The use of sodium DL-3-Hydroxybutyrate in severe acute neuro-metabolic compromise in patients with inherited ketone body synthetic disorders

Case I is a female child of non-consanguineous Caucasian parents, born at term having a hypoglycaemic episode on day two of life. Despite increased feed frequency, she developed hypothermia on day three and was empirically managed as having sepsis with intravenous 10% dextrose and antibiotics. On day 4, after expressed breast milk reintroduction, she became lethargic with an apnoeic episode and seizures. The blood gas demonstrated pH 7∙51 (7∙35–7∙45), pCO2 23 mmHg (32–45) with serum ammonia of 800 μmol/L (10–80). The baby was again placed nil by mouth, restarted 10% dextrose, administered a loading dose of phenobarbitone and was referred to a tertiary metabolic unit. The serum ammonia and blood gas returned to normal in 24 h without any adjunctive ammonia lowering therapy. Initial urine organic acids indicated significant medium and long chain dicarboxylic aciduria without evidence of ketones being produced, indicating a presumptive diagnosis of a long chain MFAO disorder. Initial feeds on day five comprised 90% glucose polymer and 10% expressed breast milk with supplemental S DL-3-OHB of 300 mg/kg/day (Special Products Ltd., UK - (Veriton Pharma)). On day six, the baby deteriorated with multi-organ failure comprising severe cardiac dysfunction with factional shortening 16% (28–45), liver dysfunction and seizures, with her having feeds discontinue, anti-convulsants commence and being invasively ventilated.. However, S DL-3-OHB was continued at a dose of 600 mg/kg/day. Brain MRI demonstrated extensive white matter changes (Fig. 1a). Carbohydrate and MCT based feeds (Polyjoule and Monogen respectively, Nutricia Ltd., USA) restricting long chain dietary fat < 5% of total energy intake were cautiously introduced on day seven per Table 1a. Cardiac fractional shortening had improved to 41% on day nine and she continued to make steady improvement thereafter, being extubated on day nine and discharged home independently feeding on day twenty-three. She had normal early milestones of development and is currently aged 9 years attending normal mainstream school with additional support for attention deficit hyperactivity disorder and mild learning difficulties. There was recovery on brain MRI performed at 2 years of age (Fig. 1b). The diagnosis was subsequently confirmed with skin fibroblast fat oxidation flux studies indicative of either CACTD or CPT2D with leucocyte activity of CPT2 being normal (93% activity of CPT2 relative to controls.) Subsequent molecular studies indicated c.326 + 1 delG mutation and c.50G > C variant of unknown significance of SLC25A20. Contemporary bedside ketone measurements were not performed.

Case 2 was the second male child of non-consanguineous Slovakian parents. He had an uneventful birth and infancy, presenting after four months with hypoglycaemia after switching from breast milk to formula. HMGCL2D was diagnosed on the basis of typical biochemistry including gross elevation of urinary 3-hydroxy-3-methlylglutarate. He was stabilised on a low protein and fat diet but was lost to follow up from age 1 year until the age of 16. At this age he attended normal mainstream education with normal achievement. He presented to the local emergency department after 48 h of persistent vomiting, and was admitted into hospital with lethargy, disorientation and slurred speech. The baseline assessment noted that he had tachycardia, tachypnoea and a core of temperature of 34.7 degrees centigrade. His Glasgow Coma Scale (GCS) was 15. Initial biochemistry demonstrated pH 7.12; Bicarbonate of 6.8 mmol/L (18∙0–24∙0), lactate 16 mmol/L (0–2∙0), Base Excess − 20 (− 2∙0 to + 2∙0), Anion gap 29 mmol/L (8–18) with a blood glucose of 2 mmol/L (3.0–5.5). Acetoacetate level was subsequently reported as 0.07 mmol/L (0.05–0.15) and betahydroxybutyrate 0.01 mmol/L (0.03–3.0). He was resuscitated with dextrose and normal saline boluses, treated with antibiotics and anti-viral agents and maintained on 5% dextrose maintenance fluids. On day two of admission his consciousness level deteriorated with a GCS of 9, being unable to follow commands. He had three beats of clonus on his right side and bilateral extensor plantar responses. Pupils were noted to be reacting sluggishly. A brain CT showed confluent white matter hypodensity and evidence of small ventricles consistent with significantly raised intra-cranial pressure. Serum ammonia was elevated at 455 μmol/L (< 50). Due to compromised neurology, intravenous fluids were restricted to 50 mls/kg/day but were changed to 10% dextrose. Further neurological compromise occurred on day three when he had bilateral fixed and dilated pupils of 7 mm diameter. Repeat CT Brain revealed worsening cerebral oedema (Fig. 2a). A trans-cranial bolt was surgically applied with an opening pressure of 30 mmHg. 600 mg/kg/day of S DL-3-OHB was commenced on day four of hospital admission in tandem with attempts to provide higher energy enteral nutrition as indicated in Table 1b. Aetoacetate measurement increased to 0.11 mmol/L and betahydroxybutyrate to 0.08 mmol/L. Intracranial pressure continued to fluctuate over the subsequent three days but he gradually began to recover, self-ventilating in air by day twenty-four and being discharged home independently ambulatory by day sixty-three. MRI of the brain indicated that he had suffered extensive posterior-circulation infarction, presumed to be due to herniation into the foramen magnum at pressure, and he continues to have complete cortical blindness. Extensive white matter abnormalities were demonstrated at the time of his presentation and persisted three years later on repeat scanning (Fig. 2b and c). The remainder of his neurology remains normal aged 24 years.

Case 3 is the first child of non-consanguineous parents from Syria. She was diagnosed at 3 weeks of age after borderline newborn screening results indicative of CACTD or CPT2D at which time, she was thriving on exclusive breast feeds. Skin fibroblast, white cell enzymology and genetic testing was initiated and subsequently confirmed CPT2D with leucocyte activity being 3% relative to controls. The baby was discharged on a feeding regimen comprising 1/3 of total energy from MCT and 2/3 from breast feeds. At three months of age, over a 48 h period, the baby started refusing MCT based bottle feeds. On the morning of admission, the baby had two vomits over a six hour period and was advised to attend the emergency department (ED). She was assessed in ED to be lethargic but alert with her heart rate of 140 beats per minute (BPM) and core temperature being 37 degrees. Her venous blood gas demonstrated a whole blood glucose level of 1∙5 mmol/L, pH 7∙40, pCO2 27 mmHg, and base excess of − 7∙1 She was treated with two consecutive boluses of 2 ml/kg 10% dextrose and placed on 150% standard maintenance 10% dextrose and normal saline. Two hours after admission she suddenly became flaccid and unresponsive to pain with a core temperature of 32∙6 degrees and heart rate of 100 BPM. Pupils were reactive, the fontanelle not bulging, but there was sustained clonus > 15 beats bilaterally. Venous whole blood glucose was normal at 6∙6 mmol/L with serum ammonia subsequently reported to be 300 μmol/L (10–80).) Bedside beta-hydroxybutyrate measurement was < 0∙2 mmol/L and contemporary measurements of free fatty acid was 3∙96 mmol/L with laboratory beta-hydroxybuyrate of < 0∙18 mmol/L (ratio > 20 implying hypoketosis). Echocardiography performed in the emergency department showed mild septal hypertrophy with no significant cardiac dysfunction. She had clinical evidence of hepatomegaly. After fluid resuscitation and empirical use of intravenous antibiotics, the baby was administered 150 mg/kg/dose of S DL-3-OHB four hourly with the first dose administered less than three hours after the hypothermia event (Table 1c). After twelve hours and three doses of S DL-3-OHB, the baby was awake and beginning to suck with the neurological examination being normal after a further 24 h. Because of the rapid neurological recovery, brain MRI was delayed until one month showing some prominence in frontal extra-axial space, but was otherwise normal (Fig. 3). At one year of age of age, at last review, development was within normal limits being able to pull to stand and standing with support but she does have peripheral hypertonia.. Nonetheless her neurological prognosis remains guarded.