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Refeeding syndrome in a SGA micro-preemie 715
Refeeding syndrome in a small-for-dates micro-preemie receiving
early parenteral nutrition ped_3590 715..740
Hiroshi Mizumoto, Masamitsu Mikami, Hirotsugu Oda and Daisuke Hata
Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
Abstract This report describes a small-for-date extremely low birth weight infant who manifested bradycardic events, respiratory
failure, and hemolytic jaundice during her first week of life. These complications were attributed to severe hypophos-
phatemia and hypokalemia. Inadequate supply and refeeding syndrome triggered by early aggressive parenteral nutrition
were responsible for electrolyte abnormalities.
Key words early aggressive parenteral nutrition, hypokalemia, hypophosphatemia, refeeding syndrome, small for gestational age.
Case report potassium were maintained within normal range without any
A female infant was delivered by emergency cesarean section at additional supply.
29 weeks gestation due to maternal preeclampsia. Her weight
Discussion
was 740 g (-3.5SD). Her Apgar scores were 5 and 6 at 1 and
5 min, respectively. She had no major organ anomaly or dysmor- Severe hypophosphatemia, typically describing phosphorous
phic features. She displayed respiratory distress, necessitating levels less than 1 mg/dL, can affect every organ in the body
mechanical ventilation. We provided parenteral nutrition with because phosphorus plays a critical role in maintaining the energy
2.5 g/kg/day of amino acids within the first 5 days of life. balance of cells. Clinical manifestations of acute hypophos-
Glucose infusion was controlled to maintain blood glucose levels phatemia include myocardial impairment, respiratory failure, and
above 60 mg/dL; the rate was initially 4.2 mg/kg/min, and was rhabdomyolysis. Severe hypophosphatemia causes a reduction in
elevated to more than 10 mg/kg/min after day 2 (Fig. 1). After intracellular adenosine triphosphate levels, which increases eryth-
day 2, the patient was given three doses of indomethacin for rocyte rigidity, predisposing patients to hemolysis.1 Hypokalemia
patent ductus arteriosus. Although her urine output subsequently is well known to cause a variety of arrhythmias including sinus
decreased and serum creatinine increased, diuretics were not bradycardia and atrioventricular block.2 In the present case,
used. On day 4, sudden onset of severe bradycardic events with a although the drop in hemoglobin was partially the result of
heart rate of less than 60/min was reported. The next day, inten- hemodilution, an abrupt rise in unbound bilirubin suggested
sive phototherapy and albumin infusion were initiated for hemolysis. The bradycardic events were not associated with
abruptly elevated serum unbound bilirubin. The patient’s respi- desaturation or tracheal tube troubles, and symptoms recovered
ratory condition deteriorated and antibiotics were started for sus- along with the normalization of serum phosphate and potassium.
pected pneumonia. Her serum phosphate level was measured
again. Although normal on admission, it had fallen precipitously
to 0.3 mg/dL. Profound hypokalemia was also confirmed
(Table 1). Urinary excretion of phosphate was below detectable
levels (<0.5 mg/dL) and fractional excretion of potassium was
4.5%. Rapid intravenous replacement was prescribed in the form
of potassium phosphate (1.3 mmol/kg given over 6 h), but serum
phosphate decreased to less than 0.2 mg/dL. Subsequently, more
aggressive replacement (3.5 mmol/kg given in 6 h) raised the
phosphate level to 1.7 mg/dL. Serum phosphate and potassium
levels returned to within the reference range by day 6. Both the
bradycardia episodes and signs of hemolytic jaundice resolved
simultaneously. After 2 weeks of age, her serum phosphate and
Correspondence: Hiroshi Mizumoto, MD, Department of Pediatrics,
Kitano Hospital Tazuke Kofukai, Medical Research Institute. 2-4-20
Ohgimachi, Kita-ku, Osaka 530-8480, Japan. Email: h-mizumoto@
kitano-hp.or.jp
Received 21 June 2011; revised 31 October 2011; accepted 1 Fig. 1 Clinical course. Serum potassium was evaluated every day
February 2012. using bedside electrolytes analyzer (Stat Profile) ( ). Serum phos-
doi: 10.1111/j.1442-200X.2012.03590.x phorus (䉬) was not checked between days 1 and 4.
© 2012 The Authors
Pediatrics International © 2012 Japan Pediatric Society
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716 H Mizumoto et al.
Table 1 Laboratory data. Data on days 3 and 4 were obtained through a bedside analyzer (Stat Profile); the results of potassium were inconsistent,
presumably because of sample hemolysis. Other data were obtained from a central laboratory (potassium by electrode method, phosphate by
enzymatic method).
Reference range Day
0 3 4 5 6 7
Sodium (mmol/L) 136–147 133 134 133 135 134 137
Potassium (mmol/L) 3.6–5.0 4.5 2.9–5.1? 2.5–5.8? 1.9 3.3 5.0
Phosphate (mg/dL) 2.5–4.5 4.2 – – <0.2 3.2 3.2
Calcium (mg/dL) 8.5–10.3 8.8 – – 10.8 6.8 9.6
Magnesium (mmol/L) 1.7–2.2 1.6 – – 1.9 1.2 1.4
Glucose (mg/dL) 90 61 81 90 141 150
Creatinine (mg/dL) 0.78 1.49 1.37 1.27
Total protein (g/dL) 6.5–8.0 4.1 3.0 3.7 3.7
Hemoglobin (g/dL) 18.7 14.2 15.7 11.7 11.5 10.6
Total bilirubin (mg/dL) 3.5 4.2 6.0 7.7 4.9 3.6
Unbound bilirubin (mg/dL) <0.08 <0.08 0.13 0.65 0.25 0.13
C-reactive protein (mg/dL) 0–0.3 0.0 0.2 2.5 2.4 1.5
There are three major mechanisms by which hypophos- movement of phosphate and potassium into the cells, thereby
phatemia can occur: decreased nutritional intake; transcellular decreasing serum concentrations.5 Furthermore, tissue anabolism
shifts; and renal loss. In the present case, symptoms appeared increases the cellular demand for phosphate, glucose, potassium,
within several days of birth in correlation with limited urinary and water.6 Our patient was a severely growth-retarded extremely
excretion. We therefore inferred that inadequate perinatal supply low birth weight (ELBW) infant who had probably received
and internal redistribution were responsible for the hypophos- inadequate nutrition during her fetal life. It is probable that not
phatemia. Most bone mineralization, along with calcium and only electrolyte abnormalities but also an increased glucose
phosphate accretion, occurs during the third trimester of preg- requirement resulted from the refeeding syndrome.
nancy. Therefore, infants born before this period show depleted Many studies demonstrate that inadequate early nutrition
stores of these elements. Although hypophosphatemia often adversely influences long-term neurodevelopmental and growth
occurs along with sepsis, clinical and laboratory evidence sug- outcomes of ELBW infants.7 Early administration of amino acids
gested that severe infection was unlikely in this case. Calcium is known to be safe. It promotes glucose tolerance in preterm
overdose was unlikely because we gave only 0.5 to 1 mmol/kg/ infants.8 Early aggressive parenteral nutrition is associated with a
day of calcium for the first 3 days. Serum electrolytes were reduced risk of hyperkalemia.9 This suggests that early postnatal
monitored every day using a bedside electrolyte analyzer (Stat renutrition promotes moderate insulin secretion and protects
Profile, Nova Biomedical, Nova Biomedical K.K., Tokyo, Japan), ELBW infants from developing hyperkalemia, but it can cause
which tested sodium, potassium, and calcium levels. The results severe hypophosphatemia and hypokalemia in cases of severe
of potassium were inconsistent, presumably because of sample malnourishment. Since the introduction of this new nutritional
hemolysis. We did not start potassium phosphate supply until day strategy, glucose-insulin treatment for early onset hyperkalemia
5 because we assumed that true hypokalemia was unlikely under has never been performed in ELBW infants. Testing and making
the condition of renal insufficiency induced by indomethacin. provisions for potential hypokalemia and hypophosphatemia
Initial intravenous replacement therapy failed, which compelled must be done as early as around 3–4 days after birth even if urine
us to administer much higher doses of potassium phosphate than output is decreased. It remains unknown whether a prophylactic
those reported previously.3 Such hypophosphatemia could not be low-caloric dietary regimen is beneficial for growth-retarded
explained solely by decreased nutritional intake. babies. At the very least, clinical and biochemical parameters
Refeeding syndrome triggered by early aggressive parenteral must be monitored closely in ELBW infants receiving early
nutrition was believed to be the main cause of severe hypophos- aggressive parenteral nutrition.
phatemia and hypokalemia in the present case. Refeeding syn-
drome is a commonly overlooked condition in cases of severe, Acknowledgment
acute electrolyte, fluid-balance, and metabolic abnormalities in We thank Dr. K. Omura (Yamanaka Spa Medical Center) for
chronically malnourished patients undergoing renutrition. The valuable suggestions.
principal biochemical hallmark of refeeding syndrome is severe
acute hypophosphatemia that usually occurs within 3–4 days of References
refeeding.4,5 For humans in a severely starved state, the body
stores of phosphate and potassium might be depleted, although 1 Jacob HS, Amsden T. Acute hemolytic anemia with rigid red cells in
hypophosphatemia. N. Engl. J. Med. 1971; 285: 1446–50.
serum levels are often maintained.4 Once nutrition is reintro- 2 Rose BD, Post TW. Hypokalemia. In: Rose BD, Post TW (eds).
duced, a shift back to carbohydrate metabolism occurs, with a Clinical Physiology of Acid-base and Electrolyte Disorders, 5th edn.
concomitant increase in insulin levels. Insulin stimulates the McGraw-Hill Professional, New York, 2001; 836.
© 2012 The Authors
Pediatrics International © 2012 Japan Pediatric Society
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Refeeding syndrome in a SGA micro-preemie 717
3 Brown KA, Dickerson RN, Morgan LM et al. A new graduated outcomes of extremely low birth weight infants. Pediatrics 2006;
dosing regimen for phosphorus replacement in patients receiving 117: 1253–61.
nutrition support. JPEN J. Parenter. Enteral Nutr. 2006; 30: 209–14. 8 Ibrahim HM, Jeroudi MA, Baier RJ et al. Aggressive early total
4 Hearing SD. Refeeding syndrome. BMJ 2004; 328 (7445): 908–9. parenteral nutrition in low-birth-weight infants. J. Perinatol. 2004;
5 Marinella MA. The refeeding syndrome and hypophosphatemia. 24: 482–6.
Nutr. Rev. 2003; 61 (9): 320–3. 9 Lacobelli S, Bonsante F, Vintejoux A et al. Standardized parenteral
6 Marinella MA. Refeeding syndrome: implications for the inpatient nutrition in preterm infants: early impact on fluid and electrolyte
rehabilitation unit. Am. J. Phys. Med. Rehabil. 2004; 83: 65–8. balance. Neonatology 2010; 98: 84–90.
7 Ehrenkranz RA, Dusick AM, Vohr BR et al. Growth in the neonatal
intensive care unit influences neurodevelopmental and growth
Diagnostic tools of metabolic and structural brain disturbances in
neonatal non-ketotic hyperglycinemia ped_3591 717..742
Demet Terek,1 Ozge Altun Koroglu,1 Sezgin Gunes,1 Mehmet Yalaz,1 Mete Akisu,1 Sema Kalkan Uçar,2 Sarenur Gokben,3
Mahmut Çoker2 and Nilgün Kultursay1
Divisions of 1Neonatology, 2Metabolism and Nutrition and 3Neurology, Department of Pediatrics, Ege University Faculty of
Medicine, Bornova, Izmir, Turkey
Abstract Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder of glycine metabolism. We report a newborn
case of NKH and discuss the effects of this rare disease on brain metabolism and structure together with amplitude-
integrated electroencephalography, cranial magnetic resonance and magnetic resonance spectroscopy findings which are
very rarely reported together so far.
Key words amplitude integrated electroencephalography, glycin encephalopathy, magnetic resonance spectroscopy, metabolic
disorder, newborn.
Non-ketotic hyperglycinemia (NKH) is a rare autosomal reces- Case report
sive disorder affecting glycine metabolism with a reported preva- A female infant was born at term (39 weeks gestation) with a
lence of 1:60.000–100.000. The biochemical defect is in the birth weight of 3200 g, to a gravida 3 para 0 mother, (second-
glycine cleavage system which consists of a mitochondrial degree consanguineous parents had an unremarkable family
enzyme complex. There are four forms of glycine encephalopa- history) after a pregnancy complicated with chronic hyperten-
thy: neonatal; infantile; transient; and late.1 The enzyme level is sion. The infants Apgar scores were 7 and 9 at 5 and 10 min,
close to zero in the neonatal form which is the most common and respectively.
severe form. The clinical manifestations of poor sucking, hypo- On day 2, the infant was admitted to the neonatal intensive
tonicity, lethargy, hiccups and seizures develop within 6 h to 8 care unit because of decreased movements, shallow breathing
days of birth of an otherwise healthy newborn. Acute neurologi- and poor sucking. The physical findings were hypotonicity, leth-
cal deterioration rapidly progresses to coma and often leads argy, decreased newborn reflexes and pes equinovarus. The
to death in a short period. If patients survive the ventilator- patient was intubated and mechanical ventilation was initiated
dependent period, they will suffer from severe mental and devel- because of respiratory acidosis.
opmental retardation and seizures. Routine biochemical and hematological tests including blood
We report a case of newborn NKH and discuss the effects of glucose and complete blood count were unremarkable. Since
this rare disease on brain metabolism and structure, we also look neonatal sepsis could not be ruled out, ampicillin and netilmicin
at using amplitude-integrated electroencephalography (aEEG), antibiotherapy was initiated. Blood, cerebrospinal fluid and urine
cranial magnetic resonance imaging (MRI) and magnetic reso- cultures were negative. On her 4th day of life the patient began to
nance (MR) spectroscopy findings, which have been very rarely have persistent hiccups and myoclonic seizures unresponsive to
reported together previously. treatment. A continuous burst suppression pattern indicating
severe–moderate brain damage was observed on aEEG (Fig. 1).
Correspondence: Demet Terek, MD, Ege University Faculty of Medi- Metabolic disorders were investigated because of parental con-
cine, Children’s Hospital, Bornova 35100, Izmir, Turkey. Email: sanguinity, and clinical and aEEG findings. Blood lactate, pyru-
demet.terek@yahoo.com
Received 14 June 2011; revised 21 December 2011; accepted 26 vate and ammonia levels were normal. Initially, conventional
January 2012. electroencephalography (EEG) showed low-voltage baseline
doi: 10.1111/j.1442-200X.2012.03591.x rhythm. However, a later EEG performed after the onset of
© 2012 The Authors
Pediatrics International © 2012 Japan Pediatric Society
