facial mask to Most cases in the literature report congenital causes. Recent maintain saturations above 95%. Normal clinical examination reports of acquired methemoglobinemia where drugs have been

1Neonatal Intensive Care Unit, Homerton University Hospital, Homerton Row, London, UK; 2Paediatric Department, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK and 3Department of Child Health, SDM College of Medical Sciences and Hospital Dharwad, Dharwad, India. Correspondence: Dr M van de Vijver, Homerton University Hospital, Homerton Row, Flat 4, 8 Wimpole Street, London E9 6SR, UK. E-mail: [email protected] Received 2 April 2013; revised 17 May 2013; accepted 24 May 2013 Thinking outside of the blue box M van de Vijver et al 904 identified as the causative factor, prilocaine, benzocaine and This neonate most likely has lower oxygen saturations than nitrate solutions are most widely reported.1–3 recorded as the oxygen saturation values measured by a pulse Bupivacaine is a long-acting local anesthetic with rapid oximeter are inaccurate and may be falsely elevated. An oxygen onset of action and a half-life in neonates of 8.1 h. His saturation gap, meaning a difference in calculated arterial oxygen maximum MetHb level of 13.8% was at 8 h from administration saturation versus oxygen saturation by pulse oximetry, is a feature of the spinal anesthetic. Bupivacaine is acknowledged as a of methemoglobinaemia. Methemoglobin does not bind to oxygen, cause of methemoglobinemia but not reported to occur following therfore the remaining oxyhemoglobin has a greater affinity for obstetric use. Kuhnert et al. acknowledged that bupivacaine oxygen thus, shifting the oxygen-hemoglobin dissociation curve to crosses the placenta and metabolites can be found in the the left resulting in tissue hypoxia and a functional anaemia. neonate’s urine up to 36 h following delivery.4 Whereas In methemoglobinemia and as in this neonate, the MetHb McGuinness et al. showed bupivacaine is detectable in the percentage concentration of total hemoglobin is raised above 2% neonatal venous circulation from 4 h post-delivery up to 24 h and the arterial partial oxygen pressure is normal. This is the after cesarean section.5 diagnostic criteria of methemoglobinemia. Clinical examination Local anesthetics cross the placenta by passive diffusion. and all further investigations were normal and therefore the The higher the level of protein binding in the maternal circulation Bupivacaine was the most likely causative agent for this neonate’s the less unbound drug there is to diffuse. Bupivacaine is widely methemoglobinemia. used in obstetric practice as it has a low fetal/maternal ratio with a protein-binding capacity of up to 95%. However, if bupivacaine does enter the fetal circulation, it is proposed there is an increased CONCLUSION risk of uptake in fetal tissues due to the high protein-binding Bupivacaine is the first-line anesthetic used in spinal anesthesia for capacity.5 The rate of systemic absorption is dependent upon the cesarean delivery and physicians should therefore be aware total dose and concentration of drug administered, the route of of the potential complication of neonatal methemoglobinemia. administration and the vascularity of the administration site. The presentation of clinical cyanosis in a relatively well neonate As the systemic concentration increases the risk of complications in the absence of cardiopulmonary symptoms and normal pO2 from toxicity increases exponentially. The fetal pH affects the should alert clinicians to the possibility of methemoglobinemia. transfer of local anesthetics across the placenta.6 In this case, the acidotic state of the mother secondary to intrapartum respiratory arrest will have compromised the neonate and may have CONFLICT OF INTEREST increased his susceptibility to trans-placental transfer of The authors declare no conflict of interest. bupivacaine. Red blood cells contain approximately 1% MetHb levels (range: 0 to 3% MetHb). This is maintained by two mechanisms; the ACKNOWLEDGEMENTS hexose-monophosphate shunt pathway and the nicotine adenine We acknowledge the family for providing consent to write this case report. dinucleotide (NADH) diaphorase I and nicotine adenine dinucleo- tide phosphate (NADPH) diaphorase II system. The NADPH diaphorase II system can be pharmacologically activated. This is REFERENCES the basis for treatment of methemoglobinemia with methylene 1 Chou TD, Gibran NS, Urdahl K, Lin EY, Heimbach DM, Engrav LH. Methemoglo- blue. The first line treatment for drug mediated methemoglobi- binaemia secondary to topical silver nitrate therapy - a case report. Burns 1999; naemia is stopping the offending oxidising agent. Treatment with 25(6): 549–552. methylene blue should be considered when the MetHb is 30% in 2 Couper RT. Methemoglobinemia secondary to topical lignocaine/prilocaine in a an asymptomatic patient and 20% in a symptomatic patient circumcised neonate. J Paediatr Child Health 2000; 36: 406–407. 3 Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical unless significant co-morbidities exist in which case one would benzocaine use during endoscopy in a toddler: a case report and review of the consider a lower treatment threshold. This neonate did not meet literature. 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Journal of Perinatology (2013), 903 – 904 & 2013 Nature America, Inc.